Miracle-dz/UniFAR-FTUs huggingface dataset:
Vascular priming with RRx-001 to increase the uptake and accumulation of temozolomide and irinotecan in orthotopically implanted gliomas

Abstract Vascular normalisation refers to a ‘remodeling’ of the dysfunctional tumour capillary network, which regresses under the influence of anti-VEGF treatment, resulting in improved blood flow and oxygenation. RRx-001 is an anti-CD47-SIRPα small molecule with vascular normalising properties under investigation in clinical trials for the treatment of glioblastoma, brain metastases, lung cancer and colorectal cancer, with FDA Orphan Drug Designation in glioblastoma and other tumour types. This study investigated whether the improved oxygenation and perfusion that has been previously observed with RRx-001 both preclinically and clinically in the context of a brain metastasis trial was correlated with increased penetration and accumulation of the cytotoxic chemotherapies, irinotecan and temozolomide, in orthotopically implanted gliomas, priming tumours for improved response. The experiments demonstrate that administration of RRx-001 prior to temozolomide or irinotecan results in significantly increased uptake of irinotecan and temozolomide in orthotopic glioma tumours. Since the success of chemotherapy in the brain (and outside of it) is limited by subtherapeutic tumoral drug concentrations, vascular normalisation-enhanced delivery of standard cytotoxics as demonstrated with RRx-001 may mitigate or reverse clinical drug resistance and thereby improve the outcome of cancer therapy, particularly in the brain.
Incidence and time trends of herpes zoster among patients with head and neck cancer who did and did not undergo radiotherapy: A population-based cohort study

Purpose This study aimed to determine the risk and time trends of herpes zoster among patients with head and neck cancer, with or without radiotherapy. Methods A total of 2160 patients with head and neck cancer were enrolled. The radiotherapy and non- radiotherapy cohorts were frequency-matched at a 1:1 ratio according to sex, age, and index date. Moreover, 1080 matched non-cancer individuals were considered normal controls. Data were obtained from the National Health Insurance Research Database and Cancer Registry. The primary end point was the incidence of herpes zoster, and the adjusted confounding factors were age, sex, comorbidities, oncological surgery, and chemotherapy. Results The incidence of herpes zoster was higher in cancer patients than in non-cancer individuals but did not significantly differ (13.67 vs. 8.06 per 1,000 person-years, p = 0.18). The risk of herpes zoster was significantly higher in the radiotherapy cohort than in the non-radiotherapy cohort (18.55 vs. 9.06 per 1,000 person-years, p = 0.03). The 5-year incidence rates in the radiotherapy and non-radiotherapy cohorts were 8.9% and 5%, respectively (p < 0.0001). Survival analysis indicated there was no immortal time bias. The time trends in the radiotherapy cohort persistently showed a high risk within the first 2 years, which decreased thereafter. Only patients with comorbid rheumatoid arthritis showed a significantly high risk of herpes zoster (p = 0.02). Oncological surgery and chemotherapy had no impact on the development of herpes zoster. Conclusions This nationwide population-based study showed that patients with head and neck cancer receiving radiotherapy are at an increased risk of herpes zoster. Health care professionals should pay more attention to this vulnerable group to improve their quality of life.
Synthesis of 3‐O‐Carboxyalkyl Morphine Derivatives and Characterization of Their Acid‐Base Properties

The C‐3 phenolic hydroxy group containing morphine derivatives (morphine, oxymorphone, naloxone, naltrexone) are excellent candidates for the synthesis of 3‐O‐functionalized molecules. Achieving free carboxylic group containing derivatives gives the opportunity for further modification and conjugation that could be used for immunization and immunoassays. For this purpose ethyl bromo‐ and chloroacetate can be used as O‐alkylating agents. Hydrolyzing the products affords the appropriate free carboxylic group containing 3‐O‐carboxyalkyl derivatives. As these molecules contain an acidic and a basic functional group the protonation macro‐ and microconstants were determined too, using pH‐potentiometry and NMR‐pH titration, beside fully characterizing their structure using IR, CD, NMR and HR‐MS measurements.
Minimal Clinically Important Differences for Patient-Reported Outcomes After TKA Depend on Central Sensitization

Background: To our knowledge, it is still unknown if central sensitization (CS) influences the magnitude of the minimal clinically important difference (MCID) for patient-reported outcome measures after total knee arthroplasty (TKA). The purpose of this study was to determine the influence of CS on the MCID for the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score in patients who underwent TKA for knee osteoarthritis. Methods: A total of 422 patients who underwent unilateral TKA and completed a 2-year follow-up were enrolled in this study. CS was measured using the Central Sensitization Inventory (CSI). The WOMAC score was used to evaluate preoperative and postoperative patient-reported outcomes. The measurement of the MCID was performed separately for patients with and without CS using both the anchor-based method and the distribution method. The change difference method defined the MCID as the difference in preoperative-to-postoperative change between the minimal-improvement group and the no-change group. In addition, the MCID was calculated using receiver operating characteristic (ROC) curve analysis. The percentage of MCID achievement in each group was also compared. Results: According to the change difference method, the MCID for the WOMAC total score was 23.4 points for patients with CS and 14.7 points for patients without CS. The MCID using the ROC cutoff value for the WOMAC total score was 29.5 points for the patients with CS and 26.5 points for the patients without CS. MCID achievement rates in WOMAC pain, function, and total scores were all found to be significantly higher in the patients without CS through the change difference method and the ROC method (all p < 0.05). Conclusions: The MCID for the WOMAC score of patients with CS after TKA was greater than that for patients without CS. Furthermore, by applying the calculated MCID to the group to which the patients belonged (with or without CS), we determined that patients with CS showed a lower MCID achievement rate than patients without CS. Level of Evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.
Anxiety and fear of COVID‐19 among nursing students during the COVID‐19 pandemic: A descriptive correlation study

Abstract Purpose The aim of this study was to assess current situations regarding anxiety and fear of coronavirus disease 2019 (COVID‐19) level among nursing students. Design and Methods A descriptive correlation design was adopted. The sample consisted of 234 nursing students. Data were collected using sociodemographic form, Beck Anxiety Inventory (BAI), and Fear of COVID‐19 scale. Findings The mean BAI score of the students was 26.56 ± 8.86 and Fear of COVID‐19 total score was 18.95 ± 7.00. A positive correlation between total scores of the BAI and Fear of COVID‐19. The results of this study reveal that anxiety and fear of COVID‐19 levels were high among nursing students. Practice Implications These findings have underlined there is an urgent need for interventions to reduce anxiety and fear of COVID‐19 among nursing students.
Molecular clock REV-ERBα regulates cigarette smoke–induced pulmonary inflammation and epithelial-mesenchymal transition

Cigarette smoke (CS) is the main etiological factor in the pathogenesis of emphysema/chronic obstructive pulmonary disease (COPD), which is associated with abnormal epithelial-mesenchymal transition (EMT). Previously, we have shown an association among circadian rhythms, CS-induced lung inflammation, and nuclear heme receptor α (REV-ERBα), acting as an antiinflammatory target in both pulmonary epithelial cells and fibroblasts. We hypothesized that molecular clock REV-ERBα plays an important role in CS-induced circadian dysfunction and EMT alteration. C57BL/6J WT and REV-ERBα heterozygous (Het) and –KO mice were exposed to CS for 30 days (subchronic) and 4 months (chronic), and WT mice were exposed to CS for 10 days with or without REV-ERBα agonist (SR9009) administration. Subchronic/chronic CS exposure caused circadian disruption and dysregulated EMT in the lungs of WT and REV-ERBα–KO mice; both circadian and EMT dysregulation were exaggerated in the REV-ERBα–KO condition. REV-ERBα agonist, SR9009 treatment reduced acute CS-induced inflammatory response and abnormal EMT in the lungs. Moreover, REV-ERBα agonist (GSK4112) inhibited TGF-β/CS–induced fibroblast differentiation in human fetal lung fibroblast 1 (HFL-1). Thus, CS-induced circadian gene alterations and EMT activation are mediated through a Rev-erbα–dependent mechanism, which suggests activation of REV-ERBα as a novel therapeutic approach for smoking-induced chronic inflammatory lung diseases.
A meta-analysis of the correlation between non-steroidal anti-inflammatory drugs and recurrent colorectal adenomatous polyps.

AIM The purpose of this study was to evaluate the effect of non-steroidal anti-inflammatory drugs (NSAIDs) on the recurrence risk of colorectal adenomas through a meta-analysis of published studies. METHODS A meta-analysis was performed to evaluate the effect of NSAIDs on the incidence rates of colorectal adenomatous polyps, using PubMed, Ovid, Elsevier, and other journal databases. Data were processed using Review Manager 5.3 and random errors were calculated using trial sequential analysis (TSA). RESULTS A total of 8 studies published between 2003 and 2014 were selected. In the data collected, the patients on long-term usage of low-dose NSAIDs were shown to have significantly lower risk of colorectal adenoma compared with those on placebos (RR=0.80, 95% CI=0.70-0.92), with relatively low random errors. Long-term usage of low-dose NSAIDs was also found to have inhibitory effects on advanced adenomas (RR=0.66, 95% CI=0.44-0.99), but with relatively high random errors. Besides, high-dose NSAIDs were also shown to have inhibitory but inconsistent effects on adenomas and advanced adenomas (RR=0.66, 95% CI=0.59-0.72), and the withdrawal was associated with increased risks of the disease. CONCLUSION These results suggest that low-dose NSAIDs have an inhibitory effect on recurrent adenomas, but the efficacy for late-stage adenomas remain inconclusive. The withdrawal of the drug might be associated with increased risks of the disease.
Comparing Symptomatic and Asymptomatic Carotid Artery Atherosclerosis in Patients With Bilateral Carotid Vulnerable Plaques Using Magnetic Resonance Imaging

We compared plaque characteristics between symptomatic and asymptomatic sides in patients with bilateral carotid vulnerable plaques using magnetic resonance imaging (MRI). Participants (n = 67; mean age: 65.8 ± 7.7 years, 61 males) with bilateral carotid vulnerable plaques were included. Vulnerable plaques were characterized by intraplaque hemorrhage (IPH), large lipid-rich necrotic core (LRNC), or fibrous cap rupture (FCR) on MRI. Symptomatic vulnerable plaques showed greater plaque burden, LRNC volume (median: 221.4 vs 134.8 mm3, P = .003), IPH volume (median: 32.2 vs 22.5 mm3, P = .030), maximum percentage (Max%) LRNC (median: 51.3% vs 41.8%, P = .002), Max%IPH (median: 13.4% vs 9.5%, P = .022), cumulative slices of LRNC (median: 10 vs 8, P = .005), and more juxtaluminal IPH and/or thrombus (29.9% vs 6.0%, P = .001) and FCR (37.3% vs 16.4%, P = .007) than asymptomatic ones. After adjusting for plaque burden, differences in juxtaluminal IPH and/or thrombus (odds ratio [OR]: 5.49, 95% CI: 1.61-18.75, P = .007) and FCR (OR: 2.90, 95% CI: 1.16-7.24, P = .022) between bilateral sides remained statistically significant. For patients with bilateral carotid vulnerable plaques, symptomatic plaques had greater burden, more juxtaluminal IPH and/or thrombus, and FCR compared with asymptomatic ones. The differences in juxtaluminal IPH and/or thrombus and FCR between bilateral sides were independent of plaque burden.
Meningioma: not always a benign tumor. A review of advances in the treatment of meningiomas

Meningiomas are the most common primary intracranial tumors. The majority of meningiomas are benign, but they can present different grades of dedifferentiation from grade I to grade III (anaplastic/malignant) that are associated with different outcomes. Radiological surveillance is a valid option for low-grade asymptomatic meningiomas. In other cases, the treatment is usually surgical, aimed at achieving a complete resection. The use of adjuvant radiotherapy is the gold standard for grade III, is debated for grade II and is not generally indicated for radically resected grade I meningiomas. The use of systemic treatments is not standardized. Here we report a review of the literature on the clinical, radiological and molecular characteristics of meningiomas, available treatment strategies and ongoing clinical trials.
Effects of cardiorespiratory fitness and exercise training on cerebrovascular blood flow and reactivity: a systematic review with meta-analyses.

BACKGROUND We address two aims; Aim 1 (Fitness Review) compare the effect of higher cardiorespiratory fitness (CRF) (e.g. endurance athletes) with lower CRF (e.g. sedentary adults) on cerebrovascular outcomes, including middle cerebral artery velocity (MCAv) as assessed by Transcranial Doppler (TCD) or Magnetic Resonance Imaging (MRI). Aim 2 (Exercise Training Review) determine the effect of exercise training on cerebrovascular outcomes. METHODS Systematic review of studies with meta-analyses where appropriate. Certainty of evidence was assessed by Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS Twenty studies (18 using TCD) met the eligibility criteria for Aim 1 and 14 studies (8 using TCD) were included for Aim 2. There was a significant effect of higher compared with lower CRF on cerebrovascular resistance index (effect size, 95% confidence interval), (-0.54, -0.91 to -0.16) and cerebrovascular reactivity (0.98, 0.41 to 1.55). Studies including males only demonstrated a greater effect of higher CRF on cerebrovascular resistance index than mixed or female studies (male only: -0.69, -1.06 to -0.32, mixed and female studies (0.10, -0.28 to 0.49). Exercise training did not increase MCAv (0.05, -0.21 to 0.31), although there was a small improvement trending to significant in cerebrovascular reactivity (0.60, -0.08 to 1.28; p=0.09). Exercise training showed heterogeneous effects on regional, but little effect on global cerebral blood flow as measured by MRI. CONCLUSIONS High CRF positively effects cerebrovascular function, including decreased CVRi and increased CVRCO2 however, global cerebral blood flow and MCAv is primarily unchanged following an exercise intervention in healthy and clinical populations.
Genome sequence of Bovine Ephemeral fever virus vaccine strain of South African origin

Abstract Bovine Ephemeral fever virus (BEFV) is endemic in South Africa and has a negative economic impact on the meat and dairy industries. Bovine ephemeral fever or three‐day stiff‐sickness is controlled through annual vaccination with a live attenuated virus manufactured by Onderstepoort Biological Products (South Africa). We announce the genome sequences of two South African Bovine Ephemeral Virus strains; the live attenuated vaccine strain (14 876 nucleotides) and a field strain (14 883 nucleotides). A mutation in the alpha 3 open reading frame rendered the gene non‐functional in both genomes. Phylogenetic analysis based on the glycoprotein gene showed that the two strains clustered with the South African lineage.
Cerebral Amyloid Angiopathy–Related Transient Focal Neurologic Episodes

Transient focal neurologic episodes (TFNEs) are brief disturbances in motor, somatosensory, visual, or language functions that can occur in patients with cerebral amyloid angiopathy (CAA) and may be difficult to distinguish from TIAs or other transient neurologic syndromes. They herald a high rate of future lobar intracerebral hemorrhage, making it imperative to differentiate them from TIAs to avoid potentially dangerous use of antithrombotic drugs. Cortical spreading depression or depolarization triggered by acute or chronic superficial brain bleeding, a contributor to brain injury in other neurologic diseases, may be the underlying mechanism. This review discusses diagnosis, pathophysiology, and management of CAA-related TFNEs.
Rheumatoid arthritis and osteoporosis: a bi-directional Mendelian randomization study

Many observation studies have demonstrated a close relationship between rheumatoid arthritis (RA) and osteoporosis (OP). However, the causal genetic correlation between RA and OP remains unclear. In this study, we performed bi-directional Mendelian randomization (MR) analyses to explore causal inference between these two traits. The instrumental variables for RA were selected from a large-scale genome-wide association study (GWAS) (1,523 cases and 461,487 controls). Bone mineral density (BMD) at five different sites (heel (n=265,627), forearm (FA) (n=8,143), femoral neck (FN) (n=32,735), lumbar spine (LS) (n=28,498), and total body (n=28,498)) were used as phenotypes for OP. The inverse variance weighted (IVW) method did not detect any causal effect of BMDs on RA except heel BMD (beta = -7.57 × 10-4, p = 0.02). However, other methods (MR-Egger, weighted median, weighted mode, MR-PRESSO, and MR-RAPS) showed no causal association between heel BMD and RA. Likewise, we did not find a causal effect of RA on BMD at any sites. In conclusion, we found no evidence that RA is causally associated with OP/BMD, or vice versa. We suggested that the associations found in previous observational studies between RA and OP/BMD are possibly related to secondary effects such as antirheumatic treatment and reduced physical activity.
Youth‒Police Contact: Burdens and Inequities in an Adverse Childhood Experience, 2014‒2017.

Objectives. To assess police contact as a potential adverse childhood experience by measuring its prevalence, nature, and distribution among urban adolescents.Methods. Detailed US population-based data on youth‒police contact were collected in the Fragile Families and Child Wellbeing Study (n = 2478) from 2014 to 2017. Using regression modeling, I assessed adolescents' police exposure and the magnitude and robustness of racial disparities in police contact. Sensitivity analyses examined disparities by behavior and socioeconomic context.Results. Urban youths are heavily policed, beginning in preadolescence. Exposure to policing is unevenly distributed, with non-White adolescents-particularly Black boys-reporting more, and more aggressive, contact than their White counterparts. Hispanic‒White differences and disparities in girls' experiences were less pronounced but present, particularly in how intrusive stops were. Intrusion disparities were robust to most behavioral controls, but not observed among youths with higher socioeconomic status.Conclusions. Given extant literature documenting adverse health consequences of police encounters, findings implicate policing as a driver of health disparities in adolescence and throughout the life course. Public health infrastructure dedicated to the prevention and treatment of adverse childhood experiences is well suited for mitigating these harms and inequities. (Am J Public Health. Published online ahead of print May 20, 2021: e1-e9. https://doi.org/10.2105/AJPH.2021.306259).
Caenorhabditis elegans as a Diagnostic Aid for Pancreatic Cancer

Supplemental digital content is available in the text. Objectives Early detection of pancreatic cancer is notoriously difficult. A novel cancer diagnostic method using the ability of nematodes to detect odor of urine samples has been developed (N-NOSE). This method has a high sensitivity and specificity for various cancers; however, it has not yet been verified in pancreatic cancer. We examined the usefulness of this method to aid early diagnosis of pancreatic cancer in a cancer center. Methods We collected urine samples and clinical data from patients hospitalized in our division, between July 2017 and February 2019. We excluded patients with a known current or past history of other cancers. We investigated the relationship between the results of N-NOSE and the presence of pancreatic cancer. Results There were 95 noncancer cases and 104 pancreatic cancer cases. The sensitivity and specificity of N-NOSE for pancreatic cancer were 84.6% (88/104) and 60% (57/95), respectively. N-NOSE was able to detect stages 0 to I pancreatic cancer and had a higher correlation with early-stage pancreatic cancer than advanced stage. Conclusions N-NOSE has sufficient sensitivity and specificity for use in clinical practice, and it holds great potential as a diagnostic aid for pancreatic cancer, especially for early-stage pancreatic cancer.
Thirst interneurons that promote water seeking and limit feeding behavior in Drosophila

Thirst is a motivational state that drives behaviors to obtain water for fluid homeostasis. We identified two types of central brain interneurons that regulate thirsty water seeking in Drosophila, that we term the Janu neurons. Janu-GABA, a local interneuron in the subesophageal zone, is activated by water deprivation and is specific to thirsty seeking. Janu-AstA projects from the subesophageal zone to the superior medial protocerebrum, a higher order processing area. Janu-AstA signals with the neuropeptide Allatostatin A to promote water seeking and to inhibit feeding behavior. NPF (Drosophila NPY) neurons are postsynaptic to Janu-AstA for water seeking and feeding through the AstA-R2 galanin-like receptor. NPF neurons use NPF to regulate thirst and hunger behaviors. Flies choose Janu neuron activation, suggesting that thirsty seeking up a humidity gradient is rewarding. These findings identify novel central brain circuit elements that coordinate internal state drives to selectively control motivated seeking behavior.
Thromboembolic Complications in the First Year After Acute Pancreatitis Diagnosis

Supplemental digital content is available in the text. Objectives This study aimed to quantify the prevalence of venous thromboembolic (VTE) events in patients with pancreatitis requiring hospitalization and its impact on outcomes. Methods Adult patients admitted from 2011 to 2018 for pancreatitis were identified. Every admission for pancreatitis in the first year after diagnosis was evaluated for a VTE (pulmonary embolism, deep vein thrombosis, or mesenteric vessel thrombosis) within 30 days of discharge. Characteristics of patients who developed a thromboembolic event were compared with those who did not. Results There were 4613 patients with pancreatitis identified, 301 of whom developed a VTE (6.5%). Patients who developed a VTE were more likely to be male (P < 0.01), older (P = 0.03), and have an underlying coagulopathy (P < 0.01). Those with VTEs were more likely to die (27% vs 13%, P < 0.01), have more readmissions for pancreatitis (1.7 vs 1.3, P < 0.01), longer length of stay (16 vs 5.5 days, P < 0.01), and be discharged to acute or long-term rehabilitation rather than home (P < 0.01). Conclusions Acute pancreatitis requiring hospitalization is associated with high risk of VTE in the first year after diagnosis. Thromboembolic disease is associated with worse morbidity and mortality.