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This study assesses the acceptability, appropriateness, feasibility, and efficacy of a novel asynchronous video‐based intervention for teaching respiratory physiology and anatomy to medical students in resource‐limited settings. A series of short video lectures on pleural anatomy, pulmonary physiology, and pathophysiology was created using Lightboard and screen capture technology. These were uploaded to YouTube and Google Drive and made available to 1st‐3rd year medical students at two Latin American universities for 1 week. Employing a parallel‐convergent mixed methods design, we conducted surveys, focus groups, interviews, and pre/post testing for qualitative and quantitative data. Thematic Analysis was used to analyze qualitative data and McNemar's test for quantitative analysis. Seventy‐six students participated. The videos' short format, interactivity, and Lightboard style were highly valued for their flexibility, time efficiency, and educational impact. Students recognized their clinical relevance and trusted their content, suggesting potential applicability in similar settings. Despite infrastructure and connectivity challenges, the use of flexible streaming and downloadable options facilitated learning. Survey results indicated high levels of feasibility (99%), appropriateness (95%), and acceptability (95%), with significant knowledge gains observed (37% correct pre‐test answers vs. 56% post‐test, p < 0.0001). Our findings demonstrate high acceptability, appropriateness, feasibility, and efficacy of a targeted asynchronous education centered on short‐format videos in resource‐limited settings, enabling robust learning despite local barriers. Flexible access is key for overcoming localized barriers. Taking an adaptive, learner‐centered approach to content creation and delivery to address constraints was pivotal to success. Our modular videos could serve as versatile models for flexible education in resource‐constrained settings. [ABSTRACT FROM AUTHOR]

Allergic disease prevalence has increased globally with the subset of type 2 inflammatory diseases playing a substantial role. Type 2 inflammatory diseases may differ in clinical presentation, but they exhibit shared pathophysiology that is targeted by the unique pharmacology of dupilumab. Dupilumab binds to the interleukin (IL)‐4 receptor alpha subunit (IL‐4Rα) that blocks IL‐4 and IL‐13 signaling, two key drivers of type 2 inflammation. Herein, we review the mechanism of action and pharmacology of dupilumab, and the clinical evidence that led to the regulatory approvals of dupilumab for the treatment of numerous type 2 inflammatory diseases: atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyposis, eosinophilic esophagitis, and prurigo nodularis. [ABSTRACT FROM AUTHOR]

Interleukin‐33 (IL‐33) is a proinflammatory alarmin cytokine released by damaged epithelial tissue cells that initiates and amplifies both type 1 and type 2 inflammatory cascades. A role for IL‐33 in atopic dermatitis (AD; a chronic, relapsing type 2 inflammatory disease of the skin) has been proposed. Itepekimab is a novel human IgG4P monoclonal antibody against IL‐33, currently in clinical development for chronic obstructive pulmonary disease (COPD). Two global phase II studies—a dose‐ranging itepekimab monotherapy study (NCT03738423) and a proof‐of‐concept study of itepekimab alone and in combination with dupilumab (NCT03736967)—were conducted in patients with moderate‐to‐severe AD to assess safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy; both studies were terminated following an interim analysis of the proof‐of‐concept study, which failed to demonstrate the efficacy of itepekimab. In these two studies, itepekimab exhibited linear and dose‐proportional pharmacokinetics. Pharmacodynamics of total IL‐33 indicated that itepekimab saturated binding to the target in serum at 300 mg q2w and q4w doses, and decreased blood eosinophil counts. Concentration–time profiles of itepekimab and total IL‐33 were similar for itepekimab with or without dupilumab, and between East Asian and non‐East Asian subgroups. Itepekimab was generally well tolerated, both alone and in combination with dupilumab. The lack of clinical efficacy for itepekimab observed in these studies suggests that IL‐33 may not be a key pathogenic driver in moderate‐to‐severe AD. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) pain management options are currently limited. Fasinumab, an anti‐nerve growth factor monoclonal antibody, has been investigated in healthy volunteers and patients with OA‐related pain, among other conditions. Data from 12 Phase I‐III clinical trials of 92 healthy volunteers and 7430 patients with OA were used to develop a population pharmacokinetic model to characterize fasinumab concentration‐time profiles and assess the covariates' effect on fasinumab pharmacokinetic parameters. Participants received single or repeated fasinumab doses intravenously (IV)/subcutaneously (SC), based on body weight (0.03‐1 mg/kg IV or 0.1‐0.3 mg/kg SC)/fixed dose (9‐12 mg IV or 1‐12 mg SC). Fasinumab concentration‐time data following IV and SC administration in healthy volunteers and patients with OA‐related pain were adequately described by a 2‐compartment model. Bioavailability increased with higher doses; estimated at 55.1% with 1 mg SC dose, increasing in a greater‐than‐proportional manner above this. Body weight had the largest predicted impact on fasinumab steady‐state exposures, participants at the 5th and 95th percentiles had a 43%‐45% higher/22%‐23% lower exposure versus reference, respectively. Other covariates had small but clinically irrelevant impacts. [ABSTRACT FROM AUTHOR]

Mibavademab (previously known as REGN4461), a fully human monoclonal antibody, is being investigated for the treatment of conditions associated with leptin deficiency. Here, we report pharmacokinetics (PKs), pharmacodynamics, and immunogenicity from a phase I study in healthy participants (NCT03530514). In part A, lean or overweight healthy participants were randomized to single‐ascending‐dose cohorts of 0.3, 1.0, 3.0, 10, and 30 mg/kg intravenous (i.v.), or 300 and 600 mg subcutaneous doses of mibavademab or placebo. In part B, overweight or obese participants were randomized to receive multiple doses of mibavademab (15 mg/kg i.v. loading dose and 10 mg/kg i.v. at weeks 3, 6, and 9) or placebo, stratified by body mass index and baseline leptin levels: low leptin (<5 ng/mL) or relatively low leptin (5–8 ng/mL in men and 5–24 ng/mL in women). Fifty‐six and 55 participants completed the single‐ascending‐dose and multiple‐dose parts, respectively. In the single‐ascending‐dose cohorts, mibavademab PKs were nonlinear with target‐mediated elimination, greater than dose‐proportional increases in exposure, and there were no dose‐dependent differences in total soluble leptin receptor (sLEPR) levels in serum over time. Following multiple‐dose administration of mibavademab in participants with leptin <8 ng/mL, lower mean mibavademab concentrations, higher mean total sLEPR concentrations, and larger mean decreases in body weight than in the relatively low leptin cohorts were observed. Baseline leptin was correlated with mibavademab PKs and pharmacodynamics. No treatment‐emergent anti‐mibavademab antibodies were observed in any mibavademab‐treated participant. Results from this study collectively inform further development of mibavademab to treat conditions associated with leptin deficiency. [ABSTRACT FROM AUTHOR]

Objective: The focus of this study was to assess changes in the cumulative incidence of extra‐articular manifestations of rheumatoid arthritis (ExRAs) and associated mortality risk. Methods: This study evaluated trends in occurrence of ExRAs using a population‐based inception cohort that included all adult patients with incident rheumatoid arthritis (RA) from 1985 through 2014 meeting the 1987 American College of Rheumatology criteria. Patients were divided into two cohorts based on the incidence date of RA, 1985 to 1999 and 2000 to 2014. The occurrence of ExRAs was determined by manual chart review, and the 10‐year cumulative incidence was estimated for each ExRA in both cohorts. Cox proportional hazard models were used to determine associations between specific demographic and RA disease characteristics and ExRAs and between ExRAs and mortality. Results: There were 907 patients included, 296 in the 1985 to 1999 cohort and 611 in the 2000 to 2014 cohort. The 10‐year cumulative incidence of any ExRA decreased significantly between the earlier and later cohorts (45.1% vs 31.6%, P < 0.001). This was largely driven by significant declines in subcutaneous rheumatoid nodules (30.9% vs 15.8%, P < 0.001) and nonsevere ExRAs (41.4% vs 28.8%, P = 0.001). Identified risk factors for the development of any ExRAs include rheumatoid factor positivity (hazard ratio [HR] 2.02, 95% confidence interval [CI] 1.43–2.86) and current smoking (HR 1.61, 95% CI 1.10–2.34). Mortality was increased in patients with either nonsevere (HR 1.83, 95% CI 1.18–2.85) or severe ExRAs (HR 3.05, 95% CI 1.44–6.49). Conclusions: The incidence of ExRAs has decreased over time. Mortality remains increased in patients with ExRAs. [ABSTRACT FROM AUTHOR]

Subcutaneous (s.c.) administration of monoclonal antibodies (mAbs) can reduce treatment burden for patients and healthcare systems compared with intravenous (i.v.) infusion through shorter administration times, made possible by convenient, patient‐centric devices. A deeper understanding of clinical pharmacology principles related to efficacy and safety of s.c.‐administered mAbs over the past decade has streamlined s.c. product development. This review presents learnings from key constituents of the s.c. mAb development pathway, including pharmacology, administration variables, immunogenicity, and delivery devices. Restricted mAb transportation through the hypodermis explains their incomplete absorption at a relatively slow rate (pharmacokinetic (PK)) and may impact mAb‐cellular interactions and/or onset and magnitude of physiological responses (pharmacodynamic). Injection volumes, formulation, rate and site of injection, and needle attributes may affect PKs and the occurrence/severity of adverse events like injection‐site reactions or pain, with important consequences for treatment adherence. A review of immunogenicity data for numerous compounds reveals that incidence of anti‐drug antibodies (ADAs) is generally comparable across i.v. and s.c. routes, and complementary factors including response magnitude (ADA titer), persistence over time, and neutralizing antibody presence are needed to assess clinical impact. Finally, four case studies showcase how s.c. biologics have been clinically developed: (i) by implementation of i.v./s.c. bridging strategies to streamline PD‐1/PD‐L1 inhibitor development, (ii) through co‐development with i.v. presentations for anti‐severe acute respiratory syndrome‐coronavirus 2 antibodies to support rapid deployment of both formulations, (iii) as the lead route for bispecific T cell engagers (BTCEs) to mitigate BTCE‐mediated cytokine release syndrome, and (iv) for pediatric patients in the case of dupilumab. [ABSTRACT FROM AUTHOR]

Here, we report the clinical pharmacology data from LUMINA‐1 (NCT03188666), a Phase 2 trial that evaluated garetosmab (a monoclonal antibody against activin A) in patients with fibrodysplasia ossificans progressiva. Forty‐four patients were randomly assigned to intravenous 10 mg/kg of garetosmab or placebo every 4 weeks in a double‐blind 28‐week treatment period, followed by a 28‐week open‐label treatment period with garetosmab, and subsequent open‐label extension. Serum samples were obtained to assess pharmacokinetics (PK), immunogenicity, and bone morphogenetic protein 9 (BMP9). Comparative exposure–response analyses for efficacy and safety were performed with trough concentrations (Ctrough) of garetosmab prior to dosing. Steady‐state PK was reached 12‐16 weeks after the first dose of garetosmab, with mean (standard deviation) Ctrough of 105 ± 30.8 mg/L. Immunogenicity assessments showed anti‐garetosmab antibody formation in 1 patient (1/43; 2.3%); titers were low, and did not affect PK or clinical efficacy. Median concentrations of BMP9 in serum were approximately 40 pg/mL at baseline. There were no meaningful differences in PK or BMP9 concentration–time profiles between patients who did and did not experience epistaxis or death. The comparative exposure–response analyses demonstrated no association between Ctrough and efficacy or safety. PK findings were consistent with prior data in healthy volunteers and were typical for a monoclonal antibody administered at doses sufficient to saturate target‐mediated clearance. There were no trends that suggested patients with higher serum exposures to garetosmab were more likely to experience a reduction in heterotopic ossification or adverse events. Garetosmab is being further evaluated in the Phase 3 OPTIMA trial. [ABSTRACT FROM AUTHOR]

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This paper details the progress to date of the Indigenous Knowledge Systems Lab (IKS Lab) at Deakin University in establishing organisational processes and methods of inquiry grounded in Indigenous protocols. Continuity of traditional knowledge and practice in the Lab requires a deep‐time perspective of complex systems both local and nonlocal, ensuring that ancient psycho‐technologies are retrieved forward for context‐dependent, collectively responsive thought leadership and projects stewarding relational systems increase during phase shifts anticipated from future inflection points of wicked proportions. This work requires abductive reasoning, the eradication of discrete discipline boundaries, continuous adaptive responsiveness, distributed authority, agentic dyads of individual and group sovereignties, kinship protocols for solitary/pair/group/multigroup activity, traditional embassy protocols for dialogue between diverse systems and traditional Law‐based principles translated into propositions that can inform innovative systems functions and theory. [ABSTRACT FROM AUTHOR]

The article evaluates how the Minor Threat band inverted mainstream and punk fashion cycles to create a meaningful impact in the U.S. Topics include the influences and motivations that drove the punk band's aesthetic and its lasting impact on punk, the reason for the relevance of punk, several variables that shaped Minor Threat's style such as the endemic aspects of Washington, D.C. life and mainstream fashion trends, and the release of their music album "Salad Days."

Objective: We aimed to determine the population‐based incidence, prevalence, and mortality of dermatomyositis (DM) using European Alliance of Associations for Rheumatology (EULAR)/American College of Rheumatology (ACR) criteria. Methods: This population‐based cohort study included incident DM from January 1, 1995 to December 31, 2019. We manually reviewed all individuals with at least 1 code for DM or polymyositis to determine if they met EULAR/ACR criteria, subspecialty physician diagnosis, and/or Bohan and Peter criteria. We age‐ and sex‐adjusted incidence and prevalence estimates to the US non‐Hispanic White year 2000 population and estimated prevalence on January 1, 2015. Standardized mortality ratios (SMRs) with 95% confidence intervals (95% CIs) compared observed to expected mortality adjusting for age, sex, and year. Results: We identified 40 cases of verified DM, with 29 cases incident in Olmsted County from 1995 to 2019. The mean age was 57 years, 26 (90%) were female, and 12 (41%) had clinically amyopathic DM (CADM). The median follow‐up time was 8.2 years. The overall adjusted incidence of DM was 1.1 (95% CI 0.7–1.5) per 100,000 person‐years, and prevalence was 13 (95% CI 6–19) per 100,000. The SMR was significantly elevated among the myopathic DM cases (3.1 [95% CI 1.1–6.8]) but not CADM cases (1.1 [95% CI 0.2–3.3]). The positive predictive value of ≥2 DM codes was only 40 of 82 (49%). Conclusion: This population‐based study found that DM incidence and prevalence were higher than previously reported. Mortality was significantly elevated for myopathic DM but not for CADM. [ABSTRACT FROM AUTHOR]

Objective: To identify clusters of comorbidities in patients with rheumatoid arthritis (RA) using 4 methods and to compare to patients without RA. Methods: In this retrospective, population‐based study, residents of 8 Minnesota counties with prevalent RA as of January 1, 2015 were identified. Age‐, sex‐, and county‐matched non‐RA comparators were selected from the same underlying population. Diagnostic codes were retrieved for 5 years before January 1, 2015. Using 2 codes ≥30 days apart, 44 previously defined morbidities and 11 nonoverlapping chronic disease categories based on Clinical Classifications Software were defined. Unsupervised machine learning methods of interest included hierarchical clustering, factor analysis, K‐means clustering, and network analysis. Results: Two groups of 1,643 patients with and without RA (72% female; mean age 63.1 years in both groups) were studied. Clustering of comorbidities revealed strong associations among mental/behavioral comorbidities and among cardiovascular risk factors and diseases. The clusters were associated with age and sex. Differences between the 4 clustering methods were driven by comorbidities that are rare and those that were weakly associated with other comorbidities. Common comorbidities tended to group together consistently across approaches. The instability of clusters when using different random seeds or bootstrap sampling impugns the usefulness and reliability of these methods. Clusters of common comorbidities between RA and non‐RA cohorts were similar. Conclusion: Despite the higher comorbidity burden in patients with RA compared to the general population, clustering comorbidities did not identify substantial differences in comorbidity patterns between the RA and non‐RA cohorts. The instability of clustering methods suggests caution when interpreting clustering using 1 method. [ABSTRACT FROM AUTHOR]

Objective: To identify differences in multimorbidity and individual comorbidities among individuals with rheumatoid arthritis (RA), separated by race and ethnicity. Methods: This case–control study within OptumLabs Data Warehouse from 2010 to 2019 matched RA cases (defined by 2 codes plus prescription of an RA drug) to non‐RA controls 1:1 on age, sex, race and ethnicity, region, index date of RA, and insurance coverage duration. We defined multimorbidity as the presence of ≥2 or ≥5 validated comorbidities. Logistic regression models calculated adjusted odds of multimorbidity with 95% confidence intervals (95% CIs) within each race and ethnicity. Results: We identified 154,391 RA cases and 154,391 controls (mean age 59.6, 76% female). Black enrollees had the most multimorbidity ≥2/≥5 (73.1%, 34.3%); Asian enrollees had the least (52.4%, 17.3%). Adjusted odds of multimorbidity ≥2 and ≥5 in RA cases versus controls was 2.19 (95% CI 2.16–2.23) and 2.06 (95% CI 2.02–2.09), respectively. This increase was similar across race and ethnicity. However, we observed elevated occurrence of certain comorbidities by race and ethnicity versus controls (P < 0.001), including renal disease in White enrollees (4.7% versus 3.2%) and valvular heart disease in Black and White enrollees (3.2% and 2.8% versus 2.6% and 2.2%). Conclusion: Multimorbidity is a problem for all RA patients. Targeted identification of certain comorbidities by race and ethnicity may be a helpful approach to mitigate multimorbidity. [ABSTRACT FROM AUTHOR]

Nomination is a scholarly activity, not unlike writing a manuscript or grant proposal.Nomination is elevated by recognizing both recipients and nominators.A nominagraph adds a dimension to the pairwise listing of recipients and nominators on ASA/CSSA/SSSA directories. [ABSTRACT FROM AUTHOR]

Recognized limitations of fishery‐dependent data under rapidly changing management regimes have resulted in significant effort during recent years to improve the availability of fishery‐independent data in the southeastern United States. These fishery‐independent surveys target numerous species and habitats with various sampling methods, including the use of trawls, longlines, gill nets, traps, and visual surveys. Although passively fished hooked gear (e.g., longlines) are often used to assess the abundance and life history of managed reef fishes, such types of gear are often limited by the habitats they can fish effectively and are species selective. To address these shortcomings, we developed and implemented an actively fished approach to provide fishery‐independent data: the repetitive timed‐drop hooked‐gear method (RTD method). Despite the high degree of standardization applied to the RTD method, important questions remain as to whether active fishing imparts strong angler variability that may reduce the utility of survey data. Accordingly, we analyzed data from 2014 to 2018 to evaluate potential angler bias and how angler‐associated variability compares to other factors often thought to be important predictors of reef fish abundance and community structure. During this study, 962 stations were sampled, representing a variety of artificial and natural reef habitats. In total, 5,770 fish were caught, representing 92 taxa. Sampling was conducted by 103 unique anglers, including 42 commercial or charter fishers and 61 scientists. Results from both population‐ and assemblage‐level analyses found that most of the variability in the catch could be explained by hook size, habitat, water depth, and year. Angler type was rarely correlated with reef fish abundance or assemblages. Our analyses suggest that the RTD method is effective in gathering fishery‐independent abundance and life history data for reef fishes in the eastern Gulf of Mexico and that the resulting data are not strongly biased by an angler effect. [ABSTRACT FROM AUTHOR]

Objective: To identify the incidence, risk factors, and outcomes of rheumatoid arthritis–associated interstitial lung disease (RA‐ILD) and to assess time trends in the incidence and mortality in RA‐ILD. Methods: We included adult residents of Olmsted County, Minnesota with incident RA between 1999 and 2014. Subjects were followed until death, emigration, or April 30, 2019. ILD was defined as the presence of a radiologist‐defined pattern consistent with ILD on chest computed tomography (CT). When chest CT was absent, the combination of chest radiograph abnormalities compatible with ILD and restrictive pattern on pulmonary function testing was considered consistent with ILD. Potential risk factors included age, sex, smoking, obesity, seropositivity, extraarticular manifestations (EAMs), and medications. For survival analysis, we matched RA‐ILD patients to RA–non‐ILD comparators. The frequency and mortality from clinician‐diagnosed RA‐ILD from 1999 to 2014 was compared against a cohort from 1955 to 1994. Results: During the 1999–2014 time period, 645 individuals (70% women) had incident RA, were a median age of 55.3 years, and 53% never smoked. Twenty‐two patients had ILD before RA, and 51 (67% women) developed ILD during follow‐up. The 20‐year cumulative incidence of RA‐ILD was 15.3%. Ever‐smoking (hazard ratio [HR] 1.92), age at RA onset (HR 1.89 per 10‐year increase), and severe EAMs (HR 2.29) were associated with incident RA‐ILD. The RA‐ILD cases had higher mortality than their matched RA comparators (HR 2.42). Incidence of RA‐ILD was non‐significantly lower from 1999 to 2014 than from 1955 to1994, but mortality was improved. Conclusions: RA‐ILD occurs in nearly 1 in 6 patients with RA within 20 years and is associated with shorter survival. Lack of significant change in RA‐ILD incidence over 6 decades deserves further investigation. [ABSTRACT FROM AUTHOR]

A population pharmacokinetic (PopPK) model was previously developed for cemiplimab in patients with solid tumors, including advanced cutaneous squamous cell carcinoma (CSCC). Here, we update the existing PopPK model and characterize exposure‐response relationships using efficacy and safety data obtained in patients with recurrent or metastatic cervical cancer (R/M CC). To improve model stability and robustness of the existing PopPK model in 1062 patients, the random‐effect error model was revised, and structural covariates were removed from the base model to be tested in the covariate analysis. The updated model was used for external validation of cemiplimab pharmacokinetics (PK) in patients with R/M CC on cemiplimab monotherapy (350 mg every 3 weeks intravenously) from a phase III study (NCT03257267). Exposure‐response relationships for cemiplimab efficacy (overall survival [OS], progression‐free survival [PFS], duration of response [DOR], objective response rate [ORR]), and safety (immune‐related adverse events [irAEs]) were analyzed in 295 patients with R/M CC from the aforementioned study. The updated PopPK model showed improved stability with 94.8% successful bootstrap runs vs. 47.6% in the prior model. Cemiplimab exposure was similar across tumor types, including basal cell carcinoma, CSCC, and non‐small cell lung cancer. External validation showed the updated model adequately described cemiplimab PK in patients with R/M CC. In exposure‐response efficacy analyses, Cox proportional hazard modeling (CPHM) showed no trend between exposure and OS, Kaplan–Meier plots showed no trend between exposure and PFS or DOR, and logistic regression analyses conducted on ORR showed no exposure‐response relationship. In exposure‐response safety analyses, CPHM showed no trend between exposure and irAEs. [ABSTRACT FROM AUTHOR]

The pharmacokinetics (PKs) and exposure–efficacy of dupilumab have not been fully described for adults with atopic dermatitis (AD). Our objectives were to analyze the PKs and exposure–efficacy of dupilumab in adults with AD and compare the results of Japanese and overall populations. Adults with moderate‐to‐severe AD were randomly assigned to dupilumab (300 mg weekly [qw] or every 2 weeks [q2w], 200 mg q2w, 300 mg every 4 weeks [q4w], or 100 mg q4w) or placebo for 16 weeks in a randomized, double‐blind, placebo‐controlled, dose‐ranging phase IIb trial (NCT01859988). This analysis included 379 patients (58 Japanese). Functional dupilumab concentrations increased in a dose‐dependent manner; at lower concentrations, increases were greater than dose‐proportional because of nonlinear, target‐mediated clearance. Dupilumab pharmacokinetics were comparable in Japanese and non‐Japanese patients with similar body weights. Week 16 efficacy parameters, including Investigator's Global Assessment score 0/1, greater than or equal to 75% reduction from baseline in the Eczema Area and Severity Index (EASI), and percentage change from baseline in EASI and pruritus Numerical Rating Scale, generally increased with week 16 trough concentration; the plateau of these exposure–efficacy relationships occurred for most patients at exposures associated with the 300 mg q2w and 300 mg qw regimens. Japanese ethnicity did not remain in the population PK model as covariate with or without accounting for body weight differences. In Japanese and non‐Japanese patients, efficacy responses increased with week 16 dupilumab trough concentrations in a similar manner. Dupilumab 300 mg qw and q2w regimens were recommended for further evaluation in larger phase III studies. [ABSTRACT FROM AUTHOR]

Distributed acoustic sensing (DAS) systems are a recent technological development for seismic observations over a broad range of frequencies with a wide variety of applications. Typically, fibre‐optic cables are buried underground or cemented into well casings where the cables are well‐coupled to the ground. Quick and temporary surface deployment of cables has great potential utility in areas where rapid surveying and minimal disturbance of the subsurface are desired. However, proper mechanical coupling between the fibre and the ground is still a challenge for temporary surface deployments. Here we test four different coupling strategies for a DAS system deployed in a grassy field, including uncoupled, pinned under tension to the ground, weighted down by carpeting, and weighted down by a sandbag. We compare the DAS data to vertical component geophone data and estimated horizontal geophone data to assess the fidelity of DAS ground motion recordings. We find a completely uncoupled fibre is capable of recording seismic energy up to ∼10 m away from the source, while the pinned and weighted fibre record signals over several tens of metres. The DAS recordings compare favourably with the estimated horizontal displacement records from the multi‐channel seismic system. There is a good agreement between the phase of the signals acquired by the DAS system with that of the geophones, but there is a mismatch of up to a factor of two in the absolute amplitude at some frequencies. We perform several standard analysis techniques, including refraction and multi‐channel analysis of surface waves, on the coupled DAS data. Finally, the instrument response of the coupled DAS data to ground motions is determined using the estimated horizontal component from the multi‐channel seismic system. Surface deployments of DAS systems provide a complementary set of observations to standard vertical geophone deployments, for instance, if multi‐component geophones are not available. Also, there are some advantages in speed and ease of deployment of DAS in comparison to geophones depending on the coupling strategy used. [ABSTRACT FROM AUTHOR]

REGN‐EB3 (Inmazeb) is a cocktail of three human monoclonal antibodies approved for treatment of Ebola infection. This paper describes development of a mathematical model linking REGN‐EB3's inhibition of Ebola virus to survival in a non‐human primate (NHP) model, and translational scaling to predict survival in humans. Pharmacokinetic/pharmacodynamic data from single‐ and multiple‐dose REGN‐EB3 studies in infected rhesus macaques were incorporated. Using discrete indirect response models, the antiviral mechanism of action was used as a forcing function to drive the reversal of key Ebola disease hallmarks over time, for example, liver and kidney damage (elevated alanine [ALT] and aspartate aminotransferases [AST], blood urea nitrogen [BUN], and creatinine), and hemorrhage (decreased platelet count). A composite disease characteristic function was introduced to describe disease severity and integrated with the ordinary differential equations estimating the time course of clinical biomarkers. Model simulation results appropriately represented the concentration‐dependence of the magnitude and time course of Ebola infection (viral and pathophysiological), including time course of viral load, ALT and AST elevations, platelet count, creatinine, and BUN. The model estimated the observed survival rate in rhesus macaques and the dose of REGN‐EB3 required for saturation of the pharmacodynamic effects of viral inhibition, reversal of Ebola pathophysiology, and survival. The model also predicted survival in clinical trials with appropriate scaling to humans. This mathematical investigation demonstrates that drug‐disease modeling can be an important translational tool to integrate preclinical data from an NHP model recapitulating disease progression to guide future translation of preclinical data to clinical study design. [ABSTRACT FROM AUTHOR]

Assessing the persistence of chemicals in the environment is a key element in existing regulatory frameworks to protect human health and ecosystems. Persistence in the environment depends on many fate processes, including abiotic and biotic transformations and physical partitioning, which depend on substances' physicochemical properties and environmental conditions. A main challenge in persistence assessment is that existing frameworks rely on simplistic and reductionist evaluation schemes that may lead substances to be falsely assessed as persistent or the other way around—to be falsely assessed as nonpersistent. Those evaluation schemes typically assess persistence against degradation half‐lives determined in single‐compartment simulation tests or against degradation levels measured in stringent screening tests. Most of the available test methods, however, do not apply to all types of substances, especially substances that are poorly soluble, complex in composition, highly sorptive, or volatile. In addition, the currently applied half‐life criteria are derived mainly from a few legacy persistent organic pollutants, which do not represent the large diversity of substances entering the environment. Persistence assessment would undoubtedly benefit from the development of more flexible and holistic evaluation schemes including new concepts and methods. A weight‐of‐evidence (WoE) approach incorporating multiple influencing factors is needed to account for chemical fate and transformation in the whole environment so as to assess overall persistence. The present paper's aim is to begin to develop an integrated assessment framework that combines multimedia approaches to organize and interpret data using a clear WoE approach to allow for a more consistent, transparent, and thorough assessment of persistence. Integr Environ Assess Manag 2022;18:868–887. © 2021 ExxonMobil Biomedical Sciences, Inc. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC). Key Points: Weight of Evidence (WoE) is needed to utilize different standard and non‐standard data types.A WoE framework is presented to organize the comparisons and make use of all available data.Overall persistence (Pov) supports holistic assessments that account for emission patterns and physicochemical properties of a substance.Combined WoE and Pov frameworks will support improved persistence assessments. [ABSTRACT FROM AUTHOR]

Objective: To test the ability of machine learning (ML) approaches with clinical and genomic biomarkers to predict methotrexate treatment response in patients with early rheumatoid arthritis (RA). Methods: Demographic, clinical, and genomic data from 643 patients of European ancestry with early RA (mean age 54 years; 70% female) subdivided into a training (n = 336) and validation cohort (n = 307) were used. The genomic data comprised 160 single‐nucleotide polymorphisms (SNPs) previously associated with RA or methotrexate metabolism. Response to methotrexate monotherapy was defined as good or moderate by the European Alliance of Associations for Rheumatology (EULAR) response criteria at the 3‐month follow‐up. Supervised ML methods were trained with 5 repeats and 10‐fold cross‐validation using the training cohort. Prediction performance was validated in the independent validation cohort. Results: Supervised ML methods combining age, sex, smoking, rheumatoid factor, baseline Disease Activity Score in 28 joints (DAS28) scores and 160 SNPs predicted EULAR response at 3 months with the area under the receiver operating curve of 0.84 (P = 0.05) in the training cohort and achieved a prediction accuracy of 76% (P = 0.05) in the validation cohort (sensitivity 72%, specificity 77%). Intergenic SNPs rs12446816, rs13385025, rs113798271, and ATIC (rs2372536) had variable importance above 60.0 and along with baseline DAS28 scores were among the top predictors of methotrexate response. Conclusion: Pharmacogenomic biomarkers combined with baseline DAS28 scores can be useful in predicting response to methotrexate in patients with early RA. Applying ML to predict treatment response holds promise for guiding effective RA treatment choices, including timely escalation of RA therapies. [ABSTRACT FROM AUTHOR]

Patients with moderate to severe allergic rhinitis may benefit from subcutaneous immunotherapy (SCIT), despite the risk of systemic allergic reaction. Dupilumab is a fully human monoclonal antibody that blocks the shared receptor component for interleukin‐4 and interleukin‐13, key drivers of the type 2 inflammation seen in allergic rhinitis, thereby inhibiting their signaling. In the LIBERTY Grass AID trial (NCT03558997), 16 weeks of treatment with 300 mg of dupilumab every 2 weeks plus timothy grass (TG) SCIT did not reduce TG allergen challenge nasal symptom scores compared with SCIT only but did improve tolerability of SCIT up‐titration in patients with a history of grass pollen–induced seasonal allergic rhinitis. Here, we present the pharmacokinetics of functional serum dupilumab and concentration‐response relationships in 52 patients enrolled in this trial. Functional dupilumab concentrations and concentrations of TG‐specific IgE and IgG4 were assessed in blood samples collected from dupilumab‐only and SCIT + dupilumab–treated groups. Mean functional dupilumab concentrations were similar in both groups and reached a steady state of ≈70–80 mg/L at week 5. One week after the end of treatment, TG‐specific IgG4 concentrations were increased in the SCIT + dupilumab group, but not in the dupilumab‐only group, over the range of dupilumab concentrations evaluated, whereas no changes were seen for TG‐specific IgE concentrations. This study demonstrates that SCIT does not alter functional concentrations of serum dupilumab, and the impact of SCIT on TG‐specific immunoglobulins is not affected by functional dupilumab concentrations over the range studied, indicating that maximum response was achieved in all patients. [ABSTRACT FROM AUTHOR]

Dupilumab, a human monoclonal antibody against interleukin‐4 receptor alpha, has demonstrated efficacy and an acceptable safety profile in adult and pediatric patients with moderate‐to‐severe atopic dermatitis (AD) and other type 2 inflammatory diseases. Dupilumab is available in 200‐ and 300‐mg strengths as a prefilled syringe with a needle shield (PFS‐S), and more recently as an autoinjector (AI) device. This study was designed to assess the pharmacokinetic (PK) comparability of a single subcutaneous (SC) dose of dupilumab 200 mg, delivered by 2 different devices, AI (test) versus PFS‐S (reference). A total of 130 healthy male and female participants were enrolled in this phase 1 parallel design study, with 128 evaluable for PK. Following dupilumab 200‐mg SC injection, dupilumab exposure in serum was similar for both AI and PFS‐S. The geometric mean ratios of PK parameters with 90% confidence intervals were 1.08 (0.97‐1.21) for maximum serum concentration (Cmax) and 1.11 (0.96‐1.28) for area under the serum concentration–time curve until the last quantifiable concentration (AUClast). Dupilumab administration by both devices was well tolerated, and there were no serious adverse events, or severe treatment‐emergent adverse events experienced during the study. Overall, exposure to dupilumab 200 mg was comparable when administered via the AI or PFS‐S devices in healthy male and female study participants. [ABSTRACT FROM AUTHOR]

Sensory features (i.e., atypical responses to sensory stimuli) are included in the current diagnostic criteria for autism spectrum disorder. Yet, large population‐based studies have not examined these features. This study aimed to determine the prevalence of sensory features among autistic children, and examine associations between sensory features, demographics, and co‐occurring problems in other areas. Analysis for this study included a sample comprised of 25,627 four‐ or eight‐year‐old autistic children identified through the multistate Autism and Developmental Disabilities Monitoring Network (2006–2014). We calculated the prevalence of sensory features and applied multilevel logistic regression modeling. The majority (74%; 95% confidence interval: 73.5%–74.5%) of the children studied had documented sensory features. In a multivariable model, children who were male and those whose mothers had more years of education had higher odds of documented sensory features. Children from several racial and ethnic minority groups had lower odds of documented sensory features than White, non‐Hispanic children. Cognitive problems were not significantly related to sensory features. Problems related to adaptive behavior, emotional states, aggression, attention, fear, motor development, eating, and sleeping were associated with higher odds of having documented sensory features. Results from a large, population‐based sample indicate a high prevalence of sensory features in autistic children, as well as relationships between sensory features and co‐occurring problems. This study also pointed to potential disparities in the identification of sensory features, which should be examined in future research. Disparities should also be considered clinically to avoid reduced access to supports for sensory features and related functional problems. Lay Summary: In a large, population‐based sample of 25,627 autistic children, 74% had documented differences in how they respond to sensation. We also identified significant associations of sensory features with adaptive behavior and problems in other domains. Sensory features were less common among girls, children of color, and children of mothers with fewer years of education, suggesting potential disparities in identification. [ABSTRACT FROM AUTHOR]

Odronextamab is a fully‐human IgG4‐based CD20xCD3 bispecific antibody that binds to CD3 on T cells and CD20 on B cells, triggering T‐cell‐mediated cytotoxicity independent of T‐cell‐receptor recognition. Adequate safety, tolerability, and encouraging durable complete responses have been observed in an ongoing first‐in‐human (FIH) study of odronextamab in patients with relapsed/refractory (R/R) B‐cell non‐Hodgkin lymphoma (B‐NHL; NCT02290951). We retrospectively evaluated the pharmacokinetic, pharmacodynamic, and antitumor characteristics of odronextamab in a series of in vitro/in vivo preclinical experiments, to assess their translational value to inform dose escalation for the FIH study. Half‐maximal effective concentration values from in vitro cytokine release assays (range: 0.05–0.08 mg/L) provided a reasonable estimate of odronextamab concentrations in patients associated with cytokine release at a 0.5 mg dose (maximum serum concentration: 0.081 mg/L) on week 1/day 1, which could therefore be used to determine the week 1 clinical dose. Odronextamab concentrations resulting in 100% inhibition of tumor growth in a Raji xenograft tumor mouse model (1–10 mg/L) were useful to predict efficacious concentrations in patients and inform dose‐escalation strategy. Although predicted human pharmacokinetic parameters derived from monkey data overestimated projected odronextamab exposure, they provided a conservative estimate for FIH starting doses. With step‐up dosing, the highest‐tested weekly odronextamab dose in patients (320 mg) exceeded the 1 mg/kg single dose in monkeys without step‐up dosing. In conclusion, combination of odronextamab in vitro cytokine data, efficacious concentration data from mouse tumor models, and pharmacokinetic evaluations in monkeys has translational value to inform odronextamab FIH study design in patients with R/R B‐NHL. [ABSTRACT FROM AUTHOR]

Access to the cyclic depsipeptide FR900359 (FR), a selective Gq/11 protein inhibitor of high pharmacological interest and a potential lead molecule for targeted therapy of cancers with oncogenic GNAQ or GNA11 mutations (encoding Gq and G11 respectively), has been challenging ever since its initial discovery more than three decades ago. The recent discovery of Chromobacterium vaccinii as a cultivable FR producer enables the development of approaches leading to a high‐yielding, scalable and sustainable biotechnological process for production of FR, thereby removing this bottleneck. Here we characterize different promoters in exchange of the native promoter of the FR assembly line, resulting in an overexpression mutant with significantly increased production of FR. Thereby, the isolation and structure elucidation of novel FR analogs of low abundance is enabled. Further, we explore the antiproliferative activities of fifteen chromodepsins against uveal melanoma cell lines harboring Gq/11 mutations and characterize the major metabolite of FR formed in plasma. [ABSTRACT FROM AUTHOR]

Itepekimab is a monoclonal antibody that targets interleukin (IL‐33) and has been shown to reduce airway inflammation and associated tissue damage in preclinical studies. We assessed the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamic profiles of single‐ascending and multiple‐ascending doses of itepekimab in two randomized, double‐blind, placebo‐controlled phase I studies. Healthy adults (N = 40) were randomized to the single‐dose study and patients with moderate asthma (N = 23) to the multiple‐dose study. Itepekimab was administered intravenously (0.3, 1, 3, or 10 mg/kg infusion) or subcutaneously (150 mg) in the single‐dose study and subcutaneously (75 or 150 mg weekly for 4 weeks) in the multiple‐dose study. Itepekimab exhibited linear PKs across studies and dose‐proportional increases in mean maximum concentration in serum and area under the concentration–time curve following single intravenous or multiple subcutaneous doses. Itepekimab demonstrated mean subcutaneous bioavailability of 59–73% and a long terminal half‐life (30.0–31.6 days). IL‐33 concentrations in most healthy participants and patients with asthma were undetectable at baseline. Following administration of itepekimab in both studies, total IL‐33 concentrations increased and blood eosinophils decreased, both with durable effect. Itepekimab was well‐tolerated in both studies with no detection of treatment‐emergent anti‐drug antibody responses. [ABSTRACT FROM AUTHOR]

Motivation: The public needs to be better informed on the reasons for providing aid, especially that which supports the Sustainable Development Goals. How aid is framed by donors directly affects levels of public support. Purpose: The article investigates support for aid among English‐speaking Canadians, and how this varies by the framing of aid spending, socioeconomic markers, personal values and political engagement. Approach and methods: Statistical analysis is undertaken of data from a representative survey of English‐speaking Canadians on their knowledge and attitudes with respect to aid to developing countries. A particular focus of the analysis is the influence of the framing of aid spending on public support for aid spending, while controlling for the influence of socioeconomic factors. Findings: Support for increased spending rises when spending is framed relative to the size of the economy, whether in dollar or percentage terms, rather than when framed relative to government taxation or spending. Providing information on the current level of aid spending also raises support for increased aid spending. Overall, when informed about the level of aid spending, most respondents support maintaining or increasing aid. Views on aid vary little by age, education and other socioeconomic markers. People's values, however, did affect support for aid. Respondents who believe in "Canada first" were considerably more likely to support aid cuts than others. Those who see kindness as part of Canadian identity tend to favour aid, while those who see economic prosperity as part of national identity tend to want aid cuts. While voting intention does not affect views on aid, respondents who have been either politically active or involved in collective action on media/social media are a little more likely to favour increased aid. Policy implications: The findings confirm the importance of the framing of aid spending for designing and implementing programmes to inform, engage and elicit support from the public. Given how values influence public support for aid, engagement needs to be tailored to different target audiences. [ABSTRACT FROM AUTHOR]

Objective: To identify longitudinal predictors of discordance between patients with rheumatoid arthritis (RA) and their health care providers, where patient global assessment of disease activity is substantially higher than provider global assessment.Methods: This retrospective case-control study included 102 cases with positive discordance (i.e., ≥25 mm between patient and provider global assessments) and 102 controls without discordance who were matched for age, sex, RA duration, and Clinical Disease Activity Index (CDAI) score. Data were collected at the baseline visit (date of diagnosis or earliest available visit), the index visit (participation in a previous cross-sectional study), and at up to 11 additional visits before the index visit. Data included patient characteristics, disease activity measures, Disease Activity Score in 28 joints (3-variable) using the C-reactive protein level (DAS28-CRP), and medications. Data were analyzed by using linear and logistic regression models with smoothing splines for nonlinear trends.Results: Overall, the mean age was 63 years, 75% of patients were female, and the mean RA duration was 10 years. Compared with controls, cases had higher rates of discordant visits during the 4 years before the index visit, and they had a higher CDAI score and DAS28-CRP earlier in the disease course. Cases more frequently had antinuclear antibodies, nonerosive disease, prior depression, or prior use of antidepressants or fibromyalgia medications. Disease-modifying medication use was not different between cases and controls.Conclusion: The findings inform new hypotheses about the relationships of disease activity and antinuclear antibodies to the later occurrence of positive discordance among patients with RA. [ABSTRACT FROM AUTHOR]

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Objective: Treat‐to‐target (T2T) and shared decision‐making are valued features of current guidelines for rheumatoid arthritis (RA) management. Although T2T has demonstrated value for improving RA outcomes, implementation remains inconsistent and lacks standardization and procedures for including patient input. We sought to better understand the impact of shared decisions on T2T and how treatment goal discussions between patients and providers impact RA treatment improvement and satisfaction. Methods: An anonymous, web‐based questionnaire was presented to United States residents aged 18 years or older with a self‐reported diagnosis of RA by a medical professional with 28 questions regarding socio‐demographics, RA disease activity (DA), diagnosis, treatments, outcomes, and goals. Analyses included descriptive statistics with χ2 and rank sum tests for comparisons. Results: The questionnaire was completed by 907 people (mean age of 58 years; mean 11 years since diagnosis; 90% female). The majority (571; 63%) did not discuss RA treatment goals with providers. Patients engaging in treatment goal discussions with their providers were three times more likely to be satisfied with their treatment plans. Patients discussing treatment goals with their providers were more likely to have improved DA levels and 68% more likely to reach remission. Conclusion: A majority of patients with RA report having no treatment goal discussion with their providers; however, these discussions are associated with greater DA improvement and treatment satisfaction. Further research should seek understanding of how shared treatment goal discussions relate to successful RA management and explore the development of practical tools to implement them in regular clinic practice as part of a T2T regimen. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Previous work suggests supplementation with omega‐3 polyunsaturated fatty acids (PUFAs) may improve mood symptoms in bipolar disorder (BD) although findings remain unclear. In this study, we assess the efficacy of omega‐3 PUFA administration for prophylaxis in BD using a clinical trial design over 52‐weeks (ClinicalTrials.gov Identifier: NCT04210804). METHODS: Individuals with BD (n = 80) were randomised to receive placebo (n = 40) or 1 g eicosapentaenoic acid (EPA) plus 1 g docosahexaenoic acid (DHA; n = 40) adjunctively for 52‐weeks. The primary outcome measure comprised the number of mood episode relapses including hospital admissions and medication changes experienced. Secondary outcome measures included time to first mood episode relapse and change in psychometric measures of depression and elation (Hamilton Depression Rating Scale and Young Mania Rating Scale). RESULTS: No significant differences in the number of mood episode relapses (U = 490.00, p = 0.14) or the number of individuals requiring admission to hospital (χ2 = 0.67, p = 0.41) or medication adjustment in the omega‐3 PUFA compared to the placebo group were noted. Time to relapse was not significantly different between groups (Log Rank χ2 = 0.41, p = 0.52). Change in Young Manic Rating Scale (F(3.12, 152.86) = 2.71, p = 0.05) was significantly different between treatment groups over 12‐months, with scores at 9‐months and 12‐months significantly lower than those at 3‐months in the omega‐3 group and not in the placebo group. Change in Hamilton Depression Rating Scale, Global Clinical Impression and Global Assessment of Functioning were not different between groups. CONCLUSIONS: Despite a minor reduction in hypomania scores in the omega‐3 PUFA group compared to placebo, we find little evidence that the supplementation of omega‐3‐PUFAs exhibits prophylactic benefit in BD. [ABSTRACT FROM AUTHOR]

Dupilumab demonstrated efficacy with an acceptable safety profile in two randomized, double‐blind, placebo‐controlled, parallel‐group, phase III trials in adolescents (12–17 years; LIBERTY AD ADOL) and children (6–11 years; LIBERTY AD PEDS) with atopic dermatitis (AD) treated for 16 weeks. Here, we present the pharmacokinetic profiles and exposure‐response (E‐R) relationships of dupilumab that guided the posology in these populations. A total of 251 adolescent patients with moderate‐to‐severe AD were randomized to subcutaneous dupilumab monotherapy every 2 weeks (q2w; 200 mg q2w, baseline weight < 60 kg; 300 mg q2w, ≥ 60 kg), dupilumab 300 mg every 4 weeks (q4w; non‐weight tiered), or placebo; 367 children with severe AD were randomized to dupilumab q2w (100 mg q2w, baseline weight < 30 kg; 200 mg q2w, ≥ 30 kg), dupilumab 300 mg q4w, or placebo. Children received concomitant topical corticosteroids in addition to dupilumab, and loading doses were administered at the start of therapy. Mean dupilumab trough concentrations at week 16 for weight subcategories in each dosing regimen were compared with adult exposures for the approved dupilumab 300 mg q2w regimen. Positive E‐R relationships were demonstrated between dupilumab trough concentrations and AD outcome measures across patient populations and regimens; no relationship was observed with treatment‐emergent conjunctivitis. Based on these analyses, a weight‐tiered posology was proposed for adolescents (200/300 mg q2w in patients 30–< 60 kg/≥ 60 kg) and children (300 mg q4w in patients 15–< 30 kg, 200 mg q2w in patients 30–< 60 kg) with moderate‐to‐severe AD. [ABSTRACT FROM AUTHOR]

Population pharmacokinetic (PK) base and covariate analyses were conducted using data from adolescents with moderate‐to‐severe atopic dermatitis (AD) and children ≥6 to <12 years of age with severe AD. Two phase 3 studies were analyzed (165 adolescents and 241 children on active treatment). A 2‐compartment model with linear and Michaelis‐Menten elimination and 3 transit compartments describing lag time in absorption was utilized. Weight, albumin, body mass index, and Eczema Area and Severity Index score were statistically significant covariates in at least 1 of the age populations. Only body weight had a consequential effect on central volume. Although an absorption rate and target‐mediated clearance somewhat decreased with age, no dose adjustment was needed in addition to the adjustment for weight already implemented in the phase 3 studies. Otherwise, population PK parameters and covariates were similar across the 2 pediatric subpopulations and in adults. No allometric changes in elimination rate and beta half‐life were observed with weight. Parameterization of models in terms of rates was a useful alternative to parameterization in terms of clearances, allowing for an absence of repeated covariates and preventing overparameterization. The model adequately described dupilumab pharmacokinetics in the pediatric populations. [ABSTRACT FROM AUTHOR]

Evinacumab, an angiopoietin‐like protein 3 (ANGPTL3) inhibitor, has been shown to significantly reduce low‐density lipoprotein cholesterol (LDL‐C) in patients with homozygous familial hypercholesterolemia (HoFH). This work characterized the population pharmacokinetics (PK)/pharmacodynamics (PD) of evinacumab using pooled phase III clinical data. Total evinacumab PK were described by a two‐compartment model with combined linear and saturable (Michaelis–Menten) elimination, and first‐order absorption. At clinically relevant concentrations, plasma drug concentrations were mainly influenced by the linear clearance pathway. Although the maximum target‐mediated rate of elimination (Vmax) parameter for the saturable pathway was found to be positively related to baseline ANGPLTL3, variability in body weight contributed more to the variability in evinacumab exposure than variability in ANGPTL3. An effect of HoFH versus healthy volunteers on Vmax was also identified. Weight‐based dosing regimens resulted in consistent evinacumab exposure across weight ranges. An indirect exposure–response model adequately described the relationship between evinacumab and LDL‐C, where drug concentration is assumed to inhibit LDL‐C production. The final population PK/PD model included two nonclinically significant covariates (race and baseline body weight) on the maximum drug‐induced inhibitory effect (Imax) and one (baseline LDL‐C) on the evinacumab concentration inducing 50% of Imax (IC50). A smaller IC50 was observed in patients with higher baseline LDL‐C, suggesting greater sensitivity to treatment. Population exposure–response analysis permitted estimation of derived PD parameters and individual LDL‐C levels over time for patients with HoFH. The model accurately predicted the proportion of patients with HoFH achieving prespecified LDL‐C goals with evinacumab during the ELIPSE HoFH study, further supporting a dosing strategy. [ABSTRACT FROM AUTHOR]

A model to quantitatively characterize the effect of evinacumab, an investigational monoclonal antibody against angiopoietin‐like protein 3 (ANGPTL3) on lipid trafficking is needed. A quantitative systems pharmacology (QSP) approach was developed to predict the transient responses of different triglyceride (TG)‐rich lipoprotein particles in response to evinacumab administration. A previously published hepatic lipid model was modified to address specific queries relevant to the mechanism of evinacumab and its effect on lipid metabolism. Modifications included the addition of intermediate‐density lipoprotein and low‐density lipoprotein compartments to address the modulation of lipoprotein lipase (LPL) activity by evinacumab, ANGPTL3 biosynthesis and clearance, and a target‐mediated drug disposition model. A sensitivity analysis guided the creation of virtual patients (VPs). The drug‐free QSP model was found to agree well with clinical data published with the initial hepatic liver model over simulations ranging from 20 to 365 days in duration. The QSP model, including the interaction between LPL and ANGPTL3, was validated against clinical data for total evinacumab, total ANGPTL3, and TG concentrations as well as inhibition of apolipoprotein CIII. Free ANGPTL3 concentration and LPL activity were also modeled. In total, seven VPs were created; the lipid levels of the VPs were found to match the range of responses observed in evinacumab clinical trial data. The QSP model results agreed with clinical data for various subjects and was shown to characterize known TG physiology and drug effects in a range of patient populations with varying levels of TGs, enabling hypothesis testing of evinacumab effects on lipid metabolism. [ABSTRACT FROM AUTHOR]

REGN1908‐1909, a 1:1 cocktail of two fully human IgG4 monoclonal antibodies (mAbs), REGN1908 and REGN1909, is being evaluated for treatment of cat allergy. Both REGN1908 and REGN1909 bind to the dominant cat allergen, Fel d 1. Adults with cat allergy confirmed by skin prick test (SPT) were randomized to single subcutaneous administration of placebo (n = 6) or REGN1908‐1909 at doses of 150 (n = 6), 300 (n = 6), or 600 mg (n = 6). Blood samples were taken at prespecified time points for pharmacokinetic (PK) analysis and exploratory evaluation of biomarkers (IgE and SPT). Safety was assessed. Drug concentration‐time profiles in serum for ascending doses of REGN1908‐1909 were consistent with linear PKs. Noncompartmental analysis showed that maximum concentration (Cmax) and exposure increased proportionately with dose, with similar time to maximum concentration (Tmax) for REGN1908 and REGN1909 (6.2 to 8.2 days across doses), and a longer terminal half‐life for REGN1908 (~ 30 days) relative to REGN1909 (~ 21 days). Adverse events were not dose dependent; there were no dose‐limiting toxicities. REGN1908‐1909 is characterized by linear and dose‐proportional kinetics of the two individual mAb components. A single 600 mg dose maintains total mAb mean concentrations in serum above the target (mean of ~ 10 mg/L) for 8–12 weeks. Maintaining this mean target concentration resulted in translational pharmacodynamic effects: maximal mast cell degranulation in a passive cutaneous anaphylaxis mouse model, and maintenance of clinical efficacy measured by Total Nasal Symptom Score in a previous proof‐of‐mechanism study. [ABSTRACT FROM AUTHOR]

Objective: To determine the incidence of psoriatic arthritis (PsA) in a US population and describe trends in incidence and mortality over 5 decades. Methods: The previously identified population‐based cohort that included Olmsted County, Minnesota residents ≥18 years of age who fulfilled PsA criteria during 1970–1999 was extended to include patients with incident PsA during 2000–2017. Age‐ and sex‐specific incidence rates and point prevalence, adjusted to the 2010 US White population, were reported. Results: There were 164 incident cases of PsA in 2000–2017 (mean ± SD age 46.4 ± 12.0 years; 47% female). The overall age‐ and sex‐adjusted annual incidence of PsA per 100,000 population was 8.5 (95% confidence interval [95% CI] 7.2–9.8) and was higher in men (9.3 [95% CI 7.4–11.3]) than women (7.7 [95% CI 5.9–9.4]) in 2000–2017. Overall incidence was highest in the 40–59 years age group. The incidence rate was relatively stable during 2000–2017, with no evidence of an overall increase or an increase in men only (but a modest increase of 3% per year in women), compared to 1970–1999 when a 4%‐per‐year increase in incidence was observed. Point prevalence was 181.8 per 100,000 population (95% CI 156.5–207.1) in 2015. The percentage of women among those with PsA increased from 39% in 1970–1999 and 41% in 2000–2009 to 54% in 2010–2017 (P = 0.08). Overall survival in PsA did not differ from the general population (standardized mortality ratio 0.85 [95% CI 0.61–1.15]). Conclusion: The incidence of PsA in this predominantly White US population was stable in 2000–2017, in contrast to previous years. However, an increasing proportion of women with PsA was found in this study. [ABSTRACT FROM AUTHOR]

Perhaps the most important lesson learned from the COVID‐19 pandemic is that of preparedness. Enhanced surveillance systems for early threat detection will be crucial to maximizing response time for implementation of public health measures and mobilization of resources in containing an emerging pandemic. Recent outbreaks have been dominated by viral pathogens, with RNA respiratory viruses being the most likely to have pandemic potential. These should therefore be a preparedness priority. Tools in the areas of virology, drug discovery, clinical pharmacology, translational medicine and pharmacometrics should be considered key components in the rapid identification and development of existing and novel interventions for a pandemic response. Prioritization of therapeutics should be based on in vitro activity, likelihood of achieving effective drug concentrations at the site of action, and safety profile at the doses that will be required for clinical efficacy. Deployment strategies must be tailored to the epidemiology of the disease, and the adequacy of the response should be re‐evaluated in view of evolving epidemiological factors. An interdisciplinary framework integrating drug pharmacology, viral kinetics, epidemiology and health economics could help optimize the deployment strategy by improving decision‐making around who to treat, when to treat, and with what type of intervention for optimal outcomes. Lastly, while an effective vaccine will ultimately end a pandemic, antiviral drug intervention guided by clinical pharmacology principles will continue to play a critical role in any pandemic response. [ABSTRACT FROM AUTHOR]

A population pharmacokinetic model was developed using data from healthy subjects and patients with moderate‐to‐severe asthma receiving intravenous or subcutaneous dupilumab doses. A total of nine phase I to phase III studies were pooled (202 healthy subjects and 1912 patients with asthma including 68 adolescents) in the model development. The best model was a two‐compartment model with parallel linear and nonlinear Michaelis–Menten elimination with first order absorption. The PK parameter estimates were distribution volume of central compartment 2.76 L, linear elimination rate 0.0418 1/day, and subcutaneous bioavailability 60.9%. Pharmacokinetics (PK) properties of dupilumab in patients with asthma were determined to be comparable to those of healthy subjects and patients with atopic dermatitis. Only body weight exerts a notable effect explaining between‐subject variability in dupilumab PK, but dose adjustment for weight is not warranted based on results from clinical studies. There is no PK difference between adolescent and adult patients with asthma after correction for body weight. [ABSTRACT FROM AUTHOR]

As the consequences of climate change become better understood, there is growing agreement among development practitioners and academics on the need for mainstreaming climate adaptation into social protection. This review paper assesses the progress in mainstreaming efforts, revealing that there has been considerable progress made to date. However, a number of critical issues relating to the challenges of such mainstreaming in the context of developing countries and the conceptual framework needed to assess the outcomes of such developmental programmes are yet to be addressed. These issues are examined in this paper. [ABSTRACT FROM AUTHOR]

Cardiac response to prolonged, intense exercise induces phenotypic and physiologic adaptive changes that improve myocardial ability to meet oxygen demands. These adaptations, termed "athletes' heart," have been extensively studied. The importance of this entity arises from the increasing numbers of athletes as well as the drive for physical fitness in the general population leading to adaptive cardiac changes that need to be differentiated from life‐threatening cardiovascular diseases. A number of pathologic entities may share phenotypic changes with the athletes' heart such as hypertrophic cardiomyopathy, dilated cardiomyopathy, Marfan's syndrome, and arrhythmogenic right ventricular cardiomyopathy. Cardiologists need to be cognizant of these overlapping findings to appropriately diagnose diseases and prevent catastrophic outcomes especially in young and healthy individuals who may not show any symptoms until they engage in intense exercise. It is equally important to recognize and distinguish normal, exercise‐adaptive cardiac changes to provide accurate screening and guidance to young elite athletes. Echocardiography is a valuable modality that allows comprehensive initial evaluation of cardiac structures, function, and response to exercise. Several different echocardiographic techniques including M‐Mode, 2D echo, Doppler, tissue Doppler, color tissue Doppler, and speckle tracking have been used in the evaluation of cardiac adaptation to exercise. The following discussion is a review of literature that has expanded our knowledge of the athlete's heart. [ABSTRACT FROM AUTHOR]

Aim: A growing number of studies suggest a role of neuroinflammation and oxidative stress in the pathophysiology of psychosis. Sulforaphane (SFN), a natural compound extracted from cruciferous vegetables, has shown anti‐inflammatory and anti‐oxidative effects which imply a potential effect on decreasing the risk of psychosis. However, there is no study testing the efficacy of SFN for this purpose. It's necessary to evaluate its efficacy on individuals at clinical high risk (CHR) for psychosis. Methods: This is a randomized, double‐blind, placebo‐controlled, multi‐centre trial. A total of 300 CHR subjects will be identified in the course of face‐to‐face interviews using the Structured Interview for Prodromal Syndromes. All participants will be randomly allocated to SFN group (n = 150) or placebo group (n = 150). The study duration includes an intervention for 52 consecutive weeks, and additional 1‐year follow‐up. Results: The primary outcome is 2‐year conversion rate of psychosis. Secondary outcomes include 1‐year conversion rate of psychosis, the severity and duration of prodromal symptoms, predictive risk of psychosis conversion, neurocognitive functioning and peripheral blood biomarkers of inflammation, oxidative stress and metabolism. Safety monitoring will be performed using scales for side effect, serious adverse events recording, and laboratory tests. Conclusion: This trial is expected to clarify the efficacy of SFN in improving prodromal symptoms, and its role in decreasing the risk and conversion rate of psychosis among CHR subjects. The results will also provide solid evidence about the efficacy and safety of SFN in CHR population. Potential challenges and their solutions in performing the present trial are discussed. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to describe differences in the clinical course of patients with rheumatoid arthritis (RA) who are antinuclear antibody (ANA)–positive compared with those who are ANA‐negative. Methods: This was a retrospective population‐based cohort study of residents in Olmsted County, Minnesota, who first fulfilled 1987 American College of Rheumatology criteria for RA in 2009‐2014. Data were collected on first documentation of joint swelling. Data on rheumatoid factor or anti‐cyclic citrullinated peptide antibody testing and the ANA level were also collected. Comparisons between groups were performed by using χ2 and rank sum tests. Results: In this cohort, 64% of patients were tested for ANA within ±90 days of RA criteria fulfillment. In the161 patients with ANA testing, 25% were ANA‐positive. Patients who were ANA‐positive were younger, female, and less likely to be current smokers. ANA positivity did not differ between patients with RA who were seropositive and seronegative. In seropositive patients who were ANA‐positive, there was an increased time to fulfillment of RA criteria, increased time to treatment with disease‐modifying antirheumatic drugs (DMARDs), and increased likelihood of being treated with hydroxychloroquine as opposed to methotrexate. Other outcomes, including disease activity and mortality, did not differ significantly between groups. Conclusion: In patients with RA, important differences exist between those who are ANA‐positive and ANA‐negative in terms of time to fulfillment of RA criteria and time to DMARD initiation as well as choice of initial pharmacotherapy. These findings could indicate a difference in clinical presentation or perception of patients with RA who are ANA‐positive. Further research is needed to study the long‐term outcomes of patients with RA who are ANA‐positive. [ABSTRACT FROM AUTHOR]