bluuebunny/crossref_metadata_2025 huggingface dataset:
The Pregnancy and EARly Life study (PEARL) - a longitudinal study to understand how gut microbes contribute to maintaining health during pregnancy and early life
Authors: Phillips Sarah , Watt Rachel , Atkinson Thomas , Savva George M , Hayhoe Antonietta , Hall Lindsay J ,   on behalf of the PEARL study team, Hall Lindsay J , Philips Sarah , Watt Rachel , Cameron Martin , Clarke Paul , Lartey Jon , Hayhoe Antonietta , Savva George , Atkinson Thomas , Cambell-Kelly Melissa , Harris Laura , Summerfield Hayley
Published: August 2021

Background

The early life period represents the first step in establishing a beneficial microbial ecosystem, which in turn affects both short and longer-term health. Changes during pregnancy influence the neonatal microbiome; through transmission of maternal microbes during childbirth, and beyond, through nutritional programming. However, in-depth exploration of longitudinal maternal-infant cohorts, with sampling of multiple body sites, complemented by clinical and nutritional metadata, and use of cutting-edge experimental systems are limited.

The PEARL study will increase our knowledge of; how microbes (including viruses/phages, bacteria, fungi and archaea) change in composition and functional capacity during pregnancy; transmission pathways from mother to infant; the impact of various factors on microbial communities across pregnancy and early life (e.g. diet), and how these microbes interact with other microbes and modulate host processes, including links to disease onset.

Methods

PEARL is a longitudinal observational prospective study of 250 pregnant women and their newborns, with stool and blood samples, questionnaires and routine clinical data collected during pregnancy, labour, birth and up to 24 months post birth.

Metagenomic sequencing of samples will be used to define microbiome profiles, and allow for genus, species and strain-level taxonomic identification and corresponding functional analysis. A subset of samples will be analysed for host (immune/metabolite) molecules to identify factors that alter the host gut environment. Culturing will be used to identify new strains of health-promoting bacteria, and potential pathogens. Various in vitro and in vivo experiments will probe underlying mechanisms governing microbe-microbe and microbe-host interactions.

Discussion

Longitudinal studies, like PEARL, are critical if we are to define biomarkers, determine mechanisms underlying microbiome profiles in health and disease, and develop new diet- and microbe-based therapies to be tested in future studies and clinical trials.

Trial registration

This study is registered in the ClinicalTrials.gov Database with ID: NCT03916874.
Should we abandon the patient-specific instrumentation ship in total knee arthroplasty? Not quite yet!
Authors: Török László , Jávor Péter , Hartmann Petra , Bánki László , Varga Endre
Published: August 2021

Patient-specific Instrumentation (PSI) is an innovative technique aiding the precise implementation of the preoperative plan during total knee arthroplasty (TKA) by using patient-specific guides and cutting blocks. Despite of the theoretical advantages, studies have reported contradictory results, thus there is no consensus regarding the overall effectiveness of PSI. Through the critical assessment of a meta-analysis published lately, this correspondence aims to highlight the complexity of comparing the efficacy of PSI to standard instrumentation (SI). The accuracy of component alignment, patient-reported outcome measures (PROMs), surgery time, blood loss, transfusion rate, and postoperative complications are commonly used outcomes for investigating the efficacy of PSI-aided TKA. By assessing component alignment, the expertise of the surgeon(s) should be taken into consideration, since PSI may not provide benefits for expert surgeons but might improve accuracy and patient safety during the learning curve of novice surgeons. With respect to PROMs and postoperative complications, PSI may not improve short-term results; however, long-term follow up data is missing. Regarding transfusion rates, favorable trends can be observed, but further studies utilizing recent data are needed for a clear conclusion. When assessing surgery time, we suggest focusing on operating room turnover instead of procedure time.
Relationship between bone mineral density and fragility fracture risk: a case-control study in Changsha, China
Authors: Li Hong-Li , Shen Yi , Tan Li-Hua , Fu Song-bo , Dai Ru-Chun , Yuan Ling-Qing , Sheng Zhi-Feng , Xie Zhong-Jian , Wu Xian-Ping , Liao Er-Yuan , Tang Xu-Lei , Wu Xi-Yu
Published: August 2021

Background

Fragility fracture is associated with bone mineral density (BMD), and most databases used in related researches are instrument-matched. Little is known about the relationship between BMD and fragility fracture risk of native Chinese, especially using local databases as reference databases.

Objective

To investigate relationship between BMD and risk of fragility fracture in native China.

Methods

3,324 cases, including 2,423 women (67.7 ± 8.9 years) and 901 men (68.4 ± 11.6 years) having radiological fragility fractures and 3,324 age- and gender-matched controls participated in the study. We measured BMD at posteroanterior spine and hip using dual-energy X-ray absorptiometry (DXA), calculated BMD measurement parameters based on our own BMD reference database.

Results

BMDs and mean T-scores were lower in case group (with clinical fragility) than in control group (without clinical fragility). In patients with fragility fractures, prevalence of lumbar osteoporosis, low bone mass, and normal BMD were 78.9 %, 19.3 %, and 1.8 %, respectively, in women, and 49.5, 44.8 %, and 5.7 %, respectively, in men. In hip, these prevalence rates were 67.2 %, 28.4 %, and 4.4 % in females, and 43.2 %, 45.9 %, and 10.9 % in males, respectively, showing differences between females and males. Multivariate Cox regression analysis showed that after adjusting age, height, weight, and body mass index, fracture hazard ratio (HR) increased by 2.7–2.8 times (95 % CI 2.5–3.1) and 3.6–4.1 times (95 %CI 3.0–5.1) for women and men respectively with decreasing BMD parameters. In both sexes, risk of fragility fracture increased approximately 1.6–1.7 times (95 % CI 1.5–1.8) for every 1 T-score reduction in BMD.

Conclusions

Risk of clinical fragility fracture increases with decreasing BMD measurement parameters and anthropometric indicators in native China, and fracture HR varies from gender and site.
An economical and highly adaptable optogenetics system for individual and population-level manipulation of Caenorhabditis elegans
Authors: Koopman M. , Janssen L. , Nollen E. A. A.
Published: August 2021

Background

Optogenetics allows the experimental manipulation of excitable cells by a light stimulus without the need for technically challenging and invasive procedures. The high degree of spatial, temporal, and intensity control that can be achieved with a light stimulus, combined with cell type-specific expression of light-sensitive ion channels, enables highly specific and precise stimulation of excitable cells. Optogenetic tools have therefore revolutionized the study of neuronal circuits in a number of models, includingCaenorhabditis elegans. Despite the existence of several optogenetic systems that allow spatial and temporal photoactivation of light-sensitive actuators inC. elegans, their high costs and low flexibility have limited wide access to optogenetics. Here, we developed an inexpensive, easy-to-build, modular, and adjustable optogenetics device for use on different microscopes and worm trackers, which we called the OptoArm.

Results

The OptoArm allows for single- and multiple-worm illumination and is adaptable in terms of light intensity, lighting profiles, and light color. We demonstrate OptoArm’s power in a population-based multi-parameter study on the contributions of motor circuit cells to age-related motility decline. We found that individual components of the neuromuscular system display different rates of age-dependent deterioration. The functional decline of cholinergic neurons mirrors motor decline, while GABAergic neurons and muscle cells are relatively age-resilient, suggesting that rate-limiting cells exist and determine neuronal circuit ageing.

Conclusion

We have assembled an economical, reliable, and highly adaptable optogenetics system which can be deployed to address diverse biological questions. We provide a detailed description of the construction as well as technical and biological validation of our set-up. Importantly, use of the OptoArm is not limited toC. elegansand may benefit studies in multiple model organisms, making optogenetics more accessible to the broader research community.
Reduced risk of placental parasitemia associated with complement fixation on Plasmodium falciparum by antibodies among pregnant women
Authors: Opi D. Herbert , Boyle Michelle J. , McLean Alistair R. D. , Reiling Linda , Chan Jo-Anne , Stanisic Danielle I. , Ura Alice , Mueller Ivo , Fowkes Freya J. I. , Rogerson Stephen J. , Beeson James G.
Published: August 2021

Background

The pathogenesis of malaria in pregnancy (MiP) involves accumulation of P. falciparum-infected red blood cells (pRBCs) in the placenta, contributing to poor pregnancy outcomes. Parasite accumulation is primarily mediated by P. falciparum erythrocyte membrane protein 1 (PfEMP1). Magnitude of IgG to pRBCs has been associated with reduced risk of MiP in some studies, but associations have been inconsistent. Further, antibody effector mechanisms are poorly understood, and the role of antibody complement interactions is unknown.

Methods

Studying a longitudinal cohort of pregnant women (n=302) from a malaria-endemic province in Papua New Guinea (PNG), we measured the ability of antibodies to fix and activate complement using placental binding pRBCs and PfEMP1 recombinant domains. We determined antibody-mediated complement inhibition of pRBC binding to the placental receptor, chondroitin sulfate A (CSA), and associations with protection against placental parasitemia.

Results

Some women acquired antibodies that effectively promoted complement fixation on placental-binding pRBCs. Complement fixation correlated with IgG1 and IgG3 antibodies, which dominated the response. There was, however, limited evidence for membrane attack complex activity or pRBC lysis or killing. Importantly, a higher magnitude of complement fixing antibodies was prospectively associated with reduced odds of placental infection at delivery. Using genetically modified P. falciparum and recombinant PfEMP1 domains, we found that complement-fixing antibodies primarily targeted a specific variant of PfEMP1 (known as VAR2CSA). Furthermore, complement enhanced the ability of antibodies to inhibit pRBC binding to CSA, which was primarily mediated by complement C1q protein.

Conclusions

These findings provide new insights into mechanisms mediating immunity to MiP and reveal potential new strategies for developing malaria vaccines that harness antibody-complement interactions.
The severity and risk factors for mortality in immunocompromised adult patients hospitalized with influenza-related pneumonia
Authors: Chen Liang , Han Xiudi , Li YanLi , Zhang Chunxiao , Xing Xiqian
Published: August 2021

Objective

To explore disease severity and risk factors for 30-day mortality of adult immunocompromised (IC) patients hospitalized with influenza-related pneumonia (Flu-p).

Method

A total of 122 IC and 1191 immunocompetent patients hospitalized with Flu-p from January 2012 to December 2018 were recruited retrospectively from five teaching hospitals in China.

Results

After controlling for confounders, multivariate logistic regression analysis showed that immunosuppression was associated with increased risks for invasive ventilation [odds ratio: (OR) 2.475, 95% confidence interval (CI): 1.511–4.053, p < 0.001], admittance to the intensive care unit (OR: 3.247, 95% CI 2.064–5.106, p < 0.001), and 30-day mortality (OR: 3.206, 95% CI 1.926–5.335, p < 0.001) in patients with Flu-p. Another multivariate logistic regression model revealed that baseline lymphocyte counts (OR: 0.993, 95% CI 0.990–0.996, p < 0.001), coinfection (OR: 5.450, 95% CI 1.638–18.167, p = 0.006), early neuraminidase inhibitor therapy (OR 0.401, 95% CI 0.127–0.878, p = 0.001), and systemic corticosteroid use at admission (OR: 6.414, 95% CI 1.348–30.512, p = 0.020) were independently related to 30-day mortality in IC patients with Flu-p. Based on analysis of the receiver operating characteristic curve (ROC), the optimal cutoff for lymphocyte counts was 0.6 × 109/L [area under the ROC (AUROC) = 0.824, 95% CI 0.744—0.887], sensitivity: 97.8%, specificity: 73.7%].

Conclusions

IC conditions are associated with more severe outcomes in patients with Flu-p. The predictors for mortality that we identified may be valuable for the management of Flu-p among IC patients.
Early postpartum abnormal glucose metabolism subtype differs according to mid-trimester lipid profile in women with gestational diabetes mellitus
Authors: Lai Fenghua , Li Zeting , Yue Shufan , Pei Ling , Xiao Huangmeng , Li Zhuyu , Li Yanbing , Xiao Haipeng , Cao Xiaopei
Published: August 2021

Background

It is unknown whether early postpartum abnormal glucose metabolism (AGM) in women with previous gestational diabetes mellitus (GDM) is related to their mid-trimester lipid profile. The aim of this study was to characterize the mid-trimester lipid profile of women who experienced GDM and developed into different pathophysiologic subtypes of early postpartum AGM.

Methods

A retrospective cohort study of 498 women with history of GDM was conducted. A 75-g oral glucose tolerance test (OGTT) and plasma lipid measurements were performed at 24–28 weeks of gestation and 6–12 weeks of postpartum. Insulin secretion and sensitivity were estimated using early postpartum OGTT-based indices.

Results

Women in the mid-trimester dyslipidemia group had higher postpartum 30-min and 2-h plasma glucose, higher postpartum 2-h plasma insulin, higher postpartum triglyceride (TG), higher postpartum low density lipoprotein cholesterol (LDL-c) concentrations, lower postpartum 30-min insulinogenic index (IGI30), lower postpartum insulin sensitivity index (ISI), and lower postpartum disposition index than those in the normal lipid group (all P < 0.05). Abnormal mid-trimester TG and LDL-c concentrations were associated with postpartum AGM (adjusted odds ratio [OR] = 1.786, 95 % confidence interval [CI] = 1.142–2.425; and adjusted OR = 1.621, 95 % CI = 1.323–2.051, respectively; both P < 0.05). AGM women with low IGI30 and low ISI had higher mid-trimester total cholesterol and LDL-c concentrations, and AGM women with low ISI had higher mid-trimester TG concentrations than women with NGT or other subtypes of AGM (all P < 0.05).

Conclusions

GDM women with abnormal mid-trimester TG and LDL-c were predisposed to early postpartum AGM. Postpartum AGM women who experienced GDM had heterogeneous mid-trimester lipid profile when classified according to their pathophysiologic subtype.
Emergency cardiac imaging for coronavirus disease 2019 (COVID-19) in practice: a case of takotsubo stress cardiomyopathy
Authors: Belli Oriana , Ardissino Maddalena , Bottiroli Maurizio , Soriano Francesco , Blanda Calogero , Oreglia Jacopo , Mondino Michele , Moreo Antonella
Published: August 2021

Background

Cardiovascular complications of severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV2) are known to be associated with poor outcome. A small number of case series and reports have described cases of myocarditis and ischaemic events, however, knowledge on the aetiology of acute cardiac failure in SARS-CoV2 remains limited. We describe the occurrence and risk stratification imaging correlates of ‘takotsubo’ stress cardiomyopathy presenting in a patient with Coronavirus Disease 2019 (COVID-19) in the intensive care unit.

Case summary

An intubated 53-year old patient with COVID19 suffered acute haemodynamic collapse in the intensive care unit, and was thus investigated with transthoracic echocardiography (TTE), 12-lead electrocardiograms (ECG) and serial troponins and blood tests, and eventually coronary angiography due to clinical suspicion of ischaemic aetiology. Echocardiography revealed a reduced ejection fraction, with evident extensive apical akinesia spanning multiple coronary territories. Troponins and NT-proBNP were elevated, and ECG revealed ST elevation: coronary angiography was thus performed. This revealed no significant coronary stenosis. Repeat echocardiography performed within the following week revealed a substantial recovery of ejection fraction and wall motion abnormalities. Despite requirement of a prolonged ICU stay, the patient now remains clinically stable, and is on spontaneous breathing.

Conclusion

This case report presents a case of takotsubo stress cardiomyopathy occurring in a critically unwell patient with COVID19 in the intensive care setting. Stress cardiomyopathy may be an acute cardiovascular complication of COVID-19 infection. In the COVID19 critical care setting, urgent bedside echocardiography is an important tool for initial clinical assessment of patients suffering haemodynamic compromise.
Education policies to increase rural physicians in Japan: a nationwide cohort study
Authors: Matsumoto Masatoshi , Matsuyama Yasushi , Kashima Saori , Koike Soichi , Okazaki Yuji , Kotani Kazuhiko , Owaki Tetsuhiro , Ishikawa Shizukiyo , Iguchi Seitaro , Okazaki Hitoaki , Maeda Takahiro
Published: August 2021

Background

Japan has established comprehensive education-scholarship programs to supply physicians in rural areas. Their entrants now comprise 16% of all medical students, and graduates must work in rural areas for a designated number of years. These programs are now being adopted outside Japan, but their medium-term outcomes and inter-program differences are unknown.

Methods

A nationwide prospective cohort study of newly licensed physicians 2014–2018 (n = 2454) of the four major types of the programs—Jichi Medical University (Jichi); regional quota with scholarship; non-quota with scholarship (scholarship alone); and quota without scholarship (quota alone)—and all Japanese physicians in the same postgraduate year (n = 40,293) was conducted with follow-up workplace information from the Physician Census 2018, Ministry of Health, Labour and Welfare. In addition, annual cross-sectional survey for prefectural governments and medical schools 2014–2019 was conducted to obtain information on the results of National Physician License Examination and retention status for contractual workforce.

Results

Passing rate of the National Physician License Examination was highest in Jichi, followed in descending order by quota with scholarship, the other two programs, and all medical graduates. The retention rate for contractual rural service of Jichi graduates 5 years after graduation (n = 683; 98%) was higher than that of quota with scholarship (2868; 90%; P < 0.001) and scholarship alone (2220; 81% < 0.001). Relative risks of working in municipalities with the least population density quintile in Jichi, quota with scholarship, scholarship alone, and quota alone in postgraduate year 5 were 4.0 (95% CI 3.7–4.4; P < 0.001), 3.1 (2.6–3.7; < 0.001), 2.5 (2.1–3.0; < 0.001), and 2.5 (1.9–3.3; < 0.001) as compared with all Japanese physicians. There was no significant difference between each program and all physicians in the proportion of those who specialized in internal medicine or general practice in postgraduate years 3 to 5

Conclusions

Japan’s education policies to produce rural physicians are effective but the degree of effectiveness varies among the programs. Policymakers and medical educators should plan their future rural workforce policies with reference to the effectiveness and variations of these programs.
Global research publications on irrational use of antimicrobials: call for more research to contain antimicrobial resistance
Authors: Sweileh Waleed M.
Published: August 2021

Background

Irrational use of antimicrobials is highly prevalent. It is a major driving factor for antimicrobial resistance (AMR). Research on irrational antimicrobial use is important for developing policies and regulations to combat and contain AMR. The present study aims to provide an overview of research publications on the irrational use of antimicrobials at the national and global levels.

Methods

Publications on irrational use of antimicrobials were extracted from Scopus using a wide range of relevant keywords for the study period from 1980 to 2020.

Results

In total, 656 publications on irrational use of antimicrobials were found. The bulk of publications in this field were about irrational use in humans. A limited number of publications were found on the irrational use of antimicrobials in the context of veterinary and environment. The number of publications, contributing countries, and the mean number of authors per article increased with time, most notably in the last decade. Authors from 105 different countries participated in publishing the retrieved articles with 22 (21.0%) participated in 10 or more publications. The United States led with 140 (21.6%) articles followed distantly by China (n = 49, 7.5%), India (n = 45, 6.9%), and the United Kingdom (n = 45, 6.9%). Countries in the South-East Asian region (n = 69, 10.5%) and the African region (n = 42, 6.4%) made the least contribution. The list of most frequent author keywords included “antimicrobial stewardship” and “community pharmacies”. The research themes focused on the hospital-based rational use of antimicrobials and the self-medication practices with antimicrobials in the community. In total, 420 different journals participated in publishing the retrieved documents. The Plos One journal (17, 2.6%) ranked first. The retrieved articles received an average of 15.6 citations per article and an h-index of 52. The most frequent antimicrobials encountered in the retrieved literature were penicillin, cephalosporin, and fluoroquinolones while the most frequently encountered pathogens were S. aureus and P. aeruginosa.

Conclusion

Research on the irrational use of antimicrobials is needed from all countries and regions to implement appropriate policies to contain the AMR. Research on irrational use of antimicrobials in the context of veterinary is needed.
Hepatitis C in healthcare personnel: follow-up analysis of treatments with direct-acting antiviral agents
Authors: Westermann Claudia , Wendeler Dana , Nienhaus Albert
Published: August 2021

Background

Hepatitis C infections (HCV) are associated with an increase in morbidity and mortality. The aim of this study is to update the results of treatment with direct-acting antiviral agents (DAAs) using a larger population of healthcare personnel (HP) and a longer observation period.

Methods

Secondary data analysis of DAA treatment administered to HP (with confirmed occupational acquired HCV infection) between 1 January 2014 and 30 December 2018, is based on statutory accident insurance data from Germany. The end points of the study were results of a monitoring carried out 12 and 24 weeks after the end of treatment (sustained virological response, SVR), as well as side effects and the assessment of reduced work ability after treatment. Multivariate logistic regression models were constructed to investigate predictors of SVR.

Results

The study population (n = 305) mainly comprised HP with a genotype 1 infection. The average age was 63 (SD 10) and 77% were female. Two thirds of the HP suffered from fibrosis or cirrhosis, and had experience of treatment. Statistically, men were significantly more likely to suffer from cirrhosis than women (60% compared to 21%, p < 0.001). The end-of-treatment response (ETR) rate was 99% and the SVR12 and SVR24 rates were 98%. Liver cirrhosis proved to be a predictor of a statistically significant reduction in success rates.

Conclusion

DAA treatment leads to high SVR. Early HCV treatment is associated with higher SVR.
Small-scale sequencing enables quality assessment of Ribo-Seq data: an example from Arabidopsis cell culture
Authors: Mahboubi Amir , Delhomme Nicolas , Häggström Sara , Hanson Johannes
Published: August 2021

Background

Translation is a tightly regulated process, controlling the rate of protein synthesis in cells. Ribosome sequencing (Ribo-Seq) is a recently developed tool for studying actively translated mRNA and can thus directly address translational regulation. Ribo-Seq libraries need to be sequenced to a great depth due to high contamination by rRNA and other contaminating nucleic acid fragments. Deep sequencing is expensive, and it generates large volumes of data, making data analysis complicated and time consuming.

Methods and results

Here we developed a platform for Ribo-Seq library construction and data analysis to enable rapid quality assessment of Ribo-Seq libraries with the help of a small-scale sequencer. Our data show that several qualitative features of a Ribo-Seq library, such as read length distribution, P-site distribution, reading frame and triplet periodicity, can be effectively evaluated using only the data generated by a benchtop sequencer with a very limited number of reads.

Conclusion

Our pipeline enables rapid evaluation of Ribo-Seq libraries, opening up possibilities for optimization of Ribo-Seq library construction from difficult samples, and leading to better decision making prior to more costly deep sequencing.
The biomechanical effect of preexisting different types of disc herniation in cervical hyperextension injury
Authors: Wang Jian-jie , Xu Meng-lei , Zeng Hui-zi , Zheng Liang-dong , Zhu Shi-jie , Jin Chen , Zeng Zhi-li , Cheng Li-ming , Zhu Rui
Published: August 2021

Objective

Preexisting severe cervical spinal cord compression is a significant risk factor in cervical hyperextension injury, and the neurological function may deteriorate after a slight force to the forehead. There are few biomechanical studies regarding the influence of pathological factors in hyperextension loading condition. The aim of this study is to analyze the effects of preexisting different types of cervical disc herniation and different degrees of compression on the spinal cord in cervical hyperextension.

Method

A 3D finite element (FE) model of cervical spinal cord was modeled. Local type with median herniation, local type with lateral herniation, diffuse type with median herniation, and diffuse type with lateral herniation were simulated in neutral and extention positions. The compressions which were equivalent to 10%, 20%, 30%, and 40% of the sagittal diameter of the spinal cord were modeled.

Results

The results of normal FE model were consistent with those of previous studies. The maximum von Mises stresses appeared in the pia mater for all 32 loading conditions. The maximum von Mises stresses in extension position were much higher than in neutral position. In most cases, the maximum von Mises stresses in diffuse type were higher than in local type.

Conclusion

Cervical spinal cord with preexisting disc herniation is more likely to be compressed in hyperextension situation than in neutral position. Diffuse type with median herniation may cause more severe compression with higher von Mises stresses concentrated at the anterior horn and the peripheral white matter, resulting in acute central cord syndrome from biomechanical point of view.
Sex dependent glial-specific changes in the chromatin accessibility landscape in late-onset Alzheimer’s disease brains
Authors: Barrera Julio , Song Lingyun , Gamache Julia E. , Garrett Melanie E. , Safi Alexias , Yun Young , Premasinghe Ivana , Sprague Daniel , Chipman Danielle , Li Jeffrey , Fradin Hélène , Soldano Karen , Gordân Raluca , Ashley-Koch Allison E. , Crawford Gregory E. , Chiba-Falek Ornit
Published: August 2021

Background

In the post-GWAS era, there is an unmet need to decode the underpinning genetic etiologies of late-onset Alzheimer’s disease (LOAD) and translate the associations to causation.

Methods

We conducted ATAC-seq profiling using NeuN sorted-nuclei from 40 frozen brain tissues to determine LOAD-specific changes in chromatin accessibility landscape in a cell-type specific manner.

Results

We identified 211 LOAD-specific differential chromatin accessibility sites in neuronal-nuclei, four of which overlapped with LOAD-GWAS regions (±100 kb of SNP). While the non-neuronal nuclei did not show LOAD-specific differences, stratification by sex identified 842 LOAD-specific chromatin accessibility sites in females. Seven of these sex-dependent sites in the non-neuronal samples overlapped LOAD-GWAS regions including APOE. LOAD loci were functionally validated using single-nuclei RNA-seq datasets.

Conclusions

Using brain sorted-nuclei enabled the identification of sex-dependent cell type-specific LOAD alterations in chromatin structure. These findings enhance the interpretation of LOAD-GWAS discoveries, provide potential pathomechanisms, and suggest novel LOAD-loci.

Graphical Abstract
Apatinib triggers autophagic and apoptotic cell death via VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling in lung cancer
Authors: Xie Chunfeng , Zhou Xu , Liang Chunhua , Li Xiaoting , Ge Miaomiao , Chen Yue , Yin Juan , Zhu Jianyun , Zhong Caiyun
Published: August 2021

Background

Recently, a variety of clinical trials have shown that apatinib, a small-molecule anti-angiogenic drug, exerts promising inhibitory effects on multiple solid tumors, including non-small cell lung cancer (NSCLC). However, the underlying molecular mechanism of apatinib on NSCLC remains unclear.

Methods

MTT, EdU, AO/EB staining, TUNEL staining, flow cytometry, colony formation assays were performed to investigate the effects of apatinib on cell proliferation, cell cycle distribution, apoptosis and cancer stem like properties. Wound healing and transwell assays were conducted to explore the role of apatinib on migration and invasion. The regulation of apatinib on VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling were detected. Furthermore, we collected conditioned medium (CM) from A549 and H1299 cells to stimulate phorbol myristate acetate (PMA)-activated THP-1 cells, and examined the effect of apatinib on PD-L1 expression in macrophages. The Jurkat T cells and NSCLC cells co-culture model was used to assess the effect of apatinib on T cells activation. Subcutaneous tumor formation models were established to evaluate the effects of apatinib in vivo. Histochemical, immunohistochemical staining and ELISA assay were used to examine the levels of signaling molecules in tumors.

Results

We showed that apatinib inhibited cell proliferation and promoted apoptosis in NSCLC cells in vitro. Apatinib induced cell cycle arrest at G1 phase and suppressed the expression of Cyclin D1 and CDK4. Moreover, apatinib upregulated Cleaved Caspase 3, Cleaved Caspase 9 and Bax, and downregulated Bcl-2 in NSCLC cells. The colony formation ability and the number of CD133 positive cells were significantly decreased by apatinib, suggesting that apatinib inhibited the malignant and stem-like features of NSCLC cells. Mechanistically, apatinib inhibited PD-L1 and c-Myc expression by targeting VEGFR2/STAT3 signaling. Apatinib also inhibited PD-L1 expression in THP-1 derived macrophages stimulated by CM from NSCLC cells. Furthermore, apatinib pretreatment increased CD69 expression and IFN-γ secretion in stimulated Jurkat T cells co-cultured with NSCLC cells. Apatinib also promoted ROS production and inhibited Nrf2 and p62 expression, leading to the autophagic and apoptotic cell death in NSCLC. Moreover, apatinib significantly inhibited tumor growth in vivo.

Conclusion

Our data indicated that apatinib induced autophagy and apoptosis in NSCLC via regulating VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling.
Deterministic transition of enterotypes shapes the infant gut microbiome at an early age
Authors: Xiao Liwen , Wang Jinfeng , Zheng Jiayong , Li Xiaoqing , Zhao Fangqing
Published: August 2021

Background

The succession of the gut microbiota during the first few years plays a vital role in human development. We elucidate the characteristics and alternations of the infant gut microbiota to better understand the correlation between infant health and microbiota maturation.

Results

We collect 13,776 fecal samples or datasets from 1956 infants between 1 and 3 years of age, based on multi-population cohorts covering 17 countries. The characteristics of the gut microbiota are analyzed based on enterotype and an ecological model. Clinical information (n= 2287) is integrated to understand outcomes of different developmental patterns. Infants whose gut microbiota are dominated by Firmicutes andBifidobacteriumexhibit typical characteristics of early developmental stages, such as unstable community structure and low microbiome maturation, while those driven byBacteroidesandPrevotellaare characterized by higher diversity and stronger connections in the gut microbial community. We further reveal a geography-related pattern in global populations. Through ecological modeling and functional analysis, we demonstrate that the transition of the gut microbiota from infants towards adults follows a deterministic pattern; as infants grow up, the dominance of Firmicutes andBifidobacteriumis replaced by that ofBacteroidesandPrevotella, along with shifts in specific metabolic pathways.

Conclusions

By leveraging the extremely large datasets and enterotype-based microbiome analysis, we decipher the colonization and transition of the gut microbiota in infants from a new perspective. We further introduce an ecological model to estimate the tendency of enterotype transitions, and demonstrated that the transition of infant gut microbiota was deterministic and predictable.
CRISTAL (a cluster-randomised, crossover, non-inferiority trial of aspirin compared to low molecular weight heparin for venous thromboembolism prophylaxis in hip or knee arthroplasty, a registry nested study): statistical analysis plan
Authors: Sidhu Verinder Singh , Kelly Thu-Lan , Pratt Nicole , Graves Steven , Buchbinder Rachelle , Naylor Justine , de Steiger Richard , Ackerman Ilana , Adie Sam , Lorimer Michelle , Bastiras Durga , Cashman Kara , Harris Ian
Published: August 2021

Background

This a priori statistical analysis plan describes the analysis for CRISTAL.

Methods

CRISTAL (cluster-randomised, crossover, non-inferiority trial of aspirin compared to low molecular weight heparin for venous thromboembolism prophylaxis in hip or knee arthroplasty, a registry nested study) aims to determine whether aspirin is non-inferior to low molecular weight heparin (LMWH) in preventing symptomatic venous thromboembolism (VTE) following hip arthroplasty (HA) or knee arthroplasty (KA). The study is nested within the Australian Orthopaedic Association National Joint Replacement Registry. The trial was commenced in April 2019 and after an unplanned interim analysis, recruitment was stopped (December 2020), as the stopping rule was met for the primary outcome.

The clusters comprised hospitals performing > 250 HA and/or KA procedures per annum, whereby all adults (> 18 years) undergoing HA or KA were recruited. Each hospital was randomised to commence with aspirin, orally, 85–150 mg daily or LMWH (enoxaparin), 40 mg, subcutaneously, daily within 24 h postoperatively, for 35 days after HA and 14 days after KA. Crossover was planned once the registration target was met for the first arm.

The primary end point is symptomatic VTE within 90 days. Secondary outcomes include readmission, reoperation, major bleeding and death within 90 days, and reoperation and patient-reported pain, function and health status at 6 months.

The main analyses will focus on the primary and secondary outcomes for patients undergoing elective primary total HA and KA for osteoarthritis. The analysis will use an intention-to-treat approach with cluster summary methods to compare treatment arms. As the trial stopped early, analyses will account for incomplete cluster crossover and unequal cluster sizes.

Conclusions

This paper provides a detailed statistical analysis plan for CRISTAL.

Trial registration

Australian and New Zealand Clinical Trials Registry ACTRN12618001879257. Registered on 19/11/2018.
Patient- and physician-reported outcomes from two phase 3 randomized studies (RAJ3 and RAJ4) of peficitinib (ASP015K) in Asian patients with rheumatoid arthritis
Authors: Tanaka Yoshiya , Takeuchi Tsutomu , Izutsu Hiroyuki , Kaneko Yuichiro , Kato Daisuke , Fukuda Musashi , Rokuda Mitsuhiro , Schultz Neil M.
Published: August 2021

Background

Peficitinib (ASP015K), a novel oral Janus kinase inhibitor, has demonstrated efficacy and safety in the treatment of patients with rheumatoid arthritis (RA). This study evaluated the effect of peficitinib on patient- and physician-reported outcomes in Asian patients with RA and an inadequate response to prior disease-modifying antirheumatic drugs (DMARDs).

Methods

Patients from two randomized, placebo-controlled, double-blind, phase 3 trials (RAJ3 and RAJ4) received once-daily peficitinib 100 mg, peficitinib 150 mg, or placebo, alone or in combination with DMARDs (RAJ3), or in combination with methotrexate (RAJ4). Mean changes in Work Productivity and Activity Impairment (WPAI) questionnaire domain scores from baseline, and percentages of patients achieving minimal clinically important differences (MCIDs) for patient- and physician-reported outcomes (WPAI, Health Assessment Questionnaire – Disability Index [HAQ-DI], and Subject’s Global Assessment of Pain [SGAP]), and Physician’s Global Assessment of disease activity (PGA) were evaluated at weeks 4, 8, 12, and 12/early termination (ET).

Results

Data from 1025 patients were analyzed. At week 12/ET in both studies, patients who received peficitinib 100 mg or 150 mg reported significantly improved WPAI domain scores from baseline (except for absenteeism in RAJ4) compared with placebo (both doses, p<0.05). A higher proportion of peficitinib- versus placebo-treated patients achieved MCID in WPAI, HAQ-DI, SGAP, and PGA in studies RAJ3 and RAJ4. Significant differences with peficitinib versus placebo were evident in both studies as early as week 4 in HAQ-DI (peficitinib 150 mg only), SGAP, and PGA, and week 8 in WPAI loss of work productivity and daily activity impairment. At week 12/ET, significantly higher proportions of patients receiving peficitinib versus placebo achieved MCID in HAQ-DI, SGAP, PGA, and WPAI domains of presenteeism (RAJ3 only), loss of work productivity (RAJ3 only), and daily activity impairment (p<0.05 for all comparisons).

Conclusions

Peficitinib 100 mg or 150 mg administered daily over 12 weeks resulted in clinically meaningful improvements in outcomes that are important to RA patients, including pain, physical function, and work productivity and activity. These observations were reinforced through similar improvements in physicians’ rating of disease activity.

Trial registration

RAJ3: ClinicalTrials.gov, NCT02308163, registered 4 December 2014.

RAJ4: ClinicalTrials.gov, NCT02305849, registered 3 December 2014.
Incidence and severity of G6PI-induced arthritis are not increased in genetically distinct mouse strains upon aging
Authors: Andreas Nico , Müller Sylvia , Templin Nicole , Jordan Paul M. , Schuhwerk Harald , Müller Michael , Gerstmeier Jana , Miek Laura , Andreas Saskia , Werz Oliver , Kamradt Thomas
Published: August 2021

Background

The incidence of rheumatoid arthritis is correlated with age. In this study, we analyzed the association of the incidence and severity of glucose-6-phosphate isomerase (G6PI)-induced arthritis with age in two different mouse strains.

Methods

Young and very old mice from two different arthritis-susceptible wild-type mouse strains were analyzed after a single subcutaneous injection of G6PI s.c. The metabolism and the function of synoviocytes were analyzed in vitro, the production of bioactive lipid mediators by myeloid cells and synoviocytes was assessed in vitro and ex vivo by UPLC-MS-MS, and flow cytometry was used to verify age-related changes of immune cell composition and function.

Results

While the severity of arthritis was independent from age, the onset was delayed in old mice. Old mice showed common signs of immune aging like thymic atrophy associated with decreased CD4+ effector T cell numbers. Despite its decrease, the effector T helper (Th) cell compartment in old mice was reactive and functionally intact, and their Tregs exhibited unaltered suppressive capacities. In homeostasis, macrophages and synoviocytes from old mice produced higher amounts of pro-inflammatory cyclooxygenase (COX)-derived products. However, this functional difference did not remain upon challenge in vitro nor upon arthritis reactions ex vivo.

Conclusion

While old mice show a higher baseline of inflammatory functions, this does not result in increased reaction towards self-antigens in arthritis-susceptible mouse strains. Together, our data from two different mouse strains show that the susceptibility for G6PI-induced arthritis is not age-dependent.
Maternal age at first childbirth and under-five morbidity in sub-Saharan Africa: analysis of cross-sectional data of 32 countries
Authors: Ahinkorah Bright Opoku
Published: August 2021

Background

The prevalence of childhood morbidity remains high in low-and middle-income countries, including sub-Saharan Africa (SSA). In this study, the association between maternal age at first childbirth and under-five morbidity in SSA was examined.

Methods

This was a cross-sectional study involving nationally-representative data from the most recent Demographic and Health Surveys conducted in 32 countries in SSA from 2010 to 2019. A sample size of 311,603 mothers of children under-five was considered. The outcome variable for this study was under-five morbidity. This variable was derived from the experience of fever, cough, and diarrhoea among children under-five. Both multilevel and binary logistic regression models were used to test the hypothesis that adolescent childbirth is associated with under-five morbidity. The results were presented as crude odds ratios (cORs) and adjusted odds ratios (aORs), with 95 % confidence intervals (CIs).

Results

Children born to mothers whose first childbirth occurred at < 20 years were 16 % times more likely to suffer from under-five morbidity, compared to those whose mothers’ first childbirth occurred at age ≥ 20 years [cOR = 1.16; CI = 1.13–1.19], and this persisted but with reduced odds after controlling for covariates [aOR = 1.10; CI = 1.07–1.12]. At the country level, children born to mothers whose first childbirth occurred at < 20 years were more likely to suffer from under-five morbidity, compared to those whose mothers’ first childbirth occurred at age ≥ 20 years in Angola, Burundi, Congo DR, Guinea, Kenya, and Uganda.

Conclusions

In this study, an association between adolescent childbirth and morbidity in children under five in SSA has been established. The study concludes that under-five morbidity is higher among children born to mothers whose first childbirth occurred before 20 years compared to those whose mothers’ first childbirth occurred at 20 years and above. The findings indicate that in order to reduce under-five morbidity, there is the need to deal with adolescent childbearing through cultural and social change, coupled with engagement of adolescents and stakeholders in adolescent sexual and reproductive health programmes.
Diversifying a resource-dependent economy: private–public relationships in the Kuwaiti economy
Authors: Gelan Ayele , Hewings Geoffrey J. D. , Alawadhi Ahmad
Published: August 2021

The Kuwaiti economy is characterized by two major structural imbalances—heavy dependence on oil production and dominance of the public ownership. Kuwait has struggled over the years to implement a two-pronged development strategy —diversifying the country’s economic base away from the oil sector and promoting private sector development. This paper explores the economic impact of some policy reform options currently being considered. It employs a unique set of input–output tables, derived from supply–use tables, that distinguishes transactions made by private and public enterprises as well as providing a matrix of imports by industry. The public–private sector interdependence analysis revealed interesting results regarding sectoral differences in strengths of forward and backward linkages. For instance, the findings indicated that the strength of the publicly owned oil sectors lie in their forward linkages, supplying other sectors with their outputs, but their backward linkages is weak. On the other hand, the chemicals industry is identified as one of a few sectors with balanced and relatively strong forward and backward linkages in both public and private sector. The policy analyses conducted in this paper are highly relevant to the ongoing policy debate in Kuwait over the design of the economic reform programs. The public–private linkage analysis has revealed insights into policy synergies through which one instrument can affect more than one policy target.
Monitoring and assessment of endangered UNESCO World Heritage Sites using space technology: a case study of East Rennell, Solomon Islands
Authors: Huo Sijia , Wang Mengmeng , Chen Guolong , Shu Huiqin , Yang Ruixia
Published: August 2021

Space technology offers effective tools to monitor the status of World Natural Heritage sites. East Rennell Island, which covers approximately 37,000 hectares (ha) and a marine area extending three nautical miles into the sea, was added to the list of endangered World Natural Heritage sites in 2013. Deforestation and natural disasters have increasingly threatened sustainable development on the island. Based on analyses of multi-source time series of remote sensing data (e.g., MODIS and Worldview), the forest cover change on Rennell Island from 2000 to 2020 and its future trends were mapped and analysed using Sen + Mann–Kendall and Hurst index models. A land cover classification system derived from high-resolution Worldview images was developed as a baseline for monitoring and analysing future forest cover changes on the island. Our results showed that (1) the areas of vegetation degradation and improvement were basically equal from 2000 to 2020. (2) The forest cover change trend had weak continuity, and significant improvements could be achieved in areas with damaged vegetation given sufficient protection measures and financial input. (3) This heritage site has a strong vegetation regeneration ability, and human activities such as mining, logging, and road construction, which could greatly disturb the unique ecosystem, should be restricted.