bluuebunny/crossref_metadata_2025 huggingface dataset:
K-SEMISTABILITY OF OPTIMAL DEGENERATIONS
Authors: Dervan Ruadhaí
Published: July 2020

K-polystability of a polarized variety is an algebro-geometric notion conjecturally equivalent to the existence of a constant scalar curvature Kähler metric. When a variety is K-unstable, it is expected to admit a ‘most destabilizing’ degeneration. In this note we show that if such a degeneration exists, then the limiting scheme is itself relatively K-semistable.
Assessment of radiographic progression in patients with rheumatoid arthritis treated with tofacitinib in long-term studies
Authors: van der Heijde Désirée , Landewé Robert B M , Wollenhaupt Jürgen , Strengholt Sander , Terry Ketti , Kwok Kenneth , Wang Lisy , Cohen Stanley
Published: July 2020

Objectives

Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. We evaluated radiographic progression in tofacitinib-treated patients with RA for up to 3 years in two pooled long-term extension (LTE) studies (ORAL Sequel; A3921041) (primary analysis), and for up to 5 years using data integrated from one phase (P)2 (A3921068), two P3 (ORAL Start; ORAL Scan) and two LTE studies (exploratory analysis).

Methods

In LTE studies, patients received tofacitinib 5 mg twice daily (BID) or 10 mg BID as monotherapy or with conventional synthetic (cs)DMARDs. Radiographic outcomes up to 3 years: least squares mean (LSM) change from baseline in van der Heijde modified Total Sharp Score (ΔmTSS), erosion score (ΔES) and joint space narrowing (ΔJSN) score; proportion of patients with no radiographic progression (ΔmTSS ≤0.5); proportion of patients with no new erosions (ΔES ≤0.5). ΔmTSS was evaluated for up to 5 years in an exploratory analysis.

Results

For all tofacitinib-treated patients with radiographic data available at LTE month 36 (n = 414), LSM ΔmTSS was 1.14, LSM ΔES was 0.66, LSM ΔJSN was 0.74, and 74.3% and 86.2% of patients showed no radiographic progression and no new erosions, respectively. Similar values were observed regardless of tofacitinib dose, or whether patients received tofacitinib as monotherapy or with csDMARDs. In an exploratory analysis of integrated P2/P3/LTE studies, LSM ΔmTSS was 3.34 at month 60 (n = 269).

Conclusion

Limited progression of structural damage was observed in tofacitinib-treated patients up to 5 years, with similar results for tofacitinib used as monotherapy or combination therapy up to 3 years.

Trial registration

ClinicalTrials.gov (http://clinicaltrials.gov): NCT01164579; NCT01039688; NCT00847613; NCT00413699; NCT00661661.
Antisaccade Deficits in Schizophrenia Can Be Driven by Attentional Relevance of the Stimuli
Authors: Bansal Sonia , Gaspar John M , Robinson Benjamin M , Leonard Carly J , Hahn Britta , Luck Steven J , Gold James M
Published: July 2020

The antisaccade task is considered a test of cognitive control because it creates a conflict between the strong bottom-up signal produced by the cue and the top-down goal of shifting gaze to the opposite side of the display. Antisaccade deficits in schizophrenia are thought to reflect impaired top-down inhibition of the prepotent bottom-up response to the cue. However, the cue is also a highly task-relevant stimulus that must be covertly attended to determine where to shift gaze. We tested the hypothesis that difficulty in overcoming the attentional relevance of the cue, rather than its bottom-up salience, is key in producing impaired performance in people with schizophrenia (PSZ). We implemented 3 versions of the antisaccade task in which we varied the bottom-up salience of the cue while holding its attentional relevance constant. We found that difficulty in performing a given antisaccade task—relative to a prosaccade version using the same stimuli—was largely independent of the cue’s bottom-up salience. The magnitude of impairment in PSZ relative to control subjects was also independent of bottom-up salience. The greatest impairment was observed in a version where the cue lacked bottom-up salience advantage over other locations. These results indicate that the antisaccade deficit in PSZ does not reflect an impairment in overcoming bottom-up salience of the cue, but PSZ are instead impaired at overcoming its attentional relevance. This deficit may still indicate an underlying inhibitory control impairment but could also reflect a hyperfocusing of attentional resources on the cue.
Cutting the Gordian knot: a historical and taxonomic revision of the Jurassic crocodylomorphMetriorhynchus
Authors: Young Mark T , Brignon Arnaud , Sachs Sven , Hornung Jahn J , Foffa Davide , Kitson James J N , Johnson Michela M , Steel Lorna
Published: July 2020

Metriorhynchidae was a clade of extinct crocodylomorphs that adapted to a pelagic lifestyle, becoming a key component of Mesozoic lagoonal and coastal marine ecosystems. The type genus Metriorhynchus is one of the best-known genera of Mesozoic crocodylomorphs, and since the mid-19th century, the ‘concept’ of Metriorhynchus has become associated with the referred species Me. superciliosus. Historically Metriorhynchus has been the most species-rich genus in Metriorhynchidae, with most Middle Jurassic species and many Late Jurassic species referred to the genus at some point in their history. However, the type species Me. geoffroyii has largely been omitted in the literature. Its type series is a chimera of multiple metriorhynchid species, and a type specimen has never been designated. Moreover, phylogenetic analyses have repeatedly shown that the 19th–20th century concept of Metriorhynchus is not monophyletic – to the point where only referring every metriorhynchid species, and some basal metriorhynchoids, to the genus would render it monophyletic. Herein we designate a lectotype for Me. geoffroyii, re-describe it and restrict the genus Metriorhynchus to the type species. We also establish the new genus Thalattosuchus for Me. superciliosus, thereby cutting the ‘Gordian knot’ of Metriorhynchus with Th. superciliosus.
Sorghum Root Flavonoid Chemistry, Cultivar, and Frost Stress Effects on Rhizosphere Bacteria and Fungi
Authors: Cloutier Mara , Chatterjee Debamalya , Elango Dinakaran , Cui Jin , Bruns Mary Ann , Chopra Surinder
Published: July 2020

Biotic stresses, including fungal infections, result in increased production of flavonoid compounds, including 3-deoxyanthocyanidins (3-DAs), in the leaf tissues of Sorghum bicolor. Our objectives were to determine whether sorghum genotypic variation influenced root flavonoid and 3-DA concentrations and rhizosphere microbial communities and to identify how these relationships were affected by abiotic stress. We evaluated root chemicals and rhizosphere microbiomes of five near-isogenic lines of sorghum before and after a late-season frost. Roots were analyzed for total flavonoids, total phenolics, 3-DA concentrations, and antioxidant activity. Amplicon sequencing of 16S ribosomal RNA genes and internal transcribed spacer regions was performed on rhizosphere soils. Concentrations of luteolinidin (a 3-DA) and total flavonoids differed between several lines before frost; however, these relationships changed after frost. Luteolinidin increased in three lines after frost, whereas total flavonoids decreased in all the lines after frost. Lines that differed in luteolinidin and total flavonoid concentrations before frost were different from those after frost. Rhizosphere community compositions also differed before and after frost but only fungal community compositions differed among sorghum lines. Bacterial community compositions were highly correlated with total flavonoid and luteolinidin concentrations. Furthermore, a greater number of bacterial taxa were correlated with total flavonoids and luteolinidin compared with fungal taxa. Collectively, this study provides evidence that plant genotypic variation influences root flavonoids and rhizosphere community composition and that these relationships are affected by frost. Plant–microbe interactions and secondary metabolite production may be important components to include for selective breeding of sorghum for frost stress tolerance.
Albumin Use After Cardiac Surgery
Authors: Matebele Mbakise P. , Ramanan Mahesh , Thompson Kelly , Cornmell George , Naidoo Rishendran V. , Shekar Kiran
Published: July 2020

Objectives:

To investigate the effect of albumin exposure in ICU after cardiac surgery on hospital mortality, complications, and costs.

Design:

A retrospective, single-center cohort study with economic evaluation.

Setting:

Cardiothoracic ICU in Australia.

Patients:

Adult patients admitted to the ICU after cardiac surgery.

Interventions:

None.

Measurements and Main Results:

Comparison of outcomes and costs in ICU after cardiac surgery based on 4% human albumin exposure. During the study period, 3,656 patients underwent cardiac surgery. After exclusions, 2,594 patients were suitable for analysis. One-thousand two-hundred sixty-four (48.7%) were exposed to albumin and 19 (1.4%) of those died. The adjusted hospital mortality of albumin exposure compared with no albumin was not significant (odds ratio, 1.24; 95% CI, 0.56–2.79; p = 0.6). More patients exposed to albumin returned to the operating theater for bleeding and/or tamponade (6.1% vs 2.1%; odds ratio, 2.84; 95% CI, 1.81–4.45; p < 0.01) and received packed red cell transfusions (p < 0.001). ICU and hospital lengths of stay were prolonged in those exposed to albumin (mean difference, 18 hr; 95% CI, 10.3–25.6; p < 0.001 and 87.5 hr; 95% CI, 40.5–134.6; p < 0.001). Costs (U.S. dollar) were higher in patients exposed to albumin, compared with those with no albumin exposure (mean difference in ICU costs, $2,728; 95% CI, $1,566–3,890 and mean difference in hospital costs, $5,427; 95% CI, $3,294–7,560).

Conclusions:

There is no increased mortality in patients who are exposed to albumin after cardiac surgery. The patients exposed to albumin had higher illness severity, suffered more complications, and incurred higher healthcare costs. A randomized controlled trial is required to determine whether albumin use is effective and safe in this setting.
Regulation of Retinal Melanopsin on Lens-induced Myopia in Guinea Pigs
Authors: Zheng Wei , Chen Yao , Zhou Xuezhi , Zhang Xueyong , Chen Yuanyuan , Guan Xinyu , Mao Junfeng
Published: July 2020

SIGNIFICANCE

Investigation of the mechanism and the role of melanopsin in lens-induced myopia is necessary to find out potential targets in the prevention of myopia development.

PURPOSE

We aimed to study the effect and mechanism of retinal melanopsin on lens-induced myopia in guinea pigs, as well as the interactions between melanopsin and other myopic regulation neurotransmitters such as dopamine and melatonin, and to explore the possible role of melanopsin in the prevention of myopia development.

METHODS

Twenty-day-old tricolor guinea pigs were randomly divided into four groups: control group, defocus group, defocus + AA92593 group, and defocus + dimethyl sulfoxide (DMSO) group. The defocus eyes wore −6.00 D lens. In the defocus + AA92593 group, the vitreous cavities were injected with melanopsin antagonist AA92593. In the defocus + DMSO group, the vitreous cavities were injected with 5% DMSO as the administration control. The expression of retinal melanopsin protein was measured with immunofluorescence staining and Western blot. The content of dopamine and melatonin in the retina was determined by the high-performance liquid chromatography electrochemical method.

RESULTS

Compared with the defocus group, intravitreal injection of AA92593 resulted in increased axial length of the defocus eyes (defocus, 8.05 ± 0.09 mm; defocus + AA92593, 8.15 ± 0.11 mm; P = .008), lower refractive degree (defocus, −1.98 ± 0.82 D; defocus + AA92593, −2.59 ± 0.97 D; P = .05), decreased relative expression of retinal melanopsin protein (defocus, 0.67 ± 0.11; defocus + AA92593, 0.20 ± 0.06; P < .0001), and increased melatonin content in the defocus eyes (defocus, 0.38 ± 0.09 ng/mg; defocus + AA92593, 0.55 ± 0.13 ng/mg; P = .01), but it had no obvious effect on dopamine content (defocus, 0.64 ± 0.18 ng/mg; defocus + AA9259, 0.61 ± 0.17 ng/mg; P > .99). The melatonin content of retina in the defocus + AA92593 group was correlated with refractive error (Pearson correlation coefficient = −0.68, P = .006) and eye axis length (Pearson correlation coefficient = 0.74, P = .02).

CONCLUSIONS

Retinal melanopsin has inhibitory effect on lens-induced myopia development in guinea pigs, and such effect may be related to retinal melatonin.
Validation of a More Reliable Method of Eye Drop Self-Administration
Authors: Freddo Thomas F. , Ho Derek Y. , Steenbakkers Michelle , Furtado Nadine
Published: July 2020

SIGNIFICANCE

We propose an alternative method for eye drop self-administration. Similar IOP reductions were found with this method compared with clinician instillation. The alternative method of self-administration potentially benefits patients who have trouble successfully instilling drops.

PURPOSE

The purpose of this study was to validate the efficacy of an alternative method of drop instillation.

METHODS

This study is a randomized controlled crossover clinical trial. Thirty participants were recruited. A drop of 0.5% timolol maleate was instilled into subject's eye on two separate visits. On one visit, eye drop instillation was by a trained clinician, and on the other, self-instillation using an alternative method was used. The order was randomly chosen. Intraocular pressure was measured before drop instillation and 2 hours after drop instillation. The investigator was masked during measurement, and an observer recorded the IOP measurements.

RESULTS

Mean ± SD IOP measurement before 0.5% timolol maleate instillation measured 13.89 ± 2.29 mmHg. An average reduction 3.75 ± 2.36 mmHg was found with clinician administration, and an average reduction of 3.32 ± 2.31 mmHg was recorded with the new method. No significance was found in IOP reduction between two groups P < .45. Percent reduction was 25.17 ± 16.21% and 24.38 ± 16.31% in clinician instillation and alternative instillation method group, respectively. No significant difference was found. This percentage reduction was similar to previously reported studies. No reported cases of eye infection or irritation were found in any case, within a 3-month follow-up period.

CONCLUSIONS

We have proposed a more reliable method for instillation that provides a larger area for instillation and lessen the risk of contamination and patient's fear for eye drops. Similar efficacy was found compared with that of having a clinician directly administer the drop. This alternative method could potentially benefit patients who require topical eye drop therapy and result in increased compliance.
Topical Review: Optic Disc Pits and Associated Maculopathy
Authors: Anglo Miriam
Published: July 2020

SIGNIFICANCE

Although the treatment of optic disc pit maculopathy is controversial, this review concludes that the most successful current intervention is pars plana vitrectomy with peeling of the internal limiting membrane and induction of posterior vitreous detachment.

Initially described in 1882, an optic disc pit is a rare defect of the optic nerve. This anomaly can result in sight-threatening retinopathy in the form of macular detachment and/or schisis. Outlined in this review of the literature are the incidence, clinical presentation, ancillary testing, pathogenesis, and management of optic disc pits and optic disc pit maculopathy.
The Effect of a Photochromic Contact Lens on Visual Function Indoors: A Randomized, Controlled Trial
Authors: Renzi-Hammond Lisa M. , Buch John R. , Hacker Lauren , Cannon Jessica , Hammond Billy R.
Published: July 2020

SIGNIFICANCE

Photochromic soft contact lenses contain light-sensitive additives that allow them to darken when exposed to ultraviolet or violet light. One question, however, is whether the lenses influence vision indoors (minimally activated). In this study, we found that the minimally activated lenses improved many aspects of visual function under bright light.

PURPOSE

Photochromic contact lenses were designed to darken when exposed to outdoor sunlight. The filtering that results improves visual function under bright light conditions. Not all bright light exposures occur outdoors. In this study, we tested whether a photochromic contact lens improved visual function under conditions where the lens was minimally activated (i.e., no more than it normally would be in an indoor environment).

METHODS

A subject-masked contralateral design was used comparing a photochromic contact lens randomized to one eye against a nonphotochromic contact in the other eye of the same subject. Sixty subjects (mean = 34.90 ± 11.24 years) were tested. The primary endpoints consisted of four visual function outcomes: photostress recovery, glare disability, glare discomfort, and chromatic contrast. Photostress recovery was quantified by measuring the time needed to recover visual acquisition of a grating target after 5 seconds of an intense xenon white flash exposure; glare disability was evaluated as the energy in a surrounding xenon white annulus necessary to veil a central grating target; and glare discomfort was assessed using bioimaging of the squint response. Chromatic contrast was measured as thresholds for a green-yellow (580 nm) grating target superposed on a blue (460 nm) background.

RESULTS

The minimally activated photochromic contact demonstrated improved visual performance compared with the nonphotochromic control across all visual functions tested (P < .01).

CONCLUSIONS

Even under conditions of exiguous activation (e.g., as would be expected indoors or while driving at night), a photochromic contact will improve many of the more deleterious aspects of bright light.
Validation of the International Reading Speed Texts in a Canadian Sample
Authors: Morrice Elliott , Hughes Julian , Stark Zoey , Wittich Walter , Johnson Aaron
Published: July 2020

SIGNIFICANCE

The International Reading Speed Texts (IReST) is a valid measure of reading speed in a Canadian sample. However, if clinicians desire to assess reading comprehension using the IReST, this will significantly reduce reading speeds of individuals with normal vision or reduced visual acuity and therefore should use the values presented here.

PURPOSE

The purposes of this study are (1) to validate the IReST in an English-speaking Canadian sample and (2) to examine how reading comprehension questions and reduced visual acuity affect reading speed on the IReST.

METHODS

For study 1, Canadian English speakers (n = 25) read all 10 IReST following the procedures used in the original IReST validation. For study 2, Canadian English speakers (n = 50) read all 10 IReST, half with normal/corrected-to-normal vision and half with reduced visual acuity, and were asked reading comprehension questions.

RESULTS

No significant differences were found between Canadian sample and the published IReST values (in all cases, P > .05; mean difference [M
diff] = −5.30 to +11.43; Cohen d = −0.15 to +0.27; Bayes factors = 0.41, 0.09). Assessing reading comprehension with multiple-choice questions on the IReST significantly reduced reading speeds in the normal vision condition (M
diff = 25.3; 95% confidence interval, −16.7 to −34.1) and in the simulated impairment condition (M
diff = 59.3; 95% confidence interval, −47.7 to −71).

CONCLUSIONS

The IReST is a valid measure that can be used to assess reading speed in a Canadian English-speaking sample. If researchers/clinicians wish to assess both reading speed and comprehension, using multiple-choice reading comprehension questions, then the values provided by the IReST will likely underestimate an individual's true reading speed in individuals with normal/corrected-to-normal vision or reduced visual acuity.
Task-level regulation enhances global stability of the simplest dynamic walker
Authors: Patil Navendu S. , Dingwell Jonathan B. , Cusumano Joseph P.
Published: July 2020

Much remains unknown about how considerations such as stability and energy minimization shape the way humans walk. While active neuromotor control keeps humans upright, they also need to choose from multiple stepping regulation strategies to achieve one or more task goals, such as maintaining a desired speed or direction. Experiments on human treadmill walking motivate an important question: why do humans prefer one task-level regulation strategy over another—perhaps to enhance their ability to reject large disturbances? Here, we study the relationship between task-level regulation and global stability in a powered compass walker on a treadmill, with added step-to-step speed and position regulators. For treadmill walking, we find that speed regulation greatly enlarges and regularizes the unregulated walker’s stability region, i.e. its basin of attraction, much more than position regulation. Thus, our results suggest a possible explanation for the experimental finding that humans strongly prioritize regulating speed from one stride to the next, even as they walk economically on average. Furthermore, our work suggests a functional connection between task-level motor regulation and global stability—and, thus, perhaps even fall risk.
Functional significance of graded properties of insect cuticle supported by an evolutionary analysis
Authors: Jafarpour M. , Eshghi Sh. , Darvizeh A. , Gorb S. , Rajabi H.
Published: July 2020

The exoskeleton of nearly all insects consists of a flexible core and a stiff shell. The transition between these two is often characterized by a gradual change in the stiffness. However, the functional significance of this stiffness gradient is unknown. Here by combining finite-element analysis and multi-objective optimization, we simulated the mechanical response of about 3000 unique gradients of the elastic modulus to normal contacts. We showed that materials with exponential gradients of the elastic modulus could achieve an optimal balance between the load-bearing capacity and resilience. This is very similar to the elastic modulus gradient observed in insect cuticle and, therefore, suggests cuticle adaptations to applied mechanical stresses; this is likely to facilitate the function of insect cuticle as a protective barrier. Our results further indicate that the relative thickness of compositionally different regions in insect cuticle is similar to the optimal estimation. We expect our findings to inform the design of engineered materials with improved mechanical performance.
Gordonia mangrovi sp. nov., a novel actinobacterium isolated from mangrove soil in Hainan
Authors: Xie Yuhui , Zhou Shuangqing , Xu Yun , Wu Wenqiang , Xia Wei , Zhang Rongping , Huang Dongyi , Huang Xiaolong
Published: July 2020

A novel actinobacterium, designated strain HNM0687T, was isolated from mangrove soil samples collected from Hainan Province, PR China and its polyphasic taxonomy was studied. Based on the results of 16S rRNA gene sequence analysis, strain HNM0687T was closely related to

Gordonia bronchialis

NBRC 16047T (98.7 %),

Gordonia rhizosphera

NBRC 16068T (98.2 %),

Gordonia oryzae

RS15-1ST (97.9 %),

Gordonia polyisoprenivorans

NBRC 16320T (97.7 %) and

Gordonia sediminis

AMA 120T (97.7 %). Genome-based comparisons revealed a clear distinction in average nucleotide identity values between strain HNM0687T and its closely related strains (74.4–78.3 %). Strain HNM0687T contained meso-diaminopimelic acid, arabinose and galactose in whole-cell hydrolysates. Mycolic acid was present. The menaquinones of strain HNM0687T were MK-9(H2) and MK-7(H2). The phospholipids of the isolate were composed of diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylinositol. The major fatty acids were C16 : 0, C16 : 1
 ω7c/C16 : 1
 ω6c, C18 : 010-methyl (TBSA), C18 : 0 and C18 : 1
 ω9c. Based on its genotypic, chemotaxonomic and phenotypic characteristics, it is concluded that strain HNM0687T represents a novel species of the genus

Gordonia

for which the name Gordonia mangrovi sp. nov. is proposed. The type strain is HNM0687T (=CCTCC AA 2019074 T=KCTC 49383 T).
Mucilaginibacter agri sp. nov. and Mucilaginibacter humi sp. nov., isolated from soil
Authors: Seo Ye Lin , Khan Shehzad Abid , Kim Hyung Min , Chun Byung Hee , Han Dong Min , Jeon Che Ok
Published: July 2020

Two Gram-stain-negative, facultative anaerobic and non-motile bacteria, strains R11T and S1162T, were isolated from soil in the Republic of Korea. Both strains were catalase- and oxidase-positive and contained menaquinone-7 as the major isoprenoid quinone. Strain R11T contained summed feature 3 (C16:1 ω7c and/or C16:1 ω6c), iso-C15:0, C16:0 and iso-C17:0 3-OH as major fatty acids and phosphatidylethanolamine, an unidentified aminophospholipid and an unidentified aminolipid as major polar lipids; while strain S1162T contained summed feature 3 (C16:1 ω7c and/or C16:1 ω6c), iso-C15:0, iso-C17:0 3-OH, C16:0 and summed feature 9 (10-methyl C16:0 and/or iso-C17:1 ω9c) as major fatty acids and phosphatidylethanolamine and an unidentified aminophospholipid as major polar lipids. The DNA G+C contents of strains R11T and S1162T calculated from their whole genomes were 42.7 and 42.9 mol%, respectively. Results of phylogenetic analysis based on 16S rRNA gene sequences showed that strain R11T formed a phylogenetic lineage with

Mucilaginibacter jinjuensis

YC7004T and strain S1162T formed a distinct phyletic lineage from closely related type strains within the genus

Mucilaginibacter

. Strains R11T and S1162T were most closely related to

M. jinjuensis

YC7004T and

Mucilaginibacter panaciglaebae

BXN5-31T with 97.78 and 97.23% 16S rRNA gene sequence similarities, respectively. On the basis of phenotypic, chemotaxonomic and molecular analysis, strains R11T and S1162T represent two novel species of the genus

Mucilaginibacter

, for which the names Mucilaginibacter agri sp. nov. and Mucilaginibacter humi sp. nov. are proposed, respectively. The type strains of M. agri and M. humi are R11T (=KACC 21228T=JCM 33472T) and S1162T (=KACC 21669T=JCM 33916T), respectively.
Solving the trade-off by differences in handling of intracellular K+: why substrate translocation by the dopamine transporter but not by the serotonin transporter is voltage-dependent
Authors: Bhat Shreyas , Niello Marco , Schicker Klaus , Pifl Christian , Sitte Harald H. , Freissmuth Michael , Sandtner Walter
Published: July 2020

The dopamine transporter (DAT) retrieves dopamine into presynaptic terminals after synaptic release. The concentrative power of DAT is thought to be fueled by the transmembrane Na+gradient, but it is conceivable that DAT can also rely on other energy sources, e.g. membrane voltage and/or the K+gradient. Here, we recorded uptake of dopamine or the fluorescent substrate APP+((4-(4-dimethylamino)phenyl-1-methylpyridinium) in DAT-expressing cells under voltage control. We show that DAT differs substantially from the closely related serotonin transporter (SERT): substrate uptake by DAT was voltage-dependent, intracellular K+binding to DAT was electrogenic but transient in nature thus precluding antiport of K+by DAT. There is a trade-off between maintaining constant uptake and harvesting membrane potential for concentrative power. Based on our observations, we conclude that subtle differences in the kinetics of co-substrate ion binding allow closely related transporters to select between voltage-independent uptake and high concentrative power.
Mendelian randomisation analyses of eosinophils and other blood cell types in relation to lung function and disease
Authors: Guyatt Anna L , John Catherine , Williams Alexander T , Shrine Nick , Reeve Nicola ,   SpiroMeta consortium, Hall Ian P , Wain Louise V , Sheehan Nuala A , Dudbridge Frank , Tobin Martin D
Published: July 2020

Background

Eosinophils are granulocytes associated with airway inflammation in respiratory disease. Eosinophil production and survival is controlled by interleukin-5: anti-interleukin-5 agents reduce asthma and COPD exacerbation frequency, and response correlates with baseline eosinophil counts. However, causal relationships between eosinophils and other respiratory phenotypes are less studied.

Methods

We investigated causality between eosinophils and: lung function, acute exacerbations of COPD (AECOPD), asthma-COPD overlap (ACO), moderate-to-severe asthma, and respiratory infections. We performed Mendelian randomization (MR) using 151 genetic variants from genome-wide association studies of blood eosinophil counts in UK Biobank/INTERVAL, and respiratory data from UK Biobank, using MR methods relying on different assumptions for validity. Multivariable MR using eight blood cell type exposures was performed for outcomes showing evidence of causation by eosinophils.

Findings

There was evidence that higher eosinophils reduce FEV1/FVC and FEV1 (weighted median estimator, SD change FEV1/FVC per SD eosinophils: −0.054 [95%CI −0.078,−0.029]. There was also evidence that eosinophils cause ACO (weighted median OR 1.44 [95%CI 1.19,1.74]), and asthma (weighted median OR 1.50 [95%CI 1.23,1.83]). Multivariable MR for FEV1/FVC, FEV1, ACO and asthma suggested that eosinophils were the cell type with the most important effect. Causal estimates of individual variants were heterogeneous, which may arise from pleiotropy.

Interpretation

We found evidence that eosinophils reduce lung function, and increase ACO and asthma risk, on average over the set of genetic variants studied. Eosinophils appear to be causal determinants of fixed airflow obstruction among individuals with features of both asthma and COPD.

Funding

Wellcome, BHF, MRC, BBSRC CASE studentship with GSK, GSK/BLF.
Accurate classification of secondary progression in multiple sclerosis
Authors: Ramanujam Ryan , Zhu Feng , Fink Katharina , Danylaitė Karrenbauer Virginija , Lorscheider Johannes , Benkert Pascal , Kingwell Elaine , Tremlett Helen , Hillert Jan , Manouchehrinia Ali ,   The BeAMS Study group
Published: July 2020

Transition from a relapsing-remitting to the secondary progressive phenotype is an important milestone in the clinical evolution of multiple sclerosis. In the absence of reliable imaging or biological markers of phenotype transition, assignment of current phenotype status relies on retrospective evaluation of the medical history of an individual. Here, we sought to determine if demographic and clinical information from multiple sclerosis patients can be used to accurately assign current disease phenotypes: either relapsing-remitting or secondary progressive status. Data from the most recent clinical visit of 14,387 multiple sclerosis patients were extracted from the Swedish Multiple Sclerosis Registry. Decision trees based on sex, symptom onset age, Expanded Disability Scale Status score, and age & disease duration at the most recent clinic visit, were examined to build a classifier to determine disease phenotype. Validation was conducted using an independent cohort of multiple sclerosis patients from British Columbia, Canada, and a previously published classifier to assign phenotype was also tested. Clinical records of 100 randomly selected patients were used to manually categorize phenotype by three independent neurologists. A decision tree (the classifier) containing only most recently available disability score and age obtained 89.3% (95% confidence intervals (CI): 88.8% to 89.8%) classification accuracy, defined as concordance with the latest reported status in the registry. Replication in an independent cohort from British Columbia resulted in 82.0% (95%CI: 81.0% to 83.1%) accuracy. A previously published classification algorithm with slight modifications achieved 77.8% (95%CI: 77.1% to 78.4%) accuracy when assigning disease phenotype. With complete patient history data, three neurologists obtained 84.7% accuracy on average compared with 85 for the classifier using the same data. The model is easily interpretable and could allow research studies and randomized clinical trials to estimate the probability of patients having already reached the secondary progressive stage when they have not yet been retrospectively assigned this status, and to standardize definitions of disease phenotype across different cohorts. Clinically, this model could assist neurologists by providing additional information about the probability of having secondary progressive disease. This could also benefit patients who may be introduced to new therapies targeting progressive multiple sclerosis.
Estimating the causal effect of genetic liability to prevalent disease on hospital costs using Mendelian Randomization
Authors: Dixon Padraig , Harrison Sean , Hollingworth William , Davies Neil M , Smith George Davey
Published: July 2020

BACKGROUND

Accurate measurement of the effects of disease status on healthcare cost is important in the pragmatic evaluation of interventions but is complicated by endogeneity biases due to omitted variables and reverse causality. Mendelian Randomization, the use of random perturbations in germline genetic variation as instrumental variables, can avoid these limitations. We report a novel Mendelian Randomization analysis of the causal effect of liability to disease on healthcare costs.

METHODS

We used Mendelian Randomization to model the causal impact on inpatient hospital costs of liability to six highly prevalent diseases: asthma, eczema, migraine, coronary heart disease, type 2 diabetes, and major depressive disorder. We identified genetic variants from replicated genome-wide associations studies and estimated their association with inpatient hospital costs using data from UK Biobank, a large prospective cohort study of individuals linked to records of hospital care. We assessed potential violations of the instrumental variable assumptions, particularly the exclusion restriction (i.e. variants affecting costs through alternative paths). We also conducted new genome wide association studies of hospital costs within the UK Biobank cohort as a further “split sample”sensitivity analysis.

RESULTS

We analyzed data on 307,032 individuals. Genetic variants explained only a small portion of the variance in each disease phenotype. Liability to coronary heart disease had substantial impacts (mean per person per year increase in costs from allele score Mendelian Randomization models: £712 (95% confidence interval: £238 to £1,186)) on inpatient hospital costs in causal analysis, but other results were imprecise. There was concordance of findings across varieties of sensitivity analyses, including stratification by sex, and those obtained from the split sample analysis.

CONCLUSION

A novel Mendelian Randomization analysis of the causal effect of liability to disease on healthcare cost demonstrates that this type of analysis is feasible and informative in this context. There was concordance across data sources and across methods bearing different assumptions. Selection into the relatively healthy UK Biobank cohort and the modest proportion of variance in disease status accounted for by the allele scores reduced the precision of our estimates. We therefore could not exclude the possibility of substantial costs due to these diseases.

JEL Classification Numbers

H51, I10, I11, I18,
Transcription Factor EB regulates phosphatidylinositol-3-phosphate levels on endomembranes and alters lysosome positioning in the bladder cancer model
Authors: Mathur Pallavi , Santos Camilla De Barros , Lachuer Hugo , Latgé Bruno , Radvanyi François , Goud Bruno , Schauer Kristine
Published: July 2020

Lysosomes orchestrate degradation and recycling of exogenous and endogenous material, thus controlling cellular homeostasis. Little is known how this organelle changes during malignant transformation. We investigate the intracellular landscape of lysosomes in a cellular model of bladder cancer. Employing standardized cell culture on micropatterns we identify a phenotype of peripheral lysosome positioning prevailing in bladder cancer but not normal urothelium. We show that lysosome positioning is controlled by transcription factor EB (TFEB) and that lysosomal dispersion results from TFEB activation downstream of lysosomal Ca2+release. Remarkably, we find that TFEB regulates phosphatidylinositol-3-phosphate (PtdIns3P) levels on endomembranes which recruit FYVE-domain containing proteins, such as the motor adaptor protrudin, for anterograde movement of lysosomes. Altogether, we uncover lysosome positioning as result of PtdIns3P activation downstream of TFEB as a potential biomarker for bladder cancer. Moreover, we reveal a novel role of TFEB in regulating cellular PtdIns levels, conceptually clarifying the dual role of TFEB as regulator of endosomal maturation and autophagy, two distinct processes controlled by PtdIns3P.

Statement of significance

Here we provide the first atlas for the landscape of the lysosomal compartment in bladder cancer and reveal the mechanistic role of TFEB in regulating endosomal PtdIns3P levels and subsequent lysosomal dispersion. We unveiled lysosomal positioning as a potential biomarker for malignant bladder cancer which might arise as an actionable target for cancer therapy.
The Canadian ALS Neuroimaging Consortium (CALSNIC) - a multicentre platform for standardized imaging and clinical studies in ALS
Authors: Kalra Sanjay , Khan Muhammad , Barlow Laura , Beaulieu Christian , Benatar Michael , Briemberg Hannah , Chenji Sneha , Clua Miriam Garrido , Das Sumit , Dionne Annie , Dupré Nicolas , Emery Derek , Eurich Dean , Frayne Richard , Genge Angela , Gibson Summer , Graham Simon , Hanstock Christopher , Ishaque Abdullah , Joseph Jeffrey T. , Keith Julia , Korngut Lawrence , Krebs Dennell , McCreary Cheryl R. , Pattany Pradip , Seres Peter , Shoesmith Christen , Szekeres Trevor , Tam Fred , Welsh Robert , Wilman Alan , Yang Yee Hong , Yunusova Yana , Zinman Lorne ,   for the Canadian ALS Neuroimaging Consortium
Published: July 2020

Background

Amyotrophic lateral sclerosis (ALS) is a disabling and rapidly progressive neurodegenerative disorder. Increasing age is an important risk factor for developing ALS, thus the societal impact of this devastating disease will become more profound as the population ages. A significant hurdle to finding effective treatment has been an inability to accurately quantify cerebral degeneration associated with ALS in humans. Advanced magnetic resonance imaging (MRI) techniques hold promise in providing a set of biomarkers to assist in aiding diagnosis and in efficiently evaluating new drugs to treat ALS.

Methods

The Canadian ALS Neuroimaging Consortium (CALSNIC) was founded to develop and evaluate advanced MRI-based biomarkers that delineate biological heterogeneity, track disease progression, and predict survival in a large and heterogeneous sample of ALS patients.

Findings

CALSNIC has launched two studies to date (CALSINC-1, CALSNIC-2), acquiring multimodal neuroimaging, neurological, neuropsychological data, and neuropathological data from ALS patients and healthy controls in a prospective and longitudinal fashion from multiple centres in Canada and, more recently, the United States. Clinical and MRI protocols are harmonized across research centres and different MR vendors.

Interpretation

CALSNIC provides a multicentre platform for studying ALS biology and developing MRI-based biomarkers.

Funding

Canadian Institutes of Health Research, ALS Society of Canada, Brain Canada Foundation, Shelly Mrkonjic Research Fund
Serological Tests for SARS-CoV-2 Coronavirus by Commercially Available Point-of-Care and Laboratory Diagnostics in Pre-COVID-19 Samples in Japan
Authors: Sassa Mariko Harada , Lyu Zhaoqing , Fujitani Tomoko , Harada Kouji H.
Published: July 2020

Serological tests for SARS-CoV-2 coronavirus in pre-COVID-19 samples in Japan showed 1.5%–1.75% positives, and previous surveys might overestimate COVID-19 seroprevalence in several population of Japan. These false negatives could be excluded by combination of different diagnostics to 0.25%.
Sample Size Calculation for Phylogenetic Case Linkage
Authors: Wohl Shirlee , Giles John R. , Lessler Justin
Published: July 2020

Sample size calculations are an essential component of the design and evaluation of scientific studies. However, there is a lack of clear guidance for determining the sample size needed for phylogenetic studies, which are becoming an essential part of studying pathogen transmission. We introduce a statistical framework for determining the number of true infector-infectee transmission pairs identified by a phylogenetic study, given the size and population coverage of that study. We then show how characteristics of the criteria used to determine linkage and aspects of the study design can influence our ability to correctly identify transmission links, in sometimes counterintuitive ways. We test the overall approach using outbreak simulations and provide guidance for calculating the sensitivity and specificity of the linkage criteria, the key inputs to our approach. The framework is freely available as the R package phylosamp, and is broadly applicable to designing and evaluating a wide array of pathogen phylogenetic studies.
Estimating the Effect of Social Distancing Interventions on COVID-19 in the United States
Authors: Olney Andrew M. , Smith Jesse , Sen Saunak , Thomas Fridtjof , Unwin H. Juliette T.
Published: July 2020

Since its global emergence in 2020, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused multiple epidemics in the United States. Because medical treatments for the virus are still emerging and a vaccine is not yet available, state and local governments have sought to limit its spread by enacting various social distancing interventions such as school closures and lockdown, but the effectiveness of these interventions is unknown. We applied an established, semi-mechanistic Bayesian hierarchical model of these interventions on SARS-CoV-2 spread in Europe to the United States. We estimated the effect of interventions across all states, contrasted the estimated reproduction number, Rt, for each state before and after lockdown, and contrasted predicted future fatalities with actual fatalities as a check on the model’s validity. Overall, school closures and lockdown are the only interventions modeled that have a reliable impact on Rt, and lockdown appears to have played a key role in reducing Rt below 1.0. We conclude that reversal of lockdown, without implementation of additional, equally effective interventions, will enable continued, sustained transmission of SARS-CoV-2 in the United States.
Cell type-aware analysis of RNA-seq data
Authors: Jin Chong , Chen Mengjie , Lin Danyu , Sun Wei
Published: July 2020

Most tissue samples are composed of different cell types. Differential expression analysis without accounting for cell type composition cannot separate the changes due to cell type composition or cell type-specific expression. We propose a computational framework to address these limitations:Cell TypeAware analysis ofRNA-seq(CARseq). CARseq employs a negative binomial distribution that appropriately models the count data from RNA-seq experiments. Simulation studies show that CARseq has substantially higher power than a linear model-based approach and it also provides more accurate estimate of the rankings of differentially expressed genes. We have applied CARseq to compare gene expression of schizophrenia/autism subjects versus controls, and identified the cell types underlying the difference and similarities of these two neuron-developmental diseases. Our results are consistent with the results from differential expression analysis using single cell RNA-seq data.
Single-nucleotide conservation state annotation of the SARS-CoV-2 genome
Authors: Kwon Soo Bin , Ernst Jason
Published: July 2020

Given the global impact and severity of COVID-19, there is a pressing need for a better understanding of the SARS-CoV-2 genome and mutations. Multi-strain sequence alignments of coronaviruses (CoV) provide important information for interpreting the genome and its variation. We apply a comparative genomics method, ConsHMM, to the multi-strain alignments of CoV to annotate every base of the SARS-CoV-2 genome with conservation states based on sequence alignment patterns among CoV. The learned conservation states show distinct enrichment patterns for genes, protein domains, and other regions of interest. Certain states are strongly enriched or depleted of SARS-CoV-2 mutations, which can be used to predict potentially consequential mutations. We expect the conservation states to be a resource for interpreting the SARS-CoV-2 genome and mutations.
Biologic Drug Survival in Psoriasis: A Systematic Review & Comparative Meta-Analysis
Authors: Mourad A. I. , Gniadecki R.
Published: July 2020

Background

Drug survival studies have been utilized to evaluate the real-world effectiveness of biologics used in psoriasis. However, the increasing volume of drug survival data suffers from large variability due to regional differences in drug availability, patient selection and biologic reimbursement.

Objectives

To conduct a meta-analysis of biologic drug survival to determine comparative effectiveness of the biologics in a real-world setting.

Methods

Studies reporting drug survival for biologic therapy in psoriasis were identified by a systematic literature search. Hazard ratio data for drug discontinuation were estimated directly from published Kaplan-Meier estimator curves at year 1, 2 and 5 of treatment and compared pairwise for the following biologics: ustekinumab, adalimumab, etanercept, infliximab, secukinumab and ixekizumab. This pooled hazard ratios were used to estimate 2- and 5-year overall drug survival rates.

Results

Ustekinumab had the longest persistence at 2 years and 5 years among all biologics included in this meta-analysis. Adalimumab was superior to etanercept and infliximab at 5 years. Pooled 5-year drug survival rates for adalimumab, etanercept, and infliximab were 46.3%, 35.9% and 34.7%, respectively. 2- and 5-year data were not available for anti-IL-17 drugs, but at 1-year ustekinumab outperformed secukinumab, the latter being equal to anti-TNFs.

Conclusions

Ustekinumab is characterized by longer drug survival than TNF inhibitors and IL-17 inhibitors. Estimated pooled 2- and 5-year drug survival rates may serve as a useful tool for patient communication and clinical decision-making.
Clinical Electroencephalography Findings and Considerations in Hospitalized Patients with Coronavirus SARS-CoV-2
Authors: Ayub Neishay , Cohen Joseph , Jing Jin , Jain Aayushee , Tesh Ryan , Mukerji Shibani S. , Zafar Sahar F. , Westover M. Brandon , Kimchi Eyal Y.
Published: July 2020

Background and Purpose

Reports have suggested that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes neurologic manifestations including encephalopathy and seizures. However, there has been relatively limited electrophysiology data to contextualize these specific concerns and to understand their associated clinical factors. Our objective was to identify EEG abnormalities present in patients with SARS-CoV-2, and to determine whether they reflect new or preexisting brain pathology.

Methods

We studied a consecutive series of hospitalized patients with SARS-CoV-2 who received an EEG, obtained using tailored safety protocols. Data from EEG reports and clinical records were analyzed to identify EEG abnormalities and possible clinical associations, including neurologic symptoms, new or preexisting brain pathology, and sedation practices.

Results

We identified 37 patients with SARS-CoV-2 who underwent EEG, of whom 14 had epileptiform findings (38%). Patients with epileptiform findings were more likely to have preexisting brain pathology (6/14, 43%) than patients without epileptiform findings (2/23, 9%; p=0.042). There were no clear differences in rates of acute brain pathology. One case of nonconvulsive status epilepticus was captured, but was not clearly a direct consequence of SARS-CoV-2.

Abnormalities of background rhythms were common, and patients recently sedated were more likely to lack a posterior dominant rhythm (p=0.022).

Conclusions

Epileptiform abnormalities were common in patients with SARS-CoV-2 referred for EEG, but particularly in the context of preexisting brain pathology and sedation. These findings suggest that neurologic manifestations during SARS-CoV-2 infection may not solely relate to the infection itself, but rather may also reflect patients’ broader, preexisting neurologic vulnerabilities.