Miracle-dz/UniFAR-FTUs huggingface dataset:
The RPA inhibitor HAMNO sensitizes Fanconi anemia pathway-deficient cells

ABSTRACT The Fanconi anemia (FA) DNA repair pathway is required for DNA inter-strand crosslink (ICL) repair. Besides its role in ICL repair, FA proteins play a central role in stabilizing stalled replication forks, thereby ensuring genome integrity. We previously demonstrated that depletion of replication protein A (RPA) induces the activation of FA pathway leading to FANCD2 monoubiquitination and FANCD2 foci formation. Thus, we speculated that FA-deficient cells would be more sensitive to RPA inhibition compared to FA-proficient cells. Following treatment with RPA inhibitor HAMNO, we observed significant induction in FANCD2 monoubiquitination and foci formation as observed in RPA depletion. In addition, HAMNO treatment caused increased levels of γ-H2AX and S-phase accumulation in FA-deficient cells. Importantly, FA-deficient cells showed more increased sensitivity to HAMNO than FA-proficient cells. Moreover, in combination with cisplatin, HAMNO further enhanced the cytotoxicity of cisplatin in FA-deficient cells, while being less toxic against FA-proficient cells. This result suggests that RPA inhibition might be a potential therapeutic candidate for the treatment of FA pathway-deficient tumors.
Use of combined treatment of 3rd-generation cephalosporin, azithromycin and antiviral agents on moderate SARs-CoV-2 patients in South Korea: A retrospective cohort study

Objectives To assess efficacy and safety of the combined treatment of antibiotics (3rd-generation cephalosporin and azithromycin) and antiviral agents (lopinavir/ritonavir or hydroxychloroquine) on moderate COVID-19 patients in South Korea. Methods A retrospective cohort study of the 358 laboratory-confirmed SARS-CoV-2 (COVID-19) patients was conducted. 299 patients met inclusion criteria for analysis. Propensity score matching (PSM) and Cox regression method were used to control and adjust for confounding factors. Mild to moderate COVID-19 patients were managed with either CA/LoP (cephalosporin, azithromycin, and lopinavir/ritonavir) (n = 57), CA/HQ (cephalosporin, azithromycin, and hydroxychloroquine) (n = 25) or standard supportive care (n = 217). We analyzed the association between treatment group and standard supportive group in terms of three endpoints: time to symptom resolution, time to viral clearance, and hospital stay duration. Using propensity-score matching analysis, three rounds of propensity-matching analysis were performed to balance baseline characteristics among three cohorts. Results Kaplan-Meier curves fitted using propensity score-matched data revealed no significant differences on time to symptom resolution, time to viral clearance, hospital stay duration among the three treatment arms (CA/LoP vs Standard, log-rank p-value = 0.2, 0.58, and 0.74 respectively for the three endpoints) (CA/HQ vs Standard, log-rank p-value = 0.46, 0.99, and 0.75 respectively). Similarly, Cox regression analysis on matched cohorts of CA/LoP and standard supportive group showed that hazard ratios of time to symptom resolution (HR: 1.447 [95%-CI: 0.813–2.577]), time to viral clearance(HR: 0.861, [95%-CI: 0.485–1.527]), and hospital stay duration (HR: 0.902, [95%-CI: 0.510–1.595]) were not significant. For CA/HQ and standard supportive group, hazard ratios of the three endpoints all showed no statistical significance (HR: 1.331 [95%-CI:0.631–2.809], 1.005 [95%-CI:0.480–2.105], and 0.887, [95%-CI:0.422–1.862] respectively). No severe adverse event or death was observed in all groups. Conclusions Combined treatment of 3rd cephalosporin, azithromycin and either low-dose lopinavir/ritonavir or hydroxychloroquine was not associated with better clinical outcomes in terms of time to symptom resolution, time to viral clearance, and hospital stay duration compared to standard supportive treatment alone. Microbiological evidence should be closely monitored when treating SARS-CoV-2 patients with antibiotics to prevent indiscreet administration of empirical antimicrobial treatments.
Effect of Early vs Standard Approach to Tracheostomy on Functional Outcome at 6 Months Among Patients With Severe Stroke Receiving Mechanical Ventilation: The SETPOINT2 Randomized Clinical Trial.

Importance Many patients with severe stroke have impaired airway protective reflexes, resulting in prolonged invasive mechanical ventilation. Objective To test whether early vs standard tracheostomy improved functional outcome among patients with stroke receiving mechanical ventilation. Design, Setting, and Participants In this randomized clinical trial, 382 patients with severe acute ischemic or hemorrhagic stroke receiving invasive ventilation were randomly assigned (1:1) to early tracheostomy (≤5 days of intubation) or ongoing ventilator weaning with standard tracheostomy if needed from day 10. Patients were randomized between July 28, 2015, and January 24, 2020, at 26 US and German neurocritical care centers. The final date of follow-up was August 9, 2020. Interventions Patients were assigned to an early tracheostomy strategy (n = 188) or to a standard tracheostomy (control group) strategy (n = 194). Main Outcomes and Measures The primary outcome was functional outcome at 6 months, based on the modified Rankin Scale score (range, 0 [best] to 6 [worst]) dichotomized to a score of 0 (no disability) to 4 (moderately severe disability) vs 5 (severe disability) or 6 (death). Results Among 382 patients randomized (median age, 59 years; 49.8% women), 366 (95.8%) completed the trial with available follow-up data on the primary outcome (177 patients [94.1%] in the early group; 189 patients [97.4%] in the standard group). A tracheostomy (predominantly percutaneously) was performed in 95.2% of the early tracheostomy group in a median of 4 days after intubation (IQR, 3-4 days) and in 67% of the control group in a median of 11 days after intubation (IQR, 10-12 days). The proportion without severe disability (modified Rankin Scale score, 0-4) at 6 months was not significantly different in the early tracheostomy vs the control group (43.5% vs 47.1%; difference, -3.6% [95% CI, -14.3% to 7.2%]; adjusted odds ratio, 0.93 [95% CI, 0.60-1.42]; P = .73). Of the serious adverse events, 5.0% (6 of 121 reported events) in the early tracheostomy group vs 3.4% (4 of 118 reported events) were related to tracheostomy. Conclusions and Relevance Among patients with severe stroke receiving mechanical ventilation, a strategy of early tracheostomy, compared with a standard approach to tracheostomy, did not significantly improve the rate of survival without severe disability at 6 months. However, the wide confidence intervals around the effect estimate may include a clinically important difference, so a clinically relevant benefit or harm from a strategy of early tracheostomy cannot be excluded. Trial Registration ClinicalTrials.gov Identifier: NCT02377167.
A cross‐sectional survey to evaluate prescribers' knowledge and understanding of safety messages following Dengvaxia® product information update

We evaluated the effectiveness of additional risk minimisation measures (aRMMs; i.e., educational materials) distributed to prescribers to ensure that only individuals with evidence of prior dengue infection (PDI, i.e., dengue seropositive) would be vaccinated with the tetravalent dengue vaccine (CYD‐TDV; Dengvaxia®).
The prevalence of mental distress changes before and during the COVID-19 pandemic: a study on physicians in Turkey

Abstract Background The emergence of the COVID-19 pandemic may adversely affect the physicians’ mental health differently. Aims This study aimed to investigate the degree of changes in mental distress in physicians through two cross-sectional studies before and during the COVID-19 pandemic and explore factors associated with the change of mental distress status of participants between two-time periods. Methods This cross-sectional, web-based survey collected demographic data and mental health measurements with the 12-item General Health Questionnaire from 416 and 522 physicians before and during COVID-19, respectively. Mixed-effects ordinal logistic regression analyses were performed to assess the factors associated with the change of mental distress status. Results During the outbreak, a total of 319 of the 522 participants reported a clinically significant level of mental distress compared with 123 of 416 participants before COVID-19. Higher levels of mental distress were observed in all socio-demographic groups during COVID-19 compared with before, with more than two-fold higher prevalence of mental health deterioration in general. Conclusions This study suggests a significant deterioration in mental health status after the occurrence of COVID-19 compared with before. The mental health of physicians working in all medical specialty groups, especially those in internal and surgical specialties, may require special attention.
Anatomical study of the scleral ring and eyeball of the long‐eared owl (Asio otus) with anatomical methods and diagnostic imaging techniques

Abstract Background The scleral ring in birds consists of ossicles that are fixed as small plates by cartilage joints and have no articulation to other parts of the skeleton. Objective Due to inadequate examination of the scleral ring anatomy and its specific form in owls, this study aimed to investigate the exact structure of the scleral ring and some morphometric characteristics of the eyeball in a long‐eared owl (Asio otus). Methods The eyes of 20 alive and 10 dead male and female owls were examined. In addition to common anatomical methods, computed tomography scans and radiographic and ultrasonographic imaging techniques were used in this study. Results The structure consisted of 15 ossicles. In the ventral part of the ring, these tubercles were observed in the scleral rings of all owls; in each ring, there were four bones with these tubercles. Additionally, there was no significant difference between the left and right eye parameters. Most ocular parameters in female owls were larger than those in males, but in the case of some parameters, such as optic nerve length and optic nerve sheath diameter, this difference was not observed. Conclusions According to this study, the scleral ring in the Asio otus has anterior and posterior parts, and the lens is in the immediate vicinity of the anterior part. The right and left scleral rings and eyeballs are bilaterally symmetrical in terms of the shape, size, and number of ossicles that form the ring.
Infants prenatally exposed to SARS-CoV-2 show the absence of fidgety movements and are at higher risk for neurological disorders: A comparative study

Congenital viral infections are believed to damage the developing neonatal brain. However, whether neonates exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) show manifestations of such damage remains unclear. For neurodevelopment evaluation, general movement assessments have been shown to be effective in identifying early indicators of neurological dysfunction, including the absence of fidgety movements. This study compared the early motor repertoire by general movement assessment at three to five months of age in neonates who were or were not prenatally exposed to SARS-CoV-2 to determine whether infants prenatally exposed to SARS-CoV-2 are at risk of developing neurological disorders. Fifty-six infants, including 28 in the exposed group of mothers without vaccination who had no need for intensive care and likely had SARS-CoV-2 infection close to the time of pregnancy resolution and 28 infants in the nonexposed group, were videotaped to compare their detailed early motor repertoires, in which a motor optimality score-revised (MOS-R) was calculated using Prechtl’s method by using the chi-square or Mann–Whitney U tests. In the exposed group, 3 (11%) infants showed the absence of fidgety movements with a total MOS-R<14 points, and 3 (11%) other infants showed abnormal fidgety movements. Between groups, atypical body symmetry (p = 0.009) and MOS-R values were significantly lower (Z = -3.08, p = 0.002), with a large size effect (Cohen’s d = 0.97). The consequences of this new virus go beyond the health of the pregnant mother, and these consequences in some of the infants in the exposed group are likely not transitory because of the absence of fidgety movements between 3–5 months; thus, these babies are at increased risk of developing a serious neurological disorder.
Percutaneous dilatation tracheotomy in patients on extracorporeal membrane oxygenation after cardiac surgery

Background Current practices regarding percutaneous dilatational tracheostomy in adult patients treated with extracorporeal membrane oxygenation (ECMO) after cardiac surgery is not completely defined. This study aimed to evaluate the safety of the percutaneous dilatational tracheostomy in patients with ECMO after cardiac surgery. Methods Between July 2017 and May 2021, 371 ECMO procedures were performed in more than 35,000 adult patients who underwent cardiac surgery in our hospital. Sixty-two patients underwent percutaneous dilatational tracheostomy (PDT) during or after ECMO. A retrospective analysis was performed comparing the incidence of complications and clinical outcomes of the two groups. Results Of the 371 patients treated with ECMO after adult cardiac surgery during the enrollment period, 22 (7.1%) and 40 (12.8%) underwent PDT during or after ECMO, respectively. The platelet count (PLT) of the day was significantly lower in the PDT during ECMO group (54 (34, 68) vs. 108 (69, 162) (thousands), p < 0.001)). The prothrombin time (PT) and activated partial thromboplastin time (APTT) of the day were longer in the PDT during ECMO group (15.8 (14.6, 19.9) vs. 13.8 (13.2, 15.2) seconds, p = 0.001, 43.8 (38.0, 49.4) vs. 35.2 (28.2, 40.9) seconds, p < 0.001, respectively). There was no significant difference in tracheotomy-related complications between the two groups. Significantly decreased ventilator time was observed in the PDT during ECMO group. Conclusions Despite poor coagulation of the day, PDT during ECMO is safe and can appropriately reduce the duration of mechanical ventilation compared with PDT after ECMO weaning in adult patients who have undergone cardiac surgery.
The Development of Sound Localization Latency in Infants and Young Children with Normal Hearing

With the advances in eye tracking, saccadic reflexes towards auditory stimuli have become an easily accessible behavioral response. The present study investigated the development of horizontal sound localization latency quantified by saccadic reflexes in infants and young children with normal hearing (0.55 to 5.6 years, n = 22). The subject was seated in front of an array of 12 loudspeaker/display-pairs arranged equidistantly in an arc from −55 to + 55° azimuth. An ongoing auditory-visual stimulus was presented at 63 dB SPL and shifted to another randomly selected pair at 24 occasions. At each shift, the visual part of the stimulus was blanked for 1.6 s providing auditory-only localization cues. A sigmoid model was fitted to the gaze samples following the azimuthal sound shifts. The overall sound localization latency (SLL) for a subject was defined as the mean of the latencies for all trials included by objective criteria. The SLL was assessed in 21 of 22 children with a mean of 6.1 valid trials. The SLL ranged 400 to 1400 ms (mean = 860 ms). An inverse model demonstrated a significant relationship between SLL and age (R2 = 0.79, p < 0.001), reflecting a distinct reduction of latency with increasing age. No partial correlation between SLL and sound localization accuracy was found when controlling for age (p = 0.5), suggesting that localization latency may provide diagnostic value beyond accuracy.
Paranormal beliefs and cognitive function: A systematic review and assessment of study quality across four decades of research

Background Research into paranormal beliefs and cognitive functioning has expanded considerably since the last review almost 30 years ago, prompting the need for a comprehensive review. The current systematic review aims to identify the reported associations between paranormal beliefs and cognitive functioning, and to assess study quality. Method We searched four databases (Scopus, ScienceDirect, SpringerLink, and OpenGrey) from inception until May 2021. Inclusion criteria comprised papers published in English that contained original data assessing paranormal beliefs and cognitive function in healthy adult samples. Study quality and risk of bias was assessed using the Appraisal tool for Cross-Sectional Studies (AXIS) and results were synthesised through narrative review. The review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was preregistered as part of a larger registration on the Open Science Framework (https://osf.io/uzm5v). Results From 475 identified studies, 71 (n = 20,993) met our inclusion criteria. Studies were subsequently divided into the following six categories: perceptual and cognitive biases (k = 19, n = 3,397), reasoning (k = 17, n = 9,661), intelligence, critical thinking, and academic ability (k = 12, n = 2,657), thinking style (k = 13, n = 4,100), executive function and memory (k = 6, n = 810), and other cognitive functions (k = 4, n = 368). Study quality was rated as good-to-strong for 75% of studies and appears to be improving across time. Nonetheless, we identified areas of methodological weakness including: the lack of preregistration, discussion of limitations, a-priori justification of sample size, assessment of nonrespondents, and the failure to adjust for multiple testing. Over 60% of studies have recruited undergraduates and 30% exclusively psychology undergraduates, which raises doubt about external validity. Our narrative synthesis indicates high heterogeneity of study findings. The most consistent associations emerge for paranormal beliefs with increased intuitive thinking and confirmatory bias, and reduced conditional reasoning ability and perception of randomness. Conclusions Although study quality is good, areas of methodological weakness exist. In addressing these methodological issues, we propose that authors engage with preregistration of data collection and analysis procedures. At a conceptual level, we argue poorer cognitive performance across seemingly disparate cognitive domains might reflect the influence of an over-arching executive dysfunction.
Altered hippocampal volume and functional connectivity in patients with Cushing's disease

Stress‐related brain disorders can be associated with glucocorticoid disturbance and hippocampal alteration. However, it remains largely unknown how cortisol affects the structure and function of hippocampus. Cushing's disease (CD) provides a unique “hyperexpression model” to explore the effects of excessive cortisol on hippocampus as well as the relation between these effects and neuropsychological deficits.
Comparison of planned-start, early-start and deferred-start strategies for peritoneal dialysis initiation in end-stage kidney disease.

INTRODUCTION In patients with end-stage kidney disease (ESKD) suitable for peritoneal dialysis (PD), PD should ideally be planned and initiated electively (planned-start PD). If patients present late, some centres initiate PD immediately with an urgent-start PD strategy. However, as urgent-start PD is resource intensive, we evaluated another strategy where patients first undergo emergent haemodialysis (HD), followed by early PD catheter insertion, and switch to PD 48-72 hours after PD catheter insertion (early-start PD). Conventionally, late-presenting patients are often started on HD, followed by deferred PD catheter insertion before switching to PD≥14 days after catheter insertion (deferred start PD). METHODS This is a retrospective study of new ESKD patients, comparing the planned-start, early-start and deferred-start PD strategies. Outcomes within 1 year of dialysis initiation were studied. RESULTS Of 148 patients, 57 (38.5%) patients had planned-start, 23 (15.5%) early-start and 68 (45.9%) deferred-start PD. Baseline biochemical parameters were similar except for a lower serum urea with planned-start PD. No significant differences were seen in the primary outcomes of technique and patient survival across all 3 subgroups. Compared to planned-start PD, early-start PD had a shorter time to catheter migration (hazard ratio [HR] 14.13, 95% confidence interval [CI] 1.65-121.04, P=0.016) while deferred-start PD has a shorter time to first peritonitis (HR 2.49, 95% CI 1.03-6.01, P=0.043) and first hospital admission (HR 2.03, 95% CI 1.35-3.07, P=0.001). CONCLUSION Planned-start PD is the best PD initiation strategy. However, if this is not possible, early-start PD is a viable alternative. Catheter migration may be more frequent with early-start PD but does not appear to impact technique survival.
Pomegranate peel polyphenols interaction with intestinal flora and its metabolic transformation

Abstract 1. Pomegranate peel polyphenols (PPPs) have anti-oxidation, anti-atherosclerosis, anti-obesity effects, and so on. However, few studies have been conducted on the absorption and transformation of pomegranate polyphenols in the gut and the biologically active forms that ultimately work in the body. 2. In this study, PPPs (300 mg/kg/day) was given to normal rats and relatively sterile rats by gavage respectively. The relatively sterile rats were obtained by neomycin sulphate (250 mg/kg/day) gavage to rats. The purpose of this study is to elaborate on the relationship between intestinal flora and polyphenol metabolism of pomegranate peel and to quantitatively analyse the transformation process of its metabolite urolithin in rats. 3. The results showed that decreased bacterial diversity could significantly reduce the abundance of PPPs metabolites in faeces and urine in relatively sterile rats. PPPs can regulate intestinal flora structure, significantly enhance the content of Clostrida Firmicutes (P < 0.05), and effectively promote acetic acid, propionic acid, butyric acid, iso-butyric acid and valeric acid production in the rat (P < 0.05 or P < 0.01 or P < 0.001). PPPs can significantly elevate the relative proportion of Ruminococcaceae (P < 0.05). Ruminococcaceae_NK4A214_group, Ruminococcaceae_UCG-014 and Ruminococcaceae_UCG-005 can promote the metabolic transformation of PPPs and make the utilisation of Urolithin A more effective.
Host succinate inhibits influenza virus infection through succinylation and nuclear retention of the viral nucleoprotein

Influenza virus infection causes considerable morbidity and mortality, but current therapies have limited efficacy. We hypothesized that investigating the metabolic signaling during infection may help to design innovative antiviral approaches. Using bronchoalveolar lavages of infected mice, we here demonstrate that influenza virus induces a major reprogramming of lung metabolism. We focused on mitochondria‐derived succinate that accumulated both in the respiratory fluids of virus‐challenged mice and of patients with influenza pneumonia. Notably, succinate displays a potent antiviral activity in vitro as it inhibits the multiplication of influenza A/H1N1 and A/H3N2 strains and strongly decreases virus‐triggered metabolic perturbations and inflammatory responses. Moreover, mice receiving succinate intranasally showed reduced viral loads in lungs and increased survival compared to control animals. The antiviral mechanism involves a succinate‐dependent posttranslational modification, that is, succinylation, of the viral nucleoprotein at the highly conserved K87 residue. Succinylation of viral nucleoprotein altered its electrostatic interactions with viral RNA and further impaired the trafficking of viral ribonucleoprotein complexes. The finding that succinate efficiently disrupts the influenza replication cycle opens up new avenues for improved treatment of influenza pneumonia.