Downregulation of PIK3IP1/TrIP on T cells is controlled by TCR signal strength, PKC, and metalloprotease-mediated cleavage.

The protein known as PI3K-interacting protein (PIK3IP1), or transmembrane inhibitor of PI3K (TrIP), is highly expressed by T cells and can modulate PI3K activity in these cells. Several studies have also revealed that TrIP is rapidly downregulated following T cell activation. However, it is unclear as to how this downregulation is controlled. Using a novel monoclonal antibody that robustly stains cell-surface TrIP, we demonstrate that TrIP is lost from the surface of activated T cells in a manner dependent on the strength of signaling through the T cell receptor (TCR) and specific downstream signaling pathways. In addition, TrIP expression returns after 24 hours, suggesting that it may play a role in resetting TCR signaling at later time points. Finally, by expressing truncated forms of TrIP in cells, we identify the region in the extracellular stalk domain of TrIP that is targeted for proteolytic cleavage by metalloprotease ADAM17.

Relative sarcolipin (SLN) and sarcoplasmic reticulum Ca2+ ATPase (SERCA1) transcripts levels in closely related endothermic and ectothermic scombrid fishes: Implications for molecular basis of futile calcium cycle non-shivering thermogenesis (NST).

Regional endothermy is the ability of an animal to elevate the temperature of specific regions of the body above that of the surrounding environment and has evolved independently among several fish lineages. Sarcolipin (SLN) is a small transmembrane protein that uncouples the sarcoplasmic reticulum calcium ATPase pump (SERCA1b) resulting in futile Ca2+ cycling and is thought to play a role in non-shivering thermogenesis (NST) in cold-challenged mammals and possibly some fishes. This study investigated the relative expression of sln and serca1 transcripts in three regionally-endothermic fishes (the skipjack, Katsuwonus pelamis, and yellowfin tuna, Thunnus albacares, both of which elevate the temperatures of their slow-twitch red skeletal muscle (RM) and extraocular muscles (EM), as well as the cranial endothermic swordfish, Xiphias gladius), and closely related ectothermic scombrids (the Eastern Pacific bonito, Sarda chiliensis, and Pacific chub mackerel, Scomber japonicus). Using Reverse Transcription quantitative PCR (RT-qPCR) and species-specific primers, relative sln expression trended higher in both the RM and EM for all four scombrid species compared to white muscle. In addition, relative serca1 expression was found to be higher in RM of skipjack and yellowfin tuna in comparison to white muscle. However, neither sln nor serca1 transcripts were higher in swordfish RM, EM or cranial heater tissue in comparison to white muscle. A key phosphorylation site in sarcolipin, threonine 5, is conserved in the swordfish, but is mutated to alanine or valine in tunas and the endothermic smalleye Pacific opah, Lampris incognitus, which should result in increased uncoupling of the SERCA pump. Our results support the role of potential SLN-NST in endothermic tunas and the lack thereof for swordfish.

Simultaneous proteome localization and turnover analysis reveals spatiotemporal features of protein homeostasis disruptions.

The spatial and temporal distributions of proteins are critical to protein function, but cannot be directly assessed by measuring protein bundance. Here we describe a mass spectrometry-based proteomics strategy, Simultaneous Proteome Localization and Turnover (SPLAT), to measure concurrently protein turnover rates and subcellular localization in the same experiment. Applying the method, we find that unfolded protein response (UPR) has different effects on protein turnover dependent on their subcellular location in human AC16 cells, with proteome-wide slowdown but acceleration among stress response proteins in the ER and Golgi. In parallel, UPR triggers broad differential localization of proteins including RNA-binding proteins and amino acid transporters. Moreover, we observe newly synthesized proteins including EGFR that show a differential localization under stress than the existing protein pools, reminiscent of protein trafficking disruptions. We next applied SPLAT to an induced pluripotent stem cell derived cardiomyocyte (iPSC-CM) model of cancer drug cardiotoxicity upon treatment with the proteasome inhibitor carfilzomib. Paradoxically, carfilzomib has little effect on global average protein half-life, but may instead selectively disrupt sarcomere protein homeostasis. This study provides a view into the interactions of protein spatial and temporal dynamics and demonstrates a method to examine protein homeostasis regulations in stress and drug response.

Imidazo[1,2-b]pyridazines as inhibitors of DYRK kinases.

Selective inhibitors of DYRK1A are of interest for the treatment of cancer, Type 2 diabetes and neurological disorders. Optimization of imidazo [1,2-b]pyridazine fragment 1 through structure-activity relationship exploration and in silico drug design efforts led to the discovery of compound 17 as a potent cellular inhibitor of DYRK1A with selectivity over much of the kinome. The binding mode of compound 17 was elucidated with X-ray crystallography, facilitating the rational design of compound 29, an imidazo [1,2-b]pyridazine with improved kinase selectivity with respect to closely related CLK kinases.

Simultaneous proteome localization and turnover analysis reveals spatiotemporal features of protein homeostasis disruptions.

The functions of proteins depend on their spatial and temporal distributions, which are not directly measured by static protein abundance. Under endoplasmic reticulum (ER) stress, the unfolded protein response (UPR) pathway remediates proteostasis in part by altering the turnover kinetics and spatial distribution of proteins. A global view of these spatiotemporal changes has yet to emerge and it is unknown how they affect different cellular compartments and pathways. Here we describe a mass spectrometry-based proteomics strategy and data analysis pipeline, termed Simultaneous Proteome Localization and Turnover (SPLAT), to measure concurrently the changes in protein turnover and subcellular distribution in the same experiment. Investigating two common UPR models of thapsigargin and tunicamycin challenge in human AC16 cells, we find that the changes in protein turnover kinetics during UPR varies across subcellular localizations, with overall slowdown but an acceleration in endoplasmic reticulum and Golgi proteins involved in stress response. In parallel, the spatial proteomics component of the experiment revealed an externalization of amino acid transporters and ion channels under UPR, as well as the migration of RNA-binding proteins toward an endosome co-sedimenting compartment. The SPLAT experimental design classifies heavy and light SILAC labeled proteins separately, allowing the observation of differential localization of new and old protein pools and capturing a partition of newly synthesized EGFR and ITGAV to the ER under stress that suggests protein trafficking disruptions. Finally, application of SPLAT toward human induced pluripotent stem cell derived cardiomyocytes (iPSC-CM) exposed to the cancer drug carfilzomib, identified a selective disruption of proteostasis in sarcomeric proteins as a potential mechanism of carfilzomib-mediated cardiotoxicity. Taken together, this study provides a global view into the spatiotemporal dynamics of human cardiac cells and demonstrates a method for inferring the coordinations between spatial and temporal proteome regulations in stress and drug response.

Clonality, local population structure and gametophyte sex ratios in cryptic species of the Sphagnum magellanicum complex.

BACKGROUND AND AIMS: Sphagnum (peatmoss) comprises a moss (Bryophyta) clade with ~300-500 species. The genus has unparalleled ecological importance because Sphagnum-dominated peatlands store almost a third of the terrestrial carbon pool and peatmosses engineer the formation and microtopography of peatlands. Genomic resources for Sphagnum are being actively expanded, but many aspects of their biology are still poorly known. Among these are the degree to which Sphagnum species reproduce asexually, and the relative frequencies of male and female gametophytes in these haploid-dominant plants. We assess clonality and gametophyte sex ratios and test hypotheses about the local-scale distribution of clones and sexes in four North American species of the S. magellanicum complex. These four species are difficult to distinguish morphologically and are very closely related. We also assess microbial communities associated with Sphagnum host plant clones and sexes at two sites. METHODS: Four hundred and five samples of the four species, representing 57 populations, were subjected to restriction site-associated DNA sequencing (RADseq). Analyses of population structure and clonality based on the molecular data utilized both phylogenetic and phenetic approaches. Multi-locus genotypes (genets) were identified using the RADseq data. Sexes of sampled ramets were determined using a molecular approach that utilized coverage of loci on the sex chromosomes after the method was validated using a sample of plants that expressed sex phenotypically. Sex ratios were estimated for each species, and populations within species. Difference in fitness between genets was estimated as the numbers of ramets each genet comprised. Degrees of clonality [numbers of genets/numbers of ramets (samples)] within species, among sites, and between gametophyte sexes were estimated. Sex ratios were estimated for each species, and populations within species. Sphagnum-associated microbial communities were assessed at two sites in relation to Sphagnum clonality and sex. KEY RESULTS: All four species appear to engage in a mixture of sexual and asexual (clonal) reproduction. A single ramet represents most genets but two to eight ramets were dsumbers ansd text etected for some genets. Only one genet is represented by ramets in multiple populations; all other genets are restricted to a single population. Within populations ramets of individual genets are spatially clustered, suggesting limited dispersal even within peatlands. Sex ratios are male-biased in S. diabolicum but female-biased in the other three species, although significantly so only in S. divinum. Neither species nor males/females differ in levels of clonal propagation. At St Regis Lake (NY) and Franklin Bog (VT), microbial community composition is strongly differentiated between the sites, but differences between species, genets and sexes were not detected. Within S. divinum, however, female gametophytes harboured two to three times the number of microbial taxa as males. CONCLUSIONS: These four Sphagnum species all exhibit similar reproductive patterns that result from a mixture of sexual and asexual reproduction. The spatial patterns of clonally replicated ramets of genets suggest that these species fall between the so-called phalanx patterns, where genets abut one another but do not extensively mix because of limited ramet fragmentation, and the guerrilla patterns, where extensive genet fragmentation and dispersal result in greater mixing of different genets. Although sex ratios in bryophytes are most often female-biased, both male and female biases occur in this complex of closely related species. The association of far greater microbial diversity for female gametophytes in S. divinum, which has a female-biased sex ratio, suggests additional research to determine if levels of microbial diversity are consistently correlated with differing patterns of sex ratio biases.

PAs in the Republic of Ireland.

ABSTRACT: The physician associate/assistant (PA) profession was introduced into the Republic of Ireland following a 2-year pilot project with the Irish Department of Health between 2015 and 2017. Four PAs from North America were recruited into four designated surgical services at a large teaching hospital in Dublin. To date, the PA numbers are small in Ireland, with one university, in Dublin, running the program and 61 graduates working mostly in the hospital setting, with a small number in primary care. The cautious introduction of PAs partly is due to a delay in follow-up from the Department of Health after the pilot project and in the university's decision to increase the student intake slowly to ensure all graduates secure employment.

Identification of Inhibitors of the Schistosoma mansoni VKR2 Kinase Domain.

Schistosomiasis is a neglected tropical disease caused by parasitic flatworms. Current treatment relies on just one partially effective drug, praziquantel (PZQ). Schistosoma mansoni Venus Kinase Receptors 1 and 2 (SmVKR1 and SmVKR2) are important for parasite growth and egg production, and are potential targets for combating schistosomiasis. VKRs consist of an extracellular Venus Flytrap Module (VFTM) linked via a transmembrane helix to a kinase domain. Here, we initiated a drug discovery effort to inhibit the activity of the SmVKR2 kinase domain (SmVKR2KD) by screening the GSK published kinase inhibitor set 2 (PKIS2). We identified several inhibitors, of which four were able to inhibit its enzymatic activity and induced phenotypic changes in ex vivo S. mansoni. Our crystal structure of the SmVKR2KD displays an active-like state that sheds light on the activation process of VKRs. Our data provide a basis for the further exploration of SmVKR2 as a possible drug target.

The m6A reader IGF2BP2 regulates glutamine metabolism and represents a therapeutic target in acute myeloid leukemia.

N6-Methyladenosine (m6A) modification and its modulators play critical roles and show promise as therapeutic targets in human cancers, including acute myeloid leukemia (AML). IGF2BP2 was recently reported as an m6A binding protein that enhances mRNA stability and translation. However, its function in AML remains largely elusive. Here we report the oncogenic role and the therapeutic targeting of IGF2BP2 in AML. High expression of IGF2BP2 is observed in AML and associates with unfavorable prognosis. IGF2BP2 promotes AML development and self-renewal of leukemia stem/initiation cells by regulating expression of critical targets (e.g., MYC, GPT2, and SLC1A5) in the glutamine metabolism pathways in an m6A-dependent manner. Inhibiting IGF2BP2 with our recently identified small-molecule compound (CWI1-2) shows promising anti-leukemia effects in vitro and in vivo. Collectively, our results reveal a role of IGF2BP2 and m6A modification in amino acid metabolism and highlight the potential of targeting IGF2BP2 as a promising therapeutic strategy in AML.

Surface Plasmon Resonance Screening to Identify Active and Selective Adenosine Receptor Binding Fragments.

Surface plasmon resonance (SPR) is a widely used method to study ligand-protein interactions. The throughput and sensitivity of SPR has made it an important technology for measuring low-affinity, ultralow weight fragments (<200 Da) in the early stages of drug discovery. However, the biochemistry of membrane proteins, such as G-protein-coupled receptors (GPCRs), makes their SPR fragment screening particularly challenging, especially for native/wild-type, nonthermostabilized mutant receptors. In this study, we demonstrate the use of SPR-based biosensors to study the entire human family of adenosine receptors and present biologically active novel binders with a range of selectivity to human adenosine 2a receptor (hA2AR) from an ultralow weight fragment library and the public GlaxoSmithKline (GSK) kinase library. Thus, we demonstrate the ability of SPR to screen ultra-low-affinity fragments and identify biologically meaningful chemical equity and that SPR campaigns are highly effective "chemical filters" for screening small building block fragments that can be used to enable drug discovery programs.

Potential for Antigen-Specific Tolerizing Immunotherapy in Systematic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a chronic complex systemic autoimmune disease characterized by multiple autoantibodies and clinical manifestations, with the potential to affect nearly every organ. SLE treatments, including corticosteroids and immunosuppressive drugs, have greatly increased survival rates, but there is no curative therapy and SLE management is limited by drug complications and toxicities. There is an obvious clinical need for safe, effective SLE treatments. A promising treatment avenue is to restore immunological tolerance to reduce inflammatory clinical manifestations of SLE. Indeed, recent clinical trials of low-dose IL-2 supplementation in SLE patients showed that in vivo expansion of regulatory T cells (Treg cells) is associated with dramatic but transient improvement in SLE disease markers and clinical manifestations. However, the Treg cells that expanded were short-lived and unstable. Alternatively, antigen-specific tolerance (ASIT) approaches that establish long-lived immunological tolerance could be deployed in the context of SLE. In this review, we discuss the potential benefits and challenges of nanoparticle ASIT approaches to induce prolonged immunological tolerance in SLE.

Discovery and Characterization of Selective and Ligand-Efficient DYRK Inhibitors.

Dual-specificity tyrosine-regulated kinase 1A (DYRK1A) regulates the proliferation and differentiation of neuronal progenitor cells during brain development. Consequently, DYRK1A has attracted interest as a target for the treatment of neurodegenerative diseases, including Alzheimer's disease (AD) and Down's syndrome. Recently, the inhibition of DYRK1A has been investigated as a potential treatment for diabetes, while DYRK1A's role as a mediator in the cell cycle has garnered interest in oncologic indications. Structure-activity relationship (SAR) analysis in combination with high-resolution X-ray crystallography leads to a series of pyrazolo[1,5-b]pyridazine inhibitors with excellent ligand efficiencies, good physicochemical properties, and a high degree of selectivity over the kinome. Compound 11 exhibited good permeability and cellular activity without P-glycoprotein liability, extending the utility of 11 in an in vivo setting. These pyrazolo[1,5-b]pyridazines are a viable lead series in the discovery of new therapies for the treatment of diseases linked to DYRK1A function.

Bispecific repurposed medicines targeting the viral and immunological arms of COVID-19.

Effective agents to treat coronavirus infection are urgently required, not only to treat COVID-19, but to prepare for future outbreaks. Repurposed anti-virals such as remdesivir and human anti-inflammatories such as barcitinib have received emergency approval but their overall benefits remain unclear. Vaccines are the most promising prospect for COVID-19, but will need to be redeveloped for any future coronavirus outbreak. Protecting against future outbreaks requires the identification of targets that are conserved between coronavirus strains and amenable to drug discovery. Two such targets are the main protease (Mpro) and the papain-like protease (PLpro) which are essential for the coronavirus replication cycle. We describe the discovery of two non-antiviral therapeutic agents, the caspase-1 inhibitor SDZ 224015 and Tarloxotinib that target Mpro and PLpro, respectively. These were identified through extensive experimental screens of the drug repurposing ReFRAME library of 12,000 therapeutic agents. The caspase-1 inhibitor SDZ 224015, was found to be a potent irreversible inhibitor of Mpro (IC50 30 nM) while Tarloxotinib, a clinical stage epidermal growth factor receptor inhibitor, is a sub micromolar inhibitor of PLpro (IC50 300 nM, Ki 200 nM) and is the first reported PLpro inhibitor with drug-like properties. SDZ 224015 and Tarloxotinib have both undergone safety evaluation in humans and hence are candidates for COVID-19 clinical evaluation.

Distal tibia allograft glenoid reconstruction for shoulder instability: outcomes after lesser tuberosity osteotomy.

BACKGROUND: Distal tibia allograft reconstruction of the glenoid in shoulder instability has garnered significant attention over the last decade. Prior studies demonstrate significant improvement in all reported patient outcomes albeit the approach is through a subscapularis split. There have not been prior studies evaluating outcomes after lesser tuberosity osteotomy which provides excellent exposure to the anterior glenoid.We hypothesize there is significant improvement in functional outcomes and no deleterious effects after lesser tuberosity osteotomy for distal tibia allograft reconstruction of the glenoid for shoulder instability. METHODS: A retrospective review was performed from 2016 of 2019 of patients undergoing distal tibia allograft reconstruction of the glenoid through a lesser tuberosity osteotomy. Patients were indicated if they had recurrent anterior shoulder instability with >20% glenoid bone loss and evidence of an off-track lesion. Clinical, imaging, and operative data were evaluated. Objective follow-up data evaluated at minimum 2 years included radiographs, range of motion, DASH, SANE, VAS, SST, ASES, and Constant scores. RESULTS: A total of 12 patients were available with average follow-up 28 months, average age 26 years old, and average glenoid bone loss of 33%. The patients demonstrated significant improvement in their clinical outcomes at final follow-up: DASH 42.9-8.9 (P = .004), SANE 32.2-85 (P = .00005), VAS 4.6-1.1 (P = .003), SST 7-11.4 (P = .01), ASES 50.2-90.5 (P = .001), and Constant 37.6-86.2 (P = .01). Range of motion at final follow-up was forward flexion to 161.4° (135-170°), external rotation 49.5° (40-65°), and internal rotation to T12-L1 (T7-L2) vertebral body. CONCLUSION: The present study demonstrates the effectiveness of a lesser tuberosity osteotomy in exposure of the glenoid for reconstruction with a distal tibia allograft. The functional integrity of the subscapularis is maintained and the patient-reported outcomes are comparable with current literature.

Conductive, Large-Area, and Continuous 7,7,8,8-Tetracyanoquinodimethane@HKUST-1 Thin Films Fabricated Using Solution Shearing.

Most metal-organic frameworks (MOFs) have an insulating nature due to their porosity and redox-inactive organic components. The electrical conductivity of the prototypical MOF, HKUST-1, can be tuned by infiltrating a small-molecule organic semiconductor, 7,7,8,8-tetracyanoquinodimethane (TCNQ), into the HKUST-1 pores, creating TCNQ@HKUST-1. However, current processes of creating TCNQ@HKUST-1 films have many roadblocks such as slow crystallization rates, which limit high throughput production, and the formation of Cu(TCNQ) as a byproduct, which affects the electrical conductivity and degrades the chemical structure of HKUST-1. In this work, we show that HKUST-1 films can be rapidly synthesized over large areas with consistent thickness and no pinholes via a meniscus-guided coating technique called solution shearing. The subsequent pore activation process and TCNQ impregnation can be completed via solvent exchange to minimize the formation of the Cu(TCNQ) byproduct, and we obtain an increase in electrical conductivity of the solution-sheared TCNQ@HKUST-1 thin films of over 7 orders of magnitude, reaching a maximum value of 2.42 × 10-2 S m-1 when TCNQ is incorporated for 10 days. The conductivity of solution-sheared TCNQ@HKUST-1 is higher compared to films formed by high-pressure pelletization of TCNQ@HKUST-1. We show that solution shearing can produce large-area thin films rapidly and reduce the formation of grain boundaries better than pelletization, allowing for large-area electronics with both charge transport and porosity for applications as sensors and electronics.

Recognition of oral potentially malignant disorders and transformation to oral cancer.

Oral potentially malignant disorders refer to oral mucosal disorders with increased risk for malignant transformation, primarily to oral squamous cell carcinoma (SCC). Leukoplakia and erythroplakia are the most common of these disorders, but others have been identified. Transformation rates to oral cancer vary based on multiple factors. Healthcare providers should be aware of risk factors and clinical manifestations of these disorders and should intervene early to monitor and/or treat them to reduce the potential for malignant transformation.

Mining Public Domain Data to Develop Selective DYRK1A Inhibitors.

Kinases represent one of the most intensively pursued groups of targets in modern-day drug discovery. Often it is desirable to achieve selective inhibition of the kinase of interest over the remaining ∼500 kinases in the human kinome. This is especially true when inhibitors are intended to be used to study the biology of the target of interest. We present a pipeline of open-source software that analyzes public domain data to repurpose compounds that have been used in previous kinase inhibitor development projects. We define the dual-specificity tyrosine-regulated kinase 1A (DYRK1A) as the kinase of interest, and by addition of a single methyl group to the chosen starting point we remove glycogen synthase kinase ß (GSK3ß) and cyclin-dependent kinase (CDK) inhibition. Thus, in an efficient manner we repurpose a GSK3ß/CDK chemotype to deliver 8b, a highly selective DYRK1A inhibitor.

Orthopedic Injuries in Professional Surfers: A Retrospective Study at a Single Orthopedic Center.

BACKGROUND: Literature regarding surfing injuries is scarce and most studies report a high number of minor injuries. Recent literature suggests that musculoskeletal injuries are more common than previously reported. In the mid 2000s, competitive surfing has seen an increase in aerial maneuvers, as they have become more highly rewarded by the judging panel, which may be contributing to a change in injury patterns. Our goal was to evaluate orthopedic injuries in professional surfers. HYPOTHESIS: Orthopedic injuries in professional surfers are diverse and have evolved with skill and technology. STUDY DESIGN: Retrospective observational study. LEVEL OF EVIDENCE: Level 4 Case Series. METHODS: Medical records of professional surfers from a single orthopedic center between 1991 and 2016 were reviewed. Injuries sustained while surfing and chronic injuries related to surfing were included. Site of injury, diagnosis, and treatment were recorded along with demographic data. RESULTS: In total, 163 injuries in 86 athletes were recorded. The median injury age was 28.5 years (range 12-62 years) and 92.6% of patients were male. The most frequently injured body parts were the knee (28.2%), ankle (22.1%), and shoulder (19%). Most knee injuries were of the medial collateral ligament at 49%, with 75% of ankle injuries being sprains, and in shoulder, 48% had instability, 42% had a rotator cuff tear, and 35% had a superior anterior-posterior labral tear. Lower extremity injuries primarily affected the surfers' back leg (72.5%). In all, 34.6% of all injuries required surgical intervention and involved shoulder injuries most the time. CONCLUSIONS: The most common orthopedic injuries in professional surfers involve the knee, ankle, shoulder, hip, and back. Surfers' rear extremities were preferentially injured which is the extremity responsible for power and torque. Shoulder injuries increased the probability of an operative intervention. Last, overuse injuries (femoral-acetabular impingement, rotator cuffs) occurred in the older surf population compared with more acute injuries (ankle sprains/fractures, anterior cruciate ligament tears) which is also consistent with time to surgery.

Prevalence of Musculoskeletal Symptoms in Interventional Radiologists.

PURPOSE: To investigate the prevalence of musculoskeletal symptoms, defined as aches, pains, discomfort, or numbness, by using a validated assessment tool among interventional radiologists. MATERIALS AND METHODS: A Web-based survey using the Nordic Musculoskeletal Questionnaire was disseminated to interventional radiologist members by email in November 2015. Musculoskeletal symptoms were evaluated in 9 body areas. Information regarding participant demographics, practice details, use of radio-protective equipment, and exercise routines was also gathered. Univariate and multivariate analyses were performed to determine risk factors associated with more severe symptoms. RESULTS: Of 4,096 SIR members at the time of the survey, 640 completed the questionnaire in its entirety (16% response rate). Respondents consisted of 69 females (11%) and 571 males (89%), with a mean age of 47.5 ± 10.2 years old, a mean body mass index of 25.5 ± 3.9 kg/m2, and a mean practice length of 17.1 ± 9.8 years. Prevalence of musculoskeletal symptoms was 88% in the 12 months preceding the survey. For those reporting musculoskeletal issues, 58% attributed the symptoms to work-related activities. Lower back (61%), neck (56%), and shoulder complaints (46%) were the most common. Symptoms prevented 21.2% of respondents from being able to work over the same time period. Multivariate analysis identified female gender, above-normal body mass index, and a practice length of 10 years or more as factors associated with a higher risk of moderate-to-severe symptoms. CONCLUSIONS: Musculoskeletal symptoms are prevalent among interventional radiologists, the majority of which are attributed to work-related causes.