Population pharmacokinetics of molnupiravir in adults with COVID-19: Lack of clinically important exposure variation across individuals.

Effective antiviral treatments for coronavirus disease 2019 (COVID-19) are needed to reduce the morbidity and mortality associated with severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection, particularly in patients with risk factors for severe disease. Molnupiravir (MK-4482, EIDD-2801) is an orally administered, ribonucleoside prodrug of ß-D-N4-hydroxycytidine (NHC) with submicromolar potency against SARS-CoV-2. A population pharmacokinetic (PopPK) analysis for molnupiravir exposure was conducted using 4202 NHC plasma concentrations collected in 1207 individuals from a phase I trial in healthy participants, a phase IIa trial in non-hospitalized participants with COVID-19, a phase II trial in hospitalized participants with COVID-19, and a phase II/III trial in non-hospitalized participants with COVID-19. Molnupiravir pharmacokinetics (PK) was best described by a two-compartment model with a transit-compartment absorption model and linear elimination. Molnupiravir apparent elimination clearance increased with body weight less-than-proportionally (power 0.412) and was estimated as 70.6 L/h in 80-kg individuals with a moderate interindividual variability (43.4% coefficient of variation). Additionally, effects of sex and body mass index on apparent central volume and food status and formulation on the absorption mean transit time were identified as statistically significant descriptors of variability in these PK parameters. However, none of the identified covariate effects caused clinically relevant changes in the area under the NHC concentration versus time curve between doses, the exposure metric most closely related to clinical response. Overall, the PopPK model indicates that molnupiravir can be administered in adults without dose adjustment based on age, sex, body size, food, and mild-to-moderate renal or mild hepatic impairment.

A Model-Based Approach to Bridging Plasma and Dried Blood Spot Concentration Data for Phase 3 Verubecestat Trials.

In-clinic venous dried blood spot (DBS) pharmacokinetic (PK) sampling was incorporated into two phase 3 studies of verubecestat for Alzheimer's disease (EPOCH [NCT01739348] and APECS [NCT01953601]), as a potential alternative to plasma PK sampling. Initially, plasma and DBS PK samples were collected concurrently to better understand the DBS-plasma verubecestat concentration relationship, with the intention of discontinuing DBS or plasma sampling following interim analysis. Following initial analyses and comparison of results with prespecified selection criteria, plasma PK sampling was discontinued; however, a stability issue resulting in generally lower DBS verubecestat concentrations with longer collection-to-assay times was subsequently discovered (associated with non-compliance in DBS sample handling), prompting reintroduction of plasma sampling. To enable inclusion of DBS data in population PK analyses, a conversion algorithm for calculating plasma-equivalent concentrations (accounting for DBS sample instability) was developed using paired (time-matched) plasma and DBS data from the EPOCH study. Verubecestat population PK models developed from pooled phase 1/1b and EPOCH data using either (1) plasma-only data or (2) plasma and plasma-equivalent concentrations (calculated from non-paired DBS samples) yielded similar results. The algorithm robustness was demonstrated using DBS data from paired samples from the APECS study and comparison between plasma and plasma-equivalent concentrations. The population PK model was updated with APECS data (both plasma and, if no plasma sample available, plasma equivalents). The results demonstrated similar PK in the two phase 3 populations and exposures consistent with expectations from phase 1 data. This case study illustrates challenges with employing new sampling techniques in large, global trials and describes lessons learned.

Safety Nets Work Both Ways: The Influence of Available Paid Leave on Employee Risk Taking During the COVID-19 Pandemic.

BACKGROUND: During the COVID-19 pandemic, use of symptom-screening tools to limit attendance of infected workers has been widespread. However, it remains unknown how the reliability of responses to these tools may be compromised by individual and social factors. We aimed to determine whether personal concern over lost wages impacts responses to COVID-19 symptom-screening questionnaires making them less useful in limiting person-to-person transmission. METHODS: We utilized an anonymous online questionnaire, administered through personal social media networks and those of two U.S. private colleges between September 16, 2020 and November 2, 2020 and distributed to currently or recently employed individuals 18 years of age or older. Participants considered ambiguous hypothetical scenarios involving possible COVID-19 symptoms or exposure and responded to a COVID-19 symptom screen (N = 219). FINDINGS: In response to symptom-related scenarios (i.e., elevated temperature or slight cough), respondents lacking access to paid sick leave were 2.2 to 2.7 times more likely to attend work than those with access to paid leave (p < .05). This was not true for contact-related scenarios. Pay type and income level also significantly influenced screening responses. CONCLUSION/APPLICATION TO PRACTICE: Risk of acute wage loss and overall financial stability appear to influence work-attendance decisions with regard to COVID-19 symptom screens. Broadened availability of paid leave and additional specificity within screening questionnaires would likely improve symptom-screen reliability.

Changes in growth performance, plasma metabolite concentrations, and myogenic gene expression in growing pigs fed a methionine-restricted diet.

Background: Methionine (Met) is usually the second or third limiting amino acid in swine diets and plays vital roles in promoting the growth, especially, the muscle growth of pigs. This research evaluated the effects of dietary Met restriction on the growth performance, plasma metabolite concentrations, and myogenic gene expression in growing pigs. Materials and methods: Eight genes in two families (myogenic regulatory factor family and myocyte enhancer factor 2 family) were selected for the analysis. Twenty individually penned barrows (crossbred, 23.6 ± 2.4 kg) were randomly allotted to two dietary treatments (n = 10). A diet based on corn and soybean meal (Diet 1, Met-restricted) was formulated to meet or exceed the energy and nutrient requirements, except for Met. Diet 2 (Met-adequate) was formulated by adding crystalline DL-Met to Diet 1 to meet the Met requirement. During the 4-week feeding trial, average daily gain (ADG), average daily feed intake (ADFI), and gain to feed ratio (G:F) were measured. Immediately before and after the feeding trial, blood was sampled via jugular venipuncture for plasma nutrient metabolite analysis, while Longissimus dorsi muscle were sampled via aseptic biopsy for gene expression analysis. Data were analyzed with Student t-test. Results: Pigs fed the Met-restricted diet had lower ADG and G:F (P < 0.01). Plasma Met, cysteine, and taurine concentrations were lower (P < 0.05), while glycine and histidine concentrations were higher (P < 0.05), in pigs fed the Met-restricted diet. Furthermore, the pigs fed the Met-restricted diet tended to express less myogenic factor 6 (Myf6) and myocyte enhancer factor 2D (Mef2D) mRNA in longissimus dorsi muscle (P < 0.09). Conclusion: Given the fact that Myf6, assisted by Mef2D, is involved in myocyte differentiation, this study suggests that the reduced growth performance in the Met-restricted pigs may be associated with a reduced muscle cell differentiation.

Population Pharmacokinetic Analysis of the Cathepsin K Inhibitor Odanacatib: Insights Into Intrinsic and Extrinsic Factor Effects on Exposure in Postmenopausal and Elderly Women.

This analysis developed a population pharmacokinetic (PK) model for odanacatib, characterized demographic and concomitant medication covariates effect, and provided odanacatib exposure estimates for subjects in phase 2/3 studies. Data from multiple phase 1 (P005, P025, and P014), phase 2b (P004 and P022), and phase 3 (Long-Term Odanacatib Fracture Trial; P018) studies were pooled to create a data set of 1280 postmenopausal women aged 45 to 91 years (102 from phase 1, 514 from phase 2b, and 664 from phase 3) who received weekly oral odanacatib doses ranging from 3 to 100 mg. A 1-compartment model with first-order absorption, dose-dependent relative bioavailability (F1), and first-order elimination best described odanacatib PK. F1 decreased from the 100% reference bioavailability for a 3-mg oral dose to 24.5% for a 100-mg dose. Eight statistically significant covariates were included in the final PK model: body weight, age, race, and concomitant cytochrome P450 (CYP)3A inhibitors on apparent clearance; body weight on apparent central volume of distribution; and concomitant hydrochlorothiazide, high-fat breakfast, and a study effect on F1. All fixed- and random-effects parameters were estimated with good precision (%standard error of the mean ≤29.5%). This population PK analysis provides insights into intrinsic- and extrinsic-factor effects on odanacatib exposure in postmenopausal and elderly women with osteoporosis. The magnitude of the intrinsic-factor effects was generally modest (odanacatib exposure geometric mean ratios, 0.80-1.21) even in subjects aged >80 years, or in subsets with multiple combinations of factors.

Army Physician Career Satisfaction Based on a Medical Corps Survey.

INTRODUCTION: It is critical the U.S. Army retains skilled physicians in the Medical Corps (MC) to ensure direct support to military operations and medical readiness. The purpose of this study was to examine U.S. Army physicians' opinions concerning: readiness to perform required duties, work environment, support and recognition they receive, military career intentions, and how these factors may relate to Army physician job satisfaction. MATERIALS AND METHODS: A cross-sectional study of Army physicians was conducted using a 45-item web-based survey tool, "Army Medicine Medical Corps (MC) Engagement/Satisfaction Survey 2018." The survey used a combination of multiple choice (Likert-scaled and categorical) and open text statements and questions. Satisfaction with their Army physician career was measured using a 5-point unipolar Likert scale response on level of satisfaction. Chi-square tests of independence were conducted on all demographic characteristics to examine if levels of satisfaction with Army physician career were associated with a particular demographic profile. Agreement opinions expressed on 20 statements about professional readiness, work environment, and job recognition were summarized and rank-ordered by percentage of "strongly agree" responses. Categorical responses to several questions related to career intentions were summarized overall and by career satisfaction level. Multivariate logistic regression was performed to identify demographic factors, which may influence career satisfaction as an Army physician. RESULTS: Approximately 47% (2,050/4,334) of U.S. Army physicians participated in the MC 2018 survey. Career satisfaction percentages overall were: "extremely satisfied" (10.0%), "quite satisfied" (24.8%), "moderately satisfied" (33.9%), "slightly satisfied" (22.6%), and "not at all satisfied" (8.3%). Respondents were in least agreement to statements about sufficient administrative support and recognition of doing good work. Logistic regression results showed military rank as a significant predictor of negative career satisfaction as an Army physician. For Captains, the odds for being "not at all satisfied" with their military career were almost nine times that of Colonels. Also, compared to their baseline group, physicians who completed their graduate medical education training, mission critical surgeons, and physicians who worked in military treatment facilities that were either a hospital (not a medical center) or a clinic-ambulatory surgery center had a greater risk of being "not at all satisfied" with their career as an Army physician. CONCLUSIONS: There is significant room for improvement in MC officer career satisfaction. The drivers of satisfaction are multiple and apply differently among MC officers of varied ranks and experience. Senior officers are the ones who are the most satisfied with their military career. Results of this novel MC officer study may serve as an impetus to identify existing shortcomings and make necessary changes to retain skilled Army physicians. Army leaders should invest resources to develop and sustain initiatives that improve military career satisfaction and retention of MC officers.

Data-driven Casualty Estimation and Disease Nonbattle Injury/Battle Injury Rates in Recent Campaigns.

To ensure Soldiers are properly equipped and mission capable to perform full spectrum operations, Army medical planners use disease nonbattle injury (DNBI) and battle injury (BI) admission rates in the Total Army Analysis process to support medical deployment and force structure planning for deployed settings. For more than a decade, as the proponent for the DNBI/BI methodology and admission rates, the Statistical Analysis Cell (previously Statistical Analysis Branch, Center for Army Medical Department Strategic Studies) has provided Army medical planners with DNBI/BI rates based upon actual data from recent operations. This article presents the data-driven methodology and casualty estimation rates developed by the Statistical Analysis Cell and accredited for use by 2 Army Surgeon Generals, displays the top 5 principal International Classification of Disease, 9th Revision, Clinical Modification (ICD-9-CM) diagnoses for DNBI/BI in Operation Iraqi Freedom/Operation New Dawn (OIF/OND), and discusses trends in DNBI rates in OIF/OND during the stabilization period. Our methodology uses 95th percentile daily admission rates as a planning factor to ensure that 95% of days in theater are supported by adequate staff and medical equipment. We also present our DNBI/BI estimation methodology for non-Army populations treated at Role 3 US Army medical treatment facilities.

Risk of dental disease non-battle injuries and severity of dental disease in deployed U.S. Army personnel.

Dental Disease and Non-Battle Injuries (D-DNBI) continue to be a problem among U.S. Army active duty (AD), U.S. Army National Guard (ARNG), and U.S. Army Reserve (USAR) deployed soldiers to Operation Iraqi Freedom/Operation New Dawn in Iraq and Operation Enduring Freedom in Afghanistan. A previous study reported the annual rates to be 136 D-DNBI per 1,000 personnel for AD, 152 for ARNG, and 184 for USAR. The objectives of this study were to describe D-DNBI incidence and to determine risk factors for dental encounters and high severity diagnoses for deployed soldiers. The 78 diagnoses were classified into three categories based on severity. Poisson regression was used to compare D-DNBI rates and logistic regression was used to analyze the risk of high severity D-DNBI. In both campaigns, Reserve had a higher risk of D-DNBI than active duty. For Afghanistan, ARNG and USAR demonstrated over 50% increased risk of D-DNBI compared to AD. In Iraq, USAR had a 17% increased risk over AD. Females had a higher risk of D-DNBI (>50%) compared to males in both campaigns. High severity D-DNBI made up 2.77% of all diagnoses. Within Afghanistan, there was a 4.6% increased risk of high severity D-DNBI for each additional deployment month.

Spinal injury hospitalizations among U.S. Army soldiers deployed to Iraq and Afghanistan.

This retrospective study examined spinal-related hospitalizations of U.S. Army soldiers deployed to Afghanistan and Iraq. Spinal cord injuries (SCI) and vertebral column injuries (VCI) were identified using International Classification of Disease, 9th Revision, Clinical Modification diagnosis codes. In our study, spinal hospitalizations represented 8.2% of total injury admissions. Risk factors for SCI and VCI incidences were determined using Poisson regression. Lack of previous deployment experience increased risk of having SCI by 33% and VCI by 24% in Iraq (similar increases, but not statistically significant in Afghanistan). Male soldiers had 4.85 times higher risk for SCI in Iraq and 69% higher risk in Afghanistan than female soldiers. In Afghanistan, almost 60% of spinal episodes included traumatic brain injury (TBI), compared to about 40% in Iraq. In both theaters, mild TBI accounted for more than 50% of all TBI-spinal episodes. Sixteen percent of SCI inpatient episodes in Afghanistan and 13% in Iraq were associated with paralysis, with median bed days of 46 and 33 days compared to a median of 6 days in both theaters for nonparalysis spinal injuries. The mortality rate was 2.5 times lower in Afghanistan than in Iraq.

The influence of ethnicity and gender on navigating an acute coronary syndrome event.

BACKGROUND: Ethnicity and gender may influence acute coronary syndrome patients recognizing symptoms and making the decision to seek care. OBJECTIVE: To examine these potential differences in European (Caucasian), Chinese and South Asian acute coronary syndrome patients. METHODS: In-depth interviews were conducted with 20 European (Caucasian: 10 men/10 women), 18 Chinese (10 men/eight women) and 19 South Asian (10 men/nine women) participants who were purposively sampled from those participating in a large cohort study focused on acute coronary syndrome. Analysis of transcribed interviews was undertaken using constant comparative methods. RESULTS: Participants followed the process of: having symptoms; waiting/denying; justifying; disclosing/ discovering; acquiescing; taking action. The core category was 'navigating the experience'. Certain elements of this process were in the forefront, depending on participants' ethnicity and/or gender. For example, concerns regarding language barriers and being a burden to others varied by ethnicity. Women's tendency to feel responsibility to their home and family negatively impacted the timeliness in their decisions to seek care. Men tended to disclose their symptoms to receive help, whereas women often waited for their symptoms to be discovered by others. Finally, the thinking that symptoms were 'not-urgent' or something over which they had no control and concern regarding potential costs to others were more prominent for Chinese and South Asian participants. CONCLUSION: Ethnic- and gender-based differences suggest that education and support, regarding navigation of acute coronary syndrome and access to care, be specifically targeted to ethnic communities.

Traumatic brain injury hospitalizations of U.S. army soldiers deployed to Afghanistan and Iraq.

BACKGROUND: Traumatic brain injury (TBI) is a life-altering condition that has affected many of our soldiers returning from war. In the current conflicts, the improvised explosive device (IED) has greatly increased the potential for soldiers to sustain a TBI. This study's objective was to establish benchmark admission rates for U.S. Army soldiers with TBIs identified during deployment to Iraq and Afghanistan. METHODS: The study population consisted of U.S. Army soldiers deployed to Iraq and Afghanistan from September 11, 2001, through September 30, 2007. Population data were merged with admission data to identify hospitalizations during deployment. Using the international Barell Injury Diagnosis Matrix, TBI-related admissions were categorized into Type 1 (the most severe), Type 2, and Type 3 (the least severe). All analyses were performed in 2008. RESULTS: Of the 2898 identified TBI inpatient episodes of care, 46% were Type 1, 54% were Type 2, and less than 1% were Type 3. Over 65% of Type 1 injuries resulted from explosions, while almost half of all TBIs were non-battle-related. Overall TBI admission rates were 24.6 for Afghanistan and 41.8 for Iraq per 10,000 soldier-years. TBI hospitalization rates rose over time for both campaigns, although U.S. Army soldiers in Iraq experienced 1.7 times higher rates overall and 2.2 times higher Type 1 admission rates than soldiers in Afghanistan. The TBI-related proportion of all injury hospitalizations showed an ascending trend. CONCLUSIONS: Future surveillance of TBI hospitalization rates is needed to evaluate the effectiveness of implementation of preventive measures.

U.S. Army disease and nonbattle injury model, refined in Afghanistan and Iraq.

Previous analysis of Operation Desert Shield/Operation Desert Storm data yielded a disease and nonbattle injury (DNBI) model using distinct 95th percentile daily admission rates during the three phases of a war-fighting operation to predict medical requirements. This study refines the model with data from Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF). Inpatient health care records of U.S. Army soldiers deployed to OEF and OIF who were admitted with DNBI diagnoses were analyzed. DNBI admission rates for OEF and OIF were compared with rates for Operation Desert Shield/Operation Desert Storm. DNBI admission rates for OEF and OIF were lower than those for Operation Desert Shield/Operation Desert Storm. Rates among the phases of OIF were distinctly different. DNBI admission rates have been reduced during recent deployments. The concepts of the original model based on Operation Desert Shield/Operation Desert Storm data were validated by experiences during OEF and OIF. Continuous surveillance of DNBI admission rates is recommended.

Comparison of Operation Iraqi Freedom and Patient Workload Generator injury distributions.

The Patient Workload Generator (PATGEN) simulation model is an important part of the Army Medical Department force requirement planning. The current version of the PATGEN model is based on historical major combat operations such as World War II and the Korean War. The purpose of this study was to determine whether there was a significant difference between injury distributions used in the PATGEN model and the injury distributions based on the data from Operation Iraqi Freedom (OIF). To make the comparison feasible, the PATGEN injury categories were created using the Barell Injury Matrix. Analyses were performed using two independent OIF data sources, the Joint Theater Trauma Registry and the Standard Inpatient Data Record. Based on X2 test results, both analyses suggest a significant difference between PATGEN and OIF injury distributions. A major concern is the underestimation by PATGEN of battle injuries with multiple wounds. The findings support future use of data-driven diagnosis-based injury distributions for current operations and new more flexible simulation models that will allow for changes in injury probability distributions.

A monitoring programme for 1,3-dichloropropene and metabolites in groundwater in five EU countries.

BACKGROUND: 1,3 Dichloropropene (1,3-D) is a preplanting soil fumigant for the control of cyst and free-living nematodes and is currently undergoing a resubmission under Annex 1 listing of Directive 91/414/EEC. The characteristics of 1,3-D are such that the risk of it or its soil metabolites leaching through the soil profile cannot be excluded. As such, groundwater monitoring programmes were established in five EU countries representing a wide range of agricultural, climatic and hydrogeological situations, covering a range of groundwater vulnerability scenarios. All monitoring was conducted in areas where there has been historical use of 1,3-D. RESULTS: Over 5000 groundwater samples were analysed for the presence of 1,3-D and its metabolites over a 2 year period. Almost all analyses (for parent and metabolites) yielded concentrations of <0.1 microg L(-1). There were just two detections of >0.1 microg L(-1) (0.12 microg L(-1) and 0.4 microg L(-1)) for the 3-chloroacrylic acid metabolite in shallow groundwater samples of the alluvial gravels of the River Tiétar in the Caceres region of Spain. CONCLUSION: Groundwater monitoring programmes have been conducted in the EU in five countries. These have demonstrated that there is negligible contamination of groundwater with 1,3-D or its metabolites across a range of agroclimatic regions where 1,3-D is known to have been used for a number of years. Local scientific knowledge of geological features, hydrology, agricultural practice and specific local issues was essential to the conduct of the study.

A disease and non-battle injury model based on Persian Gulf War admission rates.

BACKGROUND: Military planners must ensure adequate medical care for deployed troops-including care for disease and non-battle injuries (DNBI). This study develops a heuristic model with the three distinct phases of a warfighting operation (build-up, ground combat, post-combat) to assist in predicting DNBI incidence during warfighting deployments. METHODS: Inpatient healthcare records of soldiers deployed to the Persian Gulf War who were admitted with DNBI diagnoses were analyzed. DNBI admission rates for the three phases of the operation were examined and compared to rates for US Army Forces Command (FORSCOM) posts in the US. RESULTS: DNBI admission rates among the phases were distinctly different. The operation's overall rate and 95th percentile daily rate were less than the FORSCOM FY 1990 annual rate. CONCLUSIONS: The level of combat must be considered. The traditional use of average or overall rates should be abandoned when forecasting DNBI rates. Medical support projections should use separate 95th percentile DNBI admission rates for each of the phases.