Multiligament knee injury (MLKI): an expert consensus statement on nomenclature, diagnosis, treatment and rehabilitation.

Multiligament knee injuries (MLKIs) represent a broad spectrum of pathology with potentially devastating consequences. Currently, disagreement in the terminology, diagnosis and treatment of these injuries limits clinical care and research. This study aimed to develop consensus on the nomenclature, diagnosis, treatment and rehabilitation strategies for patients with MLKI, while identifying important research priorities for further study. An international consensus process was conducted using validated Delphi methodology in line with British Journal of Sports Medicine guidelines. A multidisciplinary panel of 39 members from 14 countries, completed 3 rounds of online surveys exploring aspects of nomenclature, diagnosis, treatment, rehabilitation and future research priorities. Levels of agreement (LoA) with each statement were rated anonymously on a 5-point Likert scale, with experts encouraged to suggest modifications or additional statements. LoA for consensus in the final round were defined 'a priori' if >75% of respondents agreed and fewer than 10% disagreed, and dissenting viewpoints were recorded and discussed. After three Delphi rounds, 50 items (92.6%) reached consensus. Key statements that reached consensus within nomenclature included a clear definition for MLKI (LoA 97.4%) and the need for an updated MLKI classification system that classifies injury mechanism, extent of non-ligamentous structures injured and the presence or absence of dislocation. Within diagnosis, consensus was reached that there should be a low threshold for assessment with CT angiography for MLKI within a high-energy context and for certain injury patterns including bicruciate and PLC injuries (LoA 89.7%). The value of stress radiography or intraoperative fluoroscopy also reached consensus (LoA 89.7%). Within treatment, it was generally agreed that existing literature generally favours operative management of MLKI, particularly for young patients (LoA 100%), and that single-stage surgery should be performed whenever possible (LoA 92.3%). This consensus statement will facilitate clinical communication in MLKI, the care of these patients and future research within MLKI.

Pathogenic diversification of the gut commensal Providencia alcalifaciens via acquisition of a second type III secretion system.

Providencia alcalifaciens is a Gram-negative bacterium found in various water and land environments and organisms, including insects and mammals. Some P. alcalifaciens strains encode gene homologs of virulence factors found in pathogenic Enterobacterales members, such as Salmonella enterica serovar Typhimurium and Shigella flexneri. Whether these genes are pathogenic determinants in P. alcalifaciens is not known. In this study, we investigated P. alcalifaciens-host interactions at the cellular level, focusing on the role of two type III secretion systems (T3SS) belonging to the Inv-Mxi/Spa family. T3SS1b is widespread in Providencia spp. and encoded on the chromosome. A large plasmid that is present in a subset of P. alcalifaciens strains, primarily isolated from diarrheal patients, encodes for T3SS1a. We show that P. alcalifaciens 205/92 is internalized into eukaryotic cells, lyses its internalization vacuole, and proliferates in the cytosol. This triggers caspase-4-dependent inflammasome responses in gut epithelial cells. The requirement for the T3SS1a in entry, vacuole lysis, and cytosolic proliferation is host cell type-specific, playing a more prominent role in intestinal epithelial cells than in macrophages or insect cells. In a bovine ligated intestinal loop model, P. alcalifaciens colonizes the intestinal mucosa and induces mild epithelial damage with negligible fluid accumulation in a T3SS1a- and T3SS1b-independent manner. However, T3SS1b was required for the rapid killing of Drosophila melanogaster. We propose that the acquisition of two T3SS has allowed P. alcalifaciens to diversify its host range, from a highly virulent pathogen of insects to an opportunistic gastrointestinal pathogen of animals.

Long-term Outcomes of Partial Meniscectomy for Degenerative Medial Meniscus Posterior Root Tears.

Background: Previous studies have demonstrated that medial meniscus posterior root tear (MMPRT) repair is superior to debridement in terms of patient-reported outcomes, rates of conversion to total knee arthroplasty (TKA), and long-term costs. Despite the known poor midterm outcomes, there is a paucity of long-term results of partial meniscectomy for degenerative MMPRTs. Purpose: To 1) evaluate long-term patient-reported and radiographic outcomes of patients who underwent partial medial meniscectomy (PMM) for MMPRTs, and 2) determine the rate of and risk factors for conversion to total knee TKA. Study Design: Case series; Level of evidence, 4. Methods: A previously identified cohort of 26 patients treated with partial meniscectomy for isolated MMPRTs between 2005 and 2013 was prospectively followed for long-term outcomes at a minimum 10-year follow-up. Patients were evaluated for International Knee Documentation Committee (IKDC) outcome score, reoperation, and conversion to TKA. Failure was defined as conversion to arthroplasty or a severely abnormal IKDC subjective score <75.4. Results: This study included 26 patients (10 men, 16 women; mean age, 54 ± 8.7 years [range, 38-71 years] at diagnosis; body mass index, 32.9 ± 5.5) who were followed for a mean of 14.0 ± 3.6 years (range, 10.1-19.6 years). At the final follow-up, 1 patient was deceased and 18 (72%) of the remaining 25 patients had progressed to TKA, with 1 (4%) patient undergoing repeat meniscectomy. The 6 (24%) patients who had not progressed to TKA or revision surgery reported a mean IKDC score of 57 ± 23. Nineteen patients underwent subsequent surgery and 5 demonstrated severely abnormal IKDC scores resulting in a clinical failure rate of 96% (24 of the 25 living patients) at a mean 14-year follow-up. Conclusion: PMM for medial meniscus posterior horn root tears demonstrated 72% progression to TKA and 96% failure according to subjective clinical outcomes at a minimum 10-year follow-up.

Gene expression responses of CF airway epithelial cells exposed to elexacaftor/tezacaftor/ivacaftor (ETI) suggest benefits beyond improved CFTR channel function.

The combination of elexacaftor/tezacaftor/ivacaftor (ETI, Trikafta) reverses the primary defect in Cystic Fibrosis (CF) by improving CFTR mediated Cl - and HCO 3 - secretion by airway epithelial cells (AEC), leading to improved lung function and less frequent exacerbations and hospitalizations. However, studies have shown that CFTR modulators like ivacaftor, a component of ETI, has numerous effects on CF cells beyond improved CFTR channel function. Because little is known about the effect of ETI on CF AEC gene expression we exposed primary human AEC to ETI for 48 hours and interrogated the transcriptome by RNA-seq and qPCR. ETI increased defensin gene expression ( DEFB1 ) an observation consistent with reports of decreased bacterial burden in the lungs of people with CF (pwCF). ETI also decreased MMP10 and MMP12 gene expression, suggesting that ETI may reduce proteolytic induced lung destruction in CF. ETI also reduced the expression of the stress response gene heme oxygenase ( HMOX1 ). qPCR analysis confirmed DEFB1, HMOX1, MMP10 and MMP12 gene expression results observed by RNA-seq. Gene pathway analysis revealed that ETI decreased inflammatory signaling, cellular proliferation and MHC Class II antigen presentation. Collectively, these findings suggest that the clinical observation that ETI reduces lung infections in pwCF is related in part to drug induced increases in DEFB1 , and that ETI may reduce lung damage by reducing MMP10 and MMP12 gene expression, which is predicted to reduce matrix metalloprotease activity. Moreover, pathway analysis also identified several genes responsible for the ETI induced reduction in inflammation observed in people with CF. New and Noteworthy: Gene expression responses by CF AEC exposed to ETI suggest that in addition to improving CFTR channel function, ETI is likely to increase resistance to bacterial infection by increasing levels of beta defensin 1 (hBD-1). ETI may also reduce lung damage by suppressing MMP10, and reduce airway inflammation by repressing proinflammatory cytokine secretion by AEC cells.

A novel antigen biomarker for detection of high-level of Loa loa microfilaremia.

BACKGROUND: Loiasis is a disease caused by the nematode Loa loa. Serious adverse events sometimes occur in people with heavy L. loa microfilaremia after ivermectin treatment. In regions of Central Africa where loiasis is endemic, this significantly impedes global elimination programs for lymphatic filariasis and onchocerciasis that use mass distribution of ivermectin. Improved diagnostic tests to identify individuals at increased risk of serious adverse events could facilitate efforts to eliminate lymphatic filariasis and onchocerciasis in this region. METHODS AND FINDINGS: We previously identified the L. loa protein Ll-Bhp-1 in loiasis patient sera. Here, we further characterize Ll-Bhp-1 and report development of an antigen capture ELISA to detect this antigen. This assay detected Ll-Bhp-1 in 74 of 116 (63.8%) loiasis patient sera. Ll-Bhp-1 levels were significantly correlated with L. loa microfilarial counts, and the sensitivity of the assay was highest for samples from people with high counts, (94% and 100% in people with ≥20,000 and ≥50,000 microfilaria per milliliter of blood, respectively). The antigen was not detected in 112 sera from people with other filarial infections, or in 34 control sera from the USA. CONCLUSIONS: This Ll-Bhp-1 antigen assay is specific for loiasis, and highly sensitive for identifying people with high L. loa microfilarial counts who are at increased risk for serious adverse events after ivermectin treatment. L. loa antigen detection has the potential to facilitate loiasis mapping efforts and programs to eliminate lymphatic filariasis and onchocerciasis in Central Africa.

B cell and aquaporin-4 antibody relationships with neuromyelitis optica spectrum disorder activity.

This post hoc analysis of the randomized, placebo-controlled N-MOmentum study (NCT02200770) of inebilizumab in neuromyelitis optica spectrum disorder (NMOSD) evaluated relationships between circulating B-cell subsets and aquaporin-4 immunoglobulin G (AQP4-lgG) titers and attacks. Among participants receiving placebo, CD20+ and CD27+ B-cell counts were modestly increased from the pre-attack visit to attack; plasmablast/plasma cell gene signature was increased from baseline to the pre-attack visit (p = 0.016) and from baseline to attack (p = 0.009). With inebilizumab treatment, B-cell subset counts decreased and did not increase with attacks. No difference in change of AQP4-IgG titers from baseline to time of attack was observed.

Talar and Calcaneal Coordinate Axes Definitions across Foot Pathologies.

The understanding of foot and ankle biomechanics is improving as new technology provides more detailed information about the motion of foot and ankle bones with biplane fluoroscopy, as well as the ability to analyze the hindfoot under weightbearing conditions with weightbearing computed tomography. Three-dimensional anatomical coordinate systems are necessary to describe the 3D alignment and kinematics of the foot and ankle. The lack of standard coordinate systems across research study sites can significantly alter experimental data analyses used for pre-surgical evaluation and post-operative outcome assessments. Clinical treatment paradigms are changing based on the expanding knowledge of complex pes planovalgus morphologies or progressive collapsing foot deformity, which is present in both neurologic and non-neurologic populations. Four patient cohorts were created from 10 flexible PCFD, 10 rigid PCFD, 10 adult cerebral palsy, and 10 asymptomatic control patients. Six coordinate systems were tested on both the talus and calcaneus for all groups. The aim of this study was to evaluate axes definitions for the subtalar joint across four different patient populations to determine the influence of morphology on the implementation of previously defined coordinate systems. Different morphologic presentations from various pathologies have a substantial impact on coordinate system definitions, given that numerous axes definitions are defined through geometric fits or manual landmark selection. Automated coordinate systems that align with clinically relevant anatomic planes are preferred. Principal component axes are automatic, but do not align with clinically relevant planes and should not be used for such analysis where anatomic planes are critical.

Biodetection of an odor signature in white-tailed deer associated with infection by chronic wasting disease prions.

Chronic wasting disease (CWD) has become a major concern among those involved in managing wild and captive cervid populations. CWD is a fatal, highly transmissible spongiform encephalopathy caused by an abnormally folded protein, called a prion. Prions are present in a number of tissues, including feces and urine in CWD infected animals, suggesting multiple modes of transmission, including animal-to-animal, environmental, and by fomite. CWD management is complicated by the lack of practical, non-invasive, live-animal screening tests. Recently, there has been a focus on how the volatile odors of feces and urine can be used to discriminate between infected and noninfected animals in several different species. Such a tool may prove useful in identifying potentially infected live animals, carcasses, urine, feces, and contaminated environments. Toward this goal, dogs were trained to detect and discriminate CWD infected individuals from non-infected deer in a laboratory setting. Dogs were tested with novel panels of fecal samples demonstrating the dogs' ability to generalize a learned odor profile to novel odor samples based on infection status. Additionally, dogs were transitioned from alerting to fecal samples to an odor profile that consisted of CWD infection status with a different odor background using different sections of gastrointestinal tracts. These results indicated that canine biodetectors can discriminate the specific odors emitted from the feces of non-infected versus CWD infected white-tailed deer as well as generalizing the learned response to other tissues collected from infected individuals. These findings suggest that the health status of wild and farmed cervids can be evaluated non-invasively for CWD infection via monitoring of volatile metabolites thereby providing an effective tool for rapid CWD surveillance.

Association of Dialysate Bicarbonate with Arrhythmia in the Monitoring in Dialysis (MiD) Study.

BACKGROUND: Sudden death accounts for ∼25% of deaths among maintenance hemodialysis (HD) patients, occurring more frequently on HD days. Higher dialysate bicarbonate (DBIC) may predispose to alkalemia and arrhythmogenesis. METHODS: We conducted a 12-month analysis of session-level data from 66 patients with implantable loop recorders. We fit logistic regression and negative binomial mixed effects regression models to assess the association of DBIC with clinically significant arrhythmia (CSA - ventricular tachycardia ≥115 beats per minute (BPM) for at least 30 seconds, bradycardia ≤40 BPM for at least 6 seconds, or asystole for at least 3 seconds) and reviewer confirmed arrhythmia (RCA - implantable-loop-recorder-identified or patient-marked event for which a manual review of the stored ECG tracing confirmed the presence of atrial fibrillation, supraventricular tachycardia, sinus tachycardia with rate >130 BPM, ventricular tachycardia, asystole, or bradycardia). Models adjusted for age, sex, race, HD vintage, vascular access, and pre-HD serum bicarbonate and additionally for serum and dialysate potassium levels. RESULTS: Mean age was 56 ± 12 years, 70% were male, 53% were Black, and 35% were Asian. Fewer RCA episodes were associated with DBIC >35 than 35 mEq/L (incidence rate ratio [IRR] 0.45 (0.27, 0.75) and aIRR 0.54 (0.30, 0.97)), but the association was not significant when adjusting for serum and dialysate potassium levels (aIRR 0.60 (0.32, 1.11)). Otherwise, no associations between DBIC and arrhythmia were identified. CONCLUSIONS: We observed a lower frequency of RCA with higher DBIC, compared with DBIC of 35 mEql/L, contrary to our original hypothesis, but this association was attenuated in fully adjusted models. Validation of these findings in larger studies is required, with a further need for interventional studies to explore the optimal DBIC concentration.

Lesion characteristics using high-frequency low-tidal volume ventilation versus standard ventilation during ablation of paroxysmal atrial fibrillation.

INTRODUCTION: High-frequency low-tidal-volume (HFLTV) ventilation during radiofrequency catheter ablation (RFCA) for paroxysmal atrial fibrillation (PAF) has been shown to be superior to standard ventilation (SV) in terms of procedural efficiency, acute and long-term clinical outcomes. Our study aimed to compare ablation lesions characteristics utilizing HFLTV ventilation versus SV during RFCA of PAF. METHODS: A retrospective analysis was conducted on patients who underwent pulmonary vein isolation (PVI) for PAF between August 2022 and March 2023, using high-power short-duration ablation. Thirty-five patients underwent RFCA with HFLTV ventilation and were matched with another cohort of 35 patients who underwent RFCA with SV. Parameters including ablation duration, contact force (CF), impedance drop, and ablation index were extracted from the CARTONET database for each ablation lesion. RESULTS: A total of 70 patients were included (HFLTV = 35/2484 lesions, SV = 35/2830 lesions) in the analysis. There were no differences in baseline characteristics between the groups. While targeting the same ablation index, the HFLTV ventilation group demonstrated shorter average ablation duration per lesion (12.3 ± 5.0 vs. 15.4 ± 8.4 s, p < .001), higher average CF (17.0 ± 8.5 vs. 10.5 ± 4.6 g, p < .001), and greater impedance reduction (9.5 ± 4.6 vs. 7.7 ± 4.1 ohms, p < .001). HFLTV ventilation group also demonstrated shorter total procedural time (61.3 ± 25.5 vs. 90.8 ± 22.8 min, p < .001), ablation time (40.5 ± 18.6 vs. 65.8 ± 22.5 min, p < .001), and RF time (15.3 ± 4.8 vs. 22.9 ± 9.7 min, p < .001). CONCLUSION: HFLTV ventilation during PVI for PAF was associated with improved ablation lesion parameters and procedural efficiency compared to SV.

The Society of Thoracic Surgeons Preoperative Beta Blocker Working Group Interim Report.

BACKGROUND: Atrial fibrillation (AF) occurs commonly following cardiac surgery and is associated with multiple adverse outcomes. Older randomized trials suggested that perioperative beta blockade reduced postoperative AF, and the Society of Thoracic Surgeons (STS) CABG composite measure includes beta blocker administration preoperatively within 24 hours of surgery and at discharge. However, some more recent studies suggest preoperative beta blockade has limited value and question its continuation as an STS quality measure. METHODS: In 2022, an STS Preoperative Beta Blocker Working Group was formed with representatives from the STS and the Society of Cardiovascular Anesthesiologists. Published randomized trials, observational studies, societal guidelines, and the current state of available data from the STS Adult Cardiac Surgery Database (ACSD) were reviewed. RESULTS: Review of existing studies reveals substantial heterogeneity or insufficient detail regarding specific beta blockers used; timing of initiation; management of patients on chronic beta blockade; and whether other pro- or anti-arrhythmic drugs were used concurrently. Further, beta blocker data currently collected in the STS ACSD lack sufficient granularity. CONCLUSIONS: As a new randomized trial seems unlikely, the working group believes that more granular data on real-world practice would facilitate assessment of the value of preoperative beta blockade in the current era, development of best practice recommendations, and evaluation of their continued appropriateness as an STS quality metric. STS ACSD participants have been invited to participate in a voluntary survey whose additional data, when linked to STS ACSD records, will better delineate contemporary beta blocker practice and outcomes.

Empowering Hospitalized Patients With Diabetes: Implementation of a Hospital-wide CGM Policy With EHR-Integrated Validation for Dosing Insulin.

OBJECTIVE: We aimed to assess the feasibility, clinical accuracy, and acceptance of a hospital-wide continuous glucose monitoring (CGM) policy with electronic health record (EHR)-integrated validation for insulin dosing. RESEARCH DESIGN AND METHODS: A hospital policy was developed and implemented at Stanford Health Care for using personal CGMs in lieu of fingerstick blood glucose (FSBG) monitoring. It included requirements specific to each CGM, accuracy monitoring protocols, and EHR integration. User experience surveys were conducted among a subset of patients and nurses. RESULTS: From November 2022 to August 2023, 135 patients used the CGM protocol in 185 inpatient encounters. This included 27% with type 1 diabetes and 24% with automated insulin delivery systems. The most-used CGMs were Dexcom G6 (44%) and FreeStyle Libre 2 (43%). Of 1,506 CGM validation attempts, 87.8% met the %20/20 criterion for CGM-based insulin dosing and 99.3% fell within Clarke zones A or B. User experience surveys were completed by 27 nurses and 46 patients. Most nurses found glucose management under the protocol effective (74%), easy to use (67%), and efficient (63%); 80% of nurses preferred inpatient CGM to FSBG. Most patients liked the CGM protocol (63%), reported positive CGM interactions with nursing staff (63%), and felt no significant interruptions to their diabetes management (63%). CONCLUSIONS: Implementation of a hospital-wide inpatient CGM policy supporting multiple CGM types with real-time accuracy monitoring and integration into the EHR is feasible. Initial feedback from nurses and patients was favorable, and further investigation toward broader use and sustainability is needed.

Impact of COVID-19 infection among patients hospitalized for conventional pacemaker implantation: Analysis of the Nationwide Inpatient Sample (NIS) 2020.

Introduction: The cardiac pacemaker is indicated for treating various types of bradyarrhythmia, providing lifelong cardiovascular benefits. Recent data showed that COVID-19 has impacted procedure numbers and led to adverse long-term outcomes in patients with cardiac pacemakers. However, the impact of COVID-19 infection on the in-hospital outcome of patients undergoing conventional pacemaker implantation remains unclear. Method: Patients aged above 18 years who were hospitalized for conventional pacemaker implantation in the Nationwide In-patient Sample (NIS) 2020 were identified using relevant ICD-10 CM and PCS codes. Multivariable logistic and linear regression models were used to analyze pre-specified outcomes, with the primary outcome being in-patient mortality and secondary outcomes including system-based and procedure-related complications. Results: Of 108 020 patients hospitalized for conventional pacemaker implantation, 0.71% (765 out of 108 020) had a concurrent diagnosis of COVID-19 infection. Individuals with COVID-19 infection exhibited a lower mean age (73.7 years vs. 75.9 years, p = .027) and a lower female proportion (39.87% vs. 47.60%, p = .062) than those without COVID-19. In the multivariable logistic and linear regression models, adjusted for patient and hospital factors, COVID-19 infection was associated with higher in-hospital mortality (aOR 4.67; 95% CI 2.02 to 10.27, p < .001), extended length of stay (5.23 days vs. 1.04 days, p < .001), and linked with various in-hospital complications, including sepsis, acute respiratory failure, post-procedural pneumothorax, and venous thromboembolism. Conclusion: Our study suggests that COVID-19 infection is attributed to higher in-hospital mortality, extended hospital stays, and increased adverse in-hospital outcomes in patients undergoing conventional pacemaker implantation.

Impact of COVID-19 infection on the in-hospital outcome of patients hospitalized for heart failure with comorbid atrial fibrillation: Insight from the National Inpatient Sample (NIS) database 2020.

Introduction: Atrial fibrillation (AF) and heart failure (HF) commonly coexist, resulting in adverse health and economic consequences such as declining ventricular function, heightened mortality, and reduced quality of life. However, limited information exists on the impact of COVID-19 on AF patients that hospitalized for HF. Methods: We analyzed the 2020 U.S. National Inpatient Sample to investigate the effects of COVID-19 on AF patients that primarily hospitalized for HF. Participants aged 18 and above were identified using relevant ICD-10 CM codes. Adjusted odds ratios for outcomes were calculated through multivariable logistic regression. The primary outcome was inpatient mortality, with secondary outcomes including system-based complications. Results: We identified 322,090 patients with primary discharge diagnosis of HF with comorbid AF. Among them, 0.73% (2355/322,090) also had a concurrent diagnosis of COVID-19. In a survey multivariable logistic and linear regression model adjusting for patient and hospital factors, COVID-19 infection was associated with higher in-hospital mortality (aOR 3.17; 95% CI 2.25, 4.47, p < 0.001), prolonged length of stay (ß LOS 2.82; 95% CI 1.71, 3.93, p < 0.001), acute myocarditis (aOR 6.64; 95% CI 1.45, 30.45, p 0.015), acute kidney injury (AKI) (aOR 1.48; 95% CI 1.21, 1.82, p < 0.001), acute respiratory failure (aOR 1.24; 95% CI 1.01, 1.52, p 0.045), and mechanical ventilation (aOR 2.00; 95% CI 1.28, 3.13, p 0.002). Conclusion: Our study revealed that COVID-19 is linked to higher in-hospital mortality and increased adverse outcomes in AF patients hospitalized for HF.

Applying technologies to simplify strategies for exercise in type 1 diabetes.

Challenges and fears related to managing glucose levels around planned and spontaneous exercise affect outcomes and quality of life in people living with type 1 diabetes. Advances in technology, including continuous glucose monitoring, open-loop insulin pump therapy and hybrid closed-loop (HCL) systems for exercise management in type 1 diabetes, address some of these challenges. In this review, three research or clinical experts, each living with type 1 diabetes, leverage published literature and clinical and personal experiences to translate research findings into simplified, patient-centred strategies. With an understanding of limitations in insulin pharmacokinetics, variable intra-individual responses to aerobic and anaerobic exercise, and the features of the technologies, six steps are proposed to guide clinicians in efficiently communicating simplified actions more effectively to individuals with type 1 diabetes. Fundamentally, the six steps centre on two aspects. First, regardless of insulin therapy type, and especially needed for spontaneous exercise, we provide an estimate of glucose disposal into active muscle meant to be consumed as extra carbohydrates for exercise ('ExCarbs'; a common example is 0.5 g/kg body mass per hour for adults and 1.0 g/kg body mass per hour for youth). Second, for planned exercise using open-loop pump therapy or HCL systems, we additionally recommend pre-emptive basal insulin reduction or using HCL exercise modes initiated 90 min (1-2 h) before the start of exercise until the end of exercise. Modifications for aerobic- and anaerobic-type exercise are discussed. The burden of pre-emptive basal insulin reductions and consumption of ExCarbs are the limitations of HCL systems, which may be overcome by future innovations but are unquestionably required for currently available systems.

Examiner-Examinee Gender Concordance Does Not Impact Ratings on the American Board of Surgery Vascular Surgery Certifying Examination.

OBJECTIVE: Implicit bias is a potential factor in the severity of examinee rating during oral examinations. Ratings may be impacted by examinee characteristics, such as gender, that are independent of examinee knowledge-base, clinical judgment or test-taking ability. The effects of examiner-examinee gender concordance in the Vascular Surgery Certifying Examination (VCE) have not been previously studied. We explored whether examiner ratings and likelihood of passing the exam were influenced by gender concordance amongst examiners and examinees. METHODS: Data collected from examinees who first attempted the VCE between 2018 and 2023 were analyzed. There were 1,005 examinees (69.3% male, 30.1% female) and 121 examiners (71.9% male, 28.1% female). Linear Mixed- Effects Models and Generalized Linear Mixed-Effects Models were used to evaluate the effects of examinee and examiner gender on VCE ratings and likelihood of passing the exam. RESULTS: Examiner-examinee gender concordance had no significant impact on examiner ratings or likelihood of passing the exam. Additionally, examinee gender alone had no significant impact on VCE rating or pass rates. Only Vascular Qualifying Exam (VQE) scores explained more than 1% of the variance in total VCE scores for the gender model (F(1,1003.5)=71.08, p-value < 0.01, R2 = 3%). VQE scores were positively related to total VCE scores. CONCLUSIONS: While implicit bias has the potential to impact examiner scoring, there is no evidence that this is the case with respect to gender in the Vascular Surgery Certifying Examination of the American Board of Surgery.

The presence of differentiated C2C12 muscle cells enhances toxin production and growth by Clostridium perfringens type A strain ATCC3624.

Clostridium perfringens type A causes gas gangrene, which involves muscle infection. Both alpha toxin (PLC), encoded by the plc gene, and perfringolysin O (PFO), encoded by the pfoA gene, are important when type A strains cause gas gangrene in a mouse model. This study used the differentiated C2C12 muscle cell line to test the hypothesis that one or both of those toxins contributes to gas gangrene pathogenesis by releasing growth nutrients from muscle cells. RT-qPCR analyses showed that the presence of differentiated C2C12 cells induces C. perfringens type A strain ATCC3624 to upregulate plc and pfoA expression, as well as increase expression of several regulatory genes, including virS/R, agrB/D, and eutV/W. The VirS/R two component regulatory system (TCRS) and its coupled Agr-like quorum sensing system, along with the EutV/W TCRS (which regulates expression of genes involved in ethanolamine [EA] utilization), were shown to mediate the C2C12 cell-induced increase in plc and pfoA expression. EA was demonstrated to increase toxin gene expression. ATCC3624 growth increased in the presence of differentiated C2C12 muscle cells and this effect was shown to involve both PFO and PLC. Those membrane-active toxins were each cytotoxic for differentiated C2C12 cells, suggesting they support ATCC3624 growth by releasing nutrients from differentiated C2C12 cells. These findings support a model where, during gas gangrene, increased production of PFO and PLC in the presence of muscle cells causes more damage to those host cells, which release nutrients like EA that are then used to support C. perfringens growth in muscle.

GSK3 inhibition reduces ECM production and prevents age-related macular degeneration-like pathology.

Malattia Leventinese/Doyne honeycomb retinal dystrophy (ML/DHRD) is an age-related macular degeneration-like (AMD-like) retinal dystrophy caused by an autosomal dominant R345W mutation in the secreted glycoprotein, fibulin-3 (F3). To identify new small molecules that reduce F3 production in retinal pigmented epithelium (RPE) cells, we knocked-in a luminescent peptide tag (HiBiT) into the endogenous F3 locus that enabled simple, sensitive, and high-throughput detection of the protein. The GSK3 inhibitor, CHIR99021 (CHIR), significantly reduced F3 burden (expression, secretion, and intracellular levels) in immortalized RPE and non-RPE cells. Low-level, long-term CHIR treatment promoted remodeling of the RPE extracellular matrix, reducing sub-RPE deposit-associated proteins (e.g., amelotin, complement component 3, collagen IV, and fibronectin), while increasing RPE differentiation factors (e.g., tyrosinase, and pigment epithelium-derived factor). In vivo, treatment of 8-month-old R345W+/+ knockin mice with CHIR (25 mg/kg i.p., 1 mo) was well tolerated and significantly reduced R345W F3-associated AMD-like basal laminar deposit number and size, thereby preventing the main pathological feature in these mice. This is an important demonstration of small molecule-based prevention of AMD-like pathology in ML/DHRD mice and may herald a rejuvenation of interest in GSK3 inhibition for the treatment of retinal degenerative diseases, including potentially AMD itself.