Perceptions of general surgery residents at military treatment facilities: Excellent training with crisis of confidence.

BACKGROUND: The declining operative volume at Military Treatment Facilities (MTFs) has resulted in Program Directors finding alternate civilian sites for resident rotations. The continued shift away from MTFs for surgical training is likely to have unintended negative consequences. METHODS: An anonymous survey was generated and sent to the program directors of military general surgery training programs for distribution to their residents. RESULTS: A total of 42 residents responded (response rate 21%) with adequate representation from all PGY years. Ninety-five percent of residents believed that their programs provided the training needed to be a competent general surgeon. However, when asked about career choices, only 30.9% reported being likely/extremely likely to remain in the military beyond their initial service obligation, while 54.7% reported that it was unlikely/extremely unlikely and 19% reported uncertainty. Eighty-eight percent reported that decreasing MTF surgical volume directly influenced their decision to stay in the military, and half of respondents regretted joining the military. When asked to assess their confidence in the military to provide opportunities for skill sustainment as a staff surgeon, 90.4% were not confident or were neutral. CONCLUSION: Although military surgical residents have a generally positive perception of their surgical training, they also lack confidence in their future military surgical careers. Our findings suggest that declining MTF surgical volume will likely negatively impact long-term retention of military surgeons and may negatively impact force generation for Operational Commander. LEVEL OF EVIDENCE: Prognostic and Epidemiological, Level IV.

A New Method for Documenting Sign Language Productions in Schools.

PURPOSE: There are well-established guidelines for the recording, transcription, and analysis of spontaneous oral language samples by researchers, educators, and speech pathologists. In contrast, there is presently no consensus regarding methods for the written documentation of sign language samples. The Handshape Analysis Recording Tool (HART) is an innovative method for documenting and analyzing word level samples of signed languages in real time. Fluent sign language users can document the expressive sign productions of children to gather data on sign use and accuracy. METHOD: The HART was developed to document children's productions in Australian Sign Language (Auslan) in a bilingual-bicultural educational program for the Deaf in Australia. This written method was piloted with a group of fluent signing Deaf educational staff in 2014-2016, then used in 2022-2023 with a group of fluent signing professionals to examine inter- and intrarater reliability when coding parameters of sign accuracy. RESULTS: Interrater reliability measured by Gwet's Agreement Coefficient, was "good" to "very good" across the four phonological parameters that are components of every sign: location, movement, handshape, and orientation. CONCLUSIONS: The findings of this study indicate that the HART can be a reliable tool for coding the accuracy of location, orientation, movement, and handshape parameters of Auslan phonology when used by professionals fluent in Auslan. The HART can be utilized with any sign language to gather word level sign language samples in a written form and document the phonological accuracy of signed productions.

Occupational therapy students' perceptions of their experience in a role-emerging Level II fieldwork within higher education student services.

BACKGROUND: Role-emerging settings - those where occupational therapy (OT) services have not traditionally been provided - are common sites for practice placements of entry-level occupational therapy students. A growing body of literature has attempted to determine the value and drawbacks of such practice placements on the professional preparedness of OT students with mixed findings. Benefits have been identified, including increased cultural understanding, advocacy, creativity, initiative, and problem-solving skills. However, OT students have been reported to perceive such placement as limiting their professional growth and preparedness to practice compared to traditional placements. METHODS: A phenomenological study was conducted seeking the perceptions of OT students (n = 14) about their clinical placement at a role-emerging site. Recorded semi-structured interviews were conducted by trained interviewers within two weeks of the end of clinical placement. The recordings were transcribed verbatim and then coded using an iterative multi-coder inductive approach. Inter-coder agreement, reflectivity, and audit trail were maintained. RESULTS: Three themes emerged from the analysis: (1) integrating independence and support, (2) becoming occupational therapists, and (3) filling a gap. These themes reflect students' positive perceptions of their role-emerging clinical placement. They felt that this placement allowed them to develop self-confidence and professional identity as occupational therapists and learn new skills while simultaneously filling a gap in services for clients. Most importantly, they felt that this placement prepared them for their future OT practice. CONCLUSION: This finding and their resounding support of the experience suggest that OT students can perceive role-emerging placement as a solid foundation for clinical practice. Factors, included in this placement, that may have contributed to their experience include the level of support provided, time available for learning including space to make mistakes, and freedom from productivity and payor requirements.

A Multicenter Validity Study of Four Smartphone Hearing Test Apps in Optimized and Home Environments.

OBJECTIVE: Pure tone audiometry (PTA) is the gold standard for hearing assessment. However, it requires access to specialized equipment. Smartphone audiometry applications (apps) have been developed to perform automated threshold audiometry and could allow patients to perform self-administered screening or monitoring. This study aimed to assess the validity and feasibility of patients using apps to self-assess hearing thresholds at home, with comparison to PTA. METHODS: A multi-center, prospective randomized study was conducted amongst patients undergoing PTA in clinics. Participants were randomly allocated to one of four publicly-available apps designed to measure pure tone thresholds. Participants used an app once in optimal sound-treated conditions and a further three times at home. Ear-specific frequency-specific thresholds and pure tone average were compared using Pearson correlation coefficient. The percentage of app hearing tests with results within ±10 dB of PTA was calculated. Patient acceptability was assessed via an online survey. RESULTS: One hundred thirty-nine participants submitted data. The results of two at-home automated smartphone apps correlated strongly/very strongly with PTA average and their frequency-specific median was within ±10 dB accuracy. Smartphone audiometry performed in sound-treated and home conditions were very strongly correlated. The apps were rated as easy/very easy to use by 90% of participants and 90% would be happy/very happy to use an app to monitor their hearing. CONCLUSION: Judicious use of self-performed smartphone audiometry was both valid and feasible for two of four apps. It could provide frequency-specific threshold estimates at home, potentially allowing assessments of patients remotely or monitoring of fluctuating hearing loss. LEVEL OF EVIDENCE: 2 Laryngoscope, 134:2864-2870, 2024.

Race Does Not Affect Rates of Surgical Complications at Military Treatment Facility.

INTRODUCTION: Racial minorities have been found to have worse health care outcomes, including perioperative adverse events. We hypothesized that these racial disparities may be mitigated in a military treatment facility, where all patients have a military service connection and are universally insured. MATERIALS AND METHODS: This is a single institution retrospective review of American College of Surgeons National Surgical Quality Improvement Program data for all procedures collected from 2017 to 2020. The primary outcome analyzed was risk-adjusted 30-day postoperative complications compared by race. RESULTS: There were 6,941 patients included. The overall surgical complication rate was 6.9%. The complication rate was 7.3% for White patients, 6.5% for Black patients, 12.6% for Asian patients, and 3.4% for other races. However, after performing patient and procedure level risk adjustment using multivariable logistic regression, race was not independently associated with surgical complications. CONCLUSIONS: Risk-adjusted surgical complication rates do not vary by race at this military treatment facility. This suggests that postoperative racial disparities may be mitigated within a universal health care system.

Complement in human disease: approved and up-and-coming therapeutics.

The complement system is recognised as a protector against blood-borne pathogens and a controller of immune system and tissue homoeostasis. However, dysregulated complement activity is associated with unwanted or non-resolving immune responses and inflammation, which induce or exacerbate the pathogenesis of a broad range of inflammatory and autoimmune diseases. Although the merit of targeting complement clinically has long been acknowledged, the overall complement drug approval rate has been modest. However, the success of the humanised anti-C5 antibody eculizumab in effectively treating paroxysmal nocturnal haemoglobinuria and atypical haemolytic syndrome has revitalised efforts to target complement therapeutically. Increased understanding of complement biology has led to the identification of novel targets for drug development that, in combination with advances in drug discovery and development technologies, has resulted in a surge of interest in bringing new complement therapeutics into clinical use. The rising number of approved drugs still almost exclusively target rare diseases, but the substantial pipeline of up-and-coming treatment options will possibly provide opportunities to also expand the clinical targeting of complement to common diseases.

Distinct use of super-enhancer elements controls cell type-specific CD25 transcription and function.

The IL-2 receptor α chain (IL-2Rα/CD25) is constitutively expressed on double-negative (DN2/DN3 thymocytes and regulatory T cells (Tregs) but induced by IL-2 on T and natural killer (NK) cells, with Il2ra expression regulated by a STAT5-dependent super-enhancer. We investigated CD25 regulation and function using a series of mice with deletions spanning STAT5-binding elements. Deleting the upstream super-enhancer region mainly affected constitutive CD25 expression on DN2/DN3 thymocytes and Tregs, with these mice developing autoimmune alopecia, whereas deleting an intronic region decreased IL-2-induced CD25 on peripheral T and NK cells. Thus, distinct super-enhancer elements preferentially control constitutive versus inducible expression in a cell type-specific manner. The mediator-1 coactivator colocalized with specific STAT5-binding sites. Moreover, both upstream and intronic regions had extensive chromatin interactions, and deletion of either region altered the super-enhancer structure in mature T cells. These results demonstrate differential functions for distinct super-enhancer elements, thereby indicating previously unknown ways to manipulate CD25 expression in a cell type-specific fashion.

Loss of CD4+ T cell-intrinsic arginase 1 accelerates Th1 response kinetics and reduces lung pathology during influenza infection.

Arginase 1 (Arg1), the enzyme catalyzing the conversion of arginine to ornithine, is a hallmark of IL-10-producing immunoregulatory M2 macrophages. However, its expression in T cells is disputed. Here, we demonstrate that induction of Arg1 expression is a key feature of lung CD4+ T cells during mouse in vivo influenza infection. Conditional ablation of Arg1 in CD4+ T cells accelerated both virus-specific T helper 1 (Th1) effector responses and its resolution, resulting in efficient viral clearance and reduced lung pathology. Using unbiased transcriptomics and metabolomics, we found that Arg1-deficiency was distinct from Arg2-deficiency and caused altered glutamine metabolism. Rebalancing this perturbed glutamine flux normalized the cellular Th1 response. CD4+ T cells from rare ARG1-deficient patients or CRISPR-Cas9-mediated ARG1-deletion in healthy donor cells phenocopied the murine cellular phenotype. Collectively, CD4+ T cell-intrinsic Arg1 functions as an unexpected rheostat regulating the kinetics of the mammalian Th1 lifecycle with implications for Th1-associated tissue pathologies.

Complosome - the intracellular complement system.

The complement system is a recognized pillar of host defence against infection and noxious self-derived antigens. Complement is traditionally known as a serum-effective system, whereby the liver expresses and secretes most complement components, which participate in the detection of bloodborne pathogens and drive an inflammatory reaction to safely remove the microbial or antigenic threat. However, perturbations in normal complement function can cause severe disease and, for reasons that are currently not fully understood, the kidney is particularly vulnerable to dysregulated complement activity. Novel insights into complement biology have identified cell-autonomous and intracellularly active complement - the complosome - as an unexpected central orchestrator of normal cell physiology. For example, the complosome controls mitochondrial activity, glycolysis, oxidative phosphorylation, cell survival and gene regulation in innate and adaptive immune cells, and in non-immune cells, such as fibroblasts and endothelial and epithelial cells. These unanticipated complosome contributions to basic cell physiological pathways make it a novel and central player in the control of cell homeostasis and effector responses. This discovery, together with the realization that an increasing number of human diseases involve complement perturbations, has renewed interest in the complement system and its therapeutic targeting. Here, we summarize the current knowledge about the complosome across healthy cells and tissues, highlight contributions from dysregulated complosome activities to human disease and discuss potential therapeutic implications.

Impact of exacerbations on lung function, resource utilization, and productivity: results from an observational, prospective study in adults with uncontrolled asthma.

Background: Exacerbations have a major impact on the well-being of patients with uncontrolled asthma. This study evaluated lung function, healthcare resource utilization (HCRU), and productivity loss following asthma exacerbations.Methods: This single-center, observational, prospective cohort study recruited US patients presenting clinically with an acute asthma exacerbation; a reference group without exacerbations was included for comparison. Lung function (forced expiratory volume in 1 second [FEV1]) was collected at baseline, daily during Month 1, and monthly for Months 2-5, and reported as FEV1 percent predicted (FEV1pp). HCRU (outpatient visits to a healthcare practitioner, emergency room [ER] visits, and hospitalizations for asthma), oral corticosteroid (OCS) use, and asthma-related work/school absence were collected monthly for 6 months.Results: Overall, 150 patients were recruited (exacerbation: n=102; reference: n=48; mean [SD] age: 42.7 [15.2] and 49.6 [12.4] years; female: 73% and 71%). In both groups, similar trends were observed in FEV1, with significant improvement from baseline to Week 1 (p<0.05), followed by a continuous decline. FEV1p was 7.7% lower at baseline and 8.6% lower at Month 5 in the exacerbation group versus the reference group. The exacerbation group had significantly higher rates of OCS prescription during follow-up versus reference group (p=0.04). Over half (52.9%) of patients in the exacerbation group had a recurrent exacerbation during follow-up, increased HCRU (outpatient visits, ER visits, and hospitalizations), and impaired productivity.Conclusion: Although patients with exacerbations had rapid recovery of lung function, this was not maintained and declined faster than in patients without exacerbations. Additionally, patients experienced increased HCRU after exacerbations.

Systematic single-cell pathway analysis to characterize early T cell activation.

Pathway analysis is a key analytical stage in the interpretation of omics data, providing a powerful method for detecting alterations in cellular processes. We recently developed a sensitive and distribution-free statistical framework for multisample distribution testing, which we implement here in the open-source R package single-cell pathway analysis (SCPA). We demonstrate the effectiveness of SCPA over commonly used methods, generate a scRNA-seq T cell dataset, and characterize pathway activity over early cellular activation. This reveals regulatory pathways in T cells, including an intrinsic type I interferon system regulating T cell survival and a reliance on arachidonic acid metabolism throughout T cell activation. A systems-level characterization of pathway activity in T cells across multiple tissues also identifies alpha-defensin expression as a hallmark of bone-marrow-derived T cells. Overall, this work provides a widely applicable tool for single-cell pathway analysis and highlights regulatory mechanisms of T cells.

"I Could Really Use This": Occupational Therapy Students' Perceptions of Learning to Coach.

Coaching, an evidence-based approach in other fields, is relatively novel within occupational therapy (OT) and is not yet widely taught in OT programs. In recent studies, experienced occupational therapists have reported that coaching added value to their practice, but OT students' perspectives are missing from the literature. This phenomenological study explored OT students' (n = 14) perceptions of the value of learning to coach while in fieldwork. Three themes emerged from the inductive qualitative analysis: Coaching Requires a Mindset Shift, Change is a Journey, and Impact on Clients. Occupational therapy students perceived that coaching required a different way of thinking and reimagining their role, saw the value of learning to coach in the clients' outcomes, and recognized the potential for their future practice regardless of settings. The study findings suggest that incorporating coaching skills into OT education could be beneficial to students when they enter the profession.

PD-1 combination therapy with IL-2 modifies CD8+ T cell exhaustion program.

Combination therapy with PD-1 blockade and IL-2 is highly effective during chronic lymphocytic choriomeningitis virus infection1. Here we examine the underlying basis for this synergy. We show that PD-1 + IL-2 combination therapy, in contrast to PD-1 monotherapy, substantially changes the differentiation program of the PD-1+TCF1+ stem-like CD8+ T cells and results in the generation of transcriptionally and epigenetically distinct effector CD8+ T cells that resemble highly functional effector CD8+ T cells seen after an acute viral infection. The generation of these qualitatively superior CD8+ T cells that mediate viral control underlies the synergy between PD-1 and IL-2. Our results show that the PD-1+TCF1+ stem-like CD8+ T cells, also referred to as precursors of exhausted CD8+ T cells, are not fate-locked into the exhaustion program and their differentiation trajectory can be changed by IL-2 signals. These virus-specific effector CD8+ T cells emerging from the stem-like CD8+ T cells after combination therapy expressed increased levels of the high-affinity IL-2 trimeric (CD25-CD122-CD132) receptor. This was not seen after PD-1 blockade alone. Finally, we show that CD25 engagement with IL-2 has an important role in the observed synergy between IL-2 cytokine and PD-1 blockade. Either blocking CD25 with an antibody or using a mutated version of IL-2 that does not bind to CD25 but still binds to CD122 and CD132 almost completely abrogated the synergistic effects observed after PD-1 + IL-2 combination therapy. There is considerable interest in PD-1 + IL-2 combination therapy for patients with cancer2,3, and our fundamental studies defining the underlying mechanisms of how IL-2 synergizes with PD-1 blockade should inform these human translational studies.

Long COVID Through a Public Health Lens: An Umbrella Review.

Objectives: To synthesize existing evidence on prevalence as well as clinical and socio-economic aspects of Long COVID. Methods: An umbrella review of reviews and a targeted evidence synthesis of their primary studies, including searches in four electronic databases, reference lists of included reviews, as well as related article lists of relevant publications. Results: Synthesis included 23 reviews and 102 primary studies. Prevalence estimates ranged from 7.5% to 41% in non-hospitalized adults, 2.3%-53% in mixed adult samples, 37.6% in hospitalized adults, and 2%-3.5% in primarily non-hospitalized children. Preliminary evidence suggests that female sex, age, comorbidities, the severity of acute disease, and obesity are associated with Long COVID. Almost 50% of primary studies reported some degree of Long COVID-related social and family-life impairment, long absence periods off work, adjusted workloads, and loss of employment. Conclusion: Long COVID will likely have a substantial public health impact. Current evidence is still heterogeneous and incomplete. To fully understand Long COVID, well-designed prospective studies with representative samples will be essential.

The incremental value of the contribution of a biostatistician to the reporting quality in health research-A retrospective, single center, observational cohort study.

BACKGROUND: The reporting quality in medical research has recently been critically discussed. While reporting guidelines intend to maximize the value from funded research, and initiatives such as the EQUATOR network have been introduced to advance high quality reporting, the uptake of the guidelines by researchers could be improved. The aim of this study was to assess the contribution of a biostatistician to the reporting and methodological quality of health research, and to identify methodological knowledge gaps. METHODS: In a retrospective, single center, observational cohort study, two groups of publications were compared. The group of exposed publications had an academic biostatistician on the author list, whereas the group of non-exposed publications did not include a biostatistician of the evaluated group. Rating of reporting quality was done in blinded fashion and in duplicate. The primary outcome was a sum score based on six dimensions, ranging between 0 (worst) and 11 (best). The study protocol was reviewed and approved as a registered report. RESULTS: There were 131 publications in the exposed group published between 2017 and 2018. Of these, 95 were either RCTs, observational, or prediction / prognostic studies. Corresponding matches in the group of non-exposed publications were identified in a reproducible manner. Comparison of reporting quality overall revealed a 1.60 (95%CI from 0.92 to 2.28, p <0.0001) units higher reporting quality for exposed publications. A subgroup analysis within study types showed higher reporting quality across all three study types. CONCLUSION: Our study is the first to report an association of a higher reporting quality and methodological strength in health research publications with a biostatistician on the author list. The higher reporting quality persisted through subgroups of study types and dimensions. Methodological knowledge gaps were identified for prediction / prognostic studies, and for reporting on statistical methods in general and missing values, specifically.

The Corona Immunitas Digital Follow-Up eCohort to Monitor Impacts of the SARS-CoV-2 Pandemic in Switzerland: Study Protocol and First Results.

Objectives: To describe the rationale, organization, and procedures of the Corona Immunitas Digital Follow-Up (CI-DFU) eCohort and to characterize participants at baseline. Methods: Participants of Corona Immunitas, a population-based nationwide SARS-CoV-2 seroprevalence study in Switzerland, were invited to join the CI-DFU eCohort in 11 study centres. Weekly online questonnaires cover health status changes, prevention measures adherence, and social impacts. Monthly questionnaires cover additional prevention adherence, contact tracing apps use, vaccination and vaccine hesitancy, and socio-economic changes. Results: We report data from the 5 centres that enrolled in the CI-DFU between June and October 2020 (covering Basel City/Land, Fribourg, Neuchâtel, Ticino, Zurich). As of February 2021, 4636 participants were enrolled and 85,693 weekly and 27,817 monthly questionnaires were collected. Design-based oversampling led to overrepresentation of individuals aged 65+ years. People with higher education and income were more likely to enroll and be retained. Conclusion: Broad enrolment and robust retention of participants enables scientifically sound monitoring of pandemic impacts, prevention, and vaccination progress. The CI-DFU eCohort demonstrates proof-of-principle for large-scale, federated eCohort study designs based on jointly agreed principles and transparent governance.

Seroprevalence of SARS-CoV-2 antibodies, associated factors, experiences and attitudes of nursing home and home healthcare employees in Switzerland.

BACKGROUND: Many studies in hospital settings exist and have shown healthcare employees to be particularly exposed to SARS-CoV-2. While research focused on hospital staff, little evidence exists for employees in nursing homes and home care. The aims of this study were to assess the seroprevalence in nursing homes and home care employees in the Canton of Zurich, compare it to the general population, assess factors associated with seropositivity and explore the perspective of the employees regarding how the pandemic changed their daily work. METHODS: This cross-sectional study is part of the national Corona Immunitas research program of coordinated, seroprevalence studies in Switzerland. Six nursing homes and six home healthcare organizations providing at home care services in Zurich were selected and 296 and 131 employees were recruited, respectively. Assessments included standardized questionnaires, blood sampling for antibodies, and additional work-specific questions. All participants were recruited between 21st September and 23rd October 2020, before the second wave of the pandemic hit Switzerland, and were possibly exposed to SARS-CoV-2 at their work during the first wave in spring 2020. RESULTS: Seroprevalence of SARS-CoV-2 was 14.9% (95% CI 11.1%-19.6%; range 3.8% to 24.4%) for nursing home employees and 3.8% (95% CI 1.4-9.1%; range 0% to 10%) for home healthcare employees, compared to the general population of Zurich at 3.5% in September 2020 for those aged 20-64. Nurses were 2.6 times more likely to have SARS-CoV-2 antibodies than those employees who were not nurses (95% CI 1.1-6.2). The employees (nursing homes vs. home healthcare) perceived the implementation of general safety measures (44.9% vs. 57.3%) and wearing masks during work (36.8% vs. 43.5%), especially due to the limited communication with residents/clients, as the most crucial changes. CONCLUSIONS: Nursing home employees who worked through SARS-CoV-2 outbreaks at their work were substantially more affected by SARS-CoV-2 infection compared to the general population and to home healthcare employees who similarly worked through outbreaks in their communities. Employees reported that important resources to cope with the burdensome changes they perceived in their daily work were personal resources and team support. TRIAL REGISTRATION: Current Controlled Trials ISRCTN18181860 dated 09/07/2020. Retrospectively registered.

Autocrine vitamin D signaling switches off pro-inflammatory programs of TH1 cells.

The molecular mechanisms governing orderly shutdown and retraction of CD4+ type 1 helper T (TH1) cell responses remain poorly understood. Here we show that complement triggers contraction of TH1 responses by inducing intrinsic expression of the vitamin D (VitD) receptor and the VitD-activating enzyme CYP27B1, permitting T cells to both activate and respond to VitD. VitD then initiated the transition from pro-inflammatory interferon-γ+ TH1 cells to suppressive interleukin-10+ cells. This process was primed by dynamic changes in the epigenetic landscape of CD4+ T cells, generating super-enhancers and recruiting several transcription factors, notably c-JUN, STAT3 and BACH2, which together with VitD receptor shaped the transcriptional response to VitD. Accordingly, VitD did not induce interleukin-10 expression in cells with dysfunctional BACH2 or STAT3. Bronchoalveolar lavage fluid CD4+ T cells of patients with COVID-19 were TH1-skewed and showed de-repression of genes downregulated by VitD, from either lack of substrate (VitD deficiency) and/or abnormal regulation of this system.

Mitochondrial C5aR1 activity in macrophages controls IL-1ß production underlying sterile inflammation.

While serum-circulating complement destroys invading pathogens, intracellularly active complement, termed the "complosome," functions as a vital orchestrator of cell-metabolic events underlying T cell effector responses. Whether intracellular complement is also nonredundant for the activity of myeloid immune cells is currently unknown. Here, we show that monocytes and macrophages constitutively express complement component (C) 5 and generate autocrine C5a via formation of an intracellular C5 convertase. Cholesterol crystal sensing by macrophages induced C5aR1 signaling on mitochondrial membranes, which shifted ATP production via reverse electron chain flux toward reactive oxygen species generation and anaerobic glycolysis to favor IL-1ß production, both at the transcriptional level and processing of pro­IL-1ß. Consequently, atherosclerosis-prone mice lacking macrophage-specific C5ar1 had ameliorated cardiovascular disease on a high-cholesterol diet. Conversely, inflammatory gene signatures and IL-1ß produced by cells in unstable atherosclerotic plaques of patients were normalized by a specific cell-permeable C5aR1 antagonist. Deficiency of the macrophage cell-autonomous C5 system also protected mice from crystal nephropathy mediated by folic acid. These data demonstrate the unexpected intracellular formation of a C5 convertase and identify C5aR1 as a direct modulator of mitochondrial function and inflammatory output from myeloid cells. Together, these findings suggest that the complosome is a contributor to the biologic processes underlying sterile inflammation and indicate that targeting this system could be beneficial in macrophage-dependent diseases, such as atherosclerosis.