Evidence-based hierarchy of pain outcome measures for osteoarthritis clinical trials and meta-analyses.

OBJECTIVE: To rank commonly used patient-reported outcome measures (PROMs) for assessing pain in osteoarthritis trials according to their assay sensitivity, defined as the ability of a PROM to distinguish an effective from a less effective intervention or placebo, proposing a hierarchy for PROM selection in trials and data-extraction in meta-analyses. DESIGN: Analysis of trials with placebo, sham, or non-intervention control that included ≥100 patients per arm with knee/hip osteoarthritis, reporting treatment effects on ≥2 pain PROMs. Treatment effects from all PROMs were standardized on a 0-100 scale. Negative mean differences indicated a larger effect of the experimental treatment compared to control. We ranked PROMs by assay sensitivity using a Bayesian multi-outcome synthesis random-effects model. RESULTS: 135 trials comprising 57,141 participants were included. The ranking of PROMs from highest to lowest assay sensitivity was as follows: pain overall, pain on stairs, pain at night, pain on walking, pain at rest, WOMAC pain, WOMAC global, Lequesne index. Pain overall, the highest-ranked PROM, had a pooled mean difference of -6.96 (95%CrI -7.94, -6.02), while WOMAC pain, the most reported PROM in our study, had a pooled mean difference of -4.90 (95%CrI -5.55, -4.26). The pooled ratio of mean differences between pain overall and WOMAC pain was 1.42 (95%CrI 1.30, 1.55), representing a 42% larger effect size with pain overall. CONCLUSIONS: Pain overall has better assay sensitivity than other pain PROMs. Investigators should consider the hierarchy proposed in this study to guide PROM selection in osteoarthritis clinical trials and data extraction in osteoarthritis meta-analyses.

Local carbon reserves are insufficient for phloem terpene induction during drought in Pinus edulis in response to bark beetle-associated fungi.

Stomatal closure during drought inhibits carbon uptake and may reduce a tree's defensive capacity. Limited carbon availability during drought may increase a tree's mortality risk, particularly if drought constrains trees' capacity to rapidly produce defenses during biotic attack. We parameterized a new model of conifer defense using physiological data on carbon reserves and chemical defenses before and after a simulated bark beetle attack in mature Pinus edulis under experimental drought. Attack was simulated using inoculations with a consistent bluestain fungus (Ophiostoma sp.) of Ips confusus, the main bark beetle colonizing this tree, to induce a defensive response. Trees with more carbon reserves produced more defenses but measured phloem carbon reserves only accounted for c. 23% of the induced defensive response. Our model predicted universal mortality if local reserves alone supported defense production, suggesting substantial remobilization and transport of stored resin or carbon reserves to the inoculation site. Our results show that de novo terpene synthesis represents only a fraction of the total measured phloem terpenes in P. edulis following fungal inoculation. Without direct attribution of phloem terpene concentrations to available carbon, many studies may be overestimating the scale and importance of de novo terpene synthesis in a tree's induced defense response.

Trends and outcomes of inpatient cardiac implantable electronic device transvenous lead extractions: a nationwide analysis.

BACKGROUND: Higher rates of CIED implantations have been associated with an increased rate of lead failures and complications resulting in higher rates of transvenous lead extractions (TLE). OBJECTIVE: To assess the trends TLE admissions and evaluate the patient related predictors of safety outcomes. METHODS: National Readmission Database was queried to identify patients who underwent TLE from January 2016 to December 2019. We conducted a multivariate regression analysis to identify variables associated with in-hospital mortality in patients undergoing TLE. Additionally, we compared trends and outcomes of TLE among patients with prior sternotomy versus those without prior sternotomy and analyzed sex-based differences among patients undergoing TLE. RESULTS: We identified 30,128 hospitalizations for TLE. The index admission in-hospital mortality rate was 3.21% with cardiac tamponade happening in 1.46% of the admissions. Age, infective endocarditis, CKD, congestive heart failure and anemia were associated with higher in-hospital mortality rates. There was a lower rate of in-hospital mortality in patients with history of prior sternotomy versus patients without (OR 0.72, CI: 0.59-0.87, p-value < 0.001). There was no difference in in-hospital mortality rate between males and females. Females had a shorter length and a higher cost of stay when compared to male gender. CONCLUSION: TLE admissions continue to increase. Overall rates of mortality and complications are relatively low. Patients with prior sternotomy had better outcomes and less complications when compared to those without prior sternotomy. Female gender is associated with higher rates of cardiac tamponade, yet shorter length of stay with lower cost.

Quantifying Forms and Functions of Enterohepatic Bile Acid Pools in Mice.

BACKGROUNDS & AIMS: Bile acids (BAs) are core gastrointestinal metabolites with dual functions in lipid absorption and cell signaling. BAs circulate between the liver and distal small intestine (ie, ileum), yet the dynamics through which complex BA pools are absorbed in the ileum and interact with host intestinal cells in vivo remain poorly understood. Because ileal absorption is rate-limiting in determining which BAs in the intestinal lumen gain access to host intestinal cells and receptors, and at what concentrations, we hypothesized that defining the rates and routes of ileal BA absorption in vivo would yield novel insights into the physiological forms and functions of mouse enterohepatic BA pools. METHODS: Using ex vivo mass spectrometry, we quantified 88 BA species and metabolites in the intestinal lumen and superior mesenteric vein of individual wild-type mice, and cage-mates lacking the ileal BA transporter, Asbt/Slc10a2. RESULTS: Using these data, we calculated that the pool of BAs circulating through ileal tissue (ie, the ileal BA pool) in fasting C57BL/6J female mice is ∼0.3 mmol/g. Asbt-mediated transport accounted for ∼80% of this pool and amplified size. Passive permeability explained the remaining ∼20% and generated diversity. Compared with wild-type mice, the ileal BA pool in Asbt-deficient mice was ∼5-fold smaller, enriched in secondary BA species and metabolites normally found in the colon, and elicited unique transcriptional responses on addition to ex vivo-cultured ileal explants. CONCLUSIONS: This study defines quantitative traits of the mouse enterohepatic BA pool and reveals how aberrant BA metabolism can impinge directly on host intestinal physiology.

How Does the Physician Patient Fare After Primary Total Hip and Knee Arthroplasty?

Background: Physician patients requiring surgery present with occupational risks and personality traits that may affect outcomes. This study compared implant survivorship, complications, and clinical outcomes of physicians undergoing primary total hip arthroplasty (THA) or total knee arthroplasty (TKA). Methods: A retrospective review of our institutional total joint registry identified 185 physicians undergoing primary THA (n = 94) or TKA (n = 91). Physicians were matched 1:2 with nonphysician controls according to age, sex, body mass index, joint (hip or knee), and surgical year. Physician type (medical, n = 132 vs surgical, n = 53) subanalysis was performed. Implant survivorship was assessed via Kaplan-Meier methods. Clinical outcomes were evaluated by Harris hip scores and Knee Society Scores. Mean follow-up was 5 years. Results: There was no significant difference in 5-year implant survivorship free of any reoperation (P > .5) or any revision (P > .2) between physician and nonphysician patients after THA and TKA. Similarly, the 90-day complication risk was not significantly different after THA or TKA (P = 1.0 for both). Physicians and nonphysicians demonstrated similar improvement in Harris hip scores (P = .6) and Knee Society Scores (P = .4). When comparing physician types, there was no difference in implant survivorship (P > .4), complications (P > .6), or patient reported outcomes (P > .1). Conclusions: Physician patients have similar implant survivorship, complications, and clinical outcomes when compared to nonphysicians after primary THA and TKA. Physicians should feel reassured that their profession does not appear to increase risks when undergoing lower extremity total joint arthroplasty.

A mediational theory of equivalence relations and transformation of function.

In this article, we describe a mediational theory of emergent or derived relations resulting from matching-to-sample procedures that produce equivalence and transformation of function. According to a mediational theory, behaviors that occur at the time of reinforcement mediate subsequent behavioral relations referred to as "derived" or "emergent." Such relations have been documented for decades in studies using mostly matching-to-sample procedures with humans and nonhumans. In both verbal human and nonhuman participants, the mediating behaviors consist of differential responding to the sample stimulus. In humans, such behaviors are mostly, but not necessarily, verbal; in nonhumans they include a variety of sample-specific responses, sometimes called "coding." The proposed mediational theory, based only on the four-term contingency and the basic principles of operant learning, makes specific predictions and explains results from a broad range of experiments. There are at least three important implications of a mediational theory. First, if by "derived" or "emergent" one means untrained or unreinforced, then derived relations may not exist. Second, if there are no derived relations, then theories of such relations may not be necessary. Third, a mediational theory of relational responding has potentially important implications for clinical practice.

Longitudinal Phospho-tau217 Predicts Amyloid Positron Emission Tomography in Asymptomatic Alzheimer's Disease.

BACKGROUND: Blood-based AD biomarkers such as plasma P-tau217 are increasingly used in clinical trials as a screening tool. OBJECTIVES: To assess the utility of an electrochemiluminescence (ECL) immunoassay in predicting brain amyloid PET status in cognitively unimpaired individuals. SETTING: Plasma samples collected at baseline, week 12, and week 240 or endpoint originated from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial and the companion Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study. PARTICIPANTS: Both A4 and LEARN enrolled eligible cognitively unimpaired persons 65 to 85 years. Individuals with elevated brain amyloid PET levels were eligible for the A4 Study, while those without elevated brain amyloid PET levels were eligible for the LEARN Study. INTERVENTION: Participants in the A4 Study received intravenous solanezumab (up to 1600 mg) or placebo every 4 weeks. The LEARN Study is an observational study without intervention. MEASUREMENTS: Plasma P-tau217 concentration levels from A4 Study participants were measured using an ECL immunoassay. Receiver Operating Characteristic (ROC) curve analysis was performed for each biomarker against amyloid positivity, defined by ≥22 CL and ≥ 33 CL. RESULTS: Receiver operating characteristic curve (ROC) analysis indicates high diagnostic value of P-tau217 in individuals with amyloid PET ≥ 20 (Area under the ROC (AUROC): 0.87) and ≥ 33 CL (AUROC: 0.89). Repeated testing with the placebo group taken 12 weeks apart (range: 68 to 143 days) and the LEARN participants taken between 1.4 and 1.75 years resulted in a strong positive correlation (Corr. 0.91 (0.90 to 0.92)). CONCLUSION: An ECL immunoassay testing plasma P-tau217 accurately predicts amyloid PET positivity in cognitively unimpaired individuals. Our future analyses aim to determine if use of this assay may reduce the screening burden of preclinical individuals into anti-amyloid clinical trials.

Relationship between Plasma P-Tau217 and Amyloid PET in Racial and Ethnic Underrepresented Groups (RE-URG) Compared with Non RE-URG in LEARN and A4.

BACKGROUND: Individuals from diverse racial and ethnic groups are severely underrepresented in Alzheimer's disease trials in part due to disproportionate biomarker ineligibility. Evidence from recent studies support plasma phosphorylated tau 217 (P-tau217) as an early marker for brain Aß pathology and a reliable marker in predicting elevated brain amyloid PET in cognitively unimpaired adults. OBJECTIVES: To examine whether the relationship between P-tau217 and 18-F florbetapir PET standard uptake value ratios (SUVR) is influenced by race and ethnicity in the Anti-Amyloid treatment in Asymptomatic Alzheimer's disease (A4) preclinical AD studies. DESIGN: We conducted a retrospective analysis of A4 clinical trial and the LEARN natural history companion study data to evaluate the relationship between baseline P-tau217 and PET SUVR concentration levels by race and ethnicity. SETTING: The analysis was conducted on samples from participants enrolled across 65 study sites in the United States and Canada. PARTICIPANTS: Cognitively unimpaired adults aged 65-85 enrolled at North American sites in the A4 preclinical AD trial, pre-dose, (N=1018), and the LEARN (N=480) study. Participants were grouped into 2 categories, racial and ethnic underrepresented group (RE-URG) and non-RE-URG (nRE-URG) based on self-identification. MEASUREMENTS: A mixed-effects regression model was fit to determine differences in the relationship between P-tau217 and PET SUVR by race and ethnicity, adjusting for age, and APOE ε4 carrier status. RESULTS: Results from the linear mixed-effects model support that there was no statistically significant effect of race and ethnicity on the relationship between P-tau217 and PET SUVR. CONCLUSION: These findings suggest that the relationship between plasma P-tau217 and PET SUVR is the same across race and ethnicity. Future analyses should corroborate these findings in a larger sample and examine whether plasma P-tau217 reflects the differential amyloid prevalence previously reported for other biomarkers of amyloid.

Pre-Randomization Predictors of Study Discontinuation in a Preclinical Alzheimer's Disease Randomized Controlled Trial.

BACKGROUND: Participant discontinuation from study treatment in a clinical trial can leave a trial underpowered, produce bias in statistical analysis, and limit interpretability of study results. Retaining participants in clinical trials for the full study duration is therefore as important as participant recruitment. OBJECTIVE: This analysis aims to identify associations of pre-randomization characteristics of participants with premature discontinuation during the blinded phase of the Anti-Amyloid treatment in Asymptomatic AD (A4) Study. DESIGN: All A4 trial randomized participants were classified as having prematurely discontinued study during the blinded period of the study for any reason (dropouts) or completed the blinded phase of the study on treatment (completers). SETTING: The trial was conducted across 67 study sites in the United States, Canada, Japan and Australia through the global COVID-19 pandemic. PARTICIPANTS: The sample consisted of all 1169 A4 trial randomized participants. MEASUREMENTS: Pre-randomization demographic, clinical, amyloid PET and genetic predictors of study discontinuation were evaluated using a univariate generalized linear mixed model (GLMM), with discontinuation status as the binary outcome, each predictor as a fixed effect, and site as a random effect to account for differences among study sites in the trial. Characteristics significant at p<0.10 were then included in a multivariable GLMM. RESULTS: Among randomized participants, 339 (29%) discontinued the study during the blinded period (median follow-up time in trial: 759 days). From the multivariable analysis, the two main predictors of study discontinuation were screening State-Trait Anxiety Inventory (STAI) scores (OR = 1.07 [95%CI = 1.02; 1.12]; p=0.002) and age (OR = 1.06 [95%CI = 1.03; 1.09]; p<0.001). Participants with a family history of dementia (OR = 0.75 [95%CI = 0.55; 1.01]; p=0.063) and APOE ε4 carriers (OR = 0.79 [95%CI = 0.6; 1.04]; p=0.094) were less likely to discontinue from the study, with the association being marginally significant. In these analyses, sex, race and ethnicity, cognitive scores and amyloid/tau PET scores were not associated with study dropout. CONCLUSIONS: In the A4 trial, older participants and those with higher levels of anxiety at baseline as measured by the STAI were more likely to discontinue while those who had a family history of dementia or were APOE ε4 carriers were less likely to drop out. These findings have direct implications for future preclinical trial design and selection processes to identify those individuals at greatest risk of dropout and provide information to the study team to develop effective selection and retention strategies in AD prevention studies.

Soybean Oil, Linoleic Acid Source, in Lamb Diets: Intake, Digestibility, Performance, Ingestive Behaviour, and Blood Metabolites.

The objective of the current study was to evaluate the effects of soybean oil inclusion in diets on feeding behaviour, digestibility, performance, and blood metabolites of feedlot lambs. Forty non-castrated Santa Inês lambs with a mean age of 5 months and initial body weight of 34.88 ± 3.19 kg were used in a 40-day feeding trial. The lambs were distributed in five experimental diets with the inclusion of increasing soybean oil (SO) levels: 0, 30, 60, 90, and 120 g/kg DM. The SO inclusion promoted a linear reduction in DM intake (p < 0.001), crude protein (CP, p < 0.001), non-fibrous carbohydrates (NFC, p < 0.001), and total digestible nutrients (TDN, p = 0.004). There was an increasing quadratic effect on the intake of ether extract (EE; p = 0.002) and decreasing for neutral detergent fiber (p = 0.005). The soybean oil inclusion promoted the greater apparent digestibility of CP (p = 0.016), EE (p = 0.005), NDFom (p < 0.001), and TDN (p < 0.001); on the other hand, the apparent digestibility of NFC (p = 0.005) was decreased. The average daily gain decreased (p < 0.001) with SO inclusion. The SO inclusion increased feeding time (p = 0.004), reduced the efficiency of DM rumination (p = 0.001), and reduced the concentration of blood N-ureic (p < 0.001). Considering the productive parameters, SO can be included in diets and it is recommended that we include SO of up to 41 g/kg DM in diets for fattening lambs as the ideal maximum level. The strategy implemented to adapt lambs to increasing levels of high-fat diet mitigated the detrimental effects of lipids on the rumen, with high-density energy intake being the constraining factor on performance.

Neuromodulation for Vasovagal Syncope and Bradyarrhythmias.

Catheter-based neuromodulation of intrinsic cardiac autonomic nervous system is increasingly being used to improve outcomes in patients with vasovagal syncope and bradyarrhythmias caused by vagal overactivity. However, there is still no consensus for patient selection, technical steps, and procedural end points. This review takes the reader on a practical exploration of neuromodulation for bradyarrhythmias, concentrating on the critical aspects of proper patient selection, evidence-based insights, and anatomic intricacies within the intrinsic cardiac autonomic nervous system. Also discussed are different mapping techniques and outcome measures. Future directions to optimize the utilization of this technique in clinical practice are highlighted.

Procedural and Intermediate-term Results of the Electroanatomical-guided Cardioneuroablation for the Treatment of Supra-Hisian Second- or Advanced-degree Atrioventricular Block: the PIRECNA multicentre registry.

AIMS: Prior case series showed promising results for cardioneuroablation in patients with vagally induced atrioventricular blocks (VAVBs). We aimed to examine the acute procedural characteristics and intermediate-term outcomes of electroanatomical-guided cardioneuroablation (EACNA) in patients with VAVB. METHODS AND RESULTS: This international multicentre retrospective registry included data collected from 20 centres. Patients presenting with symptomatic paroxysmal or persistent VAVB were included in the study. All patients underwent EACNA. Procedural success was defined by the acute reversal of atrioventricular blocks (AVBs) and complete abolition of atropine response. The primary outcome was occurrence of syncope and daytime second- or advanced-degree AVB on serial prolonged electrocardiogram monitoring during follow-up. A total of 130 patients underwent EACNA. Acute procedural success was achieved in 96.2% of the cases. During a median follow-up of 300 days (150, 496), the primary outcome occurred in 17/125 (14%) cases with acute procedural success (recurrence of AVB in 9 and new syncope in 8 cases). Operator experience and use of extracardiac vagal stimulation were similar for patients with and without primary outcomes. A history of atrial fibrillation, hypertension, and coronary artery disease was associated with a higher primary outcome occurrence. Only four patients with primary outcome required pacemaker placement during follow-up. CONCLUSION: This is the largest multicentre study demonstrating the feasibility of EACNA with encouraging intermediate-term outcomes in selected patients with VAVB. Studies investigating the effect on burden of daytime symptoms caused by the AVB are required to confirm these findings.

Pseudofilariasis, a Presenting Sign of Alkaptonuria.

PURPOSE: To report the association of Pseudofilariasis as a presenting sign of Alkaptonuria. METHOD: Case Report. RESULTS: A 49-year-old Indian man was referred because of wormlike objects in his left conjunctiva. Ocular and family history was non-contributory. He had not been to India in 15 years. Past medical history revealed hypertension, hypercholesterolemia, arthritis, and a myocardial infarct. He had undergone two stents, bilateral Achilles tendon repairs and bilateral knee replacements. ROS showed longstanding back stiffness and pain. On ocular examination the vision was 20/25 in each eye and positive findings were in the left eye bulbar conjunctival which showed stationary black vermiform (filarial in appearance) foreign bodies along with 2 small corneal limbal pigmented deposits. Conjunctival biopsy showed dilated lymph channels with interstitial proteinaceous material of a light brown color consistent with Ochronotic pigment; hence diagnostic of Alkaptonuria. CONCLUSIONS: Pseudofilariasis may be a presenting sign of Alkaptonuria and occur years before a clinical diagnosis is made. Filariasis is always involves white worms and never black. Knowing the ophthalmic signs of this rare disease may lead to an accurate diagnosis earlier thusly avoiding unnecessary tests and examinations.

Detection of carbapenemase producing Acinetobacter baumannii ST19 from Georgia and Ukraine carrying bla OXA-23, bla OXA-72, and/or bla NDM-5, December 2019 to June 2023.

In 2003-2023, amid 5,436 Acinetobacter baumannii isolates collected globally through the Multidrug-Resistant Organism Repository and Surveillance Network, 97 were ST19PAS, 34 of which carbapenem-resistant. Strains (n = 32) sampled after 2019 harboured either bla OXA-23, bla OXA-72, and/or bla NDM-5. Phylogenetic analysis of the 97 isolates and 11 publicly available ST19 genomes revealed three sub-lineages of carbapenemase-producing isolates from mainly Ukraine and Georgia, including an epidemic clone carrying all three carbapenemase genes. Infection control and global surveillance of carbapenem-resistant A. baumannii remain important.

Low Risk of Periprosthetic Joint Infection After Aseptic Revision Total Knee Arthroplasty With Intraosseous Vancomycin.

BACKGROUND: Aseptic revisions are the most common reason for revision total knee arthroplasty (rTKA). Previous literature reports early periprosthetic joint infection (PJI) rates after aseptic rTKA to range from 3 to 9.4%. Intraosseous (IO) regional administration of vancomycin has previously been shown to produce high local tissue concentrations in primary and rTKA. However, no data exist on the effect of prophylactic IO vancomycin on early PJI rates in the setting of aseptic rTKA. The aim of this study was to determine the following: (1) what is the rate of early PJI during the first year after surgery in aseptic rTKA performed with IO vancomycin; and (2) how does this compare to previously published PJI rates after rTKA. METHODS: A consecutive series of 117 cases were included in this study who underwent rTKA between January 2016 and March 2022 by 1 of 2 fellowship-trained adult reconstruction surgeons and received IO vancomycin at the time of surgery in addition to standard intravenous antibiotic prophylaxis. Rates of PJI at 3 months, 1 year, and the final follow-up were evaluated and compared to prior literature. RESULTS: Follow-up at 3 months was available for 116 of the 117 rTKAs, with 1 lost to follow-up. The rate of PJI was 0% at 3 months postoperatively. Follow-up at 1 year was obtained for 113 of the 117 rTKAs, and the PJI rate remained 0%. The rate of PJI at the final follow-up of ≥ 1 year was 0.88% (95% confidence interval: -0.84 to 2.61). Previous literature reports PJI rates in aseptic rTKA to range from 3 to 9.4%. CONCLUSIONS: Dual prophylactic antibiotics with IO vancomycin in conjunction with intravenous cephalosporins or clindamycin were associated with a substantial reduction in early PJI compared to prior published literature. These data supplement the early evidence about the potential clinical benefits of IO vancomycin for infection prevention in high-risk cases. LEVEL OF EVIDENCE: Level III, therapeutic study.