Carbapenem Heteroresistance Mdr Enterobacter Cloacae in a Post-Covid-19 Obese Patient: An Antibiotic Susceptibility Conversion

Intro: Background: Obesity affects drug delivery and clearance owing to the patient's altered pharmacokinetics. In treating infection, this presents as a conundrum antibiotic dosing to achieve optimal antibiotic concentration at the same time avoiding drug toxicity. Particularly in the case of antimicrobial agents, underdosing may lead to antibiotic resistance. Method(s): Case description: We report a case of a morbidly obese (BMI=58) COVID-19 patient infected with carbapenem-sensitive multi-drug resistant (MDR) Enterobacter cloacae bacteremia, treated with ertapenem 1g twice daily and intravenous polymyxin E 9MU stat and 4.5MU twice daily for MDR Acinetobacter baumanii co-infection. He had infected huge grade IV sacral sore one month later in which intraoperative tissue culture grew phenotypically heterogeneous colonies of MDR Enterobacter cloacae with carbapenem-sensitive and carbapenem-intermediate-resistant non-carbapenemase producing colonies. He responded well clinically and biochemically with an increased dose of intravenous ciprofloxacin 800mg BD based on his actual body weight. He was discharged with oral ciprofloxacin 750mg BD for a total of six weeks. Finding(s): Discussion: Obesity is a public health crisis that has reached epidemic proportions. Obesity affects the volume distribution and renal clearance of many drugs including antibiotics. Obese patients are shown to have higher drug clearance than normal-weighted patients resulting in inadequate systemic exposure. This puts patients at risk of developing antibiotic resistant organisms. Our patient, weighing 162kg was given three different beta-lactam antibiotics to treat his infection including ertapenem in which a standard adult dose was given without body weight consideration. Possible underdosing contributed to the conversion of carbapenem susceptibility from sensitive to resistant strain. Conclusion(s): Obese individuals may need a larger ertapenem dose than their non-obese counterparts. Clinical and laboratory assessment may help in monitoring treatment response in this group of patients.Copyright © 2023

A PHASE 1B STUDY OF ZOTATIFIN FOR THE TREATMENT OF MILD TO MODERATE COVID (PROpel)

Background: Zotatifin (eFT226) is a potent and selective inhibitor of eukaryotic initiation factor 4A (eIF4A), a host RNA helicase required for SARS-CoV-2 replication. In vitro, zotatifin demonstrates broad spectrum antiviral activity against all human coronaviruses tested. Zotatifin has physicochemical and pharmacokinetic (PK) properties suitable for convenient, single subcutaneous (sc) injection. This study assessed the safety, antiviral activity, and PK of zotatifin in non-hospitalized patients (pts) with mild/moderate COVID. Method(s): PROPEL is a randomized, placebo-controlled, double-blind study in non-hospitalized pts with mild/moderate COVID. At randomization, pts must have had a SARS-CoV-2 positive test within 7 days and at least 1 COVID symptom. Pts were randomized (3:1) to zotatifin or placebo sc in 3 cohorts of 12 pts each. Cohort 1, 2 and 3 received a single dose (SD) of zotatifin of 0.01. 0.02 and 0.035 mg/kg or matching placebo. Safety (adverse event (AE) and laboratory tests), antiviral activity (mid-turbinate nasal swabs and saliva), and plasma PK were collected over 30 days. The primary endpoint was safety;key secondary endpoints included SARS-CoV-2 viral load (VL) and PK. The study was not powered for statistical inferential testing. Result(s): 36 pts were enrolled across all three cohorts and completed a 30-day follow up. Data is currently available for pts in cohorts 1 and 2, 18 and 6 of whom received zotatifin and placebo, respectively. Baseline characteristics were comparable between groups. The most common AE was erythema at injection site in cohort 1 (44%) and cohort 2 (89%), vs. 0% in the zotatifin and pooled placebo groups, respectively. Other AE frequencies were comparable between zotatifin and placebo and no serious AEs were reported. The concentrationtime profile of zotatifin from cohorts 1 and 2 following sc administration was similar to that reported previously following IV administration, demonstrated a terminal elimination half-life (t1/2) of ~ 4 days, high steady-state volume of distribution (Vss) of 31 L/kg, and low plasma clearance (Cl) of 3.9 mL/min/kg. A faster time to viral RNA undetectability was observed with zotatifin vs. placebo (see Fig 1. Not statistically significant). Conclusion(s): Zotatifin was safe, well tolerated and demonstrated a trend in clinical antiviral activity in patients with mild to moderate COVID which supports further clinical development. Zotatifin sc route of administration supports a point of care treatment for COVID.

Population pharmacokinetics of dexamethasone in critically ill COVID-19 patients: inflammation might play a role

Introduction: One of the common causes of COVID-19 related death is acute respiratory distress syndrome (C-ARDS). Dexamethasone is the cornerstone in the therapy of C-ARDS and reduces mortality probably by suppressing inflammatory levels in ICU patients. Its anti-inflammatory effects may be concentration-related. However, no pharmacokinetic studies of dexamethasone have been conducted in ICU patients. Therefore, we designed a population pharmacokinetic study to gain a deeper understanding of the pharmacokinetics of dexamethasone in critically ill patients in order to identify relevant covariates that can be used to personalize dosing regimens and improve clinical outcomes. Method(s): This was a retrospective pilot study at the ICU of the Erasmus Medical Center. Blood samples were collected in adults at the ICU with COVID who were treated with fixed dose intravenous dexamethasone (6 mg/day). The data were analyzed using Nonlinear Mixed Effects Modelling (NONMEM) software for population pharmacokinetic analysis and clinically relevant covariates were selected and evaluated. Result(s): A total of 51 dexamethasone samples were measured in 18 patients. A two-compartment model with first-order kinetics best fitted the data. The mean population estimates for drug clearance and inter-compartment clearance were 2.85 L/h (IIV 62.9%) and 2.11 L/h, respectively, and central and peripheral volumes of distribution were 15.4 L and 12.3 L, respectively. The covariate analysis showed a significant correlation between dexamethasone clearance and CRP. Dexamethasone clearance decreased significantly with increasing CRP in the range of 0-50 mg/L and a correlation was observed with CRP up to 100 mg/L. Conclusion(s): The dexamethasone PK parameters of ICU COVID patients were quite different from those come from healthy populations. Inflammation might play an important role in dexamethasone clearance and the dosing should be more individualized in order to achieve best therapeutic effect in ICU patients.

Sotrovimab Pharmacokinetics and Covariate Effects in Hematopoietic Stem Cell Transplant Recipients

Hematopoietic cell transplant (HCT) recipients are at increased risk of morbidity and mortality from COVID-19. They may have lower SARS-CoV-2-directed antibody levels due to protein loss from the gastrointestinal (GI) tract as a result of preparative regimen-related toxicity and graft-vs.-host disease (GVHD). In fact, previous studies suggested that GI GVHD or diarrhea from other etiologies were associated with a reduction in the half-life of monoclonal antibodies (mAbs). Hence, understanding the pharmacokinetic (PK) profile of mAbs targeting SARS-CoV-2 in this vulnerable population is critical for dose-selection and predicting the duration of protection against COVID-19. This analysis aims to use a population pharmacokinetics (popPK) approach to evaluate the PK of sotrovimab and the effect of covariates in HCT recipients. In a Phase I trial (COVIDMAB), all participants received 500 mg sotrovimab IV prophylactically within one week prior to starting transplant conditioning. Sotrovimab serum concentrations were determined weekly for up to 12 weeks in autologous (n=5) and allogeneic (n=15) HCT recipients (129 observations). Sotrovimb PK and the effect of covariates were analyzed using popPK modeling in NONMEM (version 7.4). GVHD and diarrhea severity data were collected weekly via survey and included as time-dependent covariates during the covariate screening process. The final PK model with covariates was validated using simulation-based validation and goodness of fit plots. PK data were compared to non-transplant patients from 1891 patients with COVID-19 in COMET-ICE, COMET-PEAK, BLAZE-4, and COMET-TAIL and 38 healthy individuals enrolled in GlaxoSmithKline Pharma Study 217653. A two-compartment model best described sotrovimab PK in HCT recipients. In comparison to non-transplant patients, sotrovimab clearance (CL) was 14.0% higher in HCT recipients. Weight was a significant covariate on sotrovimab CL and (Figure Presented) volume of distribution in the central compartment (V2). With every 10 kg increase in body weight, sotrovimab CL and V2 were estimated to increase by 9.5% and 5.5%, respectively. Diarrhea severity was also a significant covariate on sotrovimab CL. HCT recipients with grade 3 diarrhea showed an increase in CL by 1.5-fold compared to those without diarrhea. Based on popPK analyses, sotrovimab CL was higher in HCT recipients compared to non-transplant patients. Higher bodyweight as well as diarrhea resulted in increased sotrovimab CL. There were only 3 patients with GI GVHD, and larger studies are needed to determine whether diarrhea due to GI GVHD or conditioning toxicity was responsible for the observed increase in sotrovimab CL. Further validation of these findings in a larger number of HCT recipients is also warranted to help optimize mAb dosing for COVID-19 prophylaxis and determine whether presence of large-volume diarrhea may require intensified dosing strategiesCopyright © 2023 American Society for Transplantation and Cellular Therapy

In Silico Analysis of Bioactive Compounds from Sea Urchin (Echinometra mathaei) against SARS-COV-2

SARS-CoV-2 is a kind of coronavirus that produces Covid-19 illness, which is still a public health concern in Indonesia. Meanwhile, an effective drug has not yet been found and although vaccination has been carried out, in several regions and neighboring countries there is still an increase in Covid-19 cases. This study aimed to obtain bioactive compounds from sea urchins (Echinometra mathaei) that have greater antiviral potential and lower toxicity than remdesivir. This research was started by predicting druglikeness with SwissADME, followed ADMET predicition with pkCSM online, and docking of molecule using the Molegro Virtual Docker (MVD) 5.5 software against the main protease (Mpro) target (PDB ID: 6W63). The results showed that six compounds from sea urchins (Echinometra mathaei) had antiviral activity, where the bioactive compound from sea urchins (Echinometra mathaei) with the highest affinity was shown by Spinochrome C a smaller rerank score compared with Remdesivir and native ligand (X77). So that Spinochrome C compounds are candidates as SARS-CoV-2 inhibitors potential developed drug.Copyright Published by Oriental Scientific Publishing Company © 2023.

Pharmacokinetics of Teicoplanin in a Patient with Coronavirus Disease 2019 Receiving Veno-venous Extracorporeal Membrane Oxygenation.

Introduction: Patients with severe coronavirus disease 2019 (COVID-19) receiving ventilation or pulmonary support via veno-venous extracorporeal membrane oxygenation (VV-ECMO) can be infected with drug-resistant bacteria. When introducing VV-ECMO, the changes in serum antibiotic concentration should be considered due to an increased volume of distribution (Vd). However, no pharmacokinetic study has assessed teicoplanin (TEIC) treatment in patients with COVID-19 receiving VV-ECMO. Case presentation: A 71-year-old man diagnosed with COVID-19 visited a primary hospital. His oxygenation conditions worsened despite treatment with favipiravir and methylprednisolone as well as oxygen therapy. After his transfer to our center, tracheal intubation and steroid pulse therapy were initiated. Seven days after admission, VV-ECMO was performed. TEIC was administered for secondary bacterial infection. The serum TEIC concentration remained within the therapeutic range, indicating that VV-ECMO did not significantly affect TEIC pharmacokinetics. VV-ECMO was discontinued 17 days after admission. However, he developed multi-organ disorder and died 42 days after admission. Conclusion: As TEIC prevents viral invasion, it may be used with ECMO in patients with COVID-19 requiring ventilation; however, the altered pharmacokinetics of TEIC, such as increased Vd, should be considered. Therefore, TEIC pharmacokinetics in VV-ECMO should be assessed in future studies with an appropriate number of patients.

A Pharmacokinetic Modeling Approach to Evaluate the Current Dosing Recommendations for Molnupiravir, a Novel Oral SARS-CoV-2 Antiviral, in the Egyptian Population

Introduction: Molnupiravir, a prodrug of the antiviral Nhydroxycytidine (NHC), is one of the limited treatment options that has recently gained emergency use authorization for treating mild-tomoderate SARS-CoV-2 cases. While NHC is shown to follow linear pharmacokinetics with similar exposures in healthy and SARS-CoV-2 subjects, its pharmacokinetics has not been characterized in the Egyptian population. Research Question or Hypothesis: We aimed to develop a population pharmacokinetic model for NHC and evaluate through simulations the current molnupiravir dosage of 800 mg twice daily for five days in the Egyptian population. Study Design: An open label, single arm pharmacokinetic study. Methods: Twelve healthy volunteers received 800 mg molnupiravir oral dose. Model development using non-linear mixed effect modeling and internal validation using bootstrapping and visual predictive check were conducted in MonolixSuite. Simulation-based maximum concentration (Cmax) 'the safety metric' and area under the curve (AUC0-12h) 'the efficacy metric' were computed for 1000 virtual subjects. Geometric mean ratios (GMR) and 90% confidence intervals (CI) compared to previously reported values were calculated. Results: A total of 132 NHC plasma concentrations were analyzed. Six transit compartments for absorption and one-compartment with weight on apparent clearance (CL/F) and volume of distribution (Vd/F) for disposition best described NHC's pharmacokinetics. The pharmackokinetic parameters were estimated with good precision and the population estimates for mean transit time, first-order absorption rate constant, CL/F and Vd/F were 0.49 hours, 2.32 hour-1, 75.12 L/hour.70 kg and 118 L/70 kg, respectively. Geometric means of simulation-based Cmax and AUC0-12 were 3827 ng/mL (GMR = 1.05;90% CI= 0.96-1.15) and 9320 ng.hr/mL (GMR = 1.04;90% CI= 0.97-1.11), respectively. Conclusion: Population pharmacokinetic model was developed for NHC. Simulations showed that current molnupiravir dosage can achieve the therapeutic targets and dose adjustment may not be required for the Egyptian population. The developed model could be used in the future to refine molnupiravir's dosage once further therapeutic targets are identified.

Use of Monte Carlo simulation to prevent pharmacokinetics impairment of amiodarone under VV ECMO

Introduction: Acute Respiratory Distress Syndrome (ARDS) became a leading cause of ICU admission since the COVID-19 outbreak. Refractory ARDS can benefit from Veno-Venous Extra Corporeal Membrane Oxygenation (VV ECMO). Amiodarone is used for treating cardiac arrhythmias and shockable cardiac arrest during cardiopulmonary resuscitation (CPR). Data about amiodarone under VV ECMO are still lacking. In a previous work led on a model of ARDS in pigs ongoing CPR, we showed a pharmacokinetics impairment of amiodarone under VV ECMO. We aimed to establish a PK modelling of amiodarone concentrations. Material and methods: Nonlinear mixed effects modelling approach was used to analyse plasma concentrations. Impact of VV ECMO on amiodarone pharmacokinetic profile were investigated. Using our final model, different dosing schemes for amiodarone (10 000 Monte Carlo simulations) were simulated in animals on ECMO VV. Results: A two-compartment model with first-order absorption and elimination was able to accurately describe amiodarone plasma concentrations. Interindividual variability was retained for clearance and central volume of distribution. Amiodarone PK parameters were influenced by the ECMO covariable. All parameters were well estimated. Goodness of fit plots comforted the accuracy of the model. Predicted-corrected visual predictive check of the final model was satisfactory. Simulated amiodarone exposure showed that amiodarone 600 mg bolus is required under VV ECMO to achieve similar AUC observed in the control group. Discussion/Conclusion: In our model of ARDS in pigs with cardiac arrest and benefiting from CPR and VV ECMO, a two-compartment model with first-order absorption and elimination was able to accurately describe amiodarone plasma concentrations. VV ECMO significantly modified both central distribution volume and amiodarone clearance. From Monte-Carlo simulation, we showed that a 2-fold increase of amiodarone doses should be considered to reach efficient drug exposure under VV ECMO.

Managing Delirium in a patient with Extracorporeal Membrane Oxygenation (ECMO) machine for bridge to lung transplant: A Case report

Background: Due to COVID pandemic, there have been increased needs for ECMO circuits to support patients with respiratory failure1. Unfortunately, due to pharmacokinetics alteration of commonly used sedative and psychotropic medications by the ECMO circuits2,new sedation approaches to manage delirium and agitation is required. We present a case of COVID pneumonia patient on ECMO support, whose delirium symptoms were managed with a novel psychopharmacotherapy protocol. Case: Mr. M is a 57-year-old male patient with past medical history of obesity, hypertension, admitted to Stanford Hospital due to COVID pneumonia, complicated by respiratory failure, required to be on Veno-Venous ECMO support with bridge to transplant. He had significant hyperactive delirium with Richmond Agitation-Sedation Scale (RASS) score of +3 and ICDSC score of 7 for most of the days, despite heavy conventional pharmacological sedation. We observe the same problems with most patients placed on the ECMO system, leading to an investigation and development of a new protocol. Discussion: Patient on ECMO support requires adequate sedation to prevent clinical deterioration that can result from hyperactive delirium (ie., chugging, blood clots or decannulation)2. Nevertheless, ECMO circuit’s significant alterations of drug pharmacokinetics, such as increased volume of distribution and sequestration of lipophilic and protein bound medications, with no clear guidelines on managing sedation/delirium in patients with ECMO support at this time2, we conducted an extensive literature search and developed a novel protocol. This new sedation approach includes alpha-2 agonists, opioids, barbiturates and calcium channel modulators with the lowest lipophilicity and protein binding potential of each medication in its class4,5,thus overcoming the challenges introduced by ECMO circuits. The new protocol allowed the patient to participate in lung transplant work-up, physical therapy, and eventually facilitated receiving bilateral lung transplantation. Conclusion/Implications: ECMO is a life saving device that can help patient with cardiac-respiratory failure, and its use has been increasing in clinical practice. However, there needs to be an improvement in successful sedation/delirium management to minimize adverse events, and optimize the success of this lifesaving technologies. References: 1. Cho HJ, et al. ECMO use in COVID-19: lessons from past respiratory virus outbreaks-a narrative review. Crit Care. 2020 Jun 6;24(1):301 2. deBacker J, et al. Sedation Practice in Extracorporeal Membrane Oxygenation-Treated Patients with Acute Respiratory Distress Syndrome: A Retrospective Study. ASAIO J. 2018 Jul/Aug;64(4):544-551 3. Lemaitre F, et al. Propofol, midazolam, vancomycin and cyclosporine therapeutic drug monitoring in extracorporeal membrane oxygenation circuits primed with whole human blood. Crit Care. 2015;19(1):40 4. Hansch C, et al. Hydrophobicity and central nervous system agents: on the principle of minimal hydrophobicity in drug design. J Pharm Sci. 1987 Sep;76(9):663-87 5. Bockbrader HN, et al. A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. Clin Pharmacokinet. 2010 Oct;49(10):661-9

Advantages of Allometric Scaling Methods for Predicting Human Pharmacokinetics of Novel JAK Inhibitor -Baricitinib and Dose Extrapolation

The primary motive of this study was to examine advantages of allometry scaling strategies for correct prediction of pharmacokinetics of Baricitinib in human from preclinical species. Baricitinib is basically Janus kinase (JAK) inhibitor used for the treatment of rheumatoid arthritis. Currently approved by FDA in combination with remdesivir for treatment of COVID-19 hospitalized patient. The literature published pharmacokinetic parameters (Cl and Vd) of preclinical species (Rat, Dog and monkey) were utilized for the allometry scaling of Baricitinib. The connection among the primary pharmacokinetic parameters [Volume of distribution (Vd) and clearance (Cl)] and body weight (BW) were studied across three preclinical species, we used the double logarithmic plots for prediction of the human pharmacokinetic parameters i.e. Cl and Vd with use of simple allometry and with additional correction factors for better prediction. The dose extrapolation of baricitinib was carried out by FDA guidelines. By application of the allometric scaling methods and principles correlation was found to be satisfactory for the prediction of intravenous human Cl and Vd for baricitinib. The volume of distribution (Vd) predicted by simple allometry (65.3 L) was found to be in agreement with the reported value (75.5 L);clearance (Cl) prediction by simple allometry was found to be at least 1.06 -closer to the reported value (245 mL/min);CF were used to predict the clearance. Both brain weight (B.W) and maximum life span potential (MLP) predicted the Cl with 0.52- and 0.61 -fold difference. The application of monkey liver blood flow predicted Cl with 0.81 fold which was also in close agreement with reported value. The Cl prediction was also extrapolated using LBF (Liver blood flow) method and observed that the higher species (Dog and Monkey) have predicted Cl with better accuracy than rat. Overall, the simple allometry (SA), monkey liver blood flow (MLBF) and application of liver blood flow (LBF) methods showed excellent correlation with human. The time vs. plasma concentration simulated graph also showed the similar closeness with human profile. The inclusion of plasma protein binding factor didn't improve the prediction accuracy. The FIH dose extrapolation were showed that PK guided approach and exponent for BSA based approach was found closer to actual human dose of 4.0 mg/Kg. Oriental Scientific Publishing Company

Targeting vimentin impacts multiple cellular processes, blocks the spike protein-ACE2-mediated pseudoviral infection in vitro and reduces the symptom and lung injury in aged mice with mouse-adapted SARS-CoV-2 infection in vivo

Vimentin intermediate filament is involved in multiple steps of viral infection such as viral entry, trafficking and egress, as well as in various mechanisms of hyperinflammation such as the restraint of Treg cell functions and the activation of NLRP3 inflammasome. We evaluated a vimentin-binding small molecule compound ALD-R491 for its effects on cellular processes related to viral infection and for its efficacy in treating SARS-CoV2 infection in vitro and in vivo. In cultured cells, the compound could reduce endocytosis by 10%, endosomal trafficking by 40% and exosomal release by over 30%. In an infection system consisting of a lentiviral pseudotype bearing the SARS-CoV-2 spike protein and HEK293 cells over-expressing the human ACE2 receptor with multiplicity of infection (MOI) of 1, 10 and 100, the compound inhibited the infection up to a maximum of over 90%, with IC 50 < 50 nM, CC50 > 10 μM, and SI > 200. After oral administration of ALD-R491 in rats, the plasma concentration of the compound reached the peak (Tmax) at around 5 h with a half-life (T1/2) of about 5 h. The compound was widely distributed and enriched in tissues in vivo in rats with a volume of distribution (Vd) of over 2,000 ml/kg. The lung and the lymph nodes were among the tissues with high drug exposures. In rats receiving oral gavage of the compound at 30 mg/kg, the drug exposure in the lung and the lymph nodes maintained at levels over 1 μM from 1 h to 6 h after the oral dosing. In the syngeneic mouse tumor CT26 model, ALD-R491 was found to activate regulatory T cells (Tregs) in vivo and enhance de novo generation of Tregs in lymph nodes of the mice. In the Mouse-Adapted SARS-CoV2 model, aged mice (11-12 months) were used to provide a harder test of recovery from infection that reflects the severeness of COVID-19 in old patients. For therapeutic treatment, the mice were orally administered with the compound 24 h after the SARS-CoV2 infection once per day on Day 1, Day 2 and Day 4. At 10 mg/kg, ALD-R491 significantly reduced the body weight loss of the mice (p<0.01 on Day 5 post-infection). At both 3 mg/kg and 10 mg/kg, the compound significantly reduced the hemorrhagic score for the lungs (p<0.01 and p<0.05, respectively, on Day 5). These results indicate that vimentin intermediate filament is an effective host-directed antiviral target. Importantly, the vimentin-binding small molecule ALD-R491 impacts multiple aspects of SARS-CoV2 infection, has a favorable oral pharmacokinetics and a wide therapeutic window, and therefore may be a promising therapeutic candidate for treating COVID-19. Statement: Aluda Pharmaceuticals, Inc. has utilized the non-clinical and pre-clinical services program offered by the National Institute of Allergy and Infectious Diseases.

Biomimetic properties and estimated in vivo distribution of chloroquine and hydroxy-chloroquine enantiomers.

Chloroquine and hydroxy-chloroquine already established as anti-malarial and lupus drugs have recently gained renewed attention in the fight against the Covid-19 pandemic. Bio-mimetic HPLC methods have been used to measure the protein and phospholipid binding of the racemic mixtures of the drugs. The tissue binding and volume of distribution of the enantiomers have been estimated. The enantiomers can be separated using Chiralpak AGP HPLC columns. From the α-1-acid-glycoprotein (AGP) binding, the lung tissue binding can be estimated for the enantiomers. The drugs have a large volume of distribution, showed strong and stereoselective glycoprotein binding, medium-strong phospholipid-binding indicating only moderate phospholipidotic potential, hERG inhibition and promiscuous binding. The drug efficiency of the compounds was estimated to be greater than 2 % which indicates a high level of free biophase concentration relative to dose. The biomimetic properties of the compounds support the well-known tolerability of the drugs.