bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of real-world data and evidence for medical devices: a qualitative study of key informant interviews
Authors: Polisena Julie , Jayaraman Gayatri
Published: November 2020

Introduction

Health Canada is committed to the modernization of the use of real-world data (RWD) and evidence (RWE) to support regulatory decisions. As such, telephone interviews with stakeholders, including government decision makers, health technology assessment (HTA) producers, industry, and patients, to understand their experiences with and perspectives on how to enhance RWE use for medical devices were performed.

Methods

Thirty-four semi-structured telephone interviews with forty key informants were conducted. Transcripts were reviewed independently by one individual to identify, define, and categorize key concepts and were verified by a second reviewer.

Key Findings

There are expectations for Health Canada to provide a framework and guidance on RWE use, identify relevant outcomes for data collection and criteria for data quality, conduct post-market surveillance more systematically, and partner with HTA organizations to develop methods for RWE generation. Stakeholders interviewed support the RWE use for regulatory decisions and HTA recommendations. Moreover, robust scientific methods for RWE generation will be critical to ensure that relevant questions are asked and rigorous statistical analyses are done to answer them. Patients are likely to consent to share their anonymized or de-identified medical information for nonprofit purposes.

Conclusions

Key concepts from the interviews centered on the current and future RWE use for medical devices, considerations for the organizational, medical, scientific, and legal aspects and privacy issues of RWD collection or RWE generation, and options to implement the use of RWD and RWE. Our study findings will help inform the development of an RWE framework for regulatory decisions and HTA recommendations.
lncRNA SNHG14 involved in trophoblast cell proliferation, migration, invasion and epithelial–mesenchymal transition by targeting miR-330-5p in preeclampsia
Authors: Zhang Yulei , Zhang Muling
Published: November 2020

Preeclampsia (PE), a pregnancy-specific disease, has become one of the leading causes of maternal and neonatal morbidity and mortality. Pathogenesis of PE has still not been fully addressed and there is a great need to develop early diagnosis markers and effective therapy. This study aimed to determine if lncRNA SNHG14 has a protective effect on placental trophoblast and prevents PE. SNHG14 levels in the peripheral blood from patients with PE or from women with healthy pregnancies were detected using RT-qPCR. The relationship between SNHG14 and miR-330-5p was determined using a dual-luciferase reporter assay. In addition, cell proliferation and cell cycle were evaluated by performing CCK8 assays and flow-cytometric analysis, respectively. Wound-healing and transwell assays were performed to assess cell migration and invasion ability. lncRNA SNHG14 was downregulated in PE patients; it was involved in trophoblast proliferation and regulated cell proliferation during G1/S transition. In addition, lncRNA SNHG14 promoted migration, invasion and epithelial–mesenchymal transition (EMT) in HTR-8/SVneo cells. Luciferase reporter assay indicated that lncRNA SNHG14 served as a molecular sponge for miR-330-5p and negatively regulated miR-330-5p expression in PE. Furthermore, the effects of silenced SNHG14 on trophoblast proliferation, migration, invasion and EMT were reversed by addition of miR-330-5p inhibitor, suggesting that in PE lncRNA SNHG14 functions by competitively binding to miR-330-5p. Taken together, the current study demonstrated that in PE lncRNA SNHG14 is a vital regulator by binding to miR-330-5p. SNHG14 might serve as a therapeutic application in PE progression.
Evaluation of two commercial fungal inoculants for improving phosphorus supply to crops grown in soils with contrasting management histories
Authors: Knight J. Diane
Published: November 2020

Two fungal inoculants are commercially available in Canada and the USA that target improving plant access to soil phosphorus (P). Arbuscular mycorrhizal fungi andPenicillium bilaiaewere used to inoculate wheat, lentil and flax grown in an organically-managed and a conventionally-managed soil. A second crop was grown after freezing the soil to evaluate if the inoculants carried over to a second crop. Crops in the organically managed soil were smaller and took up less P than the same crop in the conventionally managed soil. Inoculation with either inoculant improved shoot growth and P uptake in wheat grown in the organically-managed soil and in lentil grown in the conventionally-managed soil. Co-application of the inoculants was never superior to the single inoculants. Carry-over effects were slight and inconsistent.
Response of seashore paspalum and bermudagrass to topramezone and triclopyr mixtures
Authors: Gonçalves Clebson G. , Brown Austin M. , Basak Suma , McElroy J. Scott
Published: November 2020

Few options are available for controlling bermudagrass invasion of seashore paspalum. Bermudagrass and seashore paspalum tolerance to topramezone, triclopyr, or the combination of these two herbicides were evaluated in both greenhouse and field conditions. Field treatments included two sequential applications of topramezone (15.6 g ai ha−1) alone and five rates of topramezone + triclopyr (15.6 + 43.2, 15.6 + 86.3, 15.6 + 172.6, 15.6 + 345.2, or 15.6 g ai ha−1+ 690.4 g ae ha−1). Secondary greenhouse treatments included a single application of topramezone (20.8 g ha−1) or triclopyr (258.9 g ha−1) alone, or in combination at 20.8 + 258.9 or 20.8 + 517.8 g ha−1, respectively. Greenhouse and field results showed that topramezone applications in combination with triclopyr present opposite responses between bermudagrass and seashore paspalum. Topramezone increased bermudagrass injury and decreased seashore paspalum bleaching injury compared to topramezone alone. In field evaluations, topramezone + triclopyr at 15.6 + 690.4 g ha−1used in sequential applications resulted in >90% injury to bermudagrass, however, injury decreased over time. Furthermore, sequential applications of topramezone + triclopyr at 15.6 + 690.4 g ha−1resulted in >50% injury to seashore paspalum. Application programs including topramezone plus triclopyr should increase bermudagrass suppression and reduce seashore paspalum injury compared to topramezone alone. However, additional studies are needed because such practices will likely require manipulation of topramezone rate, application timing, application interval, and number of applications in order to maximize bermudagrass control and minimize seashore paspalum injury.
Hairy buttercup (Ranunculus sardous) and cutleaf evening primrose (Oenothera laciniata) control using halauxifen-methyl based programs in Mississippi and Oklahoma winter wheat
Authors: Ferguson J. Connor , Manuchehri Misha R. , Calhoun Justin S. , Childers Justin T. , Merritt Luke H. , Broster Kayla L. , Treadway Zachary R. , Ugljic Zaim , Wesley Michael T.
Published: November 2020

Hairy buttercup and cutleaf evening primrose are winter annual weeds that have become more problematic for winter wheat growers in the southern Great Plains and the midsouthern United States in recent years. Little research exists on which to base recommendations for controlling hairy buttercup in wheat, and little research has been published on cutleaf evening primrose control in recent years. With growing concerns of increased herbicide resistance among winter annual weeds, incorporating new herbicide sites of action has become necessary. The objective of this study was to assess halauxifen-methyl as a novel herbicide to control these two problematic winter annual broadleaf weeds in winter wheat in Mississippi and Oklahoma. Studies were conducted across four site-years in Mississippi and one site-year in Oklahoma comparing 15 herbicide programs with and without halauxifen-methyl. Hairy buttercup and cutleaf evening-primrose control was the greatest when a synthetic auxin was combined with an acetolactate synthase–inhibiting herbicide. Treatments including halauxifen-methyl resulted in the greatest control of hairy buttercup, whereas a synthetic auxin herbicide plus chlorsulfuron and metsulfuron resulted in the greatest control of cutleaf evening primrose. Halauxifen-methyl is an effective addition for control of winter annual broadleaf weeds like hairy buttercup and cutleaf evening primrose in winter wheat.
The p53/p73 - p21CIP1 tumor suppressor axis guards against chromosomal instability by restraining CDK1 in human cancer cells
Authors: Schmidt Ann-Kathrin , Pudelko Karoline , Boekenkamp Jan-Eric , Berger Katharina , Kschischo Maik , Bastians Holger
Published: November 2020

Whole chromosome instability (W-CIN) is a hallmark of human cancer and contributes to the evolvement of aneuploidy. W-CIN can be induced by abnormally increased microtubule plus end assembly rates during mitosis leading to the generation of lagging chromosomes during anaphase as a major form of mitotic errors in human cancer cells. Here, we show that loss of the tumor suppressor genes TP53 and TP73 can trigger increased mitotic microtubule assembly rates, lagging chromosomes, and W-CIN. CDKN1A, encoding for the CDK inhibitor p21CIP1, represents a critical target gene of p53/p73. Loss of p21CIP1 unleashes CDK1 activity which causes W-CIN in otherwise chromosomally stable cancer cells. Consequently, induction of CDK1 is sufficient to induce abnormal microtubule assembly rates and W-CIN. Vice versa, partial inhibition of CDK1 activity in chromosomally unstable cancer cells corrects abnormal microtubule behavior and suppresses W-CIN. Thus, our study shows that the p53/p73 - p21CIP1 tumor suppressor axis, whose loss is associated with W-CIN in human cancer, safeguards against chromosome missegregation and aneuploidy by preventing abnormally increased CDK1 activity.
Educational attainment reduces the risk of suicide attempt among individuals with and without psychiatric disorders independent of cognition: a bidirectional and multivariable Mendelian randomization study with more than 815,000 participants
Authors: Rosoff Daniel B. , Kaminsky Zachary A. , McIntosh Andrew M. , Davey Smith George , Lohoff Falk W.
Published: November 2020

Rates of suicidal behavior are increasing in the United States and identifying causal risk factors continues to be a public health priority. Observational literature has shown that educational attainment (EA) and cognitive performance (CP) influence suicide attempt risk; however, the causal nature of these relationships is unknown. Using summary statistics from genome-wide association studies (GWAS) of EA, CP, and suicide attempt risk with > 815,000 combined white participants of European ancestry, we performed multivariable Mendelian randomization (MR) to disentangle the effects of EA and CP on attempted suicide. In single-variable MR (SVMR), EA and CP appeared to reduce suicide attempt risk (EA odds ratio (OR) per standard deviation (SD) increase in EA (4.2 years), 0.524, 95% CI, 0.412–0.666, P = 1.07 × 10−7; CP OR per SD increase in standardized score, 0.714, 95% CI, 0.577–0.885, P = 0.002). Conversely, bidirectional analyses found no effect of a suicide attempt on EA or CP. Using various multivariable MR (MVMR) models, EA seems to be the predominant risk factor for suicide attempt risk with the independent effect (OR, 0.342, 95% CI, 0.206–0.568, P = 1.61 × 10−4), while CP had no effect (OR, 1.182, 95% CI, 0.842–1.659, P = 0.333). In additional MVMR analyses accounting simultaneously for potential behavioral and psychiatric mediators (tobacco smoking; alcohol consumption; and self-reported nerves, tension, anxiety, or depression), the effect of EA was little changed (OR, 0.541, 95% CI, 0.421–0.696, P = 3.33 × 10−6). Consistency of results across complementary MR methods accommodating different assumptions about genetic pleiotropy strengthened causal inference. Our results show that even after accounting for psychiatric disorders and behavioral mediators, EA, but not CP, may causally influence suicide attempt risk among white individuals of European ancestry, which could have important implications for health policy and programs aimed at reducing the increasing rates of suicide. Future work is necessary to examine the EA–suicide relationship populations of different ethnicities.
A circumpolar dust conveyor in the glacial Southern Ocean
Authors: Struve Torben , Pahnke Katharina , Lamy Frank , Wengler Marc , Böning Philipp , Winckler Gisela
Published: November 2020

The increased flux of soluble iron (Fe) to the Fe-deficient Southern Ocean by atmospheric dust is considered to have stimulated the net primary production and carbon export, thus promoting atmospheric CO2 drawdown during glacial periods. Yet, little is known about the sources and transport pathways of Southern Hemisphere dust during the Last Glacial Maximum (LGM). Here we show that Central South America (~24‒32°S) contributed up to ~80% of the dust deposition in the South Pacific Subantarctic Zone via efficient circum-Antarctic dust transport during the LGM, whereas the Antarctic Zone was dominated by dust from Australia. This pattern is in contrast to the modern/Holocene pattern, when South Pacific dust fluxes are thought to be primarily supported by Australian sources. Our findings reveal that in the glacial Southern Ocean, Fe fertilization critically relies on the dynamic interaction of changes in dust-Fe sources in Central South America with the circumpolar westerly wind system.
Transient circular dichroism and exciton spin dynamics in all-inorganic halide perovskites
Authors: Zhao Weijie , Su Rui , Huang Yuqing , Wu Jinqi , Fong Chee Fai , Feng Jiangang , Xiong Qihua
Published: November 2020

All-inorganic metal halides perovskites (CsPbX3, X = Br or Cl) show strong excitonic and spin-orbital coupling effects, underpinning spin-selective excitonic transitions and therefore exhibiting great promise for spintronics and quantum-optics applications. Here we report spin-dependent optical nonlinearities in CsPbX3 single crystals by using ultrafast pump-probe spectroscopy. Many-body interactions between spin-polarized excitons act like a pseudo-magnetic field and thus lift the degeneracy of spin states resulting in a photoinduced circular dichroism. Such spontaneous spin splitting between “spin-up” and “spin-down” excitons can be several tens of milli-electron volts under intense excitations. The exciton spin relaxation time is ~20 picoseconds at very low pump fluence, the longest reported in the metal halides perovskites family at room temperature. The dominant spin-flip mechanism is attributed to the electron-hole exchange interactions. Our results provide essential understandings towards realizing practical spintronics applications of perovskite semiconductors.
Sequentially amplified circularly polarized ultraviolet luminescence for enantioselective photopolymerization
Authors: Han Dongxue , Yang Xuefeng , Han Jianlei , Zhou Jin , Jiao Tifeng , Duan Pengfei
Published: November 2020

Chiral optical materials based on circularly polarized luminescence (CPL) have emerged rapidly due to their feasible applications in diverse fields of research. However, limited to the small luminescence dissymmetry factor (glum), real application examples have rarely been reported. Here, we present a complex system, which show intense circularly polarized ultraviolet luminescence (CPUVL) with large glum value, enabling a chiral UV light triggered enantioselective polymerization. By integrating sensitized triplet-triplet annihilation upconversion and CPL, both visible-to-UV upconversion emission and upconverted circularly polarized ultraviolet luminescence (UC-CPUVL) were obtained in the systems, built of chiral annihilator R(S)-4,12-biphenyl[2,2]paracyclophane (R-/S-TP), and a thermally activated delayed fluorescence (TADF) sensitizer. After dispersing this upconversion system into room-temperature nematic liquid crystal, induced chiral nematic liquid crystal could significantly amplify the glum value (0.19) of UC-CPUVL. Further, the UC-CPUVL emission has been used to trigger the enantioselective photopolymerization of diacetylene. This work paves the way for the further development of functional application of CPL active materials.
Co-administered antibody improves penetration of antibody–dye conjugate into human cancers with implications for antibody–drug conjugates
Authors: Lu Guolan , Nishio Naoki , van den Berg Nynke S. , Martin Brock A. , Fakurnejad Shayan , van Keulen Stan , Colevas Alexander D. , Thurber Greg M. , Rosenthal Eben L.
Published: November 2020

Poor tissue penetration remains a major challenge for antibody-based therapeutics of solid tumors, but proper dosing can improve the tissue penetration and thus therapeutic efficacy of these biologics. Due to dose-limiting toxicity of the small molecule payload, antibody-drug conjugates (ADCs) are administered at a much lower dose than their parent antibodies, which further reduces tissue penetration. We conducted an early-phase clinical trial (NCT02415881) and previously reported the safety of an antibody-dye conjugate (panitumumab-IRDye800CW) as primary outcome. Here, we report a retrospective exploratory analysis of the trial to evaluate whether co-administration of an unconjugated antibody could improve the intratumoral distribution of the antibody-dye conjugate in patients. By measuring the multiscale distribution of the antibody-dye conjugate, this study demonstrates improved microscopic antibody distribution without increasing uptake (toxicity) in healthy tissue when co-administered with the parent antibody, supporting further clinical investigation of the co-administration dosing strategy to improve the tumor penetration of ADCs.
Quest for quantum states via field-altering technology
Authors: Cao Gang , Zhao Hengdi , Hu Bing , Pellatz Nicholas , Reznik Dmitry , Schlottmann Pedro , Kimchi Itamar
Published: November 2020

We report quantum phenomena in spin-orbit-coupled single crystals that are synthesized using an innovative technology that “field-alters” crystal structures via application of magnetic field during crystal growth. This study addresses a major challenge facing the research community today: A great deal of theoretical work predicting exotic states for strongly spin-orbit-coupled, correlated materials has thus far met very limited experimental confirmation. These conspicuous discrepancies are due in part to the extreme sensitivity of these materials to structural distortions. The results presented here demonstrate that the field-altered materials not only are much less distorted but also exhibit phenomena absent in their non-altered counterparts. The field-altered materials include an array of4dand5dtransition metal oxides, and three representative materials presented here are Ba4Ir3O10, Ca2RuO4, and Sr2IrO4. This study provides an approach for discovery of quantum states and materials otherwise unavailable.
Uncovering cancer gene regulation by accurate regulatory network inference from uninformative data
Authors: Seçilmiş Deniz , Hillerton Thomas , Morgan Daniel , Tjärnberg Andreas , Nelander Sven , Nordling Torbjörn E. M. , Sonnhammer Erik L. L.
Published: November 2020

The interactions among the components of a living cell that constitute the gene regulatory network (GRN) can be inferred from perturbation-based gene expression data. Such networks are useful for providing mechanistic insights of a biological system. In order to explore the feasibility and quality of GRN inference at a large scale, we used the L1000 data where ~1000 genes have been perturbed and their expression levels have been quantified in 9 cancer cell lines. We found that these datasets have a very low signal-to-noise ratio (SNR) level causing them to be too uninformative to infer accurate GRNs. We developed a gene reduction pipeline in which we eliminate uninformative genes from the system using a selection criterion based on SNR, until reaching an informative subset. The results show that our pipeline can identify an informative subset in an overall uninformative dataset, allowing inference of accurate subset GRNs. The accurate GRNs were functionally characterized and potential novel cancer-related regulatory interactions were identified.
Evaluation of pathogen specific urinary peptides in tick-borne illnesses
Authors: Magni Ruben , Almofee Raghad , Yusuf Sameen , Mueller Claudius , Vuong Ngoc , Almosuli Mahmood , Hoang Minh Thu , Meade Katherine , Sethi Ish , Mohammed Nuha , Araujo Robyn , McDonald Teresa Kaza , Marcelli Paul , Espina Virginia , Kim Brianna , Garritsen Anja , Green Christine , Russo Paul , Zhou Weidong , Vaisman Iosif , Petricoin Emanuel F. , Hoadley Deborah , Molestina Robert E. , McIntyre Hope , Liotta Lance A. , Luchini Alessandra
Published: November 2020

Mass spectrometry enhanced by nanotechnology can achieve previously unattainable sensitivity for characterizing urinary pathogen-derived peptides. We utilized mass spectrometry enhanced by affinity hydrogel particles (analytical sensitivity = 2.5 pg/mL) to study tick pathogen-specific proteins shed in the urine of patients with (1) erythema migrans rash and acute symptoms, (2) post treatment Lyme disease syndrome (PTLDS), and (3) clinical suspicion of tick-borne illnesses (TBI). Targeted pathogens were Borrelia, Babesia, Anaplasma, Rickettsia, Ehrlichia, Bartonella, Francisella, Powassan virus, tick-borne encephalitis virus, and Colorado tick fever virus. Specificity was defined by 100% amino acid sequence identity with tick-borne pathogen proteins, evolutionary taxonomic verification for related pathogens, and no identity with human or other organisms. Using a cut off of two pathogen peptides, 9/10 acute Lyme Borreliosis patients resulted positive, while we identified zero false positive in 250 controls. Two or more pathogen peptides were identified in 40% of samples from PTLDS and TBI patients (categories 2 and 3 above, n = 59/148). Collectively, 279 distinct unique tick-borne pathogen derived peptides were identified. The number of pathogen specific peptides was directly correlated with presence or absence of symptoms reported by patients (ordinal regression pseudo-R2 = 0.392, p = 0.010). Enhanced mass spectrometry is a new tool for studying tick-borne pathogen infections.
Sequential laxative-probiotic usage for treatment of irritable bowel syndrome: a novel method inspired by mathematical modelling of the microbiome
Authors: Li Ming , Xu Ri , Li Yan-qing
Published: November 2020

The gut microbiome plays an important role in human health. However, its response to external intervention is complex. A previous study showed that the response to Clostridium butyricum (CB) treatment of irritable bowel syndrome (IBS) is heterogeneous. We proposed that mathematical model simulation of the microbiota may help to optimize the management of IBS-associated microbiota. In this study, a novel mathematical non-extinction and defecation normalized (NEDN) model was generated for stable simulation of the dynamic nature of gut microbiota. In silico simulation revealed that a laxative may create a favourable opportunity for Clostridium cluster XIVa to shift the microbiota. An explorative clinical trial was conducted to compare three CB regimens in an IBS cohort: laxative, interval of 2 weeks and CB administration for 2 weeks (L2P); laxative immediately followed by CB administration (LP) for 2 weeks; and CB administration for 2 weeks (P). The LP regimen optimally relieved the IBS symptoms and shifted the microbiota closer to those of the healthy subjects during 2 weeks of CB intake. These results indicate that integration of biological/mathematical approaches and clinical scenarios is a promising method for management of microbiota. Additionally, the optimal effect of sequential laxative-CB usage for IBS treatment warrants further validation.

Clinical trial registration numbers: NCT02254629.

Date of registration: October 2, 2014.
Drivers and impacts of the most extreme marine heatwave events
Authors: Sen Gupta Alex , Thomsen Mads , Benthuysen Jessica A. , Hobday Alistair J. , Oliver Eric , Alexander Lisa V. , Burrows Michael T. , Donat Markus G. , Feng Ming , Holbrook Neil J. , Perkins-Kirkpatrick Sarah , Moore Pippa J. , Rodrigues Regina R. , Scannell Hillary A. , Taschetto Andréa S. , Ummenhofer Caroline C. , Wernberg Thomas , Smale Dan A.
Published: November 2020

Prolonged high-temperature extreme events in the ocean, marine heatwaves, can have severe and long-lasting impacts on marine ecosystems, fisheries and associated services. This study applies a marine heatwave framework to analyse a global sea surface temperature product and identify the most extreme events, based on their intensity, duration and spatial extent. Many of these events have yet to be described in terms of their physical attributes, generation mechanisms, or ecological impacts. Our synthesis identifies commonalities between marine heatwave characteristics and seasonality, links to the El Niño-Southern Oscillation, triggering processes and impacts on ocean productivity. The most intense events preferentially occur in summer, when climatological oceanic mixed layers are shallow and winds are weak, but at a time preceding climatological maximum sea surface temperatures. Most subtropical extreme marine heatwaves were triggered by persistent atmospheric high-pressure systems and anomalously weak wind speeds, associated with increased insolation, and reduced ocean heat losses. Furthermore, the most extreme events tended to coincide with reduced chlorophyll-aconcentration at low and mid-latitudes. Understanding the importance of the oceanic background state, local and remote drivers and the ocean productivity response from past events are critical steps toward improving predictions of future marine heatwaves and their impacts.
GENetic characteristics and REsponse to lipid-lowering therapy in familial hypercholesterolemia: GENRE-FH study
Authors: Kim Hyoeun , Lee Chan Joo , Pak Hayeon , Kim Doo-Il , Rhee Moo-Yong , Lee Byoung Kwon , Ahn Youngkeun , Cho Byung-Ryul , Woo Jeong-Taek , Hur Seung-Ho , Jeong Jin-Ok , Lee Ji Hyun , Lee Sang-Hak
Published: November 2020

Among the 146 patients enrolled in the Korean FH registry, 83 patients who had undergone appropriate LLT escalation and were followed-up for ≥ 6 months were analyzed for pathogenic variants (PVs). The achieved percentage of expected low-density lipoprotein-cholesterol (LDL-C) reduction (primary variable) and achievement rates of LDL-C < 70 mg/dL were assessed. The correlations between the treatment response and the characteristics of PVs, and the weighted 4 SNP-based score were evaluated. The primary variables were significantly lower in the PV-positive patients than in the PV-negative patients (p = 0.007). However, the type of PV did not significantly correlate with the primary variable. The achievement rates of LDL-C < 70 mg/dL was very low, regardless of the PV characteristics. Patients with a higher 4-SNP score showed a lower primary variable (R2 = 0.045, p = 0.048). Among evolocumab users, PV-negative patients or those with only defective PVs revealed higher primary variable, whereas patients with at least one null PV showed lower primary variables. The adjusted response of patients with FH to LLT showed significant associations with PV positivity and 4-SNP score. These results may be helpful in managing FH patients with diverse genetic backgrounds.
Comparison of variables measured with a Scheimpflug device for evaluation of progression and detection of keratoconus
Authors: Neuhann Sophie , Schuh Anna , Krause Daniel , Liegl Raffael , Schmelter Valerie , Kreutzer Thomas , Mayer Wolfgang J. , Kohnen Thomas , Priglinger Siegfried , Shajari Mehdi
Published: November 2020

Keratoconus is a progressive ectatic corneal disorder, which can result in severe visual impairment. The new ABCD keratoconus classification system allows differentiated description of the disease. Aim of the study was to evaluate the components of this novel staging system (ARC, PRC, thinnest pachymetry) as well as topometric indices, deviation of normality indices, and other parameters in terms of repeatability and reliability. 317 eyes with keratoconus were examined twice with a Scheimpflug device (Pentacam, Oculus). Bland Altman analysis and intraclass correlations were carried out to evaluate the parameters repeatability and reliability. Apart from IHA (ICC = 0.730), all parameters showed excellent reliability (ICC > 0.900). ARC, PRC, thinnest pachymetry, Kmax, CKI, KI, Rmin, and Progression Avg were the best repeatable parameters with relative repeatability values < 2.5%. Other parameters performing well in terms of repeatability were IHD, ISV, IVA, and final D (RR < 13%). Regression analysis revealed consistently high repeatability along all stages of keratoconus for PRC, thinnest pachymetry, and CKI. All parameters of the ABCD staging system showed excellent reliability and repeatability, PRC and thinnest pachymetry even at all stages of keratoconus and can consequently be reliably used in the determination of keratoconus progression.
Plastic deformation as nature of femtosecond laser writing in YAG crystal
Authors: Fedotov S. S. , Butvina L. N. , Okhrimchuk A. G.
Published: November 2020

Longitudinal inhomogeneity of tracks inscribed in a YAG crystal and the statistics of nonlinear transmittance of the writing beam is studied under conditions of direct femtosecond laser writing in non-thermal mode. Nonlinear transmittance fluctuations inherent in the laser writing were discovered, and their correlation with track inhomogeneity is established. A model of femtosecond laser writing in crystals is built that includes three modes of plastic deformation in the laser impact zone. The modification threshold of the femtosecond direct laser writing is identified with reaching yield stress.
Naturally-occurring myopia and loss of cone function in a sheep model of achromatopsia
Authors: Ross Maya , Ofri Ron , Aizenberg Itzhak , Abu–Siam Mazen , Pe’er Oren , Arad Dikla , Rosov Alexander , Gootwine Elisha , Dvir Hay , Honig Hen , Obolensky Alexey , Averbukh Edward , Banin Eyal , Gantz Liat
Published: November 2020

Achromatopsia is an inherited retinal disease characterized by loss of cone photoreceptor function. Day blindCNGA3mutant Improved Awassi sheep provide a large animal model for achromatopsia. This study measured refractive error and axial length parameters of the eye in this model and evaluated chromatic pupillary light reflex (cPLR) testing as a potential screening test for loss of cone function. Twenty-oneCNGA3mutant, Improved Awassi, 12 control Afec-Assaf and 12 control breed-matched wild-type (WT) Awassi sheep were examined using streak retinoscopy and B-mode ocular ultrasonography. FourCNGA3mutant and four Afec-Assaf control sheep underwent cPLR testing. Statistical tests showed that day-blind sheep are significantly more myopic than both Afec-Assaf and WT Awassi controls. Day-blind sheep had significantly longer vitreous axial length compared to WT Awassi (1.43 ± 0.13 and 1.23 ± 0.06 cm, respectively, p < 0.0002) and no response to bright red light compared to both controls. Lack of response to bright red light is consistent with cone dysfunction, demonstrating that cPLR can be used to diagnose day blindness in sheep. Day-blind sheep were found to exhibit myopia and increased vitreous chamber depth, providing a naturally occurring large animal model of myopia.
Lateral position during severe mono-lateral pneumonia: an experimental study
Authors: Meli Andrea , Barbeta Viñas Enric , Battaglini Denise , Li Bassi Gianluigi , Yang Hua , Yang Minlan , Bobi Joaquim , Motos Ana , Fernández-Barat Laia , Chiumello Davide , Pelosi Paolo , Torres Antoni
Published: November 2020

Patients with mono-lateral pneumonia and severe respiratory failure can be positioned in lateral decubitus, with the healthy lung dependent, to improve ventilation-perfusion coupling. Oxygenation response to this manoeuvre is heterogeneous and derecruitment of dependent lung has not been elucidated. Nine pigs (32.2 ± 1.2 kg) were sedated and mechanically ventilated. Mono-lateral right-sided pneumonia was induced with intrabronchial challenge of Pseudomonas aeruginosa. After 24 h, lungs were recruited and the animals were randomly positioned on right or left side. After 3 h of lateral positioning, the animals were placed supine; another recruitment manoeuvre was performed, and the effects of contralateral decubitus were assessed. Primary outcome was lung ultrasound score (LUS) of the dependent lung after 3-h lateral positioning. LUS of the left non-infected lung worsened while positioned in left-lateral position (from 1.33 ± 1.73 at baseline to 6.78 ± 4.49; p = 0.005). LUS of the right-infected lung improved when placed upward (9.22 ± 2.73 to 6.67 ± 3.24; p = 0.09), but worsened in right-lateral position (7.78 ± 2.86 to 13.33 ± 3.08; p < 0.001). PaO2/FiO2 improved in the left-lateral position (p = 0.005). In an animal model of right-lung pneumonia, left-lateral decubitus improved oxygenation, but collapsed the healthy lung. Right-lateral orientation further collapsed the diseased lung. Our data raise potential clinical concerns for the use of lateral position in mono-lateral pneumonia.
Variability in somatic embryo-forming capacity of spinach
Authors: Belić Maja , Zdravković-Korać Snežana , Uzelac Branka , Ćalić Dušica , Pavlović Suzana , Milojević Jelena
Published: November 2020

High variability in somatic embryo (SE)-forming capacity has previously been observed in several spinach cultivars. Such variability frequently accounted for more variation in embryogenic response of the explants than the factor being investigated. Hence, the variability in embryogenic capacity was examined in the present study at both the population and the single-seedling level, using seeds of spinach cultivar Matador obtained from nine European seed companies. Seed population obtained from Slovenia (Sl) was superior to others, with the highest regeneration frequency (100%) and the highest mean SE number (14.4). A total of 82% of these seedlings had 80–100% of regenerating explants, while in populations with intermediate embryogenic capacity approximately 40% of seedlings had 20–60% of regenerating explants. The explants from the majority of seedlings (52–100%) in the least responsive populations were irresponsive. Furthermore, the explants from Sl seedlings regenerated from 10–20 (43.5%) up to > 20 (27.6%) SEs on average, while the explants from the majority of seedlings belonging to other populations regenerated 1–10 SEs. The present study strongly indicates that the variability of plant material must not be overlooked, because choosing more responsive individuals for one treatment and less responsive ones for another may lead to misinterpretation of the data.
Speech in noise perception improved by training fine auditory discrimination: far and applicable transfer of perceptual learning
Authors: Gao Xiang , Yan Tingting , Huang Ting , Li Xiaoli , Zhang Yu-Xuan
Published: November 2020

A longstanding focus of perceptual learning research is learning specificity, the difficulty for learning to transfer to tasks and situations beyond the training setting. Previous studies have focused on promoting transfer across stimuli, such as from one sound frequency to another. Here we examined whether learning could transfer across tasks, particularly from fine discrimination of sound features to speech perception in noise, one of the most frequently encountered perceptual challenges in real life. Separate groups of normal-hearing listeners were trained on auditory interaural level difference (ILD) discrimination, interaural time difference (ITD) discrimination, and fundamental frequency (F0) discrimination with non-speech stimuli delivered through headphones. While ITD training led to no improvement, both ILD and F0 training produced learning as well as transfer to speech-in-noise perception when noise differed from speech in the trained feature. These training benefits did not require similarity of task or stimuli between training and application settings, construing far and wide transfer. Thus, notwithstanding task specificity among basic perceptual skills such as discrimination of different sound features, auditory learning appears readily transferable between these skills and their “upstream” tasks utilizing them, providing an effective approach to improving performance in challenging situations or challenged populations.
A first look at the metabolic rate of Greenland sharks (Somniosus microcephalus) in the Canadian Arctic
Authors: Ste-Marie Eric , Watanabe Yuuki Y. , Semmens Jayson M. , Marcoux Marianne , Hussey Nigel E.
Published: November 2020

Metabolic rate is intricately linked to the ecology of organisms and can provide a framework to study the behaviour, life history, population dynamics, and trophic impact of a species. Acquiring measures of metabolic rate, however, has proven difficult for large water-breathing animals such as sharks, greatly limiting our understanding of the energetic lives of these highly threatened and ecologically important fish. Here, we provide the first estimates of resting and active routine metabolic rate for the longest lived vertebrate, the Greenland shark (Somniosus microcephalus). Estimates were acquired through field respirometry conducted on relatively large-bodied sharks (33–126 kg), including the largest individual shark studied via respirometry. We show that despite recording very low whole-animal resting metabolic rates for this species, estimates are within the confidence intervals predicted by derived interspecies allometric and temperature scaling relationships, suggesting this species may not be unique among sharks in this respect. Additionally, our results do not support the theory of metabolic cold adaptation which assumes that polar species maintain elevated metabolic rates to cope with the challenges of life at extreme cold temperatures.
Differences in static postural control between top level male volleyball players and non-athletes
Authors: Borzucka Dorota , Kręcisz Krzysztof , Rektor Zbigniew , Kuczyński Michał
Published: November 2020

It is argued that elite athletes often demonstrate superior body balance. Despite the apparent significance of perfect balance ability in volleyball, little is known about the specific nature of postural control adjustments among first-rate volleyball competitors. This study compared postural performance and strategies in quiet stance between world vice-champions and young, healthy, physically active male subjects. The center-of-pressure (COP) signals recorded on a force plate were used to compute several measures of sway. In both axes of movement, athletes had lower COP range, but not its standard deviation and higher COP speed and frequency than controls. These findings indicate that postural regulation in athletes was more precise and less vulnerable to external disturbances which support optimal timing and precision of actions. Postural strategies in athletes standing quietly were similar to those exhibited by non-athletes performing dual tasks. It demonstrates a significant effect of sport practice on changes in postural control. In anterior–posterior axis, athletes displayed a much higher COP fractal dimension and surprisingly lower COP–COG frequency than controls. This accounts for their high capacity to use diversified postural strategies to maintain postural stability and significantly reduced the contribution of proprioception to save this function for carrying out more challenging posture-motor tasks.
CRISPR/Cas9 as an antiviral against Orthopoxviruses using an AAV vector
Authors: Siegrist Cathryn M. , Kinahan Sean M. , Settecerri Taylor , Greene Adrienne C. , Santarpia Joshua L.
Published: November 2020

A vaccine for smallpox is no longer administered to the general public, and there is no proven, safe treatment specific to poxvirus infections, leaving people susceptible to infections by smallpox and other zoonotic Orthopoxviruses such as monkeypox. Using vaccinia virus (VACV) as a model organism for other Orthopoxviruses, CRISPR–Cas9 technology was used to target three essential genes that are conserved across the genus, including A17L, E3L, and I2L. Three individual single guide RNAs (sgRNAs) were designed per gene to facilitate redundancy in rendering the genes inactive, thereby reducing the reproduction of the virus. The efficacy of the CRISPR targets was tested by transfecting human embryonic kidney (HEK293) cells with plasmids encoding both SaCas9 and an individual sgRNA. This resulted in a reduction of VACV titer by up to 93.19% per target. Following the verification of CRISPR targets, safe and targeted delivery of the VACV CRISPR antivirals was tested using adeno-associated virus (AAV) as a packaging vector for both SaCas9 and sgRNA. Similarly, AAV delivery of the CRISPR antivirals resulted in a reduction of viral titer by up to 92.97% for an individual target. Overall, we have identified highly specific CRISPR targets that significantly reduce VACV titer as well as an appropriate vector for delivering these CRISPR antiviral components to host cells in vitro.
Association of dietary approaches to stop hypertension eating style and risk of sarcopenia
Authors: Soltani Sanaz , Hashemi Rezvan , Heshmat Ramin , Motlagh Ahmadreza Dorosty , Esmaillzadeh Ahmad
Published: November 2020

The association between habitual intake of the “dietary approaches to stop hypertension” (DASH) eating plan and sarcopenia has received limited attention. The present study aimed to investigate the association between adherence to DASH dietary pattern and sarcopenia and its components including muscle mass, muscle strength, and muscle performance among community-dwelling older adults population. This population-based cross-sectional study was performed in 2011 among 300 older people (150 men and 150 women) aged ≥ 55 years, who were selected using cluster random sampling method. Dietary intake of study participants were examined by the use of a Block-format 117-item food frequency questionnaire (FFQ). The DASH score was constructed based on eight main foods and nutrients emphasized or minimized in the DASH diet. All components of sarcopenia was measured using standard protocols and sarcopenia was defined based on both former and new European Working Group on Sarcopenia in Older People (EWGSOP) guidelines. Mean age and BMI of study participants were 66.7 ± 7.7 years and 27.3 ± 4.2 kg/m2, respectively. Totally, 31 individuals meet the criteria of EWGSOP2-sarcopenia. We found no significant association between adherence to the DASH diet and EWGSOP2-sarcopenia either before (OR 1.08; 95% CI 0.45–2.54) or after adjustment for potential confounders (OR 1.04; 95% CI 0.39–2.75). The same findings were obtained in the gender-stratified analyses (men: OR 2.29; 95% CI 0.39–13.29 and women: 0.75; 95% CI 0.23–2.45). In conclusion, we found that adherence to the DASH-style diet was not significantly associated with odds of sarcopenia. Future prospective studies are required to confirm these findings.
A fast and fully-automated deep-learning approach for accurate hemorrhage segmentation and volume quantification in non-contrast whole-head CT
Authors: Arab Ali , Chinda Betty , Medvedev George , Siu William , Guo Hui , Gu Tao , Moreno Sylvain , Hamarneh Ghassan , Ester Martin , Song Xiaowei
Published: November 2020

This project aimed to develop and evaluate a fast and fully-automated deep-learning method applying convolutional neural networks with deep supervision (CNN-DS) for accurate hematoma segmentation and volume quantification in computed tomography (CT) scans. Non-contrast whole-head CT scans of 55 patients with hemorrhagic stroke were used. Individual scans were standardized to 64 axial slices of 128 × 128 voxels. Each voxel was annotated independently by experienced raters, generating a binary label of hematoma versus normal brain tissue based on majority voting. The dataset was split randomly into training (n = 45) and testing (n = 10) subsets. A CNN-DS model was built applying the training data and examined using the testing data. Performance of the CNN-DS solution was compared with three previously established methods. The CNN-DS achieved a Dice coefficient score of 0.84 ± 0.06 and recall of 0.83 ± 0.07, higher than patch-wise U-Net (< 0.76). CNN-DS average running time of 0.74 ± 0.07 s was faster than PItcHPERFeCT (> 1412 s) and slice-based U-Net (> 12 s). Comparable interrater agreement rates were observed between “method-human” vs. “human–human” (Cohen’s kappa coefficients > 0.82). The fully automated CNN-DS approach demonstrated expert-level accuracy in fast segmentation and quantification of hematoma, substantially improving over previous methods. Further research is warranted to test the CNN-DS solution as a software tool in clinical settings for effective stroke management.
A model of visual limitation in patients with keratoconus
Authors: Pérez-Rueda Antonio , Castro-Luna Gracia
Published: November 2020

This paper aims to calculate a relevance model of visual limitation (V.L.) in keratoconus patients based on refractive and topographic parameters. A cross-sectional study was carried out in Torrecárdenas Hospital, Almería, Spain, between February 2018 and July 2019. It included 250 keratoconus patients. Two groups were created according to a grading system of V.L. based on RETICS (Red Temática de Investigación Cooperativa en Salud) classification: keratoconus patients with no V.L. (best spectacle-corrected visual acuity (BSCVA) ≤ 0.05 logMAR) and keratoconus patients with V.L. (BSCVA > 0.05 logMAR). Correlations and a binary logistic regression were established. V.L. was correlated with maximum curvature (r = 0.649, p < 0.001) and root mean square higher-order aberrations (HOARMS) (r = 0.625, p < 0.001). Binary logistic regression included V.L. as the dependent variable and spherical equivalent, HOARMS, spherical aberration and interaction between the anterior and posterior vertical coma as independent variables. The model was a good fit. Area under the curve (A.U.C.) of receiver operating characteristic (R.O.C.) curve was 0.924, sensitivity 91.90%, specificity 83.60%, accuracy 88.94%; and precision 91.17%. Binary logistic regression model of V.L. is a good fit model to predict the early loss of visual acuity in keratoconus patients.
Biases in national and continental flood risk assessments by ignoring spatial dependence
Authors: Nguyen Viet Dung , Metin Ayse Duha , Alfieri Lorenzo , Vorogushyn Sergiy , Merz Bruno
Published: November 2020

Recently, flood risk assessments have been extended to national and continental scales. Most of these assessments assume homogeneous scenarios, i.e. the regional risk estimate is obtained by summing up the local estimates, whereas each local damage value has the same probability of exceedance. This homogeneity assumption ignores the spatial variability in the flood generation processes. Here, we develop a multi-site, extreme value statistical model for 379 catchments across Europe, generate synthetic flood time series which consider the spatial correlation between flood peaks in all catchments, and compute corresponding economic damages. We find that the homogeneity assumption overestimates the 200-year flood damage, a benchmark indicator for the insurance industry, by 139%, 188% and 246% for the United Kingdom (UK), Germany and Europe, respectively. Our study demonstrates the importance of considering the spatial dependence patterns, particularly of extremes, in large-scale risk assessments.