Guillain-Barré syndrome: History, pathogenesis, treatment, and future directions.

BACKGROUND AND PURPOSE: Since its description by Guillain, Barré, and Strohl in 1916, Guillain-Barré syndrome (GBS) has attracted a large literature. The author reviews the history of research into its pathogenesis and treatment to highlight promising avenues for future research. METHODS: This is a nonsystematic personal review. RESULTS: Since the early 1900s, the clinical picture of GBS has been illustrated in multiple series culminating in the ongoing International Guillain-Barré Syndrome study of 2000 patients. In the 1950s and 1960s, the inflammatory nature of the commonest form, acute inflammatory demyelinating polyradiculoneuropathy (AIDP), was described. In the 1990s, two axonal forms, acute motor-sensory axonal neuropathy and acute motor axonal neuropathy, were recognized. In the 1990s and early 2000s, these forms were shown to be due to antibodies against Campylobacter jejuni glycans cross-reacting with glycolipids on axonal membranes. The pathogenesis of AIDP remains unknown, but T-cell responses to the compact myelin proteins, P2 and P0, which cause experimental autoimmune neuritis, suggest that T cells are important. Randomized controlled trials in the 1970s and 1980s showed no benefit from corticosteroids. Trials in the 1980s showed benefit from plasma exchange and in the 1990s from intravenous immunoglobulin. CONCLUSIONS: Future research should seek biomarkers to identify subgroups with different treatment responses, define the true natural history of the disease with population-based epidemiological studies, study the pathology in autopsies early in the disease, seek causative antibodies and confirm autoimmune T-cell responses in AIDP, and expand treatment trials to include anti-T-cell agents.

Artificial Intelligence Assistive Software Tool for Automated Detection and Quantification of Amyloid-Related Imaging Abnormalities.

Importance: Amyloid-related imaging abnormalities (ARIA) are brain magnetic resonance imaging (MRI) findings associated with the use of amyloid-ß-directed monoclonal antibody therapies in Alzheimer disease (AD). ARIA monitoring is important to inform treatment dosing decisions and might be improved through assistive software. Objective: To assess the clinical performance of an artificial intelligence (AI)-based software tool for assisting radiological interpretation of brain MRI scans in patients monitored for ARIA. Design, Setting, and Participants: This diagnostic study used a multiple-reader multiple-case design to evaluate the diagnostic performance of radiologists assisted by the software vs unassisted. The study enrolled 16 US Board of Radiology-certified radiologists to perform radiological reading with (assisted) and without the software (unassisted). The study encompassed 199 retrospective cases, where each case consisted of a predosing baseline and a postdosing follow-up MRI of patients from aducanumab clinical trials PRIME, EMERGE, and ENGAGE. Statistical analysis was performed from April to July 2023. Exposures: Use of icobrain aria, an AI-based assistive software for ARIA detection and quantification. Main Outcomes and Measures: Coprimary end points were the difference in diagnostic accuracy between assisted and unassisted detection of ARIA-E (edema and/or sulcal effusion) and ARIA-H (microhemorrhage and/or superficial siderosis) independently, assessed with the area under the receiver operating characteristic curve (AUC). Results: Among the 199 participants included in this study of radiological reading performance, mean (SD) age was 70.4 (7.2) years; 105 (52.8%) were female; 23 (11.6%) were Asian, 1 (0.5%) was Black, 157 (78.9%) were White, and 18 (9.0%) were other or unreported race and ethnicity. Among the 16 radiological readers included, 2 were specialized neuroradiologists (12.5%), 11 were male individuals (68.8%), 7 were individuals working in academic hospitals (43.8%), and they had a mean (SD) of 9.5 (5.1) years of experience. Radiologists assisted by the software were significantly superior in detecting ARIA than unassisted radiologists, with a mean assisted AUC of 0.87 (95% CI, 0.84-0.91) for ARIA-E detection (AUC improvement of 0.05 [95% CI, 0.02-0.08]; P = .001]) and 0.83 (95% CI, 0.78-0.87) for ARIA-H detection (AUC improvement of 0.04 [95% CI, 0.02-0.07]; P = .001). Sensitivity was significantly higher in assisted reading compared with unassisted reading (87% vs 71% for ARIA-E detection; 79% vs 69% for ARIA-H detection), while specificity remained above 80% for the detection of both ARIA types. Conclusions and Relevance: This diagnostic study found that radiological reading performance for ARIA detection and diagnosis was significantly better when using the AI-based assistive software. Hence, the software has the potential to be a clinically important tool to improve safety monitoring and management of patients with AD treated with amyloid-ß-directed monoclonal antibody therapies.

Recommendations and feedback from the European Bioanalysis Forum Workshop: 1 year into ICH M10 - keeping our finger on the pulse.

The ICH M10 guideline on bioanalytical method validation and sample analysis is being adopted since 2023. However, and inevitably, some paragraphs or requirements remain ambiguous and are open for different interpretations. In support of a harmonized interpretation by the industry and health authorities, the European Bioanalysis Forum organized a workshop on 14 November 2023 in Barcelona, Spain, to discuss unclear and/or ambiguous paragraphs which were identified by the European Bioanalysis Forum community and delegates of the workshop prior to the workshop. This manuscript reports back from the workshop with recommendations and aims at continuing an open scientific discussion within the industry and with regulators in support of a science-driven guideline for the bioanalytical community and in line with the ICH mission - that is, achieve greater harmonization worldwide to ensure that safe, effective and high-quality medicines are developed and registered in the most resource-efficient manner.

Genome-Wide Association Studies of ARIA From the Aducanumab Phase 3 ENGAGE and EMERGE Studies.

BACKGROUND AND OBJECTIVES: Amyloid-related imaging abnormalities (ARIA) were the most common adverse events reported in the phase 3 ENGAGE and EMERGE trials of aducanumab, an anti-amyloid monoclonal antibody. APOE ε4 carrier status has been shown to increase risk of ARIA in prior trials of aducanumab and other anti-amyloid therapies; however, the remainder of the human genome has not been evaluated for ARIA risk factors. Therefore, we sought to determine in a hypothesis-free manner whether genetic variants beyond APOE influence risk of ARIA in aducanumab-treated patients. METHODS: We performed genome-wide association studies (GWAS) of ARIA in participants in the ENGAGE and EMERGE trials. Participants had mild cognitive impairment due to Alzheimer disease or mild Alzheimer disease dementia and were amyloid-positive on PET scans. All participants underwent regular MRI monitoring to detect and diagnose ARIA. RESULTS: Of the 3,285 participants in the intent-to-treat population, this analysis included 1,691 with genotyping array data who received at least one dose of aducanumab with at least one post-baseline MRI. All participants in the study cohort were of European ancestry; 51% were female. The mean age was 70.3 years. 31% had ARIA-E, 19% had ARIA-H microhemorrhage, and 14% had ARIA-H superficial siderosis. We identified one genome-wide significant (p < 5.0 × 10-8) association at the chromosome 19 locus encompassing APOE. The APOE association with ARIA was stronger in ε4/ε4 homozygotes (OR = 4.28, 4.58, 7.84; p < 2.9 × 10-14 for ARIA-E, ARIA-H microhemorrhage, and ARIA-H superficial siderosis, respectively) than in ε3/ε4 heterozygotes (OR = 1.74, 1.46, 3.14; p ≤ 0.03). We found greater odds of radiographically severe ARIA (OR = 7.04-24.64, p ≤ 2.72 × 10-5) than radiographically mild ARIA (OR = 3.19-5.00, p ≤ 1.37 × 10-5) among ε4/ε4 homozygotes. APOE ε4 was also significantly associated with both symptomatic (ε4/ε4 OR = 3.64-9.52; p < 0.004) and asymptomatic (ε4/ε4 OR = 4.20-7.94, p < 1.7 × 10-11) cases, although among ARIA cases, APOE did not appear to modulate symptomatic status. No other genome-wide significant associations were found. DISCUSSION: We identified a strong, genome-wide significant association between APOE and risk of ARIA. Future, larger studies may be better powered to detect associations beyond APOE. These findings indicate that APOE is the strongest genetic risk factor of ARIA incidence, with implications for patient management and risk-benefit treatment decisions. TRIAL REGISTRATION INFORMATION: Both trials (ENGAGE [221AD301]: NCT02477800 and EMERGE [221AD302]: NCT02484547) were registered in June 2015 at clinicaltrials.gov and enrolled patients from August 2015 to July 2018.

Precision medicine analysis of heterogeneity in individual-level treatment response to amyloid beta removal in early Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) is a neurological disorder with variability in pathology and clinical progression. AD patients may differ in individual-level benefit from amyloid beta removal therapy. METHODS: Random forest models were applied to the EMERGE trial to create an individual-level treatment response (ITR) score which represents individual-level benefit of high-dose aducanumab relative to the placebo. This ITR score was used to test the existence of heterogeneity in treatment effect (HTE). RESULTS: We found statistical evidence of HTE in the Clinical Dementia Rating-Sum of Boxes (CDR-SB;P =  0.034). The observed CDR-SB benefit was 0.79 points greater in the group with the top 25% of ITR score compared to the remaining 75% (P = 0.020). Of note, the highest treatment responders had lower hippocampal volume, higher plasma phosphorylated tau 181 and a shorter duration of clinical AD at baseline. DISCUSSION: This ITR analysis provides a proof of concept for precision medicine in future AD research and drug development. HIGHLIGHTS: Emerging trials have shown a population-level benefit from amyloid beta (Aß) removal in slowing cognitive decline in early Alzheimer's disease (AD). This work demonstrates significant heterogeneity of individual-level treatment effect of aducanumab in early AD. The greatest clinical responders to Aß removal therapy have a pattern of more severe neurodegenerative process.

A singlicate immunogenicity method to detect anti-polyethylene glycol antibodies: pre- and post-dose of PEGylated therapies.

Aim: Preexisting anti-polyethylene glycol (PEG) antibodies (APAs) may affect the efficacy and safety of PEGylated compounds. Omontys® and Krystexxa® withdrawal and SARS-CoV-2 RNA vaccine anaphylaxis have all been linked to APAs. This project aimed to develop and validate a method to detect total antibodies against PEG, pre- and post-dose. Materials & methods: The repetitive, linear PEG structure prevented the use of a bridging homogenous format, hence the requirement to use a solid-phase extraction and acid dissociation assay coupled with the Meso Scale Discovery® platform. Results & conclusion: Using singlicate analysis, the method was validated to successfully detect APA pre- and post-dose, with a crucial aspect of the method being the preparation of an appropriate negative control.

The Differential Effect of COVID on Total Joint Arthroplasty Between Hospital and Ambulatory Surgery Centers/Hospital Outpatient Departments: A Michigan Arthroplasty Registry Collaborative Quality Initiative Analysis.

Background: Coronavirus disease (COVID) created unprecedented challenges, especially for high-volume elective subspecialties like total joint arthroplasty. Limited inpatient capacity and resource conservation led to new outpatient selection criteria and site of service changes. As a Michigan Arthroplasty Registry Quality Collaborative Initiative quality project, demographic changes, complications, and differential effects on inpatient vs outpatient centers pre- and post-COVID were analyzed. Methods: The registry identified all total joint arthroplasty at hospitals and ASCs/HOPDs between 07/2019-12/2019 and 07/2020-12/2020. These intervals represented pre-COVID and post-COVID elective surgery shutdowns. Case volumes, demographics, and 90-day complications were compared. Results: Comparing 2020 to 2019, hospital volumes decreased (-9% total hip arthroplasty [THA], -17% total knee arthroplasty [TKA]), and ambulatory surgery center (ASC)/hospital outpatient department (HOPD) increased (+84% THA, +125% TKA). Entering 2020, ASC/HOPD patients were older (P = .0031, P < .0001: THA, TKA), had more American Society of Anesthesiologists score 3-4 (P = .0105, P = .0021), fewer attended joint class (P < .0001, P < .0001), and more hips were women (P = .023). Hospital patients had higher preoperative pain scores (P = .0117, P < .0001; THA, TKA), less joint education attendance (P < .0001, P < .0001), younger TKAs (P = .0169), and more American Society of Anesthesiologists score 3-4 (0.0009). After propensity matching, there were no significant differences between site of service for 90-day fractures, deep vein thromboses or pulmonary embolisms, infection, or hip dislocations. Hospital THAs had higher readmissions (P = .0003) and TKAs had higher 30-day emergency department visits (P = .005). ASC/HOPD patients were prescribed higher oral morphine equivalents (P < .0001, P < .0001; THA, TKA). Conclusions: COVID's elective surgery shutdown caused a dramatic site of service shift. Traditional preoperative education was negatively impacted, and older and sicker patients became outpatients. But short-term complications were not increased in ASCs/HOPDs. These site of service and associated patient demographic changes may be safely sustained.

Total Hip and Knee Arthroplasty Implant Revision Risk to 5 Years From a State-wide Arthroplasty Registry in Michigan.

Background: Information on the revision risk of implants is useful for improving the quality of care for elective hip and knee arthroplasty. The purpose of this study was to report on the revision risk of implants using a state-wide registry in the United States. Methods: The Michigan Arthroplasty Registry Collaborative Quality Initiative systematically collects data on elective primary and revision hip and knee arthroplasty cases in Michigan. It contained data on 139,970 hip and 245,499 knee arthroplasty cases from February 15, 2012, to December 31, 2021. Kaplan-Meier estimates of revision risk were computed using time to first revision as the dependent variable, and the results were computed and expressed as the cumulative percent revision (CPR). CPR estimates were computed for all implants having at least 500 cases in the Michigan Arthroplasty Registry Collaborative Quality Initiative dataset. Results: At 5-years postoperatively, elective primary conventional total hip arthroplasty implant stem/cup combinations had CPR values from 0.95% (0.39%-2.30%, 95% confidence intervals [CI]) to 5.77% (4.22%-7.85%, 95% CI), and elective primary total knee arthroplasty CPR ranged from 1.10% (0.64%-1.89%, 95% CI) to 12.52% (8.37%-18.50%, 95% CI). Unicondylar knee arthroplasty CPR at 5-years went from 4.23% (3.54%-5.06%, 95% CI) to 7.13% (6.20%-8.20%, 95% CI). Conclusions: The wide variation in CPR points to the need for surgeons to choose implants wisely to improve quality of care.

An innovative phase 2 proof-of-concept trial design to evaluate SAR445088, a monoclonal antibody targeting complement C1s in chronic inflammatory demyelinating polyneuropathy.

BACKGROUND AND AIMS: Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare immune-mediated disease of the peripheral nerves, with significant unmet treatment needs. Clinical trials in CIDP are challenging; thus, new trial designs are needed. We present design of an open-label phase 2 study (NCT04658472) evaluating efficacy and safety of SAR445088, a monoclonal antibody targeting complement C1s, in CIDP. METHODS: This phase 2, proof-of-concept, multicenter, open-label trial will evaluate the efficacy, and safety of SAR445088 in 90 patients with CIDP across three groups: (1) currently treated with standard-of-care (SOC) therapies, including immunoglobulin or corticosteroids (SOC-Treated); (2) refractory to SOC (SOC-Refractory); and (3) naïve to SOC (SOC-Naïve). Enrolled participants undergo a 24-week treatment period (part A), followed by an optional treatment extension for up to an additional 52 weeks (part B). In part A, the primary endpoint for the SOC-Treated group is the percentage of participants with a relapse after switching from SOC to SAR445088. The primary endpoint for the SOC-Refractory and SOC-Naïve groups is the percentage of participants with a response, compared to baseline. Secondary endpoints include safety, tolerability, immunogenicity, and efficacy of SAR445088 during 12-week overlapping period (SOC-Treated). Part B evaluates long-term safety and durability of efficacy. Data analysis will be performed using Bayesian statistics (predefined efficacy thresholds) and historical data-based placebo assumptions to support program decision-making. INTERPRETATION: This innovative trial design based on patient groups and Bayesian statistics provides an efficient paradigm to evaluate new treatment candidates across the CIDP spectrum and can help accelerate development of new therapies.

Early Survivorship of Uncemented Total Knee Arthroplasty Varies by Age and Sex Based on Data From the Michigan Arthroplasty Registry Collaborative Quality Initiative.

BACKGROUND: Outcome data for newer uncemented total knee arthroplasty (TKA) designs has been mixed. Registry studies showed worse survivorship, but clinical trials have not demonstrated differences compared to cemented designs. There has been renewed interest in uncemented TKA with modern designs and improved technology. The utilizations of uncemented knees in Michigan, 2-year outcomes, and the effects of age and sex were evaluated. METHODS: A statewide database from 2017 through 2019 was analyzed for incidence, distribution, and early survivorship of cemented versus uncemented TKAs. There was 2-year minimum follow-up. Kaplan-Meier survival analysis was used to generate time to first revision cumulative percent revision curves. The impacts of age and sex were examined. RESULTS: Use of uncemented TKAs increased from 7.0 to 11.3%. Uncemented TKAs were more commonly men, younger, heavier, American Society of Anesthesiologists score > 2, and opioid users (P < .05). At 2 years, overall cumulative percent revision was higher in uncemented (2.44% [2.00, 2.99]) versus cemented (1.76% [1.64, 1.89]), particularly in women uncemented (2.41 [1.87, 3.12]) versus cemented (1.64 [1.50, 1.80]). Revision rates were greater with uncemented women >70 years (1.2% 1 year, 1.02% 2 years) versus < 70 years (0.56%, 0.53%), notably uncemented were inferior in both groups (P < .05). Men, regardless of age, had similar survivorships with both cemented and uncemented designs. CONCLUSION: The use of an uncemented TKA had an increased risk of early revision compared to cemented. This finding, however, was only apparent in women, especially those >70 years old. Surgeons should consider cement fixation in women >70 years.

How Much Perioperative Pain and Dysfunction Underlie the HOOS JR and KOOS JR?

BACKGROUND: The Hip Disability and Osteoarthritis Outcome Score Joint Replacement (HOOS JR) and Knee Injury and Osteoarthritis Outcome Score Joint Replacement (KOOS JR) scores represent pain and dysfunction as a single number ranging from 0 (extreme pain and dysfunction) to 100 (no pain or functional limitations). However, scores between 0 and 100 lack a simple interpretation because they reflect varying combinations of pain levels and dysfunction. Given that most adverse events and improvement occur within the first 90 days after surgery, a deeper understanding of the level of pain and dysfunction may reveal missed opportunities for patient care. QUESTIONS/PURPOSES: (1) What does a given preoperative or postoperative HOOS JR and KOOS JR score indicate about pain and ability to perform daily activities? (2) How much of a change in score (that is, delta) is needed to indicate significant improvement in pain control and daily functioning? METHODS: The Michigan Arthroplasty Registry Collaborative Quality Initiative contains more than 95% of THAs and TKAs performed in Michigan. Between January 2017 and March 2019, 84,175 people in the registry underwent primary THA or TKA and were potentially eligible for this retrospective, comparative study of the first 90 postoperative days. Eighty-four percent (70,608 of 84,175) were excluded because their surgeons did not attain a target survey collection proportion of 70% and another 6% (5042) were missing covariate information or surveys, leaving 10% (8525) for analysis. The mean age and percentage of women were 65 ± 11 years and 55% (2060 of 3716), respectively, for patients undergoing THA and 67 ± 9 years and 61% (2936 of 4809), respectively, for those undergoing TKA. There were no clinically meaningful differences between patients who were analyzed and those who were excluded except for lower representation of non-White patients in the analyzed group. For interpretation, patient responses to Question 7 (pain) and Question 6 (function) from the Patient-Reported Outcomes Measurement Information System global items (PROMIS-10) were dichotomized into "much pain" (rating of pain 4 to 10 of 10) versus "less pain" (rating of ≤ 3) and "good function" (able to perform most activities) versus "poor function" (not able to perform most activities) and combined into four pain-function categories. We examined the mean preoperative and postoperative HOOS JR and KOOS JR scores for each pain-function category, adjusted for patient characteristics. We calculated the size of the delta associated with an increase to a more favorable category postoperatively (versus staying in the same or worse category) via multivariable logistic regression that controlled for patient characteristics. RESULTS: Patients in the least favorable "much pain, poor function" category preoperatively had adjusted mean scores of 40 (95% confidence interval 39 to 41) for both the HOOS JR and KOOS JR. Those with mixed levels of pain and function had mean scores between 46 and 55. Those in the most favorable "less pain, good function" category had means of 60 (95% CI 58 to 62) and 59 (95% CI 58 to 61) for the HOOS JR and KOOS JR, respectively. The adjusted delta to achieve a pain level of ≤ 3 or the ability to perform most activities was 30 (95% CI 26 to 36) on the HOOS JR and 27 (95% CI 22 to 29) on the KOOS JR scales. CONCLUSION: These adjusted means of the HOOS JR and KOOS JR provide context for understanding the levels of pain and dysfunction for individuals as well for patients reported in other studies. Potential quality improvement efforts could include tracking the proportion of patients with THA or TKA who achieved a sufficient delta to attain pain levels of ≤ 3 or the ability to perform most activities. Future studies are needed to understand pain and function represented by the HOOS JR and KOOS JR at 1 to 2 years, how these may differ by patient subgroups, and whether scores can be improved through quality improvement efforts. LEVEL OF EVIDENCE: Level III, therapeutic study.

A Reduction in Opioid Prescription Size After Total Joint Arthroplasty Can be Safely Performed Without an Increase in Complications.

BACKGROUND: Excessive opioid prescriptions after total joint arthroplasty (TJA) increase risks for adverse opioid-related events, chronic opioid use, and unlawful opioid diversion. Decreasing postoperative prescriptions may improve quality after TJA. Concerns exist that a decrease in opioids prescribed may increase complications, such as readmissions, emergency department (ED) visits, or worsened patient-reported outcomes (PROs). The purpose of this study was to explore whether a reduction in opioids prescribed after TJA resulted in increased complications. METHODS: Data originated from a statewide database prospectively abstracted, including oral morphine equivalents prescribed at discharge, readmissions, ED visits, and PROs. Data were collected from 84,998 TJA occurring 1 year before and after the creation of an opioid-prescribing protocol that had decreased prescriptions by approximately 50%. Trends were monitored using Shewhart control charts. Regression models were used to determine statistically significant changes over time. RESULTS: All groups showed a reduction in opioids prescribed by almost 50% without an increase in emergency room visits or readmissions and without a detrimental effect on PROs. Compared to baseline data before opioid reduction, opioid-naive total knee arthroplasty had significant improvements in all outcomes (P = .03, P = .02, P < .001, P < .001). Opioid-tolerant total knee arthroplasty and total hip arthroplasty had no worsened outcomes and significant improvement in (Knee Injury and Osteoarthritis Outcome score for Joint Replacement P = .03) and (Hip Disability and Osteoarthritis Outcome Score for Joint Replacement P = .03). Opioid-naive total hip arthroplasty had significant improvements in Hip Disability and Osteoarthritis Outcome Score Joint Replacement (P = .003) and Patient Reported Outcomes Measurement Information System (P = .001). CONCLUSIONS: Postoperative opioid prescription recommendations from a statewide registry decreased prescribing by approximately 50% without decreasing PROs or increasing ED visits or readmissions. A reduction in opioids prescribed after TJA can be accomplished safely and without increased complications.

Are Short Stems Associated With Higher Fracture Rates and Early Revision Rates in Primary Total Hip Arthroplasty? A Noninferiority Analysis.

BACKGROUND: This study aimed to determine if "short" femoral stems were noninferior to (at least as good as) standard-length stems in regards to 90-day periprosthetic fracture and 1-year revision rates. METHODS: Using the MARCQI implant registry, a retrospective study of statewide data was carried out on 64,084 total hip arthroplasties (THAs) between 2012 and 2017. We noticed an increase in the use of "short" uncemented femoral hip stems during THA. Chi-square tests were used to test homogeneity of categorical variables. The covariates included in the analyses were identified using modern epidemiological methods. A Type I probability of 0.05 was used as the level of statistical significance. Inverse probability of treatment weighting (IPTW) was used to mitigate confounding variables. RESULTS: One hundred and seven stems were implanted by surgeons in the state of Michigan. They were classified according to the Khanuja Classification System as Type 2A (trapezoidal, double-tapered calcar loading, n = 3,281), Type 3 (calcar loading with lateral flare, n = 1,898), and Type 4 (shortened, tapered, conventional, n = 19,580), and were compared to standard-length, type 5, stems (n = 33,322) in regards to the 2 outcomes (periprosthetic fractures and 1-year revision rates). Overall, 1-year revision and the 90-day fracture rates were 1.3% (791/57,853) and 1.1% (631/57,968), respectively. Noninferiority was established for all short stems at the clinical threshold of an odds ratio (OR) of 1.5 with P-values <0.05 for 90-day fractures. In regards to 1-year revision rates, noninferiority was also established for Type 3 and 4 stems (P < .05). CONCLUSION: The increased use of "short stems" in Michigan did not lead to increased 1-year revision or 90-day fracture rates.

Progressive multifocal leukoencephalopathy outcomes in patients with multiple sclerosis treated with dimethyl fumarate.

Background and objectives: Dimethyl fumarate (DMF), an oral disease-modifying therapy with an established benefit and well-described safety profile, is among the most commonly used therapies for relapsing forms of multiple sclerosis. As of 31 December 2021, >560,000 patients have been treated with DMF, representing >1,190,000 person-years of exposure. Of these, 6413 patients (14,292 person-years) were from clinical trials. Methods and results: Progressive multifocal leukoencephalopathy (PML) has occurred in the setting of lymphopenia (<0.91 × 109/L) in patients treated with DMF. We present detailed clinical characteristics and outcomes of the 12 confirmed PML cases occurring in MS patients on DMF as of 21 July 2021. The PML incidence in DMF-treated patients is 1.07 per 100,000 person-years of DMF exposure. Lymphopenia is the common risk for PML in DMF treatment. Discussion: DMF-related PML is rare but has occurred in the setting of lymphopenia, supporting the current recommendations for absolute lymphocyte count monitoring in all patients, regardless of age and time on therapy.

State-Based and National U.S. Registries: The Michigan Arthroplasty Registry Collaborative Quality Initiative (MARCQI), California Joint Replacement Registry (CJRR), and American Joint Replacement Registry (AJRR).

ABSTRACT: The concept of a total joint registry as a tool to gather and compare longitudinal clinical outcome data emerged in the early 1970s; although initially begun as a single-institution effort, it soon spread to the development of large nationwide registries, first in Scandinavia and subsequently around the world. These national registries established the value of population-wide results, large cohorts, and the importance of ongoing implant surveillance efforts, as detailed elsewhere in this series. In the United States, concerted efforts to establish a national total joint registry for the hip and knee began in earnest in the early 2000s and culminated with the incorporation of the American Joint Replacement Registry (AJRR) in 2009. Parallel efforts soon followed to establish state-based total joint registries, either as stand-alone entities or in affiliation with the AJRR. Some of these state-based efforts succeeded, and some did not.In the first section of this article, Brian Hallstrom, MD, details the highly successful Michigan Arthroplasty Registry Collaborative Quality Initiative (MARCQI). This state-based effort was made possible by a unique partnership between a single dominant statewide private payer and the Michigan orthopaedic surgery community; it has already successfully advanced the quality of care for patients in Michigan, and efforts are ongoing.The second section, by James I. Huddelston, MD, details a different path to the establishment of a focused state-based registry. The California Joint Replacement Registry (CJRR) was the result of a partnership with representatives of the statewide business community and resulted in a pioneering effort to successfully collect and publicly report patient-reported outcome measures as part of the registry data set. Further discussed are the establishment, development, and status of the AJRR and its current place among the family of American Academy of Orthopaedic Surgeons (AAOS) registries, which were inspired by the AJRR and span a range of orthopaedic specialties.

Predators and habitat association of post-settlement snapper (Chrysophrys auratus).

Structured habitats play an important nursery role during the crucial early juvenile or post-settlement stages of many fish species. Predominantly, the utility of structured habitats to juvenile fish is thought to be associated with the provisioning of food or as a refuge from predation. Although snapper (Chrysophrys auratus) in New Zealand also have a strong affinity for structured habitats during their post-settlement phase, their predators are unknown as is the role of predation in determining habitat association. Here the authors investigated potential predators of post-settlement snapper by remotely observing interactions of restrained post-settlement snapper with potential predators and investigating the diet of potential predators. They also conducted tank experiments with a potential predator, both with and without the presence of structure. Restrained snapper were infrequently approached by predators, but two new nocturnal predators were identified. No snapper were observed in the diet of potential predators, although two piscivores were identified as potential candidates. No predation occurred during tank experiments, but there was a non-significant indication that under threat of predation post-settlement snapper may use habitat when it is present and aggregate together when it is not. The findings suggest that the pulsed nature of predation may have made it difficult to observe given the methods employed and that the threat of predation may be sufficient to drive the habitat selection of post-settlement snapper. Investigating the significance of predation via methods that do not require direct observations may therefore be more appropriate given this context.

Multicenter Validation of Natural Language Processing Algorithms for the Detection of Common Data Elements in Operative Notes for Total Hip Arthroplasty: Algorithm Development and Validation.

BACKGROUND: Natural language processing (NLP) methods are powerful tools for extracting and analyzing critical information from free-text data. MedTaggerIE, an open-source NLP pipeline for information extraction based on text patterns, has been widely used in the annotation of clinical notes. A rule-based system, MedTagger-total hip arthroplasty (THA), developed based on MedTaggerIE, was previously shown to correctly identify the surgical approach, fixation, and bearing surface from the THA operative notes at Mayo Clinic. OBJECTIVE: This study aimed to assess the implementability, usability, and portability of MedTagger-THA at two external institutions, Michigan Medicine and the University of Iowa, and provide lessons learned for best practices. METHODS: We conducted iterative test-apply-refinement processes with three involved sites-the development site (Mayo Clinic) and two deployment sites (Michigan Medicine and the University of Iowa). Mayo Clinic was the primary NLP development site, with the THA registry as the gold standard. The activities at the two deployment sites included the extraction of the operative notes, gold standard development (Michigan: registry data; Iowa: manual chart review), the refinement of NLP algorithms on training data, and the evaluation of test data. Error analyses were conducted to understand language variations across sites. To further assess the model specificity for approach and fixation, we applied the refined MedTagger-THA to arthroscopic hip procedures and periacetabular osteotomy cases, as neither of these operative notes should contain any approach or fixation keywords. RESULTS: MedTagger-THA algorithms were implemented and refined independently for both sites. At Michigan, the study comprised THA-related notes for 2569 patient-date pairs. Before model refinement, MedTagger-THA algorithms demonstrated excellent accuracy for approach (96.6%, 95% CI 94.6%-97.9%) and fixation (95.7%, 95% CI 92.4%-97.6%). These results were comparable with internal accuracy at the development site (99.2% for approach and 90.7% for fixation). Model refinement improved accuracies slightly for both approach (99%, 95% CI 97.6%-99.6%) and fixation (98%, 95% CI 95.3%-99.3%). The specificity of approach identification was 88.9% for arthroscopy cases, and the specificity of fixation identification was 100% for both periacetabular osteotomy and arthroscopy cases. At the Iowa site, the study comprised an overall data set of 100 operative notes (50 training notes and 50 test notes). MedTagger-THA algorithms achieved moderate-high performance on the training data. After model refinement, the model achieved high performance for approach (100%, 95% CI 91.3%-100%), fixation (98%, 95% CI 88.3%-100%), and bearing surface (92%, 95% CI 80.5%-97.3%). CONCLUSIONS: High performance across centers was achieved for the MedTagger-THA algorithms, demonstrating that they were sufficiently implementable, usable, and portable to different deployment sites. This study provided important lessons learned during the model deployment and validation processes, and it can serve as a reference for transferring rule-based electronic health record models.

Causes of Early Hip Revision Vary by Age and Gender: Analysis of Data From a Statewide Quality Registry.

BACKGROUND: While total hip arthroplasty (THA) is extremely successful, early failures do occur. The purpose of this study was to determine the cause of revision in specific patient demographic groups at 3 time points to potentially help decrease the revision risk. METHODS: Data for cases performed between 2012 and 2018 from a statewide, quality improvement arthroplasty registry were used. The database included 79,205 THA cases and 1,433 revisions with identified etiology (1,584 in total). All revisions performed at <5 years from the primary THA were reviewed. Six groups, men/women, <65, 65-75, and >75 years, were compared at revision time points <6 months, <1 year, and <5 years. RESULTS: There were obvious and significant differences between subgroups based on demographics and time points (P < .0001). Seven hundred and fifty-six (53%) of all revisions occurred within 6 months. The most common etiologies within 6 months (756 revisions) were fracture (316, 41.8%), dislocation/instability (194, 25.7%), and infection (98, 12.9%). At this early time point, the most common revision cause was fracture for all age/gender-stratified groups, ranging from 27.6% in young men to 60% in older women. Joint instability became the leading cause for revision after 1 year in all groups. CONCLUSION: This quality improvement project demonstrated clinically meaningful differences in the reason for THA revision between gender, age, and time from surgery. Strategies based on these data should be employed by surgeons to minimize the factors that lead to revision.