Healthcare can't stop evolving: innovation as the catalyst for unleashing the managerial potential of value-based healthcare by stimulating intangible assets and enhancing organizational resilience.

Background: With increasing healthcare service utilization and the introduction of costly therapies, healthcare organizations are pressured to deliver cost-effective services within constrained budgets. Rising costs and the need for efficient healthcare delivery are major concerns for governments, insurers, and health plans. Objectives: It aims to understand the impact of these intangible assets on creating value and organizational resilience in healthcare, informing better practices and strategies for VBHC implementation. Methods: An applied research approach using the Work Breakdown Structure (WBS) methodology was adopted. The research was divided into seven interconnected Work Packages (WPs), each designed to investigate different aspects of the integration between VBHC and intangible assets, with a focus on enhancing organizational resilience through innovative health processes. Key methodologies included literature reviews and qualitative analyses, employing Open Innovation and Design Thinking. Results: The study revealed a dynamic interplay between VBHC, organizational resilience, and intangible assets. It showed that managerial effectiveness is influenced by direct patient outcomes and elements like intellectual capital and organizational reputation. Data integration from various Work Packages provided new insights into how intangible assets underpin VBHC strategies, proposing novel management approaches. Findings highlight the essential role of intangible assets in enhancing service delivery and fostering sustainable healthcare practices. Discussion: The study highlights a significant oversight in the integration of intangible assets within healthcare organizations, despite their crucial role in optimizing VBHC. It supports literature emphasizing the importance of intellectual capital and organizational culture in enhancing healthcare management efficiency and resilience. A paradigm shift in VBHC to include these assets is needed for building a more adaptable and sustainable healthcare system. This integration can lead to better clinical outcomes, patient satisfaction, and overall healthcare efficiency, aligning more closely with VBHC goals. Conclusion: Recognizing and effectively managing intangible assets are paramount for the successful implementation of VBHC and enhanced organizational resilience. Strategic integration of these assets into healthcare management practices can significantly improve patient outcomes and create a more sustainable, patient-centered, and resilient healthcare system. Future studies should develop methodologies for robust measurement and integration of these assets to fully realize the potential of VBHC.

Impact of double stent retriever configuration on first-pass effect in stroke: a multicenter study.

BACKGROUND: Efficient recanalization of occluded cerebral arteries is crucial in the treatment of acute ischemic stroke. Double stent retrievers have shown the potential to enhance the rates of recanalization on the first pass. This study aims to evaluate the efficacy and safety of the double stent retriever technique and the predictors of achieving first-pass effect in patients with acute ischemic stroke. METHODS: This prospective multicenter study involved 209 patients from 16 comprehensive stroke centers in Spain. Patients with occlusions in the anterior circulation were treated using the Aperio Hybrid double stent retriever. The study examined various deployment techniques, including simultaneous and sequential deployment and stent configurations, comparing the Y-shaped and parallel configurations. RESULTS: The double stent retriever technique achieved a first-pass effect in 72.7% of cases and a final successful recanalization rate of 99.5%. The Y-shaped configuration was significantly associated with higher recanalization rates on the first pass (OR 2.59, 95% CI 1.18 to 5.68, P=0.02). Procedural complications were mild to moderate in 6.7% and severe in 1.5% of cases, with symptomatic intracranial hemorrhage occurring in 3.3% of patients. At 3 months follow-up, 57.2% of patients achieved a good clinical outcome, with a mortality rate of 15.1%. CONCLUSION: The findings support the efficacy of the double stent retriever technique, particularly the Y-shaped configuration, in achieving high recanalization rates on the first pass with an acceptable safety profile. This technique may offer clinical benefits for future acute ischemic stroke treatment protocols.

MK-5475, an inhaled soluble guanylate cyclase stimulator, for treatment of pulmonary arterial hypertension: the INSIGNIA-PAH study.

BACKGROUND: MK-5475 is an investigational inhaled soluble guanylate cyclase stimulator hypothesised to avoid most side-effects of systemic vasodilation. METHODS: The phase 2 INSIGNIA-PAH (NCT04732221) trial randomised adults with pulmonary arterial hypertension (PAH) on stable background therapy 1:1:1:1 to once-daily dosing with placebo, MK-5475 32 µg, 100 µg or 380 µg via dry powder inhalation for 12 weeks. OBJECTIVES: The objectives were to evaluate pulmonary vascular resistance (PVR; primary), 6-min walk distance (6MWD; secondary), additional selected haemodynamic parameters, and safety and tolerability in participants with PAH. RESULTS: 168 participants were randomised to placebo (n=41), MK-5475 32 µg (n=42), 100 µg (n=44), and 380 µg (n=41). Median age was 51 years. Most participants were female (73.8%), diagnosed with idiopathic PAH (63.7%), receiving concomitant phosphodiesterase type 5 inhibitors (PDE5i; 93.5%), and treated with double or triple combination therapy (85.1%). At week 12, the placebo-corrected changes in PVR by least-squares means were -9.2% (95% CI -21.3%, 2.9%; p=0.068) with 32 µg, -22.0% (95% CI -33.7%, -10.3%; p<0.001) with 100 µg, and -19.9% (95% CI -33.4%, -6.4%; p=0.002) with 380 µg MK-5475. No treatment differences versus placebo were observed in 6MWD. Treatment-related adverse events and serious adverse events were similar across treatment groups. Three participants died: two on placebo and one on MK-5475 100 µg. One participant had symptomatic hypotension and one had haemoptysis (both on MK-5475 100 µg). CONCLUSIONS: In participants with PAH on stable background therapy, including PDE5i, inhaled MK-5475 reduced PVR and was well tolerated, without evidence of systemic side-effects such as hypotension, suggesting a pulmonary selective pharmacodynamic effect.

Content validity of the Leicester Cough Questionnaire in adults with refractory or unexplained chronic cough: a qualitative interview study.

BACKGROUND: Chronic cough, a cough lasting >8 weeks, includes refractory chronic cough (RCC) and unexplained chronic cough (UCC). Patient-reported outcome (PRO) measures are needed to better understand chronic cough impacts that matter most to patients. The 19-item Leicester Cough Questionnaire (LCQ), an existing PRO measure of chronic cough, assesses impacts of cough across physical, psychological, and social domains. However, the content validity of the LCQ evaluating these concepts in patients with RCC/UCC had not been established. OBJECTIVES: To evaluate the content validity of the LCQ in patients with RCC/UCC. DESIGN: A cross-sectional, qualitative interview study. METHODS: First, previously completed qualitative interview results in adults with RCC/UCC (N = 30) were evaluated and mapped to LCQ concepts. Next, a clinical cough expert reviewed each LCQ item and assessed the salience of its concepts for patients with RCC/UCC. Finally, semistructured interviews-including both concept elicitation and cognitive debriefing-were conducted in adults with RCC/UCC (N = 20) to elicit a comprehensive set of participant experiences and to assess the appropriateness of using the LCQ in this population. RESULTS: Concepts reported in the past and present qualitative interviews were included across all LCQ items, and most impacts reported to be the "most bothersome" were assessed in the LCQ. In the current study, all participants indicated that reduced cough frequency would be an important treatment target. During cognitive debriefing, each LCQ item was endorsed by ⩾70% of participants. Additionally, participants were generally able to understand, recall, and select a response for each LCQ item. All participants and the clinical expert indicated that the LCQ was appropriate and assessed the impacts most relevant to patients with RCC/UCC. CONCLUSION: Our findings support the content validity of the LCQ and demonstrate that this measure is fit-for-purpose and includes important cough impacts in adults with RCC/UCC.

Efficacy and safety of gefapixant in women with chronic cough and cough-induced stress urinary incontinence: a phase 3b, randomised, multicentre, double-blind, placebo-controlled trial.

BACKGROUND: Approximately two-thirds of women with chronic cough have cough-induced stress urinary incontinence (CSUI). We aimed to evaluate the efficacy and safety of gefapixant in reducing CSUI episodes in women with refractory or unexplained chronic cough. METHODS: This phase 3b, double-blind, randomised, placebo-controlled trial done at 90 sites in 12 countries enrolled women aged 18 years or older who had chronic cough for at least 1 year, a diagnosis of refractory or unexplained chronic cough, a cough severity visual analogue scale score of 40 mm or more (100 mm maximum), and CSUI for 3 months or more. Participants were randomised 1:1 to oral gefapixant or placebo for 12 weeks. The primary outcome was percentage change from baseline in daily CSUI episodes (7-day average) at week 12. This study is registered with ClinicalTrials.gov (NCT04193176). FINDINGS: From May 10, 2020, to Sept 2, 2022, 375 participants were randomised to and treated with gefapixant 45 mg twice daily (n=185) or placebo (n=190). Mean age was 56·4 years (SD 11·4), with mean chronic cough duration of 5·2 years (SD 6·6) and SUI duration of 4·0 years (SD 5·9). Least-squares mean percentage change from baseline in daily CSUI episodes was -52·8% (95% CI -58·4 to -47·1%) for gefapixant and -41·1% (-46·7 to -35·4%) for placebo (estimated treatment difference: -11·7% [95% CI -19·7 to -3·7]; p=0·004). 129 (70%) of 185 participants who received gefapixant and 71 (37%) of 190 participants who received placebo had at least one adverse event. Safety and tolerability were consistent with previous trials of gefapixant; the most frequent adverse events were taste related. INTERPRETATION: Gefapixant 45 mg twice daily is the first treatment to show efficacy versus placebo in reducing CSUI episodes in participants with refractory or unexplained chronic cough. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.

Translational insights into the hormetic potential of carbon dioxide: from physiological mechanisms to innovative adjunct therapeutic potential for cancer.

Background: Carbon dioxide (CO2), traditionally viewed as a mere byproduct of cellular respiration, plays a multifaceted role in human physiology beyond simple elimination through respiration. CO2 may regulate the tumor microenvironment by significantly affecting the release of oxygen (O2) to tissues through the Bohr effect and by modulating blood pH and vasodilation. Previous studies suggest hypercapnia (elevated CO2 levels) might trigger optimized cellular mechanisms with potential therapeutic benefits. The role of CO2 in cellular stress conditions within tumor environments and its impact on O2 utilization offers a new investigative area in oncology. Objectives: This study aims to explore CO2's role in the tumor environment, particularly how its physiological properties and adaptive responses can influence therapeutic strategies. Methods: By applying a structured translational approach using the Work Breakdown Structure method, the study divided the analysis into six interconnected work packages to comprehensively analyze the interactions between carbon dioxide and the tumor microenvironment. Methods included systematic literature reviews, data analyses, data integration for identifying critical success factors and exploring extracellular environment modulation. The research used SMART criteria for assessing innovation and the applicability of results. Results: The research revealed that the human body's adaptability to hypercapnic conditions could potentially inform innovative strategies for manipulating the tumor microenvironment. This could enhance O2 utilization efficiency and manage adaptive responses to cellular stress. The study proposed that carbon dioxide's hormetic potential could induce beneficial responses in the tumor microenvironment, prompting clinical protocols for experimental validation. The research underscored the importance of pH regulation, emphasizing CO2 and carbonic acid's role in modulating metabolic and signaling pathways related to cancer. Conclusion: The study underscores CO2 as vital to our physiology and suggests potential therapeutic uses within the tumor microenvironment. pH modulation and cellular oxygenation optimization via CO2 manipulation could offer innovative strategies to enhance existing cancer therapies. These findings encourage further exploration of CO2's therapeutic potential. Future research should focus on experimental validation and exploration of clinical applications, emphasizing the need for interdisciplinary and collaborative approaches to tackle current challenges in cancer treatment.

Analyzing morphometry among extant and extinct species: A case study of genus Agassizia (Spatangoida: Echinoidea) / Análisis de la morfometría entre especies existentes y extintas: Un estudio de caso del género Agassizia (Spatangoida: Echinoidea)

Abstract Introduction: The genus Agassizia in Mexico is represented both in the fossil record by the species Agassizia regia† during the Miocene of Chiapas and by the extant species Agassizia excentrica on the Atlantic coast and Agassizia scrobiculata on the Pacific coast. Qualitative diagnosis and descriptions make it hard to distinguish morphological boundaries between species, especially in groups with fossils and recent representatives, increasing the level of complexity by having samples of disparate qualities and quantities. Objective: We propose the use of little explored statistical methods in the comparison of paleontological and biological populations. This methodology allowed us to resolve issues of missing values in a morphometric data set for the genus Agassizia. Methods: Using samples recently collected and specimens already housed in collections, we explore a routine of recovery of missing data MICE and the numerical and graphic analyses PERMANOVA, PCA, and SIMPER to compare morphometric parameters between these species for recognizing diagnostic characters. Results: Our results show a morphological difference in the length of the ambulacrum II and the length and width of the periproct and peristome structures, these being greater in A. scrobiculata, with a consistent pattern in both population samples not previously described. Conclusions: Quantitative morphometric comparisons can be an assertive and complementary tool to determine distinctive differentiation characteristics in species of the same genus. Comparative morphology reviews should be an ongoing exercise to keep taxonomic knowledge on both extinct and extant species up to date. Our research encourage the scientific community studying fossil populations to utilize quantitative and multivariate methods to strengthen their investigations.

Resumen Introducción: El género Agassizia en México está representado tanto en el registro fósil por la especie Agassizia regia† del Mioceno de Chiapas, como por las especies actuales Agassizia excentrica de la costa del Atlántico y Agassizia scrobiculata de la costa del Pacífico. Las descripciones y diagnosis cualitativas dificultan reconocer los limites morfológicos entre especies, especialmente en grupos con representantes fósiles y recientes, e incrementando el nivel de complejidad al tener muestras de cantidad y calidad desiguales. Objetivo: Proponemos el uso de métodos estadísticos poco explorados en la comparación de poblaciones paleontológicas y biológicas. Esta metodología nos permitió resolver problemas de valores faltantes en un conjunto de datos morfométricos para el género Agassizia. Métodos: Usando muestras recolectadas para este fin, así como provenientes de colecciones científicas, exploramos una rutina de recuperación de datos faltantes MICE, y los análisis numéricos y gráficos PERMANOVA, PCA y SIMPER para comparar parámetros morfométricos entre estas especies y reconocer caracteres de diagnóstico. Además, comparamos cuidadosamente los caracteres morfológicos descritos previamente en la literatura taxonómica y la descripción ambiental del hábitat actual de A. scrobiculata. Resultados: Nuestros resultados muestran una diferencia morfológica en la longitud del ambulacrum II y la longitud y anchura de las estructuras del periprocto y peristoma, siendo estas mayores en A. scrobiculata, con un patrón consistente en ambas muestras poblacionales no descrito previamente. El hábitat actual de las muestras de A. scrobiculata en la costa del Pacífico es un sistema costero poco profundo con sedimentos arenosos y temperaturas tropicales. Bahía Chamela comparte varias similitudes con la fauna y las condiciones ambientales previamente descritas en el Mioceno de Chiapas. Conclusiones: Las comparaciones morfométricas cuantitativas pueden ser una herramienta poderosa y complementaria para determinar caracteres distintivos de diferenciación en especies del mismo género. Las revisiones de morfología comparativa deben ser un ejercicio continuo para mantener actualizado el conocimiento taxonómico sobre las especies existentes y extintas. Nuestro trabajo busca incentivar a la comunidad científica que trabaja con poblaciones fósiles a explorar estos y otros métodos cuantitativos y multivariados para fortalecer sus investigaciones.

Critical evaluation of the potential of ICP-MS-based systems in toxicological studies of metallic nanoparticles.

The extensive application of metallic nanoparticles (NPs) in several fields has significantly impacted our daily lives. Nonetheless, uncertainties persist regarding the toxicity and potential risks associated with the vast number of NPs entering the environment and human bodies, so the performance of toxicological studies are highly demanded. While traditional assays focus primarily on the effects, the comprehension of the underlying processes requires innovative analytical approaches that can detect, characterize, and quantify NPs in complex biological matrices. Among the available alternatives to achieve this information, mass spectrometry, and more concretely, inductively coupled plasma mass spectrometry (ICP-MS), has emerged as an appealing option. This work critically reviews the valuable contribution of ICP-MS-based techniques to investigate NP toxicity and their transformations during in vitro and in vivo toxicological assays. Various ICP-MS modalities, such as total elemental analysis, single particle or single-cell modes, and coupling with separation techniques, as well as the potential of laser ablation as a spatially resolved sample introduction approach, are explored and discussed. Moreover, this review addresses limitations, novel trends, and perspectives in the field of nanotoxicology, particularly concerning NP internalization and pathways. These processes encompass cellular uptake and quantification, localization, translocation to other cell compartments, and biological transformations. By leveraging the capabilities of ICP-MS, researchers can gain deeper insights into the behaviour and effects of NPs, which can pave the way for safer and more responsible use of these materials.

Association of initial opioid prescription duration and an opioid refill by pain diagnosis: Evidence from outpatient settings in ten US health systems.

OBJECTIVE: The Centers for Disease Control and Prevention's 2022 Clinical Practice Guideline for Prescribing Opioids for Pain cautioned that inflexible opioid prescription duration limits may harm patients. Information about the relationship between initial opioid prescription duration and a subsequent refill could inform prescribing policies and practices to optimize patient outcomes. We assessed the association between initial opioid duration and an opioid refill prescription. METHODS: We conducted a retrospective cohort study of adults ≥19 years of age in 10 US health systems between 2013 and 2018 from outpatient care with a diagnosis for back pain without radiculopathy, back pain with radiculopathy, neck pain, joint pain, tendonitis/bursitis, mild musculoskeletal pain, severe musculoskeletal pain, urinary calculus, or headache. Generalized additive models were used to estimate the association between opioid days' supply and a refill prescription. RESULTS: Overall, 220,797 patients were prescribed opioid analgesics upon an outpatient visit for pain. Nearly a quarter (23.5%) of the cohort received an opioid refill prescription during follow-up. The likelihood of a refill generally increased with initial duration for most pain diagnoses. About 1 to 3 fewer patients would receive a refill within 3 months for every 100 patients initially prescribed 3 vs. 7 days of opioids for most pain diagnoses. The lowest likelihood of refill was for a 1-day supply for all pain diagnoses, except for severe musculoskeletal pain (9 days' supply) and headache (3-4 days' supply). CONCLUSIONS: Long-term prescription opioid use increased modestly with initial opioid prescription duration for most but not all pain diagnoses examined.

Critical evaluation of key parameters in single particle ICP-MS data processing for the correct determination of platinum nanoparticles in complex environmental and biological matrices.

There is an urgent need for the harmonization of critical parameters in single particle inductively coupled plasma mass spectrometry (SP-ICP-MS) and they have been deeply studied and optimized in the present work using platinum nanoparticles (PtNPs) as a representative case of study. Special attention has been paid to data processing in order to achieve an adequate discrimination between signals. Thus, a comparison between four different algorithms has been performed and the method for transport efficiency calculation has also been thorougly evaluated (finding the use of a well-characterized solution of the same targeted analyte (30 nm PtNPs) as adequate). The best results have been obtained after the application of a deconvolution approach for the data processing and using 5 ms as dwell time and 40,000 data points for data acquisition. Under the optimized conditions, a correct discrimination between NP events and background signal up to 100 or 750 ng L-1 of added ionic Pt was reached for 30 and 50 nm PtNPs, respectively. The suitability of the developed method for the characterization of PtNPs in relevant environmental (water samples) and biological (cell culture media) matrices has also been demonstrated.

Prescription Opioid Dose Reductions and Potential Adverse Events: a Multi-site Observational Cohort Study in Diverse US Health Systems.

BACKGROUND: In response to the opioid crisis in the United States, population-level prescribing of opioids has been decreasing; there are concerns, however, that dose reductions are related to potential adverse events. OBJECTIVE: Examine associations between opioid dose reductions and risk of 1-month potential adverse events (emergency department (ED) visits, opioid overdose, benzodiazepine prescription fill, all-cause mortality). DESIGN: This observational cohort study used electronic health record and claims data from eight United States health systems in a prescription opioid registry (Clinical Trials Network-0084). All opioid fills (excluding buprenorphine) between 1/1/2012 and 12/31/2018 were used to identify baseline periods with mean morphine milligram equivalents daily dose of  ≥ 50 during six consecutive months. PATIENTS: We identified 60,040 non-cancer patients with  ≥ one 2-month dose reduction period (600,234 unique dose reduction periods). MAIN MEASURES: Analyses examined associations between dose reduction levels (1- < 15%, 15- < 30%, 30- < 100%, 100% over 2 months) and potential adverse events in the month following a dose reduction using logistic regression analysis, adjusting for patient characteristics. KEY RESULTS: Overall, dose reduction periods involved mean reductions of 18.7%. Compared to reductions of 1- < 15%, dose reductions of 30- < 100% were associated with higher odds of ED visits (OR 1.14, 95% CI 1.10, 1.17), opioid overdose (OR 1.41, 95% CI 1.09-1.81), and all-cause mortality (OR 1.39, 95% CI 1.16-1.67), but lower odds of a benzodiazepine fill (OR 0.83, 95% CI 0.81-0.85). Dose reductions of 15- < 30%, compared to 1- < 15%, were associated with higher odds of ED visits (OR 1.08, 95% CI 1.05-1.11) and lower odds of a benzodiazepine fill (OR 0.93, 95% CI 0.92-0.95), but were not associated with opioid overdose and all-cause mortality. CONCLUSIONS: Larger reductions for patients on opioid therapy may raise risk of potential adverse events in the month after reduction and should be carefully monitored.

Implementation of substance use screening in rural federally-qualified health center clinics identified high rates of unhealthy alcohol and cannabis use among adult primary care patients.

BACKGROUND: Screening for substance use in rural primary care clinics faces unique challenges due to limited resources, high patient volumes, and multiple demands on providers. To explore the potential for electronic health record (EHR)-integrated screening in this context, we conducted an implementation feasibility study with a rural federally-qualified health center (FQHC) in Maine. This was an ancillary study to a NIDA Clinical Trials Network study of screening in urban primary care clinics (CTN-0062). METHODS: Researchers worked with stakeholders from three FQHC clinics to define and implement their optimal screening approach. Clinics used the Tobacco, Alcohol, Prescription Medication, and Other Substance (TAPS) Tool, completed on tablet computers in the waiting room, and results were immediately recorded in the EHR. Adult patients presenting for annual preventive care visits, but not those with other visit types, were eligible for screening. Data were analyzed for the first 12 months following implementation at each clinic to assess screening rates and prevalence of reported unhealthy substance use, and documentation of counseling using an EHR-integrated clinical decision support tool, for patients screening positive for moderate-high risk alcohol or drug use. RESULTS: Screening was completed by 3749 patients, representing 93.4% of those with screening-eligible annual preventive care visits, and 18.5% of adult patients presenting for any type of primary care visit. Screening was self-administered in 92.9% of cases. The prevalence of moderate-high risk substance use detected on screening was 14.6% for tobacco, 30.4% for alcohol, 10.8% for cannabis, 0.3% for illicit drugs, and 0.6% for non-medical use of prescription drugs. Brief substance use counseling was documented for 17.4% of patients with any moderate-high risk alcohol or drug use. CONCLUSIONS: Self-administered EHR-integrated screening was feasible to implement, and detected substantial alcohol, cannabis, and tobacco use in rural FQHC clinics. Counseling was documented for a minority of patients with moderate-high risk use, possibly indicating a need for better support of primary care providers in addressing substance use. There is potential to broaden the reach of screening by offering it at routine medical visits rather than restricting to annual preventive care visits, within these and other rural primary care clinics.

Population pharmacokinetic analysis of the P2X3-receptor antagonist gefapixant.

Gefapixant, a P2X3-receptor antagonist, demonstrated objective and subjective efficacy in individuals with refractory or unexplained chronic cough. We report a population pharmacokinetic (PopPK) analysis that characterizes gefapixant pharmacokinetics (PKs), quantifies between- and within-participant variability, and evaluates the impact of intrinsic and extrinsic factors on gefapixant exposure. The PopPK model was initially developed using PK data from six phase I studies. Stepwise covariate method was utilized to identify covariates impacting PK parameters; the model was re-estimated and covariate effects were re-assessed after integrating PK data from three phase II and III studies. Simulations were conducted to evaluate the magnitude of covariate effects on gefapixant exposure. Of 1677 participants included in this data set, 1618 had evaluable PK records. Age, body weight, and sex had statistically significant, but not clinically relevant, effects on exposure. Degree of renal impairment (RI) had statistically significant and clinically relevant effects on exposure; exposure was 17% to 89% higher in those with versus without RI. Simulation results indicated that gefapixant 45 mg administered once daily to patients with severe RI has similar exposure to gefapixant 45 mg administered twice daily to patients with normal renal function. There were no significant effects of proton pump inhibitors or food. Of evaluated intrinsic and extrinsic factors, only RI had a clinically relevant effect on gefapixant exposure. Patients with mild or moderate RI do not require dosage adjustments; however, for patients with severe RI who are not on dialysis, gefapixant 45 mg once daily is recommended.

The Efficacy and Safety of Gefapixant in a Phase 3b Trial of Patients with Recent-Onset Chronic Cough.

PURPOSE: We evaluated gefapixant, a P2X3 receptor antagonist, in participants with recent-onset (≤ 12 months) refractory chronic cough (RCC) or unexplained chronic cough (UCC). METHODS: Participants (≥ 18 years of age; ≥ 40 mm on a 100-mm cough severity visual analog scale [VAS] at screening and randomization) with chronic cough for < 12 months were enrolled in this phase 3b, double-blind, placebo-controlled, parallel group, multicenter study (NCT04193202). Participants were randomized 1:1 to gefapixant 45 mg BID or placebo for 12 weeks with a 2-week follow-up. The primary efficacy endpoint was change from baseline at Week 12 in Leicester Cough Questionnaire (LCQ) total score. Adverse events were monitored and evaluated. RESULTS: There were 415 participants randomized and treated (mean age 52.5 years; median [range] duration 7.5 [1-12] months): 209 received placebo and 206 received gefapixant 45 mg BID. A statistically significant treatment difference of 0.75 (95% CI: 0.06, 1.44; p = 0.034) for gefapixant vs. placebo was observed for change from baseline in LCQ total score at Week 12. The most common AE was dysgeusia (32% gefapixant vs. 3% placebo participants); serious AEs were rare (1.5% gefapixant vs. 1.9% placebo participants). CONCLUSION: Gefapixant 45 mg BID demonstrated significantly greater improvement in cough-specific health status from baseline compared to placebo, in participants with recent-onset chronic cough. The most common AEs were related to taste and serious AEs were rare.

Electrical asymmetric-flow field-flow fractionation with a multi-detector array platform for the characterization of metallic nanoparticles with different coatings.

Electrical asymmetric-flow field-flow fractionation (EAF4) is a new and interesting analytical technique recently proposed for the characterization of metallic nanoparticles (NPs). It has the potential to simultaneously provide relevant information about size and electrical parameters, such as electrophoretic mobility (µ) and zeta-potential (ζ), of individual NP populations in an online instrumental setup with an array of detectors. However, several chemical and instrumental conditions involved in this technique are definitely influential, and only few applications have been proposed until now. In the present work, an EAF4 system has been used with different detectors, ultraviolet-visible (UV-vis), multi-angle light scattering (MALS), and inductively coupled plasma with triple quadrupole mass spectrometry (ICP-TQ-MS) for the characterization of gold, silver, and platinum NPs with both citrate and phosphate coatings. The behavior of NPs has been studied in terms of retention time and signal intensity under both positive and negative current with results depending on the coating. Carrier composition, particularly ionic strength, was found to be critical to achieve satisfactory recoveries and a reliable measurement of electrical parameters. Dynamic light scattering (DLS) has been used as a comparative technique for these parameters. The NovaChem surfactant mix (0.01%) showed a quantitative recovery (93 ± 1%) of the membrane, but the carrier had to be modified by increasing the ionic strength with 200 µM of Na2CO3 to achieve consistent µ values. However, ζ was one order of magnitude lower in EAF4-UV-vis-MALS than in DLS, probably due to different electric processes in the channel. From a practical point of view, EAF4 technique is still in its infancy and further studies are necessary for a robust implementation in the characterization of NPs.

The association between buprenorphine treatment duration and mortality: a multi-site cohort study of people who discontinued treatment.

BACKGROUND AND AIMS: Buprenorphine is an effective medication for opioid use disorder that reduces mortality; however, many patients are not retained in buprenorphine treatment, and an optimal length of treatment after which patients can safely discontinue treatment has not been identified. This study measured the association between buprenorphine treatment duration and all-cause mortality among patients who discontinued treatment. Secondary objectives were to measure the association between treatment duration and drug overdose and opioid-related overdoses. DESIGN: Multi-site cohort study. SETTING: Eight US health systems. PARTICIPANTS: Patients who initiated and discontinued buprenorphine treatment between 1 January 2012 and 31 December 2018 (n = 6550). Outcomes occurring after patients discontinued buprenorphine treatment were compared between patients who initiated and discontinued treatment after 8-30, 31-90, 91-180, 181-365 and > 365 days. MEASUREMENTS: Covariate data were obtained from electronic health records (EHRs). Mortality outcomes were derived from EHRs and state vital statistics. Non-fatal opioid and drug overdoses were obtained from diagnostic codes. Four sites provided cause-of-death data to identify fatal drug and opioid-related overdoses. Adjusted frailty regression was conducted on a propensity-weighted cohort to assess associations between duration of the final treatment episode and outcomes. FINDINGS: The mortality rate after buprenorphine treatment was 1.82 per 100 person-years (n = 191 deaths). In regression analyses with > 365 days as the reference group, treatment duration was not associated with all-cause mortality and drug overdose (P > 0.05 for both). However, compared with > 365 days of treatment, 91-180 days of treatment was associated with increased opioid overdose risk (hazard ratio = 2.94, 95% confidence interval = 1.11-7.79). CONCLUSIONS: Among patients who discontinue buprenorphine treatment, there appears to be no treatment duration period associated with a reduced risk for all-cause mortality. Patients who discontinue buprenorphine treatment after 91-180 days appear to be at heightened risk for opioid overdose compared with patients who discontinue after > 365 days of treatment.

Demographic, clinical, and patient-reported outcome data from 2 global, phase 3 trials of chronic cough.

BACKGROUND: The current characterization of patients with refractory or unexplained chronic cough (RCC and UCC, respectively) primarily stems from relatively small clinical studies. OBJECTIVE: To report the baseline medical history and clinical characteristics of individuals with RCC or UCC who were enrolled in COUGH-1 and COUGH-2, 2 large, global, phase 3 trials of gefapixant, a P2 × 3-receptor antagonist. METHODS: Adults with a chronic cough lasting for more than 1 year, diagnosis of RCC or UCC, and score greater than 40 mm on a 100-mm cough severity visual analog scale at both screening and baseline were eligible for enrollment. Demographics, medical history, and cough characteristics were collected at baseline. Cough-related measures included objective cough frequency, cough severity visual analog scale, Leicester Cough Questionnaire, and Hull Airway Reflux Questionnaire. The data were summarized using descriptive statistics. RESULTS: Of 2044 participants, 75% were women; mean age was 58 years, and mean cough duration was approximately 11 years. Among all participants, 73% were previously diagnosed with asthma, gastroesophageal reflux disease, or upper airway cough syndrome. The mean Leicester Cough Questionnaire total score was 10.4, with domain scores reflecting impaired cough-specific quality of life across physical, psychological, and social domains. The mean Hull Airway Reflux Questionnaire score was 39.6, with some of the most burdensome reported items being consistent with features of cough-reflex hypersensitivity. Participant characteristics and cough burden were comparable across geographic regions. CONCLUSION: Participants with RCC or UCC had characteristics consistent with published demographics associated with chronic cough. These data reflect a global population with burdensome cough of long duration and substantial impairment to quality of life. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: COUGH-1, NCT03449134 (https://www. CLINICALTRIALS: gov/ct2/show/NCT03449134); COUGH-2, NCT03449147 (https://clinicaltrials.gov/ct2/show/NCT03449147).

Validation and Meaningful Change Thresholds for an Objective Cough Frequency Measurement in Chronic Cough.

PURPOSE: Objective cough frequency is used to assess efficacy of chronic cough (CC) treatments. The objective of this study was to explore the relationship between objective cough frequency and cough-specific patient-reported outcomes (PROs) and estimate a clinically meaningful change threshold (MCT) for objective cough frequency. METHODS: Data collected in a phase 2b study in participants with refractory or unexplained CC were used to investigate the relationship between 24-h cough frequency (measured using an ambulatory cough monitor) and cough-specific PROs (i.e., cough severity visual analog scale, cough severity diary, Leicester Cough Questionnaire). Convergent validity was assessed using Spearman ρ. An MCT for 24-h cough frequency was estimated using the patient global impression of change (PGIC) scale as an anchor. RESULTS: Correlations between 24-h cough frequency and cough-specific PROs at baseline, Week 4, and Week 12 were significant (P < 0.0001) but low to moderate in strength (ρ = 0.30-0.58). Participants categorized as very much improved/much improved (i.e., PGIC of 1 or 2) or minimally improved (i.e., PGIC of 3) had mean 24-h cough frequency reductions of 55% and 30%, respectively. Receiver operating characteristic curve analysis suggested that a 24-h cough frequency reduction of 38% optimizes sensitivity and specificity for predicting a PGIC score of 1-3. CONCLUSION: Objective 24-h cough frequency is significantly associated with cough-specific PROs, but cough frequency and PROs most likely capture distinct aspects of CC. A ≥ 30% reduction in 24-h cough frequency is a reasonable MCT to define treatment response in CC clinical trials.

Improvements in Objective and Subjective Measures of Chronic Cough with Gefapixant: A Pooled Phase 3 Efficacy Analysis of Predefined Subgroups.

INTRODUCTION: In phase 3 trials (COUGH-1/COUGH-2), gefapixant 45 mg twice daily significantly reduced 24-h cough frequency vs placebo in refractory or unexplained chronic cough (RCC or UCC). METHODS: Here, the efficacy of gefapixant 45 mg vs placebo was evaluated across COUGH-1/COUGH-2 in predefined subgroups based on sex, region, age, cough duration, cough severity, cough frequency, and diagnosis (RCC, UCC). Awake cough frequency reductions at Week 12 and LCQ response rates (i.e., ≥ 1.3-point improvement) at Week 24 were assessed. RESULTS: Among 1360 participants analyzed, gefapixant 45 mg resulted in consistent awake cough frequency reductions overall and across predefined subgroups at Week 12. Gefapixant also resulted in improved LCQ scores across subgroups at Week 24; ≥ 70% of participants in each subgroup treated with gefapixant 45 mg had an LCQ response. CONCLUSION: These data suggest gefapixant 45 mg provides consistent objective and subjective efficacy across subgroups of individuals with RCC or UCC.