bluuebunny/crossref_metadata_2025 huggingface dataset:
OPUS-Rota4: a gradient-based protein side-chain modeling framework assisted by deep learning-based predictors
Authors: Xu Gang , Wang Qinghua , Ma Jianpeng
Published: November 2021

Accurate protein side-chain modeling is crucial for protein folding and protein design. In the past decades, many successful methods have been proposed to address this issue. However, most of them depend on the discrete samples from the rotamer library, which may have limitations on their accuracies and usages. In this study, we report an open-source toolkit for protein side-chain modeling, named OPUS-Rota4. It consists of three modules: OPUS-RotaNN2, which predicts protein side-chain dihedral angles; OPUS-RotaCM, which measures the distance and orientation information between the side chain of different residue pairs and OPUS-Fold2, which applies the constraints derived from the first two modules to guide side-chain modeling. OPUS-Rota4 adopts the dihedral angles predicted by OPUS-RotaNN2 as its initial states, and uses OPUS-Fold2 to refine the side-chain conformation with the side-chain contact map constraints derived from OPUS-RotaCM. Therefore, we convert the side-chain modeling problem into a side-chain contact map prediction problem. OPUS-Fold2 is written in Python and TensorFlow2.4, which is user-friendly to include other differentiable energy terms. OPUS-Rota4 also provides a platform in which the side-chain conformation can be dynamically adjusted under the influence of other processes. We apply OPUS-Rota4 on 15 FM predictions submitted by AlphaFold2 on CASP14, the results show that the side chains modeled by OPUS-Rota4 are closer to their native counterparts than those predicted by AlphaFold2 (e.g. the residue-wise RMSD for all residues and core residues are 0.588 and 0.472 for AlphaFold2, and 0.535 and 0.407 for OPUS-Rota4).
Profitability of small- and medium-sized enterprises in Marshall’s time: sector and spatial heterogeneity in the nineteenth century
Authors: Bennett Robert J , Smith Harry , Montebruno Piero , van Lieshout Carry
Published: November 2021

New data on profit heterogeneity of small- and medium-sized firms for 1861–81 in England and Wales are used to reinterpret Marshall's contemporary insights. Profit level differences are chiefly explained by location, mainly urbanisation effects. But profitability (profit per worker) is mainly explained by sectors, at both 1-digit and 5-digit level. Sector market opportunities reflected barriers to market entry which limited substitutability for the services of the professions, some manufacturing and maker-dealing industries. Localisation mainly reflected urban/rural differences, accessibility to railways and to a lesser extent waterways. Differences in firm-level organisation (measured by portfolio diversification and partnerships) were less significant for explaining profit heterogeneity than sector or localisation. Demographic effects such as an entrepreneur's age had little significance. Marshall's insight of convergence to mean industry-sector profitability, with localisation as a secondary influence, is confirmed, but there remain unexplained elements of heterogeneity indicating important roles of entrepreneurial agency.
Non-lipid-rich low attenuation plaque with intraplaque haemorrhage assessed by multimodality imaging: a case report
Authors: Matsumoto Hidenari , Xie Yibin , Li Debiao , Shinke Toshiro
Published: November 2021

Background

The lipid-rich necrotic core is a major pathological hallmark of acute coronary syndrome. Low attenuation plaque (LAP) on coronary computed tomography angiography (CCTA), defined as plaque CT attenuation of <30 Hounsfield units, is commonly believed to correspond to the lipid component. This report presents a non-lipid-rich LAP with intraplaque haemorrhage of the left main coronary artery (LM), as assessed by CCTA, near-infrared spectroscopy (NIRS), and non-contrast magnetic resonance imaging (MRI) using coronary atherosclerosis T1-weighted characterization with integrated anatomical reference technique, recently developed by our group.

Case summary

A 75-year-old woman presented with chest discomfort on exertion. Coronary computed tomography angiography revealed severe stenosis of the mid-left circumflex coronary artery and minimal stenosis with a large eccentric LM plaque. The LM lesion had an LAP, with a minimum plaque attenuation of 25 Hounsfield units. On non-contrast T1-weighted MRI, a high-intensity plaque with a plaque-to-myocardium signal intensity ratio of 3.02 was observed within the vessel wall, indicating intraplaque haemorrhage. Near-infrared spectroscopy categorized the lesion as non-lipid-rich, with a maximum lipid core burden index in 4 mm of 169.

Discussion

Intraplaque haemorrhage is a key feature of plaque instability, which is different from the lipid-rich necrotic core. Non-contrast T1-weighted MRI is ideal for detecting intraplaque haemorrhage with short T1 values. The imaging findings suggest that LAP on CCTA may represent not only lipid-rich plaques but also intraplaque haemorrhage. Magnetic resonance imaging provides a unique insight into plaque vulnerability from a different perspective than lipid assessment. Multimodality imaging, including MRI, facilitates the understanding of complicated plaque morphologies.

Keywords

Atherosclerosis • Case report • Computed tomography • Intraplaque haemorrhage • Lipid-rich plaque • Magnetic resonance imaging • Near-infrared spectroscopy-intravascular ultrasound
The association of PRECISE-DAPT score with ischaemic outcomes in patients taking dual antiplatelet therapy following percutaneous coronary intervention: a meta-analysis
Authors: Clifford Cole R , Boudreau Rene , Visintini Sarah , Orr Nathan , Fu Angel Y N , Malhotra Nikita , Barry Quinton , So Derek Y F
Published: November 2021

Aims

The PRECISE-DAPT (Predicting Bleeding Complication in Patients Undergoing Stent Implantation and Subsequent Dual Antiplatelet Therapy) score identifies patients at high risk of bleeding complications following percutaneous coronary intervention (PCI). International guidelines recommend the PRECISE-DAPT score to identify patients at high risk for bleeding, who may benefit from shortened dual antiplatelet therapy. The association of the PRECISE-DAPT score with ischaemic outcomes remains unclear. We performed a meta-analysis investigating the association between a high PRECISE-DAPT score and ischaemic outcomes.

Methods and results

A comprehensive literature search was conducted on articles published between 11 March 2017 and 5 June 2021. Two reviewers independently screened articles for inclusion using pre-defined criteria. The outcome measures extracted included composite ischaemic events, major bleeding events, and all-cause mortality. A random effects model was applied to obtain combined risk estimates for outcomes. From 12 included studies, there were 39 459 patients with PRECISE-DAPT <25 and 14 761 patients with PRECISE-DAPT ≥25. PRECISE-DAPT score ≥25 was associated with increased risk of composite ischaemic events [odds ratio (OR) 2.16; 95% confidence interval (CI) 1.77–2.65], myocardial infarction (OR 2.06; 95% CI 1.38–3.08), and ischaemic stroke (OR 2.90; 95% CI 1.76–4.78). Patients with a PRECISE-DAPT score ≥25 had increased risk of major bleeding (OR 3.62; 95% CI 2.62–4.99). Patients with a PRECISE-DAPT score ≥25 had higher risk of all-cause mortality (OR 5.83; 95% CI 5.37–6.33).

Conclusion

Patients with a PRECISE-DAPT score ≥25 are at increased risk for ischaemic events, bleeding, and all-cause mortality. Prospective evaluation of a PRECISE-DAPT guided approach to antiplatelet therapy is required to demonstrate benefit in this high-risk population.
Chronic kidney disease and subclinical abnormalities of left heart mechanics in the community
Authors: Iwama Kentaro , Nakanishi Koki , Daimon Masao , Yoshida Yuriko , Sawada Naoko , Hirose Kazutoshi , Yamamoto Yuko , Ishiwata Jumpei , Hirokawa Megumi , Kaneko Hidehiro , Nakao Tomoko , Mizuno Yoshiko , Morita Hiroyuki , Di Tullio Marco R , Homma Shunichi , Komuro Issei
Published: November 2021

Aims

Cardiovascular disease is the leading cause of death in chronic kidney disease (CKD) patients, although the pathophysiological mechanisms are not fully studied. This study aimed to determine whether CKD could adversely affect subclinical left heart function in a sample of the general population without cardiac disease.

Methods and results

We examined 1158 participants who voluntarily underwent extensive cardiovascular examination including laboratory test and two-dimensional speckle-tracking echocardiography to assess left ventricular global longitudinal strain (LVGLS) and left atrial (LA) reservoir, conduit, and pump strain. According to the estimated glomerular filtration rate (eGFR), participants were classified into four groups; Stage 1 (n = 112; eGFR ≥90 mL/min/1.73 m2), Stage 2 (n = 818; 60–89 mL/min/1.73 m2), Stage 3a (n = 191; 45–59 mL/min/1.73 m2), and Stage 3b–5 (n = 37; eGFR <45 mL/min/1.73 m2). Progressive declines of LVGLS, LA reservoir, and conduit strain were observed according to the severity of CKD (P < 0.001), while LA pump strain did not differ between the groups. In multivariable analyses, eGFR was associated with LVGLS (standardized β = −0.068, P = 0.019) as well as LA reservoir (standardized β = 0.117, P < 0.001) and conduit strain (standardized β = 0.130, P < 0.001), independent of traditional cardiovascular risk factors, pertinent biomarkers, and LV geometry and diastolic function. The independent association between eGFR and LA strain persisted even after adjustment for LVGLS.

Conclusion

Worsening renal function was independently associated with impaired LV/LA strain in an unselected community-based cohort. The assessment of LV and LA strain may allow better risk stratification in CKD patients.
Pre-Colonial Warfare and Long-Run Development in India
Authors: Dincecco Mark , Fenske James , Menon Anil , Mukherjee Shivaji
Published: November 2021

Does pre-colonial history—and in particular the role of interstate warfare—help explain long-run development patterns across India? To address this question, we construct a new geocoded database of historical conflicts on the Indian subcontinent. We document a robust positive relationship between pre-colonial conflict exposure and local economic development today. Drawing on archival and secondary data, we show that districts that were more exposed to pre-colonial conflict experienced greater early state-making, followed by lower political violence and higher investments in physical and human capital in the long term.
Teacher strategies in implementing English medium instruction
Authors: Richards Jack C , Pun Jack
Published: November 2021

With the expanding role of English medium instruction (EMI) worldwide there has been an increasing use of English to teach content subjects at tertiary level. In implementing EMI a common assumption has been that the primary issue affecting successful EMI is the English proficiency level of the EMI instructor. This paper reviews this assumption by exploring three dimensions of EMI—the cognitive, the genre, and the academic task dimensions of teaching in a discipline—and the role that English plays in developing disciplinary literacy and competence. From a review of EMI teachers’ accounts of EMI in Hong Kong as well as other EMI contexts, information is presented to demonstrate the ways in which EMI teachers adapt their teaching in order to prepare for and manage EMI. Goals are suggested for the professional development of EMI teachers.
The cold chain and the COVID-19 pandemic: an unusual increase in histamine content in fish samples collected in Southern Italy during lockdown
Authors: Galluzzo Francesco Giuseppe , Cammilleri Gaetano , Cicero Antonello , Pantano Licia , Pulvirenti Andrea , Macaluso Andrea , Cicero Nicola , Calabrese Vittorio , Ferrantelli Vincenzo
Published: November 2021

Objectives

We analysed 900 samples of fresh (250) and processed (650) fish products collected in Sicily (Southern Italy) in 2020 during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic (hereafter: COVID-19).

Materials and methods

The samples were divided temporally based on four phases relating to the various restrictions imposed by the Italian government in this period. The validated method of ultrahigh-performance liquid chromatography combined with a diode array detector was then employed for the analysis.

Results

The samples collected during the Phase I lockdown period and after it had ended (Phase II) revealed significant increases in the mean histamine levels: (41.89±87.58) mg/kg and (24.91±76.76) mg/kg, respectively. The 11 (1.3% of the total) fresh fish samples that were identified as being non-compliant with Regulation (EC) No.2073/2005 were only found during these two periods. All the processed samples were always compliant. The histamine values decreased as the restrictions eased, achieving a mean value of (11.16±9.3) mg/kg (Phase III).

Conclusions

There was an increase in the incidence of fish samples that were non-compliant with Regulation (EC) No.2073/2005 compared to previous surveillance data. These results provide a first report on the effect of lockdown measures on food safety and the cold chain. Our findings must cause food safety operators to intensify their controls over fresh fish products in such periods to safeguard consumer health. Further studies are required to evaluate whether the same trend would be observed with other food contaminants.
Cecropins contribute toDrosophilahost defense against a subset of fungal and Gram-negative bacterial infection
Authors: Carboni Alexia L , Hanson Mark A , Lindsay Scott A , Wasserman Steven A , Lemaitre Bruno
Published: November 2021

Cecropins are small helical secreted peptides with antimicrobial activity that are widely distributed among insects. Genes encoding Cecropins are strongly induced upon infection, pointing to their role in host defense. In Drosophila, four cecropin genes clustered in the genome (CecA1, CecA2, CecB, and CecC) are expressed upon infection downstream of the Toll and Imd pathways. In this study, we generated a short deletion ΔCecA-C removing the whole cecropin locus. Using the ΔCecA-C deficiency alone or in combination with other antimicrobial peptide (AMP) mutations, we addressed the function of Cecropins in the systemic immune response. ΔCecA-C flies were viable and resisted challenge with various microbes as wild-type. However, removing ΔCecA-C in flies already lacking 10 other AMP genes revealed a role for Cecropins in defense against Gram-negative bacteria and fungi. Measurements of pathogen loads confirm that Cecropins contribute to the control of certain Gram-negative bacteria, notably Enterobacter cloacae and Providencia heimbachae. Collectively, our work provides the first genetic demonstration of a role for Cecropins in insect host defense and confirms their in vivo activity primarily against Gram-negative bacteria and fungi. Generation of a fly line (ΔAMP14) that lacks 14 immune inducible AMPs provides a powerful tool to address the function of these immune effectors in host–pathogen interactions and beyond.
Genome-wide association mapping of transcriptome variation inMimulus guttatusindicates differing patterns of selection oncis- versustrans-acting mutations
Authors: Brown Keely E , Kelly John K
Published: November 2021

We measured the floral bud transcriptome of 151 fully sequenced lines of Mimulus guttatus from one natural population. Thousands of single nucleotide polymorphisms (SNPs) are implicated as transcription regulators, but there is a striking difference in the allele frequency spectrum of cis-acting and trans-acting mutations. Cis-SNPs have intermediate frequencies (consistent with balancing selection) while trans-SNPs exhibit a rare-alleles model (consistent with purifying selection). This pattern only becomes clear when transcript variation is normalized on a gene-to-gene basis. If a global normalization is applied, as is typically in RNAseq experiments, asymmetric transcript distributions combined with “rarity disequilibrium” produce a superabundance of false positives for trans-acting SNPs. To explore the cause of purifying selection on trans-acting mutations, we identified gene expression modules as sets of coexpressed genes. The extent to which trans-acting mutations influence modules is a strong predictor of allele frequency. Mutations altering expression of genes with high “connectedness” (those that are highly predictive of the representative module expression value) have the lowest allele frequency. The expression modules can also predict whole-plant traits such as flower size. We find that a substantial portion of the genetic (co)variance among traits can be described as an emergent property of genetic effects on expression modules.
Diet effects on mouse meiotic recombination: a warning for recombination studies
Authors: Belmonte-Tebar Angela , San Martin Perez Estefania , Nam Cha Syonghyun , Soler Valls Ana Josefa , Singh Nadia D , de la Casa-Esperon Elena
Published: November 2021

Meiotic recombination is a critical process for sexually reproducing organisms. This exchange of genetic information between homologous chromosomes during meiosis is important not only because it generates genetic diversity, but also because it is often required for proper chromosome segregation. Consequently, the frequency and distribution of crossovers are tightly controlled to ensure fertility and offspring viability. However, in many systems, it has been shown that environmental factors can alter the frequency of crossover events. Two studies in flies and yeast point to nutritional status affecting the frequency of crossing over. However, this question remains unexplored in mammals. Here, we test how crossover frequency varies in response to diet in Mus musculus males. We use immunohistochemistry to estimate crossover frequency in multiple genotypes under two diet treatments. Our results indicate that while crossover frequency was unaffected by diet in some strains, other strains were sensitive even to small composition changes between two common laboratory chows. Therefore, recombination is both resistant and sensitive to certain dietary changes in a strain-dependent manner and, hence, this response is genetically determined. Our study is the first to report a nutrition effect on genome-wide levels of recombination. Moreover, our work highlights the importance of controlling diet in recombination studies and may point to diet as a potential source of variability among studies, which is relevant for reproducibility.
Establishment of local adaptation in partly self-fertilizing populations
Authors: Trickovic Bogi , Glémin Sylvain
Published: November 2021

Populations often inhabit multiple ecological patches and thus experience divergent selection, which can lead to local adaptation if migration is not strong enough to swamp locally adapted alleles. Conditions for the establishment of a locally advantageous allele have been studied in randomly mating populations. However, many species reproduce, at least partially, through self-fertilization, and how selfing affects local adaptation remains unclear and debated. Using a two-patch branching process formalism, we obtained a closed-form approximation under weak selection for the probability of establishment of a locally advantageous allele (P) for arbitrary selfing rate and dominance level, where selection is allowed to act on viability or fecundity, and migration can occur via seed or pollen dispersal. This solution is compared to diffusion approximation and used to investigate the consequences of a shift in a mating system on P, and the establishment of protected polymorphism. We find that selfing can either increase or decrease P, depending on the patterns of dominance in the two patches, and has conflicting effects on local adaptation. Globally, selfing favors local adaptation when locally advantageous alleles are (partially) recessive, when selection between patches is asymmetrical and when migration occurs through pollen rather than seed dispersal. These results establish a rigorous theoretical background to study heterogeneous selection and local adaptation in partially selfing species.
Interpreting ciliopathy-associated missense variants of uncertain significance (VUS) inCaenorhabditis elegans
Authors: Lange Karen I , Best Sunayna , Tsiropoulou Sofia , Berry Ian , Johnson Colin A , Blacque Oliver E
Published: November 2021

Better methods are required to interpret the pathogenicity of disease-associated variants of uncertain significance (VUS), which cannot be actioned clinically. In this study, we explore the use of an animal model (Caenorhabditis elegans) for in vivo interpretation of missense VUS alleles of TMEM67, a cilia gene associated with ciliopathies. CRISPR/Cas9 gene editing was used to generate homozygous knock-in C. elegans worm strains carrying TMEM67 patient variants engineered into the orthologous gene (mks-3). Quantitative phenotypic assays of sensory cilia structure and function (neuronal dye filling, roaming and chemotaxis assays) measured how the variants impacted mks-3 gene function. Effects of the variants on mks-3 function were further investigated by looking at MKS-3::GFP localization and cilia ultrastructure. The quantitative assays in C. elegans accurately distinguished between known benign (Asp359Glu, Thr360Ala) and known pathogenic (Glu361Ter, Gln376Pro) variants. Analysis of eight missense VUS generated evidence that three are benign (Cys173Arg, Thr176Ile and Gly979Arg) and five are pathogenic (Cys170Tyr, His782Arg, Gly786Glu, His790Arg and Ser961Tyr). Results from worms were validated by a genetic complementation assay in a human TMEM67 knock-out hTERT-RPE1 cell line that tests a TMEM67 signalling function. We conclude that efficient genome editing and quantitative functional assays in C. elegans make it a tractable in vivo animal model for rapid, cost-effective interpretation of ciliopathy-associated missense VUS alleles.
PAR-1 Antagonism to Promote Gut Mucosa Healing in Crohn’s Disease Patients: A New Avenue for CVT120165
Authors: Motta Jean-Paul , Deraison Celine , Le Grand Sylvie , Le Grand Bruno , Vergnolle Nathalie
Published: November 2021

A new paradigm has been added for the treatment of inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis. In addition to resolving symptoms and inflammatory cell activation, the objective of tissue repair and mucosal healing is also now considered a primary goal. In the search of mediators that would be responsible for delayed mucosal healing, protease-activated receptor-1 (PAR-1) has emerged as a most interesting target. Indeed, in Crohn’s disease, the endogenous PAR-1 agonist thrombin is drastically activated. Activation of PAR-1 is known to be associated with epithelial dysfunctions that hamper mucosal homeostasis. This review gathers the scientific evidences of a potential role for PAR-1 in mucosal damage and mucosal dysfunctions associated with chronic intestinal inflammation. The potential clinical benefits of PAR-1 antagonism to promote mucosal repair in CD patients are discussed. Targeted local delivery of a PAR-1 antagonist molecule such as CVT120165, a formulated version of the FDA-approved PAR-1 antagonist vorapaxar, at the mucosa of Crohn’s disease patients could be proposed as a new indication for IBD that could be rapidly tested in clinical trials.
Primary Versus Staged Reconstruction and Risk of Surgical Failure in Patients With Ulcerative Colitis: a Nation-wide Cohort Study
Authors: Westberg Karin , Olén Ola , Söderling Jonas , Bengtsson Jonas , Ludvigsson Jonas F , Everhov Åsa H , Myrelid Pär , Nordenvall Caroline
Published: November 2021

Background

Restorative surgery after colectomy due to ulcerative colitis (UC) may be performed simultaneously with colectomy (primary) or as a staged procedure. Risk factors for failure after restorative surgery are not fully explored. This study aimed to compare the risk of failure after primary and staged reconstruction.

Methods

This is a national register-based cohort study of all patients 15 to 69 years old in Sweden treated with colectomy due to UC and who received an ileorectal anastomosis (IRA) or ileal pouch-anal anastomosis (IPAA) between 1997 and 2017. Failure was defined as a reoperation with new ileostomy after restorative surgery or a remaining defunctioning ileostomy after 2 years. Risk of failure was calculated using the Kaplan-Meier method and Cox regression adjusted for sex, age, calendar period, primary sclerosing cholangitis, and duration of UC.

Results

Of 2172 included patients, 843 (38.8%) underwent primary reconstruction, and 1329 (61.2%) staged reconstruction. Staged reconstruction was associated with a decreased risk of failure compared with primary reconstruction (hazard ratio, 0.73; 95% CI, 0.58–0.91). The 10-year cumulative risk of failure was 15% vs 20% after staged and primary reconstruction, respectively. In all, 1141 patients (52.5%) received an IPAA and 1031 (47.5%) an IRA. In stratified multivariable models, staged reconstruction was more successful than primary reconstruction in both IRA (hazard ratio, 0.75; 95% CI, 0.54–1.04) and IPAA (hazard ratio, 0.73; 95% CI, 0.52–1.01), although risk estimates failed to attain statistical significance.

Conclusions

In UC patients undergoing colectomy, postponing restorative surgery may decrease the risk of failure.
RAID Prediction: Pilot Study of Fecal Microbial Signature With Capacity to Predict Response to Anti-TNF Treatment
Authors: Busquets David , Oliver Lia , Amoedo Joan , Ramió-Pujol Sara , Malagón Marta , Serrano Marta , Bahí Anna , Capdevila Montse , Lluansí Aleix , Torrealba Leyanira , Peries Laia , Chavero Rosa , Gilabert Pau , Sàbat Miriam , Guardiola Jordi , Serra-Pagès Mariona , Garcia-Gil Jesús , Aldeguer Xavier
Published: November 2021

Background and Aims

Crohn’s disease and ulcerative colitis evolve with alternate outbreaks and remissions of variable duration in both cases. Despite the advances, about 10-30% of patients do not respond to the treatment after the induction period. Besides, between 20% to 50% further patients need an optimization of the dose to respond the treatment. Recent studies have pointed gut microbiota can play a role in the anti-TNF treatment response. This study aimed to define a bacterial signature that could be used to predict the response of patients to anti-TNF treatment.

Methods

There were obtained 38 stool samples from 38 IBD patients before starting anti-TNF treatments: Adalimumab, Golimumab or Infliximab. Patients were differentiated in 2 groups: responders and non-responders to biological treatment. From each sample, DNA was purified and used in a qPCR for the quantification of the 8 microbial markers.

Results

In this proof of concept, the predictive ability to identify anti-TNF treatment responders was analyzed. An algorithm consisting in the combination of 4 bacterial markers showed a high capacity to discriminate between responders and non- responders. The algorithm proved high sensitivity and specificity reporting values of 93.33% and 100% respectively, with a positive predictive value of 100% and a negative predictive value of 75% for predicting response to biologic treatment.

Conclusions

A specific bacterial signature could beneficiate patients with inflammatory bowel disease predicting the therapeutic effectiveness of an anti-TNF treatment, leading to a personalized therapy, improving the patients’ quality of life, saving costs and gaining time in patient improvement.
A phase 1b open-label dose-finding study of ustekinumab in young adults with type 1 diabetes
Authors: Marwaha Ashish K , Chow Samuel , Pesenacker Anne M , Cook Laura , Sun Annika , Long S Alice , Yang Jennie H M , Ward-Hartstonge Kirsten A , Williams Evangelia , Domingo-Vila Clara , Halani Khalif , Harris Kristina M , Tree Timothy I M , Levings Megan K , Elliott Thomas , Tan Rusung , Dutz Jan P
Published: November 2021

Objectives

We assessed the safety of ustekinumab (a monoclonal antibody used in psoriasis to target the IL-12 and IL-23 pathways) in a small cohort of recent-onset (<100 days of diagnosis) adults with type 1 diabetes (T1D) by conducting a pilot open-label dose-finding and mechanistic study (NCT02117765) at the University of British Columbia.

Methods

We sequentially enrolled 20 participants into four subcutaneous dosing cohorts: (i) 45 mg loading weeks 0/4/16, (ii) 45 mg maintenance weeks 0/4/16/28/40, (iii) 90 mg loading weeks 0/4/16, and (iv) 90 mg maintenance weeks 0/4/16/28/40. The primary endpoint was safety as assessed by an independent data and safety monitoring board (DSMB) but we also measured mixed meal tolerance test C-peptide, insulin use/kg, and HbA1c. Immunophenotyping was performed to assess immune cell subsets and islet antigen-specific T cell responses.

Results

Although several adverse events were reported, only two (bacterial vaginosis and hallucinations) were thought to be possibly related to drug administration by the study investigators. At 1 year, the 90 mg maintenance dosing cohort had the smallest mean decline in C-peptide area under the curve (AUC) (0.1 pmol/ml). Immunophenotyping showed that ustekinumab reduced the percentage of circulating Th17, Th1, and Th17.1 cells and proinsulin-specific T cells that secreted IFN-γ and IL-17A.

Conclusion

Ustekinumab was deemed safe to progress to efficacy studies by the DSMB at doses used to treat psoriasis in adults with T1D. A 90 mg maintenance dosing schedule reduced proinsulin-specific IFN-γ and IL-17A-producing T cells. Further studies are warranted to determine if ustekinumab can prevent C-peptide AUC decline and induce a clinical response.
Long-Time Estimates for Heat Flows on Asymptotically Locally Euclidean Manifolds
Authors: Kröncke Klaus , Petersen Oliver L
Published: November 2021

We consider the heat equation associated to Schrödinger operators acting on vector bundles on asymptotically locally Euclidean (ALE) manifolds. Novel $L^p - L^q$ decay estimates are established, allowing the Schrödinger operator to have a non-trivial $L^2$-kernel. We also prove new decay estimates for spatial derivatives of arbitrary order, in a general geometric setting. Our main motivation is the application to stability of non-linear geometric equations, primarily Ricci flow, which will be presented in a companion paper. The arguments in this paper use that many geometric Schrödinger operators can be written as the square of Dirac-type operators. By a remarkable result of Wang, this is even true for the Lichnerowicz Laplacian, under the assumption of a parallel spinor. Our analysis is based on a novel combination of the Fredholm theory for Dirac-type operators on ALE manifolds and recent advances in the study of the heat kernel on non-compact manifolds.
Hierarchy in Regime Complexes: Understanding Authority in Antarctic Governance
Authors: Green Jessica F
Published: November 2021

Many scholars argue that regime complexes are nonhierarchical. However, if that is true, then how does authority function? This article argues that the conceptualization of regime complexes as largely devoid of hierarchy is mistaken. Instead, it offers a new definition of regime complexes: emergent patterns of authority among state and non-state actors, which vary in their degree of hierarchy. Hierarchy in regime complexes looks different from political scientists’ traditional conceptualization. It is systemic, emergent, and positional. I present two dimensions of variation in hierarchy: deference and autonomy. These dimensions provide both a conceptual and an empirical strategy for understanding how authority relations are constituted. Conceptually, they allow us to “see” hierarchy in regime complexes. Empirically, they provide transparent, replicable and variable measures, which have eluded much of the work to date. I use topic modeling coupled with network analysis to detect hierarchy in the regime complex for Antarctica. I demonstrate that the inclusion of non-state actors and their governance activities changes our understanding of the Antarctic regime complex. This approach reveals a hierarchical regime complex, where some non-state actors have considerable authority and are governing issues not regulated by formal rules.
Aminoglycoside- and glycopeptide-induced ototoxicity in children: a systematic review
Authors: Diepstraten F A , Hoetink A E , van Grotel M , Huitema A D R , Stokroos R J , van den Heuvel-Eibrink M M , Meijer A J M
Published: November 2021

Background

Ototoxicity has been reported after administration of aminoglycosides and glycopeptides.

Objectives

To identify available evidence for the occurrence and determinants of aminoglycoside- and glycopeptide-related ototoxicity in children.

Materials and methods

Systematic electronic literature searches that combined ototoxicity (hearing loss, tinnitus and/or vertigo) with intravenous aminoglycoside and/or glycopeptide administration in children were performed in PubMed, EMBASE and Cochrane Library databases. Studies with sample sizes of ≥50 children were included. The QUIPS tool and Cochrane criteria were used to assess the quality and risk of bias of included studies.

Results

Twenty-nine aminoglycoside-ototoxicity studies met the selection criteria (including 7 randomized controlled trials). Overall study quality was medium/low. The frequency of hearing loss within these studies ranged from 0%–57%, whereas the frequency of tinnitus and vertigo ranged between 0%–53% and 0%–79%, respectively. Two studies met the criteria on glycopeptide-induced ototoxicity and reported hearing loss frequencies of 54% and 55%. Hearing loss frequencies were higher in gentamicin-treated children compared to those treated with other aminoglycosides. In available studies aminoglycosides had most often been administered concomitantly with platinum agents, diuretics and other co-medication.

Conclusions

In children the reported occurrence of aminoglycoside/glycopeptide ototoxicity highly varies and seems to depend on the diagnosis, aminoglycoside subtype and use of co-administered medication. More research is needed to investigate the prevalence and determinants of aminoglycoside/glycopeptide ototoxicity. Our results indicate that age-dependent audiological examination may be considered for children frequently treated with aminoglycosides/glycopeptides especially if combined with other ototoxic medication.
Examining perspectives on the adoption and use of computer-based patient-reported outcomes among clinicians and health professionals: a Q methodology study
Authors: Burton Shirley V , Valenta Annette L , Starren Justin , Abraham Joanna , Nelson Therese , Kochendorfer Karl , Hughes Ashley , Harris Bhrandon , Boyd Andrew
Published: November 2021

Objective

To determine factors that influence the adoption and use of patient-reported outcomes (PROs) in the electronic health record (EHR) among users.

Materials and Methods

Q methodology, supported by focus groups, semistructured interviews, and a review of the literature was used for data collection about opinions on PROs in the EHR. An iterative thematic analysis resulted in 49 statements that study participants sorted, from most unimportant to most important, under the following condition of instruction: “What issues are most important or most unimportant to you when you think about the adoption and use of patient-reported outcomes within the electronic health record in routine clinical care?” Using purposive sampling, 50 participants were recruited to rank and sort the 49 statements online, using HTMLQ software. Principal component analysis and Varimax rotation were used for data analysis using the PQMethod software.

Results

Participants were mostly physicians (24%) or physician/researchers (20%). Eight factors were identified. Factors included the ability of PROs in the EHR to enable: efficient and reliable use; care process improvement and accountability; effective and better symptom assessment; patient involvement for care quality; actionable and practical clinical decisions; graphical review and interpretation of results; use for holistic care planning to reflect patients’ needs; and seamless use for all users.

Discussion

The success of PROs in the EHR in clinical settings is not dependent on a “one size fits all” strategy, demonstrated by the diversity of viewpoints identified in this study. A sociotechnical approach for implementing PROs in the EHR may help improve its success and sustainability.

Conclusions

PROs in the EHR are most important to users when the technology is used to improve patient outcomes. Future research must focus on the impact of embedding this EHR functionality on care processes.
The role of electronic health record developers in hospital patient sharing
Authors: Pylypchuk Yuriy , Meyerhoefer Chad D , Encinosa William , Searcy Talisha
Published: November 2021

Objective

To determine whether hospital adoption of a new electronic health record (EHR) developer increases patient sharing with hospitals using the same developer.

Materials and Methods

We extracted data on patients shared with other hospitals for 3076 US nonfederal acute care hospitals from the 2011 to 2016 Centers for Medicare & Medicaid Services Physician Shared Patient Patterns database. We calculated the ratio of patients shared with hospitals outside of the focal hospital’s network that use the same EHR developer as the focal hospital, and estimated difference-in-differences models to compare same-developer patient sharing among hospitals that switched to a new developer with those that did not switch developer.

Results

Switching to a new EHR developer increased the ratio of patients shared with other hospitals having the same EHR developer by 4.1–19.3%, depending on model specification. The magnitude of this effect varied by EHR developer and was increasing in developer market share.

Discussion

Consolidation in the EHR industry has led to higher patient sharing among hospitals with the same EHR developer. Contributing factors could include the growth of developer-based health information exchanges, customizable referral management systems, and provider preferences for easy and reliable data exchange. However, hospital transfers that are significantly influenced by EHR developer could lead to poor patient-provider matches.

Conclusion

Hospitals’ choice of EHR developer impacts the flow of patients across hospitals, which could have both desirable and undesirable effects on patient care. Future research should investigate whether health outcomes decline with greater same-developer patient sharing.
An analysis of the structure and content of dashboards used to monitor patient safety in the inpatient setting
Authors: Kuznetsova Masha , Frits Michelle L , Dulgarian Sevan , Iannaccone Christine , Mort Elizabeth , Bates David W , Salmasian Hojjat
Published: November 2021

The objective of this study is to review and compare patient safety dashboards used by hospitals and identify similarities and differences in their design, format, and scope. We reviewed design features of electronic copies of patient safety dashboards from a representative sample of 10 hospitals. The results show great heterogeneity in the format, presentation, and scope of patient safety dashboards. Hospitals varied in their use of performance indicators (targets, trends, and benchmarks), style of color coding, and timeframe for the displayed metrics. The average number of metrics per dashboard display was 28, with a wide range from 7 to 84. Given the large variation in dashboard design, there is a need for future work to assess which approaches are associated with the best outcomes, and how specific elements contribute to usability, to help customize dashboards to meet the needs of different clinical, and operational stakeholders.
Effect of fiber source and crude protein level on nursery pig performance and fecal microbial communities
Authors: Batson Kelsey L , Neujahr Alison C , Burkey Thomas , Fernando Samodha C , Tokach Mike D , Woodworth Jason C , Goodband Robert D , DeRouchey Joel M , Gebhardt Jordan T , Calderón Hilda I
Published: November 2021

Reduction in dietary crude protein and addition of fiber could mitigate the incidence and severity of post-weaning diarrhea, a common gastrointestinal condition in newly weaned pigs. Therefore, 360 weanling pigs, initially 5.0 ± 0.10 kg, were used to evaluate the effects of crude protein (CP) level and fiber source on growth performance and fecal microbial communities. At weaning, pigs were randomly assigned to pens and allotted to 1 of 8 dietary treatments in a 2 × 4 factorial with main effects of CP (21 or 18%) and fiber source (none, coarse wheat bran, oat hulls, or cellulose). There were 5 pigs per pen and 9 pens per treatment. Experimental diets were formulated in two dietary phases from d 0 to 10 and 10 to 24, with a common post-treatment diet fed from 24 to 45. The 21% CP diets contained 1.40% standardized ileal digestible (SID) Lys in phase 1 and 1.35% SID Lys in phase 2. By using a maximum SID Lys:digestible CP ratio of 6.35%, the 18% CP diets contained 1.25% SID Lys in both phases. Diets containing a fiber source were formulated to the level of insoluble fiber provided by 4% coarse wheat bran, resulting in the addition of 1.85% oat hulls and 1.55% cellulose. No fiber source × CP level interactions (P > 0.05) were observed. Decreasing CP (and subsequently SID lysine) decreased (P = 0.05) ADG and G:F during the experimental period. From d 0 to 45, ADG decreased (P = 0.05) for pigs fed 18% CP diets compared to pigs fed 21% CP. No effect of fiber source was observed for growth performance. Fecal DM on d 17 increased (P < 0.001) for pigs fed 18% CP diets compared to pigs fed 21% CP diets. Pigs fed diets with added cellulose had increased (P < 0.05) fecal dry matter during the experimental period compared to pigs fed no fiber source or wheat bran. Bacterial community structure was investigated by sequencing the V4 region of the 16S rRNA gene. Analysis indicated a significant difference between CP content at d 24 (P = 0.023) using a Weighted UniFrac distance matrix. Further investigation identified five differential Amplicon Sequence Variants associated with CP content at d 24. In conclusion, reducing crude protein (and subsequently SID Lys) decreased growth performance but increased fecal dry matter content. The source of dietary fiber in nursery diets had no impact on growth performance; but pigs fed added cellulose had increased fecal DM compared with other treatments. Microbial analysis identified differential taxa associated with CP content.
Reverse Chemical Ecology Suggests Putative Primate Pheromones
Authors: Zaremska Valeriia , Fischer Isabella Maria , Renzone Giovanni , Arena Simona , Scaloni Andrea , Knoll Wolfgang , Pelosi Paolo
Published: November 2021

Pheromonal communication is widespread among living organisms, but in apes and particularly in humans there is currently no strong evidence for such phenomenon. Among primates, lemurs use pheromones to communicate within members of the same species, whereas in some monkeys such capabilities seem to be lost. Chemical communication in humans appears to be impaired by the lack or malfunctioning of biochemical tools and anatomical structures mediating detection of pheromones. Here, we report on a pheromone-carrier protein (SAL) adopting a “reverse chemical ecology” approach to get insights on the structures of potential pheromones in a representative species of lemurs (Microcebus murinus) known to use pheromones, Old-World monkeys (Cercocebus atys) for which chemical communication has been observed, and humans (Homo sapiens), where pheromones and chemical communication are still questioned. We have expressed the SAL orthologous proteins of these primate species, after reconstructing the gene encoding the human SAL, which is disrupted due to a single base mutation preventing its translation into RNA. Ligand-binding experiments with the recombinant SALs revealed macrocyclic ketones and lactones as the best ligands for all three proteins, suggesting cyclopentadecanone, pentadecanolide, and closely related compounds as the best candidates for potential pheromones. Such hypothesis agrees with the presence of a chemical very similar to hexadecanolide in the gland secretions of Mandrillus sphinx, a species closely related to C. atys. Our results indicate that the function of this carrier protein has not changed much during evolution from lemurs to humans, although its physiological role has been certainly impaired in humans.
Results 25 years after hemiarthroplasty for chondrolysis of the shoulder: A report of two cases
Authors: Tamai Kazuya , Watanabe Hisato , Kodama Rie , Tarui Takashi , Tanaka Sakae
Published: November 2021

Two patients (aged 34 and 52 years) underwent an open repair of concealed rotator cuff tear with the aid of colour arthrography using gentian violet. Postoperatively, they developed chondrolysis of the shoulder, which was treated with hemiarthroplasty. Twenty-five years after hemiarthroplasty, both patients showed good shoulder function without significant glenoid erosion on radiographs. Satisfactory long-term results are most probably due to maintenance of humeral head centring and glenohumeral conformity. These are the longest follow-up cases of arthroplasty for chondrolysis of the shoulder in the literature. We conclude that hemiarthroplasty can be a reasonable option for patients with this unfortunate disorder.
EPCO-05. GENOME-WIDE ANALYSIS OF TEAD1 OCCUPANCY IN BIOLOGICALLY DISTINCT GLIOBLASTOMA SAMPLES
Authors: Joshi Tanvi , Nudelman German , Zaslavsky Elena , Tsankova Nadejda
Published: November 2021

The diffusely infiltrative nature of glioblastoma (GBM) cells is a major contributor to the disease’s aggressive behavior, including its rapid progression and therapeutic resistance. Moreover, current treatment options do not target the invasive nature of GBM. Recent chromatin accessibility studies prioritized enrichment of the TEAD1 transcription factor motif in glioblastoma stem cell biology and subsequent knockout and overexpression studies confirmed a critical role for TEAD1 in GBM migration, in vitro and in vivo. However, the downstream mechanisms through which TEAD1 regulates GBM cell migration remain poorly understood. In this study, we performed chromatin immunoprecipitation (ChIP-seq) using TEAD1-specific antibody and IgG as non-specific binding control, to characterize TEAD1 occupancy across GBM samples with unique genomic alterations. ChIP-seq peaks were called using MACS2, filtered for duplicates and blacklisted regions, and normalized per sample to their respective genomic input. Initial functional enrichment analyses were performed on three GBM samples with the highest number of TEAD1 occupancy peaks using CistromeGO, which ranked genes based on their TEAD1-specific regulatory potential (RP) score, as a function of peak number and distance from the transcription start site. Analyses of the top 1000 genes with highest TEAD1 RP scores identified 132 common targets across all samples, including known TEAD target genes ETV1 and Cyr61, which related to angiogenesis, cadherin and integrin signaling, cell adhesion, and chromatin regulation gene ontology terms, among others. Interestingly, KEGG pathway analysis also revealed Hippo pathway enrichment across all GBM samples, suggesting a possible TEAD1 regulatory feedback loop in GBM. Analysis of TEAD1 ChIP-seq peaks in non-GBM negative control tissue did not show functional enrichment for any of the terms seen in the GBM samples. Ongoing analyses are focused on characterizing TEAD1 occupancy at active cis-regulatory regions using parallel H3K27ac ChIP-seq data, in order to prioritize the most salient TEAD1-regulatory targets in GBM.