Miracle-dz/UniFAR-FTUs huggingface dataset:
The initiation of Otx2 expression in the developing mouse retina requires a unique enhancer and either Ascl1 or Neurog2 activity.

During retinal development, a large subset of progenitors upregulates the transcription factor Otx2, which is required for photoreceptor and bipolar cell formation. How these retinal progenitor cells initially activate Otx2 expression is unclear. To address this, we investigated the cis-regulatory network that controls Otx2 expression. We identified a minimal enhancer element, DHS-4D, that drove expression in newly formed OTX2+ cells. CRISPR/Cas9 mediated deletion of DHS-4D reduced OTX2 expression, but this effect was diminished in postnatal development. Systematic mutagenesis of the enhancer revealed that three basic helix-loop-helix (bHLH) transcription factor binding sites were required for its activity. Single cell RNA-sequencing of nascent Otx2+ cells identified the bHLH factors Ascl1 and Neurog2 as candidate regulators. CRISPR/Cas9 targeting of these factors showed that only the simultaneous loss of Ascl1 and Neurog2 prevented OTX2 expression. Our findings suggest that Ascl1 and Neurog2 act redundantly or in a compensatory fashion to activate the DHS-4D enhancer and Otx2 expression. We observed redundancy or compensation at both the transcriptional and enhancer utilization levels, suggesting that the mechanisms governing Otx2 regulation in the retina are flexible and robust.
Neonatal outcome of small for gestational age infants born at 26–33 weeks’ gestation in Chinese neonatal intensive care units

Background Rate and outcomes of small for gestational age (SGA) infants admitted to Chinese neonatal intensive care units (NICU) has been poorly demonstrated. We aimed to describe the rate and outcomes of SGA preterm infants in Chinese NICU, and to evaluate the association of SGA status with neonatal outcomes in different gestational age (GA) and birth weight percentile groups. Methods This cohort study included all infants born at 26–33 weeks’ gestation and admitted to 25 tertiary Chinese NICUs from April 2015 to May 2018. SGA was defined as a birthweight <10th percentile for GA based on the Chinese neonatal birth weight curve. Results A total of 24,596 infants were included, and 1,867 (7.6%) infants were SGA. SGA infants had significantly higher rates of death or any major morbidity (29.8% vs. 20.5%), mortality (7.0% vs. 4.1%), bronchopulmonary dysplasia (BPD, 17.6% vs. 9.8%), necrotizing enterocolitis (NEC, 4.8% vs. 3.2%) and sepsis (7.3% vs. 4.8%) than non-SGA infants. SGA status was independently associated with increased risk of death or any major morbidity [adjusted odds ratio: 2.37 (2.08–2.71)] as well as increased risks of death, BPD, ROP, death or BPD, death or ROP, NEC and sepsis. The increased risks of adverse outcomes for SGA infants existed across GA groups. The risks of adverse outcomes were highest among infants with a birthweight <3rd percentile. Conclusions SGA contributes significantly to adverse neonatal outcomes. Specific attentions are warranted when caring for SGA preterm infants.
The Association Between Periodontitis and Erectile Dysfunction: A Systematic Review and Meta-Analysis

The objective of this study is to investigate the association between periodontitis (PD) and erectile dysfunction (ED). A systematic review and meta-analysis on data was extracted and conducted according to PRISMA. Relevant articles were selected from a literature search using MEDLINE, EMBASE, Scopus, Web of Science and CENTRAL from inception until August 2, 2020. Both randomized and nonrandomized controlled studies were included. Case reports, case series, nonsystematic reviews and trials published as abstract were excluded. Odds ratios (ORs) and corresponding 95% conﬁdence intervals (CIs) were used to estimate the association between PD and the risk of ED. The meta-analysis was conducted with RevMan 5.3. Methodological quality assessment was carried out using the Newcastle-Ottawa Quality Assessment Scale and the quality of evidence was assessed using the GRADE approach. Six articles (215008 subjects) were included for analysis. Of the participants, 38,675 cases were compared to 1,76,333 healthy controls. Based on the random effects model, periodontitis was associated with an increased risk of ED (OR = 2.56, 95% CI: 1.70–3.85) as compared with the non-periodontitis individuals. The findings were statistically significant with a p < . 0001. The statistical heterogeneity was high across all studies (I2 = 98%, p < .00001). Estimates of total effects were generally consistent with the sensitivity and subgroup analyses. Within the limits of the available evidence, our review and meta-analysis showed that a significant association exists between the PD and ED. The results should be interpreted with caution due to high degree of inconsistency across all the studies.
Stage III N2 non-small cell lung cancer treatment: decision-making among surgeons and radiation oncologists

Background Stage III N2 non-small cell lung cancer (NSCLC) is a very heterogeneous disease associated with a poor prognosis. A number of therapeutic options are available for patients with Stage III N2 NSCLC, including surgery [with neoadjuvant or adjuvant chemotherapy (CTx)/neoadjuvant chemoradiotherapy (CRT)] or CRT potentially followed by adjuvant immunotherapy. We have no clear evidence demonstrating a significant survival benefit for either of these approaches, the selection between treatments is not always straightforward and can come down to physician and patient preference. The very heterogeneous definition of resectability of N2 disease makes the decision-making process even more complex. Methods We evaluated the treatment strategies for preoperatively diagnosed stage III cN2 NSCLC among Swiss thoracic surgeons and radiation oncologists. Treatment strategies were converted into decision trees and analysed for consensus and discrepancies. We analysed factors relevant to decision-making within these recommendations. Results For resectable “non-bulky” mediastinal lymph node involvement, there was a trend towards surgery. Numerous participants recommend a surgical approach outside existing guidelines as long as the disease was resectable, even in multilevel N2. With increasing extent of mediastinal nodal disease, multimodal treatment based on radiotherapy was more common. Conclusions Both, surgery- or radiotherapy-based treatment regimens are feasible options in the management of Stage III N2 NSCLC. The different opinions reflected in the results of this manuscript reinforce the importance of a multidisciplinary setting and the importance of shared decision-making with the patient.
Olig2 knockdown alleviates hypoxic-ischemic brain damage in newborn rats.

OBJECTIVES Neuronal damage is an important pathological mechanism in neonatal hypoxic-ischemic brain damage (HIBD). We found in our previous studies that oligodendrocyte transcription factor 2 (Olig2) downregulation was able to increase cell survival in the brain. However, the specific mechanism has yet to be clarified. METHODS Sprague-Dawley rats aged 3 d were randomly divided into three groups: the normal control group, the Olig2-RNAi group, and the RNAi-negative control group. The normal control group received no treatment, the Olig2-RNAi group received the Olig2 RNAi adenovirus, and the RNAi-negative control group was given the control adenovirus after the completion of the HIBD model. Infarct lesions and their volumes were observed by triphenyltetrazolium chloride (TTC) staining 3 d after the completion of the adenovirus local injection. The condition of the tissue was characterized by hematoxylin-eosin staining 7 d after the model was established, and cell viability was determined by azure methylene blue staining. Subcellular damage was analyzed by transmission electron microscopy. Rotarod analysis was performed to detect moving behavior ability and an MWM assay was conducted to evaluate the memory. RESULTS TTC staining showed a smaller brain injury area in the Olig2-RNAi group than in the RNAi-negative control group. Hematoxylin-eosin staining indicated the presence of severe cell injury in the hippocampal region after HIBD, which improved after Olig2 knockdown. Azure methylene blue staining and electron microscopy results suggested that the cells improved after Olig2 knockdown. The rats stayed longer on the rotating rod, and their latency in the water maze test was gradually shortened relative to that of the rats in the Olig2-RNAi negative control group. CONCLUSION Olig2 knockdown can promote the repair of hypoxic-ischemic brain damage in newborn rats.
Adjuvant pembrolizumab in genomically selected high-risk patients with muscle-invasive bladder cancer

Introduction Patients with muscle-invasive urothelial bladder cancer post neoadjuvant cisplatin-based chemotherapy with pathologic advanced disease (ypT3, ypT4, ypN+) at radical cystectomy have a significantly worse five-year overall survival. There is currently no preferred adjuvant therapy to reduce risk of cancer recurrence in this high-risk patient cohort and surveillance remains the standard-of-care. Case report We present a case series of two patients who received cisplatin-based neoadjuvant chemotherapy and had pathologic node-positive urothelial carcinoma at the time of radical cystectomy. Tumor next generation sequencing revealed high mutational burden in both patients and positive PD-L1 in one patient. Management and outcome: Patients were treated with adjuvant pembrolizumab and experienced long-term disease free intervals. Discussion Use of adjuvant checkpoint inhibitors in patients post neoadjuvant cisplatin-based chemotherapy with pathologic advanced disease at the time of radical cystectomy at high-risk of cancer recurrence sounds appealing. Careful patient selection based on tumor-specific genomic alterations may be key. Large trials addressing this question are ongoing.
Unraveling the unbinding pathways of SARS-CoV-2 Papain-like proteinase known inhibitors by Supervised Molecular Dynamics simulation

The COVID-19 disease has infected and killed countless people all over the world since its emergence at the end of 2019. No specific therapy for COVID-19 is not currently available, and urgent treatment solutions are needed. Recent studies have found several potential molecular targets, and one of the most critical proteins of the SARS-CoV-2 virus work machine is the Papain-like protease (Plpro). Potential inhibitors are available, and their X-ray crystallographic structures in complex with this enzyme have been determined recently. However, their activities against this enzyme are insufficient and need to be characterized and improved to be of clinical values. Therefore, in this work, by utilizing the Supervised Molecular Dynamics (SuMD) simulation method, we achieved multiple unbinding events of Plpro inhibitors, GRL0617, and its derivates, and captured and understood the details of the unbinding pathway. We found that residues of the BL2 loop, such as Tyr268 and Gln269, play major roles in the unbinding pathways, but the most important contributing factor is the natural movements and behavior of the BL2 loop, which can control the entire process. We believe that the details found in this study can be used to refine and optimize potential inhibitors like GRL0617 and design more efficacious inhibitors as a treatment for the SARS-CoV-2 virus.
Near-Infrared Autofluorescence in Atherosclerosis Associates With Ceroid and Is Generated by Oxidized Lipid-Induced Oxidative Stress

Supplemental Digital Content is available in the text. Objective: Near-infrared autofluorescence (NIRAF) of atherosclerosis associates with intraplaque hemorrhage and is detectable in living patients with coronary artery disease. However, further mechanisms underlying NIRAF generation have not been fully characterized. Here, we investigated the role of lipids and oxidative stress in NIRAF generation in atherosclerosis and in vitro in human macrophages. Approach and Results: In N=15 human carotid endarterectomy specimens, we investigated the spatial distribution of lipid, intraplaque hemorrhage, and NIRAF (ex/em 630/650 nm). Plaque NIRAF associated with both Sudan black-positive lipids (r=0.53, P=0.023) and GPA (glycophorin A)-positive intraplaque hemorrhage (r=0.48, P=0.043). Plaque NIRAF also localized with lipid and specifically insoluble lipid (ceroid) and iron. Intriguingly, some NIRAF-positive areas were Sudan black-positive but GPA-negative. Studies on human macrophages investigated further the role of lipids in NIRAF generation. OxLDL (Oxidized low-density lipoprotein) and hemoglobin, but not LDL, generated NIRAF in both THP-1 cells and monocyte-derived macrophages. In oxLDL-treated THP-1 cells, higher NIRAF, lipid peroxidation products, and intracellular oxidative stress markers evolved (P<0.001 versus LDL). The antioxidants α-tocopherol and N-acetylcysteine suppressed NIRAF generation and oxidative stress. Conclusions: In human atherosclerosis and human macrophages in vitro, NIRAF colocalizes with lipid and specifically insoluble lipid or ceroid. In vitro studies further show that oxidized LDL generates NIRAF, oxidative stress, and lipid peroxidation products. These results demonstrate a new pathway for NIRAF generation through oxidized lipid-driven oxidative stress and support ceroid as a source of NIRAF in human atherosclerosis. These findings may inform future clinical intracoronary NIRAF imaging studies of patients with coronary artery disease.
Greater extent of blood‐tumor TCR repertoire overlap is associated with favorable clinical responses to PD‐1 blockade

With the widespread use of programmed death receptor‐1 (PD‐1) blockade therapy, sensitive and specific predictive biomarkers that guide patient selection are urgently needed. T‐cell receptor (TCR) repertoire, which reflects antitumor T‐cell responses based on antigen specificity, is expected as a novel biomarker for PD‐1 blockade therapy. In the present study, the TCR repertoire of eight patients with gastrointestinal cancer treated with anti‐PD‐1 antibody (nivolumab) was analyzed. To analyze the tumor‐associated T‐cell clones in the blood and their mobilization into the tumor, we focused on T‐cell clones that presented in both blood and tumor (blood‐tumor overlapping clones). Responders to PD‐1 blockade tended to exhibit a higher number of overlapping clones in the tumor and a higher total frequency in the blood. Moreover, a higher total frequency of overlapping clones in blood CD8+ T cells before treatment was associated with a favorable clinical response. Collectively, these results suggest the possibility of blood‐tumor TCR repertoire overlap to predict clinical response to PD‐1 blockade and guide patient selection before the treatment.
Triboelectric Nanogenerators for Therapeutic Electrical Stimulation

Current solutions developed for the purpose of in and on body (IOB) electrical stimulation (ES) lack autonomous qualities necessary for comfortable, practical, and self‐dependent use. Consequently, recent focus has been placed on developing self‐powered IOB therapeutic devices capable of generating therapeutic ES for human use. With the recent invention of the triboelectric nanogenerator (TENG), harnessing passive human biomechanical energy to develop self‐powered systems has allowed for the introduction of novel therapeutic ES solutions. TENGs are especially effective at providing ES for IOB therapeutic systems given their bioconformability, low cost, simple manufacturability, and self‐powering capabilities. Due to the key role of naturally induced electrical signals in many physiological functions, TENG‐induced ES holds promise to provide a novel paradigm in therapeutic interventions. The aim here is to detail research on IOB TENG devices applied for ES‐based therapy in the fields of regenerative medicine, neurology, rehabilitation, and pharmaceutical engineering. Furthermore, considering TENG‐produced ES can be measured for sensing applications, this technology is paving the way to provide a fully autonomous personalized healthcare system, capable of IOB energy generation, sensing, and therapeutic intervention. Considering these grounds, it seems highly relevant to review TENG‐ES research and applications, as they could constitute the foundation and future of personalized healthcare.
External quality assessment of Rift Valley fever diagnosis in countries at risk of the disease: African, Indian Ocean and Middle-East regions

Rift Valley fever virus (RVFV), an arbovirus belonging to the Phlebovirus genus of the Phenuiviridae family, causes the zoonotic and mosquito-borne RVF. The virus, which primarily affects livestock (ruminants and camels) and humans, is at the origin of recent major outbreaks across the African continent (Mauritania, Libya, Sudan), and in the South-Western Indian Ocean (SWIO) islands (Mayotte). In order to be better prepared for upcoming outbreaks, to predict its introduction in RVFV unscathed countries, and to run efficient surveillance programmes, the priority is harmonising and improving the diagnostic capacity of endemic countries and/or countries considered to be at risk of RVF. A serological inter-laboratory proficiency test (PT) was implemented to assess the capacity of veterinary laboratories to detect antibodies against RVFV. A total of 18 laboratories in 13 countries in the Middle East, North Africa, South Africa, and the Indian Ocean participated in the initiative. Two commercial kits and two in-house serological assays for the detection of RVFV specific IgG antibodies were tested. Sixteen of the 18 participating laboratories (88.9%) used commercial kits, the analytical performance of test sensitivity and specificity based on the seroneutralisation test considered as the reference was 100%. The results obtained by the laboratories which used the in-house assay were correct in only one of the two criteria (either sensitivity or specificity). In conclusion, most of the laboratories performed well in detecting RVFV specific IgG antibodies and can therefore be considered to be prepared. Three laboratories in three countries need to improve their detection capacities. Our study demonstrates the importance of conducting regular proficiency tests to evaluate the level of preparedness of countries and of building a network of competent laboratories in terms of laboratory diagnosis to better face future emerging diseases in emergency conditions.
A diamidobenzimidazole STING agonist protects against SARS-CoV-2 infection

Coronaviruses are a family of RNA viruses that cause acute and chronic diseases of the upper and lower respiratory tract in humans and other animals. SARS-CoV-2 is a recently emerged coronavirus that has led to a global pandemic causing a severe respiratory disease known as COVID-19 with significant morbidity and mortality worldwide. The development of antiviral therapeutics are urgently needed while vaccine programs roll out worldwide. Here we describe a diamidobenzimidazole compound, diABZI-4, that activates STING and is highly effective in limiting SARS-CoV-2 replication in cells and animals. diABZI-4 inhibited SARS-CoV-2 replication in lung epithelial cells. Administration of diABZI-4 intranasally before or even after virus infection conferred complete protection from severe respiratory disease in K18-ACE2-transgenic mice infected with SARS-CoV-2. Intranasal delivery of diABZI-4 induced a rapid short-lived activation of STING, leading to transient proinflammatory cytokine production and lymphocyte activation in the lung associated with inhibition of viral replication. Our study supports the use of diABZI-4 as a host-directed therapy which mobilizes antiviral defenses for the treatment and prevention of COVID-19. Pharmacological activation of STING protects against SARS-CoV-2 infection.
Comparative efficacy and safety of intravenous ferric carboxymaltose and iron sucrose for iron deficiency anemia in obstetric and gynecologic patients

Supplemental Digital Content is available in the text Abstract Introduction: Iron deficiency anemia (IDA) is common among obstetric and gynecologic patients. This systematic review aimed to assess the comparative efficacy and safety of commonly used intravenous (IV) iron formulations, ferric carboxymaltose (FCM), and iron sucrose (IS) in the treatment of IDA in obstetric and gynecologic patients. Methods: We systematically searched PubMed, EMBASE, Cochrane CENTRAL, and Google Scholar for eligible randomized controlled trials (RCTs) comparing IV iron replacement using FCM and IS up to October 2019. The primary outcome was to compare the efficacy of FCM and IS, assessed by measuring serum hemoglobin (Hb) and ferritin levels before and after iron replacement. The secondary outcome was to compare the safety of FCM and IS, assessed by the incidence of adverse events during iron replacement. The meta-analysis was performed using RevMan 5.3. Results: We identified 9 RCTs with 910 patients (FCM group, n = 456; IS group, n = 454). Before iron replacement, FCM and IS group patients had similar baseline Hb (mean difference [MD], 0.04 g/dL; 95% confidence interval [CI], −0.07 to 015; I2 = 0%; P = 0.48) and ferritin levels (MD, −0.42 ng/mL; 95% CI, −1.61 to 0.78; I2 = 45%; P = 0.49). Following iron replacement, patients who received FCM had higher Hb (MD, 0.67; 95% CI, 0.25–1.08; I2 = 92%; P = 0.002) and ferritin levels (MD, 24.41; 95% CI, 12.06–36.76; I2 = 75%; P = 0.0001) than patients who received IS. FCM group showed a lower incidence of adverse events following iron replacement than IS group (risk ratio, 0.53; 95% CI, 0.35–0.80; I2 = 0%; P = 0.003). Serious adverse events were not reported in any group. Conclusion: FCM group showed better efficacy in increasing Hb and ferritin levels and a favorable safety profile with fewer adverse events compared with IS group for IDA treatment among obstetric and gynecologic patients. However, this meta-analysis was limited by the small number of RCTs and high heterogeneity. Trial registration: The review was prospectively registered with the International Prospective Registry of Systematic Reviews (https://www.crd.york.ac.uk/prospero/, registration number CRD42019148905).
Plasma D-dimer and FDP are promising biomarkers to predict perioperative fibrinolysis and bleeding following primary total joint arthroplasty

Supplemental Digital Content is available in the text Abstract Perioperative bleeding is associated with postoperative hyperfibrinolysis caused by surgical trauma in the setting of total hip and knee arthroplasty (THA/ TKA). The study aimed to clarify the dynamics of postoperative fibrinolytic activity and the values of fibrin degeneration products and thromboelastography (TEG) to guide precisive antifibrinolytic therapy. Forty three patients undergoing primary unilateral THAs and 40 TKAs were included to the prospective observational cohort study. Venous blood sample at different time points (preoperative, intraoperative, postoperative 6 hours, 12 hours, 24 hours, 48 hours) were drawn to test D-dimer, fibrin (-ogen) degradation products (FDP) and TEG. The TEG parameters associated with coagulation (R, K, α, MA, and CI) and fibrinolysis (estimate percent lysis and Ly30) were all in normal range although had a higher level than preoperative time (P < .05). The postoperative levels of D-dimer and FDP were higher than preoperative level (P < .05). The dynamics of D-dimer and FDP presented a bimodal pattern, which peaked at 6 hours postoperatively, then remained and decreased until 24 hours, but would rebound at 48 hours postoperatively with smaller amplitude. Moreover, FDP6h (P = .028), D-Dimer6h (P = .044), FDP12h (P = .009), D-dimer12h (P = .007), and FDP48h (P = .016) were all correlated with total blood loss on POD3. FDP and D-dimer were effective and practical markers for prediction of acute postoperative fibrinolytic activity, which peaked at 6 hours after end of surgery and would maintain for at least 24 hours.