Selective Inhibition of NaV1.8 with VX-548 for Acute Pain.

BACKGROUND: The NaV1.8 voltage-gated sodium channel, expressed in peripheral nociceptive neurons, plays a role in transmitting nociceptive signals. The effect of VX-548, an oral, highly selective inhibitor of NaV1.8, on control of acute pain is being studied. METHODS: After establishing the selectivity of VX-548 for NaV1.8 inhibition in vitro, we conducted two phase 2 trials involving participants with acute pain after abdominoplasty or bunionectomy. In the abdominoplasty trial, participants were randomly assigned in a 1:1:1:1 ratio to receive one of the following over a 48-hour period: a 100-mg oral loading dose of VX-548, followed by a 50-mg maintenance dose every 12 hours (the high-dose group); a 60-mg loading dose of VX-548, followed by a 30-mg maintenance dose every 12 hours (the middle-dose group); hydrocodone bitartrate-acetaminophen (5 mg of hydrocodone bitartrate and 325 mg of acetaminophen every 6 hours); or oral placebo every 6 hours. In the bunionectomy trial, participants were randomly assigned in a 2:2:1:2:2 ratio to receive one of the following over a 48-hour treatment period: oral high-dose VX-548; middle-dose VX-548; low-dose VX-548 (a 20-mg loading dose, followed by a 10-mg maintenance dose every 12 hours); oral hydrocodone bitartrate-acetaminophen (5 mg of hydrocodone bitartrate and 325 mg of acetaminophen every 6 hours); or oral placebo every 6 hours. The primary end point was the time-weighted sum of the pain-intensity difference (SPID) over the 48-hour period (SPID48), a measure derived from the score on the Numeric Pain Rating Scale (range, 0 to 10; higher scores indicate greater pain) at 19 time points after the first dose of VX-548 or placebo. The main analysis compared each dose of VX-548 with placebo. RESULTS: A total of 303 participants were enrolled in the abdominoplasty trial and 274 in the bunionectomy trial. The least-squares mean difference between the high-dose VX-548 and placebo groups in the time-weighted SPID48 was 37.8 (95% confidence interval [CI], 9.2 to 66.4) after abdominoplasty and 36.8 (95% CI, 4.6 to 69.0) after bunionectomy. In both trials, participants who received lower doses of VX-548 had results similar to those with placebo. Headache and constipation were common adverse events with VX-548. CONCLUSIONS: As compared with placebo, VX-548 at the highest dose, but not at lower doses, reduced acute pain over a period of 48 hours after abdominoplasty or bunionectomy. VX-548 was associated with adverse events that were mild to moderate in severity. (Funded by Vertex Pharmaceuticals; VX21-548-101 and VX21-548-102 ClinicalTrials.gov numbers, NCT04977336 and NCT05034952.).

Rapid sample processing for detection of food-borne pathogens via cross-flow microfiltration.

This paper reports an approach to enable rapid concentration and recovery of bacterial cells from aqueous chicken homogenates as a preanalytical step of detection. This approach includes biochemical pretreatment and prefiltration of food samples and development of an automated cell concentration instrument based on cross-flow microfiltration. A polysulfone hollow-fiber membrane module having a nominal pore size of 0.2 µm constitutes the core of the cell concentration instrument. The aqueous chicken homogenate samples were circulated within the cross-flow system achieving 500- to 1,000-fold concentration of inoculated Salmonella enterica serovar Enteritidis and naturally occurring microbiota with 70% recovery of viable cells as determined by plate counting and quantitative PCR (qPCR) within 35 to 45 min. These steps enabled 10 CFU/ml microorganisms in chicken homogenates or 10(2) CFU/g chicken to be quantified. Cleaning and sterilizing the instrument and membrane module by stepwise hydraulic and chemical cleaning (sodium hydroxide and ethanol) enabled reuse of the membrane 15 times before replacement. This approach begins to address the critical need for the food industry for detecting food pathogens within 6 h or less.

Predicting opioid use disorder and associated risk factors in a Medicaid managed care population.

OBJECTIVES: Medicaid managed care organizations are developing comprehensive strategies to reduce the impact of opioid use disorder (OUD) among their members. The goals of this study were to develop and validate a predictive model of OUD and to predict future OUD diagnosis, resulting in proactive, person-centered outreach. STUDY DESIGN: We utilized machine learning methodology to select a multivariate logistic regression and identify predictors. METHODS: Using 2016-2018 data, we used a staged approach to test and validate the predictive accuracy of our model. We identified OUD, the dependent variable, using an industry-standard definition. We included a series of patient demographic, chronic condition, social determinants of health (SDOH), opioid-related, and health utilization indicators captured in administrative data. RESULTS: Caucasian (odds ratio [OR], 1.65), male (OR, 1.57), and younger (aged 40-64 years compared with 18-39 years: OR, 0.75) members had greater odds of being diagnosed with an OUD. Members with an SDOH vulnerability had 26% higher odds than those without a documented issue. From a prescribing perspective, we found that having an opioid dose of 120 morphine milligram equivalents and contiguous 5-day supply increased odds of OUD by 1.87 times, and an opioid supply of 30 days or longer increased the odds of OUD by 1.56 times. CONCLUSIONS: We built the necessary machine learning infrastructure to identify members with greater than 50% probability of developing OUD. The generated list strategically informs and guides person-centered care and interventions. Through application of these results, we strive to proactively reduce OUD-related structural barriers and prevent OUD from occurring.

Postdischarge engagement decreased hospital readmissions in Medicaid populations.

OBJECTIVES: To investigate the effect of managed care organization (MCO)-implemented postdischarge engagement, supported by other broadly focused interventions, on 30-day hospital readmissions in 6 at-risk Medicaid populations. STUDY DESIGN: Prospective cohort study. METHODS: One-year follow-up analysis of member claims data was performed following an intervention period from January 1, 2014, to December 31, 2014. Postdischarge engagement, supported by additional MCO-initiated interventions, was implemented to reduce 30-day hospital readmissions in Medicaid members having 1 or more dominant chronic conditions. Hospital readmission rates were calculated at baseline and at 1 year post intervention. Bivariable and multivariable generalized estimating equation analysis was used to quantify the likelihood of hospital readmissions. RESULTS: Following implementation, postdischarge engagement rates increased significantly, whereas provider follow-up rates remained unchanged. Increased member engagement resulted in statistically significant reductions in weighted readmission rates enterprise-wide (-10.1%; P <.01) and in 3 of 6 MCOs (-3.9% to -15.8%; P ≤.05) in 2014. Compared with nonparticipants, members who were successfully reached for postdischarge engagement displayed a 33% decrease in 30-day readmissions enterprise-wide (adjusted odds ratio, 0.67; 95% CI, 0.62-0.73) and a comparable decrease (-23% to -39%) in 5 of the 6 MCOs. In this context, greater frequency of postdischarge engagement was associated with proportionally decreased likelihood of readmissions. CONCLUSIONS: Postdischarge engagement, against the backdrop of multifaceted MCO-implemented interventions, was associated with significantly reduced hospital readmissions in at-risk Medicaid subjects. Reduced likelihood of readmissions was observed at both the enterprise-wide and plan levels in a manner proportional to the frequency of engagement, a novel reported outcome for this population.

Defining the end-point of mastication: A conceptual model.

The great risks of swallowing are choking and aspiration of food into the lungs. Both are rare in normal functioning humans, which is remarkable given the diversity of foods and the estimated 10 million swallows performed in a lifetime. Nevertheless, it remains a major challenge to define the food properties that are necessary to ensure a safe swallow. Here, the mouth is viewed as a well-controlled processor where mechanical sensory assessment occurs throughout the occlusion-circulation cycle of mastication. Swallowing is a subsequent action. It is proposed here that, during mastication, temporal maps of interfacial property data are generated, which the central nervous system compares against a series of criteria in order to be sure that the bolus is safe to swallow. To determine these criteria, an engineering hazard analysis tool, alongside an understanding of fluid and particle mechanics, is used to deduce the mechanisms by which food may deposit or become stranded during swallowing. These mechanisms define the food properties that must be avoided. By inverting the thinking, from hazards to ensuring safety, six criteria arise which are necessary for a safe-to-swallow bolus. A new conceptual model is proposed to define when food is safe to swallow during mastication. This significantly advances earlier mouth models. PRACTICAL APPLICATIONS: The conceptual model proposed in this work provides a framework of decision-making to define when food is safe to swallow. This will be of interest to designers of dietary foods, foods for dysphagia sufferers and will aid the further development of mastication robots for preparation of artificial boluses for digestion research. It enables food designers to influence the swallow-point properties of their products. For example, a product may be designed to satisfy five of the criteria for a safe-to-swallow bolus, which means the sixth criterion and its attendant food properties define the swallow-point. Alongside other organoleptic factors, these properties define the end-point texture and enduring sensory perception of the food.

Antipyretic efficacy and tolerability of a single intravenous dose of the acetaminophen prodrug propacetamol in children: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Propacetamol is an acetaminophen prodrug that was available in Europe as an IV formu lation for the treatment of pain and fever for some time. One gram of propacetamol is hydrolyzed in blood to release 0.5 g of acetaminophen and pharmacologically inactive N,N-diethylglycine. OBJECTIVE: This study compared the antipyretic efficacy and tolerability of IV propacetamol and placebo after a single administration in children with acute fever of infectious origin. The study was performed in anticipation of an application for US registration. METHODS: This was a double-blind, placebo-controlled trial in which patients with a body temperature (tympanic probe) of 38.5 degrees C to 41 degrees C were randomized to receive propacetamol 30 mg/kg IV or a placebo of identical appearance, both administered as 15-minute infusions. Temperature was measured at baseline, 0.5 hour after drug administration, and hourly thereafter for 6 hours or until use of rescue medication. The primary efficacy variable was the change in body temperature at each evaluation time compared with baseline. Secondary efficacy variables included the number of children requiring rescue medication and the time to remedication; the number of children with a body temperature <38 degrees C during the evaluation period and the time to reach this temperature; maximal body temperature reduction; and the weighted sum of changes in body temperature over the evaluation period. Tolerability was assessed based on changes in vital signs, monitored for 6 hours after administration of study drug, and adverse events recorded during the 24 hours after administration. RESULTS: Twenty children received propacetamol and 21 received placebo. Twenty patients were white, 17 black, and 4 Hispanic; their age ranged from 3 to 12 years. The actual mean (SD) dose of propacetamol received was 25.5 (0.6) mg/kg (equivalent to acetaminophen 12.8 [0.3] mg/kg). The reduction in body temperature was significantly greater in the propacetamol group compared with the placebo group at each time point over the 6-hour follow-up period (P < 0.001). Rescue medication was administered to 10.0% of patients in the propacetamol group, compared with 52.4% of those in the placebo group (P = 0.004). The weighted mean (SD) sum of the change in body temperature indicated greater antipyretic efficacy for propacetamol compared with placebo (-7.9 [3.8] degrees C x h vs 0.1 [3.6] degrees C x h, respectively; P < 0.001). There was no difference in the number of patients with treatment-emergent adverse events in the propacetamol and placebo groups (8 [40.0%] and 8 [38.1%]). The incidence of IV-site reactions was 10.0% in the propacetamol group and 9.5% in the placebo group. CONCLUSIONS: In these 41 children with acute fever of infectious origin, a propacetamol dose of 25.5 (0.6) mg/kg IV had significantly greater antipyretic efficacy than placebo and was equally well tolerated. Comparisons of this preparation with other IV antipyretic medications are needed.

Should compliance with the Surgical Care Improvement Project (SCIP) process measures determine Medicare and Medicaid reimbursement rates?

The Surgical Care Improvement Project (SCIP) is a project that focuses on improving surgical care by reducing surgical morbidity and mortality by 25 per cent by 2010. Starting in 2011, SCIP compliance affects Medicare and Medicaid reimbursement rates. Although SCIP reinforces better practices in surgical care, does compliance with SCIP measures actually result in a decrease in surgical morbidity and mortality? This study examined compliance with the SCIP surgical site infection (SSI) module (prophylactic antibiotic received within 1 hour before surgical incision) during 2009 to 2010 (n = 703) to determine whether patients compliant with SCIP data had a correlation with SSI rates as reported by National Surgery Quality Improvement Program (NSQIP) data for the same time period. We found no statistically significant association in patients that have failed SCIP INF1 in the years 2009 to 2010 (n = 43) and the rates of SSI (n = 0) for the same time period. These data suggest that SCIP compliance should not be used to determine Medicare and Medicaid reimbursement rates because there is no correlation between failure of SCIP INF1 and SSI. Instead, further effort should be placed on developing tools designed to acknowledge outcome measures that result in decreased morbidity/mortality and change practices accordingly such as NSQIP.