5-year results of accelerated partial breast irradiation using sole interstitial multicatheter brachytherapy versus whole-breast irradiation with boost after breast-conserving surgery for low-risk invasive and in-situ carcinoma of the female breast: a randomised, phase 3, non-inferiority trial.

BACKGROUND In a phase 3, randomised, non-inferiority trial, accelerated partial breast irradiation (APBI) for patients with stage 0, I, and IIA breast cancer who underwent breast-conserving treatment was compared with whole-breast irradiation. Here, we present 5-year follow-up results. METHODS We did a phase 3, randomised, non-inferiority trial at 16 hospitals and medical centres in seven European countries. 1184 patients with low-risk invasive and ductal carcinoma in situ treated with breast-conserving surgery were centrally randomised to either whole-breast irradiation or APBI using multicatheter brachytherapy. The primary endpoint was local recurrence. Analysis was done according to treatment received. This trial is registered with ClinicalTrials.gov, number NCT00402519. FINDINGS Between April 20, 2004, and July 30, 2009, 551 patients had whole-breast irradiation with tumour-bed boost and 633 patients received APBI using interstitial multicatheter brachytherapy. At 5-year follow-up, nine patients treated with APBI and five patients receiving whole-breast irradiation had a local recurrence; the cumulative incidence of local recurrence was 1·44% (95% CI 0·51-2·38) with APBI and 0·92% (0·12-1·73) with whole-breast irradiation (difference 0·52%, 95% CI -0·72 to 1·75; p=0·42). No grade 4 late side-effects were reported. The 5-year risk of grade 2-3 late side-effects to the skin was 3·2% with APBI versus 5·7% with whole-breast irradiation (p=0·08), and 5-year risk of grade 2-3 subcutaneous tissue late side-effects was 7·6% versus 6·3% (p=0·53). The risk of severe (grade 3) fibrosis at 5 years was 0·2% with whole-breast irradiation and 0% with APBI (p=0·46). INTERPRETATION The difference between treatments was below the relevance margin of 3 percentage points. Therefore, adjuvant APBI using multicatheter brachytherapy after breast-conserving surgery in patients with early breast cancer is not inferior to adjuvant whole-breast irradiation with respect to 5-year local control, disease-free survival, and overall survival. FUNDING German Cancer Aid.

Otium et negotium. Reading processes and their cultural backgrounds in early Italian and German humanism

Reading and reading habits have radically changed in the digital age. Readers are no longer physically bound to textual objects and libraries, they deal with texts by copying, altering, and annotating them, and they mix established textual forms with other semiotic systems such as pictograms, icons and images. These circumstances also provoke a renewed research interest in the history of reading. In this talk, I will concentrate on reading processes as to how they were enacted and practised in early Italian and German humanism. I will start with some paradigmatic scenes described in Petrarch’s letters (among others the famous visit of the Mont Ventoux, where Petrarch, after having enjoyed a spectacular panorama, withdraws into the contemplative reading of St-Augustine). The transmission of Petrarch’s writings in humanist circles of Southern Germany (e.g. with the Schedel and Gossembrot families in Nurnberg, Augsburg and Strasburg) will then lead to specific reading practices documented in manuscripts that once belonged to coherent libraries and are nowadays spread all over Europe. In the case of the former tradesman and mayor Sigismund Gossembrot, complex habits of textual annotating and cross-referencing can be observed. The dichotomy of the Latin terms otium (‘rest’ and ‘leisure’) and negotium (‘activity’, but also ‘practice’, ‘negotiation’, ‘circulation of social energy’ in the sense of New Historicism) will be used as an ideal-type outline to describe the occurring processes of reading.

Otium et negotium. Reading processes and their cultural backgrounds in early Italian and German humanism

Reading and reading habits have radically changed in the digital age. Readers are no longer physically bound to textual objects and libraries, they deal with texts by copying, altering, and annotating them, and they mix established textual forms with other semiotic systems such as pictograms, icons and images. These circumstances also provoke a renewed research interest in the history of reading. In this talk, I will concentrate on reading processes as to how they were enacted and practised in early Italian and German humanism. I will start with some paradigmatic scenes described in Petrarch’s letters (among others the famous visit of the Mont Ventoux, where Petrarch, after having enjoyed a spectacular panorama, withdraws into the contemplative reading of St-Augustine). The transmission of Petrarch’s writings in humanist circles of Southern Germany (e.g. with the Schedel and Gossembrot families in Nurnberg, Augsburg and Strasburg) will then lead to specific reading practices documented in manuscripts that once belonged to coherent libraries and are nowadays spread all over Europe. In the case of the former tradesman and mayor Sigismund Gossembrot, complex habits of textual annotating and cross-referencing can be observed. The dichotomy of the Latin terms otium (‘rest’ and ‘leisure’) and negotium (‘activity’, but also ‘practice’, ‘negotiation’, ‘circulation of social energy’ in the sense of New Historicism) will be used as an ideal-type outline to describe the occurring processes of reading.

Lichen species richness is highest in non-intensively used grasslands promoting suitable microhabitats and low vascular plant competition

Lichens are very sensitive to habitat changes and their species richness is likely to decline under intensive land use. Currently, a comprehensive study analyzing lichen species richness in relation to land-use types, extending over different regions and including information on habitat variables, is missing for temperate grasslands. In three German regions we studied lichen species richness in 490 plots of 16 m2 representing different land-use types, livestock types, and habitat variables. Due to the absence of low-intensity pastures and substrates such as woody plants, deadwood and stones, there were no lichens in the 78 plots in Schorfheide-Chorin. In the two other regions, the richness of lichen species was 45 % higher in pastures than in meadows, and 77 % higher than in mown pastures, respectively. Among the pastures, the richness of all lichen species was on average 10 times higher in sheep-grazed pastures than in the ones grazed by cattle or horses. On average, the richness of all lichen species increased by 3.3 species per additional microhabitat. Furthermore, the richness of corticolous lichens increased by 1.2 species with 10 % higher cover of woody plants, lignicolous lichen species richness increased by 4.8 species with 1 % higher cover of deadwood, and saxicolous lichen species richness increased by 1.0 species with 1 % higher cover of stones. Our findings highlight the importance of low-intensity land use for lichen conservation. In particular, the degradation of grasslands rich in microhabitats and the destruction of lichen substrates by intensification, and conversion of unfertilized pastures formerly grazed at low intensity to meadows should be avoided to maintain lichen diversity.

Less invasive ventilation in extremely low birth weight infants from 1997 to 2011: survey versus evidence.

UNLABELLED Evidence for target values of arterial oxygen saturation (SaO2), CO2, and pH has changed substantially over the last 20 years. A representative survey concerning treatment strategies in extremely low-birth-weight infants (ELBW) was sent to all German neonatal intensive care units (NICUs) treating ELBW infants in 1997. A follow-up survey was conducted in 2011 and sent to all NICUs in Germany, Austria, and Switzerland. During the observation period, NICUs targeting SaO2 of 80, 85, and 90 % have increased, while units aiming for 94 and 96 % decreased (all p < 0.001). Similarly, NICUs aiming for pH 7.25 or lower increased, while 7.35 or higher decreased (both p < 0.001). Furthermore, more units targeted a CO2 of 50 mmHg (7.3 kPa) or higher (p < 0.001), while fewer targeted 40 or 35 mmHg (p < 0.001). Non-invasive ventilation (NIV) was used in 80.2 % of NICUs in 2011. The most frequently used ventilation modes were synchronized intermittent mandatory ventilation (SIMV) (67.5 %) and intermittent positive pressure ventilation (IPPV) (59.7 %) in 1997 and SIMV (77.2 %) and synchronized intermittent positive pressure ventilation (SIPPV) (26.8 %) in 2011. NICUs reporting frequent or always use of IPPV decreased to 11.0 % (p < 0.001). SIMV (77.2 %) and SIPPV (26.8 %) did not change from 1997 to 2011, while high-frequency oscillation (HFO) increased from 9.1 to 19.7 % (p = 0.018). Differences between countries, level of care, and size of the NICU were minimal. CONCLUSIONS Target values for SaO2 decreased, while CO2 and pH increased significantly during the observation period. Current values largely reflect available evidence at time of the surveys. WHAT IS KNOWN • Evidence concerning target values of oxygen saturation, CO 2 , and pH in extremely low-birth-weight infants has grown substantially. • It is not known to which extent this knowledge is transferred into clinical practice and if treatment strategies have changed. WHAT IS NEW • Target values for oxygen saturation in ELBW infants decreased between 1997 and 2011 while target values for CO 2 and pH increased. • Similar treatment strategies existed in different countries, hospitals of different size, or university versus nonuniversity hospitals in 2011.

Multiple regulatory variants located in cell type-specific enhancers within the PKP2 locus form major risk and protective haplotypes for canine atopic dermatitis in German shepherd dogs.

BACKGROUND Canine atopic dermatitis (CAD) is a chronic inflammatory skin disease triggered by allergic reactions involving IgE antibodies directed towards environmental allergens. We previously identified a ~1.5 Mb locus on canine chromosome 27 associated with CAD in German shepherd dogs (GSDs). Fine-mapping indicated association closest to the PKP2 gene encoding plakophilin 2. RESULTS Additional genotyping and association analyses in GSDs combined with control dogs from five breeds with low-risk for CAD revealed the top SNP 27:19,086,778 (p = 1.4 × 10(-7)) and a rare ~48 kb risk haplotype overlapping the PKP2 gene and shared only with other high-risk CAD breeds. We selected altogether nine SNPs (four top-associated in GSDs and five within the ~48 kb risk haplotype) that spanned ~280 kb forming one risk haplotype carried by 35 % of the GSD cases and 10 % of the GSD controls (OR = 5.1, p = 5.9 × 10(-5)), and another haplotype present in 85 % of the GSD cases and 98 % of the GSD controls and conferring a protective effect against CAD in GSDs (OR = 0.14, p = 0.0032). Eight of these SNPs were analyzed for transcriptional regulation using reporter assays where all tested regions exerted regulatory effects on transcription in epithelial and/or immune cell lines, and seven SNPs showed allelic differences. The DNA fragment with the top-associated SNP 27:19,086,778 displayed the highest activity in keratinocytes with 11-fold induction of transcription by the risk allele versus 8-fold by the control allele (pdifference = 0.003), and also mapped close (~3 kb) to an ENCODE skin-specific enhancer region. CONCLUSIONS Our experiments indicate that multiple CAD-associated genetic variants located in cell type-specific enhancers are involved in gene regulation in different cells and tissues. No single causative variant alone, but rather multiple variants combined in a risk haplotype likely contribute to an altered expression of the PKP2 gene, and possibly nearby genes, in immune and epithelial cells, and predispose GSDs to CAD.