Post-Brexit no-trade-deal scenario: Short-term consumer benefit at the expense of long-term economic development

After the United Kingdom has left the European Union it remains unclear whether the two parties can successfully negotiate and sign a trade agreement within the transition period. Ongoing negotiations, practical obstacles and resulting uncertainties make it highly unlikely that economic actors would be fully prepared to a “no-trade-deal” situation. Here we provide an economic shock simulation of the immediate aftermath of such a post-Brexit no-trade-deal scenario by computing the time evolution of more than 1.8 million interactions between more than 6,600 economic actors in the global trade network. We find an abrupt decline in the number of goods produced in the UK and the EU. This sudden output reduction is caused by drops in demand as customers on the respective other side of the Channel incorporate the new trade restriction into their decision-making. As a response, producers reduce prices in order to stimulate demand elsewhere. In the short term consumers benefit from lower prices but production value decreases with potentially severe socio-economic consequences in the longer term

Future heat stress to reduce people’s purchasing power

With increasing carbon emissions rising temperatures are likely to impact our economies and societies profoundly. In particular, it has been shown that heat stress can strongly reduce labor productivity. The resulting economic perturbations can propagate along the global supply network. Here we show, using numerical simulations, that output losses due to heat stress alone are expected to increase by about 24% within the next 20 years, if no additional adaptation measures are taken. The subsequent market response with rising prices and supply shortages strongly reduces the consumers’ purchasing power in almost all countries including the US and Europe with particularly strong effects in India, Brazil, and Indonesia. As a consequence, the producing sectors in many regions temporarily benefit from higher selling prices while decreasing their production in quantity, whereas other countries suffer losses within their entire national economy. Our results stress that, even though climate shocks may stimulate economic activity in some regions and some sectors, their unpredictability exerts increasing pressure on people’s livelihood

Larch Cellulose Shows Significantly Depleted Hydrogen Isotope Values With Respect to Evergreen Conifers in Contrast to Oxygen and Carbon Isotopes

The analysis of the stable isotope of the tree-ring cellulose is an important tool for paleo climatic investigations. Long tree-ring chronologies consist predominantly of oaks and conifers in Europe, including larch trees (Larix decidua) and cembran pines (Pinus cembra) that form very long tree ring chronologies in the Alps and grow at the treeline, where tree growth is mainly determined by temperature variations. We analyzed δ13C, δ18O and δ2H isotopes in the cellulose extracted from tree-rings of wood samples collected at high altitude in the Swiss and Tyrol Alps, covering the whole Holocene period. We found that larch cellulose was remarkably more depleted in deuterium than that of cembran pine, with mean δ2H values of −113.4 ± 9.7‰ for larch and of −65.4 ± 11.3‰ for cembran pine. To verify if these depleted values were specific to larch or a property of the deciduous conifers, we extended the analysis to samples from various living conifer species collected at the Bern Botanical Garden. The results showed that not only the larch, but also all the samples of the deciduous larch family had a cellulose composition that was highly depleted in δ2H with regard to the other evergreen conifers including cembran pine, a difference that we attribute to a faster metabolism of the deciduous conifers. The δ18O values were not statistically different among the species, in agreement with the hypothesis that they are primary signals of the source water. While the δ13C values were slightly more depleted for larch than for cembran pine, likely due to metabolic differences of the two species. We conclude that the deciduous larch conifers have specific metabolic hydrogen fractionations and that the larch unique signature of δ2H is useful to recognize it from other conifers in subfossil wood samples collected for paleoclimatic studies. For climate information the absolute δ2H values of larch should be considered carefully and separate from other species

O6-methylguanine-DNA methyltransferase (MGMT) Promoter methylation is a rare event in soft tissue sarcoma

BACKGROUND: Gene silencing of O6-methylguanine–DNA methyltransferase (MGMT) by promoter methylation improves the outcome of glioblastoma patients after combined therapy of alkylating chemotherapeutic agents and radiation. The purpose of this study was to assess the frequency of MGMT promoter methylation in soft tissue sarcoma to identify patients eligible for alkylating agent chemotherapy such as temozolomide. FINDINGS: Paraffin tumor blocks of 75 patients with representative STS subtypes were evaluated. The methylation status of the MGMT promoter was assessed by methylation-specific polymerase-chain-reaction analysis (PCR). Furthermore, immunohistochemistry was applied to verify expression of MGMT. MGMT gene silencing was assumed if MGMT promoter methylation was present and the fraction of tumor cells expressing MGMT was 20% or less. Methylation specific PCR detected methylated MGMT promoter in 10/75 cases. Immunohistochemical staining of nuclear MGMT was negative in 15/75 cases. 6/75 tumor samples showed MGMT promoter methylation and negative immunohistochemical nuclear staining of MGMT. In none of the tested STS subtypes we found a fraction of tumors with MGMT silencing exceeding 22%. CONCLUSION: MGMT gene silencing is a rare event in soft tissue sarcoma and cannot be recommended as a selection criterion for the therapy of STS patients with alkylating agents such as temozolomide

Clinical outcome of hypofractionated breath-hold image-guided SABR of primary lung tumors and lung metastases

Background: Stereotactic Ablative RadioTherapy (SABR) of lung tumors/metastases has been shown to be an effective treatment modality with low toxicity. Outcome and toxicity were retrospectively evaluated in a unique single-institution cohort treated with intensity-modulated image-guided breath-hold SABR (igSABR) without external immobilization. The dose–response relationship is analyzed based on Biologically Equivalent Dose (BED). Patients and methods: 50 lesions in 43 patients with primary NSCLC (n = 27) or lung-metastases of various primaries (n = 16) were consecutively treated with igSABR with Active-Breathing-Coordinator (ABC®) and repeat-breath-hold cone-beam-CT. After an initial dose-finding/-escalation period, 5x12 Gy for peripheral lesions and single doses of 5 Gy to varying dose levels for central lesions were applied. Overall-survival (OS), progression-free-survival (PFS), progression pattern, local control (LC) and toxicity were analyzed. Results: The median BED2 was 83 Gy. 12 lesions were treated with a BED2 of &lt;80 Gy, and 38 lesions with a BED2 of <80 Gy. Median follow-up was 15 months. Actuarial 1- and 2-year OS were 67% and 43%; respectively. Cause of death was non-disease-related in 27%. Actuarial 1- and 2-year PFS was 42% and 28%. Progression site was predominantly distant. Actuarial 1- and 2 year LC was 90% and 85%. LC showed a trend for a correlation to BED2 (p = 0.1167). Pneumonitis requiring conservative treatment occurred in 23%. Conclusion: Intensity-modulated breath-hold igSABR results in high LC-rates and low toxicity in this unfavorable patient cohort with inoperable lung tumors or metastases. A BED2 of <80 Gy was associated with reduced local control

Postoperative elective pelvic nodal irradiation compared to prostate bed irradiation in locally advanced prostate cancer – a retrospective analysis of dose-escalated patients

Background: It is uncertain if whole-pelvic irradiation (WPRT) in addition to dose-escalated prostate bed irradiation (PBRT) improves biochemical progression-free survival (bPFS) after prostatectomy for locally advanced tumors. This study was initiated to analyze if WPRT is associated with bPFS in a patient cohort with dose-escalated (&gt; 70 Gy) PBRT. Methods: Patients with locally advanced, node-negative prostate carcinoma who had PBRT with or without WPRT after prostatectomy between 2009 and 2017 were retrospectively analyzed. A simultaneous integrated boost with equivalent-doses-in-2-Gy-fractions (EQD-2) of 79.29 Gy or 71.43 Gy to the prostate bed was applied in patients with margin-positive (or detectable) and margin-negative/undetectable tumors, respectively. WPRT (44 Gy) was offered to patients at an increased risk of lymph node metastases. Results: Forty-three patients with PBRT/WPRT and 77 with PBRT-only were identified. Baseline imbalances included shorter surgery-radiotherapy intervals (S-RT-Intervals) and fewer resected lymph nodes in the WPRT group. WPRT was significantly associated with better bPFS in univariate (p = 0.032) and multivariate models (HR = 0.484, p = 0.015). Subgroup analysis indicated a benefit of WPRT (p = 0.029) in patients treated with rising PSA values who mostly had negative margins (74.1%); WPRT was not associated with a longer bPFS in the postoperative setting with almost exclusively positive margins (96.8%). Conclusion: We observed a longer bPFS after WPRT compared to PBRT in patients with locally advanced prostate carcinoma who underwent dose-escalated radiotherapy. In subset analyses, the association was only observed in patients with rising PSA values but not in patients with non-salvage postoperative radiotherapy for positive margins

Kypho-IORT - a novel approach of intraoperative radiotherapy during kyphoplasty for vertebral metastases

<p>Abstract</p> <p>Background</p> <p>Instable and painful vertebral metastases in patients with progressive visceral metastases present a common therapeutic dilemma. We developed a novel approach to deliver intraoperative radiotherapy (IORT) during kyphoplasty and report the first treated case.</p> <p>Methods/Results</p> <p>60 year old patient with metastasizing breast cancer under chemotherapy presented with a newly diagnosed painful metastasis in the 12^ththoracic vertebra. Under general anaesthesia, a bipedicular approach into the vertebra was chosen with insertion of specially designed metallic sleeves to guide the electron drift tube of the miniature X-ray generator (INTRABEAM, Carl Zeiss Surgical, Oberkochen, Germany). This was inserted with a novel sheet designed for this approach protecting the drift tube. A radiation dose of 8 Gy in 5 mm distance (50 kV X-rays) was delivered. The kyphoplasty balloons (KyphX, Kyphon Inc, Sunnyvale) were inflated after IORT and polymethylmethacrylate cement was injected. The whole procedure lasted less than 90 minutes.</p> <p>Conclusion</p> <p>In conclusion, this novel, minimally invasive procedure can be performed in standard operating rooms and may become a valuable option for patients with vertebral metastases providing immediate stability and local control. A phase I/II study is under way to establish the optimal dose prescription.</p

The Swiss Primary Hypersomnolence and Narcolepsy Cohort study (SPHYNCS): Study protocol for a prospective, multicentre cohort observational study

Narcolepsy type 1 (NT1) is a disorder with well-established markers and a suspected autoimmune aetiology. Conversely, the narcoleptic borderland (NBL) disorders, including narcolepsy type 2, idiopathic hypersomnia, insufficient sleep syndrome and hypersomnia associated with a psychiatric disorder, lack well-defined markers and remain controversial in terms of aetiology, diagnosis and management. The Swiss Primary Hypersomnolence and Narcolepsy Cohort Study (SPHYNCS) is a comprehensive multicentre cohort study, which will investigate the clinical picture, pathophysiology and long-term course of NT1 and the NBL. The primary aim is to validate new and reappraise well-known markers for the characterization of the NBL, facilitating the diagnostic process. Seven Swiss sleep centres, belonging to the Swiss Narcolepsy Network (SNaNe), joined the study and will prospectively enrol over 500 patients with recent onset of excessive daytime sleepiness (EDS), hypersomnia or a suspected central disorder of hypersomnolence (CDH) during a 3-year recruitment phase. Healthy controls and patients with EDS due to severe sleep-disordered breathing, improving after therapy, will represent two control groups of over 50 patients each. Clinical and electrophysiological (polysomnography, multiple sleep latency test, maintenance of wakefulness test) information, and information on psychomotor vigilance and a sustained attention to response task, actigraphy and wearable devices (long-term monitoring), and responses to questionnaires will be collected at baseline and after 6, 12, 24 and 36 months. Potential disease markers will be searched for in blood, cerebrospinal fluid and stool. Analyses will include quantitative hypocretin measurements, proteomics/peptidomics, and immunological, genetic and microbiota studies. SPHYNCS will increase our understanding of CDH and the relationship between NT1 and the NBL. The identification of new disease markers is expected to lead to better and earlier diagnosis, better prognosis and personalized management of CDH

Context dependence between subdomains in the DNA binding interface of the I-CreI homing endonuclease

Homing endonucleases (HE) have emerged as precise tools for achieving gene targeting events. Redesigned HEs with tailored specificities can be used to cleave new sequences, thereby considerably expanding the number of targetable genes and loci. With HEs, as well as with other protein scaffolds, context dependence of DNA/protein interaction patterns remains one of the major limitations for rational engineering of new DNA binders. Previous studies have shown strong crosstalk between different residues and regions of the DNA binding interface. To investigate this phenomenon, we systematically combined mutations from three groups of amino acids in the DNA binding regions of the I-CreI HE. Our results confirm that important crosstalk occurs throughout this interface in I-CreI. Detailed analysis of success rates identified a nearest-neighbour effect, with a more pronounced level of dependence between adjacent regions. Taken together, these data suggest that combinatorial engineering does not necessarily require the identification of separable functional or structural regions, and that groups of amino acids provide acceptable building blocks that can be assembled, overcoming the context dependency of the DNA binding interface. Furthermore, the present work describes a sequential method to engineer tailored HEs, wherein three contiguous regions are individually mutated and assembled to create HEs with engineered specificity