bluuebunny/crossref_metadata_2025_split huggingface dataset:
Overexpression of miR-101 suppresses collagen synthesis by targeting EZH2 in hypertrophic scar fibroblasts
Authors: Li Jie , Li Yan , Wang Yunchuan , He Xiang , Wang Jing , Cai Weixia , Jia Yanhui , Xiao Dan , Zhang Jian , Zhao Ming , Shen Kuo , Li Zichao , Jia Wenbin , Wang Kejia , Zhang Yue , Su Linlin , Zhu Huayu , Hu Dahai 
Published: September 2021

Abstract

Background
MicroRNA-101 (miR-101) is a tumor suppressor microRNA (miRNA) and its loss is associated with the occurrence and progression of various diseases. However, the biological function and target of miR-101 in the pathogenesis of hypertrophic scars (HS) remains unknown.

Methods
We harvested HS and paired normal skin (NS) tissue samples from patients and cultured their fibroblasts (HSF and NSF, respectively). We used quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), fluorescence in situ hybridization (FISH), enzyme-linked immunosorbent assays (ELISA) and Western blot analyses to measure mRNA levels and protein expression of miR-101, enhancer of zeste homolog 2 (EZH2), collagen 1 and 3 (Col1 and Col3) and α-smooth muscle actin (α-SMA) in different in vitro conditions. We also used RNA sequencing to evaluate the relevant signaling pathways and bioinformatics analysis and dual-luciferase reporter assays to predict miR-101 targets. We utilized a bleomycin-induced fibrosis mouse model in which we injected miR-101 mimics to evaluate collagen deposition in vivo.

Results
We found low expression of miR-101 in HS and HSF compared to NS and NSF. Overexpressing miR-101 decreased Col1, Col3 and α-SMA expression in HSF. We detected high expression of EZH2 in HS and HSF. Knockdown of EZH2 decreased Col1, Col3 and α-SMA in HSF. Mechanistically, miR-101 targeted the 3′-untranslated region (3′UTR) of EZH2, as indicated by the decreased expression of EZH2. Overexpressing EZH2 rescued miR-101-induced collagen repression. MiR-101 mimics effectively suppressed collagen deposition in the bleomycin-induced fibrosis mouse model.

Conclusions
Our data reveal that miR-101 targets EZH2 in HS collagen production, providing new insight into the pathological mechanisms underlying HS formation.
Prognostic impact of tumor-specific insulin-like growth factor binding protein 7 (IGFBP7) levels in breast cancer: a prospective cohort study
Authors: Godina Christopher , Khazaei Somayeh , Tryggvadottir Helga , Visse Edward , Nodin Björn , Jirström Karin , Borgquist Signe , Bosch Ana , Isaksson Karolin , Jernström Helena 
Published: September 2021

Abstract
The prognostic impact of insulin-like growth factor binding protein 7 (IGFBP7) in breast cancer is unclear. Host factors, including lifestyle, anthropometry and metabolic profile, might influence tumor-specific IGFBP7. This study aimed to investigate whether IGFBP7 levels and messenger ribonucleic acid (mRNA) expression are associated with the patient and tumor characteristics and prognosis in breast cancer. Patients with primary breast cancer in Lund, Sweden, were included preoperatively in the study between 2002 and 2012 (n = 1018). Tumor-specific IGFBP7 protein levels were evaluated with immunohistochemistry using tissue microarrays in tumors from 878 patients. IGFBP7 mRNA expression and its corresponding clinical data were obtained from The Cancer Genome Atlas and analyzed for 809 patients. Tumor-specific IGFBP7 protein levels were categorized based on Histo 300 scores into IGFBP7low (6.2%), IGFBP7intermediate (75.7%) and IGFBP7high (18.1%). Both low IGFBP7 protein levels and mRNA expression were associated with less aggressive tumor characteristics. Overall, IGFBP7low conferred low recurrence risk. The prognostic impact of IGFBP7high varied according to any alcohol consumption and tamoxifen treatment. IGFBP7high was associated with low recurrence risk in alcohol consumers but high recurrence risk in alcohol abstainers (Pinteraction= 0.039). Moreover, the combination of IGFBP7high and estrogen receptor-positive tumors was associated with low recurrence risk only in tamoxifen-treated patients (Pinteraction= 0.029). To conclude, IGFBP7low might be a good, independent prognosticator in breast cancer. The prognostic impact of IGFBP7high depends on host factors and treatment. IGFBP7 merits further investigation to confirm whether it could be a suitable biomarker for treatment selection.
Scaling Principles of White Matter Connectivity in the Human and Nonhuman Primate Brain
Authors: Ardesch Dirk Jan , Scholtens Lianne H , de Lange Siemon C , Roumazeilles Lea , Khrapitchev Alexandre A , Preuss Todd M , Rilling James K , Mars Rogier B , van den Heuvel Martijn P 
Published: September 2021

Abstract
Brains come in many shapes and sizes. Nature has endowed big-brained primate species like humans with a proportionally large cerebral cortex. Comparative studies have suggested, however, that the total volume allocated to white matter connectivity—the brain’s infrastructure for long-range interregional communication—does not keep pace with the cortex. We investigated the consequences of this allometric scaling on brain connectivity and network organization. We collated structural and diffusion magnetic resonance imaging data across 14 primate species, describing a comprehensive 350-fold range in brain size across species. We show volumetric scaling relationships that indeed point toward a restriction of macroscale connectivity in bigger brains. We report cortical surface area to outpace white matter volume, with larger brains showing lower levels of overall connectedness particularly through sparser long-range connectivity. We show that these constraints on white matter connectivity are associated with longer communication paths, higher local network clustering, and higher levels of asymmetry in connectivity patterns between homologous areas across the left and right hemispheres. Our findings reveal conserved scaling relationships of major brain components and show consequences for macroscale brain circuitry, providing insights into the connectome architecture that could be expected in larger brains such as the human brain.
Minimally Invasive Tissue Sampling: A Tool to Guide Efforts to Reduce AIDS-Related Mortality in Resource-Limited Settings
Authors: Letang Emilio , Rakislova Natalia , Martinez Miguel J , Carlos Hurtado Juan , Carrilho Carla , Bene Rosa , Mandomando Inacio , Quintó Llorenç , Nhampossa Tacilta , Chicamba Valéria , Luis Elvira , Ismail Mamudo R , Fernandes Fabiola , Lorenzoni Cesaltina , Ferreira Luiz , Freire Monique , Teresa Rodrigo-Calvo Maria , Guerrero José , Munguambe Khátia , Maixenchs Maria , Navarro Mireia , Casas Isaac , Marimon Lorena , Ferrando Melania , Macete Eusebio , Lacerda Marcus , Bassat Quique , Menéndez Clara , Ordi Jaume 
Published: September 2021

Abstract

Background
Available information on the causes of death among people living with human immunodeficiency virus (PLHIV) in low- and middle-income countries (LMICs) remains scarce. We aimed to provide data on causes of death in PLHIV from two LMICs, Brazil and Mozambique, to assess the impact of clinical misdiagnosis on mortality rates and to evaluate the accuracy of minimally invasive tissue sampling (MITS) in determining the cause of death in PLHIV.

Methods
We performed coupled MITS and complete autopsy on 164 deceased PLHIV (18 children, 36 maternal deaths, and 110 adults). HIV antibody levels and HIV RNA viral loads were determined from postmortem serum samples.

Results
Tuberculosis (22.7%), toxoplasmosis (13.9%), bacterial infections (13.9%), and cryptococcosis (10.9%) were the leading causes of death in adults. In maternal deaths, tuberculosis (13.9%), bacterial infections (13.9%), cryptococcosis (11.1%), and cerebral malaria (8.3%) were the most frequent infections, whereas viral infections, particularly cytomegalovirus (38.9%), bacterial infections (27.8%), pneumocystosis (11.1%), and HIV-associated malignant neoplasms (11.1%) were the leading cause among children. Agreement between the MITS and the complete autopsy was 100% in children, 91% in adults, and 78% in maternal deaths. The MITS correctly identified the microorganism causing death in 89% of cases.

Conclusions
Postmortem studies provide highly granular data on the causes of death in PLHIV. The inaccuracy of clinical diagnosis may play a significant role in the high mortality rates observed among PLHIV in LMICs. MITS might be helpful in monitoring the causes of death in PLHIV and in highlighting the gaps in the management of the infections.
Implementing Whole-Genome Sequencing for Ongoing Surveillance of Antimicrobial Resistance: Exemplifying Insights IntoKlebsiella pneumoniae
Authors: Aanensen David M , Carlos Celia C , Donado-Godoy Pilar , Okeke Iruka N , Ravikumar K L ,   NIHR Global Health Research Unit on Genomic Surveillance of Antimicrobial Resistance, Abudahab Khalil , Abrudan Monica , Argimón Silvia , Harste Harry , Kekre Mihir , Muddyman Dawn , Taylor Ben , Underwood Anthony , Wheeler Nicole , David Sophia , Fabian Bernal Johan , Arevalo Alejandra , Fernanda Valencia Maria , Osma Castro Erik C D , Nagaraj Geetha , Shamanna Varun , Govindan Vandana , Prabhu Akshata , Sravani D , Shincy M R , Rose Steffimole , Ravishankar K N , Oaikhena Anderson O , Afolayan Ayorinde O , Ajiboye Jolaade J , Ewomazino Odih Erkison , Lagrada Marietta L , Macaranas Polle Krystle V , Olorosa Agnettah M , Gayeta June M , Herrera Elmer M , Molloy Ali , Vegvari Carolin 
Published: September 2021

AbstractIn this Supplement, we detail outputs of the National Institute for Health Research Global Health Research Unit on Genomic Surveillance of Antimicrobial Resistance project, covering practical implementation of whole-genome sequencing across our consortium, which consists of laboratories in Colombia, India, Nigeria, and the Philippines.
Three-year Efficacy and Safety of Takeda’s Dengue Vaccine Candidate (TAK-003)
Authors: Rivera Luis , Biswal Shibadas , Sáez-Llorens Xavier , Reynales Humberto , López-Medina Eduardo , Borja-Tabora Charissa , Bravo Lulu , Sirivichayakul Chukiat , Kosalaraksa Pope , Martinez Vargas Luis , Yu Delia , Watanaveeradej Veerachai , Espinoza Felix , Dietze Reynaldo , Fernando LakKumar , Wickramasinghe Pujitha , Duarte MoreiraJr Edson , Fernando Asvini D , Gunasekera Dulanie , Luz Kleber , Venâncioda Cunha Rivaldo , Rauscher Martina , Zent Olaf , Liu Mengya , Hoffman Elaine , LeFevre Inge , Tricou Vianney , Wallace Derek , Alera MariaTheresa , Borkowski Astrid 
Published: September 2021

Abstract

Background
Takeda’s live attenuated tetravalent dengue vaccine candidate (TAK-003) is under evaluation in a long-term clinical trial across 8 dengue-endemic countries. Previously, we have reported its efficacy and safety in both seronegative and seropositive participants and that its performance varies by serotype, with some decline in efficacy from first to second year postvaccination. This exploratory analysis provides an update with cumulative and third-year data.

Methods
Healthy 4–16 year olds (n = 20099) were randomized 2:1 to receive TAK-003 or placebo (0, 3 month schedule). The protocol included baseline serostatus testing of all participants and detection of all symptomatic dengue throughout the trial with a serotype specific reverse transcriptase-polymerase chain reaction.

Results
Cumulative efficacy after 3 years was 62.0% (95% confidence interval, 56.6–66.7) against virologically confirmed dengue (VCD) and 83.6% (76.8–88.4) against hospitalized VCD. Efficacy was 54.3% (41.9–64.1) against VCD and 77.1% (58.6–87.3) against hospitalized VCD in baseline seronegatives, and 65.0% (58.9–70.1) against VCD and 86.0% (78.4–91.0) against hospitalized VCD in baseline seropositives. Efficacy against VCD during the third year declined to 44.7% (32.5–54.7), whereas efficacy against hospitalized VCD was sustained at 70.8% (49.6–83.0). Rates of serious adverse events were 2.9% in TAK-003 group and 3.5% in placebo group during the ongoing long-term follow-up (ie, second half of the 3 years following vaccination), but none were related. No important safety risks were identified.

Conclusions
TAK-003 was efficacious against symptomatic dengue over 3 years. Efficacy declined over time but remained robust against hospitalized dengue. A booster dose evaluation is planned.
Administration of a β-Lactam Prior to Vancomycin as the First Dose of Antibiotic Therapy Improves Survival in Patients With Bloodstream Infections
Authors: Amoah Joe , Klein Eili Y , Chiotos Kathleen , Cosgrove Sara E , Tamma Pranita D 
Published: September 2021

Abstract

Background
Prompt initiation of antibiotic therapy improves the survival of patients with bloodstream infections (BSIs). We sought to determine if the sequence of administration of the first dose of antibiotic therapy (ie, β-lactam or vancomycin, if both are deemed necessary and cannot be administered simultaneously) impacts early mortality for patients with BSI.

Methods
We conducted a multicenter, observational study of patients ≥13 years with BSIs to evaluate the association of the sequence of antibiotic administration with 7-day mortality using inverse probability of treatment weighting (IPTW) incorporating propensity scores. Propensity scores were generated based on demographics, Pitt bacteremia score, intensive care unit status, highest lactate, highest white blood cell count, Charlson comorbidity index, severe immunocompromise, administration of active empiric therapy, combination therapy, and time from emergency department arrival to first antibiotic dose.

Results
Of 3376 eligible patients, 2685 (79.5%) received a β-lactam and 691 (20.5%) received vancomycin as their initial antibiotic. In the IPTW cohort, exposed and unexposed patients were similar on all baseline variables. Administration of a β-lactam agent prior to vancomycin protected against 7-day mortality (adjusted odds ratio [aOR], 0.48 [95% confidence interval {CI}, .33–.69]). Similar results were observed when evaluating 48-hour mortality (aOR, 0.45 [95% CI, .24–.83]). Administration of vancomycin prior to a β-lactam was not associated with improved survival in the subgroup of 524 patients with methicillin-resistant Staphylococcus aureus BSI (aOR, 0.93 [95% CI, .33–2.63]).

Conclusions
For ill-appearing patients likely to be experiencing a BSI, prioritizing administration of a β-lactam over vancomycin may reduce early mortality, underscoring the significant impact of a relatively simple practice change on improving patient survival.
Defining Antibiotic Inertia: Application of a Focused Clinical Scenario Survey to Illuminate A New Target for Antimicrobial Stewardship During Transitions of Care
Authors: Kooda Kirstin , Bellolio Fernanda , Dierkhising Ross , Tande Aaron J 
Published: September 2021

Abstract
In clinical scenario surveys, inpatient providers were more likely to report continuing inappropriate (odds ratio, 2.02 [95% confidence interval, 1.35–3.03]; P&lt;.001) or broad-spectrum (1.8 [1.27–2.56]; P=.001) antibiotic therapy when initiated by emergency department providers, than to change to appropriate or narrow-spectrum therapy, respectively. Antibiotic inertia could represent a significant antibiotic stewardship target.
Remdesivir Treatment in Hospitalized Patients With Coronavirus Disease 2019 (COVID-19): A Comparative Analysis of In-hospital All-cause Mortality in a Large Multicenter Observational Cohort
Authors: Mozaffari Essy , Chandak Aastha , Zhang Zhiji , Liang Shuting , Thrun Mark , Gottlieb Robert L , Kuritzkes Daniel R , Sax Paul E , Wohl David A , Casciano Roman , Hodgkins Paul , Haubrich Richard 
Published: September 2021

Abstract

Background
Remdesivir (RDV) improved clinical outcomes among hospitalized patients with coronavirus disease 2019 (COVID-19) in randomized trials, but data from clinical practice are limited.

Methods
We examined survival outcomes for US patients hospitalized with COVID-19 between August and November 2020 and treated with RDV within 2 days of hospitalization vs those not receiving RDV during their hospitalization using the Premier Healthcare Database. Preferential within-hospital propensity score matching with replacement was used. Additionally, patients were also matched on baseline oxygenation level (no supplemental oxygen charges [NSO], low-flow oxygen [LFO], high-flow oxygen/noninvasive ventilation [HFO/NIV], and invasive mechanical ventilation/extracorporeal membrane oxygenation [IMV/ECMO]) and 2-month admission window and excluded if discharged within 3 days of admission (to exclude anticipated discharges/transfers within 72 hours, consistent with the Adaptive COVID-19 Treatment Trial [ACTT-1] study). Cox proportional hazards models were used to assess time to 14-/28-day mortality overall and for patients on NSO, LFO, HFO/NIV, and IMV/ECMO.

Results
A total of 28855 RDV patients were matched to 16687 unique non-RDV patients. Overall, 10.6% and 15.4% RDV patients died within 14 and 28 days, respectively, compared with 15.4% and 19.1% non-RDV patients. Overall, RDV was associated with a reduction in mortality at 14 days (hazard ratio [95% confidence interval]: 0.76 [0.70–0.83]) and 28 days (0.89 [0.82–0.96]). This mortality benefit was also seen for NSO, LFO, and IMV/ECMO at 14 days (NSO: 0.69 [0.57–0.83], LFO: 0.68 [0.80–0.77], IMV/ECMO: 0.70 [0.58–0.84]) and 28 days (NSO: 0.80 [0.68–0.94], LFO: 0.77 [0.68–0.86], IMV/ECMO: 0.81 [0.69–0.94]). Additionally, HFO/NIV RDV group had a lower risk of mortality at 14 days (0.81 [0.70–0.93]) but no statistical significance at 28 days.

Conclusions
RDV initiated upon hospital admission was associated with improved survival among patients with COVID-19. Our findings complement ACTT-1 and support RDV as a foundational treatment for hospitalized COVID-19 patients.
Pathogen-Specific Effects of Probiotics in Children With Acute Gastroenteritis Seeking Emergency Care: A Randomized Trial
Authors: Freedman Stephen B , Finkelstein Yaron , Pang Xiao Li , Chui Linda , Tarr Phillip I , VanBuren John M , Olsen Cody , Lee Bonita E , Hall-Moore Carla A , Sapien Robert , O’Connell Karen , Levine Adam C , Poonai Naveen , Roskind Cindy , Schuh Suzanne , Rogers Alexander , Bhatt Seema , Gouin Serge , Mahajan Prashant , Vance Cheryl , Hurley Katrina , Powell Elizabeth C , Farion Ken J , Schnadower David 
Published: September 2021

Abstract

Background
It is unknown if probiotics exert pathogen-specific effects in children with diarrhea secondary to acute gastroenteritis.

Methods
Analysis of patient-level data from 2 multicenter randomized, placebo controlled trials conducted in pediatric emergency departments in Canada and the United States. Participants were 3–48 months with &gt;3 diarrheal episodes in the preceding 24 hours and were symptomatic for &lt;72 hours and &lt;7 days in the Canadian and US studies, respectively. Participants received either placebo or a probiotic preparation (Canada-Lactobacillus rhamnosus R0011/Lactobacillus helveticus R0052; US-L. rhamnosus GG). The primary outcome was post-intervention moderate-to-severe disease (ie, ≥9 on the Modified Vesikari Scale [MVS] score).

Results
Pathogens were identified in specimens from 59.3% of children (928/1565). No pathogen groups were less likely to experience an MVS score ≥9 based on treatment allocation (test for interaction = 0.35). No differences between groups were identified for adenovirus (adjusted relative risk [aRR]: 1.42; 95% confidence interval [CI]: .62, 3.23), norovirus (aRR: 0.98; 95% CI: .56, 1.74), rotavirus (aRR: 0.86; 95% CI: .43, 1.71) or bacteria (aRR: 1.19; 95% CI: .41, 3.43). At pathogen-group and among individual pathogens there were no differences in diarrhea duration or the total number of diarrheal stools between treatment groups, regardless of intervention allocation or among probiotic sub-groups. Among adenovirus-infected children, those administered the L. rhamnosus R0011/L. helveticus R0052 product experienced fewer diarrheal episodes (aRR: 0.65; 95% CI: .47, .90).

Conclusions
Neither probiotic product resulted in less severe disease compared to placebo across a range of the most common etiologic pathogens. The preponderance of evidence does not support the notion that there are pathogen specific benefits associated with probiotic use in children with acute gastroenteritis.

Clinical Trials Registration
NCT01773967 and NCT01853124.
One-Year Sustained Cellular and Humoral Immunities in Coronavirus Disease 2019 (COVID-19) Convalescents
Authors: Zhang Jie , Lin Hao , Ye Beiwei , Zhao Min , Zhan Jianbo , Dong Shaobo , Guo Yaxin , Zhao Yingze , Li Min , Liu Sai , Zhang Hangjie , Xiao Wenling , Guo Yuanyuan , Yue Can , Zhang Danni , Yang Mengjie , Zhang Jing , Quan Chuansong , Shi Weifeng , Liu Xinxue , Liu Peipei , Jiang Yongzhong , Wu Guizhen , Gao George F , Liu William J 
Published: September 2021

Abstract

Background
The longitudinal antigen-specific immunity in COVID-19 convalescents is crucial for long-term protection upon individual re-exposure to SARS-CoV-2, and even more pivotal for ultimately achieving population-level immunity. We conducted this cohort study to better understand the features of immune memory in individuals with different disease severities at 1 year post–disease onset.

Methods
We conducted a systematic antigen-specific immune evaluation in 101 COVID-19 convalescents, who had asymptomatic, mild, moderate, or severe disease, through 2 visits at months 6 and 12 after disease onset. The SARS-CoV-2–specific antibodies, comprising neutralizing antibody (NAb), immunoglobulin (Ig) G, and IgM, were assessed by mutually corroborated assays (ie, neutralization, enzyme-linked immunosorbent assay [ELISA], and microparticle chemiluminescence immunoassay [MCLIA]). Meanwhile, T-cell memory against SARS-CoV-2 spike, membrane, and nucleocapsid proteins was tested through enzyme-linked immunospot assay (ELISpot), intracellular cytokine staining, and tetramer staining-based flow cytometry, respectively.

Results
SARS-CoV-2–specific IgG antibodies, and NAb, can persist among &gt;95% of COVID-19 convalescents from 6 to 12 months after disease onset. At least 19/71 (26%) of COVID-19 convalescents (double positive in ELISA and MCLIA) had detectable circulating IgM antibody against SARS-CoV-2 at 12 months post–disease onset. Notably, numbers of convalescents with positive SARS-CoV-2–specific T-cell responses (≥1 of the SARS-CoV-2 antigen S1, S2, M, and N proteins) were 71/76 (93%) and 67/73 (92%) at 6 and 12 months, respectively. Furthermore, both antibody and T-cell memory levels in the convalescents were positively associated with disease severity.

Conclusions
SARS-CoV-2–specific cellular and humoral immunities are durable at least until 1 year after disease onset.
Uneven development: convergence, divergence and politics
Authors: Cox Kevin R 
Published: September 2021

AbstractThe paper positions itself in contrast to some themes in work on local and regional development. These have included an emphasis on policy rather than politics, tendencies to over-generalize across countries, and to abstract from the more global context. The empirical context for the discussion is the shifting character of geographically uneven development since the Second World War: first a convergence and then, after the mid-1970s, a divergence. Convergence is held to be the result of what some have called spatial Keynesianism. The conditions for this and for its demise, resulting in divergence, are traced out with particular reference to how the shifting pressures and opportunities were refracted by the specificities of countries. State form emerges as particularly important in understanding different trajectories, along with a neo-liberal globalisation that has been in contrast to the monetary and trading regime inaugurated by the Bretton Woods agreements.