bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pallidal deep brain stimulation in primary Meige syndrome: clinical outcomes and psychiatric features
Authors: Hao Qingpei , Wang Dongliang , OuYang Jia , Ding Hu , Wu Gaungyong , Liu Zhi , Liu Ru'en 
Published: October 2020

Objectives
To study the efficacy and safety of bilateral globus pallidus internus deep brain stimulation (GPi-DBS) in refractory Meige syndrome (MS) and evaluate the psychiatric disorders before and after surgery.

Methods
Twenty-two patients with MS treated with bilateral GPi-DBS were retrospectively analysed before surgery and after continuous neurostimulation. Before surgery, patients were assessed by the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS), Self-Rating Depression Scale, Medical Outcomes Study 36-Item Short-Form General Health Survey (SF-36) and Pittsburgh Sleep Quality Index (PQSI), which corresponded to motor symptoms, depressive state, quality of life and sleep quality, respectively. The implantable pulse generator of each patient was activated at 1 month after surgery. At 1 month, 3 months, 6 months and 12 months after continuous neurostimulation, all patients were evaluated by the same scales above.

Results
The BFMDRS movement scores decreased from 15.0±5.3 before surgery to 3.5±4.5 at 12 months after neurostimulation, with a mean improvement of 78% (p<0.001). The BFMDRS disability scores improved from 7.4±4.9 before surgery to 4.0±4.6 at 12 months after neurostimulation, with a mean improvement of 56% (p<0.001). The postoperative SF-36 scores had the remarkable improvement compared with baseline scores. Impaired sleep quality was found in 82% of patients and depression in 64% before surgery, which didn’t neither obtained amelioration after continuous neurostimulation.

Conclusions
Bilateral pallidal neurostimulation is a beneficial therapeutic option for refractory MS, which could improve the motor symptoms except for depression and sleep quality.
Analysis of submissions to the EU’s public consultation on tobacco traceability and security features
Authors: Gallagher Allen William Andrew , Evans-Reeves Karen , Joshi Ayush , Hatchard Jenny , Gilmore Anna B 
Published: October 2020

BackgroundThe Protocol to Eliminate Illicit Trade in Tobacco Products requires all parties to establish a tobacco track and trace (T&T) system. In 2016, the European Commission held a public consultation on T&T implementation where parties were asked to respond online to 22 multiple-choice questions and were given additional opportunities to leave comments. In May 2019, the European Union’s (EU) T&T system became operational. This paper explores tobacco industry influence over and policy positions within the consultation process.MethodsWe identified consultation respondents and investigated any financial links with the tobacco industry and if these were transparent. Respondent’s answers to the consultation’s multiple-choice questions were collated to explore whether industry-linked respondents held the same policy positions as transnational tobacco companies (TTCs). Associations between policy positions and respondent’s financial link status were tested using χ2 and Cranmer’s V tests.FindingsOf the 197 consultation respondents identified, 131 (66.4%) had financial links to the industry; 29 (22.1%) were not transparent about these links. A large number of trade associations responded (87), the majority of which (74/87) had financial links to the industry. There was a clear divide in the policy preferences of respondents with and without a financial link. Collectively, respondents with a financial link supported an industry-operated T&T solution.ConclusionsThere was an extensive lobbying effort by the tobacco industry over the EU’s T&T system, with TTCs’ interests being represented repeatedly through multiple trade associations. The transparency requirements regarding consultation respondents’ affiliations with relevant stakeholders (eg, tobacco manufacturers) should be improved for future consultations.
Spawning season movements of transported landlocked Atlantic salmon in a newly restored river habitat
Authors: Hatanpää Aurora , Huuskonen Hannu , Janhunen Matti , Kortet Raine , Piironen Jorma 
Published: October 2020

Certain spawning areas of the critically endangered Lake Saimaa landlocked Atlantic salmon (Salmo salar m. sebago) have been recently restored by excavator- and helicopter-scattered gravel, but the success of applied methodologies has remained open. Here, we monitored the spawning-related movements and redds occurrence of transported semi-wild and hatchery-reared salmon in the restored River Ala-Koitajoki, eastern Finland, using radiotelemetry and snorkeling. Nearly all fish accepted the newly restored spawning habitats in the river that maintains a low flow rate (only 4 m3·s−1). The movements of females released up to 2 weeks before spawning time were restricted mainly to the closest rapids from the release site, and most of the movements were directed downstream. Semi-wild and hatchery background fish exhibited similar mobility, which was more variable among males. A majority of redds were found in restored areas, and both helicopter- and excavator-scattered gravels were accepted as spawning substrates. Our results indicate that natural reproduction of the studied landlocked salmon population can be successfully returned to its original spawning river by restoration of habitats and transfer of spawners.
HL-LHC and ILC sensitivities in the hunt for heavy Higgs bosons
Authors: Bahl Henning , Bechtle Philip , Heinemeyer Sven , Liebler Stefan , Stefaniak Tim , Weiglein Georg 
Published: October 2020

AbstractThe prediction of additional Higgs bosons is one of the key features of physics beyond the Standard Model (SM) that gives rise to an extended Higgs sector. We assess the sensitivity of the Large Hadron Collider (LHC) in the high luminosity (HL) run alone and in combination with a possible future International Linear Collider (ILC) to probe heavy neutral Higgs bosons. We employ the Minimal Supersymmetric Standard Model (MSSM) as a framework and assume the light$$\mathcal {CP}$$CP-even MSSM Higgs boson to be the Higgs boson observed at$$125\,\mathrm{GeV}$$125GeV. We discuss the constraints on the MSSM parameter space arising from the precision measurements of the rates of the detected signal at$$125\,\mathrm{GeV}$$125GeVand from direct searches for new heavy Higgs bosons in the$$\tau ^+\tau ^-$$τ+τ-,$$b\bar{b}$$bb¯and di-Higgs (hh) final states. A new benchmark scenario for heavy Higgs searches in the$$b\bar{b}$$bb¯channel is proposed in this context. For the future Higgs rate measurements at the HL-LHC and ILC two different scenarios are investigated, namely the case where the future rate measurements agree with the SM prediction and the case where the rates agree with the predictions of possible realizations of the MSSM Higgs sector in nature.
Dr Dorothy Helen Rayner FGS (1912–2003): vertebrate palaeontologist and academic
Authors: Boylan Patrick J. 
Published: October 2020

Abstract
Dorothy Rayner was one of the first women to be appointed to a tenured academic post in any English university geology department, joining the Geology Department of the University of Leeds in 1939 and serving for 38 years to her retirement in 1977. She had two very important early influences in her life. The first was her family, with its tradition through several generations of doctors, scientists, engineers, mathematicians, radical politics and social activism. The other was her earlier education, particularly her 7 years at the very influential Bedales School, the first of what were to become known in the twentieth century as ‘progressive’ schools. After gaining a First at Girton College in the Cambridge Natural Sciences Tripos, she undertook ground-breaking research on the taxonomy and neural systems of Jurassic fishes, for which she was awarded a Cambridge PhD in 1938, soon after which she was appointed Assistant Lecturer in Geology at Leeds. In addition to an always very heavy teaching load, she continued with a broad range of research, including further work on fossil vertebrates, and the stratigraphy of first the north of England and then the whole of the British Isles. She was also an outstanding Editor, and then President, of the Yorkshire Geological Society.
Preclinical Comparison of the Blood–brain barrier Permeability of Osimertinib with Other EGFR TKIs
Authors: Colclough Nicola , Chen Kan , Johnström Peter , Strittmatter Nicole , Yan Yumei , Wrigley Gail L. , Schou Magnus , Goodwin Richard , Varnäs Katarina , Adua Sally J. , Zhao Minghui , Nguyen Don X. , Maglennon Gareth , Barton Peter , Atkinson James , Zhang Lin , Janefeldt Annika , Wilson Joanne , Smith Aaron , Takano Akihiro , Arakawa Ryosuke , Kondrashov Mikhail , Malmquist Jonas , Revunov Evgeny , Vazquez-Romero Ana , Moein Mohammad Mahdi , Windhorst Albert D. , Karp Natasha A. , Finlay M. Raymond V. , Ward Richard A. , Yates James W.T. , Smith Paul D. , Farde Lars , Cheng Zack , Cross Darren A.E. 
Published: October 2020

Abstract

Purpose:
Osimertinib is a potent and selective EGFR tyrosine kinase inhibitor (EGFR-TKI) of both sensitizing and T790M resistance mutations. To treat metastatic brain disease, blood–brain barrier (BBB) permeability is considered desirable for increasing clinical efficacy.

Experimental Design:
We examined the level of brain penetration for 16 irreversible and reversible EGFR-TKIs using multiple in vitro and in vivo BBB preclinical models.

Results:
In vitro osimertinib was the weakest substrate for human BBB efflux transporters (efflux ratio 3.2). In vivo rat free brain to free plasma ratios (Kpuu) show osimertinib has the most BBB penetrance (0.21), compared with the other TKIs (Kpuu ≤ 0.12). PET imaging in Cynomolgus macaques demonstrated osimertinib was the only TKI among those tested to achieve significant brain penetrance (Cmax %ID 1.5, brain/blood Kp 2.6). Desorption electrospray ionization mass spectroscopy images of brains from mouse PC9 macrometastases models showed osimertinib readily distributes across both healthy brain and tumor tissue. Comparison of osimertinib with the poorly BBB penetrant afatinib in a mouse PC9 model of subclinical brain metastases showed only osimertinib has a significant effect on rate of brain tumor growth.

Conclusions:
These preclinical studies indicate that osimertinib can achieve significant exposure in the brain compared with the other EGFR-TKIs tested and supports the ongoing clinical evaluation of osimertinib for the treatment of EGFR-mutant brain metastasis. This work also demonstrates the link between low in vitro transporter efflux ratios and increased brain penetrance in vivo supporting the use of in vitro transporter assays as an early screen in drug discovery.
Improved Survival Associated with Local Tumor Response Following Multisite Radiotherapy and Pembrolizumab: Secondary Analysis of a Phase I Trial
Authors: Luke Jason J. , Onderdonk Benjamin E. , Bhave Sandeep R. , Karrison Theodore , Lemons Jeffrey M. , Chang Paul , Zha Yuanyuan , Carll Tim , Krausz Thomas , Huang Lei , Martinez Carlos , Janisch Linda A. , Hseu Robyn D. , Moroney John W. , Patel Jyoti D. , Khodarev Nikolai N. , Salama Joseph K. , Ott Patrick A. , Fleming Gini F. , Gajewski Thomas F. , Weichselbaum Ralph R. , Pitroda Sean P. , Chmura Steven J. 
Published: October 2020

Abstract

Purpose:
Multisite stereotactic body radiotherapy followed by pembrolizumab (SBRT+P) has demonstrated safety in advanced solid tumors (ASTs). However, no studies have examined the relationships between irradiated tumor response, SBRT-induced tumor gene expression, and overall survival (OS).

Patients and Methods:
Patients with AST received SBRT (30–50 Gy in 3–5 fractions) to two to four metastases followed by pembrolizumab (200 mg i.v. every 3 weeks). SBRT was prescribed to a maximum tumor volume of 65 mL. Small metastases received the complete prescribed coverage (complete-Rx), while larger metastases received partial coverage (partial-Rx). Treated metastasis control (TMC) was defined as a lack of progression for an irradiated metastasis. Landmark analysis was used to assess the relationship between TMC and OS. Thirty-five biopsies were obtained from 24 patients: 19 pre-SBRT and 16 post-SBRT (11 matched) prior to pembrolizumab and were analyzed via RNA microarray.

Results:
Sixty-eight patients (139 metastases) were enrolled with a median follow-up of 10.4 months. One-year TMC was 89.5% with no difference between complete-Rx or partial-Rx. On multivariable analysis, TMC was independently associated with a reduced risk for death (HR, 0.36; 95% confidence interval, 0.17–0.75; P = 0.006). SBRT increased expression of innate and adaptive immune genes and concomitantly decreased expression of cell cycle and DNA repair genes in the irradiated tumors. Elevated post-SBRT expression of DNASE1 correlated with increased expression of cytolytic T-cell genes and irradiated tumor response.

Conclusions:
In the context of SBRT+P, TMC independently correlates with OS. SBRT impacts intratumoral immune gene expression associated with TMC. Randomized trials are needed to validate these findings.
Spatiotemporal Heterogeneity in Multiparametric Physiologic MRI Is Associated with Patient Outcomes in IDH-Wildtype Glioblastoma
Authors: Park Ji Eun , Kim Ho Sung , Kim NakYoung , Park Seo Young , Kim Young-Hoon , Kim Jeong Hoon 
Published: October 2020

Abstract

Purpose:
Heterogeneity in glioblastomas is associated with poorer outcomes, and physiologic heterogeneity can be quantified with noninvasive imaging. We developed spatial habitats based on multiparametric physiologic MRI and evaluated associations between temporal changes in these habitats and progression-free survival (PFS) after concurrent chemoradiotherapy (CCRT) in patients with glioblastoma.

Experimental Design:
Ninety-seven patients with isocitrate dehydrogenase (IDH)-wildtype glioblastoma were enrolled and two serial MRI examinations after CCRT were analyzed. Cerebral blood volumes and apparent diffusion coefficients were grouped using k-means clustering into three spatial habitats. Associations between temporal changes in spatial habitats and PFS were investigated using Cox proportional hazard modeling. The performance of significant predictors for PFS and overall survival (OS) was measured using a discrete increase of habitat (habitat risk score) in a temporal validation set from a prospective registry (n = 53, ClinicalTrials.gov NCT02619890). The site of progression was matched with the spatiotemporal habitats.

Results:
Three spatial habitats of hypervascular cellular, hypovascular cellular, and nonviable tissue were identified. A short-term increase in the hypervascular cellular habitat (HR, 40.0; P = 0.001) and hypovascular cellular habitat was significantly associated with shorter PFS (HR, 3.78; P &lt; 0.001) after CCRT. Combined with clinical predictors, the habitat risk score showed a C-index of 0.79 for PFS and 0.74 for OS and stratified patients with short, intermediate, and long PFS (P = 0.016). An increase in the hypovascular cellular habitat predicted tumor progression sites.

Conclusions:
Hypovascular cellular habitats derived from multiparametric physiologic MRIs may be useful predictors of clinical outcomes in patients with posttreatment glioblastoma.
Dual Functional States of R406W-Desmin Assembly Complexes Cause Cardiomyopathy With Severe Intercalated Disc Derangement in Humans and in Knock-In Mice
Authors: Herrmann Harald , Cabet Eva , Chevalier Nicolas R. , Moosmann Julia , Schultheis Dorothea , Haas Jan , Schowalter Mirjam , Berwanger Carolin , Weyerer Veronika , Agaimy Abbas , Meder Benjamin , Müller Oliver J. , Katus Hugo A. , Schlötzer-Schrehardt Ursula , Vicart Patrick , Ferreiro Ana , Dittrich Sven , Clemen Christoph S. , Lilienbaum Alain , Schröder Rolf 
Published: October 2020

Background:
Mutations in the human desmin gene cause myopathies and cardiomyopathies. This study aimed to elucidate molecular mechanisms initiated by the heterozygous R406W-desmin mutation in the development of a severe and early-onset cardiac phenotype.

Methods:
We report an adolescent patient who underwent cardiac transplantation as a result of restrictive cardiomyopathy caused by a heterozygous R406W-desmin mutation. Sections of the explanted heart were analyzed with antibodies specific to 406W-desmin and to intercalated disc proteins. Effects of the R406W mutation on the molecular properties of desmin were addressed by cell transfection and in vitro assembly experiments. To prove the genuine deleterious effect of the mutation on heart tissue, we further generated and analyzed R405W-desmin knock-in mice harboring the orthologous form of the human R406W-desmin.

Results:

Microscopic analysis of the explanted heart revealed desmin aggregates and the absence of desmin filaments at intercalated discs. Structural changes within intercalated discs were revealed by the abnormal organization of desmoplakin, plectin, N-cadherin, and connexin-43. Next-generation sequencing confirmed the
DES
variant c.1216C>T (p.R406W) as the sole disease-causing mutation. Cell transfection studies disclosed a dual behavior of R406W-desmin with both its integration into the endogenous intermediate filament system and segregation into protein aggregates. In vitro, R406W-desmin formed unusually thick filaments that organized into complex filament aggregates and fibrillar sheets. In contrast, assembly of equimolar mixtures of mutant and wild-type desmin generated chimeric filaments of seemingly normal morphology but with occasional prominent irregularities. Heterozygous and homozygous R405W-desmin knock-in mice develop both a myopathy and a cardiomyopathy. In particular, the main histopathologic results from the patient are recapitulated in the hearts from R405W-desmin knock-in mice of both genotypes. Moreover, whereas heterozygous knock-in mice have a normal life span, homozygous animals die at 3 months of age because of a smooth muscle-related gastrointestinal phenotype.

Conclusions:
We demonstrate that R406W-desmin provokes its severe cardiotoxic potential by a novel pathomechanism, where the concurrent dual functional states of mutant desmin assembly complexes underlie the uncoupling of desmin filaments from intercalated discs and their structural disorganization.
Interactive Worksheets for Teaching Atmospheric Aerosols and Cloud Physics
Authors: Petters Markus 
Published: October 2020

AbstractStudent-centered active learning pedagogies improve learning outcomes and increase the engagement of underrepresented groups. Implementing such pedagogies requires interactive tools for students to manipulate inputs and use the outputs to construct knowledge. This work introduces interactive worksheets for teaching about atmospheric aerosol and cloud physics and describes the toolchain to create and deliver the content. The material is appropriate for upper-level undergraduate and graduate instruction with pedagogy based on process-oriented guided inquiry learning. Students playfully interact with physical relationships and atmospheric models. Two examples are the interaction with an aerosol–cloud parcel model for simulating the early stage of cloud formation and the interaction with the Bowen model for simulating the formation of rain by coalescence. Photos, text, figures, and software associated with the project are free to be shared and free to be adapted. In addition to focusing on discipline-based learning objectives, the worksheets emphasize interacting with real-world data and practicing graph comprehension. Hosting the content in the cloud ensures reliable and scalable delivery to any device with a browser and Internet access. The worksheets are designed to be used in a student-centered active learning classroom but can also be used in an online setting.
A Linear Inverse Model of Tropical and South Pacific Climate Variability: Optimal Structure and Stochastic Forcing
Authors: Lou Jiale , O’Kane Terence J. , Holbrook Neil J. 
Published: October 2020

AbstractA stochastically forced linear inverse model (LIM) of the combined modes of variability from the tropical and South Pacific Oceans is used to investigate the linear growth of optimal initial perturbations and to identify the spatiotemporal features of the stochastic forcing associated with the atmospheric Pacific–South American patterns 1 and 2 (PSA1 and PSA2). Optimal initial perturbations are shown to project onto El Niño–Southern Oscillation (ENSO) and South Pacific decadal oscillation (SPDO), where the inclusion of subsurface South Pacific Ocean temperature variability significantly increases the multiyear linear predictability of the deterministic system. We show that the optimal extratropical sea surface temperature (SST) precursor is associated with the South Pacific meridional mode, which takes from 7 to 9 months to linearly evolve into the final ENSO and SPDO peaks in both the observations and as simulated in an atmosphere-forced ocean model. The optimal subsurface precursor resembles its peak phase, but with a weak amplitude, representing oceanic Rossby waves in the extratropical South Pacific. The stochastic forcing is estimated as the residual by removing the deterministic dynamics from the actual tendency under a centered difference approximation. The resulting stochastic forcing time series satisfies the Gaussian white noise assumption of the LIM. We show that the PSA-like variability is strongly associated with stochastic SST forcing in the tropical and South Pacific Oceans and contributes not only to excite the optimal initial perturbations associated with ENSO and the SPDO but in general to activate the entire stochastic SST forcing, especially in austral summer.
Impact of COVID-19 on accident and emergency attendances and emergency and planned hospital admissions in Scotland: an interrupted time-series analysis
Authors: Mulholland Rachel H , Wood Rachael , Stagg Helen R , Fischbacher Colin , Villacampa Jaime , Simpson Colin R , Vasileiou Eleftheria , McCowan Colin , Stock Sarah J , Docherty Annemarie B , Ritchie Lewis D , Agrawal Utkarsh , Robertson Chris , Murray Josephine LK , MacKenzie Fiona , Sheikh Aziz 
Published: October 2020

Objectives Following the outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus and the subsequent global spread of the 2019 novel coronavirus disease (COVID-19), health systems and the populations who use them have faced unprecedented challenges. We aimed to measure the impact of COVID-19 on the uptake of hospital-based care at a national level. Design The study period (weeks ending 5 January to 28 June 2020) encompassed the pandemic announcement by the World Health Organization and the initiation of the UK lockdown. We undertook an interrupted time-series analysis to evaluate the impact of these events on hospital services at a national level and across demographics, clinical specialties and National Health Service Health Boards. Setting Scotland, UK. Participants Patients receiving hospital care from National Health Service Scotland. Main outcome measures Accident and emergency (A&E) attendances, and emergency and planned hospital admissions measured using the relative change of weekly counts in 2020 to the averaged counts for equivalent weeks in 2018 and 2019. Results Before the pandemic announcement, the uptake of hospital care was largely consistent with historical levels. This was followed by sharp drops in all outcomes until UK lockdown, where activity began to steadily increase. This time-period saw an average reduction of −40.7% (95% confidence interval [CI]: −47.7 to −33.7) in A&E attendances, −25.8% (95% CI: −31.1 to −20.4) in emergency hospital admissions and −60.9% (95% CI: −66.1 to −55.7) in planned hospital admissions, in comparison to the 2018–2019 averages. All subgroup trends were broadly consistent within outcomes, but with notable variations across age groups, specialties and geography. Conclusions COVID-19 has had a profoundly disruptive impact on hospital-based care across National Health Service Scotland. This has likely led to an adverse effect on non-COVID-19-related illnesses, increasing the possibility of potentially avoidable morbidity and mortality. Further research is required to elucidate these impacts.