Miracle-dz/UniFAR-FTUs huggingface dataset:
BRD4 Levels Determine the Response of Human Lung Cancer Cells to BET Degraders That Potently Induce Apoptosis through Suppression of Mcl-1

The current study demonstrates the potential of novel BET degraders in the treatment of lung cancer and warrants clinical validation of BET degraders in lung cancer with high levels of BRD4. Lung cancer consists of approximately 80% non–small cell lung cancer (NSCLC) and 20% small cell lung cancer (SCLC) and remains the leading cause of cancer-related deaths worldwide despite advances in early diagnosis, targeted therapy, and immunotherapy. Thus, novel therapies are still urgently needed. Bromodomain and extraterminal (BET) proteins, primarily comprised of BRD2, BRD3, and BRD4 proteins, function as epigenetic readers and master transcription coactivators and are now recognized cancer therapeutic targets. BET degraders such as ZBC260 and dBET represent a novel class of BET inhibitors that act by inducing BET degradation. The current study demonstrates the therapeutic efficacies of BET degraders, particularly ZBC260, against lung cancer, as well as understanding the underlying mechanisms and identifying molecular markers that determine cell sensitivity to BET degraders. A panel of NSCLC cell lines possessed similar response patterns to ZBC260 and dBET but different responses to BET inhibitor JQ-1. BRD levels, particularly BRD4, correlated positively with high sensitivity to BET degraders but not to JQ-1. BET degraders potently induced apoptosis in sensitive NSCLC cells and were accompanied by reduction of Mcl-1 and c-FLIP levels, which are critical for mediating induction of apoptosis and enhancement of TRAIL-induced apoptosis. Accordingly, ZBC260 exerted more potent activity than JQ-1 in vivo against the growth of NSCLC xenografts and patient-derived xenografts. These findings warrant future clinical validation of the efficacy of BET degraders in NSCLC, particularly those with high levels of BRD proteins, especially BRD4. Significance: The current study demonstrates the potential of novel BET degraders in the treatment of lung cancer and warrants clinical validation of BET degraders in lung cancer with high levels of BRD4.
Timing of Hip-fracture Surgery in Elderly Patients: Literature Review and Recommendations

The incidence of hip fractures is rapidly increasing with an aging population and is now one of the most important health concerns worldwide due to a high mortality rate. The effect of delayed surgery on postoperative outcomes has been widely discussed. Although various treatment guidelines for hip fractures in the elderly exist, most institutions recommend that operations are conducted as soon as possible to help achieve the most favorable outcomes. While opinions differ on the relationship between delayed surgery and postoperative mortality, a strong association between earlier surgery and improvement in postoperative outcomes (e.g., length of hospital stay, bedsore occurrence, return to an independent lifestyle), has been reported. Taken together, performing operations for hip fractures in the elderly within 48 hours of admission appears to be best practice. Importantly, however, existing evidence is based primarily on observational studies which are susceptible to inherent bias. Here, we share the results of a literature search to summarize data that helps inform the most appropriate surgical timing for hip fractures in the elderly and the effects of delayed surgery on postoperative outcome. In addition, we expect to be able to provide a more accurate basis for these correlations through a large-scale randomized controlled trial in the future and to present data supporting recommendations for appropriate surgical timing.
Acetaminophen Use in Pregnant Women and Their Neonates: Safe or Unsafe till Proven Otherwise?

a Division of Clinical Pharmacology, Children’s National Hospital, Washington, DC, USA; b Department of Pediatric Pharmacology and Pharmacometrics, University of Basel Children’s Hospital, Basel, Switzerland; c Department of Development and Regeneration, KU Leuven, Leuven, Belgium; d Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium; e Department of Clinical Pharmacy, Erasmus MC, Rotterdam, The Netherlands Published online: March 10, 2020
Humans Are Selectively Exposed to Pneumocystis jirovecii

Environmental exposure has a significant impact on human health. While some airborne fungi can cause life-threatening infections, the impact of environment on fungal spore dispersal and transmission is poorly understood. The democratization of shotgun metagenomics allows us to explore important questions about fungal propagation. We focus on Pneumocystis, a genus of host-specific fungi that infect mammals via airborne particles. In humans, Pneumocystis jirovecii causes lethal infections in immunocompromised patients if untreated, although its environmental reservoir and transmission route remain unclear. ABSTRACT Environmental exposure has a significant impact on human health. While some airborne fungi can cause life-threatening infections, the impact of environment on fungal spore dispersal and transmission is poorly understood. The democratization of shotgun metagenomics allows us to explore important questions about fungal propagation. We focus on Pneumocystis, a genus of host-specific fungi that infect mammals via airborne particles. In humans, Pneumocystis jirovecii causes lethal infections in immunocompromised patients if untreated, although its environmental reservoir and transmission route remain unclear. Here, we attempt to clarify, by analyzing human exposome metagenomic data sets, whether humans are exposed to different Pneumocystis species present in the air but only P. jirovecii cells are able to replicate or whether they are selectively exposed to P. jirovecii. Our analysis supports the latter hypothesis, which is consistent with a local transmission model. These data also suggest that healthy carriers are a major driver for the transmission.
A Multimodal Eye Assessment in Psoriatic Arthritis Patients sine-Psoriasis: Evidence for a Potential Association with Systemic Inflammation †

Background: Ocular involvement in Psoriatic Arthritis (PsA) patients is mainly associated with uveitis but there remains a paucity of data on dry eye and retinal abnormalities. We aimed to analyze dry eye and subclinical retinal abnormalities in a cohort of PsA patients sine-psoriasis (PsO). Methods: PsA patients sine-PsO were enrolled. Best-corrected-visual-acuity, ocular-surface-disease-index (OSDI), Schirmer test, tear film breakup-time, standard-automated-perimetry (SAP, mean deviation—MD, pattern standard deviation—PSD), fundus-perimetry (FP), and spectral-domain-optical-coherence-tomography (SD-OCT) were performed. Results: A total of 80 eyes from 40 PsA patients with moderate-severe disease activity, and 70 eyes from 35 healthy control (HC) were evaluated. Higher dry eye prevalence occurred in PsA than HC (p < 0.0001). ESR was positively related with OSDI (p < 0.001) and negatively related with Schirmer (p = 0.007). In PsA, SAP registered higher MD (p < 0.0001) and higher PSD (p = 0.005) in comparison with HC. PSD resulted positively correlated with ESR (p = 0.04) and CRP (p = 0.01), while MD showed a negative correlation with CRP (p = 0.01). Both FP mean differential sensitivity and mean defect were lower in PsA then HC (p < 0.0001). In PsA, FP differential sensitivity was directly related with cumulative steroids (p = 0.02). Conclusions: In PsA patients sine-PsO, dry eye and subclinical abnormalities in visual functions occurred being potentially related to systemic inflammation.
Changes in muscle power after usual care or early structured exercise intervention in acutely hospitalized older adults

Abstract Background A classic consequence of short‐term bed rest in older adults is the significant loss in skeletal muscle mass and muscle strength that underlies the accelerated physical performance deficits. Structured exercise programmes applied during acute hospitalization can prevent muscle function deterioration. Methods A single‐blind randomized clinical trial conducted in an acute care for elders unit in a tertiary public hospital in Navarre (Spain). Three hundred seventy hospitalized patients [56.5% female patients; mean age (standard deviation) 87.3 (4.9) years] were randomly allocated to an exercise intervention (n = 185) or a control (n = 185) group (usual care). The intervention consisted of a multicomponent exercise training programme performed during 5–7 consecutive days (2 sessions/day). The usual‐care group received habitual hospital care, which included physical rehabilitation when needed. The main endpoints were change in maximal dynamic strength (i.e. leg‐press, chest‐press, and knee extension exercises) and maximal isometric knee extensors and hip flexors strength from baseline to discharge. Changes in muscle power output at submaximal and maximal loads were also measured after the intervention. Results The physical exercise programme provided significant benefits over usual care. At discharge, the exercise group showed a mean increase of 19.6 kg [95% confidence interval (CI), 16.0, 23.2; P < 0.001] on the one‐repetition maximum (1RM) in the leg‐press exercise, 5.7 kg (95% CI, 4.7, 6.8; P < 0.001) on the 1RM in the chest‐press exercise, and 9.4 kg (95% CI, 7.3, 11.5; P < 0.001) on the 1RM in the knee extension exercise over usual‐care group. There were improvements in the intervention group also in the isometric maximal knee extension strength [14.8 Newtons (N); 95% CI, 11.2, 18.5 vs. −7.8 N; 95% CI, −11.0, −3.5 in the control group; P < 0.001] and the hip flexion strength (13.6 N; 95% CI, 10.7, 16.5 vs. −7.2 N; 95% CI, −10.1, −4.3; P < 0.001). Significant benefits were also observed in the exercise group for the muscle power output at submaximal loads (i.e. 30% 1RM, 45% 1RM, 60% 1RM, and 75% 1RM; all P < 0.001) over usual‐care group. Conclusions An individualized, multicomponent exercise training programme, with special emphasis on muscle power training, proved to be an effective therapy for improving muscle power output of lower limbs at submaximal loads and maximal muscle strength in older patients during acute hospitalization.
Dexmedetomidine Pharmacokinetics in Neonates with Hypoxic-Ischemic Encephalopathy Receiving Hypothermia

Dexmedetomidine is a promising sedative and analgesic for newborns with hypoxic-ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH). Pharmacokinetics and safety of dexmedetomidine were evaluated in a phase I, single-center, open-label study to inform future trial strategies. We recruited 7 neonates ≥36 weeks' gestational age diagnosed with moderate-to-severe HIE, who received a continuous dexmedetomidine infusion during TH and the 6 h rewarming period. Time course of plasma dexmedetomidine concentration was characterized by serial blood sampling during and after the 64.8 ± 6.9 hours of infusion. Noncompartmental analysis yielded descriptive pharmacokinetic estimates: plasma clearance of 0.760 ± 0.155 L/h/kg, steady-state distribution volume of 5.22 ± 2.62 L/kg, and mean residence time of 6.84 ± 3.20 h. Naive pooled and population analyses according to a one-compartment model provided similar estimates of clearance and distribution volume. Overall, clearance was either comparable or lower, distribution volume was larger, and mean residence time or elimination half-life was longer in cooled newborns with HIE compared to corresponding estimates previously reported for uncooled (normothermic) newborns without HIE at comparable gestational and postmenstrual ages. As a result, plasma concentrations in cooled newborns with HIE rose more slowly in the initial hours of infusion compared to predicted concentration-time profiles based on reported pharmacokinetic parameters in normothermic newborns without HIE, while similar steady-state levels were achieved. No acute adverse events were associated with dexmedetomidine treatment. While dexmedetomidine appeared safe for neonates with HIE during TH at infusion doses up to 0.4 μg/kg/h, a loading dose strategy may be needed to overcome the initial lag in rise of plasma dexmedetomidine concentration.
The development of a theoretically derived measure exploring extreme appraisals of sleep in bipolar disorder: a Delphi study with professionals

Abstract Background: Sleep and mood are known to be linked and this is particularly evident in people with a diagnosis of bipolar disorder (BD). It has been proposed that psychological interventions improving sleep can be a pathway for improving mood. In order for a psychological sleep intervention to be appropriate, the common cognitive processes maintaining the range of sleep disturbances need to be investigated. Aim: This study aimed to explore and identify expert consensus on positive and negative sleep appraisals in the context of low and high mood states, using the Integrative Cognitive Model as a theoretical guide. Method: A Delphi approach was utilized to allow clinical and research professionals, with experience in the field of BD, to be anonymously consulted about their views on sleep appraisals. These experts were invited to participate in up to three rounds of producing and rating statements that represented positive and negative sleep appraisals. Results: A total of 38 statements were developed and rated, resulting in a final list of 19 statements that were rated as ‘essential’ or ‘important’ by >80% of the participants. These statements represent the full range of extreme sleep appraisals this study had set out to explore, confirming the importance of better understanding and identifying positive and negative sleep cognitions in the context of high and low mood. Conclusion: The statements reviewed in this study will be used to inform the development of a sleep cognition measure that may be useful in cognitive therapy addressing sleep disturbances experienced along the bipolar spectrum.
Performance of Fluorescence and Diffuse Reflectance Hyperspectral Imaging for Characterization of Lutefisk: A Traditional Norwegian Fish Dish

Lutefisk is a traditional Norwegian fish dish made from dried fish, such as cod or other whitefish. In Norway and other Nordic countries, lutefisk is considered among the most popular dishes served during Christmas or other festive occasions. However, to date, little attention has been paid to this product, and available research on the quality, processing, and chemistry of lutefisk is still limited. The quality of this very delicate product, with a high pH value, depends on many factors, such as the initial quality of raw materials (stockfish), the quantity of lye used during the preparation process of lutefisk, and time during soaking in the lye and water, among others, making it challenging to both optimize processing and monitor the quality of lutefisk. In this study, four commercially available lutefisk brands (labelled as A, B, C, and D) were characterized using two online spectroscopic techniques, namely fluorescence and diffuse reflectance hyperspectral imaging, implemented on conveyor belts to mimic industrial applications. The samples were also analyzed by the use of an offline laboratory instrument based on visible/near infrared diffuse reflectance spectroscopy. Three traditional measurements, including texture, water content, and pH, were also conducted on the same samples. Supervised classification PLS-DA models were built with each dataset and relationships between the spectroscopic measurements and the traditional data were investigated using canonical correlations. The spectroscopic methods, especially fluorescence spectroscopy, demonstrated high performance for the discrimination between samples of the different brands, with high correlations between the spectral and traditional measurements. Although more validations of the results of this study are still required, these preliminary findings suggest that the destructive, laborious, and time-consuming traditional techniques can be replaced by rapid and nondestructive online measurements based on hyperspectral imaging used in fluorescence or diffuse reflectance mode.
The Relationship Between Acute: Chronic Workload Ratios and Injury Risk in Sports: A Systematic Review

Purpose Low injury rates have previously been correlated with sporting team success, highlighting the importance of injury prevention programs. Recent methods, such as acute:chronic workload ratios (ACWR) have been developed in an attempt to predict and manage injury risk; however, the relation between these methods and injury risk is unclear. The aim of this systematic review was to identify and synthesize the key findings of studies that have investigated the relationship between ACWR and injury risk. Methods Included studies were critically appraised using the Downs and Black checklist, and a level of evidence was determined. Relevant data were extracted, tabulated, and synthesized. Results Twenty-seven studies were included for review and ranged in percentage quality scores from 48.2% to 64.3%. Almost perfect interrater agreement (κ = 0.885) existed between raters. This review found a high variability between studies with different variables studied (total distance versus high speed running), as well as differences between ratios analyzed (1.50–1.80 versus ≥1.50), and reference groups (a reference group of 0.80–1.20 versus ≤0.85). Conclusion Considering the high variability, it appears that utilizing ACWR for external (eg, total distance) and internal (eg, heart rate) loads may be related to injury risk. Calculating ACWR using exponentially weighted moving averages may potentially result in a more sensitive measure. There also appears to be a trend towards the ratios of 0.80–1.30 demonstrating the lowest risk of injury. However, there may be issues with the ACWR method that must be addressed before it is confidently used to mitigate injury risk. Utilizing standardized approaches will allow for more objective conclusions to be drawn across multiple populations.
A systematic review of the impact of health information technology on nurses’ time

Abstract Objective Nursing time represents one of the highest costs for most health services. We conducted a systematic review of the literature on the impact of health information technology on nurses’ time. Materials and Methods We followed PRISMA guidelines and searched 6 large databases for relevant articles published between Jan 2004 and December 2019. Two authors reviewed the titles, abstracts, and full texts. We included articles that included a comparison group in the design, measured the time taken to carry out documentation or medication administration, documented the quantitative estimates of time differences between the 2, had nurses as subjects, and was conducted in either a care home, hospital, or community clinic. Results We identified a total of 1647 articles, of which 33 met our inclusion criteria. Twenty-one studies reported the impact of 12 different health information technology (HIT) implementations on nurses’ documentation time. Weighted averages were calculated for studies that implemented barcode medication administration (BCMA) and 2 weighted averages for those that implemented EHRs, as these studies used different sampling units; both showed an increase in the time spent in documentation (+22% and +46%). However, the time spent carrying out medication administration following BCMA implementation fell by 33% (P < .05). HIT also caused a redistribution of nurses’ time which, in some cases, was spent in more “value-adding” activities, such as delivering direct patient care as well as inter-professional communication. Discussion and Conclusions Most of the HIT systems increased nursing documentation time, although time fell for medication administration following BCMA. Many HIT systems also resulted in nurses spending more time in direct care and “value-adding” activities.
In Vitro Vascular Network Modified to Function as Culture Platform and Angiogenic Induction Potential Test for Cancer Cells

Drug treatments have been designed to inhibit tumor angiogenesis in hope of stopping tumor growth. However, not all tumor types respond to this type of treatment. A screening method which identifies angiogenesis inducing cancer types would help predict the efficacy of angiogenesis-inhibiting drugs for the patients. Our goal is to develop (1) a cell assay to assess the angiogenic induction potential of patient-derived tumor cells, and (2) a protocol for culturing cancer cells on a vascular platform. We optimized the media composition and seeding density of cells (hASC, HUVEC, and cancer cells) to 48-, 96-, and even 384-well plate sizes to allow vascular formation and cancer cell proliferation and subsequent analysis with high throughput. The angiogenic induction potential of patient-derived cancer cells was investigated by quantifying the formation of tubular structures and the drug response of cancer cells grown on a vascular platform was evaluated using gene expression and cell viability (WST-1) assay. Immunocytochemistry was performed with von Willebrand factor, collagen IV, CD44, cytokeratin 19 and ALDH1A1. The angiogenic induction potential test was shown to be responsive to the induction of angiogenesis by cancer cells. The responses of cancer cells were different when grown on a vascular platform or on plastic, seen in gene expression level and viability results. These two protocols are promising novel tools for aiding the selection of efficient cancer drugs for personalized medicine and as an alternative cancer cell culture platform.
A non-linear association between blood tumor mutation burden and prognosis in NSCLC patients receiving atezolizumab

ABSTRACT A significant association between high blood-based tumor mutational burden (bTMB) and improved progression-free survival (PFS) was observed in advanced non-small cell lung cancer (NSCLC) receiving atezolizumab. However, this result was unrepeatable in a recent prospective study. We hypothesized that there might be a non-linear association between bTMB and survival. This study used the clinical and genetic data from POPLAR (n = 105, training set) and OAK (n = 324, validation set) trials. The non-linear association between bTMB and survival was assessed using restricted cubic spline (RCS). The cutoff values for bTMB were calculated via X-tile software. Non-linear relationships were observed between bTMB and PFS and overall survival (OS) in RCS plots (both P non-linearity < 0.001). The optimal cutoff values of bTMB for predicting PFS and OS were 7 and 14 mutations/Mb, respectively. The median PFS and OS of patients with low and high bTMB were significantly longer than those of patients with medium bTMB in the training, validation, and combined sets. Low and high bTMB were also associated with longer PFS and OS in high-programmed death-ligand 1 (PD-L1) expression population. In conclusion, there was a positive non-linear association between bTMB and survival in NSCLC patients receiving atezolizumab. Patients with low bTMB could also derive benefit from immunotherapy.
miR‐210 Participates in Hepatic Ischemia Reperfusion Injury by Forming a Negative Feedback Loop With SMAD4

Hepatic ischemia‐reperfusion (IR) injury is a major complication of liver transplantation, resection, and hemorrhagic shock. Hypoxia is a key pathological event associated with IR injury. MicroRNA‐210 (miR‐210) has been characterized as a micromanager of hypoxia pathway. However, its function and mechanism in hepatic IR injury is unknown.