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Proteases are signaling molecules that specifically control cellular functions by cleaving protease-activated receptors (PARs). The four known PARs are members of the large family of G protein-coupled receptors. These transmembrane receptors control most physiological and pathological processes and are the target of a large proportion of therapeutic drugs. Signaling proteases include enzymes from the circulation; from immune, inflammatory epithelial, and cancer cells; as well as from commensal and pathogenic bacteria. Advances in our understanding of the structure and function of PARs provide insights into how diverse proteases activate these receptors to regulate physiological and pathological processes in most tissues and organ systems. The realization that proteases and PARs are key mediators of disease, coupled with advances in understanding the atomic level structure of PARs and their mechanisms of signaling in subcellular microdomains, has spurred the development of antagonists, some of which have advanced to the clinic. Herein we review the discovery, structure, and function of this receptor system, highlight the contribution of PARs to homeostatic control, and discuss the potential of PAR antagonists for the treatment of major diseases.

There is a paucity of data on the safety of cabozantinib use in combination with radiotherapy.To report the practice patterns, safety, and efficacy of cabozantinib with radiotherapy in metastatic renal cell carcinoma (mRCC).An international multicenter retrospective study was conducted. Patients with mRCC treated with cabozantinib at any line of therapy and who received radiotherapy between 30 d prior to the start date of cabozantinib and 30 d following discontinuation of cabozantinib, from 2014 to 2020, were included. Concurrent use was defined as the use of cabozantinib on radiotherapy treatment days during any course of radiotherapy.The primary outcomes of interest were the rate of grade ≥3 adverse events (AEs) occurring within 90 d of receipt of radiotherapy. Secondary outcomes included hospitalization rate and patterns of cabozantinib and radiotherapy use. Baseline characteristics and AEs were presented descriptively.A total of 127 consecutive patients were included. Most patients had clear cell histology (88%), had International Metastatic Renal Cell Carcinoma Database Consortium intermediate-risk disease (57%), and had received at least one prior line of therapy (93%). Of 127 patients, 67 (53%) received concurrent cabozantinib with radiotherapy, while the remaining held cabozantinib on radiotherapy days. Overall, grade 3-4 AEs occurred in 6.3% (n = 8/127) of patients. No grade 5 events were observed. In patients treated with conventional palliative radiotherapy (n = 88), the rate of grade 3-4 AEs in those who had concurrent versus those who had nonconcurrent cabozantinib was 6.3% (n = 3/48) versus 5.0% (n = 2/40). No patient was hospitalized due to radiotherapy-related toxicity. In patients treated with stereotactic ablative body radiotherapy (SABR; n = 50), the rate of grade 3-4 AEs in those who had concurrent versus those who had nonconcurrent cabozantinib was 3.6% (n = 1/28) versus 9.1% (n = 2/22). One patient in the nonconcurrent group was hospitalized due to muscle weakness suspected to be related to associated vasogenic edema 19 d after SABR for multiple brain metastases.In this real-world study of patients with mRCC treated with cabozantinib, 53% of patients received radiotherapy concurrently, with few grade 3-4 AEs reported within 90 d of receiving radiotherapy. The use of radiotherapy and cabozantinib requires a risk-benefit assessment of patient and disease characteristics to optimize therapy regimens.Our study reports the real-world experience of using radiotherapy in patients receiving cabozantinib for metastatic kidney cancer. Over half of the patients continued taking cabozantinib while receiving radiotherapy, and few patients developed serious side effects. The combined use of radiotherapy and cabozantinib requires a careful risk-benefit assessment to achieve optimal treatment outcomes.

Background: Women with breast cancer account for the largest cohort (23%) of over 18 million cancer survivors in the United States. Of the nearly 4 million breast cancer survivors, many, including individuals with metastatic breast cancer, will require lifelong treatment for chronic conditions. As part of a multi-site study including diverse tumor types, breast cancer survivors are being recruited to explore the feasibility and outcomes of a digital health coaching (DHC) program following the completion of primary therapy to support self-management of symptoms and general wellness. Trial design: A randomized-wait list control design will evaluate outcomes related to engagement in a DHC program following completion of primary therapy. Participants will be enrolled in a 6-month DHC program delivering evidence-based content via weekly calls, text, and email, in addition to usual support from their respective healthcare teams. The intervention group will receive coaching upon enrollment. The control group will receive coaching after a 6-month monitoring period. Twelve months of longitudinal clinical, patient-reported outcomes, activity tracking (via Fitbit), and microbiome data will be collected from both groups. Eligibility criteria: The breast cancer cohort will consist of individuals with both localized and metastatic disease within 1 year of completion of primary therapy, defined as treatment of curative intent, first-line or later, from which the individual is advancing to active surveillance or follow-up, with or without maintenance therapy. All study participants must be >18 years old, able to read and speak English, have access to mobile technology, and agree to wear and have data collected from an activity tracker. Specific aims: 1) Assess the feasibility and acceptability of a DHC program and its effect on participant health self-efficacy; 2) characterize associations between participant symptoms, physical/psychosocial well-being, and health self-management and gut microbiota changes; and 3) explore patient-generated health data outcomes among participants (patient reported and wearable biometrics outcomes). Statistical methods: Feasibility and acceptability will be assessed through descriptive statistics. Feasibility for this study is defined as a retention rate ≥70%, and acceptability is defined as ≤20% scoring “not at all helpful.” Secondary aims will be assessed using linear mixed models. Cross-cohort analysis of physical function, measured by the PROMIS Physical Function 10a, will be conducted. Assuming a power of 0.8 and significance level of .05, we will be able to detect a 2.51 difference in PROMIS score means between the control and intervention group (SD 10) with a sample of 500 total participants. Sub-group analysis will be conducted with the anticipated 250 participants in the breast cancer cohort with a focus on feasibility, acceptability, and descriptive and exploratory endpoints for this population as a whole and comparing early stage and metastatic participants. Target and present accruals: 500 individuals with diverse tumor types will be enrolled across 5 collaborating sites, of which 4 ill include individuals with breast cancer. An estimated 250 breast cancer participants (approximately 50% of the total study population), including 150 with de novo or progressive metastatic breast cancer, are planned to be recruited. To date, 1 Midwestern site has enrolled the first 7 breast cancer survivors. Two additional sites plan to enroll in July 2022, with the remaining 2 sites to begin enrollment by the end of 2022. Citation Format: Robin M. Lally, Rachael L. Schmidt, Gisele Tlusty, Elizabeth K. Arthur, Laura K. Flora, Jessica L. Krok-Schoen, Jessica T. Jones, Meagan Whisenant, Abbey Kaler, Debu Tripathy, Leorey Saligan, Marilyn Hammer, Austin Barr, Lindsey Jackson, Jennifer Loftis, Kelly J. Brassil. Breast Cancer Cohort of the Comprehensive Outcomes for After Cancer Health (COACH) Study: Study Protocol [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-06-01.

ImportanceCytokine storm due to COVID-19 can cause high morbidity and mortality and may be more common in patients with cancer treated with immunotherapy (IO) due to immune system activation.ObjectiveTo determine the association of baseline immunosuppression and/or IO-based therapies with COVID-19 severity and cytokine storm in patients with cancer.Design, Setting, and ParticipantsThis registry-based retrospective cohort study included 12 046 patients reported to the COVID-19 and Cancer Consortium (CCC19) registry from March 2020 to May 2022. The CCC19 registry is a centralized international multi-institutional registry of patients with COVID-19 with a current or past diagnosis of cancer. Records analyzed included patients with active or previous cancer who had a laboratory-confirmed infection with SARS-CoV-2 by polymerase chain reaction and/or serologic findings.ExposuresImmunosuppression due to therapy; systemic anticancer therapy (IO or non-IO).Main Outcomes and MeasuresThe primary outcome was a 5-level ordinal scale of COVID-19 severity: no complications; hospitalized without requiring oxygen; hospitalized and required oxygen; intensive care unit admission and/or mechanical ventilation; death. The secondary outcome was the occurrence of cytokine storm.ResultsThe median age of the entire cohort was 65 years (interquartile range [IQR], 54-74) years and 6359 patients were female (52.8%) and 6598 (54.8%) were non-Hispanic White. A total of 599 (5.0%) patients received IO, whereas 4327 (35.9%) received non-IO systemic anticancer therapies, and 7120 (59.1%) did not receive any antineoplastic regimen within 3 months prior to COVID-19 diagnosis. Although no difference in COVID-19 severity and cytokine storm was found in the IO group compared with the untreated group in the total cohort (adjusted odds ratio [aOR], 0.80; 95% CI, 0.56-1.13, and aOR, 0.89; 95% CI, 0.41-1.93, respectively), patients with baseline immunosuppression treated with IO (vs untreated) had worse COVID-19 severity and cytokine storm (aOR, 3.33; 95% CI, 1.38-8.01, and aOR, 4.41; 95% CI, 1.71-11.38, respectively). Patients with immunosuppression receiving non-IO therapies (vs untreated) also had worse COVID-19 severity (aOR, 1.79; 95% CI, 1.36-2.35) and cytokine storm (aOR, 2.32; 95% CI, 1.42-3.79).Conclusions and RelevanceThis cohort study found that in patients with cancer and COVID-19, administration of systemic anticancer therapies, especially IO, in the context of baseline immunosuppression was associated with severe clinical outcomes and the development of cytokine storm.Trial RegistrationClinicalTrials.gov Identifier: NCT04354701

ImportanceSex-specific differences in the commonly used cardiac biomarkers high-sensitivity cardiac troponin (hs-cTn) and N-terminal pro–brain natriuretic peptide (NT-proBNP) are apparent. There is an absence of medical literature delineating the concentration differences for these biomarkers in transgender individuals without cardiac disease.ObjectiveTo determine the distribution of hs-cTn and NT-proBNP in healthy transgender people.Design, Setting, and ParticipantsIn this cross-sectional prospective study, healthy transgender individuals prescribed testosterone or estradiol for 12 months or more were recruited from internal medicine and primary care clinics that specialize in transgender medical care between November 1, 2017, and July 1, 2018.ExposuresTestosterone or estradiol for 12 months.Main Outcomes and MeasuresConcentrations for hs-cTnI (troponin I), hs-cTnT (troponin T), and NT-proBNP were measured.ResultsTransgender people prescribed testosterone (n = 79; mean [SD] age, 28.8 [7.8] years) or estrogen (n = 93; mean [SD] age, 35.1 [11.7] years) were recruited. The concentration of hs-cTn was significantly higher in transgender men relative to transgender women. For Abbott hs-cTnI levels, the median (IQR) concentration observed in transgender men and women was 0.9 (0.6-1.7) ng/L and 0.6 (0.3-1.0) ng/L, respectively. Results were similar across 2 additional hs-cTn assays. In contrast, NT-proBNP level was higher in transgender women. The median (IQR) NT-proBNP concentration was significantly higher in transgender women ( 49 [32-86] ng/L) than in transgender men (17 [13-27] ng/L).Conclusions and RelevanceFindings of this cross-sectional study suggest that the differences in concentration for hs-cTn and NT-proBNP between transgender men and women were similar to what is observed between cisgender men and women. Sex hormones, rather than sex assigned at birth, may be a stronger driver of the observed concentration differences between healthy men and women for biomarkers of cardiac disease.

Objectives There is continuing pressure to improve the cost effectiveness of quality control (QC) for clinical laboratory testing. Risk-based approaches are promising but recent research has uncovered problems in some common methods. There is a need for improvements in risk-based methods for quality control. Methods We provide an overview of a dynamic model for assay behavior. We demonstrate the practical application of the model using simulation and compare the performance of simple Shewhart QC monitoring against Westgard rules. We also demonstrate the utility of trade-off curves for analysis of QC performance. Results Westgard rules outperform simple Shewhart control over a narrow range of the trade-off curve of false-positive and false negative risk. The risk trade-off can be visualized in terms of risk, risk vs. cost, or in terms of cost. Risk trade-off curves can be “smoothed” by log transformation. Conclusions Dynamic risk-models may provide advantages relative to static models for risk-based QC analysis.

Background Setting quality control (QC) limits involves balancing the risk of false-positive results and false-negative results. Recent approaches to QC have focused on the assessment of false-negative results. The Parvin model is the most-used model for risk analysis. The Parvin model assumes that the system makes a transition from an in-control to an out-of-control (OOC) state but makes no further transitions after moving to the OOC state. The implications of this assumption are unclear. Methods We used simulation experiments to compare the performance of QC systems based on no OOC transitions allowed (NOOCTA) vs systems where OOC transitions were allowed (OOCTA). Results The NOOCTA assumption leads to paradoxical tradeoff curves between false-positive results and false-negative results. Predictions of a false-negative result based on NOOCTA were about 10 times lower than models based on OOCTA. Conclusions The most common models for QC risk analysis underestimate false-negative results. There is a need to develop better risk-based methods for QC analysis.

Dispersal is a critical parameter for successful pest control measures as it determines the rate of movement across target control areas and influences the risk of human exposure. We used a fine-scale spatial population genomic approach to investigate the dispersal ecology and population structure of Aedes notoscriptus, an important disease transmitting mosquito at the Mornington Peninsula, Australia. We sampled and reared Ae. notoscriptus eggs at two time points from 170 traps up to 5 km apart and generated genomic data from 240 individuals. We also produced a draft genome assembly from a laboratory colony established from mosquitoes sampled near the study area. We found low genetic structure (Fst) and high coancestry throughout the study region. Using genetic data to identify close kin dyads, we found that mosquitoes had moved distances of >1 km within a generation, which is further than previously recorded. A spatial autocorrelation analysis of genetic distances indicated genetic similarity at >1 km separation, a tenfold higher distance than for a comparable population of Ae. aegypti, from Cairns, Australia. These findings point to high mobility of Ae. notoscriptus, highlighting challenges of localised intervention strategies. Further sampling within the same area 6 and 12 months after initial sampling showed that egg-counts were relatively consistent across time, and that spatial variation in egg-counts covaried with spatial variation in Wright’s neighbourhood size (NS). As NS increases linearly with population density, egg-counts may be useful for estimating relative density in Ae. notoscriptus. The results highlight the importance of acquiring species-specific data when planning control measures.

The purpose of this scoping review was to identify available sources of evidence on the epidemiology of transfusion-related acute lung injury (TRALI) and whether meta-analysis on the incidence of TRALI is feasible. TRALI is a serious complication and the second leading cause of death related to blood transfusion. Estimates of the incidence of TRALI would provide a useful benchmark for research to reduce TRALI.We searched the Medline, EMBASE, and PubMed databases for publications related to the incidence of TRALI and hemovigilance. We included all studies irrespective of language or country. Both full-text articles and conference abstracts were included. Participants of the studies must all have received a blood transfusion. Reviews and case studies were excluded.We identified 427 articles or abstracts to include for review. More than half were abstracts, and the majority were published after 2010. Reported TRALI definitions varied, but only 27.2% of studies reported any definition for TRALI. TRALI rates were reported using different denominators, such as per blood unit (54.1%), patient (34.4%), and transfusion episode (14.8%). Study populations and contexts were mostly general (75.6% and 80.3%, respectively). There was also variation in study design with most being observational (90.6%) and only 13.1% of all studies used modern donor restriction policies.There was substantial variation in reporting in studies on TRALI incidence. Meta-analysis of TRALI rates may be feasible in specific circumstances where reporting is clear. Future studies should clearly report key items, such as a TRALI definition.

Using a convergent synthetic route to enable multiple points of diversity, a series of glucocorticoid receptor modulators (GRM) were profiled for potency, selectivity, and drug-like properties

Non-pathogen reduction platelet bacterial risk control strategies in the US FDA guidance include at least one culture. Almost all of these strategies have a culture hold time of ≥12 h. Studies have reported time to detection (TTD) of bacterial cultures inoculated with bacteria from contaminated platelets, but these data and estimates of risk associated with detection failures have not been synthesized.We performed a literature search to identify studies reporting TTD for samples obtained from spiked platelet components. Using extracted data, regression analysis was used to estimate TTD for culture bottles at different inoculum sizes. Detection failures were defined as events in which contaminated components are transfused to a patient. We then used published data on time of transfusion (ToT) to estimate the risk of detection failures in practice.The search identified 1427 studies, of which 16 were included for analysis. TTD data were available for 16 different organisms, including 14 in aerobic cultures and 11 in anaerobic cultures. For inocula of 1 colony forming unit (CFU), the average TTD for aerobic organisms was 19.2 h while it was 24.9 h in anaerobic organisms, but there was substantial overall variation. A hold time of 12 versus 24 h had minimal effect for most organisms.TTD variation occurs between bacterial species and within a particular species. Under typical inventory management, the relative contribution of culture detection failures is much smaller than the residual risk from sampling failures. Increasing the hold period beyond 12 h has limited value.

The goal of this review is to describe the general features, mechanisms, technical recording factors, and clinical applications of brain evoked potentials (EPs) generated by deep brain stimulation (DBS) for Parkinson's disease (PD).Evoked potentials in response to DBS pulses occur on the timescale of milliseconds and are found both locally at the site of stimulation and remotely in the cortex. DBS evoked potentials arise from a complex integration of antidromic and orthodromic conduction pathway responses, and provide information valuable for understanding the mechanisms and circuits involved in symptom treatment. Furthermore, these signals may provide biomarkers for improving DBS outcomes and function. For example, evoked potentials may have utility as control signals for DBS programming or adaptive DBS. Despite their promise there are still critical gaps in our understanding of the mechanisms by which evoked potentials arise and how these signals may be measured and applied in the clinical setting. Technical challenges of recording a highly transient signal at sufficient resolution without the interference of stimulation artifact present a barrier to understanding better DBS-induced EPs.We describe the current scientific landscape of evoked potentials to facilitate and stimulate further investigation.

Abstract. In this study, we contribute to the ongoing incremental validation efforts of the Career Adapt-Abilities Scale (CAAS). Using primary personality and cognition data from 164 German athletes in vocational careers, we intended to replicate Zacher’s (2014) seminal work in an alternative Western environment while also extending it in two significant ways: first, by adding two components of cognitive ability, and second, by introducing an alternative outcome variable – objective career success. In line with Zacher, we observe a significant role of career adaptability in predicting subjective career success. However, we also note that this initially robust relationship stems from a different psychosocial resource than expected. Interestingly, employing CAAS seems not to possess further incremental validity when predicting objective career success.

COVID-19 disproportionately impacted patients with cancer as a result of direct infection, and delays in diagnosis and therapy. Oncological clinical trials are resource-intensive endeavors that could be particularly susceptible to disruption by the pandemic, but few studies have evaluated the impact of the pandemic on clinical trial conduct.This prospective, multicenter study assesses the impact of the pandemic on therapeutic clinical trials at two large academic centers in the Northeastern United States between December 2019 and June 2021. The primary objective was to assess the enrollment on, accrual to, and activation of oncology therapeutic clinical trials during the pandemic using an institution-wide cohort of (i) new patient accruals to oncological trials, (ii) a manually curated cohort of patients with cancer, and (ii) a dataset of new trial activations.The institution-wide cohort included 4756 new patients enrolled to clinical trials from December 2019 to June 2021. A major decrease in the numbers of new patient accruals (-46%) was seen early in the pandemic, followed by a progressive recovery and return to higher-than-normal levels (+2.6%). A similar pattern (from -23.6% to +30.4%) was observed among 467 newly activated trials from June 2019 to June 2021. A more pronounced decline in new accruals was seen among academically sponsored trials (versus industry sponsored trials) (P0.05). In the manually curated cohort, which included 2361 patients with cancer, non-white patients tended to be more likely taken off trial in the early pandemic period (adjusted odds ratio: 2.60; 95% confidence interval 1.00-6.63), and substantial pandemic-related deviations were recorded.Substantial disruptions in clinical trial activities were observed early during the pandemic, with a gradual recovery during ensuing time periods, both from an enrollment and an activation standpoint. The observed decline was more prominent among academically sponsored trials, and racial disparities were seen among people taken off trial.

Since interactions and conflicts between polar bears (Ursus maritimus) and people are reportedly increasing across the Arctic, there is a pressing need to better understand how such conflicts can be prevented or their outcomes ameliorated. A great deal of knowledge about what strategies work for both preventing and mitigating human-polar bear conflicts lies with local experts, yet this knowledge has often remained relatively inaccessible to contemporary wildlife managers. This study had three main aims: to document and synthesize local knowledge of polar bear behaviour in Churchill, Manitoba, to characterize perceptions and interpretations of polar bears, and to examine the linkage between local experts’ knowledge, perceptions, and actions. We identified a suite of bear behaviours that local experts consistently observe and interpret as cues to the bears’ intent. These behaviours are not unique to this locale. Nevertheless, differences in perspectives on the predictability of polar bear behaviour and in interpretations of the nature of bears significantly influence study participants’ strategies for responding to bears. Our findings demonstrate that human-related factors are more complex than current models of human-bear interactions account for, so there is a need to develop richer models for understanding what motivates and influences human behaviours and responses towards bears.

This large, international dataset contains survey responses from N = 12,570 students from 100 universities in 35 countries, collected in 21 languages. We measured anxieties (statistics, mathematics, test, trait, social interaction, performance, creativity, intolerance of uncertainty, and fear of negative evaluation), self-efficacy, persistence, and the cognitive reflection test, and collected demographics, previous mathematics grades, self-reported and official statistics grades, and statistics module details. Data reuse potential is broad, including testing links between anxieties and statistics/mathematics education factors, and examining instruments’ psychometric properties across different languages and contexts. Data and metadata are stored on the Open Science Framework website [https://osf.io/mhg94/].

The hypothesis that sustained G protein-coupled receptor (GPCR) signaling from endosomes mediates pain is based on studies with endocytosis inhibitors and lipid-conjugated or nanoparticle-encapsulated antagonists targeted to endosomes. GPCR antagonists that reverse sustained endosomal signaling and nociception are needed. However, the criteria for rational design of such compounds are ill-defined. Moreover, the role of natural GPCR variants, which exhibit aberrant signaling and endosomal trafficking, in maintaining pain is unknown. Herein, substance P (SP) was found to evoke clathrin-mediated assembly of endosomal signaling complexes comprising neurokinin 1 receptor (NK 1 R), Gα q/i , and βarrestin-2. Whereas the FDA-approved NK 1 R antagonist aprepitant induced a transient disruption of endosomal signals, analogs of netupitant designed to penetrate membranes and persist in acidic endosomes through altered lipophilicity and pKa caused sustained inhibition of endosomal signals. When injected intrathecally to target spinal NK 1 R+ve neurons in knockin mice expressing human NK 1 R, aprepitant transiently inhibited nociceptive responses to intraplantar injection of capsaicin. Conversely, netupitant analogs had more potent, efficacious, and sustained antinociceptive effects. Mice expressing C-terminally truncated human NK 1 R, corresponding to a natural variant with aberrant signaling and trafficking, displayed attenuated SP-evoked excitation of spinal neurons and blunted nociceptive responses to SP. Thus, sustained antagonism of the NK 1 R in endosomes correlates with long-lasting antinociception, and domains within the C-terminus of the NK 1 R are necessary for the full pronociceptive actions of SP. The results support the hypothesis that endosomal signaling of GPCRs mediates nociception and provides insight into strategies for antagonizing GPCRs in intracellular locations for the treatment of diverse diseases.