Miracle-dz/UniFAR-FTUs huggingface dataset:
Empiric Therapeutic Anticoagulation and Mortality in Critically Ill Patients With Respiratory Failure From SARS‐CoV‐2: A Retrospective Cohort Study

The pathophysiology of respiratory failure associated with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) remains under investigation. One hypothesis is that progressive endothelial damage from the virus leads to microvascular thrombosis. It is uncertain if empiric therapeutic anticoagulation provides benefit over standard deep vein thrombosis (DVT) prophylaxis in critically ill patients with SARS‐CoV‐2. A retrospective cohort study was performed to evaluate adult patients admitted to the intensive care unit at 3 hospitals with polymerase chain reaction‐confirmed SARS‐CoV‐2‐associated respiratory failure requiring invasive mechanical ventilation. A Kaplan‐Meier survival analysis was used to compare patients who were initiated on therapeutic anticoagulation prior to the time of intubation and those receiving standard DVT prophylaxis doses. The primary outcome was the difference in the 28‐day mortality of patients between the 2 groups. Twenty‐eight‐day mortality did not differ between groups, occurring in 26.1% of patients who received therapeutic anticoagulation and 29.5% of those who received a prophylactic dose only (hazard ratio, 0.52; P = .055). There was no difference in 28‐day mortality between groups in patients who were admitted with a serum D‐dimer ≥ 2 µg/mL (hazard ratio, 0.67; P = .41). Empiric therapeutic anticoagulation in patients who require invasive mechanical ventilation for confirmed SARS‐CoV‐2 infection does not improve 28‐day mortality compared with standard DVT prophylaxis, even among those with elevated D‐dimer levels.
The impact of sarcopenia and decrease in skeletal muscle mass in patients with advanced pancreatic cancer during FOLFIRINOX therapy

Abstract Sarcopenia, defined as decrease in skeletal muscle mass (SMM) and strength, might be associated with reduced survival. We investigated the impact of sarcopenia and decrease in SMM in patients with advanced pancreatic cancer during FOLFIRINOX (FX) therapy. Consecutive sixty-nine patients who received FX were evaluated. Skeletal muscle index (SMI) (cm2/m2) was used to evaluate SMM. The cut-off value of sarcopenia was defined as SMI <42 for males and <38 for females, based on the Asian Working Group for sarcopenia criteria. Sarcopenia was diagnosed in thirty-three (48 %) subjects. Comparison of baseline characteristics of the two groups (sarcopenia group: non-sarcopenia group) showed a significant difference in sex, tumour size and BMI. There was no significant difference in the incidence of adverse events with grades 3–5 and progression-free survival (PFS) during FX between the two groups (PFS 8·1 and 8·8 months; P = 0·88). On the multivariate analysis, progressive disease at the first follow-up computed tomography (hazard ratio (HR) 3·87, 95 % CI 1·53, 9·67), decreased SMI ≥ 7·9 % in 2 months (HR 4·02, 95 % CI 1·87, 8·97) and carcinoembryonic antigen ≥ 4·6 (HR 2·52, 95 % CI 1·10, 6·11) were significant risk factors associated with poor overall survival (OS), but sarcopenia at diagnosis was not. OS in patients with decreased SMI of ≥7·9 % and <7·9 % were 10·9 and 21·0 months (P < 0·01), respectively. In conclusion, decrease in SMM within 2 months after the initiation of chemotherapy had significantly shorter OS, although sarcopenia at diagnosis did not affect OS. Therefore, it might be important to maintain SMM during chemotherapy for a better prognosis.
Evaluation of Antimicrobial Coatings on Preservation and Shelf Life of Fresh Chicken Breast Fillets Under Cold Storage

Fresh poultry products such as chicken breast are very convenient for consumption due to their availability and nutritional and sensory characteristics but they have a short shelf life (3–5 days) due to their high water activity and propensity to microbial contamination and spoilage. In this work, the characteristics of edible coatings (EC) prepared from various formulations of guar gum (GG) and isolated soy protein were evaluated. From this evaluation, and due to the guar gum EC being the most suitable, antimicrobial coatings were prepared with different proportions of GG, nisin, and oregano oil to determine its effect on shelf life and change in physicochemical and microbiological properties of chicken breast fillets under refrigerated conditions. Fresh samples were coated with a coating-forming solution based on GG and stored at 4 °C for 16 days. During this time, the change in color, firmness, acidity, pH, growth of microorganisms was determined, and sensory tests of appearance, taste, and odor were performed. GG-coated samples retained color and firmness during storage. Likewise, a decrease in weight loss was achieved in the treated samples, and the sensory attributes were preserved compared to the uncoated samples. The application of the coating considerably delayed the growth of microorganisms, increasing the product shelf life (9 days) compared to the control samples (6 days).
Three decades post‐reforestation has not led to the reassembly of arbuscular mycorrhizal fungal communities associated with remnant primary forests

The negative effects of deforestation can potentially be ameliorated through ecological restoration. However, reforestation alone may not reassemble the same ecological communities or functions as primary forests. In part, this failure may be owed to forest ecosystems inherently involving complex interactions among guilds of organisms. Plants, which structure forest food webs, rely on intimate associations with symbiotic microbes such as root‐inhabiting mycorrhizal fungi. Here, we leverage a large‐scale reforestation project on Hawai‘i Island underway for over three decades to assess whether arbuscular mycorrhizal (AM) fungal communities have concurrently been restored. The reference ecosystem for this restoration project is a remnant montane native Hawaiian forest that provides critical habitat for endangered birds. We sampled soils from 12 plots within remnant and restored forest patches and characterized AM fungal communities using high‐throughput amplicon sequencing. While some AM fungal community metrics were comparable between remnant and restored forest (e.g. species richness), other key characteristics were not. Specifically, community membership and the identity of AM fungal keystone species differed between the two habitat types, as well as the primary environmental factors influencing community composition. Remnant forest AM fungal communities were strongly associated with soil chemical properties, especially pH, while restored forest communities were influenced by the spatial proximity to remnant forests. We posit that combined, these differences in soil AM fungal communities could be negatively affecting the recruitment of native plant hosts and that future restoration efforts should consider plant–microbe interactions as an important facet of forest health.
Effect of Multilevel Upper Airway Surgery vs Medical Management on the Apnea-Hypopnea Index and Patient-Reported Daytime Sleepiness Among Patients With Moderate or Severe Obstructive Sleep Apnea: The SAMS Randomized Clinical Trial.

Importance Many adults with obstructive sleep apnea (OSA) use device treatments inadequately and remain untreated. Objective To determine whether combined palatal and tongue surgery to enlarge or stabilize the upper airway is an effective treatment for patients with OSA when conventional device treatment failed. Design, Setting, and Participants Multicenter, parallel-group, open-label randomized clinical trial of upper airway surgery vs ongoing medical management. Adults with symptomatic moderate or severe OSA in whom conventional treatments had failed were enrolled from August 2014 to November 2017, with follow-up until August 2018. Interventions Multilevel surgery (modified uvulopalatopharyngoplasty and minimally invasive tongue volume reduction; n = 51) or ongoing medical management (eg, advice on sleep positioning, weight loss; n = 51). Main Outcomes and Measures Primary outcome measures were the apnea-hypopnea index (AHI; ie, the number of apnea and hypopnea events/h; 15-30 indicates moderate and >30 indicates severe OSA) and the Epworth Sleepiness Scale (ESS; range, 0-24; >10 indicates pathological sleepiness). Baseline-adjusted differences between groups at 6 months were assessed. Minimal clinically important differences are 15 events per hour for AHI and 2 units for ESS. Results Among 102 participants who were randomized (mean [SD] age, 44.6 [12.8] years; 18 [18%] women), 91 (89%) completed the trial. The mean AHI was 47.9 at baseline and 20.8 at 6 months for the surgery group and 45.3 at baseline and 34.5 at 6 months for the medical management group (mean baseline-adjusted between-group difference at 6 mo, -17.6 events/h [95% CI, -26.8 to -8.4]; P < .001). The mean ESS was 12.4 at baseline and 5.3 at 6 months in the surgery group and 11.1 at baseline and 10.5 at 6 months in the medical management group (mean baseline-adjusted between-group difference at 6 mo, -6.7 [95% CI, -8.2 to -5.2]; P < .001). Two participants (4%) in the surgery group had serious adverse events (1 had a myocardial infarction on postoperative day 5 and 1 was hospitalized for observation following hematemesis of old blood). Conclusions and Relevance In this preliminary study of adults with moderate or severe OSA in whom conventional therapy had failed, combined palatal and tongue surgery, compared with medical management, reduced the number of apnea and hypopnea events and patient-reported sleepiness at 6 months. Further research is needed to confirm these findings in additional populations and to understand clinical utility, long-term efficacy, and safety of multilevel upper airway surgery for treatment of patients with OSA. Trial Registration Australian New Zealand Clinical Trials Registry: ACTRN12614000338662.
Dietary Intervention Accelerates NASH Resolution Depending on Inflammatory Status with Minor Additive Effects on Hepatic Injury by Vitamin E Supplementation

Despite the lack of effective pharmacotherapy against nonalcoholic steatohepatitis (NASH) and liver fibrosis, vitamin E (vitE) supplementation and lifestyle modifications are recommended for the management of NASH due to promising clinical results. We recently reported a positive effect of supplementation with 800 IU vitE and atorvastatin on NASH resolution in guinea pigs. In the present study, we investigated the effect of high-dose vitE therapy combined with dietary intervention against progressive NASH and advanced fibrosis in the guinea pig model. Sixty-six guinea pigs received either high-fat (HF) or standard guinea pig chow diet (Control) for 25 weeks. Prior to eight weeks of intervention, HF animals were allocated into groups; dietary intervention (Chow) or dietary intervention with 2000 IU/d vitE supplementation (CvitE). Both Chow and CvitE reduced dyslipidemia, hepatic lipid accumulation and liver weight (p < 0.05), while CvitE further decreased hepatocellular ballooning (p < 0.05). Subanalyses of individual responses within intervention groups showed significant correlation between the hepatic hallmarks of NASH and lipid accumulation vs. inflammatory state (p < 0.05). Collectively, our results indicate that individual differences in sensitivity towards intervention and inflammatory status determine the potential beneficial effect of dietary intervention and high-dose vitE supplementation. Moreover, the study suggests that inflammation is a primary target in NASH treatment.
Enhanced Antigiardial Effect of Omeprazole Analog Benzimidazole Compounds

Giardiasis is a diarrheal disease that is highly prevalent in developing countries. Several drugs are available for the treatment of this parasitosis; however, failures in drug therapy are common, and have adverse effects and increased resistance of the parasite to the drug, generating the need to find new alternative treatments. In this study, we synthesized a series of 2-mercaptobenzimidazoles that are derivatives of omeprazole, and the chemical structures were confirmed through mass, 1H NMR, and 13C NMR techniques. The in vitro efficacy compounds against Giardia, as well as its effect on the inhibition of triosephosphate isomerase (TPI) recombinant, were investigated, the inactivation assays were performed with 0.2 mg/mL of the enzyme incubating for 2 h at 37 °C in TE buffer, pH 7.4 with increasing concentrations of the compounds. Among the target compounds, H-BZM2, O2N-BZM7, and O2N-BZM9 had greater antigiardial activity (IC50: 36, 14, and 17 µM on trophozoites), and inhibited the TPI enzyme (K2: 2.3, 3.2, and 2.8 M−1 s−1) respectively, loading alterations on the secondary structure, global stability, and tertiary structure of the TPI protein. Finally, we demonstrated that it had low toxicity on Caco-2 and HT29 cells. This finding makes it an attractive potential starting point for new antigiardial drugs.
Licochalcone A, a licorice flavonoid: antioxidant, cytotoxic, genotoxic, and chemopreventive potential

ABSTRACT Licochalcone A (LicoA) is a flavonoid derived from Glycyrrhiza spp. plants. The present study aimed to investigate the antioxidant, cytotoxic, genotoxic, and chemopreventive effects of LicoA in in vitro and in vivo systems. The results showed that LicoA (197.1 μM) scavenged 77.92% of free radicals. Concentrations of 147.75 µM or higher LicoA produced cytotoxicity in Chinese hamster ovary (CHO) fibroblasts. LicoA treatments of 4.43 to 10.34 µM did not exert genotoxic activity, but at 11.8 µM significantly lowered nuclear division indexes, compared to negative control, revealing cytotoxicity. Lower concentrations (1.85 to 7.39 µM) exhibited protective activity against chromosomal damage induced by doxorubicin (DXR) or methyl methanesulfonate (MMS) in CHO cells. LicoA exerted no marked influence on DXR-induced genotoxicity in mouse erythrocytes, but reduced pre-neoplastic lesions induced by 1,2-dimethylhydrazine (DMH) in rat colon at 3.12 to 50 mg/kg b.w. Biochemical markers and body weight indicated no apparent toxicity. These findings contribute to better understanding the mechanisms underlying LicoA-initiated activity as a promising chemopreventive compound. Abbreviations AC, aberrant crypts; ACF, aberrant crypt foci; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BOD, biochemical oxygen demand; CHO, Chinese hamster ovary fibroblast; DMH, 1,2-dimethylhydrazine; DMSO, dimethyl sulfoxide; DPPH, 2,2-diphenyl-1-picrylhydrazyl; DXR, doxorubicin hydrochloride; EDTA, ethylenediaminetetraacetic acid; GA, gallic acid; LicoA, licochalcone A; MMS, methyl methanesulfonate; MNBC, micronucleated binucleated cells; MNPCE, micronucleated polychromatic erythrocyte; NCE, normochromatic erythrocyte; NDI, nuclear division index; PBS, phosphate-buffered saline; PCE, polychromatic erythrocyte; XTT, 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide.
COVID-19 Death and BCG Vaccination Programs Worldwide

Several clinical trials are being conducted worldwide to investigate the protective effect of the bacillus Calmette-Guérin (BCG) vaccine against death in healthcare providers who are working directly with coronavirus disease 2019 (COVID-19) patients. Clinical studies suggested that certain live vaccines, particularly the BCG vaccine, could reduce the mortality due to other diseases caused by non-targeted pathogens, most probably through the nonspecific effects (heterologous effects). By the end of May 2020, the available information on the COVID-19 pandemic indicated the great effect of the BCG vaccine in reducing the number of COVID-19 death cases. The occurrence of death due to COVID-19 was found to be 21-fold lower in countries with a national BCG vaccination policy than in countries without such a policy, based on the medians of COVID-19 death case per 1 million of the population in these two groups of countries (p<0.001, MannWhitney test). Therefore, it can be concluded that the early establishment of a BCG vaccination policy in any country is a key element in reducing the number of COVID-19 and tuberculosis death cases.
Counteracting Chemoresistance with Metformin in Breast Cancers: Targeting Cancer Stem Cells

Despite the leaps and bounds in achieving success in the management and treatment of breast cancers through surgery, chemotherapy, and radiotherapy, breast cancer remains the most frequently occurring cancer in women and the most common cause of cancer-related deaths among women. Systemic therapeutic approaches, such as chemotherapy, although beneficial in treating and curing breast cancer subjects with localized breast tumors, tend to fail in metastatic cases of the disease due to (a) an acquired resistance to the chemotherapeutic drug and (b) the development of intrinsic resistance to therapy. The existence of cancer stem cells (CSCs) plays a crucial role in both acquired and intrinsic chemoresistance. CSCs are less abundant than terminally differentiated cancer cells and confer chemoresistance through a unique altered metabolism and capability to evade the immune response system. Furthermore, CSCs possess active DNA repair systems, transporters that support multidrug resistance (MDR), advanced detoxification processes, and the ability to self-renew and differentiate into tumor progenitor cells, thereby supporting cancer invasion, metastasis, and recurrence/relapse. Hence, current research is focusing on targeting CSCs to overcome resistance and improve the efficacy of the treatment and management of breast cancer. Studies revealed that metformin (1, 1-dimethylbiguanide), a widely used anti-hyperglycemic agent, sensitizes tumor response to various chemotherapeutic drugs. Metformin selectively targets CSCs and improves the hypoxic microenvironment, suppresses the tumor metastasis and inflammation, as well as regulates the metabolic programming, induces apoptosis, and reverses epithelial–mesenchymal transition and MDR. Here, we discuss cancer (breast cancer) and chemoresistance, the molecular mechanisms of chemoresistance in breast cancers, and metformin as a chemo-sensitizing/re-sensitizing agent, with a particular focus on breast CSCs as a critical contributing factor to acquired and intrinsic chemoresistance. The review outlines the prospects and directions for a better understanding and re-purposing of metformin as an anti-cancer/chemo-sensitizing drug in the treatment of breast cancer. It intends to provide a rationale for the use of metformin as a combinatory therapy in a clinical setting.
Acute rimonabant treatment promotes protein synthesis in C2C12 myotubes through a CB1‐independent mechanism

Sarcopenia is an age‐related loss of muscle mass associated with changes in skeletal muscle protein homeostasis due to lipid accumulation and anabolic resistance; changes that are also commonly described in obesity. Activation of the endocannabinoid system is associated with the development of obesity and insulin resistance, and with the perturbed skeletal muscle development. Taken together this suggests that endocannabinoids could be regulators of skeletal muscle protein homeostasis. Here we report that rimonabant, an antagonist for the CB1 receptor, can prevent dexamethasone‐induced C2C12 myotube atrophy without affecting the mRNA expression of atrogin‐1/MAFbx (a marker of proteolysis), which suggests it is involved in the control of protein synthesis. Rimonabant alone stimulates protein synthesis in a time‐ and dose‐dependent manner through mTOR‐ and intracellular calcium‐dependent mechanisms. CB1 agonists are unable to modulate protein synthesis or prevent the effect of rimonabant. Using C2C12 cells stably expressing an shRNA directed against CB1, or HEK293 cells overexpressing HA‐tagged CB1, we demonstrated that the effect of rimonabant is unaffected by CB1 expression level. In summary, rimonabant can stimulate protein synthesis in C2C12 myotubes through a CB1‐independent mechanism. These results highlight the need to identify non‐CB1 receptor(s) mediating the pro‐anabolic effect of rimonabant as potential targets for the treatment of sarcopenia, and to design new side‐effect‐free molecules that consolidate the effect of rimonabant on skeletal muscle protein synthesis.
Physiologically Based Pharmacokinetic Modeling Involving Nonlinear Plasma and Tissue Binding: Application to Prednisolone and Prednisone in Rats

The pharmacokinetics (PK) of prednisolone (PNL) exhibit nonlinearity related to plasma protein binding, tissue binding, metabolic interconversion with prednisone (PN), and renal elimination. Blood and 11 tissues were collected from male Wistar rats after steady-state (SS) infusion and after subcutaneous boluses of 50 mg/kg of PNL. Concentrations of PNL and PN were measured by liquid chromatography–tandem mass spectrometry. Plasma and tissue profiles were described using a complex physiologically based pharmacokinetics (PBPK) model. Concentrations of PN and PNL were in rapid equilibrium in plasma and tissues. The tissue partition coefficients (Kp) of PNL calculated from most subcutaneously dosed tissue and plasma areas were similar to SS infusion and in silico values. The blood-to-plasma ratio of PNL was 0.71 with similar red blood cell and unbound-plasma concentrations. Plasma protein binding (60%–90%) was related to corticosteroid-binding globulin (CBG) saturation. Tissue distribution was nonlinear. The equilibrium dissociation constant (Kd) of PNL shared by all tissues was 3.01 ng/ml, with the highest binding in muscle, followed by liver, heart, intestine, and bone and the lowest binding in skin, spleen, fat, kidney, lung, and brain. Fat and bone distribution assumed access only to interstitial space. Brain PNL concentrations (Kp = 0.05) were low owing to presumed P-glycoprotein–mediated efflux. Clearances of CBG-free PNL were 1789 from liver and 191.2 ml/h from kidney. The PN/PNL ratio was nonlinear for plasma, spleen, heart, intestine, bone, fat, and linear for the remaining tissues. Our PBPK model with multiple complexities well described the PK profiles of PNL and PN in blood, plasma, and diverse tissues. SIGNIFICANCE STATEMENT Because steroids, such as prednisolone and prednisone, have similar and complex pharmacokinetics properties in various species, receptors in most tissues, and multiple therapeutic and adverse actions, this physiologically based pharmacokinetics (PBPK) model may provide greater insights into the pharmacodynamic complexities of corticosteroids. The complex properties of these compounds require innovative PBPK modeling approaches that may be instructive for other therapeutic agents.