Quadruple pharmacotherapy for alcohol use disorder tolerable yet insufficient: a case report.

BACKGROUND: Combinations of alcohol use disorder (AUD) medications have been investigated, but few if any reports describe patients maintained on more than two options at the same time. CASE PRESENTATION: We report a case of a middle-aged man hospitalized with gastrointestinal bleeding and acute kidney injury who had been maintained on four AUD medications (naltrexone, acamprosate, disulfiram, and gabapentin) and multiple psychiatric medications simultaneously as an outpatient. Direct quotations of his experiences with each AUD medication are included, revealing some deviations from what was prescribed as well as nuanced perceptions of effects. Overall, he tolerated the regimen well, but its AUD effects were insufficient to prevent several episodes of returning to alcohol use. He had very high hospital utilization. This prompted the initiation of an involuntary commitment, which began a period of at least six months of sobriety. CONCLUSIONS: Quadruple pharmacotherapy for AUD may be well tolerated and supportive of recovery for an extended period of time. However, for our patient the regimen ultimately failed to prevent multiple episodes of returning to alcohol use and serious medical complications. In refractory cases like this, more intensive interventions such as involuntary commitment can be considered.

UncertainSCI: Uncertainty quantification for computational models in biomedicine and bioengineering.

BACKGROUND: Computational biomedical simulations frequently contain parameters that model physical features, material coefficients, and physiological effects, whose values are typically assumed known a priori. Understanding the effect of variability in those assumed values is currently a topic of great interest. A general-purpose software tool that quantifies how variation in these parameters affects model outputs is not broadly available in biomedicine. For this reason, we developed the 'UncertainSCI' uncertainty quantification software suite to facilitate analysis of uncertainty due to parametric variability. METHODS: We developed and distributed a new open-source Python-based software tool, UncertainSCI, which employs advanced parameter sampling techniques to build polynomial chaos (PC) emulators that can be used to predict model outputs for general parameter values. Uncertainty of model outputs is studied by modeling parameters as random variables, and model output statistics and sensitivities are then easily computed from the emulator. Our approaches utilize modern, near-optimal techniques for sampling and PC construction based on weighted Fekete points constructed by subsampling from a suitably randomized candidate set. RESULTS: Concentrating on two test cases-modeling bioelectric potentials in the heart and electric stimulation in the brain-we illustrate the use of UncertainSCI to estimate variability, statistics, and sensitivities associated with multiple parameters in these models. CONCLUSION: UncertainSCI is a powerful yet lightweight tool enabling sophisticated probing of parametric variability and uncertainty in biomedical simulations. Its non-intrusive pipeline allows users to leverage existing software libraries and suites to accurately ascertain parametric uncertainty in a variety of applications.

Protocol for a multi-center randomized controlled trial to evaluate the benefits of exercise incentives and corticosteroid injections in osteoarthritis of the knee (MOVE-OK).

BACKGROUND: Knee osteoarthritis (KOA) is a high-priority problem among the aging population. While exercise has been shown to be beneficial in management of the disease, scalable and low-cost interventions to improve exercise in this population are lacking. Recent controversy over the value of corticosteroid injections for palliation has also arisen. Therefore, we designed a randomized, double-blind, placebo-controlled clinical trial with a 2-period crossover design to study (1) behavioral incentives to promote exercise and (2) corticosteroid injections to reduce pain and improve function in patients with KOA when compared to lidocaine only. METHODS: The study design is a pragmatic factorial and crossover randomized clinical trial. Patients with KOA who are deemed eligible by their provider to receive knee injections and are able to walk without assistive devices will be recruited from clinical practices at four sites within the Veterans Affairs (VA) Health System in the USA. In total, 220 participants will be randomized to receive social incentives with gamification (i.e., incorporation of game elements) to promote exercise and compared to controls that receive a Fitbit but no incentive. Each patient will also be assigned to receive a blinded corticosteroid injection and a lidocaine-only injection in random order. The primary outcomes are the change in average daily step counts from baseline and the change in Knee Osteoarthritis Outcome Score (KOOS) from baseline. The study team will continuously collect step count, heart rate, and sleep data using activity monitors and patient-reported outcomes using the Way to Health (WTH) platform at two four-week intervals over eight months of follow-up. Mixed effects regression incorporating all available data points will be used for analysis. DISCUSSION: The "Marching on for Veterans with Osteoarthritis of the Knee" (MOVE-OK) trial will take a pragmatic approach to evaluate (1) whether incentives based on behaviorally enhanced gamification can improve physical activity in this patient population and (2) whether corticosteroids injections reduce pain and disability in patients with KOA. Results of this trial will help to direct clinical practice and inform management guidelines. TRIAL REGISTRATION: ClinicalTrials.gov NCT05035810 . Registered on 5 September 2021.

Relation of MRI-Detected Features of Patellofemoral Osteoarthritis to Pain, Performance-Based Function, and Daily Walking: The Multicenter Osteoarthritis Study.

OBJECTIVE: The study objective was to determine the relationship of magnetic resonance imaging (MRI)-detected features of patellofemoral joint osteoarthritis to pain and functional outcomes. METHODS: We sampled 1,099 participants from the 60-month visit of the Multicenter Osteoarthritis Study (mean ± SD age: 66.8 ± 7.5 years; body mass index: 29.6 ± 4.8; 65% female). We determined the prevalence of MRI-detected features of patellofemoral joint osteoarthritis (eg, cartilage damage, bone marrow lesions, and osteophytes) and assessed the relationship between these features and knee pain severity, knee pain on stairs, chair stand time, and walking less than 6,000 steps per day. We evaluated the relationship of MRI features to each outcome using logistic and linear regression, adjusting for potential covariates. RESULTS: Participants with cartilage damage in 3-4 subregions had the highest mean pain severity (22.0/100; 95% confidence interval [CI]: 17.6-26.4 mm). They also showed higher odds of having at least mild pain on stairs (odds ratio [OR]: 3.3; 95% CI: 1.7-6.5) and of walking less than 6,000 steps per day (OR: 2.3; 95% CI: 1.1-4.4) compared with those without cartilage damage. Participants with bone marrow lesions in 3-4 subregions had higher odds of at least mild pain on stairs than those without (OR: 3.3; 95% CI: 2.2-5.2). Participants with osteophytes in 3-4 subregions also had higher odds of walking less than 6,000 steps/day (OR 2.1, 95% CI: 1.3-3.5, respectively). CONCLUSION: MRI-detected features of osteoarthritis of the patellofemoral joint are related to pain and functional performance. This knowledge highlights the need to develop treatments for those with patellofemoral joint osteoarthritis to improve pain and maximize function.

Using UncertainSCI to Quantify Uncertainty in Cardiac Simulations.

Cardiac simulations have become increasingly accurate at representing physiological processes. However, simulations often fail to capture the impact of parameter uncertainty in predictions. Uncertainty quantification (UQ) is a set of techniques that captures variability in simulation output based on model assumptions. Although many UQ methods exist, practical implementation can be challenging. We created UncertainSCI, a UQ framework that uses polynomial chaos (PC) expansion to model the forward stochastic error in simulations parameterized with random variables. UncertainSCI uses non-intrusive methods that parsimoniously explores parameter space. The result is an efficient, stable, and accurate PC emulator that can be analyzed to compute output statistics. We created a Python API to run UncertainSCI, minimizing user inputs needed to guide the UQ process. We have implemented UncertainSCI to: (1) quantify the sensitivity of computed torso potentials using the boundary element method to uncertainty in the heart position, and (2) quantify the sensitivity of computed torso potentials using the finite element method to uncertainty in the conductivities of biological tissues. With UncertainSCI, it is possible to evaluate the robustness of simulations to parameter uncertainty and establish realistic expectations on the accuracy of the model results and the clinical guidance they can provide.

Robotic Dispersal Technique for 35 GBq of 140La in an L-polygon Pattern.

In 2018, Defence Research and Development Canada, in partnership with Natural Resources Canada, led a field trial of survey and mapping of a large dispersion of radioactivity using Unmanned Aerial Vehicles (UAVs). The intent was to disperse La material in a 3,200 m L-polygon with an approximate activity level of 10 MBq m and to measure the radioactive material using sensors carried by UAVs. Due to the potential radiological hazard to personnel, the activity was approved only if Unmanned Ground Vehicles (UGVs) were able to completely handle and disperse the material remotely. One UGV was equipped with a traditional agricultural sprayer to disperse the material, and one UGV was equipped with a force feedback manipulator arm. Due to the freezing temperatures during dispersal, the 35 GBq of La was dispersed non-uniformly as one sprayer boom failed to perform as tested. However, rough analysis of the electronic dosimetry on the UGV concluded that 99% of the material was dispersed on the ground. The dosimeter placed closest to the robot manipulator arm, used for dispersal of material, indicated a contact dose of 33.5 mSv. The electronic dosimeter placed where the driver would have sat on the sprayer vehicle if it were not unmanned indicated a dose of 22.3 mSv. Thus, the use of UGVs for material dispersion substantially reduced the external exposure to personnel. The use of UGVs eliminated the potential of internal exposure as well. The Radiation Safety Officer received the highest dose at approximately 3 µSv, with the majority of the exposure coming from the handling of the Type A container.

Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of Vaborbactam and Meropenem Alone and in Combination following Single and Multiple Doses in Healthy Adult Subjects.

Meropenem-vaborbactam is a fixed combination of the novel ß-lactamase inhibitor vaborbactam and the carbapenem antibiotic meropenem, developed for the treatment of serious infections caused by drug-resistant Gram-negative bacteria. The safety, tolerability, and pharmacokinetics (PK) of vaborbactam and meropenem following single and multiple ascending doses of each study drug administered alone or combined were evaluated in 76 healthy adult subjects in a randomized, placebo-controlled, double-blind study. Subjects were enrolled in 1 of 5 dose cohorts (receiving 250 to 2,000 mg vaborbactam and/or 1,000 to 2,000 mg meropenem) alone or in combination. No subjects discontinued the study due to adverse events (AEs), and no serious AEs were observed. The pharmacokinetics of meropenem and vaborbactam were similar when given alone or in combination; all evaluated plasma PK exposure measures (peak plasma concentration, area under the plasma concentration-time curve [AUC] from time zero to the last measurable concentration area under the plasma concentration-time curve, and AUC from time zero to infinity) were similar for the study drugs alone versus those in combination, indicating no pharmacokinetic interaction between meropenem and vaborbactam. Across all treatments, 47 to 64% of an administered meropenem dose and 75 to 95% of vaborbactam was excreted unchanged in the urine over 48 h postdose. Meropenem and vaborbactam, when given alone or in combination, have similar pharmacokinetic properties, with no plasma or urine PK drug-drug interactions, and are well tolerated. These findings supported further clinical investigation of the combination product. (This study is registered at ClinicalTrials.gov under registration no. NCT01897779.).

The Relationship between Coronary Artery Disease Risk Factors and Carotid Intima-Media Thickness in Children.

OBJECTIVE: To determine the number of coronary artery disease risk factors and the individual coronary artery disease risk factors that have a negative influence on carotid intima-media thickness in children. STUDY DESIGN: One hundred and nineteen children (mean age 10.51 ± 0.52 years; 51% female) participated. Each subject was assessed for carotid intima-media thickness, total cholesterol, high-density lipoprotein cholesterol (HDL-C), glucose, body mass index (BMI), and resting blood pressure. Surveys assessed family history of cardiovascular disease, and physical activity. Ultrasound assessment was completed on the right and left common carotid arteries. Statistical analyses included the t test, χ2 test, one-way ANOVA, and stepwise regression. RESULTS: An increase in carotid intima-media thickness was observed with 2 vs 0 coronary artery disease risk factors for left carotid intima-media thickness (P < .001). With 3+ vs 0 coronary artery disease risk factors, increases in left (P < .001) and combined left and right carotid intima-media thickness (P < .05) were observed. BMI independently predicted carotid intima-media thickness (r = 0.410; P < .01), but HDL-C did not. However, HDL-C was significantly inversely related to BMI (r = -0.534; P < .01). Combining BMI and HDL-C provided the strongest prediction of carotid intima-media thickness (r = 0.451; adjusted R2 = 0.190). Compared with children with a healthy and overweight BMI, children in the obese category had greater right (P < .00), left (P < .001), and combined right and left carotid intima-media thickness (P < .001). CONCLUSIONS: Carotid intima-media thickness is negatively influenced by 2+ coronary artery disease risk factors. Weight status appears to have the greatest negative impact on carotid intima-media thickness in children. These findings support the need for strategies to lower BMI in children.

Carbapenem-Resistant Enterobacteriaceae Infections: Results From a Retrospective Series and Implications for the Design of Prospective Clinical Trials.

BACKGROUND: The increasing incidence of multidrug-resistant Gram negatives, such as carbapenem-resistant Enterobacteriaceae (CRE), has resulted in a critical need for new antimicrobials. Most studies of new antimicrobials have been performed in patients with nondrug-resistant pathogens. We performed a retrospective analysis of patients with CRE infections to inform the design of phase 3 clinical trials. METHODS: This was a retrospective study at 22 centers in 4 countries. Baseline data, treatment, and outcomes were collected in patients with complicated urinary tract infection (cUTI)/acute pyelonephritis (AP), hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), and bacteremia due to CRE. RESULTS: Two hundred fifty-six cases of CRE infection were identified: 75 cUTI/AP, 21 HABP, 20 VABP, and 140 bacteremia. The patient population had significant comorbidities: 32.8% had chronic renal insufficiency, and 26.2% were immunocompromised. Illness severity at presentation was high: 29.3% presented with septic shock. Treatment regimens varied widely; however, a majority of patients received combination therapy. Outcomes were universally poor (28-day mortality was 28.1%) across all sites of infection, particularly in dialysis patients and those with sepsis. CONCLUSIONS: The CRE infections occured in patients with substantial comorbidities and were associated with high mortality and low rates of clinical cure with available antibiotics. Patients with these comorbidities are often excluded from enrollment in clinical trials for registration of new drugs. These results led to changes in the inclusion/exclusion criteria of a phase 3 trial to better represent the patient population with CRE infections and enable enrollment. Observational studies may become increasingly important to guide clinical trial design, inform on the existing standard of care, and provide an external control for subsequent trials.

Overview of the Full-scale Radiological Dispersal Device Field Trials.

In 2012, Defence Research and Development Canada, in partnership with a number of other Canadian and International organizations, led a series of three field trials designed to simulate a Radiological Dispersal Device (RDD). These trials, known as the Full-Scale RDD (FSRDD) Field Trials, involved the explosive dispersal of a short-lived radioactive tracer ((140)La, t1/2 = 40.293 h). The FSRDD Field Trials required a significant effort in their planning, preparation, and execution to ensure that they were carried out in a safe, efficient manner and that the scientific goals of the trials were met. The discussion presented here details the planning and execution of the trials, outlines the relevant radiation safety aspects, provides a summary of the source term and atmospheric conditions for the three dispersal events, and provides an overview of the measurements that were made to track the plumes and deposition patterns.

Pharmacokinetics and safety of MP-376 (levofloxacin inhalation solution) in cystic fibrosis subjects.

The pharmacokinetics and tolerability of nebulized MP-376 (levofloxacin inhalation solution [Aeroquin]) were determined in cystic fibrosis (CF) subjects. Ten CF subjects received single 180-mg doses of two formulations of MP-376, followed by a multiple-dose phase of 240 mg once daily for 7 days. Serum and expectorated-sputum samples were assayed for levofloxacin content. Safety was evaluated following the single- and multiple-dose study phases. Nebulized MP-376 produced high concentrations of levofloxacin in sputum. The mean maximum plasma concentration (C(max)) ranged between 2,563 and 2,932 mg/liter for 180-mg doses of the 50- and 100-mg/ml formulations, respectively. After 7 days of dosing, the mean C(max) for the 240-mg dose was 4,691 mg/liter. The mean serum levofloxacin C(max) ranged between 0.95 and 1.28 for the 180-mg doses and was 1.71 for the 240-mg dose. MP-376 was well tolerated. Nebulized MP-376 produces high sputum and low serum levofloxacin concentrations. The pharmacokinetics, safety, and tolerability were similar for the two formulations. MP-376 240 mg (100 mg/ml) is being advanced into late-stage clinical development.

Characterizing dissolved organic matter using PARAFAC modeling of fluorescence spectroscopy: a comparison of two models.

We evaluated whether fitting fluorescence excitation-emission matrices (EEMs) to a previously validated PARAFAC model is an acceptable alternative to building an original model. To do this, we built a 10-component model using 307 EEMs collected from southeast Alaskan soil and streamwater. All 307 EEMs were then fit to the existing model (CM) presented in Cory and McKnight (Environ. Sci. Technol. 2005, 39, 8142-8149). The first approach for evaluating whether the EEMs were fit well to the CM model was an evaluation of the residual EEMs, and we found 22 EEMs were fit poorly by the CM model. Our second measure for verifying whether EEMs were fit well to the CM model was a comparison of correlations between the percent contribution of PARAFAC components and DOM measurements (e.g., dissolved nutrient concentrations), and we found no significant difference Ip > 0.05) between the two models. These results support the approach of fitting EEMs to an existing model when DOM is collected from similar environments, which can potentially reduce some of the problems when building an original PARAFAC model. However, it is important to recognize that some of the sensitivity or ecological interpretative power may be lost when fitting EEMs to an existing model.

The arctic water resource vulnerability index: an integrated assessment tool for community resilience and vulnerability with respect to freshwater.

People in the Arctic face uncertainty in their daily lives as they contend with environmental changes at a range of scales from local to global. Freshwater is a critical resource to people, and although water resource indicators have been developed that operate from regional to global scales and for midlatitude to equatorial environments, no appropriate index exists for assessing the vulnerability of Arctic communities to changing water resources at the local scale. The Arctic Water Resource Vulnerability Index (AWRVI) is proposed as a tool that Arctic communities can use to assess their relative vulnerability-resilience to changes in their water resources from a variety of biophysical and socioeconomic processes. The AWRVI is based on a social-ecological systems perspective that includes physical and social indicators of change and is demonstrated in three case study communities/watersheds in Alaska. These results highlight the value of communities engaging in the process of using the AWRVI and the diagnostic capability of examining the suite of constituent physical and social scores rather than the total AWRVI score alone.