Coronary sinus reducer for the treatment of refractory angina (ORBITA-COSMIC): a randomised, placebo-controlled trial.

BACKGROUND: The coronary sinus reducer (CSR) is proposed to reduce angina in patients with stable coronary artery disease by improving myocardial perfusion. We aimed to measure its efficacy, compared with placebo, on myocardial ischaemia reduction and symptom improvement. METHODS: ORBITA-COSMIC was a double-blind, randomised, placebo-controlled trial conducted at six UK hospitals. Patients aged 18 years or older with angina, stable coronary artery disease, ischaemia, and no further options for treatment were eligible. All patients completed a quantitative adenosine-stress perfusion cardiac magnetic resonance scan, symptom and quality-of-life questionnaires, and a treadmill exercise test before entering a 2-week symptom assessment phase, in which patients reported their angina symptoms using a smartphone application (ORBITA-app). Patients were randomly assigned (1:1) to receive either CSR or placebo. Both participants and investigators were masked to study assignment. After the CSR implantation or placebo procedure, patients entered a 6-month blinded follow-up phase in which they reported their daily symptoms in the ORBITA-app. At 6 months, all assessments were repeated. The primary outcome was myocardial blood flow in segments designated ischaemic at enrolment during the adenosine-stress perfusion cardiac magnetic resonance scan. The primary symptom outcome was the number of daily angina episodes. Analysis was done by intention-to-treat and followed Bayesian methodology. The study is registered with ClinicalTrials.gov, NCT04892537, and completed. FINDINGS: Between May 26, 2021, and June 28, 2023, 61 patients were enrolled, of whom 51 (44 [86%] male; seven [14%] female) were randomly assigned to either the CSR group (n=25) or the placebo group (n=26). Of these, 50 patients were included in the intention-to-treat analysis (24 in the CSR group and 26 in the placebo group). 454 (57%) of 800 imaged cardiac segments were ischaemic at enrolment, with a median stress myocardial blood flow of 1·08 mL/min per g (IQR 0·77-1·41). Myocardial blood flow in ischaemic segments did not improve with CSR compared with placebo (difference 0·06 mL/min per g [95% CrI -0·09 to 0·20]; Pr(Benefit)=78·8%). The number of daily angina episodes was reduced with CSR compared with placebo (OR 1·40 [95% CrI 1·08 to 1·83]; Pr(Benefit)=99·4%). There were two CSR embolisation events in the CSR group, and no acute coronary syndrome events or deaths in either group. INTERPRETATION: ORBITA-COSMIC found no evidence that the CSR improved transmural myocardial perfusion, but the CSR did improve angina compared with placebo. These findings provide evidence for the use of CSR as a further antianginal option for patients with stable coronary artery disease. FUNDING: Medical Research Council, Imperial College Healthcare Charity, National Institute for Health and Care Research Imperial Biomedical Research Centre, St Mary's Coronary Flow Trust, British Heart Foundation.

Characterization of the molecular mechanisms that govern anti-Müllerian hormone synthesis and activity.

The roles of anti-Müllerian hormone (AMH) continue to expand, from its discovery as a critical factor in sex determination, through its identification as a regulator of ovarian folliculogenesis, its use in fertility clinics as a measure of ovarian reserve, and its emerging role in hypothalamic-pituitary function. In light of these actions, AMH is considered an attractive therapeutic target to address diverse reproductive needs, including fertility preservation. Here, we set out to characterize the molecular mechanisms that govern AMH synthesis and activity. First, we enhanced the processing of the AMH precursor to >90% by introducing more efficient proprotein convertase cleavage sites (RKKR or ISSRKKRSVSS [SCUT]). Importantly, enhanced processing corresponded with a dramatic increase in secreted AMH activity. Next, based on species differences across the AMH type II receptor-binding interface, we generated a series of human AMH variants and assessed bioactivity. AMHSCUT potency (EC50 4 ng/mL) was increased 5- or 10-fold by incorporating Gln484 Met/Leu535 Thr (EC50 0.8 ng/mL) or Gln484 Met/Gly533 Ser (EC50 0.4 ng/mL) mutations, respectively. Furthermore, the Gln484 Met/Leu535 Thr double mutant displayed enhanced efficacy, relative to AMHSCUT . Finally, we identified residues within the wrist pre-helix of AMH (Trp494 , Gln496 , Ser497 , and Asp498 ) that likely mediate type I receptor binding. Mutagenesis of these residues generated gain- (Trp494 Phe or Gln496 Leu) or loss- (Ser497 Ala) of function AMH variants. Surprisingly, combining activating type I and type II receptor mutations only led to modest additive increases in AMH potency/efficacy. Our study is the first to characterize AMH residues involved in type I receptor binding and suggests a step-wise receptor-complex assembly mechanism, in which enhancement in the affinity of the ligand for either receptor can increase AMH activity beyond the natural level.

Activin E is a transforming growth factor ß ligand that signals specifically through activin receptor-like kinase 7.

Activins are one of the three distinct subclasses within the greater Transforming growth factor ß (TGFß) superfamily. First discovered for their critical roles in reproductive biology, activins have since been shown to alter cellular differentiation and proliferation. At present, members of the activin subclass include activin A (ActA), ActB, ActC, ActE, and the more distant members myostatin and GDF11. While the biological roles and signaling mechanisms of most activins class members have been well-studied, the signaling potential of ActE has remained largely unknown. Here, we characterized the signaling capacity of homodimeric ActE. Molecular modeling of the ligand:receptor complexes showed that ActC and ActE shared high similarity in both the type I and type II receptor binding epitopes. ActE signaled specifically through ALK7, utilized the canonical activin type II receptors, ActRIIA and ActRIIB, and was resistant to the extracellular antagonists follistatin and WFIKKN. In mature murine adipocytes, ActE invoked a SMAD2/3 response via ALK7, like ActC. Collectively, our results establish ActE as a specific signaling ligand which activates the type I receptor, ALK7.

Performance analysis of mathematical methods used to forecast the 2022 New York City Mpox outbreak.

In mid-2022, New York City (NYC) became the epicenter of the US mpox outbreak. We provided real-time mpox case forecasts to the NYC Department of Health and Mental Hygiene to aid in outbreak response. Forecasting methodologies evolved as the epidemic progressed. Initially, lacking knowledge of at-risk population size, we used exponential growth models to forecast cases. Once exponential growth slowed, we used a Susceptible-Exposed-Infectious-Recovered (SEIR) model. Retrospectively, we explored if forecasts could have been improved using an SEIR model in place of our early exponential growth model, with or without knowing the case detection rate. Early forecasts from exponential growth models performed poorly, as 2-week mean absolute error (MAE) grew from 53 cases/week (July 1-14) to 457 cases/week (July 15-28). However, when exponential growth slowed, providing insight into susceptible population size, an SEIR model was able to accurately predict the remainder of the outbreak (7-week MAE: 13.4 cases/week). Retrospectively, we found there was not enough known about the epidemiological characteristics of the outbreak to parameterize an SEIR model early on. However, if the at-risk population and case detection rate were known, an SEIR model could have improved accuracy over exponential growth models early in the outbreak.

Efficacy of ravulizumab in patients with generalized myasthenia gravis by time from diagnosis: A post hoc subgroup analysis of the CHAMPION MG study.

INTRODUCTION/AIMS: The CHAMPION MG study demonstrated that ravulizumab significantly improved Myasthenia Gravis-Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) total scores versus placebo in adults with acetylcholine receptor antibody-positive generalized myasthenia gravis (AChR+ gMG). This post hoc analysis aimed to assess these outcomes by time from MG diagnosis. METHODS: Changes from baseline to week 26 in MG-ADL and QMG total scores were analyzed by time from MG diagnosis to study entry (≤2 vs. >2 years). Within each subgroup, least-squares (LS) mean changes for ravulizumab and placebo were compared using mixed models for repeated measures. RESULTS: In ravulizumab-treated patients, differences in LS mean (standard error of the mean) changes from baseline to week 26 were not statistically significant in the ≤2-years subgroup versus the >2-years subgroup for MG-ADL (-4.3 [0.70] vs. -2.9 [0.37]; p = .0511) or QMG (-4.3 [0.94] vs. -2.5 [0.50]; p = .0822) scores. No clear trends were observed in the placebo group. LS mean changes from baseline were significantly greater for ravulizumab versus placebo in both the ≤2 and >2 years from diagnosis subgroups for MG-ADL and QMG scores (all p < .05). The difference in treatment effect between the ≤2-years and >2-years subgroups was not statistically significant. No clinically meaningful between-subgroup differences in treatment-emergent adverse events were observed in ravulizumab-treated patients. DISCUSSION: Ravulizumab treatment improved clinical outcomes for patients with AChR+ gMG regardless of time from diagnosis. A numerical trend was observed favoring greater treatment effect with earlier versus later treatment after diagnosis. Further studies are required for confirmation.

Effect of efgartigimod on muscle group subdomains in participants with generalized myasthenia gravis: post hoc analyses of the phase 3 pivotal ADAPT study.

BACKGROUND AND PURPOSE: Generalized myasthenia gravis (gMG) is a rare, chronic, neuromuscular autoimmune disease mediated by pathogenic immunoglobulin G (IgG) autoantibodies. Patients with gMG experience debilitating muscle weakness, resulting in impaired mobility, speech, swallowing, vision and respiratory function. Efgartigimod is a human IgG1 antibody Fc fragment engineered for increased binding affinity to neonatal Fc receptor. The neonatal Fc receptor blockade by efgartigimod competitively inhibits endogenous IgG binding, leading to decreased IgG recycling and increased degradation resulting in lower IgG concentration. METHODS: The safety and efficacy of efgartigimod were evaluated in the ADAPT study. Key efficacy outcome measures included Myasthenia Gravis Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) scores. Efgartigimod demonstrated significant improvement in both the MG-ADL and QMG scores. This post hoc analysis aimed to determine whether all subdomains of MG-ADL and QMG improved with efgartigimod treatment. Individual items of MG-ADL and QMG were grouped into four subdomains: bulbar, ocular, limb/gross motor and respiratory. Change from baseline over 10 weeks in each subdomain was calculated for each group. RESULTS: Greater improvements from baseline were seen across MG-ADL subdomains in participants treated with efgartigimod compared with placebo. These improvements were typically observed 1 to 2 weeks after the first infusion and correlated with reductions in IgG. Similar results were observed across most QMG subdomains. CONCLUSIONS: These post hoc analyses of MG-ADL and QMG subdomain data from ADAPT suggest that efgartigimod is beneficial in improving muscle function and strength across all muscle groups, leading to the observed efficacy in participants with gMG.

Automating Quality Control in Cardiac MRI: AI for Discriminative Assessment of Planning and Movement Artefacts and Real-Time Reacquisition Guidance.

BACKGROUND: Accurate measurements from cardiac magnetic resonance (CMR) images require precise positioning of scan planes and elimination of movement artefacts from arrhythmia or breathing. Unidentified or incorrectly managed artefacts degrade image quality, invalidate clinical measurements and decrease diagnostic confidence. Currently, radiographers must manually inspect each acquired image to confirm diagnostic quality and decide whether reacquisition or a change in sequences is warranted. We aimed to develop an artificial intelligence (AI) to provide continuous quality scores across different quality domains, and from these, determine whether cines are clinically adequate, require replanning, or warrant a change in protocol. METHODS: A three-dimensional convolutional neural network was trained to predict cine quality graded on a continuous scale by a level 3 CMR expert, focusing separately on planning and movement artefacts. It incorporated four distinct output heads for the assessment of image quality in terms of: (a, b, c)2-, 3- and 4-chamber misplanning, and (d)long- and short-axis arrhythmia/breathing artefact. Back-propagation was selectively performed across these heads based on the labels present for each cine. Each image in the testing set was reported by four level 3 CMR experts, providing a consensus on clinical adequacy. The AI's assessment of image quality and ability to identify images requiring replanning or sequence changes were evaluated with Spearman's rho and the area under receiver operating characteristic (AUROC) respectively. RESULTS: A total of 1940 cines across 1387 studies were included. On the test set of 383 cines, AI-judged image quality correlated strongly with expert judgement, with Spearman's rho of 0.84, 0.84, 0.81 and 0.81 for 2-, 3- and 4-chamber planning quality and the extent of arrhythmia or breathing artefacts, respectively. The AI also showed high efficacy in flagging clinically inadequate cines (AUROC 0.88, 0.93, 0.93 and for identifying replanning of 2-, 3- and 4-chamber cines, and 0.90 for identifying movement artefacts). CONCLUSION: AI can assess distinct domains of CMR cine quality and provide continuous quality scores that correlate closely with a consensus of experts. These ratings could be used to identify cases where reacquisition is warranted, and guide corrective actions to optimise image quality, including replanning, prospective gating, or real-time imaging.

Aortic stenosis assessment from the 3-chamber cine: Ratio of balanced steady-state-free-precession (bSSFP) blood signal between the aorta and left ventricle predicts severity.

BACKGROUND: Cardiovascular magnetic resonance (CMR) imaging is an important tool for evaluating the severity of aortic stenosis (AS), co-existing aortic disease, and concurrent myocardial abnormalities. Acquiring this additional information requires protocol adaptations and additional scanner time, but is not necessary for the majority of patients who do not have AS. We observed that the relative signal intensity of blood in the ascending aorta on a balanced steady state free precession (bSSFP) 3-chamber cine was often reduced in those with significant aortic stenosis. We investigated whether this effect could be quantified and used to predict AS severity in comparison to existing gold-standard measurements. METHODS: Multi-centre, multi-vendor retrospective analysis of patients with AS undergoing CMR and transthoracic echocardiography (TTE). Blood signal intensity was measured in a ∼1 cm2 region of interest (ROI) in the aorta and left ventricle (LV) in the 3-chamber bSSFP cine. Because signal intensity varied across patients and scanner vendors, a ratio of the mean signal intensity in the aorta ROI to the LV ROI (Ao:LV) was used. This ratio was compared using Pearson correlations against TTE parameters of AS severity: aortic valve peak velocity, mean pressure gradient and the dimensionless index. The study also assessed whether field strength (1.5 T vs. 3 T) and patient characteristics (presence of bicuspid aortic valves (BAV), dilated aortic root and low flow states) altered this signal relationship. RESULTS: 314 patients (median age 69 [IQR 57-77], 64% male) who had undergone both CMR and TTE were studied; 84 had severe AS, 78 had moderate AS, 66 had mild AS and 86 without AS were studied as a comparator group. The median time between CMR and TTE was 12 weeks (IQR 4-26). The Ao:LV ratio at 1.5 T strongly correlated with peak velocity (r = -0.796, p = 0.001), peak gradient (r = -0.772, p = 0.001) and dimensionless index (r = 0.743, p = 0.001). An Ao:LV ratio of < 0.86 was 84% sensitive and 82% specific for detecting AS of any severity and a ratio of 0.58 was 83% sensitive and 92% specific for severe AS. The ability of Ao:LV ratio to predict AS severity remained for patients with bicuspid aortic valves, dilated aortic root or low indexed stroke volume. The relationship between Ao:LV ratio and AS severity was weaker at 3 T. CONCLUSIONS: The Ao:LV ratio, derived from bSSFP 3-chamber cine images, shows a good correlation with existing measures of AS severity. It demonstrates utility at 1.5 T and offers an easily calculable metric that can be used at the time of scanning or automated to identify on an adaptive basis which patients benefit from dedicated imaging to assess which patients should have additional sequences to assess AS.

Quality assurance of late gadolinium enhancement cardiac magnetic resonance images: a deep learning classifier for confidence in the presence or absence of abnormality with potential to prompt real-time image optimization.

BACKGROUND: Late gadolinium enhancement (LGE) of the myocardium has significant diagnostic and prognostic implications, with even small areas of enhancement being important. Distinguishing between definitely normal and definitely abnormal LGE images is usually straightforward, but diagnostic uncertainty arises when reporters are not sure whether the observed LGE is genuine or not. This uncertainty might be resolved by repetition (to remove artifact) or further acquisition of intersecting images, but this must take place before the scan finishes. Real-time quality assurance by humans is a complex task requiring training and experience, so being able to identify which images have an intermediate likelihood of LGE while the scan is ongoing, without the presence of an expert is of high value. This decision-support could prompt immediate image optimization or acquisition of supplementary images to confirm or refute the presence of genuine LGE. This could reduce ambiguity in reports. METHODS: Short-axis, phase-sensitive inversion recovery late gadolinium images were extracted from our clinical cardiac magnetic resonance (CMR) database and shuffled. Two, independent, blinded experts scored each individual slice for "LGE likelihood" on a visual analog scale, from 0 (absolute certainty of no LGE) to 100 (absolute certainty of LGE), with 50 representing clinical equipoise. The scored images were split into two classes-either "high certainty" of whether LGE was present or not, or "low certainty." The dataset was split into training, validation, and test sets (70:15:15). A deep learning binary classifier based on the EfficientNetV2 convolutional neural network architecture was trained to distinguish between these categories. Classifier performance on the test set was evaluated by calculating the accuracy, precision, recall, F1-score, and area under the receiver operating characteristics curve (ROC AUC). Performance was also evaluated on an external test set of images from a different center. RESULTS: One thousand six hundred and forty-five images (from 272 patients) were labeled and split at the patient level into training (1151 images), validation (247 images), and test (247 images) sets for the deep learning binary classifier. Of these, 1208 images were "high certainty" (255 for LGE, 953 for no LGE), and 437 were "low certainty". An external test comprising 247 images from 41 patients from another center was also employed. After 100 epochs, the performance on the internal test set was accuracy = 0.94, recall = 0.80, precision = 0.97, F1-score = 0.87, and ROC AUC = 0.94. The classifier also performed robustly on the external test set (accuracy = 0.91, recall = 0.73, precision = 0.93, F1-score = 0.82, and ROC AUC = 0.91). These results were benchmarked against a reference inter-expert accuracy of 0.86. CONCLUSION: Deep learning shows potential to automate quality control of late gadolinium imaging in CMR. The ability to identify short-axis images with intermediate LGE likelihood in real-time may serve as a useful decision-support tool. This approach has the potential to guide immediate further imaging while the patient is still in the scanner, thereby reducing the frequency of recalls and inconclusive reports due to diagnostic indecision.

Evaluation of the Effectiveness of Canadian Cardiovascular Society Guidelines in Minimizing Cardiac Events After Total Hip Arthroplasty.

BACKGROUND: The aim of the study was to analyze the Canadian Cardiovascular Society (CCS) guidelines for routine postoperative troponin testing after elective total hip arthroplasty (THA) to reduce the mortality rate resulting from myocardial injury. The purpose of this study was to assess the prognostic relevance of implementing these guidelines to minimize cardiac events in patients undergoing elective THA. METHODS: Patients who underwent THA surgery in 2020 were included in the study. The inclusion criteria were elective THA patients aged ≥45 years, while emergency, revision, and simultaneous bilateral THA surgeries were excluded. The patients were categorized into 4 groups based on the CCS guidelines. RESULTS: The study included 669 patients who had an average age of 67 years. There were 43 patients (6.4%), who experienced a rise in troponin levels ≥30 ng/L and developed myocardial injury after noncardiac surgery. Among these patients, 8 developed cardiac complications, and one experienced a serious cardiac event that resulted in death. Notably, there was a significant increase in the length of hospital stay for patients who received the postoperative screening protocol. CONCLUSIONS: The implementation of the CCS guidelines for routine postoperative troponin testing in elective THA surgery did not significantly decrease the rate of cardiac events or mortality.

Short-Term (90 Days) Clinical Outcomes Following the Day of Surgery Conversion of Inpatient to Same-Day Hip and Knee Arthroplasty.

BACKGROUND: The incidence of total joint arthroplasty is increasing, with added emphasis on shifting care toward outpatient surgery. This has demonstrated improvements in costs and care; however, safety must be prioritized. Published assessment tools highlight candidates for outpatient surgery; however, they often do not define patients who have a worse prognosis. Limited healthcare resources occasionally force patients to convert to outpatient surgery or risk cancellation, creating a dilemma for both patients and surgeons. We evaluated the short-term (90-day) outcomes of patients converted from planned inpatient admission to same-day discharge on day of surgery outpatients and sought to identify any groups at risk, who may not be appropriate for this conversion. METHODS: We identified all patients undergoing planned inpatient total hip or knee arthroplasty at a tertiary academic medical center over a 2-year period. We included patients discharged the day of surgery for analysis, excluding revision procedures and those performed for fracture care. A manual chart review identified demographic factors and primary outcome measures; including reoperation, readmission, and emergency room visits within a 90-day postoperative period. RESULTS: We identified a total of 80 patients who converted from inpatient to outpatient surgery over a 2-year interval. Over the first 90 days postoperatively 4 (5%) patients were readmitted: 2 (2.5%) for medical complications and 2 (2.5%) for reoperation. There were 2 (2.5%) reoperations; one (1.25%) for manipulation under anesthesia, and one (1.25%) for periprosthetic joint infection. There were 5 (6.3%) wound complications; however, only one (1.25%) required surgical intervention. A total of 5 (6.3%) patients returned to an emergency department, leading to a single (1.25%) hospital readmission. CONCLUSIONS: Hospital and healthcare resources are occasionally limited to the extent that patients must convert to outpatient surgery or risk cancellation. At our institution, the same-day conversion of planned inpatient hip and knee arthroplasty patients to outpatient surgery was safe and did not increase short-term clinical outcomes or complications.

Cementless Total Knee Arthroplasty: Does Age Affect Survivorship and Outcomes?

BACKGROUND: Despite the growing popularity of cementless total knee arthroplasty (TKA) in younger patients, the outcomes are unclear in the elderly population. We aimed to compare the clinical outcomes and survivorship of cementless TKA between different age groups. METHODS: Utilizing our prospectively collected institutional database, we retrospectively reviewed all patients undergoing primary cementless TKAs at a tertiary care institute. We identified 347 TKA, which were divided into 3 groups based on age at the time of surgery. Group A was ≤ 60 years, Group B was 60 to ≤ 70 years, and Group C was > 70 years. We compared clinical outcomes (Knee Society Clinical Rating System [KSCRS], Western Ontario and McMaster University Osteoarthritis Index [WOMAC], and Veterans Rand 12 Item Health Survey [VR-12]) and survivorship between the groups. RESULTS: At final follow-up, range of motion, KSCRS, WOMAC, and VR-12 physical score were comparable (P > .05). The VR-12 Mental score was higher in Group B and Group C than in Group A (P = .003). Compared to preoperative scores, the change in KSCRS, WOMAC, and VR-12 physical and mental scores was comparable at the final follow-up (P > .05). No patient underwent revision for aseptic loosening. CONCLUSIONS: There were no cases of revision surgery for aseptic loosening in our cohort of 347 cementless TKAs. Patients > 70 years of age undergoing cementless TKA can achieve clinical scores equivalent to those of younger patients at short term (2-year) follow-up. Longer-term survivorship is still required, but based on early data, cementless TKA can be a safe option for older patients.

Survivorship and Outcomes of 2-Stage Revision for Infected Total Hip Arthroplasty at a Mean of 7-Year Follow-Up.

BACKGROUND: Periprosthetic joint infection (PJI) continues to be one of the leading causes of failure following total hip arthroplasty (THA). The objectives of the study were to (1) determine the minimum 2-year infection-free survivorship of 2-stage revision THA, (2) determine the causative organisms for repeat 2-stage revision THA, and (3) characterize the results of failed 2-stage revisions and evaluate patient-reported outcome measures (PROMs). METHODS: A retrospective chart review was completed for patients who underwent 2-stage revision THA for PJI. Prospective data were collected on each patient, including demographics, causative organisms, complications, and type of reoperation. The PROMs, including Harris Hip Score, 12-item Short-Form Health Survey, and Western Ontario and McMaster Universities Osteoarthritis Index scores were obtained prior to 2-stage revision THA surgery and annually as part of standard clinical and radiographic follow-up. RESULTS: A total of 328 patients who underwent a 2-stage revision THA for a PJI were included in the study (mean age 67 years [range, 28 to 90], mean body mass index of 30.6 [range, 15 to 57]). The overall infection-free survivorship for 2-stage revision THA was 73.8% at a minimum of 2 years (range, 2 to 20). Overall, 194 (59.1%) patients who had successful infection eradication underwent a 2-revision THA only. The most common single organisms infected were Staphylococcus aureus (12.5%) and Staphylococcus epidermidis (11%). Higher reoperation rates were found in cases with methicillin-resistant Staphylococcus aureus and polymicrobial infections. All PROMs showed statistical improvement from preoperatively to the latest follow-up appointment. CONCLUSIONS: Two-stage revision THA is associated with a good success rate in the treatment of PJIs at mid-term to long-term follow-up. Polymicrobial and methicillin-resistant Staphylococcus aureus infections are poor prognostic factors, making the eradication of infection more difficult. The management of PJIs continues to be one of the most important orthopaedic challenges to treat.

Effect of Surgical Technique, Implant Design, and Time of Examination on Contact Kinematics: A Study of Bicruciate-Stabilized and Posterior-Stabilized Total Knee Arthroplasty.

BACKGROUND: Bicruciate-stabilized (BCS) total knee arthroplasty (TKA) designs attempt to approximate natural knee mechanics. Multiple surgical techniques, including gap balancing (GB) and measured resection (MR), have been developed to provide optimal implant positioning and soft-tissue balance. The goal of this study was to determine the effect of surgical technique on BCS TKA contact kinematics. Secondary goals included investigating the change of kinematics over time and comparing BCS TKA kinematics to a posterior-stabilized (PS) design. METHODS: The study included the BCS-GB, BCS-MR, and PS-MR groups. The BCS-GB and BCS-MR groups underwent weight-bearing radiostereometric analysis for multiple knee flexion angles at 3 months and 1 year postoperatively, whereas the PS-MR group was imaged at 1 year postoperatively. The medial and lateral contact kinematics were determined from implant poses. RESULTS: There were no differences in BCS TKA kinematics between the GB and MR techniques. There were differences in the mid-flexion ranges when comparing the 3-month and 1-year kinematics of the BCS design; however, they were less than 1.5 mm. Differences existed between the kinematics of the BCS and PS designs at all flexion angles for the medial condyle (P < .0006) and at 0° of flexion on the lateral condyle (P < .0001). CONCLUSIONS: Contact kinematics for a BCS design were similar for both surgical techniques, suggesting both are appropriate for this design. Small, likely clinically insignificant differences were found between 3-month and 1-year kinematics. The BCS TKA kinematics differed from the PS design; however, it is unclear whether these differences improve clinical outcomes.

Minimum 2-Year Outcomes of a Modern Monoblock Titanium Fluted Tapered Revision Stem for Complex Primary and Revision Total Hip Arthroplasty.

BACKGROUND: Modular titanium fluted tapered (TFT) stems have demonstrated excellent clinical success for femoral revision total hip arthroplasty (THA) surgery. This study reports the short-term outcomes of a novel modern monoblock TFT stem used for revision and complex primary THA with a minimum of 2 years of follow-up. METHODS: We identified 126 patients who received a single monoblock TFT stem: 26 patients for complex THA (failed fracture fixation) and 100 patients for revision THA. The reasons for revision THA included 40 for previous periprosthetic joint infection, 42 for aseptic loosening, 9 for trunnionosis, and 9 for periprosthetic fractures. The Paprosky grading for femoral bone loss at the time of surgery and the measured subsidence of femoral stems at 3-month follow-up were determined. We evaluated the number and indications for reoperations. RESULTS: The mean time from surgery was 3.9 years (range, 2.0 to 6.9). A paired t-test analysis showed significant improvement from preoperative versus postoperative clinical outcome scores (P < .001) for Harris Hip Score (38.76 ± 15.24 versus 83.42 ± 15.38), Western Ontario and McMaster Universities Arthritis Index (45.6 ± 19.0 versus 69.9 ± 21.3), Veterans RAND 12 Item Health Survey Physical component (31.7 ± 8.1 versus 37.8 ± 11.3), and Veterans RAND 12 Item Health Survey Mental component (48.2 ± 12.2 versus 51.6 ± 12.5). The Paprosky grading for femoral bone loss was Grade 1 (3.9%), Grade 2 (35.7%), Grade 3A (47.6%), Grade 3B (11.1%), and Grade 4 (1.6%) cases. There were 18 reoperations (14.7%), with 13 for periprosthetic joint infection (7 treated with implant retention and 6 treated with a 2-stage revision), 4 for instability, and 1 for acetabular aseptic loosening. There were no aseptic failures of the stem. CONCLUSIONS: This novel modern monoblock TFT stem provided reliable femoral fixation and has increasingly supplanted the use of modular TFT stems for complex primary and revision surgery in our institution.

Gap patterns and radiographic follow-up of newer-generation cementless total knee arthroplasty designs.

BACKGROUND: Interest in cementless total knee arthroplasty (TKA) has increased with advancement of biomaterials and implant design and associated improved longevity. We sought to evaluate the gap patterns and radiolucent zones radiographically for 2 newer-generation cementless TKA designs. METHODS: We retrospectively reviewed our single-institution database between January 2017 and December 2019. We identified patients with a porous keeled tibia base-plate with 4-bullet cruciform spikes and peri-apatite coated femoral component (study group 1) and patients who received a cementless porous coated femoral component and rotating platform tibia baseplate with 4 peripheral porous coated pegs around a central cone (study group 2). We identified gap patterns at 6 weeks and at 1 year or more postoperatively on radiographs, noting indications for reoperation. RESULTS: We identified 228 patients in study group 1 and 41 patients in study group 2. At 1-year follow-up, we found evidence of resolved femoral gaps in 52 (72.2%) of 72 patients in study group 1 and 10 (58.8%) of 17 patients in study group 2 (p = 0.124). We identified 27 (84.3%) of 32 patients in study group 1 and 7 (70.0%) of 10 patients in study group 2 with resolved tibia gaps (p = 0.313). After 1 year, there were significantly more Zone 3a femoral zonal radiolucent gaps (p = 0.001) and Zone 8 tibia zonal radiolucent gaps (p = 0.002) in study group 2 than in study group 1. There were 4 reoperations for study group 1 and 0 reoperations for study group 2. CONCLUSION: The modern cementless TKA systems have varied gap patterns in postoperative radiographs, which may be attributed to the implant design. Most radiolucent gaps resolve radiographically on follow-up.

Circular Dichroism Sensing: Strategies and Applications.

The analysis of the absolute configuration, enantiomeric composition, and concentration of chiral compounds are frequently encountered tasks across the chemical and health sciences. Chiroptical sensing methods can streamline this work and allow high-throughput screening with remarkable reduction of operational time and cost. During the last few years, significant methodological advances with innovative chirality sensing systems, the use of computer-generated calibration curves, machine learning assistance, and chemometric data processing, to name a few, have emerged and are now matched with commercially available multi-well plate CD readers. These developments have reframed the chirality sensing space and provide new opportunities that are of interest to a large group of chemists. This review will discuss chirality sensing strategies and applications with representative small-molecule CD sensors. Emphasis will be given to important milestones and recent advances that accelerate chiral compound analysis by outperforming traditional methods, conquer new directions, and pioneering efforts that lie at the forefront of chiroptical high-throughput screening developments. The goal is to provide the reader with a thorough understanding of the current state and a perspective of future directions of this rapidly emerging field.

Heterogeneity in Neutrophil Extracellular Traps from Healthy Human Subjects.

Neutrophil extracellular traps (NETs), a key component of early defense against microbial infection, are also associated with tissue injury. NET composition has been reported to vary with some disease states, but the composition and variability of NETs across many healthy subjects provide a critical comparison that has not been well investigated. We evaluated NETs from twelve healthy subjects of varying ages isolated from multiple blood draws over a three-and-one-half-year period to delineate the variability in extracellular DNA, protein, enzymatic activities, and susceptibility to protease inhibitors. We calculated correlations for NET constituents and loss of human bronchial epithelial barrier integrity, measured by transepithelial electrical resistance, after NET exposure. We found that although there was some variability within the same subject over time, the mean NET total DNA, dsDNA, protein, LDH, neutrophil elastase (NE), and proteinase 3 (PR3) in isolated NETs were consistent across subjects. NET serine protease activity varied considerably within the same donor from day to day. The mean NET cathepsin G and MPO were significantly different across donors. IL-8 > IL-1RA > G-CSF were the most abundant cytokines in NETs. There was no significant difference in the mean concentration or variability of IL-8, IL-1RA, G-CSF, IL-1α, IL-1ß, or TNF-α in different subjects' NETs. NET DNA concentration was correlated with increased NET neutrophil elastase activity and higher NET IL-1RA concentrations. The mean reduction in protease activity by protease inhibitors was significantly different across donors. NET DNA concentration correlated best with reductions in the barrier integrity of human bronchial epithelia. Defining NET concentration by DNA content correlates with other NET components and reductions in NET-driven epithelial barrier dysfunction, suggesting DNA is a reasonable surrogate measurement for these complex structures in healthy subjects.

An analysis of direct and indirect costs in Hidradenitis Suppurativa.

Background: Hidradenitis Suppurativa (HS) is a chronic inflammatory skin condition with recurrent nodules and abscesses that culminate in purulent discharge and scarring. It has significant physical, psychological and financial impact. Objectives: This study plans to analyse patient costs associated with HS. Direct costs include prescription items. Indirect or out-of-pocket costs include dressings, analgesia, and healthcare-related travel costs. This study will also assess disease impact on quality-of-life (QOL). Methods: Patients with HS diagnosis attending dermatology OPD at our public tertiary centre were invited to participate. Ethical approval was secured, and informed consent was obtained. Participants completed an anonymous survey which was analysed to identify costs associated with HS as well as demographics and QOL impact. Results: A total of 25 patients completed the survey; median age was 29% and 80% were female. Median time from HS onset to diagnosis was 2 years, with 24% waiting >10 years to be diagnosed. In the past 3 months, 20% spent >€200 in both categories; prescription and non-prescription items. In the non-prescription category, 36% of patients reported expenditure >€100 in the past 3 months. Dressings were the most common out-of-pocket expense (in 15/25 patients), followed by analgesia and protective clothing. Attendance at medical appointments cost 24% of patients €50-€200. Four participants reported difficulty accessing HS treatments due to associated costs. Mean number of absence days from work/education as result of HS was 8.7 in the past 3 months. Two patients reported being on disability allowance, and two on unemployment benefit as result of their skin disorder. In the QOL question; 96% reported disease impact on QOL, and 11 participants reported that it affected their life 'very much'. Conclusions: HS is a chronic inflammatory skin condition with significant financial burden alongside the well-analysed biopsychosocial disease impact. Financial burden can be divided into direct prescription costs and indirect costs such as non-prescription items, protective clothing and travel costs which we have explored in this study. Further research is needed in this area to identify and optimise both the financial and QOL implications of HS in acute flares and chronic disease management.