A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers

Somatic rearrangements contribute to the mutagenized landscape of cancer genomes. Here, we systematically interrogated rearrangements in 560 breast cancers by using a piecewise constant fitting approach. We identified 33 hotspots of large (>100 kb) tandem duplications, a mutational signature associated with homologous-recombination-repair deficiency. Notably, these tandem-duplication hotspots were enriched in breast cancer germline susceptibility loci (odds ratio (OR) = 4.28) and breast-specific 'super-enhancer' regulatory elements (OR = 3.54). These hotspots may be sites of selective susceptibility to double-strand-break damage due to high transcriptional activity or, through incrementally increasing copy number, may be sites of secondary selective pressure. The transcriptomic consequences ranged from strong individual oncogene effects to weak but quantifiable multigene expression effects. We thus present a somatic-rearrangement mutational process affecting coding sequences and noncoding regulatory elements and contributing a continuum of driver consequences, from modest to strong effects, thereby supporting a polygenic model of cancer development.DG is supported by the EU-FP7-SUPPRESSTEM project. SN-Z is funded by a Wellcome Trust Intermediate Fellowship (WT100183MA) and is a Wellcome Beit Fellow. For more information, please visit the publisher's website

Risk classification of patients referred to secondary care for low back pain

Abstract Background Nonspecific low back pain is characterized by a wide range of possible triggering and conserving factors, and initial screening needs to scope widely with multilevel addressment of possible factors contributing to the pain experience. Screening tools for classification of patients have been developed to support clinicians. The primary aim of this study was to assess the criterion validity of STarT Back Screening Tool (STarT Back) against the more comprehensive Örebro Musculoskeletal Pain Questionnaire (ÖMPSQ), in a Norwegian sample of patients referred to secondary care for low back pain. Secondary aims were to assess risk classification of the patients, as indicated by both instruments, and to compare pain and work characteristics between patients in the different STarT Back risk categories. Methods An observational, cross-sectional survey among patients with low back pain referred to outpatient secondary care assessment at Trondheim University Hospital, Norway. Cohen’s Kappa coefficient, Pearson’s r and a Bland-Altman plot were used to assess criterion validity of STarT Back against ÖMPSQ. Furthermore, linear regression was used to estimate mean differences with 95% CI in pain and work related variables between the risk groups defined by the STarT Back tool. Results A total of 182 persons participated in the study. The Pearsons correlation coefficient for correspondence between scores on ÖMPSQ and STarT Back was 0.76. The Kappa value for classification agreement between the instruments was 0.35. Risk group classification according to STarT Back allocated 34.1% of the patients in the low risk group, 42.3% in the medium risk, and 23.6% in the high risk group. According to ÖMPSQ, 24.7% of the participants were allocated in the low risk group, 28.6% in the medium risk, and 46.7% in the high risk group. Patients classified with high risk according to Start Back showed a higher score on pain and work related characteristics as measured by ÖMPSQ. Conclusion The correlation between score on the screening tools was good, while the classification agreement between the screening instruments was low. Screening for work factors may be important in patients referred to multidisciplinary management in secondary care

Louping-ill virus serosurvey of willow ptarmigan (Lagopus Lagopus Lagopus) in Norway

In Norway, the Willow Ptarmigan (Lagopus lagopus lagopus) is experiencing population declines and is nationally Red Listed as Near Threatened. Although disease has not generally been regarded as an important factor behind population fluctuations for Willow Ptarmigan in Norway, disease occurrence has been poorly investigated. Both louping-ill virus (LIV) and the closely related tick-borne encephalitis virus are found along the southern part of the Norwegian coast. We assessed whether and where Norwegian Willow Ptarmigan populations have been infected with LIV. We expected to find infected individuals in populations in the southernmost part of the country. We did not expect to find infected individuals in populations further north and at higher altitudes because of the absence of the main vector, the sheep tick (Ixodes ricinus). We collected serum samples on Nobuto filter paper and used a hemagglutination inhibition assay for antibodies against LIV. We collected data at both local and country-wide levels. For local sampling, we collected and analyzed 87 hunter-collected samples from one of the southernmost Willow Ptarmigan populations in Norway. Of these birds, only three positives (3.4%) were found. For the country-wide sampling, we collected serum samples from 163 Willow Ptarmigan carcasses submitted from selected locations all over the country. Of these birds, 32% (53) were seropositive for LIV or a cross-reacting virus. Surprisingly, we found seropositive individuals from locations across the whole country, including outside the known distribution of the sheep tick. These results suggest that either LIV or a cross-reacting virus infects ptarmigan in large parts of Norway, including at high altitudes and latitudes. Lagopus lagopus, louping-ill virus, ptarmigan, serosurvey, tick-borne viruses

Louping-ill virus serosurvey of willow ptarmigan (Lagopus Lagopus Lagopus) in Norway

In Norway, the Willow Ptarmigan (Lagopus lagopus lagopus) is experiencing population declines and is nationally Red Listed as Near Threatened. Although disease has not generally been regarded as an important factor behind population fluctuations for Willow Ptarmigan in Norway, disease occurrence has been poorly investigated. Both louping-ill virus (LIV) and the closely related tick-borne encephalitis virus are found along the southern part of the Norwegian coast. We assessed whether and where Norwegian Willow Ptarmigan populations have been infected with LIV. We expected to find infected individuals in populations in the southernmost part of the country. We did not expect to find infected individuals in populations further north and at higher altitudes because of the absence of the main vector, the sheep tick (Ixodes ricinus). We collected serum samples on Nobuto filter paper and used a hemagglutination inhibition assay for antibodies against LIV. We collected data at both local and country-wide levels. For local sampling, we collected and analyzed 87 hunter-collected samples from one of the southernmost Willow Ptarmigan populations in Norway. Of these birds, only three positives (3.4%) were found. For the country-wide sampling, we collected serum samples from 163 Willow Ptarmigan carcasses submitted from selected locations all over the country. Of these birds, 32% (53) were seropositive for LIV or a cross-reacting virus. Surprisingly, we found seropositive individuals from locations across the whole country, including outside the known distribution of the sheep tick. These results suggest that either LIV or a cross-reacting virus infects ptarmigan in large parts of Norway, including at high altitudes and latitudes. Lagopus lagopus, louping-ill virus, ptarmigan, serosurvey, tick-borne viruses.publishedVersio

Considerations made by the general practitioner when dealing with sick-listing of patients suffering from subjective and composite health complaints

Objectives. To explore GPs’ considerations in decision-making regarding sick-listing of patients suffering from SHC. Design. Qualitative analysis of data from nine focus-group interviews. Setting. Three cities in different regions of Norway. Participants. A total of 48 GPs (31 men, 17 women; aged 32–65) participated. The GPs were recruited when invited to a course dealing with diagnostic practice and assessment of sickness certificates related to patients with composite SHCs. Results. Decisions on sick-listing patients with SHCs were regarded as a very challenging task. Trust in the patient's own story and self-judgement was deemed crucial, but many GPs missed hard evidence of illness and loss of function. Several factors that might influence decision-making were identified: the patients’ ability to present their story to evoke sympathy, the GP's prior knowledge of the patient, and the GPs’ own experience as a patient and their tendency to avoid conflicts. The approach to the task of sick-listing differed from patient-led cooperation to resistant confrontation. Conclusion and implications. Issuing sickness certification in patients with composite health complaints is considered challenging and burdensome. It is seen as mainly patient-driven, and the decisions vary according to GPs’ attitudes, beliefs, and personalities. Guiding the GPs to a more focused awareness of the decision process should be considered