bluuebunny/crossref_metadata_2025 huggingface dataset:
Kincore: a web resource for structural classification of protein kinases and their inhibitors
Authors: Modi Vivek , Dunbrack Roland L
Published: September 2021

The active form of kinases is shared across different family members, as are several commonly observed inactive forms. We previously performed a clustering of the conformation of the activation loop of all protein kinase structures in the Protein Data Bank (PDB) into eight classes based on the dihedral angles that place the Phe side chain of the DFG motif at the N-terminus of the activation loop. Our clusters are strongly associated with the placement of the activation loop, the C-helix, and other structural elements of kinases. We present Kincore, a web resource providing access to our conformational assignments for kinase structures in the PDB. While other available databases provide conformational states or drug type but not both, KinCore includes the conformational state and the inhibitor type (Type 1, 1.5, 2, 3, allosteric) for each kinase chain. The user can query and browse the database using these attributes or determine the conformational labels of a kinase structure using the web server or a standalone program. The database and labeled structure files can be downloaded from the server. Kincore will help in understanding the conformational dynamics of these proteins and guide development of inhibitors targeting specific states. Kincore is available at http://dunbrack.fccc.edu/kincore.
Prioritization of regulatory variants with tissue-specific function in the non-coding regions of human genome
Authors: Dong Shengcheng , Boyle Alan P
Published: September 2021

Understanding the functional consequences of genetic variation in the non-coding regions of the human genome remains a challenge. We introduce h ere a computational tool, TURF, to prioritize regulatory variants with tissue-specific function by leveraging evidence from functional genomics experiments, including over 3000 functional genomics datasets from the ENCODE project provided in the RegulomeDB database. TURF is able to generate prediction scores at both organism and tissue/organ-specific levels for any non-coding variant on the genome. We present that TURF has an overall top performance in prediction by using validated variants from MPRA experiments. We also demonstrate how TURF can pick out the regulatory variants with tissue-specific function over a candidate list from associate studies. Furthermore, we found that various GWAS traits showed the enrichment of regulatory variants predicted by TURF scores in the trait-relevant organs, which indicates that these variants can be a valuable source for future studies.
Determination of the two-component systems regulatory network reveals core and accessory regulations across Pseudomonas aeruginosa lineages
Authors: Trouillon Julian , Imbert Lionel , Villard Anne-Marie , Vernet Thierry , Attrée Ina , Elsen Sylvie
Published: September 2021

Pseudomonas aeruginosa possesses one of the most complex bacterial regulatory networks, which largely contributes to its success as a pathogen. However, most of its transcription factors (TFs) are still uncharacterized and the potential intra-species variability in regulatory networks has been mostly ignored so far. Here, we used DAP-seq to map the genome-wide binding sites of all 55 DNA-binding two-component systems (TCSs) response regulators (RRs) across the three major P. aeruginosa lineages. The resulting networks encompass about 40% of all genes in each strain and contain numerous new regulatory interactions across most major physiological processes. Strikingly, about half of the detected targets are specific to only one or two strains, revealing a previously unknown large functional diversity of TFs within a single species. Three main mechanisms were found to drive this diversity, including differences in accessory genome content, as exemplified by the strain-specific plasmid in IHMA87 outlier strain which harbors numerous binding sites of conserved chromosomally-encoded RRs. Additionally, most RRs display potential auto-regulation or RR-RR cross-regulation, bringing to light the vast complexity of this network. Overall, we provide the first complete delineation of the TCSs regulatory network in P. aeruginosa that will represent an important resource for future studies on this pathogen.
Recurrent mutations promote widespread structural and functional divergence of MULE-derived genes in plants
Authors: Young Chae Geun , Hong Woo-Jong , Jeong Jang Min , Jung Ki-Hong , Kim Seungill
Published: September 2021

Transposable element (TE)-derived genes are increasingly recognized as major sources conferring essential traits in agriculturally important crops but underlying evolutionary mechanisms remain obscure. We updated previous annotations and constructed 18,744 FAR-RED IMPAIRED RESPONSE1 (FAR1) genes, a transcription factor family derived from Mutator-like elements (MULEs), from 80 plant species, including 15,546 genes omitted in previous annotations. In-depth sequence comparison of the updated gene repertoire revealed that FAR1 genes underwent continuous structural divergence via frameshift and nonsense mutations that caused premature translation termination or specific domain truncations. CRISPR/Cas9-based genome editing and transcriptome analysis determined a novel gene involved in fertility-regulating transcription of rice pollen, denoting the functional capacity of our re-annotated gene models especially in monocots which had the highest copy numbers. Genomic evidence showed that the functional gene adapted by obtaining a shortened form through a frameshift mutation caused by a tandem duplication of a 79-bp sequence resulting in premature translation termination. Our findings provide improved resources for comprehensive studies of FAR1 genes with beneficial agricultural traits and unveil novel evolutionary mechanisms generating structural divergence and subsequent adaptation of TE-derived genes in plants.
A balancing act in transcription regulation by response regulators: titration of transcription factor activity by decoy DNA binding sites
Authors: Gao Rong , Helfant Libby J , Wu Ti , Li Zeyue , Brokaw Samantha E , Stock Ann M
Published: September 2021

Studies of transcription regulation are often focused on binding of transcription factors (TFs) to a small number of promoters of interest. It is often assumed that TFs are in great excess to their binding sites (TFBSs) and competition for TFs between DNA sites is seldom considered. With increasing evidence that TFBSs are exceedingly abundant for many TFs and significant variations in TF and TFBS numbers occur during growth, the interplay between a TF and all TFBSs should not be ignored. Here, we use additional decoy DNA sites to quantitatively analyze how the relative abundance of a TF to its TFBSs impacts the steady-state level and onset time of gene expression for the auto-activated Escherichia coli PhoB response regulator. We show that increasing numbers of decoy sites progressively delayed transcription activation and lowered promoter activities. Perturbation of transcription regulation by additional TFBSs did not require extreme numbers of decoys, suggesting that PhoB is approximately at capacity for its DNA sites. Addition of decoys also converted a graded response to a bi-modal response. We developed a binding competition model that captures the major features of experimental observations, providing a quantitative framework to assess how variations in TFs and TFBSs influence transcriptional responses.
ASMdb: a comprehensive database for allele-specific DNA methylation in diverse organisms
Authors: Zhou Qiangwei , Guan Pengpeng , Zhu Zhixian , Cheng Sheng , Zhou Cong , Wang Huanhuan , Xu Qian , Sung Wing-kin , Li Guoliang
Published: September 2021

DNA methylation is known to be the most stable epigenetic modification and has been extensively studied in relation to cell differentiation, development, X chromosome inactivation and disease. Allele-specific DNA methylation (ASM) is a well-established mechanism for genomic imprinting and regulates imprinted gene expression. Previous studies have confirmed that certain special regions with ASM are susceptible and closely related to human carcinogenesis and plant development. In addition, recent studies have proven ASM to be an effective tumour marker. However, research on the functions of ASM in diseases and development is still extremely scarce. Here, we collected 4400 BS-Seq datasets and 1598 corresponding RNA-Seq datasets from 47 species, including human and mouse, to establish a comprehensive ASM database. We obtained the data on DNA methylation level, ASM and allele-specific expressed genes (ASEGs) and further analysed the ASM/ASEG distribution patterns of these species. In-depth ASM distribution analysis and differential methylation analysis conducted in nine cancer types showed results consistent with the reported changes in ASM in key tumour genes and revealed several potential ASM tumour-related genes. Finally, integrating these results, we constructed the first well-resourced and comprehensive ASM database for 47 species (ASMdb, www.dna-asmdb.com).
Membranoproliferative glomerulonephritis: no longer the same disease and may need very different treatment
Authors: Noris Marina , Daina Erica , Remuzzi Giuseppe
Published: September 2021

Membranoproliferative glomerulonephritis (MPGN) is a pattern of glomerular injury that may be primary or secondary to infections, autoimmune diseases and haematological disorders. Primary C3G and IC-MPGN are rare and the prognosis is unfavourable.

Based on immunofluorescence findings, MPGN has been classified into complement-mediated C3 glomerulopathy (C3G) and immune complex-mediated MPGN (IC-MPGN). However, this classification leaves a number of issues unresolved. The finding of genetic and acquired complement abnormalities in both C3G and IC-MPGN indicates that they represent a heterogeneous spectrum rather than distinct diseases. An unsupervised hierarchical clustering in a cohort of patients with primary C3G and IC-MPGN identified four distinct pathogenetic patterns, characterized by specific histologic and clinical features, and genetic and acquired complement abnormalities. These results provide the groundwork for a more accurate diagnosis and the development of targeted therapies.

The drugs that are currently used, such as corticosteroids and immunosuppressants, are frequently ineffective in primary C3G and IC-MPGN. Eculizumab, an anti-C5 monoclonal antibody, has been used occasionally in single cases or small series. However, only a few patients have achieved remission. This heterogeneous response could be related to the extent of terminal complement activation, which may vary substantially from patient to patient. Several drugs that target the complement system at different levels are under investigation for C3G and IC-MPGN. However, clinical trials to test new therapeutics will be challenging and heavily influenced by the heterogeneity of these diseases. This creates the need to characterize each patient to match the specific complement abnormality with the type of intervention.
Clinical and genetic characterization of a cohort of proteinuric patients with biallelic CUBN variants
Authors: Domingo-Gallego Andrea , Pybus Marc , Madariaga Leire , Piñero-Fernández Juan Alberto , González-Pastor Sara , López-González Mercedes , Simarro-Rueda Esther , Quintanilla-Mata María Luisa , Matoses-Ruipérez María Luisa , Ejarque-Vila Laia , Cornec-Le Gall Emilie , Guirado Lluís , Torra Roser , Ariceta Gema , Ars Elisabet
Published: September 2021

Background

Proteinuria is a well-known risk factor for progressive kidney impairment. Recently, C-terminal cubilin (CUBN) variants have been associated with isolated proteinuria without progression of kidney disease.

Methods

Genetic testing of 347 families with proteinuria of suspected monogenic cause was performed by next-generation sequencing of a custom-designed kidney disease gene panel. Families with CUBN biallelic proteinuria-causing variants were studied at the clinical, genetic, laboratory and pathologic levels.

Results

Twelve families (15 patients) bearing homozygous or compound heterozygous proteinuria-causing variants in the C-terminal CUBN gene were identified, representing 3.5% of the total cohort. We identified 14 different sequence variants, five of which were novel. The median age at diagnosis of proteinuria was 4 years (range 9 months to 44 years), and in most cases proteinuria was detected incidentally. Thirteen patients had moderate to severe proteinuria at diagnosis without nephrotic syndrome. These patients showed lack of response to angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) treatment, normal kidney biopsy and preservation of normal kidney function over time. The two remaining patients presented a more severe phenotype, likely caused by associated comorbidities.

Conclusions

Identification of C-terminal pathogenic CUBN variants is diagnostic of an entity characterized by glomerular proteinuria, normal kidney histology and lack of response to ACEi/ARB treatment. This study adds evidence and increases awareness about albuminuria caused by C-terminal variants in the CUBN gene, which is a benign condition usually diagnosed in childhood with preserved renal function until adulthood.
Detecting subtle yet fast skeletal muscle contractions with ultrasoft and durable graphene-based cellular materials
Authors: He Zijun , Qi Zheng , Liu Huichao , Wang Kangyan , Roberts Leslie , Liu Jefferson Z , Liu Yilun , Wang Stephen J , Cook Mark J , Simon George P , Qiu Ling , Li Dan
Published: September 2021

Human bodily movements are primarily controlled by the contractions of skeletal muscles. Unlike joint or skeletal movements that are generally performed in the large displacement range, the contractions of the skeletal muscles that underpin these movements are subtle in intensity yet high in frequency. This subtlety of movement makes it a formidable challenge to develop wearable and durable soft materials to electrically monitor such motions with high fidelity for the purpose of, for example, muscle/neuromuscular disease diagnosis. Here we report that an intrinsically fragile ultralow-density graphene-based cellular monolith sandwiched between silicone rubbers can exhibit a highly effective stress and strain transfer mechanism at its interface with the rubber, with a remarkable improvement in stretchability (>100%). In particular, this hybrid also exhibits a highly sensitive, broadband-frequency electrical response (up to 180 Hz) for a wide range of strains. By correlating the mechanical signal of muscle movements obtained from this hybrid material with electromyography, we demonstrate that the strain sensor based on this hybrid material may provide a new, soft and wearable mechanomyography approach for real-time monitoring of complex neuromuscular–skeletal interactions in a broad range of healthcare and human–machine interface applications. This work also provides a new architecture-enabled functional soft material platform for wearable electronics.
Trends in Tobacco Production and Prices in Malawi
Authors: Wineman Ayala , Chilora Lemekezani , Jayne Thomas S
Published: September 2021

Introduction

Diversification away from tobacco production has been identified as a priority for Malawi, historically one of the world’s most tobacco-reliant countries.

Methods

This paper refers to a nationally representative data set to characterize broad trends in production since 2000 to understand whether Malawi is shifting away from tobacco and how production has changed over time.

Results

From 2004 to 2019, the share of Malawian crop farmers producing tobacco fell from 16% to 5%, and tobacco’s share of the total value of crop production also declined sharply. Tobacco farms are generally growing larger (in size and scale of production) over time. However, land productivity remains low, with net returns of 93 000 MWK (128 USD) per hectare at the median. Farm-gate prices for tobacco have declined relative to the prices of maize or fertilizer, rendering tobacco a less lucrative avenue to generate the cash income needed to purchase these key items. In addition, the share of the export price received by farmers has also declined over time, with the median farm-gate price representing 32% of the export price in 2004 and 18% in 2019.

Conclusions

In some respects, a transition away from tobacco has already occurred. Additional research is needed to understand why the farm-gate share of tobacco export prices has declined over this period and how the livelihoods of smallholder farm-households that exited tobacco production have been affected.

Implications

To the extent that tobacco prices appear to be declining, there is a need to rigorously assess whether farmers have suitable crop alternatives (with established markets) and other livelihood options. Likely, investments are yet needed to foster strong alternatives to tobacco; such investments include research and development in on-farm technologies to raise the productivity of non-tobacco crops, as well as improvements in non-tobacco value chains to reduce transportation costs and promote private investment.
Burden of Silicosis among stone crushing workers in India
Authors: Govindagoudar M B , Singh P K , Chaudhry D , Chaudhary R , Sachdeva A , Dhankhar S , Tyagi D
Published: September 2021

Background

In North India, the mining industry is disorganized and profit-driven. It predisposes its workers towards the development of silicosis. Haryana, a major North Indian state, has developed a compensation–rehabilitation policy for mining workers.

Aims

This study is the review of the policy’s functioning and limitation from the first 4 years of implementation.

Methods

The labour department does surveillance of workers in the mining industry. All suspected cases of silicosis are evaluated by a multidisciplinary team. Based on the final diagnosis, the compensation is decided.

Results

Nearly 5000 workers were screened, and 729 appeared before the medical board. Of these 729, 465 were having silicosis, and their data are presented here (data of 7 patients were missing). All workers were males. The mean age was 44.54 ± 9.6 years, and the mean exposure (work experience) was 17.25 ± 6.7 years. Most of the workers were between the age of 40 and 50 years and had exposure for 10–20 years. Chest radiography examination showed that progressive massive fibrosis (large size type C opacities) was the most common type of presentation (23%). Smaller opacities (p, q, r and s, t, u) were combined for further analysis, given their similar prognostic significance. It was found that age and experience both had a linear and significant correlation with the severity of lung involvement.

Conclusions

Nearly a quarter of subjects were suffering from the worst type of lung involvement at screening itself. The policy has laid a foundation for the welfare of workers, but there is still a long way to go.
Impact of a Multiplex Polymerase Chain Reaction Panel on Duration of Empiric Antibiotic Therapy in Suspected Bacterial Meningitis
Authors: Choi Justin J , Westblade Lars F , Gottesdiener Lee S , Liang Kyle , Li Han A , Wehmeyer Graham T , Glesby Marshall J , Simon Matthew S
Published: September 2021

Background

Multiplex polymerase chain reaction (PCR) panels allow for rapid detection or exclusion of pathogens causing meningitis and encephalitis (ME). The clinical impact of rapid multiplex PCR ME panel results on the duration of empiric antibiotic therapy is not well characterized.

Methods

We performed a retrospective prepost study at our institution that evaluated the clinical impact of a multiplex PCR ME panel among adults with suspected bacterial meningitis who received empiric antibiotic therapy and underwent lumbar puncture in the emergency department. The primary outcome was the duration of empiric antibiotic therapy.

Results

The positive pathogen detection rates were similar between pre- and post-multiplex PCR ME panel periods (17.5%, 24 of 137 vs 20.3%, 14 of 69, respectively). The median duration of empiric antibiotic therapy was significantly reduced in the post-multiplex PCR ME panel period compared with the pre-multiplex PCR ME panel period (34.7 vs 12.3 hours, P = .01). At any point in time, 46% more patients in the post-multiplex PCR ME panel period had empiric antibiotic therapy discontinued or de-escalated compared with the pre-multiplex PCR ME panel period (sex- and immunosuppressant use-adjusted hazard ratio 1.46, P = .01). The median hospital length of stay was shorter in the post-multiplex PCR ME panel period (3 vs 4 days, P = .03).

Conclusions

The implementation of the multiplex PCR ME panel for bacterial meningitis reduced the duration of empiric antibiotic therapy and possibly hospital length of stay compared with traditional microbiological testing methods.
Against the Void: Constituency Work and Connection Building Evidence from Australia
Authors: Petter Pandanus H
Published: September 2021

Peter Mair argued that political parties and society are withdrawing from each other, thus creating a ‘void’ in the heart of representation in many established democracies. However, Members of Parliament (MPs) are increasing the time and resources devoted to constituency work. This article explores how MPs, as parties’ representatives, engage with constituents, and whether this work takes the disconnected form expected in a political void. Interviews with 20 Australian state legislators show MPs building policy, service, symbolic and partisan connections with citizens. Though parties no longer definitively structure representation, these findings highlight the importance of understanding party–society relationships in the constituency.
Of Maiming and Privilege: Rethinking War Disability through the Case of Francoist Spain, 1936–1989
Authors: Wright Stephanie
Published: September 2021

This article attempts to reconfigure current historiographical debates on war disability, which have hitherto tended to rely on ‘masculinity’ as an analytical framework. Instead, the case of the Francoist war disabled of the Spanish Civil War underscores the need to consider war disability in relation to broader social hierarchies, and the socio-political topographies in which these operate. In doing so, it is possible to understand how the Francoist war disabled occupied a relatively privileged space in twentieth-century Spain, despite and even because of the impairments they sustained in the Civil War. At the same time, Francoist war disability benefits left much to be desired, and clear differences emerged between the experiences of ‘military’ and ‘civilian’ veterans. In this sense, the Francoist war disabled were both favoured and under-served by the regime’s war disability policies. This research has broader relevance to scholars working on contexts beyond modern Spain, as it disrupts the traditional association of physical impairment with marginality, while highlighting the fluidity of perceptions and experiences of war disability according to socio-political context.
The emerging role of biomolecular condensates in plant immunity
Authors: Wang Wei , Gu Yangnan
Published: September 2021

Biomolecular condensates are dynamic nonmembranous structures that seclude and concentrate molecules involved in related biochemical and molecular processes. Recent studies have revealed that a surprisingly large number of fundamentally important cellular processes are driven and regulated by this potentially ancient biophysical principle. Here, we summarize critical findings and new insights from condensate studies that are related to plant immunity. We discuss the role of stress granules and newly identified biomolecular condensates in coordinating plant immune responses and plant–microbe interactions.
Holistic insights from pollen omics: co-opting stress-responsive genes and ER-mediated proteostasis for male fertility
Authors: Sze Heven , Palanivelu Ravishankar , Harper Jeffrey F , Johnson Mark A
Published: September 2021

Sexual reproduction in flowering plants takes place without an aqueous environment. Sperm are carried by pollen through air to reach the female gametophyte, though the molecular basis underlying the protective strategy of the male gametophyte is poorly understood. Here we compared the published transcriptomes of Arabidopsis thaliana pollen, and of heat-responsive genes, and uncovered insights into how mature pollen (MP) tolerates desiccation, while developing and germinating pollen are vulnerable to heat stress. Germinating pollen expresses molecular chaperones or “heat shock proteins” in the absence of heat stress. Furthermore, pollen tubes that grew through pistils at basal temperature showed induction of the endoplasmic reticulum (ER) stress response, which is a characteristic of stressed vegetative tissues. Recent studies show MP contains mRNA–protein (mRNP) aggregates that resemble “stress” granules triggered by heat or other stresses to protect cells. Based on these observations, we postulate that mRNP particles are formed in maturing pollen in response to developmentally programmed dehydration. Dry pollen can withstand harsh conditions as it is dispersed in air. We propose that, when pollen lands on a compatible pistil and hydrates, mRNAs stored in particles are released, aided by molecular chaperones, to become translationally active. Pollen responds to osmotic, mechanical, oxidative, and peptide cues that promote ER-mediated proteostasis and membrane trafficking for tube growth and sperm discharge. Unlike vegetative tissues, pollen depends on stress-protection strategies for its normal development and function. Thus, heat stress during reproduction likely triggers changes that interfere with the normal pollen responses, thereby compromising male fertility. This holistic perspective provides a framework to understand the basis of heat-tolerant strains in the reproduction of crops.
Deep brain stimulation for psychiatric disorders: role of imaging in identifying/confirming DBS targets, predicting, and optimizing outcome and unravelling mechanisms of action
Authors: Georgiev Dejan , Akram Harith , Jahanshahi Marjan
Published: September 2021

Following the established application of deep brain stimulation (DBS) in the treatment of movement disorders, new non-neurological indications have emerged, such as for obsessive–compulsive disorders, major depressive disorder, dementia, Gilles de la Tourette Syndrome, anorexia nervosa, and addictions. As DBS is a network modulation surgical treatment, the development of DBS for both neurological and psychiatric disorders has been partly driven by advances in neuroimaging, which has helped explain the brain networks implicated. Advances in magnetic resonance imaging connectivity and electrophysiology have led to the development of the concept of modulating widely distributed, complex brain networks. Moreover, the increasing number of targets for treating psychiatric disorders have indicated that there may be a convergence of the effect of stimulating different targets for the same disorder, and the effect of stimulating the same target for different disorders. The aim of this paper is to review the imaging studies of DBS for psychiatric disorders. Imaging, and particularly connectivity analysis, offers exceptional opportunities to better understand and even predict the clinical outcomes of DBS, especially where there is a lack of objective biomarkers that are essential to properly guide DBS pre- and post-operatively. In future, imaging might also prove useful to individualize DBS treatment. Finally, one of the most important aspects of imaging in DBS is that it allows us to better understand the brain through observing the changes of the functional connectome under neuromodulation, which may in turn help explain the mechanisms of action of DBS that remain elusive.
Floquet engineering of electric polarization with two-frequency drive
Authors: Ikeda Yuya , Kitamura Sota , Morimoto Takahiro
Published: September 2021

Electric polarization is a geometric phenomenon in solids and has a close relationship to the symmetry of the system. Here we propose a mechanism to dynamically induce and manipulate electric polarization by using an external light field. Specifically, we show that application of bicircular lights controls the rotational symmetry of the system and can generate electric polarization. To this end, we use Floquet theory to study a system subjected to a two-frequency drive. We derive an effective Hamiltonian with high-frequency expansions, for which the electric polarization is computed with the Berry phase formula. We demonstrate the dynamical control of polarization for a one-dimensional Su–Shrieffer–Heeger chain, a square lattice model, and a honeycomb lattice model.
The Impact of Total Joint Arthroplasty on Long-Term Physical Activity: A Secondary Analysis of the Health and Retirement Study
Authors: LeDoux Cherie V , Lindrooth Richard C , Stevens-Lapsley Jennifer E
Published: September 2021

Objective

Physical inactivity is the fourth-leading cause of global mortality and is prevalent among people with lower extremity osteoarthritis. Lower extremity osteoarthritis is the most common arthritis type afflicting older adults, and total joint arthroplasty (TJA) performed to address the condition is Medicare’s largest annual expense. Despite TJA intervention to address the disabling effects of osteoarthritis, physical activity (PA) level remains stable 6 months after TJA; however, the effect of TJA on long-term PA $(\ge$2 y) in a representative sample of older adults is unknown. The purpose of this study was to test the hypothesis that PA would remain stable in the long term.

Methods

In this longitudinal observational study, a probability-weighted difference-in-differences analysis was conducted to observe the predictive margins of nontraumatic hip or knee TJA on levels of vigorous and moderate PA after 2 years. A combined Health and Retirement Study data set of community-dwelling adults who were >55 years old, had symptomatic osteoarthritis, and were in need of TJA between 2008 and 2018 (N = 4652) was used.

Results

TJA was not associated with vigorous PA ($\delta$ = 2.37; SE = 5.23) or moderate PA ($\delta$ = −2.84; SE = 7.76) after 2 years.

Conclusion

TJA was not associated with increased long-term PA in older adults with osteoarthritis.

Impact

Physical therapists should not assume that there will be a natural increase in PA after functional recovery from TJA procedures. Older adults with lower extremity osteoarthritis may benefit from PA screening and promotion practices in physical therapy services.

Lay Summary

Receiving a total joint replacement does not lead to increased physical activity levels 2 years after surgery.
The association of hemoglobin drop with in-hospital outcomes in COVID-19 patients
Authors: Kuno T , Miyamoto Y , Iwagami M , Ishimaru M , So M , Takahashi M , Egorova N N
Published: September 2021

Background

Bleeding events can be critical in hospitalized patients with COVID-19, especially those with aggressive anticoagulation therapy.

Aim

We aimed to investigate whether hemoglobin drop was associated with increased risk of acute kidney injury (AKI) and in-hospital mortality among patients with COVID-19.

Design

Retrospective cohort study.

Methods

This retrospective study was conducted by review of the medical records of 6683 patients with laboratory-confirmed COVID-19 hospitalized in the Mount Sinai Health system between 1st March 2020 and 30th March 2021. We compared patients with and without hemoglobin drop >3 g/dl during hospitalization within a week after admissions, using inverse probability treatment weighted analysis (IPTW). Outcomes of interest were in-hospital mortality and AKI which was defined as serum creatine change of 0.3 mg/dl increase or 1.5 times baseline.

Results

Of the 6683 patients admitted due to COVID-19, 750 (11.2%) patients presented with a marked hemoglobin drop. Patients with hemoglobin drop were more likely to receive therapeutic anticoagulation within 2 days after admissions. Patients with hemoglobin drop had higher crude in-hospital mortality (40.8% vs. 20.0%, P < 0.001) as well as AKI (51.4% vs. 23.9%, P < 0.001) compared to those without. IPTW analysis showed that hemoglobin drop was associated with higher in-hospital mortality compared to those without (odds ratio (OR) [95% confidential interval (CI)]: 2.21 [1.54–2.88], P < 0.001) as well as AKI (OR [95% CI]: 2.79 [2.08–3.73], P < 0.001).

Conclusions

Hemoglobin drop during COVID-19 related hospitalizations was associated with a higher risk of AKI and in-hospital mortality.
Clinical assessment of cardiac impairment favored by two-dimensional speckle tracking echocardiology in patients with systemic sclerosis
Authors: Jiang Xintong , Zhang Feng , Li Yuhui , Ren Jingyi , Xu Dan , Cai Ruyi , Yi Zixi , Li Chun , Liu Tian , Zhang Xia , Yao Haihong , Zhu Tiangang , Mu Rong
Published: September 2021

Background

Cardiac involvement is a major cause of death in SSc, while early detection remains a challenge.

Objectives

The purpose of this study was to investigate the prevalence and clinical implications of cardiac impairment in SSc.

Methods

Ninety-five consecutive SSc patients [55.6  (13.8) years old, 5.3  (8.1) years from diagnosis] were included in the study. Patients with heart diseases onset prior to SSc were excluded. All patients underwent two-dimensional speckle-tracking echocardiology (2D-STE) with measuring left and right ventricular global longitudinal strain (GLS/RGLS). Clinical manifestation, laboratory evaluation (CRP, cTnI, antibodies, etc.) and ECG were collected at the same time. Comparisons between the SSc subgroups (lcSSc and dcSSc) were performed using Student’s t-test, Mann–Whitney U or Fisher’s exact test. Binary logistic regression was applied to determine the independent effects of variables in cardiac impairment.

Results

Early left and right ventricular impairment measured by GLS and RGLS were detected in 22.1% and 24.2% of the SSc patients, respectively. In comparison, only 2.1% showed reduced left ventricular ejection fraction (LVEF). Impaired GLS was mainly observed in the basal and medial segments of anterior, lateral and posterior left ventricle walls, and more profound in dcSSc. Elevated CRP (OR 3.561 95% CI: 1.071, 11.839, P <0.05) was associated with reduced GLS/RGLS. The adoption of GLS/RGLS enhanced the efficacy of routine screening for cardiac impairment that 52.6% of patients showed potential cardiac impairment.

Conclusions

Cardiac impairment is a common manifestation in SSc. Increasing awareness of early cardiac impairment is warranted with elevated CRP and dcSSc.
Knee and hip osteoarthritis and risk of nine cancers in a large real-world matched cohort study
Authors: Turkiewicz Aleksandra , Díaz Yesika , Duarte-Salles Talita , Prieto-Alhambra Daniel
Published: September 2021

Objectives

Joint replacement due to end-stage OA has been linked to incidence of several cancers. We aimed to estimate the association between newly diagnosed knee and hip OA and incidence of nine common cancer types.

Methods

We identified persons with incident knee or hip OA, aged ≥40 years, between 2009 and 2015 in the SIDIAP database in Catalonia, Spain. We matched up to three OA-free controls on age, sex and general practitioner. We followed participants from 1 year after OA diagnosis until migration, death, end of study at 31 December 2017 or incident cancer of: stomach, colorectal, liver, pancreas, lung, skin, breast, prostate and bladder. We used flexible parametric survival models, adjusted for confounders. Estimates were corrected for misclassification using probabilistic bias analysis.

Results

We included 117 750 persons with knee OA and matched 309 913 persons without, with mean (s.d.) age of 67.5 (11.1) years and 63% women. The hip cohort consisted of 39 133 persons with hip OA and 116 713 controls. For most of the included cancers, the hazard ratios (HRs) were close to 1. The HR of lung cancer for knee OA exposure was 0.80 (95% CI: 0.71, 0.89) and attenuated to 0.98 (0.76, 1.27) in non-smokers. The hazard of colorectal cancer was lower in persons with both knee and hip OA by 10–20%.

Conclusions

Knee and hip OA are not associated with studied incident cancers, apart from lower risk of colorectal cancer. The often-reported protective association of knee OA with lung cancer is explained by residual confounding.
Time in remission as an alternative outcome measure for rheumatoid arthritis: a 10-year prospective study of 2618 new users of anti-TNF
Authors: Tužil Jan , Mlčoch Tomáš , Závada Jakub , Svoboda Michal , Pavelka Karel , Doležal Tomáš
Published: September 2021

Objective

Achieving targeted disease activity (DA) is the primary therapeutic strategy in RA. Point measurements of DA are done at out-patient visits, however true DA between visits remains unobserved. This study sought to describe and validate a new outcome measure, i.e. time in remission (TIR).

Methods

Patients were enrolled in the Czech ATTRA-RA registry. TIR was calculated using linear interpolation of the DAS28-ESR determined at outpatient visits. Correlation coefficients were computed between TIR and DAS28-CRP, HAQ, Simple Disease Activity Index (SDAI), patient global assessment (PGA) and physician global assessment (PhGA). Using logistic regression, TIR was used as a predictor of remission (SDAI ≤3.3) and non-disability (HAQ <0.5). The predictive value of TIR was compared with point and sustained remission using the cross-validated area under receiver-operating curves.

Results

Since 2010, 2618 RA patients started anti-TNF therapy and were followed until 2020 or until treatment discontinuation. During the first 6 months of therapy, 56% of patients had no remission (TIR = 0), and 22% of patients reached sustained remission (TIR = 1), while 22% of patients had point remissions with 0 < TIR < 1. EULAR good responders and moderate/non-responders spent 64 ± 42% and 6 ± 18% of time in remission, respectively. The mean TIR grew during the follow-up and was correlated with DAS28-CRP, SDAI, HAQ, PGA, and PhGA (P < 0.0001). TIR at 3 and 6 months predicted remission (SDAI ≤3.3) and non-disability (HAQ <0.5) at 13 and 19 months better than point or sustained remission.

Conclusions

TIR is an intuitive way of estimating unobserved DA between scheduled visits; its calculation only requires two consecutive DA values (https://www.medevio.cz/tir-calculator/). TIR is a valid predictor of RA outcomes.
Tumour necrosis factor inhibitor dose adaptation in psoriatic arthritis and axial spondyloarthritis (TAPAS): a retrospective cohort study
Authors: Michielsens Celia A J , den Broeder Nathan , Mulder Michelle L M , van den Hoogen Frank H J , Verhoef Lise M , den Broeder Alfons A
Published: September 2021

Objectives

We investigated the effect of disease activity-guided dose optimization (DAGDO) of TNF inhibitor (TNFi) on disease activity and TNFi dose in PsA and axial spondyloarthritis (axSpA) patients with low disease activity (LDA).

Methods

A retrospective cohort study was conducted in PsA and axSpA patients doing well on TNFi and eligible for TNFi DAGDO. Three different treatment periods were defined: (i) full dose continuation period, (ii) TNFi DAGDO period, and (iii) period with stable TNFi dose after DAGDO. A mixed-model analysis was used to estimate mean Disease Activity Score 28-joint count CRP (DAS28-CRP) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) during these periods, and a mean percentage of the daily defined dose (%DDD) was calculated as secondary outcome.

Results

Three hundred and twenty-four patients (153 PsA and 171 axSpA) were included, with a mean of 6.5 DAS28-CRP and 6.4 BASDAI measurements and a median follow-up duration of 46 and 44 months, respectively. A corrected difference of 0.06 (95% CI: −0.09, 0.21) in mean DAS28-CRP was found for the TNFi DAGDO period and 0.03 (95% CI: −0.14, 0.20) for the period with stable TNFi dose, compared with full dose continuation period. Differences for BASDAI were 0.03 (95% CI: −0.21, 0.27) and 0.05 (95% CI: −0.24, 0.34), respectively. The mean %DDD for the three treatment periods was for PsA 108%, 62% and 78%, and for axSpA 108%, 62% and 72%, respectively.

Conclusion

DAGDO of TNFi reduces drug exposure and has no negative effects on disease activity in PsA and axSpA patients compared with full dose continuation.
Serum lipidomics reveals distinct metabolic profiles for asymptomatic hyperuricemic and gout patients
Authors: Liu Shijia , Wang Yingzhuo , Liu Huanhuan , Xu Tingting , Wang Ma-Jie , Lu Jiawei , Guo Yunke , Chen Wenjun , Ke Mengying , Zhou Guisheng , Lu Yan , Chen Peidong , Zhou Wei
Published: September 2021

Objectives

This study aimed to characterize the systemic lipid profile of patients with asymptomatic hyperuricemia (HUA) and gout using lipidomics, and to find potential underlying pathological mechanisms therefrom.

Methods

Sera were collected from Affiliated Hospital of Nanjing University of Chinese Medicine as centre 1 (discovery and internal validation sets) and Suzhou Hospital of Traditional Chinese Medicine as centre 2 (external validation set), including 88 normal subjects, 157 HUA and 183 gout patients. Lipidomics was performed by ultra high performance liquid chromatography plus Q-Exactive mass spectrometry (UHPLC-Q Exactive MS). Differential metabolites were identifed by both variable importance in the projection ≥1 in orthogonal partial least-squares discriminant analysis mode and false discovery rate adjusted P ≤ 0.05. Biomarkers were found by logistic regression and receiver operating characteristic (ROC) analysis.

Results

In the discovery set, a total of 245 and 150 metabolites, respectively, were found for normal subjects vs HUA and normal subjects vs gout. The disturbed metabolites included diacylglycerol, triacylglycerol (TAG), phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, etc. We also found 116 differential metabolites for HUA vs gout. Among them, the biomarker panel of TAG 18:1-20:0-22:1 and TAG 14:0-16:0-16:1 could differentiate well between HUA and gout. The area under the receiver operating characteristic ROC curve was 0.8288, the sensitivity was 82% and the specificity was 78%, at a 95% CI 0.747, 0.9106. In the internal validation set, the predictive accuracy of TAG 18:1-20:0-22:1 and TAG 14:0-16:0-16:1 panel for differentiation of HUA and gout reached 74.38%, while it was 84.03% in external validation set.

Conclusion

We identified serum biomarkers panel that have the potential to predict and diagnose HUA and gout patients.
America’s Most Divided Sport: Polarization and Inequality in Attitudes about Youth Football
Authors: Lindner Andrew M , Hawkins Daniel N
Published: September 2021

Football may be America’s most popular sport, but with growing evidence of the risk of sport-associated concussions, some adults are reconsidering which sports to encourage children to play. Using data from a nationally representative sample of 958 respondents, we examine how political party, belief in patriotic displays in sport, attention to concussion news, social class, and race are associated with support for children playing each of the five major U.S. sports: baseball, basketball, hockey, soccer, and football. Our findings suggest that unlike other sports, attitudes about youth participation in football are divided by views on patriotism in sport, age, race, education, and attention to concussion news. For many Americans, football is connected to participation in a civil religion, which celebrates national pride and respect for the military. We argue that child safety advocates who aim to steer children away from football must grapple with the deeper cultural and identity-based framework associated with the sport.
A Comparative Analysis of the Fiduciary Duties of Loyalty of Trustees in English Common Law and Chinese Law
Authors: Tian Shulun
Published: September 2021

England is the cradle of trusts and China introduced this flexible institution for its own needs and promulgated its trust law in 2001. Different to England, China does not have unified fiduciary doctrines and the Chinese trust has a strong contractarian nature. This article compares Chinese law and English law in terms of the rules about trustees’ duties of loyalty. The apparent differences reflected on micro rules may find their explanation in the macro trust structures and legislative backgrounds.
Gestational Exposure to Ultrafine Particles Reveals Sex- and Dose-Specific Changes in Offspring Birth Outcomes, Placental Morphology, and Gene Networks
Authors: Behlen Jonathan C , Lau Carmen H , Li Yixin , Dhagat Prit , Stanley Jone A , Rodrigues Hoffman Aline , Golding Michael C , Zhang Renyi , Johnson Natalie M
Published: September 2021

Particulate matter (PM) causes adverse developmental outcomes following prenatal exposure, but the underlying biological mechanisms remain uncertain. Here we elucidate the effects of diesel exhaust ultrafine particle (UFP) exposure during pregnancy on placental and fetal development. Time-mated C57Bl/6n mice were gestationally exposed to UFPs at a low dose (LD, 100 µg/m3) or high dose (HD, 500 µg/m3) for 6 h daily. Phenotypic effects on fetuses and placental morphology at gestational day (GD) of 18.5 were evaluated, and RNA sequencing was characterized for transcriptomic changes in placental tissue from male and female offspring. A significant decrease in average placental weights and crown to rump lengths was observed in female offspring in the LD exposure group. Gestational UFP exposure altered placental morphology in a dose- and sex-specific manner. Average female decidua areas were significantly greater in the LD and HD groups. Maternal lacunae mean areas were increased in the female LD group, whereas fetal blood vessel mean areas were significantly greater in the male LD and HD groups. RNA sequencing indicated several disturbed cellular functions related to lipid metabolism, which were most pronounced in the LD group and especially in female placental tissue. Our findings demonstrate the vulnerability of offspring exposed to UFPs during pregnancy, highlighting sex-specific effects and emphasizing the importance of mitigating PM exposure to prevent adverse health outcomes.