The adhesion GPCR GPR116/ADGRF5 has a dual function in pancreatic islets regulating somatostatin release and islet development.

Glucose homeostasis is maintained by hormones secreted from different cell types of the pancreatic islets and controlled by manifold input including signals mediated through G protein-coupled receptors (GPCRs). RNA-seq analyses revealed expression of numerous GPCRs in mouse and human pancreatic islets, among them Gpr116/Adgrf5. GPR116 is an adhesion GPCR mainly found in lung and required for surfactant secretion. Here, we demonstrate that GPR116 is involved in the somatostatin release from pancreatic delta cells using a whole-body as well as a cell-specific knock-out mouse model. Interestingly, the whole-body GPR116 deficiency causes further changes such as decreased beta-cell mass, lower number of small islets, and reduced pancreatic insulin content. Glucose homeostasis in global GPR116-deficient mice is maintained by counter-acting mechanisms modulating insulin degradation. Our data highlight an important function of GPR116 in controlling glucose homeostasis.

Target flow deviations on the cardiopulmonary bypass cause postoperative delirium in cardiothoracic surgery-a retrospective study evaluating temporal fluctuations of perfusion data.

OBJECTIVES: Postoperative delirium (POD) is common, costly and associated with long-term morbidity and increased mortality. We conducted a cohort study to assess the contribution of cardiopulmonary bypass (CPB) to the development of POD by means of algorithm-based data processing. METHODS: A database was compiled from 3 datasets of patients who underwent cardiac surgery between 2014 and 2019: intensive care unit discharge files, CPB protocols and medical quality management records. Following data extraction and structuring using novel algorithms, missing data were imputed. Ten independent imputations were analysed by multiple logistic regression with stepwise deletion of factors to arrive at a minimal adequate model. RESULTS: POD was diagnosed in 456/3163 patients (14.4%). In addition to known demographic risk factors and comorbidities like male sex, age, carotid disease, acute kidney failure and diabetes mellitus, cardiopulmonary parameters like total blood volume at the CPB [adjusted odds ratio (AOR) 1.001; confidence interval (CI) 1.1001-1.002] were independent predictors of POD. Higher values of the minimal blood flow were associated with a lower risk of POD (AOR 0.993; CI 0.988-0.997). Flow rates at least 30% above target did emerge in the minimal adequate model as a potential risk factor, but the confidence interval suggested a lack of statistical significance (AOR 1.819; 95% CI: 0.955-3.463). CONCLUSIONS: CPB data processing proved to be a useful tool for obtaining compact information to better identify the roles of individual operational states. Strict adherence to perfusion limits along with tighter control of blood flow and acid-base balance during CPB may help to further decrease the risk of POD.

Identifying G protein-coupled receptors involved in adipose tissue function using the innovative RNA-seq database FATTLAS.

G protein-coupled receptors (GPCRs) modulate the function of adipose tissue (AT) in general and of adipocytes, specifically. Although it is well-established that GPCRs are widely expressed in AT, their repertoire as well as their regulation and function in (patho)physiological conditions (e.g., obesity) is not fully resolved. Here, we established FATTLAS, an interactive public database, for improved access and analysis of RNA-seq data of mouse and human AT. After extracting the GPCRome of non-obese and obese individuals, highly expressed and differentially regulated GPCRs were identified. Exemplarily, we describe four receptors (GPR146, MRGPRF, FZD5, PTGER2) and analyzed their functions in a (pre)adipocyte cell model. Besides all receptors being involved in adipogenesis, MRGPRF is essential for adipocyte viability and regulates cAMP levels, while GPR146 modulates adipocyte lipolysis via constitutive activation of Gi proteins. Taken together, by implementing and using FATTLAS we describe four hitherto unrecognized GPCRs associated with AT function and adipogenesis.

Advanced Carbon Reinforced Concrete Technologies for Façade Elements of Nearly Zero-Energy Buildings.

The building sector accounts for approx. 40% of total energy consumption and approx. 36% of all greenhouse gas emissions in Europe. As the EU climate targets for 2030 call for a reduction of greenhouse gas emissions by more than half compared to the emissions of 1990 and also aim for climate neutrality by 2050, there is an urgent need to achieve a significant decrease in the energy use in buildings towards Nearly Zero-Energy Buildings (nZEBs). As the energy footprint of buildings includes the energy and greenhouse gas consumption both in the construction phase and during service life, nZEB solutions have to provide energy-efficient and less carbon-intensive building materials, specific thermal insulation solutions, and a corresponding design of the nZEB. Carbon reinforced concrete (CRC) materials have proven to be excellent candidate materials for concrete-based nZEBs since they are characterized by a significantly lower CO2 consumption during component production and much a longer lifecycle. The corresponding CRC technology has been successively implemented in the last two decades and first pure CRC-based buildings are currently being built. This article presents a novel material system that combines CRC technology and suitable multifunctional insulation materials as a sandwich system in order to meet future nZEB requirements. Because of its importance for the life cycle stage of production, cost-efficient carbon fibers (CF) from renewable resources like lignin are used as reinforcing material, and reinforcement systems based on such CF are developed. Cutting edge approaches to produce ultra-thin lightweight CF reinforced concrete panels are discussed with regard to their nZEB relevance. For the life cycle stage of the utilization phase, the thermal insulation properties of core materials are optimized. In this context, novel sandwich composites with thin CRC layers and a cellular lightweight concrete core are proposed as a promising solution for façade elements as the sandwich core can additionally be combined with an aerogel-based insulation. The concepts to realize such sandwich façade elements will be described here along with a fully automated manufacturing process to produce such structures. The findings of this study provide clear evidence on the promising capabilities of the CRC technology for nZEBs on the one hand and on the necessity for further research on optimizing the energy footprint of CRC-based structural elements on the other hand.

Succinate receptor 1 inhibits mitochondrial respiration in cancer cells addicted to glutamine.

Cancer cells display metabolic alterations to meet the bioenergetic demands for their high proliferation rates. Succinate is a central metabolite of the tricarboxylic acid (TCA) cycle, but was also shown to act as an oncometabolite and to specifically activate the succinate receptor 1 (SUCNR1), which is expressed in several types of cancer. However, functional studies focusing on the connection between SUCNR1 and cancer cell metabolism are still lacking. In the present study, we analyzed the role of SUCNR1 for cancer cell metabolism and survival applying different signal transduction, metabolic and imaging analyses. We chose a gastric, a lung and a pancreatic cancer cell line for which our data revealed functional expression of SUCNR1. Further, presence of glutamine (Gln) caused high respiratory rates and elevated expression of SUCNR1. Knockdown of SUCNR1 resulted in a significant increase of mitochondrial respiration and superoxide production accompanied by an increase in TCA cycle throughput and a reduction of cancer cell survival in the analyzed cancer cell lines. Combination of SUCNR1 knockdown and treatment with the chemotherapeutics cisplatin and gemcitabine further increased cancer cell death. In summary, our data implicates that SUCNR1 is crucial for Gln-addicted cancer cells by limiting TCA cycle throughput, mitochondrial respiration and the production of reactive oxygen species, highlighting its potential as a pharmacological target for cancer treatment.

Hydroxycarboxylic acid receptor 3 and GPR84 - Two metabolite-sensing G protein-coupled receptors with opposing functions in innate immune cells.

G protein-coupled receptors (GPCRs) are key regulatory proteins of immune cell function inducing signaling in response to extracellular (pathogenic) stimuli. Although unrelated, hydroxycarboxylic acid receptor 3 (HCA3) and GPR84 share signaling via Gαi/o proteins and the agonist 3-hydroxydecanoic acid (3HDec). Both receptors are abundantly expressed in monocytes, macrophages and neutrophils but have opposing functions in these innate immune cells. Detailed insights into the molecular mechanisms and signaling components involved in immune cell regulation by GPR84 and HCA3 are still lacking. Here, we report that GPR84-mediated pro-inflammatory signaling depends on coupling to the hematopoietic cell-specific Gα15 protein in human macrophages, while HCA3 exclusively couples to Gαi protein. We show that activated GPR84 induces Gα15-dependent ERK activation, increases intracellular Ca2+ and IP3 levels as well as ROS production. In contrast, HCA3 activation shifts macrophage metabolism to a less glycolytic phenotype, which is associated with anti-inflammatory responses. This is supported by an increased release of anti-inflammatory IL-10 and a decreased secretion of pro-inflammatory IL-1ß. In primary human neutrophils, stimulation with HCA3 agonists counteracts the GPR84-induced neutrophil activation. Our analyses reveal that 3HDec acts solely through GPR84 but not HCA3 activation in macrophages. In summary, this study shows that HCA3 mediates hyporesponsiveness in response to metabolites derived from dietary lactic acid bacteria and uncovers that GPR84, which is already targeted in clinical trials, promotes pro-inflammatory signaling via Gα15 protein in macrophages.

Outcomes in primary cutaneous diffuse large B-cell lymphoma, leg type.

Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT) is a rare, aggressive lymphoma characterized by skin involvement predominantly in the lower extremities. Immunochemotherapy with or without involved-site radiation therapy (ISRT) is considered standard front-line therapy. Over-expression of PD-L1/PD-L2 is seen in a high proportion of PCDLBCL, LT cases, but efficacy of immune checkpoint inhibitors (ICI) in relapsed/refractory, PCDLBCL, LT has not been thoroughly studied. We conducted a retrospective cohort study of patients diagnosed with PCDLBCL, LT seen at Mayo Clinic from 1 January 2000 to 31 December 2020. Using the Kaplan-Meier method, we calculated progression-free survival, duration of response, and overall survival in patients who received front-line rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with and without ISRT, and salvage ICI therapy for relapsed/refractory disease. A total of 28 patients with PCDLBCL, LT were identified. The median PFS in patients treated with R-CHOP plus ISRT was 58 months (95% CI: 18-112) compared to 14 months (95% CI: 5-not reached; p = 0.04) in those treated with R-CHOP without ISRT. The median PFS from salvage ICI therapy was 10 months (95% CI: 4-not reached), and median DOR from salvage ICI therapy was 23 months [95% CI: 4-26]. R-CHOP with ISRT had a significantly longer median PFS compared to R-CHOP without ISRT as front-line therapy for PCDLBCL, LT. ICIs may have a role in treating relapsed/refractory disease as reasonable activity in heavily pre-treated patients was observed in this study.

Activity of trastuzumab emtansine (T-DM1) in 3D cell culture.

BACKGROUND: Cell spheroids and aggregates generated from three-dimensional (3D) cell culture methods are similar to in vivo tumors in terms of tissue morphology, biology, and gene expression, unlike cells grown in 2D cell cultures. Breast cancer heterogeneity is one of the main drug resistant mechanisms and needs to be overcome in order to increase the efficacy of drug activity in its treatments. METHODS: We performed a unique 3D cell culture and drug efficacy study with trastuzumab emtansine (Kadcyla®, T-DM1) across five breast cancer cell lines (BT-474, SK-BR-3, MDA-MB-361, MDA-MB-175, and MCF-7) that were previously investigated in 2D cell culture. We performed HER2 IHC staining, cell viability experiments, Gene-protein-assay (GPA), and T-DM1 internalization studies. RESULTS: We obtained significantly different results including higher IC50 for some of the cell lines. Our GPA showed some significant heterogeneous HER2 gene and protein expression in 3D cultured spheroids or aggregates. The fluorescent images also showed that a longer incubation time is needed for T-DM1 to be internalized effectively into 3D cultured spheroids or aggregates. CONCLUSION: Our study demonstrated that the difference of T-DM1 drug activity in 3D spheroids or aggregates might be due to tumor heterogeneity and less efficient internalization of T-DM1 that is not seen using 2D cell culture models. Drug studies using 3D cell culture are expected to provide biologically relevant models for determining drug activity in tumor tissue in future drug response and resistance research.

Dipolar-stabilized first and second-order antiskyrmions in ferrimagnetic multilayers.

Skyrmions and antiskyrmions are topologically protected spin structures with opposite vorticities. Particularly in coexisting phases, these two types of magnetic quasi-particles may show fascinating physics and potential for spintronic devices. While skyrmions are observed in a wide range of materials, until now antiskyrmions were exclusive to materials with D2d symmetry. In this work, we show first and second-order antiskyrmions stabilized by magnetic dipole-dipole interaction in Fe/Gd-based multilayers. We modify the magnetic properties of the multilayers by Ir insertion layers. Using Lorentz transmission electron microscopy imaging, we observe coexisting antiskyrmions, Bloch skyrmions, and type-2 bubbles and determine the range of material properties and magnetic fields where the different spin objects form and dissipate. We perform micromagnetic simulations to obtain more insight into the studied system and conclude that the reduction of saturation magnetization and uniaxial magnetic anisotropy leads to the existence of this zoo of different spin objects and that they are primarily stabilized by dipolar interaction.

Improvisational Movement to Improve Quality of Life in Older Adults With Early-Stage Dementia: A Pilot Study.

Alzheimer's disease has profound effects on quality of life, affecting not only cognition, but mobility and opportunities for social engagement. Dance is a form of movement that may be uniquely suited to help maintain quality of life for older adults, including those with dementia, because it inherently incorporates movement, social engagement, and cognitive stimulation. Here, we describe the methods and results of the pilot study for the IMOVE trial (NCT03333837, www.clinicaltrials.gov), a clinical trial designed to use improvisational dance classes to test the effects of movement and social engagement in people with mild cognitive impairment (MCI) or early-stage dementia. The pilot study was an 8-week investigation into the feasibility and potential effects of an improvisational dance intervention on people with MCI or early-stage dementia (PWD/MCI) and their caregivers (CG). The pilot aimed to assess changes in quality of life, balance, mood, and functional brain networks in PWD/MCI and their CG. Participants were recruited as dyads (pairs) that included one PWD/MCI and one CG. Ten total dyads were enrolled in the pilot study with five dyads assigned to the usual care control group and five dyads participating in the dance intervention. The intervention arm met twice weekly for 60 min for 8 weeks. Attendance and quality of life assessed with the Quality of Life in Alzheimer's disease (QoL-AD) questionnaire were the primary outcomes. Secondary outcomes included balance, mood and brain network connectivity assessed through graph theory analysis of functional magnetic resonance imaging (fMRI). Class attendance was 96% and qualitative feedback reflected participants felt socially connected to the group. Increases in quality of life and balance were observed, but not mood. Brain imaging analysis showed increases in multiple brain network characteristics, including global efficiency and modularity. Further investigation into the positive effects of this dance intervention on both imaging and non-imaging metrics will be carried out on the full clinical trial data. Results from the trial are expected in the summer of 2022.

The M1311V variant of ATP7A is associated with impaired trafficking and copper homeostasis in models of motor neuron disease.

Disruption in copper homeostasis causes a number of cognitive and motor deficits. Wilson's disease and Menkes disease are neurodevelopmental disorders resulting from mutations in the copper transporters ATP7A and ATP7B, with ATP7A mutations also causing occipital horn syndrome, and distal motor neuropathy. A 65 year old male presenting with brachial amyotrophic diplegia and diagnosed with amyotrophic lateral sclerosis (ALS) was found to harbor a p.Met1311Val (M1311V) substitution variant in ATP7A. ALS is a fatal neurodegenerative disease associated with progressive muscle weakness, synaptic deficits and degeneration of upper and lower motor neurons. To investigate the potential contribution of the ATP7AM1311V variant to neurodegeneration, we obtained and characterized both patient-derived fibroblasts and patient-derived induced pluripotent stem cells differentiated into motor neurons (iPSC-MNs), and compared them to control cell lines. We found reduced localization of ATP7AM1311V to the trans-Golgi network (TGN) at basal copper levels in patient-derived fibroblasts and iPSC-MNs. In addition, redistribution of ATP7AM1311V out of the TGN in response to increased extracellular copper was defective in patient fibroblasts. This manifested in enhanced intracellular copper accumulation and reduced survival of ATP7AM1311V fibroblasts. iPSC-MNs harboring the ATP7AM1311V variant showed decreased dendritic complexity, aberrant spontaneous firing, and decreased survival. Finally, expression of the ATP7AM1311V variant in Drosophila motor neurons resulted in motor deficits. Apilimod, a drug that targets vesicular transport and recently shown to enhance survival of C9orf72-ALS/FTD iPSC-MNs, also increased survival of ATP7AM1311V iPSC-MNs and reduced motor deficits in Drosophila expressing ATP7AM1311V. Taken together, these observations suggest that ATP7AM1311V negatively impacts its role as a copper transporter and impairs several aspects of motor neuron function and morphology.

Natural biased signaling of hydroxycarboxylic acid receptor 3 and G protein-coupled receptor 84.

BACKGROUND: Medium-chain fatty acids and their 3-hydroxy derivatives are metabolites endogenously produced in humans, food-derived or originating from bacteria. They activate G protein-coupled receptors, including GPR84 and HCA3, which regulate metabolism and immune functions. Although both receptors are coupled to Gi proteins, share at least one agonist and show overlapping tissue expression, GPR84 exerts pro-inflammatory effects whereas HCA3 is involved in anti-inflammatory responses. Here, we analyzed signaling kinetics of both HCA3 and GPR84, to unravel signal transduction components that may explain their physiological differences. METHODS: To study the signaling kinetics and components involved in signal transduction of both receptors we applied the label-free dynamic mass redistribution technology in combination with classical cAMP, ERK signaling and ß-arrestin-2 recruitment assays. For phenotypical analyses, we used spheroid cell culture models. RESULTS: We present strong evidence for a natural biased signaling of structurally highly similar agonists at HCA3 and GPR84. We show that HCA3 signaling and trafficking depends on dynamin-2 function. Activation of HCA3 by 3-hydroxyoctanoic acid but not 3-hydroxydecanoic acid leads to ß-arrestin-2 recruitment, which is relevant for cell-cell adhesion. GPR84 stimulation with 3-hydroxydecanoic acid causes a sustained ERK activation but activation of GPR84 is not followed by ß-arrestin-2 recruitment. CONCLUSIONS: In summary, our results highlight that biased agonism is a physiological property of HCA3 and GPR84 with relevance for innate immune functions potentially to differentiate between endogenous, non-pathogenic compounds and compounds originating from e.g. pathogenic bacteria. Video Abstract.

Exploring G Protein-Coupled Receptor Signaling in Primary Pancreatic Islets.

BACKGROUND: Targeting G protein-coupled receptors (GPCRs) in pancreatic cells is feasible to modulate glucose-induced insulin secretion. Because pancreatic islets consist of several cell types and GPCRs can couple to more than one G-protein family, results obtained in pancreatic cell lines do not always match the response in primary cells or intact islets. Therefore, we set out to establish a protocol to analyze second messenger activation in mouse pancreatic islets. RESULTS: Activation of Gq/11-coupled receptor expressed in primary ß cells increased the second messenger IP1 in an accumulation assay. Applying a Gq/11 protein inhibitor completely abolished this signal. Activation of the V1 vasopressin and ghrelin receptors, predominantly expressed in the less abundant alpha and delta cells, was not sufficient to induce a significant IP1 increase in this assay. However, fura-2-based fluorescence imaging showed calcium signals upon application of arginine vasopressin or ghrelin within intact pancreatic islets. Using the here established protocol we were also able to determine changes in intracellular cAMP levels induced by receptors coupling to Gs and Gi/o proteins. CONCLUSIONS: Detection of the second messengers IP1, cAMP, and calcium, can be used to reliably analyze GPCR activation in intact islets.

Loss of Orai2-Mediated Capacitative Ca2+ Entry Is Neuroprotective in Acute Ischemic Stroke.

Background and Purpose- Ischemic stroke is one of the leading causes of disability and death. The principal goal of acute stroke treatment is the recanalization of the occluded cerebral arteries, which is, however, only effective in a very narrow time window. Therefore, neuroprotective treatments that can be combined with recanalization strategies are needed. Calcium overload is one of the major triggers of neuronal cell death. We have previously shown that capacitative Ca2+ entry, which is triggered by the depletion of intracellular calcium stores, contributes to ischemia-induced calcium influx in neurons, but the responsible Ca2+ channel is not known. Methods- Here, we have generated mice lacking the calcium channel subunit Orai2 and analyzed them in experimental stroke. Results- Orai2-deficient mice were protected from ischemic neuronal death both during acute ischemia under vessel occlusion and during ischemia/reperfusion upon successful recanalization. Calcium signals induced by calcium store depletion or oxygen/glucose deprivation were significantly diminished in Orai2-deficient neurons demonstrating that Orai2 is a central mediator of neuronal capacitative Ca2+ entry and is involved in calcium overload during ischemia. Conclusions- Our experimental data identify Orai2 as an attractive target for pharmaceutical intervention in acute stroke.

Sex Comparisons of In Vivo Anterior Cruciate Ligament Morphometry.

CONTEXT: Females have consistently higher anterior cruciate ligament (ACL) injury rates than males. The reasons for this disparity are not fully understood. Whereas ACL morphometric characteristics are associated with injury risk and females have a smaller absolute ACL size, comprehensive sex comparisons that adequately account for sex differences in body mass index (BMI) have been limited. OBJECTIVE: To investigate sex differences among in vivo ACL morphometric measures before and after controlling for femoral notch width and BMI. DESIGN: Cross-sectional study. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: Twenty recreationally active men (age = 23.2 ± 2.9 years, height = 180.4 ± 6.7 cm, mass = 84.0 ± 10.9 kg) and 20 recreationally active women (age = 21.3 ± 2.3 years, height = 166.9 ± 7.7 cm, mass = 61.9 ± 7.2 kg) participated. MAIN OUTCOME MEASURE(S): Structural magnetic resonance imaging sequences were performed on the left knee. Anterior cruciate ligament volume, width, and cross-sectional area measures were obtained from T2-weighted images and normalized to femoral notch width and BMI. Femoral notch width was measured from T1-weighted images. We used independent-samples t tests to examine sex differences in absolute and normalized measures. RESULTS: Men had greater absolute ACL volume (1712.2 ± 356.3 versus 1200.1 ± 337.8 mm3; t38 = -4.67, P < .001) and ACL width (8.5 ± 2.3 versus 7.0 ± 1.2 mm; t38 = -2.53, P = .02) than women. The ACL volume remained greater in men than in women after controlling for femoral notch width (89.31 ± 15.63 versus 72.42 ± 16.82 mm3/mm; t38 = -3.29, P = .002) and BMI (67.13 ± 15.40 versus 54.69 ± 16.39 mm3/kg/m2; t38 = -2.47, P = .02). CONCLUSIONS: Whereas men had greater ACL volume and width than women, only ACL volume remained different when we accounted for femoral notch width and BMI. This suggests that ACL volume may be an appropriate measure of ACL anatomy in investigations of ACL morphometry and ACL injury risk that include sex comparisons.

Involvement of the Adhesion GPCRs Latrophilins in the Regulation of Insulin Release.

Insulin secretion from pancreatic ß cells is a highly complex and tightly regulated process. Its dysregulation is one characteristic of type 2 diabetes, and thus, an in-depth understanding of the mechanisms controlling insulin secretion is essential for rational therapeutic intervention. G-protein-coupled receptors (GPCRs) have been established as major regulators of insulin exocytosis. Recent studies also suggest the involvement of adhesion GPCRs, a non-prototypical class of GPCRs. Here, we identify latrophilins, which belong to the class of adhesion GPCRs, to be highly expressed in different cell types of pancreatic islets. In vitro and ex vivo analyses show that distinct splice variants of the latrophilin LPHN3/ADGRL3 decrease insulin secretion from pancreatic ß cells by reducing intracellular cyclic AMP levels via the Gi-mediated pathway. Our data highlight the key role of LPHN3 in modulating insulin secretion and its potential as therapeutic target for type 2 diabetes.

Maintenance of Certification Part IV in Residency Methods and Impact on Practice.

BACKGROUND AND OBJECTIVES: The American Board of Family Medicine (ABFM) is the first medical specialty board to require all residents participate in the maintenance of certification (MOC) process prior to sitting for board certification. This study used surveys and focus groups of family medicine residents in four university-affiliated residency programs to explore participants' perceived benefits and barriers to common methods of completing the performance improvement in practice (Part IV) MOC requirement, and the perceived impact on practice. METHODS: Residents independently selected into one of three ABFM-approved methods of meeting the Part IV requirement. Following completion of the activity, participants completed a survey and then participated in a focus group. RESULTS: Residents cited time constraints as a major barrier to all Part IV methods. They also reported lack of relevance to practice, deficiencies in performance improvement skills, and access to clinical data. Ease of use was a benefit of online modules, but residents did not perceive them as relevant to practice or leading practice change. Portfolio and self-directed activities were perceived as most relevant to practice and improved patient care, and involved more team-based experiences. Most participants would not participate in Part IV if not required. CONCLUSIONS: Group quality improvement projects through the portfolio-approved and self-directed activities seemed to be the most positively reported way to complete the ABFM requirement. Regardless of method, time constraints and quality improvement expertise are significant barriers to completion of the requirement. Residency programs will need to grapple with these barriers to maximize benefits to residents as they prepare to become board certified.

Bilateral quadriceps and hamstrings muscle volume asymmetries in healthy individuals.

Determining the magnitude of quadriceps and hamstring muscle volume asymmetries in healthy individuals is a critical first step toward interpreting asymmetries as compensatory or abnormal in pathological populations. The purpose of this study was to determine the magnitude of whole and individual muscle volume asymmetries, quantified as right-left volume differences, for the quadriceps and hamstring muscles in a young and healthy population. Twenty-one healthy individuals participated: Eleven females age = 22.6 ± 2.9 years and 10 males age = 23.2 ± 3.4 years. Whole muscle group and individual muscle volume asymmetries were quantified within the context of absolute measurement error using a 95% Limits of Agreement approach. Mean muscle asymmetries ranged from -3.0 to 6.0% for all individual and whole muscle groups. Whole muscle group 95% limits of agreements represented ±11.4% and ±8.8% volume asymmetries for the hamstrings and quadriceps, respectively. Individual muscle asymmetry 95% limits of agreements ranged from ∼ ± 11-13% for the vastii muscles while the biceps femoris short-head (±33.5%), long-head (±20.9%), and the rectus femoris (±21.4%) displayed the highest relative individual asymmetries. Individual muscle asymmetries exceeded absolute measurement error in 70% of all cases, with 26% of all cases exceeding 10% asymmetry. Although whole muscle group asymmetries appear to be near the 10% assumed clinical threshold of normality, the greater magnitude of individual muscle asymmetries highlights the subject- and muscle-specific variability in volume asymmetry. Future research is warranted to determine if volume asymmetry thresholds exist that discriminate between healthy and pathological populations. Statement of Clinical Significance: Muscle volume asymmetries displayed in healthy individuals provide a reference for interpreting asymmetries in pathological populations. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:963-970, 2018.