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.

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 towards 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 two-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 re-operation, re-admission, and emergency room visits within a 90-day post-operative period. RESULTS: We identified a total of 80 patients who converted from inpatient to outpatient surgery over a two-year interval. Over the first 90 days post-operatively four (5%) patients were readmitted: two (2.5%) for medical complications and two (2.5%) for re-operation. There were two (2.5%) re-operations; one (1.25%) for manipulation under anesthesia, and one (1.25%) for periprosthetic joint infection. There were five (6.3%) wound complications; however, only one (1.25%) required surgical intervention. A total of five (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.

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

INTRODUCTION: 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 four groups based on the CCS guidelines. RESULTS: The study included 669 patients who had an average age of 67 years. There were forty-three patients (6.4%), who experienced a rise in troponin levels ≥ 30 ng/L and developed myocardial injury after noncardiac surgery (MINS). Among these patients, eight 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. CONCLUSION: 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.

Therapeutic options for neurocardiogenic syncope: a meta-analysis of randomised trials with and without blinding.

BACKGROUND: Neurocardiogenic syncope is a common condition with significant associated psychological and physical morbidity. The effectiveness of therapeutic options for neurocardiogenic syncope beyond placebo remains uncertain. METHODS: The primary endpoint was the risk ratio (RR) of spontaneously recurring syncope following any therapeutic intervention. We also examined the effect of blinding on treatment efficacy. We identified all randomised trials which evaluated the effect of any pharmacological, device-based or supportive intervention on patients with a history of syncope. A systematic search was conducted on Medline, Embase, PubMed databases and Cochrane Central Register for Controlled Trials from 1950 to 25 April 2023. Event rates, their RRs and 95% CIs were calculated, and a random-effects meta-analysis was conducted for each intervention. Data analysis was performed in R using RStudio. RESULTS: We identified 47 eligible trials randomising 3518 patients. Blinded trials assessing syncope recurrence were neutral for beta blockers, fludrocortisone and conventional dual-chamber pacing but were favourable for selective serotonin reuptake inhibitors (SSRIs) (RR 0.40, 95% CI 0.26 to 0.63, p<0.001), midodrine (RR 0.70, 95% CI 0.53 to 0.94, p=0.016) and closed-loop stimulation (CLS) pacing (RR 0.15, 95% CI 0.07 to 0.35, p<0.001). Unblinded trials reported significant benefits for all therapy categories other than beta blockers and consistently showed larger benefits than blinded trials. CONCLUSIONS: Under blinded conditions, SSRIs, midodrine and CLS pacing significantly reduced syncope recurrence. Future trials for syncope should be blinded to avoid overestimating treatment effects. PROSPERO REGISTRATION NUMBER: CRD42022330148.

N-of-1 Trial of Angina Verification Before Percutaneous Coronary Intervention.

BACKGROUND: In stable coronary artery disease, 30% to 60% of patients remain symptomatic despite successful revascularization. Perhaps not all symptoms reported by a patient with myocardial ischemia are, in fact, angina. OBJECTIVES: This study sought to determine whether independent symptom verification using a placebo-controlled ischemic stimulus could distinguish which patients achieve greatest symptom relief from percutaneous coronary intervention (PCI). METHODS: ORBITA-STAR was a multicenter, n-of-1, placebo-controlled study in patients undergoing single-vessel PCI for stable symptoms. Participants underwent 4 episodes (60 seconds each) of low-pressure balloon occlusion across their coronary stenosis, randomly paired with 4 episodes of placebo inflation. Following each episode, patients reported the similarity of the induced symptom in comparison with their usual symptom. The similarity score ranged from -10 (placebo replicated the symptom more than balloon occlusion) to +10 (balloon occlusion exactly replicated the symptom). The primary endpoint was the ability of the similarity score to predict symptom relief with PCI. RESULTS: Fifty-one patients were recruited, aged 62.9 ± 8.6 years. The median fractional flow reserve was 0.68 (Q1-Q3: 0.57-0.79), and the instantaneous wave-free ratio was 0.80 (Q1-Q3: 0.48-0.89). The median similarity score was 3 (Q1-Q3: 0.875-5.25). The similarity score was a strong predictor of symptom improvement following PCI: a patient with an upper quartile similarity score of 5.25 was significantly more likely to have lower angina frequency at follow-up (OR: 8.01; 95% credible interval: 2.39-15.86) than a patient with a lower quartile similarity score of 0.875 (OR: 1.31; 95% credible interval: 0.71-1.99), Pr(difference) >99.9%. CONCLUSIONS: Similarity score powerfully predicted symptom improvement from PCI. These data lay the foundation for independent symptom mapping to target PCI to those patients most likely to benefit. (Systematic Trial of Angina Assessment Before Revascularization [ORBITA-STAR]; NCT04280575).

Symptoms as a Predictor of the Placebo-Controlled Efficacy of PCI in Stable Coronary Artery Disease.

BACKGROUND: Placebo-controlled evidence from ORBITA-2 (Objective Randomised Blinded Investigation with Optimal Medical Therapy of Angioplasty in Stable Angina-2) found that percutaneous coronary intervention (PCI) in stable coronary artery disease with little or no antianginal medication relieved angina, but residual symptoms persisted in many patients. The reason for this was unclear. OBJECTIVES: This ORBITA-2 secondary analysis investigates the relationship between presenting symptoms and disease severity (anatomic, noninvasive, and invasive ischemia) and the ability of symptoms to predict the placebo-controlled efficacy of PCI. METHODS: Prerandomization symptom severity and nature were assessed using the ORBITA smartphone application and symptom and quality of life questionnaires including the World Health Organization Rose angina questionnaire (Rose). Disease severity was assessed using quantitative coronary angiography, stress echocardiography, fractional flow reserve, and instantaneous wave-free ratio. Bayesian ordinal regression was used. RESULTS: At prerandomization, the median number of daily angina episodes was 0.8 (Q1-Q3: 0.4-1.6), 64% had Rose angina, quantitative coronary angiography diameter stenosis was 61% (Q1-Q3: 49%-74%), stress echocardiography score was 1.0 (Q1-Q3: 0.0-2.7), fractional flow reserve was 0.63 (Q1-Q3: 0.49-0.75), and instantaneous wave-free ratio was 0.78 (Q1-Q3: 0.55-0.87). There was little relationship between symptom severity and nature and disease severity: angina symptom score with quantitative coronary angiography ordinal correlation coefficient: 0.06 (95% credible interval [CrI]: 0.00-0.08); stress echocardiography: 0.09 (95% CrI: 0.02-0.10); fractional flow reserve: 0.04 (95% CrI: -0.03 to 0.07); and instantaneous wave-free ratio: 0.04 (95% CrI: -0.01 to 0.07). However, Rose angina and guideline-based typical angina were strong predictors of placebo-controlled PCI efficacy (angina symptom score: OR: 1.9; 95% CrI: 1.6-2.1; probability of interaction [PrInteraction] = 99.9%; and OR: 1.8; 95% CrI: 1.6-2.1; PrInteraction = 99.9%, respectively). CONCLUSIONS: Although symptom severity and nature were poorly associated with disease severity, the nature of symptoms powerfully predicted the placebo-controlled efficacy of PCI.

Eculizumab in Adolescent Patients With Refractory Generalized Myasthenia Gravis: A Phase 3, Open-Label, Multicenter Study.

BACKGROUND: This study evaluated the efficacy and safety of eculizumab, a terminal complement C5 inhibitor, in juvenile generalized myasthenia gravis (gMG). METHODS: Adolescents aged 12 to 17 years with refractory anti-acetylcholine receptor (AChR) antibody-positive gMG received eculizumab (weekly induction [one to two doses of 600 mg or four doses of 900 mg] followed by maintenance doses [300 to 1200 mg] every two weeks for up to 26 weeks) in a phase 3, open-label multicenter study (NCT03759366). Change from baseline to week 26 in Quantitative Myasthenia Gravis (QMG) total score (primary end point) and secondary end points including Myasthenia Gravis-Activities of Daily Living (MG-ADL) total score, Myasthenia Gravis Composite score, Myasthenia Gravis Foundation of America postintervention status, EuroQol 5-Dimensions (Youth) and Neurological Quality-of-Life Pediatric Fatigue questionnaire scores, as well as pharmacokinetics, pharmacodynamics, and safety, were recorded. RESULTS: Eleven adolescents (mean ± S.D. age 14.8 ± 1.8 years) were enrolled; 10 completed the primary evaluation period. Least-squares mean changes from baseline at week 26 were -5.8 (standard error [SE] 1.2; P = 0.0004) for QMG total score and -2.3 (SE 0.6; P = 0.0017) for MG-ADL total score. Overall, the primary and all secondary efficacy end point analyses met statistical significance from the first assessment and were sustained throughout. Complete terminal complement inhibition was sustained through 26 weeks in all patients. Treatment-emergent adverse events were all mild/moderate and predominantly unrelated to eculizumab. CONCLUSIONS: Eculizumab was effective in reducing disease burden and was well tolerated in adolescents with refractory AChR antibody-positive gMG.

Evaluating algorithms for identifying incident Guillain-Barré Syndrome in Medicare fee-for-service claims.

Objective: Claims data can be leveraged to study rare diseases such as Guillain-Barré Syndrome (GBS), a neurological autoimmune condition. It is difficult to accurately measure and distinguish true cases of disease with claims without a validated algorithm. Our objective was to identify the best-performing algorithm for identifying incident GBS cases in Medicare fee-for-service claims data using chart reviews as the gold standard. Study design and setting: This was a multi-center, single institution cohort study from 2015 to 2019 that used Medicare-linked electronic health record (EHR) data. We identified 211 patients with a GBS diagnosis code in any position of an inpatient or outpatient claim in Medicare that also had a record of GBS in their electronic medical record. We reported the positive predictive value (PPV = number of true GBS cases/total number of GBS cases identified by the algorithm) for each algorithm tested. We also tested algorithms using several prevalence assumptions for false negative GBS cases and calculated a ranked sum for each algorithm's performance. Results: We found that 40 patients out of 211 had a true case of GBS. Algorithm 17, a GBS diagnosis in the primary position of an inpatient claim and a diagnostic procedure within 45 days of the inpatient admission date, had the highest PPV (PPV = 81.6%, 95% CI (69.3, 93.9). Across three prevalence assumptions, Algorithm 15, a GBS diagnosis in the primary position of an inpatient claim, was favored (PPV = 79.5%, 95% CI (67.6, 91.5). Conclusions: Our findings demonstrate that patients with incident GBS can be accurately identified in Medicare claims with a chart-validated algorithm. Using large-scale administrative data to study GBS offers significant advantages over case reports and patient repositories with self-reported data, and may be a potential strategy for the study of other rare diseases.

Physiological Assessment with iFR prior to FFR Measurement in Left Main Disease.

Despite guideline-based recommendation of the interchangeable use of instantaneous wave-free ratio (iFR) and fractional flow reserve (FFR) to guide revascularization decision-making, iFR/FFR could demonstrate different physiological or clinical outcomes in some specific patient or lesion subsets. Therefore, we sought to investigate the impact of difference between iFR and FFR-guided revascularization decision-making on clinical outcomes in patients with left main disease (LMD). In this international multicenter registry of LMD with physiological interrogation, we identified 275 patients in whom physiological assessment was performed with both iFR/FFR. Major adverse cardiovascular event (MACE) was defined as a composite of death, non-fatal myocardial infarction, and ischemia-driven target lesion revascularization. The receiver-operating characteristic analysis was performed for both iFR/FFR to predict MACE in respective patients in whom revascularization was deferred and performed. In 153 patients of revascularization deferral, MACE occurred in 17.0% patients. The optimal cut-off values of iFR and FFR to predict MACE were 0.88 (specificity:0.74; sensitivity:0.65) and 0.76 (specificity:0.81; sensitivity:0.46), respectively. The area under the curve (AUC) was significantly higher for iFR than FFR (0.74; 95%CI 0.62-0.85 vs. 0.62; 95%CI 0.48-0.75; p = 0.012). In 122 patients of coronary revascularization, MACE occurred in 13.1% patients. The optimal cut-off values of iFR and FFR were 0.92 (specificity:0.93; sensitivity:0.25) and 0.81 (specificity:0.047; sensitivity:1.00), respectively. The AUCs were not significantly different between iFR and FFR (0.57; 95%CI 0.40-0.73 vs. 0.46; 95%CI 0.31-0.61; p = 0.43). While neither baseline iFR nor FFR was predictive of MACE in patients in whom revascularization was performed, iFR-guided deferral seemed to be safer than FFR-guided deferral.

Randomized Trial of Remote Assessment of Patients After an Acute Coronary Syndrome.

BACKGROUND: Telemedicine programs can provide remote diagnostic information to aid clinical decisions that could optimize care and reduce unplanned readmissions post-acute coronary syndrome (ACS). OBJECTIVES: TELE-ACS (Remote Acute Assessment of Patients With High Cardiovascular Risk Post-Acute Coronary Syndrome) is a randomized controlled trial that aims to compare a telemedicine-based approach vs standard care in patients following ACS. METHODS: Patients were suitable for inclusion with at least 1 cardiovascular risk factor and presenting with ACS and were randomized (1:1) before discharge. The primary outcome was time to first readmission at 6 months. Secondary outcomes included emergency department (ED) visits, major adverse cardiovascular events, and patient-reported symptoms. The primary analysis was performed according to intention to treat. RESULTS: A total of 337 patients were randomized from January 2022 to April 2023, with a 3.6% drop-out rate. The mean age was 58.1 years. There was a reduced rate of readmission over 6 months (HR: 0.24; 95% CI: 0.13-0.44; P < 0.001) and ED attendance (HR: 0.59; 95% CI: 0.40-0.89) in the telemedicine arm, and fewer unplanned coronary revascularizations (3% in telemedicine arm vs 9% in standard therapy arm). The occurrence of chest pain (9% vs 24%), breathlessness (21% vs 39%), and dizziness (6% vs 18%) at 6 months was lower in the telemedicine group. CONCLUSIONS: The TELE-ACS study has shown that a telemedicine-based approach for the management of patients following ACS was associated with a reduction in hospital readmission, ED visits, unplanned coronary revascularization, and patient-reported symptoms. (Telemedicine in High-Risk Cardiovascular Patients Post-ACS [TELE-ACS]; NCT05015634).

Insights into microorganisms, associated factors, and the oral microbiome in infective endocarditis patients.

Introduction: Infective Endocarditis (IE) is a rare, life-threatening infection of the endocardium with multisystem effects. Culprit microorganisms derived from different niches circulate through the bloodstream and attach to the endocardium, particularly the heart valves. This study aimed to investigate culprit microorganisms among a cross-sectional cohort of IE patients, their associated factors, and to explore the potential relationship to the oral microbiome. Methods: In this observational study, we undertook a cross-sectional analysis of 392 medical records from patients diagnosed with IE. The primary outcome of this study was to analyse the association between the IE culprit microorganisms and the underlying anatomical types of IE (native valve (NVE), prosthetic valve (PVE), or cardiac device-related (CDE)). Secondary outcomes encompassed a comparative analysis of additional factors, including: the treatment approaches for IE, and the categorisation of blood cultures, extending to both genus and species levels. Additionally, we cross-referenced and compared the species-level identification of IE bacteraemia outcome measures with data from the expanded Human Oral Microbiome Database (eHOMD). Results: A culprit microorganism was identified in 299 (76.28%) case participants. Staphylococcal infections were the most common (p < 0.001), responsible for 130 (33.16%) hospitalisations. There were 277 (70.66%) cases of NVE, 104 (26.53%) cases of PVE, and 11 (2.81%) cases of CDE. The majority of PVE occurred on prosthetic aortic valves (78/104, 75%), of which 72 (93.5%) were surgical aortic valve replacements (SAVR), 6 (7.8%) were transcatheter aortic valve implants, and one transcatheter pulmonary valve implant. Overall, underlying anatomy (p = 0.042) as well as the treatment approaches for IE (p < 0.001) were significantly associated with IE culprit microorganisms. Cross-reference between IE bacteraemia outcomes with the eHOMD was observed in 267/392 (68.11%) cases. Conclusions: This study demonstrated that IE patients with a history of stroke, smoking, intravenous drug use, or dialysis were more likely to be infected with Staphylococcus aureus. CDE case participants and patients who had previous SAVR were most associated with Staphylococcus epidermidis. IE patients aged 78+ were more likely to develop enterococci IE than other age groups. Oral microorganisms indicated by the eHOMD are significantly observed in the IE population. Further research, through enhanced dental and medical collaboration, is required to correlate the presence of oral microbiota as causative factor for IE.

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.

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.

Long-term safety and efficacy of zilucoplan in patients with generalized myasthenia gravis: interim analysis of the RAISE-XT open-label extension study.

Background: Generalized myasthenia gravis (gMG) is a chronic, unpredictable disease associated with high treatment and disease burdens, with a need for more effective and well-tolerated treatments. Objectives: To evaluate the long-term safety, tolerability, and efficacy of zilucoplan in a mild-to-severe, acetylcholine receptor autoantibody-positive (AChR+) gMG population. Design: Ongoing, multicenter, phase III open-label extension (OLE) study. Methods: Eligible patients had completed a qualifying randomized, placebo-controlled phase II or phase III zilucoplan study and received daily, self-administered subcutaneous 0.3 mg/kg zilucoplan. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Secondary efficacy endpoints included change from baseline in Myasthenia Gravis Activities of Daily Living (MG-ADL) score. Results: In total, 200 patients enrolled. At the cut-off date (8 September 2022), median (range) exposure to zilucoplan in RAISE-XT was 1.2 (0.11-4.45) years. Mean age at OLE baseline was 53.3 years. A total of 188 (94%) patients experienced a TEAE, with the most common being MG worsening (n = 52, 26%) and COVID-19 (n = 49, 25%). In patients who received zilucoplan 0.3 mg/kg in the parent study, further improvements in MG-ADL score continued through to Week 24 (least squares mean change [95% confidence interval] from double-blind baseline -6.06 [-7.09, -5.03]) and were sustained through to Week 60 (-6.04 [-7.21, -4.87]). In patients who switched from placebo in the parent study, rapid improvements in MG-ADL score were observed at the first week after switching to zilucoplan; further improvements were observed at Week 24, 12 weeks after switching (-6.46 [-8.19, -4.72]), and were sustained through to Week 60 (-6.51 [-8.37, -4.65]). Consistent results were observed in other efficacy endpoints. Conclusion: Zilucoplan demonstrated a favorable long-term safety profile, good tolerability, and sustained efficacy through to Week 60 with consistent benefits in a broad AChR+ gMG population. Additional long-term data will be available in future analyses. Trial registration: ClinicalTrials.gov identifier: NCT04225871 (https://clinicaltrials.gov/ct2/show/NCT04225871).

Structural Basis of Non-Latent Signaling by the Anti-Müllerian Hormone Procomplex.

Most TGFß family ligands exist as procomplexes consisting of a prodomain noncovalently bound to a growth factor (GF); Whereas some prodomains confer latency, the Anti-Müllerian Hormone (AMH) prodomain maintains a remarkably high affinity for the GF yet remains active. Using single particle EM methods, we show the AMH prodomain consists of two subdomains: a vestigial TGFß prodomain-like fold and a novel, helical bundle GF-binding domain, the result of an exon insertion 450 million years ago, that engages both receptor epitopes. When associated with the prodomain, the AMH GF is distorted into a strained, open conformation whose closure upon bivalent binding of AMHR2 displaces the prodomain through a conformational shift mechanism to allow for signaling.

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.

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.

Biosensor and machine learning-aided engineering of an amaryllidaceae enzyme.

A major challenge to achieving industry-scale biomanufacturing of therapeutic alkaloids is the slow process of biocatalyst engineering. Amaryllidaceae alkaloids, such as the Alzheimer's medication galantamine, are complex plant secondary metabolites with recognized therapeutic value. Due to their difficult synthesis they are regularly sourced by extraction and purification from the low-yielding daffodil Narcissus pseudonarcissus. Here, we propose an efficient biosensor-machine learning technology stack for biocatalyst development, which we apply to engineer an Amaryllidaceae enzyme in Escherichia coli. Directed evolution is used to develop a highly sensitive (EC50 = 20 µM) and specific biosensor for the key Amaryllidaceae alkaloid branchpoint 4'-O-methylnorbelladine. A structure-based residual neural network (MutComputeX) is subsequently developed and used to generate activity-enriched variants of a plant methyltransferase, which are rapidly screened with the biosensor. Functional enzyme variants are identified that yield a 60% improvement in product titer, 2-fold higher catalytic activity, and 3-fold lower off-product regioisomer formation. A solved crystal structure elucidates the mechanism behind key beneficial mutations.