Physical Principles of Membrane Shape Regulation by the Glycocalyx.

Cells bend their plasma membranes into highly curved forms to interact with the local environment, but how shape generation is regulated is not fully resolved. Here, we report a synergy between shape-generating processes in the cell interior and the external organization and composition of the cell-surface glycocalyx. Mucin biopolymers and long-chain polysaccharides within the glycocalyx can generate entropic forces that favor or disfavor the projection of spherical and finger-like extensions from the cell surface. A polymer brush model of the glycocalyx successfully predicts the effects of polymer size and cell-surface density on membrane morphologies. Specific glycocalyx compositions can also induce plasma membrane instabilities to generate more exotic undulating and pearled membrane structures and drive secretion of extracellular vesicles. Together, our results suggest a fundamental role for the glycocalyx in regulating curved membrane features that serve in communication between cells and with the extracellular matrix.

Rational design of a new antibiotic class for drug-resistant infections.

The development of new antibiotics to treat infections caused by drug-resistant Gram-negative pathogens is of paramount importance as antibiotic resistance continues to increase worldwide1. Here we describe a strategy for the rational design of diazabicyclooctane inhibitors of penicillin-binding proteins from Gram-negative bacteria to overcome multiple mechanisms of resistance, including ß-lactamase enzymes, stringent response and outer membrane permeation. Diazabicyclooctane inhibitors retain activity in the presence of ß-lactamases, the primary resistance mechanism associated with ß-lactam therapy in Gram-negative bacteria2,3. Although the target spectrum of an initial lead was successfully re-engineered to gain in vivo efficacy, its ability to permeate across bacterial outer membranes was insufficient for further development. Notably, the features that enhanced target potency were found to preclude compound uptake. An improved optimization strategy leveraged porin permeation properties concomitant with biochemical potency in the lead-optimization stage. This resulted in ETX0462, which has potent in vitro and in vivo activity against Pseudomonas aeruginosa plus all other Gram-negative ESKAPE pathogens, Stenotrophomonas maltophilia and biothreat pathogens. These attributes, along with a favourable preclinical safety profile, hold promise for the successful clinical development of the first novel Gram-negative chemotype to treat life-threatening antibiotic-resistant infections in more than 25 years.

In vivo dose response and efficacy of the ß-lactamase inhibitor, durlobactam, in combination with sulbactam against the Acinetobacter baumannii-calcoaceticus complex.

Multi-drug resistant (MDR) Acinetobacter baumannii is emerging as a pathogen of increasing prevalence and concern. Infections associated with this Gram-negative pathogen are often associated with increased morbidity and mortality and few therapeutic options. The ß-lactamase inhibitor sulbactam used commonly in combination with ampicillin demonstrates intrinsic antibacterial activity against A. baumannii acting as an inhibitor of PBP1 and PBP3, which participate in cell wall biosynthesis. The production of ß-lactamases, particularly class D oxacillinases, however, has limited the utility of sulbactam resorting to increased doses and the need for alternate therapies. Durlobactam is a non-ß-lactam ß-lactamase inhibitor that demonstrates broad ß-lactamase inhibition including class D enzymes produced by A. baumannii and has shown potent in vitro activity against MDR A. baumannii, particularly carbapenem-resistant isolates in susceptibility and pharmacodynamic model systems. The objective of this study is to evaluate the exposure-response relationship of sulbactam and durlobactam in combination using in vivo neutropenic thigh and lung models to establish PK/PD exposure magnitudes to project clinically effective doses. Utilizing established PK/PD determinants of %T>MIC and AUC/MIC for sulbactam and durlobactam, respectively, non-linear regressional analysis of drug exposure was evaluated relative to the 24-hour change in bacterial burden (log10 CFU/g). Co-modeling of the data across multiple strains exhibiting a broad range of MIC susceptibility suggested net 1-log10 CFU/g0 reduction can be achieved when sulbactam T>MIC exceeds 50% of the dosing interval and durlobactam AUC/MIC is 10. These data were ultimately used to support sulbactam-durlobactam dose selection for Phase 3 clinical trials.

I n vitro pharmacokinetics/pharmacodynamics of the ß-lactamase inhibitor, durlobactam, in combination with sulbactam against Acinetobacter baumannii-calcoaceticus complex.

Infections caused by Acinetobacter baumannii are increasingly multidrug resistant and associated with high rates of morbidity and mortality. Sulbactam is a ß-lactamase inhibitor with intrinsic antibacterial activity against A. baumannii. Durlobactam is a non-ß-lactam ß-lactamase inhibitor with an extended spectrum of activity compared to other inhibitors of its class. In vitro pharmacodynamic infection models were undertaken to establish the pharmacokinetic/pharmacodynamic (PK/PD) index and magnitudes associated with sulbactam and durlobactam efficacy and to simulate epithelial lining fluid (ELF) exposures at clinical doses to understand sulbactam-durlobactam activity with and without co-administration of a carbapenem. Hollow fiber infection models (HFIMs) and one-compartment systems were used to identify the PK/PD indices and exposure magnitudes associated of 1-log10 and 2-log10 colony-forming unit (CFU)/mL reductions. Sulbactam and durlobactam demonstrated PK/PD drivers of % time above the minimum inhibition concentration (%T > MIC) and area under the plasma concentration-time curve from time 0 to 24 h (AUC0-24)/MIC, respectively. Against a sulbactam-susceptible strain, sulbactam %T > MIC of 71.5 and 82.0 were associated with 1-log10 and 2-log10 CFU/mL reductions, respectively, in the HFIM. Against a non-susceptible strain, durlobactam restored the activity of sulbactam with an AUC0-24/MICs of 34.0 and 46.8 using a polysulfone cartridge to achieve a 1-log10 and 2-log10 CFU/mL reduction. These magnitudes were reduced to 13.8 and 24.2, respectively, using a polyvinylidene fluoride cartridge with a membrane pore size of 0.1 µm. In the one-compartment model, durlobactam AUC0-24/MIC to achieve 1-log10 and 2-log10 CFU/mL reduction were 7.6 and 33.4, respectively. Simulations of clinical ELF exposures in the HFIM showed cidal activity at MICs ≤4 µg/mL. Penicillin binding protein 3 mutant strains with MICs of 8 µg/mL may benefit from the addition of a carbapenem at clinical exposures.

Anti-HMGCR myopathy: estimated five-fold higher incidence in Polynesian compared to European populations in Aotearoa New Zealand.

BACKGROUND: In 2014 the incidence of anti-HMGCR myopathy in New Zealand was ∼1.7 case/million persons/year. OBJECTIVE: Re-estimate the population incidence and assess ethnic variation in those >40-year -olds. SETTING: An incidence cohort was defined by seropositivity for immunoprecipitating anti-HMGCR autoantibodies tested at a national reference laboratory between 1 October 2019-30 September 2021.Separately, ethnicity standardized incidence in > 40-year-olds discharged from New Zealand public hospitals for idiopathic and unspecified myopathy (ICD AM codes M60.8/60.9), was examined for concordance. RESULTS: The forty patients identified in the incidence cohort were all >40-years-old and all had a prior history of statin use. Annual incidence was 4 cases/million/year (95%CI 2.8-5.5). In those >40 years the incidence in Polynesians (Maori and Pacific peoples combined) was 25cases/million/year (95% CI 15.9 -40.1), in Asians 5.7cases/million/year (95% CI 0.7 -20.5) and in Europeans 7cases/million/year (95% CI 3.1 -8.4). The risk in statin users aged > 40 years was ∼1/9000 in Polynesians and ∼1/48000 in Europeans.Ethnic difference in incidence of idiopathic and unspecified myopathy (ICD AM codes M60.8/60.9) was also found in hospital discharges. CONCLUSION: In the past half decade the estimated incidence of anti-HMGCR myopathy in New Zealand has doubled. Polynesian peoples of New Zealand >40-years-old have an estimated 5-fold higher risk compared with European and Asian peoples. The estimated absolute risk in statin users >40-year-olds was 108 cases/million/year in Polynesians vs 21 cases/million/year in Europeans.

Relationship Between Adalimumab Concentrations, Antidrug Antibodies, and Disease Activity in Rheumatoid Arthritis: A Cross-Sectional Observational Study.

OBJECTIVES: To determine the influence of patient characteristics and disease activity on adalimumab (ADA) concentrations; to assess the relationships between ADA concentrations, the presence of antidrug antibodies (ADAb), and disease activity in rheumatoid arthritis (RA); and to determine the association between cytokine concentrations and ADA concentrations. METHODS: A cross-sectional study of people with RA receiving ADA for at least 4 weeks was undertaken. Disease activity was assessed by the Disease Activity Score in 28 joints (DAS28), with responders defined as DAS28 ≤ 3.2. Serum and plasma were obtained for ADA concentrations and ADAb, and a panel of cytokines were obtained for a subgroup. ADA concentrations were compared between demographic and clinical subgroups using ANOVA. The independent associations between clinical and demographic features were analyzed using a general linear model. Variables significantly associated with ADA concentrations from the univariate analyses were entered into multivariate analyses. RESULTS: Of the 156 participants, 69.2% were female and the mean age was 57.4 (SD 12.7) years. Multivariate analysis revealed that higher C-reactive protein (P < 0.001) and higher weight (P < 0.004) were independently associated with lower ADA concentrations. ADA concentrations were higher in those with DAS28 ≤ 3.2 compared to those with DAS28 > 3.2 (median 10.8 [IQR 6.4-20.8] mg/L vs 7.1 [IQR 1.5-12.6] mg/L, P < 0.001). There was a significant negative correlation between interleukin 6 (IL-6) and ADA concentrations (r = -0.04, P < 0.01). CONCLUSION: ADA concentration correlates negatively with markers of inflammatory disease activity in RA, including IL-6. ADA concentration in the range 5 to 7 mg/L over the dose interval are associated with better disease control.

Evaluation of the Homogenous Mobility Shift Assay for Infliximab and Adalimumab Anti-drug Antibody Detection in the Clinical Laboratory.

BACKGROUND: Detecting antidrug antibodies (ADAs) against infliximab or adalimumab is useful for therapeutic drug monitoring. Various ADA detection methods exist, and antibody titer is an output in some algorithms. Homogenous mobility shift assay (HMSA) measures relative ADA concentration and determines drug-ADA complex size in vitro. However, the relevance of complex size determination in drug monitoring remains unclear. Hence, the association between complex size, ADA concentration, and sample detectable neutralizing activity was evaluated. METHODS: Sera from infliximab-treated and adalimumab-treated patients who tested positive for ADA in the National Screening Service were analyzed using 3 ADA assays. HMSA determined the relative ADA concentrations and complex sizes, competitive ligand-binding assay evaluated the sample neutralizing capacity, and enzyme-linked immunosorbent assay detected immunoglobulin (Ig)G4 ADA. RESULTS: Most ADA-positive samples (>80%) formed drug-ADA dimer complexes, whereas 17% had dimer and multimer complexes, and 3% had multimeric complexes. Multimer presence had 100% positive predictive value for detectable neutralizing activity. ADA concentration and detectable neutralizing activity were moderately correlated (r = 0.65) in adalimumab-treated patients and strongly correlated (r = 0.81) in infliximab-treated patients. In adalimumab-treated patients, multimer presence was a stronger predictor of neutralizing activity than ADA concentration was, but not in infliximab-treated patients. However, in infliximab-treated patient samples, multimer presence revealed a distinct subset with high ADA concentrations, neutralizing activity, and IgG4 ADA. CONCLUSIONS: Multimers detected using HMSA had a strong positive predictive value for competitive ligand-binding assay detectable neutralizing activity. Multimeric IgG4-containing ADA-drug complexes revealed a distinct subset of infliximab-treated patient samples, whose clinical relevance merits further investigation.

Diagnosis and subtyping of idiopathic inflammatory myopathies: caution required in the use of myositis autoantibodies.

Detection of myositis autoantibodies (MAs) has utility in both the diagnosis and subtyping of idiopathic inflammatory myopathies (IIMs). Multiplex assays such as the Euroimmun line immunoassay (LIA) have significant limitations in rare diseases like IIM. A retrospective cohort study was performed on positive MA detected on LIA in 171 patients using the manufacturer's recommended cut-off. Only 16.7% were deemed true positive after clinical correlation. Autoantibody-specific cut-offs were created and applied to the original cohort, along with generically applied higher cut-offs. Positive predictive value (PPV) improved, but there was variable increase in false negatives. False positive MA results are common using LIA, but locally derived cut-offs can improve performance. Clinicians must be aware of the limitations of LIA, which is the commonest method for MA detection in Australasia.

The Pharmacokinetics/Pharmacodynamic Relationship of Durlobactam in Combination With Sulbactam in In Vitro and In Vivo Infection Model Systems Versus Acinetobacter baumannii-calcoaceticus Complex.

Sulbactam-durlobactam is a ß-lactam/ß-lactamase inhibitor combination currently in development for the treatment of infections caused by Acinetobacter, including multidrug-resistant (MDR) isolates. Although sulbactam is a ß-lactamase inhibitor of a subset of Ambler class A enzymes, it also demonstrates intrinsic antibacterial activity against a limited number of bacterial species, including Acinetobacter, and has been used effectively in the treatment of susceptible Acinetobacter-associated infections. Increasing prevalence of ß-lactamase-mediated resistance, however, has eroded the effectiveness of sulbactam in the treatment of this pathogen. Durlobactam is a rationally designed ß-lactamase inhibitor within the diazabicyclooctane (DBO) class. The compound demonstrates a broad spectrum of inhibition of serine ß-lactamase activity with particularly potent activity against class D enzymes, an attribute which differentiates it from other DBO inhibitors. When combined with sulbactam, durlobactam effectively restores the susceptibility of resistant isolates through ß-lactamase inhibition. The present review describes the pharmacokinetic/pharmacodynamic (PK/PD) relationship associated with the activity of sulbactam and durlobactam established in nonclinical infection models with MDR Acinetobacter baumannii isolates. This information aids in the determination of PK/PD targets for efficacy, which can be used to forecast efficacious dose regimens of the combination in humans.

Optimal Management of Asymptomatic Carotid Artery Stenosis: A Systematic Review and Network Meta-Analysis.

OBJECTIVE: Management of asymptomatic carotid artery stenosis (ACAS), including carotid endarterectomy (CEA), carotid artery stenting (CAS), and best medical treatment (BMT), remains inconsistent in current practice. Early studies reported a benefit of CEA vs. BMT; however, the current risk-benefit profile of invasive therapy lacks consensus. By evaluating the effects of modern BMT vs. invasive intervention on patient outcomes, this study aimed to influence the future management of ACAS. METHODS: A systematic review and series of network meta-analyses were performed assessing peri-operative (within 30 days) and long term (30 days - 5 years) stroke and mortality risk between ACAS interventions. Total stroke, major, minor, ipsilateral, and contralateral stroke subtypes were assessed independently. Traditional (pre-2000) and modern (post-2000) BMT were compared to assess clinical improvements in medical therapy over the previous two decades. Risks of myocardial infarction (MI) and cranial nerve injury (CNI) were also assessed. RESULTS: Seventeen reports of 14 310 patients with > 50% ACAS were included. CEA reduced the odds of a peri-operative stroke event occurring vs. CAS (odds ratio [OR] 1.6, 95% confidence interval [CI] 1.1 - 2.2 [0 - 20 fewer/1 000]). CEA and CAS reduced the long term odds of minor strokes (OR 0.35, 95% CI 0.21 - 0.59 [20 fewer/1 000]) and ipsilateral strokes (OR 0.27, 95% CI 0.19 - 0.39 [30 fewer/1 000]) vs. all BMT. CEA reduced the odds of major strokes and combined stroke and mortality vs. traditional BMT; however, no difference was found between CEA and modern BMT. CAS reduced the odds of peri-operative MI (OR 0.49, 95% CI 0. 26 - 0.91) and CNI (OR 0.07, 95% CI 0.01 - 0.42) vs. CEA. CONCLUSION: Modern BMT demonstrates similar reductions in major stroke, combined stroke, and mortality to CEA. The overall risk reductions are low and data were unavailable to assess subgroups which may benefit from intervention. However, BMT carries the potential to reduce the requirement for surgical intervention in patients with ACAS.

Four-year review of New Zealand laboratory infliximab and adalimumab concentration results indicating potential for improved dosing.

A review of laboratory results across New Zealand for therapeutic drug monitoring (TDM) of infliximab and adalimumab concentrations and antidrug antibodies (ADAs) over 4 years was completed. Of 6591 results, the median serum concentration for infliximab was 5.7 mg/L and for adalimumab was 5.5 mg/L. Subtherapeutic drug concentrations (<7 mg/L) were measured in 54% of samples. Drug concentrations <2 mg/L were measured in 23% of samples, with ADAs detected in 51% of these. The high number of samples with subtherapeutic drug concentrations and common ADA detection is consistent with failing therapy but could also suggest that standard dosing is frequently too low for patients. These results reinforce the value of antitumour necrosis factor drug TDM in making decisions to adjust dosing or switch agents in patients taking infliximab and adalimumab.

Diagnosing Hip Microinstability: an international consensus study using the Delphi methodology.

PURPOSE: Hip microinstability is a relatively new diagnosis which is increasingly being discussed in the literature and yet there are no clear guidelines for making a diagnosis. Microinstability has generally been defined as persistent excessive hip motion that has become symptomatic especially with pain. This aim of this Delphi study was to seek expert opinion to formulate a diagnostic criteria for hip microinstability. METHODS: A Delphi methodology was used for this consensus study. A literature search was conducted on PubMed up to March 2019 using the keywords ((hip) and (microinstability)) to identify relevant articles on this topic. All relevant criteria used for diagnosing hip microinstability were collated to create a questionnaire and further criterion suggested by the experts were included as well. Four rounds of questionnaires were delivered via an online survey platform. Between each round the authors acted as administrating intermediaries, providing the experts with a summary of results and synthesising the next questionnaire. The expert panel was comprised of 27 members: 24 (89%) orthopaedic surgeons and 3 (11%) physiotherapists from around the world. RESULTS: Expert panel participation in rounds 1-4 was: 27 (100%), 20 (74%), 21 (78%) and 26 (96%) respectively. A literature review by the authors identified 32 diagnostic criteria to populate the first questionnaire. Experts suggested amending three criteria and creating five new criteria. The panel converged on ranking 3 (8%) of criteria as "Not important", 20 (54%) as "Minor Factors" and 14 (38%) as "Major Factors". No criteria was ranked as "Essential". Criteria were subcategorised into patient history, examination and imaging. Experts voted for a minimum requirement of four criteria in each subcategory, including at least six "Major factors". The final diagnostic tool was approved by 20 (77%) of the final round panel. CONCLUSION: This study describes the first known expert consensus on diagnosing hip microinstability. The relative complexity of the final diagnostic tool is illustrative of the difficulty clinicians' face when making this diagnosis. LEVEL OF EVIDENCE: V.

Smartphone Technology to Remotely Measure Postural Sway during Double- and Single-Leg Squats in Adults with Femoroacetabular Impingement and Those with No Hip Pain.

BACKGROUND: The COVID-19 pandemic has accelerated the demand for utilising telehealth as a major mode of healthcare delivery, with increasing interest in the use of tele-platforms for remote patient assessment. In this context, the use of smartphone technology to measure squat performance in people with and without femoroacetabular impingement (FAI) syndrome has not been reported yet. We developed a novel smartphone application, the TelePhysio app, which allows the clinician to remotely connect to the patient's device and measure their squat performance in real time using the smartphone inertial sensors. The aim of this study was to investigate the association and test-retest reliability of the TelePhysio app in measuring postural sway performance during a double-leg (DLS) and single-leg (SLS) squat task. In addition, the study investigated the ability of TelePhysio to detect differences in DLS and SLS performance between people with FAI and without hip pain. METHODS: A total of 30 healthy (nfemales = 12) young adults and 10 adults (nfemales = 2) with diagnosed FAI syndrome participated in the study. Healthy participants performed DLS and SLS on force plates in our laboratory, and remotely in their homes using the TelePhysio smartphone application. Sway measurements were compared using the centre of pressure (CoP) and smartphone inertial sensor data. A total of 10 participants with FAI (nfemales = 2) performed the squat assessments remotely. Four sway measurements in each axis (x, y, and z) were computed from the TelePhysio inertial sensors: (1) average acceleration magnitude from the mean (aam), (2) root-mean-square acceleration (rms), (3) range acceleration (r), and (4) approximate entropy (apen), with lower values indicating that the movement is more regular, repetitive, and predictable. Differences in TelePhysio squat sway data were compared between DLS and SLS, and between healthy and FAI adults, using analysis of variance with significance set at 0.05. RESULTS: The TelePhysio aam measurements on the x- and y-axes had significant large correlations with the CoP measurements (r = 0.56 and r = 0.71, respectively). The TelePhysio aam measurements demonstrated moderate to substantial between-session reliability values of 0.73 (95% CI 0.62-0.81), 0.85 (95% CI 0.79-0.91), and 0.73 (95% CI 0.62-0.82) for aamx, aamy, and aamz, respectively. The DLS of the FAI participants showed significantly lower aam and apen values in the medio-lateral direction compared to the healthy DLS, healthy SLS, and FAI SLS groups (aam = 0.13, 0.19, 0.29, and 0.29, respectively; and apen = 0.33, 0.45, 0.52, and 0.48, respectively). In the anterior-posterior direction, healthy DLS showed significantly greater aam values compared to the healthy SLS, FAI DLS, and FAI SLS groups (1.26, 0.61, 0.68, and 0.35, respectively). CONCLUSIONS: The TelePhysio app is a valid and reliable method of measuring postural control during DLS and SLS tasks. The application is capable of distinguishing performance levels between DLS and SLS tasks, and between healthy and FAI young adults. The DLS task is sufficient to distinguish the level of performance between healthy and FAI adults. This study validates the use of smartphone technology as a tele-assessment clinical tool for remote squat assessment.

Outcomes of Saphenous Vein Intervention in the Management of Superficial Venous Incompetence: A Systematic Review and Network Meta-analysis.

OBJECTIVE: To determine the most effective modality of intervention to treat saphenous vein insufficiency. SUMMARY OF BACKGROUND DATA: Endovenous therapies have instigated a paradigm shift in the management of superficial venous incompetence. When compared with open surgery, endovenous interventions (foam sclerotherapy, radiofrequency ablation, endovenous laser ablation (EVLA), mechanochemical ablation, and CAE closure) potentially offer reduced morbidity with similar procedural efficacy. METHODS: A systematic review and series of network meta-analyses of randomized controlled trials were performed assessing risks of procedural failure (within 6-weeks) and recurrence (6-weeks to 5-years), defined by ultrasound, between the different modalities of intervention for superficial venous incompetence. Treatment comparisons addressing risks of common adverse events, venous clinical severity score, and pain were also performed. RESULTS: A systematic search identified 51 articles, describing 36 randomized controlled trials, incorporating 7576 limbs. Outcome data on 10 modalities of intervention were analyzed up to 5-year follow-up. CAE resulted in the lowest risk of procedural failure within 6-weeks. Foam sclerotherapy had the highest risk of recurrence while high ligation with stripping (HLS) and Conservatrice Hemodynamique de l'Insuffisance Veineuse en Ambulatoire were ranked best to reduce long-term recurrence. No intervention increased risks of venous thromboembolism and there was minimal difference in morbidity between treatments. All interventions improved venous clinical severity score (range -1.02 to -4.95), however, radiofrequency ablation demonstrated the greatest improvement, followed by EVLA and HLS between 2 to 5-years. EVLA was associated with the highest risk of pain, while mechanochemical ablation offered the least. CONCLUSIONS: Although CAE offered the lowest risk of initial procedural failure, HLS resulted in lower rates of long-term recurrence without considerably increasing morbidity when compared with other endovenous options.

Value of the 21-gene expression assay in predicting locoregional recurrence rates in estrogen receptor-positive breast cancer: a systematic review and network meta-analysis.

PURPOSE: The Oncotype DX© 21-gene Recurrence Score (RS) estimates the risk of distant disease recurrence in early-stage estrogen receptor-positive, human epidermal growth factor receptor-2-negative (ER+/HER2- ) breast cancer. Using RS to estimate risk of locoregional recurrence (LRR) is less conclusive. We aimed to perform network meta-analysis (NMA) evaluating the RS in estimating LRR in ER+/HER2- breast cancer. METHODS: A NMA was performed according to PRISMA-NMA guidelines. Analysis was performed using R packages and Shiny. RESULTS: 16 studies with 21,037 patients were included (mean age: 55.1 years (range: 22-96)). The mean RS was 17.1 and mean follow-up was 66.4 months. Using traditional RS cut-offs, 49.7% of patients had RS < 18 (3944/7935), 33.8% had RS 18-30 (2680/7935), and 16.5% had RS > 30 (1311/7935). Patients with RS 18-30 (risk ratio (RR): 1.76, 95% confidence interval (CI): 1.32-2.37) and RS > 30 (RR: 3.45, 95% CI: 2.63-4.53) were significantly more likely to experience LRR than those with RS < 18. Using TAILORx cut-offs, 16.2% of patients had RS < 11 (1974/12,208), 65.8% had RS 11-25 (8036/12,208), and 18.0% with RS > 30 (2198/12,208). LRR rates were similar for patients with RS 11-25 (RR: 1.120, 95% CI: 0.520-2.410); however, those with RS > 25 had an increased risk of LRR (RR: 2.490, 95% CI: 0.680-9.390) compared to those with RS < 11. There was a stepwise increase in LRR rates when applying traditional and TAILORx cut-offs (both P < 0.050). CONCLUSION: RS testing accurately estimates LRR risk for patients being treated for early-stage ER+/HER2- breast cancer. Future prospective, randomized studies may validate the predictive value of RS in estimating LRR.

Initial treatment and survival in Danish patients diagnosed with non-small-cell lung cancer (2005-2015): SCAN-LEAF study.

Aim: To describe initial treatment patterns and survival of patients diagnosed with non-small-cell lung cancer (NSCLC) in Denmark, before immune checkpoint inhibitor and later-generation tyrosine kinase inhibitor use. Patients & methods: Adults diagnosed with incident NSCLC (2005-2015; follow-up: 2016). Initial treatments and overall survival (OS) are reported. Results: 31,939 NSCLC patients (51.6% stage IV) were included. Increasing use of curative radiotherapy/chemoradiation for stage I, II/IIIA and IIIB NSCLC coincided with improved 2-year OS. Systemic anticancer therapy use increased for patients with stage IV non-squamous NSCLC (53.0-60.6%) but not squamous NSCLC (44.9-47.3%). 1-year OS improved in patients with stage IV non-squamous NSCLC (23-31%) but not squamous NSCLC (22-25%). Conclusion: Trends indicated improved OS as treatments evolved between 2005 and 2015, but the effect was limited to 1-year OS in stage IV disease.

Emotional intelligence in undergraduate medical students: a scoping review.

PURPOSE: To perform a scoping review to determine what is known about emotional intelligence (EI) in undergraduate medical education (UME). Two main questions were asked: A. What medical student characteristics are associated with EI? Are there correlations with demographic or other factors? B. What research studies have been done on EI in UME? For example, is there evidence EI changes over time as a result of personal experiences? Should EI be used as an admission criterion? Can EI improve as a result of experiences or deliberate interventions? METHOD: The authors searched four databases (PubMed, PsycInfo, Education Resources Information Center, and Web of Science) for all papers published up to and including December 2020. Two reviewers independently screened articles to determine if they met inclusion criteria. All authors extracted and analyzed data. RESULTS: A set of 1520 papers on the topic of emotional intelligence was identified, with 119 papers meeting inclusion criteria. Most studies were done at international locations with only 17 done at US medical schools. Seventy-five were cohort or cross-sectional studies. Study populations were mixed among the studies, with year of medical study, inclusion of other healthcare students, and participation rates among the inter-study differences noted. CONCLUSIONS: Numerous gaps in the literature on EI exist with several points being clear: (1) there is disagreement on the definition of EI, (2) it is undetermined whether EI is a trait or an ability, and (3) there is marked variability among the instruments used to measure EI. It is also becoming apparent that using EI determination may be helpful as a component of the admission process, higher EI is likely related to improved clinical reasoning, and higher EI contributes to more effective stress management.

Criteria for the Operating Room Confirmation of the Diagnosis of Hip Instability: The Results of an International Expert Consensus Conference.

PURPOSE: The purpose of this study was to establish an international expert consensus on operating room findings that aid in the diagnosis of hip instability. METHODS: An expert panel was convened to build an international consensus on the operating room diagnosis/confirmation of hip instability. Seventeen surgeons who have published or lectured nationally or internationally on the topic of hip instability were invited to participate. Fifteen panel members completed a pre-meeting questionnaire and agreed to participate in a 1-day consensus meeting on May 15, 2021. A review of the literature was performed to identify published intraoperative reference criteria used in the diagnosis of hip instability. Studies were included for discussion if they reported and intraoperative findings associated with hip instability. The evidence for and against each criteria was discussed, followed by an anonymous voting process. For consensus, defined a priori, items were included in the final criteria set if at least 80% of experts agreed. RESULTS: A review of the published literature identified 11 operating room criteria that have been used to facilitate the diagnosis of hip instability. Six additional criteria were proposed by panel members as part of the pre-meeting questionnaire. Consensus agreement was achieved for 8 criteria, namely ease of hip distraction under anesthesia (100.0% agreement), inside-out pattern of chondral damage (100.0% agreement), location of chondral damage on the acetabulum (93.3% agreement), pattern of labral damage (93.3% agreement), anteroinferior labrum chondral damage (86.7% agreement), perifoveal cartilage damage (97.6% agreement), a capsular defect (86.7% agreement), and capsular status (80.0% agreement). Consensus was not achieved for 9 items, namely ligamentum teres tear (66.7% agreement), arthroscopic stability tests (46.7% agreement), persistent distraction after removal of traction (46.7% agreement), findings of examination under anesthesia (46.7% agreement), the femoral head divot sign (40.0% agreement), inferomedial synovitis (26.7% agreement), drive-through sign (26.7% agreement), iliopsoas irritation (26.7% agreement) and ligamentum teres-labral kissing lesion (13.3% agreement). All experts agreed on the final list of 8 criteria items reaching consensus. CONCLUSION: This expert panel identified 8 criteria that can be used in the operating room to help confirm the diagnosis of hip instability. LEVEL OF EVIDENCE: Level V expert opinion.

Can a Hip Brace Improve Short-Term Hip-Related Quality of Life for People With Femoroacetabular Impingement and Acetabular Labral Tears: An Exploratory Randomized Trial.

OBJECTIVES: To examine whether a hip brace can improve hip health quality-of-life (QoL) and is well-tolerated in people with femoroacetabular impingement syndrome (FAIS) or symptomatic labral tears after 6 weeks of wear. DESIGN: Parallel, two-arm, exploratory randomized trial. SETTING: Hospital and private clinics of orthopaedic surgeons. PARTICIPANTS: Individuals >18 years with FAIS or labral tears. INTERVENTIONS: Usual conservative care versus usual conservative care plus a hip brace. MAIN OUTCOMES: Patient-reported outcomes were assessed with the International Hip Outcome Tool (iHOT-33), and Copenhagen Hip and Groin Outcome Scores (HAGOS). Brace acceptability was measured using the Quebec User Evaluation of Satisfaction with Assistive Technology survey. Independent t-tests assessed between-group differences. RESULTS: Thirty-eight participants were recruited, 19 each group, 60% women, mean age 39.3 ± 11.8 years, body mass index 25.3 ± 4.4 kg/m2, iHOT-33 36.6 ± 24.8. Three participants dropped out (one usual care, 2 braced). The mean between-group difference for iHOT-33 was 19.4 (95% confidence interval [CI] 1.68-37.06, P = 0.03) favoring the brace. There were improvements in most HAGOS subscale scores favoring the brace. Issues with brace tolerability for some participants were perceived comfort and effectiveness. Three brace-related adverse events were reported. CONCLUSION: Between-group differences favored the braced group for hip health QoL, pain, symptoms, and function. Although these were promising results, the CIs for the estimates were wide, the small sample size likely a contributing factor. Our results suggest that further investigation of the brace is warranted, we calculated sample sizes and made recommendations for the design of a future trial.

Comparison of learning outcomes of interprofessional education simulation with traditional single-profession education simulation: a mixed-methods study.

BACKGROUND: Interprofessional collaborative practice is essential for meeting patients' needs and improving their health outcomes; thus, the effectiveness of interprofessional education (IPE) should be clearly identified. There is insufficient evidence in the literature to determine the outcomes of IPE compared to traditional single-profession education (SPE). This study aimed to compare the outcomes of IPE and SPE during a simulation training course. METHODS: The study design was a mixed-methods, incorporated cross-over design and a qualitative survey. A total of 54 students including 18 medical students and 36 nursing students were recruited from March to April 2019. The 4-week simulation course was designed based on Kolb's experimental learning theory and Bandura's social learning theory. Participants were evenly divided into group 1 (received IPE-learning followed by SPE-learning), and group 2 (received SPE-learning followed by IPE-learning). Students' medical task performance, team behavior performance, teamwork attitude, and patient safety attitude were collected at pretest, mid-test, and posttest. Descriptive statistics and repeated measures analysis of variance were used. End-of-study qualitative feedback was collected, and content analysis was performed. RESULTS: Both groups demonstrated moderate-to-large within-group improvements for multiple learning outcomes at mid-test. Group 1 students' medical task performance (F = 97.25; P < 0.001) and team behavior performance (F = 31.17; P < 0.001) improved significantly. Group 2 students' medical task performance (F = 77.77; P < 0.001), team behavior performance (F = 40.14; P < 0.001), and patient safety attitude (F = 6.82; P < 0.01) improved significantly. Outcome differences between groups were nonsignificant. Qualitative themes identified included: personal factor, professional factor, interprofessional relationship, and learning. The IPE program provided students with exposure to other professions and revealed differences in expertise and responsibilities. CONCLUSION: IPE-simulation and SPE-simulation were effective interventions that enabled medical and nursing students to develop critical medical management and team behavior performance. IPE-simulation provided more opportunities for improving competencies in interprofessional collaborative practice. In circumstances with limited teaching resources, SPE-simulation can be an acceptable alternative to IPE-simulation.