Miracle-dz/UniFAR-FTUs huggingface dataset:
Phosphodiesterase 4 mediates interleukin‐8‐induced heterologous desensitization of the β2‐adrenergic receptor

Acute respiratory distress syndrome (ARDS) is a life‐threatening illness characterized by decreased alveolar‐capillary barrier function, pulmonary edema consisting of proteinaceous fluid, and inhibition of net alveolar fluid transport responsible for resolution of pulmonary edema. There is currently no pharmacotherapy that has proven useful to prevent or treat ARDS, and two trials using beta‐agonist therapy to treat ARDS demonstrated no effect. Prior studies indicated that IL‐8‐induced heterologous desensitization of the beta2‐adrenergic receptor (β2‐AR) led to decreased beta‐agonist‐induced mobilization of cyclic adenosine monophosphate (cAMP). Interestingly, phosphodiesterase (PDE) 4 inhibitors have been used in human airway diseases characterized by low intracellular cAMP levels and increases in specific cAMP hydrolyzing activity. Therefore, we hypothesized that PDE4 would mediate IL‐8‐induced heterologous internalization of the β2‐AR and that PDE4 inhibition would restore beta‐agonist‐induced functions. We determined that CINC‐1 (a functional IL‐8 analog in rats) induces internalization of β2‐AR from the cell surface, and arrestin‐2, PDE4, and β2‐AR form a complex during this process. Furthermore, we determined that cAMP associated with the plasma membrane was adversely affected by β2‐AR heterologous desensitization. Additionally, we determined that rolipram, a PDE4 inhibitor, reversed CINC‐1‐induced derangements of cAMP and also caused β2‐AR to successfully recycle back to the cell surface. Finally, we demonstrated that rolipram could reverse CINC‐1‐mediated inhibition of beta‐agonist‐induced alveolar fluid clearance in a murine model of trauma‐shock. These results indicate that PDE4 plays a role in CINC‐1‐induced heterologous internalization of the β2‐AR; PDE4 inhibition reverses these effects and may be a useful adjunct in particular ARDS patients.
Intraprostatic injection of exosomes isolated from adipose‐derived mesenchymal stem cells for the treatment of chronic non‐bacterial prostatitis

Mesenchymal stem cells (MSCs) own the capacity to secrete trophic factors as exosomes which play significant roles in regulating the functions of other cells and preventing inflammation. Due to the inflammatory process in chronic non‐bacterial prostatitis (CNP) and the ambiguity in the treatment of this disease, the present study was aimed to investigate the therapeutic use of adipose‐derived MSC exosomes in an animal model of CNP. MSCs were first isolated from rat subcutaneous adipose tissue, and exosomes were extracted from them. Specific features of exosomes were characterized by a scanning electron microscope, western blot technique, and Dynamic Light Scattering methods. To establish CNP in rats, intraprostatic injection of Freund's complete adjuvant was done. After confirmation of prostatitis, intraprostatic injections of exosomes were performed for treatment. Histological evaluation revealed that treatment with exosomes resulted in a relative improvement of lesions caused by CNP. The expression of p‐NF‐κB and p‐IκBα proteins along with inflammatory markers was significantly increased in the CNP group, which treatment with exosomes significantly reduced their expression as well as IL‐1β and TNF‐α proteins. The antioxidant effects of exosomes were also determined by significantly regulating glutathione peroxidase and superoxide dismutase activity and malondialdehyde levels in these animals. Our results cautiously suggest the therapeutic effects of MSC‐derived exosomes against CNP‐induced prostatitis through their antioxidant and anti‐inflammatory activities, which should be further considered in the future.
Comment on “Recent global decline of CO2 fertilization effects on vegetation photosynthesis”

Description Wang et al. (Research Articles, 11 December 2020, p. 1295) reported a large decline in the CO2 fertilization effect (CFE) on global photosynthesis, on the basis of changing regression coefficients of CO2 (β) for satellite proxies/products of photosynthesis. We show that their methods cannot robustly estimate CFE, leading to incorrect attribution, and largely neglect CO2 effects on the photosynthetic enzyme ribulose-1,5-bisphosphate carboxylase-oxygenase (RuBisCO).
Understanding the burden of interstitial lung disease post-COVID-19: the UK Interstitial Lung Disease-Long COVID Study (UKILD-Long COVID)

Introduction The COVID-19 pandemic has led to over 100 million cases worldwide. The UK has had over 4 million cases, 400 000 hospital admissions and 100 000 deaths. Many patients with COVID-19 suffer long-term symptoms, predominantly breathlessness and fatigue whether hospitalised or not. Early data suggest potentially severe long-term consequence of COVID-19 is development of long COVID-19-related interstitial lung disease (LC-ILD). Methods and analysis The UK Interstitial Lung Disease Consortium (UKILD) will undertake longitudinal observational studies of patients with suspected ILD following COVID-19. The primary objective is to determine ILD prevalence at 12 months following infection and whether clinically severe infection correlates with severity of ILD. Secondary objectives will determine the clinical, genetic, epigenetic and biochemical factors that determine the trajectory of recovery or progression of ILD. Data will be obtained through linkage to the Post-Hospitalisation COVID platform study and community studies. Additional substudies will conduct deep phenotyping. The Xenon MRI investigation of Alveolar dysfunction Substudy will conduct longitudinal xenon alveolar gas transfer and proton perfusion MRI. The POST COVID-19 interstitial lung DiseasE substudy will conduct clinically indicated bronchoalveolar lavage with matched whole blood sampling. Assessments include exploratory single cell RNA and lung microbiomics analysis, gene expression and epigenetic assessment. Ethics and dissemination All contributing studies have been granted appropriate ethical approvals. Results from this study will be disseminated through peer-reviewed journals. Conclusion This study will ensure the extent and consequences of LC-ILD are established and enable strategies to mitigate progression of LC-ILD.
Leishmania tarentolae and Leishmania infantum in humans, dogs and cats in the Pelagie archipelago, southern Italy

Visceral leishmaniasis (VL) caused by Leishmania infantum is endemic in the Mediterranean basin with most of the infected human patients remaining asymptomatic. Recently, the saurian-associated Leishmania tarentolae was detected in human blood donors and in sheltered dogs. The circulation of L. infantum and L. tarentolae was investigated in humans, dogs and cats living in the Pelagie islands (Sicily, Italy) by multiple serological and molecular testing. Human serum samples (n = 346) were tested to assess the exposure to L. infantum by immunofluorescence antibody test (IFAT), enzyme-linked immunosorbent assay (ELISA) and Western blot (WB) and to L. tarentolae by IFAT. Meanwhile, sera from dogs (n = 149) and cats (n = 32) were tested for both Leishmania species by IFAT and all blood samples, including those of humans, by specific sets of real time-PCR for L. infantum and L. tarentolae. The agreement between serological tests performed for human samples, and between serological and molecular diagnostic techniques for both human and animal samples were also assessed. Overall, 41 human samples (11.8%, 95% CI: 8.9–15.7) were positive to L. infantum (5.2%, 95% CI: 3.3–8.1), L. tarentolae (5.2%, 95% CI: 3.3–8.1) and to both species (1.4%, 95% CI: 0.6–3.3) by serology and/or molecular tests. A good agreement among the serological tests was determined. Both Leishmania spp. were serologically and/or molecularly detected in 39.6% dogs and 43.7% cats. In addition to L. infantum, also L. tarentolae circulates in human and animal populations, raising relevant public health implications. Further studies should investigate the potential beneficial effects of L. tarentolae in the protection against L. infantum infection.
Clinical impact of NPM1-mutant molecular persistence after chemotherapy for acute myeloid leukemia

Key Points Postchemotherapy, of 100 CRMRD+ patients, 42% remained progression free at 1 year (spontaneous CRMRD− or low-level NPM1mut persistence). Relapse is associated with FLT3-ITD and poor NPM1mut MRD response after chemotherapy. MRD-directed preemptive therapy may prolong remission.
Combination therapies for COVID‐19: An overview of the clinical trials landscape

The COVID‐19 pandemic has driven an unprecedented level of global activity in drug discovery and clinical development for effective therapeutics targeting the coronavirus disease. There are currently 744 therapeutics being tested in 2879 clinical trials globally. Almost 90% of these clinical trials are focused on monotherapies. Combination therapies are the mainstay of antiviral therapeutics to increase the potency of the individual compounds and to combat the rapid evolution of resistance, although combination therapies have inherently complex clinical and regulatory development challenges. Increased understanding of the SARS‐CoV‐2 lifecycle and COVID‐19 pathology provides a scientific rationale for evaluating the effectiveness of different combinations. In this paper, we provide an overview of the current clinical trial landscape for combination therapeutics targeting COVID‐19 through weekly scanning of national and international clinical trial registries. Our analysis delves specifically into dual combination therapies in what can be defined as “pivotal clinical trials” (active, randomised, controlled and at least phase II), with a focus on new and repurposed therapeutic candidates that have shown positive signals and/or been granted authorisation for emergency use based on positive efficacy and safety data.
Use of Pfizer-BioNTech COVID-19 Vaccine in Persons Aged ≥16 Years: Recommendations of the Advisory Committee on Immunization Practices — United States, September 2021

The Pfizer-BioNTech COVID-19 vaccine (BNT162b2) is a lipid nanoparticle-formulated, nucleoside mRNA vaccine encoding the prefusion spike glycoprotein of SARS-CoV-2, the virus that causes COVID-19. Vaccination with the Pfizer-BioNTech COVID-19 vaccine consists of 2 intramuscular doses (30 μg, 0.3 mL each) administered 3 weeks apart. In December 2020, the vaccine was granted Emergency Use Authorization (EUA) by the Food and Drug Administration (FDA) as well as an interim recommendation for use among persons aged ≥16 years by the Advisory Committee on Immunization Practices (ACIP) (1). In May 2021, the EUA and interim ACIP recommendations for Pfizer-BioNTech COVID-19 vaccine were extended to adolescents aged 12-15 years (2). During December 14, 2020-September 1, 2021, approximately 211 million doses of Pfizer-BioNTech COVID-19 vaccine were administered in the United States. * On August 23, 2021, FDA approved a Biologics License Application for use of the Pfizer-BioNTech COVID-19 vaccine, Comirnaty (Pfizer, Inc.), in persons aged ≥16 years (3). The ACIP COVID-19 Vaccines Work Group's conclusions regarding the evidence for the Pfizer-BioNTech COVID-19 vaccine were presented to ACIP at a public meeting on August 30, 2021. To guide its deliberations regarding the Pfizer-BioNTech COVID-19 vaccine, ACIP used the Evidence to Recommendation (EtR) Framework,† and incorporated a Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. § In addition to initial clinical trial data, ACIP considered new information gathered in the 8 months since issuance of the interim recommendation for Pfizer-BioNTech COVID-19 vaccine, including additional follow-up time in the clinical trial, real-world vaccine effectiveness studies, and postauthorization vaccine safety monitoring. The additional information increased certainty that benefits from prevention of asymptomatic infection, COVID-19, and associated hospitalization and death outweighs vaccine-associated risks. On August 30, 2021, ACIP issued a recommendation¶ for use of the Pfizer-BioNTech COVID-19 vaccine in persons aged ≥16 years for the prevention of COVID-19.
The use of uncertain exposure—A method to define switching and add‐on in pharmacoepidemiology

When defining exposure to pharmacological treatments in pharmacoepidemiology, register data often do not provide information regarding if a pharmacological treatment is a switch or an add‐on. This study aims to compare two methods defining switching and add‐on therapies and their impact on exposure‐outcome associations. Additionally, to guide bias reduction, it aims to describe how the methods relate to immortal time bias and selection bias.
Fitness to drive after acquired brain injury: Results from patient cognitive screening and on-road assessment compared to age-adjusted norm values.

Fitness to drive after acquired brain injury or disease is a common question in rehabilitation settings. The aim of the study was to compare age-matched norms with patient cognitive test results used to predict fitness to drive. A second aim was to analyze the contribution from an on-road assessment to a final decision on resumption of driving after an acquired brain injury. Retrospective cognitive test results from four traffic medicine units (n = 333) were compared with results from a healthy norm population (n = 410) in Sweden. Patients were dichotomized according to the final decision as fit or unfit to drive made by the traffic medicine team. The norm group had significantly better results in all age groups for all cognitive tests compared with the patients considered unfit to drive and fit to drive. A binary regression analysis for the patient group showed an explained value for fit to drive/unfit to drive of 88%, including results for the Nordic Stroke Driver Screening Assessment total score, Useful Field of View total score and the final outcome from an on-road assessment. Results from the present study illustrate the importance of using several tests, methods and contexts for the final decision regarding fitness to drive.
Exosomes in serum-free cultures of THP-1 macrophages infected with Mycobacterium tuberculosis

It has been shown from the isolation and characterization of exosomes from cell culture media supplemented with fetal bovine serum that both their quality and purity are affected. The high abundance of serum proteins, including bovine cell derived exosomes, is also a potential source of contaminants, which may result in appreciable yields of impure exosomes, thereby leading to artifacts. Isolation and characterization of exosomes from cells maintained under serum-free conditions should therefore ensure the high quality necessary for medical applications. To meet this end, the present study aimed to characterize exosomes released from THP-1 macrophages cultured in serum-free, ultra-centrifuged medium upon infection with the human pathogen Mycobacterium tuberculosis (Mtb). Macrophages differentiated from the human cell line THP-1 were infected at a multiplicity of infection (MOI) of 5. Macrophages were cultivated in CellGenix® GMP DC serum-free ultra-centrifuged medium for 4, 24 and 48 h at 37°C in a humidified atmosphere with 5% CO2. Total exosome isolation reagent was used to extract the exosomes from the cell culture supernatants of naïve and Mtb-infected THP-1 macrophages. The size and purity of the exosomes isolated were subsequently assessed by various methods, including nanoparticle tracking analysis, flow cytometry, MACSPlex exosome analysis, and western blotting. The serum-free, ultra-centrifuged medium was found to support the proliferation of the THP-1 cells successfully. The nanoparticle tracking analysis data revealed that the majority of the isolated particles were within the size range of exosomes (i.e., 30–150 nM). The MACSPlex exosome analysis confirmed the expression of the exosomal markers, CD9, CD63 and CD81. Furthermore, western blot analysis of the isolated exosomes indicated the presence of CD9, CD63, CD81 and lysosomal associated membrane protein-1 (LAMP-1), and also confirmed the absence of Mtb proteins. Taken together, these data provide evidence that serum-free, ultra-centrifuged CellGenix® GMP DC medium is suitable for application in exosome research, and may significantly advance such studies. Therefore, the use of serum-free medium for exosome isolation purposes could offer considerable advantages, and constitute a significant improvement in the growing field of extracellular vesicle research. The use of more sensitive methods represents an advance that will enable researchers to rule out the presence of Mtb pathogenic proteins in exosomes isolated from infected serum-free cell cultures.
Letter to the Editor: Reply to Autoimmune Hepatitis and Coronavirus Disease 2019: Disease Outcomes and Tacrolimus Use

We appreciate the interest of Dr. Ng(1) in our recently published study on the outcome of coronavirus disease 2019 (COVID19) in patients with autoimmune hepatitis (AIH). (2) Some comments by the author prompt clarifications. Concerning the comment on differences between the two study cohorts, we tried to match patients with AIH and nonAIH chronic liver disease for age, sex, presence of cirrhosis, and comorbid conditions (diabetes mellitus, hypertension, and heart diseases). The distribution of prognostic factors was still not the same. The AIH group was older, more commonly women, had a higher rate of cirrhosis, and also a lower frequency of comorbid conditions. These differences were, however, numerically small and did not have a significant effect on our main results. Dr. Ng hypothesizes that similar outcomes in the patients with AIH and those with nonAIH liver disease may be related to immunosuppression. The aim of steroid therapy in AIH is different from that in COVID19. Longterm lowdose steroid therapy in patients with AIH may blunt the initial immune response to COVID19, while highdose steroid therapy for COVID19 aims to prevent an inappropriate immune response, or cytokine storm, in critically ill patients. More than half of our patients with AIH were not hospitalized, and two thirds maintained their immunosuppression unchanged. We agree that tacrolimus may be a good, albeit unlicensed, therapy when patients with AIH are nonresponders or intolerant to standard therapy; however, it may be premature to suggest that tacrolimus has protective effects in COVID19. One recent study suggested that the use of tacrolimus was associated with better survival,(3) another study did not show beneficial effects in liver transplant receipts with COVID19. (4) A third study even reported that patients treated with cyclosporine/tacrolimus (for any reason) had a significantly increased risk of hospitalization for COVID19 when compared to the general population. (5) In our study, only a few patients were on tacrolimus therapy. The limited data on AIH cohorts with COVID19 and licenserelated barriers in many countries represent limitations for the routine use of tacrolimus in patients with AIH during COVID19.
Profiles of Resilience from Early to Middle Childhood among Children Known to Child Protection Services

ABSTRACT Objective The processes facilitating resilience are likely to be influenced by individual, familial and contextual factors that are dynamic across the life-course. These factors have been less studied in relation to resilience profiles evident in the developmental period between early to middle childhood, relative to later periods of adolescence or adulthood. Method This study examined factors associated with resilience in a cohort of 4,716 children known to child protection services by age 13 years, in the Australian State of New South Wales. Latent profile and transition analyses were used to identify multi-dimensional profiles of resilience as evident in social, emotional and cognitive functioning when assessed in early childhood (time 1 [T1], age 5–6 years) and middle childhood (time 2 [T2], age 10–11 years). Logistic regression models were used to investigate factors associated with two types of resilience identified: a transition profile of stress-resistance (i.e., represented by a typically developing profile at both T1 and T2) delineated in the largest subgroup (54%) of children, and a smaller subgroup (13%) with a profile of emergent resilience (i.e., typically developing at T2 following a vulnerable profile at T1). Results Factors associated with resilience profiles included being female, and personality characteristics of openness and extraversion; other factors associated with stress-resistance, specifically, included higher socioeconomic status, non-Indigenous background, higher perceived port at home and at school, and not having a parent with a history of criminal offending. Conclusions Resilience processes appear to involve a complex interplay between individual, family, and community characteristics requiring interagency support.
PPARγ attenuates hepatic inflammation and oxidative stress of non-alcoholic steatohepatitis via modulating the miR-21-5p/SFRP5 pathway

Inflammation and oxidative stress are key steps in the progression of non-alcoholic steatohepatitis (NASH). Intervention in these two processes will therefore benefit NASH treatment. Peroxisome proliferator-activated receptor γ (PPARγ), as a multiple functional transcription factor, has been reported to be involved in the prevention of NASH progression. However, the mechanism by which PPARγ prevents NASH remains to be elucidated. The present study demonstrated that the level of PPARγ was inversely correlated with that of microRNA (miRNA/miRs)-21-5p in both mice and humans with NASH. Activation of PPARγ inhibited lipid droplet accumulation, hepatic inflammation and oxidative stress by downregulating miR-21-5p in an in vitro model. Luciferase reporter and chromatin immunoprecipitation assays demonstrated that PPARγ suppressed transcriptional activity of miR-21-5p and bound to miR-21-5p promoter region. Furthermore, PPARγ downregulated miR-21-5p while miR-21-5p upregulated secreted frizzled-related protein 5 (SFRP5) by targeting the 3′-UTR of its mRNA. In vivo experiments revealed that PPARγ repressed inflammation and oxidative stress and miR-21-5p expression while increased SFRP5 level in a NASH mouse model. In summary, PPARγ attenuates inflammation and oxidative stress in NASH by modulating the miR-21-5p/SFRP5 pathway, thus holding promise of a new target for NASH treatment.
Social Media Communication about HPV Vaccine in China: A Study Using Topic Modeling and Survey

ABSTRACT The human papillomavirus (HPV) vaccine is relatively novel to people in China. Social media is becoming an important channel for learning new health information. However, limited is known about what HPV vaccine information has been disseminated on social media, and how such online information is associated with health-related behaviors in China. Based on Longo et al.’s model of patient use of healthcare information for healthcare decision, and Longo’s model of health information seeking behaviors, this study examined HPV vaccine-related information type and information acquisition pattern. Following the mixed-methods approach, we first crawled 67,773 postings about HPV vaccine on Weibo, the largest microblogging website in China, and performed topic modeling to identify HPV vaccine-related topics that are prevalent on Weibo. The results showed six major topics about HPV vaccine, namely policy, guidance information, advertising, scandals, personal experience sharing, and HPV risks. Second, we conducted an online survey (n = 1,982) to investigate how scanning, seeking, and discussing the six HPV vaccine topics identified from big data analytics can affect HPV vaccine knowledge, safety concern, and vaccination intention. We documented significant impacts of social media health communication on users’ health knowledge, attitude and behavioral intention.