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Sarah-Jane Martin,1,2 Melanie Guenette,1 Jiwon Oh1 1Division of Neurology, Department of Medicine, St Michael’s Hospital, Toronto, Canada; 2University of Glasgow, Glasgow, UKCorrespondence: Jiwon Oh, Email jiwon.oh@unityhealth.toAbstract: B cells are critical to the pathogenesis of multiple sclerosis (MS), an autoimmune disease of the central nervous system. B cell depletion using anti-CD20 monoclonal antibodies (mAbs) has proven to be an extremely successful treatment strategy, with profound suppression of both clinical and radiological evidence of focal inflammatory disease. Several anti-CD20 mAbs are now licensed for use in MS, with ublituximab being the latest to gain regulatory approval. The unique properties of each of the anti-CD20 mAb may result in nuanced differences in timing, duration and depth of B cell depletion, with the potential for such differences to have a clinical relevance to both drug efficacy and adverse effects. In this review, we summarize the design, development, and current place in MS therapy for ublituximab.Keywords: multiple sclerosis, ublituximab, B-cell therapy, anti-CD20 monoclonal antibody

Lucas E Hepler,1 Samuel J Martin,2 Kennedy Fuglseth,1 Laney Cuddihee,3 Peter Giannulis,3 Robert W Arnold3 1College of Osteopathic Medicine, Pacific Northwest University, Yakima, WA, USA; 2School of Medicine, Loma Linda University, Loma Linda, CA, USA; 3Alaska Blind Child Discovery, Alaska Children’s EYE & Strabismus, Anchorage, AK, USACorrespondence: Robert W Arnold, Alaska Blind Child Discovery, Alaska Children’s EYE & Strabismus, 3500 Latouche &num;280, Anchorage, AK, 99508, USA, Tel +1907561-1917, Fax +1907563-5373, Email eyedoc@alaska.netPurpose: Existing and emerging visual acuity methods like dynamic and dichoptic presentation, preferential looking and eye tracking promise to afford better and earlier assessment in children with and without amblyopia so we propose methods needed to easily evaluate and compare their metrics.Subjects and Methods: Patients older than 8 years with treated amblyopia and superb vision (logMAR − 0.1 to − 0.3) normals performed timed, patched eETDRS with Sloan matching card at 3.00 m and PDI Check dichoptic near rivalry dynamic test to demonstrate test re-Test and compared disparate acuity with intraclass correlation (ICC) and Bland Altman 95% limits of agreement (LOA) to generate a simple method of qualifying acuity test matching.Results: 26 amblyopic patients and 11 superb-vision normals performed eETDRS retest, PDI Check retest and combined ICC of 0.98, 0.60 and 0.27, respectively, and Bland Altman LOA of 0.24, 2.06 and 2.28 logMAR. The time to test one eye with eETDRS had median (interquartile range; IQR) duration of 280 (205 to 346) seconds, while the PDI Check autostereoscopic dichoptic for both eyes only took 39 (30 to 47) seconds. Optimum ICC and LOA for visual acuity comparison should be > 0.95 and < 0.3 logMAR, whereas “good” ICC and should be 0.75– 0.89 ICC and 1.0– 1.49 logMAR LOA.Conclusion: Superb vision subjects (logMAR < − 0.1) and treated amblyopic patients confirmed optimum comparable eETDRS, and fair test re-Test PDI Check but suppression on near dichoptic testing confirmed disparity compared to optimized eETDRS distance acuity.Keywords: visual acuity, Bland Altman, amblyopia, suppression, superior, optimum, correlation, dichoptic

Robert W Arnold,1 Samuel J Martin,2 Joshua R Beveridge,3 Andrew W Arnold,4 Stephanie L Arnold,4 Nathanael R Beveridge,5 Kyle A Smith1,6 1Alaska Blind Child Discovery, Alaska Children’s EYE & Strabismus, Anchorage, AK, 99508, USA; 2Loma Linda Medical School, Loma Linda, CA, USA; 3Idaho College of Osteopathic Medicine, Boise, ID, USA; 4Ascension Genesys Residency Program, Grand Blanc, MI, USA; 5US Airforce Academy, Colorado Springs, CO, USA; 6Accurate Vision, Anchorage, AK, USACorrespondence: Robert W ArnoldAlaska Children’s EYE & Strabismus, 3500 Latouche Street #280, Anchorage, AK, 99508, USATel +1(907)561-1917Fax +1 9075635373Email eyedoc@alaska.netBackground: Handheld devices can automatically give an estimate of refraction. The established method for refraction comparison using spherical equivalent (M) and J0, J45 vector transformations by Bland–Altman analysis is too complex for non-eye doctors involved with vision screening and remote vision clinics. Therefore, a simpler comparison technique was developed.Methods: Based on the spectacle limit to resolve grade A 1 logMAR, B 3 logMAR and C 6 logMAR blur, J0, J45, and M are combined into the Alaska Blind Child Discovery (ABCD) composite ellipsoid GRADE system. Pediatric eye patients had confirmatory examination after dry refraction with three portable autorefractors: Plusoptix, 2WIN and Retinomax. The refractions were then compared using both Bland–Altman and ABCD composite. Performance to detect AAPOS amblyopia risk factors was also assessed.Results: A total of 202 children, mean age seven years, 28% high spectacle need and 43% AAPOS 2013 amblyopia risk factors showed high correlation with cycloplegic refraction (intraclass correlation 0.49 to 0.90) for sphere, J0 and J45 spectacle components. Plusoptix had more (10%) inconclusives due to patients out-of-range. The Retinomax was unable to screen some younger children and was less reliable for sphere but gave more precise astigmatism estimates. The proportion of autorefractions expected to give GRADE A/B high-need patients acuity improvement to 20/40 would be 41% for Plusoptix, 39% for 2WIN and 65% for Retinomax. Sensitivity/specificity for amblyopia risk factor detection was 80%/83% for Plusoptix, 72%/88% for 2WIN and 84%/73% for Retinomax.Conclusion: The simplified spectacle comparison resembled Bland–Altman and could assist lay vision screeners and non-eye doctors attempting remote spectacle donation worldwide.Keywords: spectacles, remote dispensing, autorefractors, validation

Robert W Arnold,1 Joshua S Beveridge,1 Samuel J Martin,1 Nathanael R Beveridge,1 Elise J Metzger,2 Kyle A Smith3 1The Alaska Blind Child Discovery, Anchorage, AK 99508, USA; 2Grace Christian School, Anchorage, AK, USA; 3Kyle Smith, Accurate Vision, Anchorage, AK, USACorrespondence: Robert W ArnoldThe Alaska Blind Child Discovery, Alaska Children’s EYE & Strabismus, 3500 Latouche #280, Anchorage, AK 99508, USATel +1 907 561-1917Fax +1 907 563-5373Email eyedoc@alaska.netBackground: Portable autorefractors can estimate refractive error in remote locations, but sphero-cylinder comparison and donated-spectacle dispensing are not yet simple.Methods: Normal astigmats determined best corrected acuity, then degraded 1 logMAR (Grade A), 3 logMAR (Grade B), and 6 logMAR (Grade C) to determine limits of astigmatism axis and power at these levels. The cylindrical refraction was vector transformed with J0 on the abscissa and J45 on the ordinate.Results: Ten subjects produced multiple refractions at the interfaces of Grades A, B, and C representing ovals on the J0 and J45 coordinates. When rotated, the vertical axis represented 45° or 135°, the horizontal long axis was 1.6× the short axis. The size of the ovals positively correlated with cylinder power. Given a target refraction, the comparability of a candidate lens was demonstrated on our interactive database yielding a simple A, B, C, or worse grade for cylinder, spherical equivalent, and pupillary diameter.Conclusion(s)/Relevance: Inputting a remote autorefraction, pupillary diameter and age as target and a donated spectacle as the candidate with a “B” grade similarity would be expected to attain 20/40 acuity (3 logMAR degrade) if best corrected visual acuity was 20/20. This practical Excel database could facilitate widespread remote lay dispensing of the cylinder as well as spherical spectacles. The grade similarity can also compare refracting tools such as photoscreeners and hand-held autorefractors.Clinical Trials Registry: NCT04297969.Keywords: donated recyled spectacles, remote dispensing, portable autorefraction, vision screen validation, forensic optometry

Alexa H Levitt,1 Samuel J Martin,2 Robert W Arnold3 1Human and Organizational Development, Vanderbilt University, Nashville, TN, USA; 2Research Department, Alaska Blind Child Discovery, Anchorage, AK, USA; 3Alaska Blind Child Discovery, Alaska Children’s EYE & Strabismus, Anchorage, AK, USACorrespondence: Robert W ArnoldAlaska Blind Child Discovery, Alaska Children’s EYE & Strabismus, Anchorage, AK, USAEmail eyedoc@alaska.netBackground: A low-detail, glowing fixation device was added to GoCheck Kids (GCK) photoscreener in the hope of unmasking hyperopia and amblyopia risk factors (ARF).Methods: Pediatric eye patients were screened by GCK and 2WIN photoscreeners, and Retinomax autorefractor before being compared to AAPOS ARFs.Results: Screening was attempted by 131 children who then had school bus accommodation-relaxing skiascopy (SBA-RS) before cycloplegic examination. By 2013 AAPOS uniform guidelines, sensitivity/specificity for GCK was 87%/68%, for 2WIN 87%/71% and for Retinomax 79%/68%. Detection of amblyopia had sensitivity/specificity by GCK of 78%/63%, for 2WIN 79%/65% and for Retinomax 77%/68%. Inconclusive screens were seven for GCK, six for 2WIN and 13 for Retinomax. Mean hyperopia for GCK (+2.49± 0.74 D) was similar to cycloplegic refraction (+2.93± 0.72 D) and SBA-RS (+2.80± 0.82 D) while GCK was slightly more than Retinomax (+1.59± 0.93 D, p=0.13) but significantly more than 2WIN (+1.02± 0.49 D, p< 0.01).Conclusion: GCK, 2WIN and Retinomax had similar validity detecting uniform amblyopia risk factors and amblyopia itself. The nondetailed glow fixation device allowed GCK to uncover substantial hyperopia while the detailed flashing fixation devices on 2WIN and Retinomax seemed to stimulate accommodation in some hyperopic children.Clinical Trials Registry: NCT04297969. Data Access: http://www.abcd-vision.org/references/GCK%20glow%202WIN%20deidentify.pdf.Précis: A glow fixation device on a smart phone photoscreener allowed robust detection of hyperopia.Keywords: amblyopia risk factor, vision screening, photoscreener, hyperopia

Samuel Joseph Martin,1 Hser Eh Htoo,2 Nay Hser,2 Robert W Arnold1 1Alaska Blind Child Discovery, Anchorage, AK, USA; 2Jungle School of Medicine Kawthoolei, Karen State, Burma (Myanmar)Correspondence: Robert W ArnoldAlaska Blind Child Discovery, Anchorage, AK, USATel +1 907561-1917Email eyedoc@alaska.netBackground: Photoscreeners provide valid, cost-effective early detection of amblyopia risk factors; however, they require proper illumination, flash intensity, pupil dilation and patient cooperation. The Kaleidos case for the 2WIN infrared photoscreener fixes focal distance, decreases luminance and provides electric power. GoCheck Kids (GCK) has developed a flash-concentrating case for the Apple iPhone 7 Plus smartphone to reduce exposure time.Methods: In remote Burmese and urban Alaskan clinics, Kaleidos and GCK were used before a confirmatory eye examination using 2013 AAPOS uniform guidelines validation, including some older patients. 2WIN refraction was compared to a cycloplegic examination using J0 and J45 vector transformation.Results: In total, 48 Burmese patients and 114 Alaskan patients aged 8± 6 years were evaluated utilizing 2013 amblyopia risk factor guidelines. Kaleidos, with 13 Burmese inconclusives, had a sensitivity of 84%, specificity of 65% and positive predictive value (PPV) of 63%. GCK, with only six inconclusives, had a sensitivity of 63%, specificity of 83% and PPV of 73%, with sensitivity improving to 74% with central expert interpretation. Kaleidos closely matched cycloplegic refraction, with intraclass correlations of 0.47 for J0 vector and 0.57 for J45 vector. The protective cases provided clearer images and better pupil dilation than similar devices without cases.Conclusion: Both devices detected amblyopia risk factors well. GCK gave fewer inconclusive results even with the Asian eyelid configuration, while Kaleidos matched sphere and cylinder refraction. The specialized housing enhanced the performance of the 2WIN and GCK photoscreeners, improving the speed and reliability of amblyopia screening and refraction, even in populous and luminous locations.Clinical Trials Registry: NCT04068129.Keywords: pediatric vision screening, amblyopia, instrument-based screening, validation

Food digestion is a complex, multiscale process that has recently become of interest to the food industry due to the developing links between food and health or disease. Food digestion can be studied by using either in vitro or in vivo models, each having certain advantages or disadvantages. The recent interest in food digestion has resulted in a large number of studies in this area, yet few have provided an in-depth, quantitative description of digestion processes. To provide a framework to develop these quantitative comparisons, a summary is given here between digestion processes and parallel unit operations in the food and chemical industry. Characterization parameters and phenomena are suggested for each step of digestion. In addition to the quantitative characterization of digestion processes, the multiscale aspect of digestion must also be considered. In both food systems and the gastrointestinal tract, multiple length scales are involved in food breakdown, mixing, absorption. These different length scales influence digestion processes independently as well as through interrelated mechanisms. To facilitate optimized development of functional food products, a multiscale, engineering approach may be taken to describe food digestion processes. A framework for this approach is described in this review, as well as examples that demonstrate the importance of process characterization as well as the multiple, interrelated length scales in the digestion process.

The British Virgin Islands is second only to Hong Kong as a source for foreign investment into China. Over the past two decades or so, Chinese entrepreneurs have demonstrated a preference for incorporating in the offshore finance centers of the Caribbean. Chinese offshore structures are different from earlier uses of the offshore in their unique and seemingly transparent aesthetic form. We show how equity-a legal argument and tradition that moderates the letter of the law-and these structures mutually engage one another through spatiotemporal reference and framing. We argue that this engagement is accidental, a coincidence of aesthetic form rather than an emergent phenomenon of any larger process or the product of a plan. It is also not a contingent articulation of compatible elements from the corporate and legal domains. In exploring the aesthetics of Chinese offshore incorporation and court cases that invoke equity, we argue that the accidental discovery of equity can reorient certain analytical conceits about capital and how we can know it. © 2012 by the American Anthropological Association.

Prostate cancer is known to have a variable response to androgen receptor signalling inhibitors. Here, the authors use machine learning to predict response to therapy from genomic, transcriptomic and clinical data.

A proteogenomic analysis of matching primary breast cancer and ipsilateral breast tumor recurrence (IBTR) samples provides insight into the development of IBTR and may be useful in identifying biomarkers for IBTR formation.

Abstract DNA mutations in specific genes can confer preferential benefit from drugs targeting those genes. However, other molecular perturbations can “phenocopy” pathogenic mutations, but would not be identified using standard clinical sequencing, leading to missed opportunities for other patients to benefit from targeted treatments. We hypothesized that RNA phenocopy signatures of key cancer driver gene mutations could improve our ability to predict response to targeted therapies, despite not being directly trained on drug response. To test this, we built gene expression signatures in tissue samples for specific mutations and found that phenocopy signatures broadly increased accuracy of drug response predictions in-vitro compared to DNA mutation alone, and identified additional cancer cell lines that respond well with a positive/negative predictive value on par or better than DNA mutations. We further validated our results across four clinical cohorts. Our results suggest that routine RNA sequencing of tumors to identify phenocopies in addition to standard targeted DNA sequencing would improve our ability to accurately select patients for targeted therapies in the clinic.

Prostate cancer is a highly heterogeneous disease, understanding the crosstalk between complex genomic and epigenomic alterations will aid in developing targeted therapeutics. We demonstrate that, even though snail family transcriptional repressor 2 (SNAI2) is frequently amplified in prostate cancer, it is epigenetically silenced in this disease, with dynamic changes in SNAI2 levels showing distinct clinical relevance. Integrative clinical data from 18 prostate cancer cohorts and experimental evidence showed that gene fusion between transmembrane serine protease 2 (TMPRSS2) and ETS transcription factor ERG (ERG) (TMPRSS2–ERG fusion) is involved in the silencing of SNAI2. We created a silencer score to evaluate epigenetic repression of SNAI2, which can be reversed by treatment with DNA methyltransferase inhibitors and histone deacetylase inhibitors. Silencing of SNAI2 facilitated tumor cell proliferation and luminal differentiation. Furthermore, SNAI2 has a major influence on the tumor microenvironment by reactivating tumor stroma and creating an immunosuppressive microenvironment in prostate cancer. Importantly, SNAI2 expression levels in part determine sensitivity to the cancer drugs dasatinib and panobinostat. For the first time, we defined the distinct clinical relevance of SNAI2 expression at different disease stages. We elucidated how epigenetic silencing of SNAI2 controls the dynamic changes of SNAI2 expression that are essential for tumor initiation and progression and discovered that restoring SNAI2 expression by treatment with panobinostat enhances dasatinib sensitivity, indicating a new therapeutic strategy for prostate cancer.

Background The implementation of immunological biomarkers for radiotherapy (RT) individualization in breast cancer requires consideration of tumor-intrinsic factors. This study aimed to investigate whether the integration of histological grade, tumor-infiltrating lymphocytes (TILs), programmed cell death protein-1 (PD-1), and programmed death ligand-1 (PD-L1) can identify tumors with aggressive characteristics that can be downgraded regarding the need for RT.Methods The SweBCG91RT trial included 1178 patients with stage I–IIA breast cancer, randomized to breast-conserving surgery with or without adjuvant RT, and followed for a median time of 15.2 years. Immunohistochemical analyses of TILs, PD-1, and PD-L1 were performed. An activated immune response was defined as stromal TILs ≥10% and PD-1 and/or PD-L1 expression in ≥1% of lymphocytes. Tumors were categorized as high-risk or low-risk using assessments of histological grade and proliferation as measured by gene expression. The risk of ipsilateral breast tumor recurrence (IBTR) and benefit of RT were then analyzed with 10 years follow-up based on the integration of immune activation and tumor-intrinsic risk group.Results Among high-risk tumors, an activated immune infiltrate was associated with a reduced risk of IBTR (HR 0.34, 95% CI 0.16 to 0.73, p=0.006). The incidence of IBTR in this group was 12.1% (5.6–25.0) without RT and 4.4% (1.1–16.3) with RT. In contrast, the incidence of IBTR in the high-risk group without an activated immune infiltrate was 29.6% (21.4–40.2) without RT and 12.8% (6.6–23.9) with RT. Among low-risk tumors, no evidence of a favorable prognostic effect of an activated immune infiltrate was seen (HR 2.0, 95% CI 0.87 to 4.6, p=0.100).Conclusions Integrating histological grade and immunological biomarkers can identify tumors with aggressive characteristics but a low risk of IBTR despite a lack of RT boost and systemic therapy. Among high-risk tumors, the risk reduction of IBTR conferred by an activated immune infiltrate is comparable to treatment with RT. These findings may apply to cohorts dominated by estrogen receptor-positive tumors.

Denne intervjustudien drøfter hvordan internasjonal praksismobilitet i lærerutdanning kan bidra til utvikling av lærerstudenters emosjonelle og interkulturelle kompetanse. Problemstillingen tar utgangspunkt i hvordan lærerstudenter fra Norge beskriver sine emosjonelle og interkulturelle erfaringer fra et gjennomført praksisopphold i Tanzania. Funnene viser at lærerstudentene opplever en utvikling i retning av økt interkulturell kompetanse på bakgrunn av praksismobilitet. Analysen indikerer at emosjoner medierer interkulturelle erfaringer og at regulering av emosjoner er sentralt i styrkingen av lærerstudentenes interkulturelle kompetanse. I studien avdekkes det at studentene bruker ulike emosjonsregulerende strategier. Et gjennomgående funn er at støtte fra sosiale omgivelser er blant de viktigste emosjonsregulerende strategiene på vei mot økt interkulturell kompetanse. ENGLISH ABSTRACT The emotional intercultural meeting This interview study discusses how international practicums in teacher education can contribute to the development of teacher-training students’ emotional and intercultural competence. The research is based on how teacher-training students from Norway describe emotional and intercultural experiences from a completed international practicum in Tanzania. A key finding is that international practicums may help students in the development of their intercultural competence. Furthermore, the analysis indicates that emotions mediate intercultural encounters and, thus, regulating emotions is central for teachertraining students’ intercultural competence. The study shows that the students use different emotion regulating strategies. Support from social environments appears to be among the most important emotion regulation strategies towards increased intercultural competence.

Abstract We are now in an era of molecular medicine, where specific DNA alterations can be used to identify patients who will respond to specific drugs. However, there are only a handful of clinically used predictive biomarkers in oncology. Herein, we describe an approach utilizing in vitro DNA and RNA sequencing and drug response data to create TreAtment Response Generalized Elastic-neT Signatures (TARGETS). We trained TARGETS drug response models using Elastic-Net regression in the publicly available Genomics of Drug Sensitivity in Cancer (GDSC) database. Models were then validated on additional in-vitro data from the Cancer Cell Line Encyclopedia (CCLE), and on clinical samples from The Cancer Genome Atlas (TCGA) and Stand Up to Cancer/Prostate Cancer Foundation West Coast Prostate Cancer Dream Team (WCDT). First, we demonstrated that all TARGETS models successfully predicted treatment response in the separate in-vitro CCLE treatment response dataset. Next, we evaluated all FDA-approved biomarker-based cancer drug indications in TCGA and demonstrated that TARGETS predictions were concordant with established clinical indications. Finally, we performed independent clinical validation in the WCDT and found that the TARGETS AR signaling inhibitors (ARSI) signature successfully predicted clinical treatment response in metastatic castration-resistant prostate cancer with a statistically significant interaction between the TARGETS score and PSA response (p = 0.0252). TARGETS represents a pan-cancer, platform-independent approach to predict response to oncologic therapies and could be used as a tool to better select patients for existing therapies as well as identify new indications for testing in prospective clinical trials.

It is hypothesized that there are a number of tumor specific driver genes for metastatic prostate cancer. Here, the authors perform genome-wide CRISPRi screens and integrate these data with metastatic prostate cancer functional and clinical genomics data to show that KIF4A and WDR62 drive aggressive prostate cancer phenotypes.

Sleep spindles, defining oscillations of stage II non-rapid eye movement sleep (N2), mediate sleep-dependent memory consolidation. Spindles are disrupted in several neurodevelopmental, neuropsychiatric, and neurodegenerative disorders characterized by cognitive impairment. Increasing spindles can improve memory suggesting spindles as a promising physiological target for the development of cognitive enhancing therapies. This effort would benefit from more comprehensive and spatially precise methods to characterize spindles. Spindles, as detected with electroencephalography (EEG), are often widespread across electrodes. Available evidence, however, suggests that they act locally to enhance cortical plasticity in the service of memory consolidation. Here, we present a novel method to enhance the spatial specificity of cortical source estimates of spindles using combined EEG and magnetoencephalography (MEG) data constrained to the cortex based on structural MRI. To illustrate this method, we used simultaneous EEG and MEG recordings from 25 healthy adults during a daytime nap. We first validated source space spindle detection using only EEG data by demonstrating strong temporal correspondence with sensor space EEG spindle detection (gold standard). We then demonstrated that spindle source estimates using EEG alone, MEG alone and combined EEG/MEG are stable across nap sessions. EEG detected more source space spindles than MEG and each modality detected non-overlapping spindles that had distinct cortical source distributions. Source space EEG was more sensitive to spindles in medial frontal and lateral prefrontal cortex, while MEG was more sensitive to spindles in somatosensory and motor cortices. By combining EEG and MEG data this method leverages the differential spatial sensitivities of the two modalities to obtain a more comprehensive and spatially specific source estimation of spindles than possible with either modality alone.

Experimental studies suggest that hepatocyte growth factor (HGF) and its transmembrane tyrosine kinase receptor, Met, in part also relying on Akt kinase activity, mediate radioresistance. We investigated the importance of these biomarkers for the risk of ipsilateral breast tumour recurrence (IBTR) after adjuvant radiotherapy (RT) in primary breast cancer. HGF, phosphorylated Met (pMet) and phosphorylated Akt (pAkt) were evaluated immunohistochemically on tissue microarrays from 1004 patients in the SweBCG91‐RT trial, which randomly assigned patients to breast‐conserving therapy, with or without adjuvant RT. HGF was evaluated in the stroma (HGFstr); pMet in the membrane (pMetmem); HGF, pMet and pAkt in the cytoplasm (HGFcyt, pMetcyt, pAktcyt); and pAkt in the nucleus (pAktnuc). The prognostic and treatment predictive effects were evaluated to primary endpoint IBTR as first event during the first 5 years. Patients with tumours expressing low levels of HGFcyt and pMetcyt and high levels of pAktnuc derived a larger benefit from RT [hazard ratio (HR): 0.11 (0.037–0.30), 0.066 (0.016–0.28) and 0.094 (0.028–0.31), respectively] compared to patients with high expression of HGFcyt and pMetcyt, and low pAktnuc [HR: 0.36 (0.19–0.67), 0.35 (0.20–0.64) and 0.47 (0.32–0.71), respectively; interaction analyses: P = 0.052, 0.035 and 0.013, respectively]. These differences remained in multivariable analysis when adjusting for patient age, tumour size, histological grade, St Gallen subtype and systemic treatment (interaction analysis, P‐values: 0.085, 0.027, and 0.023, respectively). This study suggests that patients with immunohistochemically low HGFcyt, low pMetcyt and high pAktnuc may derive an increased benefit from RT after breast‐conserving surgery concerning the risk of developing IBTR.

OpenModelica is a unique large-scale integrated open-source Modelica- and FMI-based modeling, simulation, optimization, model-based analysis and development environment. Moreover, the OpenModelica environment provides a number of facilities such as debugging; optimization; visualization and 3D animation; web-based model editing and simulation; scripting from Modelica, Python, Julia, and Matlab; efficient simulation and co-simulation of FMI-based models; compilation for embedded systems; Modelica-UML integration; requirement verification; and generation of parallel code for multi-core architectures. The environment is based on the equation-based object-oriented Modelica language and currently uses the MetaModelica extended version of Modelica for its model compiler implementation. This overview paper gives an up-to-date description of the capabilities of the system, short overviews of used open source symbolic and numeric algorithms with pointers to published literature, tool integration aspects, some lessons learned, and the main vision behind its development.

Abstract Dentate nuclei (DN) are involved in cerebellar modulation of motor and cognitive functions, whose impairment causes ataxia and cerebellar cognitive affective syndrome (CCAS). Friedreich ataxia (FRDA) disease progression relates to degeneration of the dentate nucleus and dentato‐thalamic pathways, causing cerebellar ataxia. Volumetric MRI also shows mild loss in the cerebellar cortex, brainstem, and motor cortex. Cognitive deficits occur in FRDA, but their relationship with ataxia progression is not fully characterized. We found a significant positive correlation between severity of patients’ ataxia and more marked CCAS as assessed with the CCAS‐Scale. This relation could be related to progressive DN impairment.

Abstract New mobility solutions, such as Mobility as a Service, have been suggested to have the potential to reduce car ownership and be part of a transition towards a more sustainable transportation system. However, research suggests that governance measures such as taxation and policies will be needed to ensure sustainability aspects. This paper explores everyday mobility by use of interventions in people’s everyday lives. The focus is on identifying underlying factors that may motivate or hinder changes that are positive from a sustainability perspective. This is then put in the perspective of new mobility services and policy making. Our findings support the view that privately owned cars are hard to replace with new mobility services that contribute to sustainability and are not based on individual cars. Economic interventions for increased sustainability will likely have limited effects, since the alternatives do not offer what car owners value most. Also, limited understanding of the car’s full costs may make the new services appear comparatively more expensive. Furthermore, urban planning to reduce the need for travel, and the capacity of the physical public transport infrastructure will continue to be important. Long vacation trips and “medium sized flows” are identified as opportunities for further research and for new solutions to support sustainable mobility transitions.

Abstract Objective Friedreich ataxia (FRDA) is the commonest hereditary ataxia in Caucasians. Most patients are homozygous for expanded GAA triplet repeats in the first intron of the frataxin (FXN) gene, involved in mitochondrial iron metabolism. Here, we used magnetoencephalography (MEG) to characterize the main determinants of FRDA‐related changes in intrinsic functional brain architecture. Methods Five minutes of MEG signals were recorded at rest from 18 right‐handed FRDA patients (mean age 27 years, 9 females; mean SARA score: 21.4) and matched healthy individuals. The MEG connectome was estimated as resting‐state functional connectivity (rsFC) matrices involving 37 nodes from six major resting state networks and the cerebellum. Source‐level rsFC maps were computed using leakage‐corrected broad‐band (3–40 Hz) envelope correlations. Post hoc median‐split was used to contrast rsFC in FRDA patients with different clinical characteristics. Nonparametric permutations and Spearman rank correlation test were used for statistics. Results High rank correlation levels were found between rsFC and age of symptoms onset in FRDA mostly between the ventral attention, the default‐mode, and the cerebellar networks; patients with higher rsFC developing symptoms at an older age. Increased rsFC was found in FRDA with later age of symptoms onset compared to healthy subjects. No correlations were found between rsFC and other clinical parameters. Conclusion Age of symptoms onset is a major determinant of FRDA patients' intrinsic functional brain architecture. Higher rsFC in FRDA patients with later age of symptoms onset supports compensatory mechanisms for FRDA‐related neural network dysfunction and position neuromagnetic rsFC as potential marker of FRDA neural reserve.

Background and Purpose: Previous studies have noted the angiographic appearance of early venous filling (EVF) following recanalisation in acute ischemic stroke. However, the prognostic implications of EVF as a novel imaging biomarker remain unclear. We aimed to evaluate the correlation between EVF with (i) the risk of subsequent reperfusion hemorrhage (RPH) and (ii) the association of EVF on both the NIHSS score at 24 h and functional outcome as assessed with the Modified Rankin Scale (mRS) score at 90 days.Methods: We conducted a retrospective cohort study of patients presenting with an acute ischemic stroke due to a proximal large-vessel occlusion of the anterior circulation treated by thrombectomy. Post-reperfusion digital subtraction angiography was reviewed to look for EVF as evidenced by the contrast opacification of any cerebral vein before the late arterial phase.Results: EVF occurred in 22.4% of the 147 cases included. The presence of EVF significantly increased the risk of RPH (p = 0.0048), including the risk of symptomatic hemorrhage (p = 0.0052). The presence of EVF (p = 0.0016) and the absence of RPH (p = 0.0021) were independently associated with a better outcome as defined by the NIHSS difference at 24 h, most significantly in the EVF+RPH− group. No significant relationship was however found between either EVF or RPH and a mRS score ≤ 2 at 90 days.Conclusion: Early venous filling on angiographic imaging is a potential predictor of reperfusion hemorrhage. The absence of subsequent RPH in this sub-group is associated with better outcomes at 24 h post-thrombectomy than in those with RPH.

In multiple sclerosis, the interplay of neurodegeneration, demyelination and inflammation leads to changes in neurophysiological functioning. This study aims to characterize the relation between reduced brain volumes and spectral power in multiple sclerosis patients and matched healthy subjects.During resting-state eyes closed, we collected magnetoencephalographic data in 67 multiple sclerosis patients and 47 healthy subjects, matched for age and gender. Additionally, we quantified different brain volumes through magnetic resonance imaging (MRI).First, a principal component analysis of MRI-derived brain volumes demonstrates that atrophy can be largely described by two components: one overall degenerative component that correlates strongly with different cognitive tests, and one component that mainly captures degeneration of the cortical grey matter that strongly correlates with age. A multimodal correlation analysis indicates that increased brain atrophy and lesion load is accompanied by increased spectral power in the lower alpha (8–10 Hz) in the temporoparietal junction (TPJ). Increased lower alpha power in the TPJ was further associated with worse results on verbal and spatial working memory tests, whereas an increased lower/upper alpha power ratio was associated with slower information processing speed.In conclusion, multiple sclerosis patients with increased brain atrophy, lesion and thalamic volumes demonstrated increased lower alpha power in the TPJ and reduced cognitive abilities.

The destruction of the Amazon is a major global environmental issue, not only because of greenhouse gas emissions or direct impacts on biodiversity and livelihoods, but also due to the forest's role as a tipping element in the Earth System. With nearly a fifth of the Amazon already lost, there are already signs of an imminent forest dieback process that risks transforming much of the rainforest into a drier ecosystem, with climatic implications across the globe. There is a large body of literature on the underlying drivers of Amazon deforestation. However, insufficient attention has been paid to the behavioral and institutional microfoundations of change. Fundamental issues concerning cooperation, as well as the mechanisms facilitating or hampering such actions, can play a much more central role in attempts to unravel and address Amazon deforestation. We thus present the issue of preventing the Amazon biome from crossing a biophysical tipping point as a large-scale collective action problem. Drawing from collective action theory, we apply a novel analytical framework on Amazon conservation, identifying six variables that synthesize relevant collective action stressors and facilitators: information, accountability, harmony of interests, horizontal trust, knowledge about consequences, and sense of responsibility. Drawing upon literature and data, we assess Amazon deforestation and conservation through our heuristic lens, showing that while growing transparency has made information availability a collective action facilitator, lack of accountability, distrust among actors, and little sense of responsibility for halting deforestation remain key stressors. We finalize by discussing interventions that can help break the gridlock.

To reach the full potential of Mobility as a Service (MaaS), especially its projected positive environmental impacts, the barriers to development and implementation processes must be identified. However, studies identifying such MaaS barriers are rare. Following an interdisciplinary approach, this paper aims to bridge this gap by adding knowledge on barriers to MaaS development and implementation using four perspectives (service design, business model, user travel attitude and behavior, and system impacts). Following a systems thinking approach, the barriers are investigated at three levels (individual, organizational and societal) to show their relationships. This paper investigates a specific type of MaaS, namely Corporate Mobility as a Service (CMaaS). The results obtained by investigating a large-scale CMaaS pilot provide implications of general barriers to MaaS development and implementation. The findings presented in this paper provide knowledge and guidance to MaaS stakeholders.

BACKGROUND:G protein-coupled estrogen receptor (GPER), or G protein-coupled receptor 30 (GPR30), is reported to mediate non-genomic estrogen signaling. GPR30 associates with breast cancer (BC) outcome and may contribute to tamoxifen resistance. We investigated the expression and prognostic significance of GPR30 in metachronous contralateral breast cancer (CBC) as a model of tamoxifen resistance. METHODS:Total GPR30 expression (GPR30TOT) and plasma membrane-localized GPR30 expression (GPR30PM) were analyzed by immunohistochemistry in primary (BC1; nBC1 = 559) and contralateral BC (BC2; nBC2 = 595), and in lymph node metastases (LGL; nLGL1 = 213; nLGL2 = 196). Death from BC (BCD), including BC death or death after documented distant metastasis, was used as primary end-point. RESULTS:GPR30PM in BC2 and LGL2 were associated with increased risk of BCD (HRBC2 = 1.7, p = 0.03; HRLGL2 = 2.0; p = 0.02). In BC1 and BC2, GPR30PM associated with estrogen receptor (ER)-negativity (pBC1

Abstract To what extent and how do men and women differ in their attitudes about poaching? Although research suggests that women can be more concerned about environmental degradation than men, inquiries about communities in protected areas are ambiguous: women are disproportionately affected by anti‐poaching laws and can have greater motivations to violate rules. We conducted a large‐scale survey in communities within the Great Limpopo Transfrontier Park in Mozambique, South Africa, and Zimbabwe and explored attitudes regarding; concern about resources, rule compliance, poaching, and anti‐poaching activities. Although women's attitudes generally are not divergent from men's, we find some differences among nonelectrified households and those with a dependence on resources; these women are less likely to condemn commercial poaching and less willing to engage in anti‐poaching activities. Men in poorer households are more likely to know a poacher. We identify a need of further understanding the causes behind gender differences in conservation attitudes.

Abstract Background Adjuvant radiotherapy is the standard of care after breast-conserving surgery for primary breast cancer, despite a majority of patients being over- or under-treated. In contrast to adjuvant endocrine therapy and chemotherapy, no diagnostic tests are in clinical use that can stratify patients for adjuvant radiotherapy. This study presents the development and validation of a targeted gene expression assay to predict the risk of ipsilateral breast tumor recurrence and response to adjuvant radiotherapy after breast-conserving surgery in primary breast cancer. Methods Fresh-frozen primary tumors from 336 patients radically (clear margins) operated on with breast-conserving surgery with or without radiotherapy were collected. Patients were split into a discovery cohort (N = 172) and a validation cohort (N = 164). Genes predicting ipsilateral breast tumor recurrence in an Illumina HT12 v4 whole transcriptome analysis were combined with genes identified in the literature (248 genes in total) to develop a targeted radiosensitivity assay on the Nanostring nCounter platform. Single-sample predictors for ipsilateral breast tumor recurrence based on a k-top scoring pairs algorithm were trained, stratified for estrogen receptor (ER) status and radiotherapy. Two previously published profiles, the radiosensitivity signature of Speers et al., and the 10-gene signature of Eschrich et al., were also included in the targeted panel. Results Derived single-sample predictors were prognostic for ipsilateral breast tumor recurrence in radiotherapy-treated ER+ patients (AUC 0.67, p = 0.01), ER+ patients without radiotherapy (AUC = 0.89, p = 0.02), and radiotherapy-treated ER- patients (AUC = 0.78, p

The activities of cotrimoxazole, ticarcillin-clavulanate, ofloxacin, and doxycycline were studied against four isolates of Stenotrophomonas maltophilia using time-kill assays at simulated peak serum concentrations. Against three susceptible strains, ofloxacin and ticarcillin-clavulanate were bactericidal alone; in combination, they were synergistic and bactericidal against one ticarcillin-clavulanate-resistant strain. The addition of co-trimoxazole to ticarcillin-clavulanate was also synergistic and bactericidal against the ticarcillin-clavulanate resistant strain. Of note, the addition of doxycycline to ticarcillin-clavulanate or ofloxacin produced antagonism in susceptible strains. [ABSTRACT FROM AUTHOR]

A new versatile polythiophene building block, 3-(3,4-ethylenedioxythiophene)prop-1-yne (pyEDOT) (3), is prepared from glycidol in four steps in 28% overall yield. pyEDOT features an ethynyl group on its ethylenedioxy bridge, allowing further functionalization by alkyne chemistry. Its usefulness is demonstrated by a series of functionalized polythiophene derivatives that were obtained by pre- and post-electropolymerization transformations, provided by the synthetic ease of the Sonogashira coupling and click chemistry.

The ease of use and the high abstraction level of equation-based object-oriented (EOO) languages such as Modelica has the drawback that performance problems and modeling errors are often hard to find. To address this problem, we have earlier developed advanced performance analysis and equation model debugging support in the OpenModelica tool. The aim of the work reported in this paper is to perform an independent investigation and evaluation of this equation model performance analysis and debugging methods and tool support on industrial models. The results turned out to be mainly positive. The integrated debugger and performance analyzer locates several kinds of errors such as division by zero, chattering, etc., and greatly facilitates finding the equations that take most of the execution time during simulation. It remains to further evaluate the performance profiler and debugger on even larger industrial models.

Li-ion batteries (LIBs) raise safety and environmental concerns, which mostly arise from their toxic and flammable electrolytes and the extraction of limited material resources by mining. Recently, water-in-salt electrolytes (WiSEs), in which a large amount of lithium salt is dissolved in water, have been proposed to allow for assembling safe and high-voltage (>3.0 V) aqueous LIBs. In addition, organic materials derived from abundant building blocks and their tunable properties could provide safe and sustainable replacements for inorganic cathode materials. In the current work, the electrochemical properties of a conducting redox polymer based on poly(3,4-ethylenedioxythiophene) (PEDOT) with hydroquinone (HQ) pendant groups have been characterized in WiSEs. The quinone redox reaction occurs within the potential region where the polymer is conducting, and fast redox conversion that involves lithium cycling during pendant group redox conversion was observed. These properties make conducting redox polymers promising candidates as cathode-active materials for safe and high-energy aqueous LIBs. An organic-based aqueous LIB, with a HQ-PEDOT as a cathode, Li4Ti5O12 (LTO) as an anode, and ca. 15 m lithium bis(trifluoromethanesulfonyl)imide water/dimethyl carbonate (DMC) as electrolyte, yielded an output voltage of 1.35 V and high rate capabilities up to 500C. Keywords: Conducting redox polymer, Organic electronics, Renewable energy storage, Lithium ion battery, Water-in-salt electrolyte, Quinone

Although subsistence poaching is a large threat to wildlife conservation in Southern Africa, this behavior is seldom researched. Our understanding of individual and community level factors that drive such behavior is limited because of both lack of data and the literature's predominant focus on commercial poaching. The main objective of this study is to contribute to this scanty literature by examining the factors that are correlated to subsistence poaching in the Great Limpopo, a transfrontier reserve spanning across Mozambique, South Africa, and Zimbabwe. We use collected primary data from a sample of 2282 respondents and 85 villages that are part of the transfrontier conservation area. We focus on two features, reported subsistence poaching incidences in the community and the previous hunting of individuals, a behavior that is now forbidden in this area. We find through multivariate regression analysis that the likelihood for reported poaching incidences was higher in communities with a larger proportion of young men, plenty of wildlife, and experiencing wildlife conflict. In addition, our survey results illustrate that there is less poaching in communities where local people trust each other, respect institutions, perceive that the management of the park is good, and view wildlife as an asset. Some of these variables can be influenced by appropriate interventions; our findings suggest that capacity building in local institutions, use of community-based crime prevention approaches, training related to wildlife management, and public awareness campaigns could be used by policy makers to affect individuals' perceptions and behaviors in this context.

A series of pyrroles functionalized in the 3-position with p-dimethoxybenzene via various linkers (CH2, CH2CH2, CH=CH, C≡C) has been synthesized. Their electronic properties have been deduced from 1H NMR, 13C NMR, and UV–vis spectra to detect possible interactions between the two aromatic subunits. The extent of conjugation between the subunits is largely controlled by the nature of the linker, with the largest conjugation found with the trans-ethene linker and the weakest with the aliphatic linkers. DFT calculations revealed substantial changes in the HOMO–LUMO gap that correlated with the extent of conjugation found experimentally. The results of this work are expected to open up for use of the investigated compounds as components of redox-active materials in sustainable, organic electrical energy storage devices.

The high abstraction level of equation-based object-oriented (EOO) languages such as Modelica has the drawback that programming and modeling errors are often hard to find. In this paper we present integrated static and dynamic debugging methods for Modelica models and a debugger prototype that addresses several of those problems. The goal is an integrated debugging framework that combines classical debugging techniques with special techniques for equation-based languages partly based on graph visualization and interaction. To our knowledge, this is the first Modelica debugger that supports both equation-based transformational and algorithmic code debugging in an integrated fashion.

What does it mean to bootstrap a compiler, and why do it? This paper reports on the first bootstrapping of a full-scale EOO (Equation-based Object-Oriented) modeling language such as Modelica. Bootstrapping means that the compiler of a language can compile itself. However, the usual application area for the Modelica is modeling and simulation of complex physical systems. Fortunately it turns out that with some minor extensions, the Modelica language is well suited for the modeling of language semantics. We use the name MetaModelica for this slightly extended Modelica. This is a prerequisite for bootstrapping which requires that the language can be used to model and/or implement itself. The OpenModelica Compiler (OMC) has been written in this MetaModelica language. It originally supported only the standard Modelica language but has been gradually extended to also cover the MetaModelica language extensions. After substantial work, OMC is able to quickly compile itself and produces an executable with good performance. The benefits include a more extensible and maintainable compiler by introducing improved language constructs and a more powerful runtime that makes it easy to add functionality such as parser generators, debuggers, and profiling tools. Future work includes extracting and restructuring parts of OMC, making the compiler smaller and more modular and extensible. This will also make it easier to interface with OMC, making it possible to create more powerful and user-friendly OpenModelica-based tools. The compiler and its bootstrapping is a major effort -- it is currently about 330 000 lines of code, and the MetaModelica extensions are used routinely by approximately ten developers on a daily basis.