DICER ribonuclease removes harmful R-loops.

R-loops, which consist of a DNA-RNA hybrid and a displaced DNA strand, are known to threaten genome integrity. To counteract this, different mechanisms suppress R-loop accumulation by either preventing the hybridization of RNA with the DNA template (RNA biogenesis factors), unwinding the hybrid (DNA-RNA helicases), or degrading the RNA moiety of the R-loop (type H ribonucleases [RNases H]). Thus far, RNases H are the only nucleases known to cleave DNA-RNA hybrids. Now, we show that the RNase DICER also resolves R-loops. Biochemical analysis reveals that DICER acts by specifically cleaving the RNA within R-loops. Importantly, a DICER RNase mutant impaired in R-loop processing causes a strong accumulation of R-loops in cells. Our results thus not only reveal a function of DICER as an R-loop resolvase independent of DROSHA but also provide evidence for the role of multi-functional RNA processing factors in the maintenance of genome integrity in higher eukaryotes.

Causal relationships between pain, medical treatments, and knee osteoarthritis: A graphical causal model to guide analyses.

OBJECTIVE: Randomized controlled trials (RCTs) are a gold standard for estimating the benefits of clinical interventions, but their decision-making utility can be limited by relatively short follow-up time. Longer-term follow-up of RCT participants is essential to support treatment decisions. However, as time from randomization accrues, loss to follow-up and competing events can introduce biases and require covariate adjustment even for intention-to-treat effects. We describe a process for synthesizing expert knowledge and apply this to long-term follow-up of an RCT of treatments for meniscal tears in patients with knee osteoarthritis (OA). METHODS: We identified 2 post-randomization events likely to impact accurate assessment of pain outcomes beyond 5 years in trial participants: loss to follow-up and total knee replacement (TKR). We conducted literature searches for covariates related to pain and TKR in individuals with knee OA and combined these with expert input. We synthesized the evidence into graphical models. RESULTS: We identified 94 potential covariates potentially related to pain and/or TKR among individuals with knee OA. Of these, 46 were identified in the literature review and 48 by expert panelists. We determined that adjustment for 50 covariates may be required to estimate the long-term effects of knee OA treatments on pain. CONCLUSION: We present a process for combining literature reviews with expert input to synthesize existing knowledge and improve covariate selection. We apply this process to the long-term follow-up of a randomized trial and show that expert input provides additional information not obtainable from literature reviews alone.

A comparative evaluation of the role of olfaction in attachment.

Olfactory information plays an important role in the attachment and bonding processes for both humans and non-human animals. Odor cues obtained via individual body odor facilitate attachment and bonding processes across species with regard to both mate selection and mother-infant bonding. The purpose of the present paper is to summarize the role of odor as it pertains to bond formation and maintenance in the mother-infant bond for human infants and non-human animal infants, and for mate selection among human adults and non-human animals. We then synthesize this summary with literature on attachment and existing evidence for the relationships between olfaction and attachment processes. Finally, we suggest avenues for areas of future research.

A preliminary analysis of the effect of individual differences on cognitive performance in young companion dogs.

Many factors influence cognitive performance in dogs, including breed, temperament, rearing history, and training. Studies in working dog populations have demonstrated age-related improvements in cognitive task performance across the first years of development. However, the effect of certain factors, such as age, sex, and temperament, on cognitive performance in puppies has yet to be evaluated in a more diverse population of companion dogs. In this study, companion dogs under 12 months of age were tested once on two tasks purported to measure aspects of executive function: the delayed-search task (DST) and the detour reversal task (DRT). Owners also filled out the Canine Behavioral Assessment and Research Questionnaire (C-BARQ) to evaluate how temperament influenced task performance. Contrary to prior research, performance did not improve with age on either task. However, the lack of age effects was likely the result of small sample sizes and individual differences across other factors influencing performance. Specifically, temperament differences as measured by the C-BARQ subscales for nonsocial fear and excitability predicted task performance on the DST, but the effect of temperament on task performance differed between males and females. Excitability also predicted performance on the DRT, but the effect depended on the age of the dog. In addition, no correlations were observed between task measures, indicating a lack of construct validity. Overall, these findings provide a preliminary analysis of factors that appear to influence cognitive task performance in young companion dogs and highlight suggestions for future research evaluating the impact of individual differences on cognitive performance.

Risk of fall or fracture with concomitant use of prescription opioids and other medications in osteoarthritis patients.

BACKGROUND: Osteoarthritis (OA) patients taking prescription opioids for pain are at increased risk of fall or fracture, and the concomitant use of interacting drugs may further increase the risk of these events. AIMS: To identify prescription opioid-related medication combinations associated with fall or fracture. MATERIALS & METHODS: We conducted a case-crossover-based screening of two administrative claims databases spanning 2003 through 2021. OA patients were aged 40 years or older with at least 365 days of continuous enrollment and 90 days of continuous prescription opioid use before their first eligible fall or fracture event. The primary analysis quantified the odds ratio (OR) between fall and non-opioid medications dispensed in the 90 days before the fall date after adjustment for prescription opioid dosage and confounding using a case-time-control design. A secondary analogous analysis evaluated medications associated with fracture. The false discovery rate (FDR) was used to account for multiple testing. RESULTS: We identified 41 693 OA patients who experienced a fall and 24 891 OA patients who experienced a fracture after at least 90 days of continuous opioid therapy. Top non-opioid medications by ascending p-value with OR > 1 for fall were meloxicam (OR 1.22, FDR = 0.08), metoprolol (OR 1.06, FDR >0.99), and celecoxib (OR 1.13, FDR > 0.99). Top non-opioid medications for fracture were losartan (OR 1.20, FDR = 0.80), alprazolam (OR 1.14, FDR > 0.99), and duloxetine (OR 1.12, FDR = 0.97). CONCLUSION: Clinicians may seek to monitor patients who are co-prescribed drugs that act on the central nervous system, especially in individuals with OA.

Thrombectomy for Stroke With Large Infarct on Noncontrast CT: The TESLA Randomized Clinical Trial.

Importance: Recent large infarct thrombectomy trials used heterogeneous imaging modalities and time windows for patient selection. Noncontrast computed tomographic (CT) scan is the most common stroke imaging approach. It remains uncertain whether thrombectomy is effective for patients with large infarcts identified using noncontrast CT alone within 24 hours of stroke onset. Objective: To evaluate the effect of thrombectomy in patients with a large infarct on a noncontrast CT scan within 24 hours of onset. Design, Setting, and Participants: Open-label, blinded-end point, bayesian-adaptive randomized trial with interim analyses for early stopping (futility or success) or population enrichment, which was conducted at 47 US academic and community-based stroke thrombectomy centers. Three hundred patients presenting within 24 hours with anterior-circulation, large-vessel occlusion and large infarct on noncontrast CT scan, with Alberta Stroke Program Early CT Scores of 2 to 5, were randomized to undergo thrombectomy or usual care. Enrollment occurred July 16, 2019 to October 17, 2022; final follow-up, January 25, 2023. Intervention: The intervention patients (n = 152) underwent endovascular treatment using standard thrombectomy devices and usual medical care. Control patients (n = 148) underwent usual medical care alone. Main Outcomes and Measures: The primary efficacy end point was improvement in 90-day functional outcome measured using mean utility-weighted modified Rankin Scale (UW-mRS) scores (range, 0 [death or severe disability] to 10 [no symptoms]; minimum clinically important difference, 0.3). A bayesian model determined the posterior probability that the intervention would be superior to usual care; statistical significance was a 1-sided posterior probability of .975 or more. The primary adverse event end point was 90-day mortality; secondary adverse event end points included symptomatic intracranial hemorrhage and radiographic intracranial hemorrhage. Results: The trial enrolled 300 patients (152 intervention, 148 control; 138 females [46%]; median age, 67 years), without early stopping or enrichment; 297 patients completed the 90-day follow-up. The mean (SD) 90-day UW-mRS score was 2.93 (3.39) for the intervention group vs 2.27 (2.98) for the control group with an adjusted difference of 0.63 (95% credible interval [CrI], -0.09 to 1.34; posterior probability for superiority of thrombectomy, .96). The 90-day mortality was similar between groups: 35.3% (53 of 150) for the intervention group vs 33.3% (49 of 147) for the control group. Six of 151 patients (4.0%) in the intervention group and 2 of 149 (1.3%) in the control group experienced 24-hour symptomatic intracranial hemorrhage. Fourteen patients of 148 (9.5%) in the intervention group vs 4 of 146 (2.7%) in the control group experienced parenchymal hematoma type 1 hemorrhages; 14 (9.5%) in the intervention group vs 5 (3.4%) in the control group experienced parenchymal hematoma type 2 hemorrhages; and 24 (16.2%) in the intervention group vs 9 (6.2%) in the control group experienced subarachnoid hemorrhages. Conclusions and Relevance: Among patients with a large infarct on noncontrast CT within 24 hours, thrombectomy did not demonstrate improvement in functional outcomes. But the width of the credible interval around the effect estimate includes the possibility of both no important effect and a clinically relevant benefit, so the potential role of thrombectomy with this imaging approach and time window will likely require additional study. Trial Registration: ClinicalTrials.gov Identifier: NCT03805308.

Ten-year trends, disparities, and clinical impact of stroke thrombectomy and thrombolysis: A single center experience 2012-2021.

OBJECTIVES: As indications for acute ischemic stroke treatment expand, it is unclear whether disparities in treatment utilization and outcome still exist. The main objective of this study was to investigate disparities in acute ischemic stroke treatment and determine impact on outcome. MATERIALS AND METHODS: Retrospective observational cohort study of consecutive ischemic stroke admissions to a comprehensive stroke center from 2012-2021 was performed. Primary exposure was intravenous thrombolysis and/or endovascular thrombectomy. Primary end points were discharge modified Rankin Scale, home disposition, and expired/hospice. Multivariable logistic regression analyses were conducted to elucidate disparities in treatment utilization and determine impact on outcome. RESULTS: Of 517,615 inpatient visits, there were 7,540 (1.46 %) ischemic stroke admissions, increasing from 1.14 % to 1.79 % from 2012-2021. Intravenous thrombolysis significantly decreased from 14.4 % to 9.8 % while endovascular thrombectomy significantly increased from 0.8 % to 10.5 %. Both intravenous thrombolysis and endovascular thrombectomy increased odds of discharge home and modified Rankin Scale 0-2, and thrombectomy decreased odds of expired/hospice. After adjusting for covariates, decreased odds of thrombectomy was associated with Medicaid insurance (Odds Ratio [95 % Confidence Interval] 0.55 [0.32-0.93]), age 80+ (0.49 [0.35-0.69]), prior stroke (0.49 [0.31-0.77]), and diabetes mellitus (0.55 [0.39-0.79]), while low median household income (<$80,000/year) increased odds of no acute treatment (1.34 [1.16-1.56]). No sex or racial disparities were observed. Medicaid and low-income were not associated with worse clinical outcomes. CONCLUSIONS: Less endovascular thrombectomy occurred in Medicaid, older, prior stroke, and diabetic patients, while low-income was associated with no treatment. The observed socioeconomic disparities did not impact discharge outcome.

Time-driven activity-based costing (TDABC) of direct-to-angiography pathway for acute ischemic stroke patients with suspected large vessel occlusion.

INTRODUCTION: Direct-to-angiography (DTA) is a novel care pathway for endovascular treatment (EVT) of acute ischemic stroke (AIS) that has been shown to reduce time-to-treatment and improve clinical outcomes for EVT-eligible patients. The institutional costs of adopting the DTA pathway and the many factors affecting costs have not been studied. In this study, we assess the costs and main cost drivers associated with the DTA pathway compared to the conventional CT pathway for patients presenting with AIS and suspected LVO in the anterior circulation. METHODS: Time driven activity based costing (TDABC) model was used to compare costs of DTA and conventional pathways from the healthcare institution perspective. Process mapping was used to outline all activities and resources (personnel, equipment, materials) needed for each step in both pathways. The cost model was developed using our institutional patient database and average New York state wages for personnel costs. Total, incremental and proportional costs were calculated based on institutional and patient factors affecting the pathways. RESULTS: DTA pathway accrued additional $82,583.61 (9%) in total costs compared to the conventional approach for all AIS patients. For EVT-ineligible patients, the DTA pathway incurred additional $82,964.37 (76%) in total costs compared to the CT pathway. For EVT eligible patients, the total and per-patient costs were greater in the CT pathway by $380.76 (0.04%) and $5.60 (0.04%) respectively. CONCLUSION: As the DTA pathway incurred additional $82,964.37 for EVT-ineligible patients, appropriate patient selection criteria are needed to avoid transferring EVT-ineligible patients to the angiography suite.

Effects of proactive interference on olfactory memory in dogs.

Proactive interference (PI) occurs when memories of past events or stimuli intrude in the present moment, causing working memory (WM) errors. These errors are often measured through WM tests such as matching-to-sample (MTS). When the repetition of individual stimuli increases, there is a greater chance of these intrusions, and thus there can be a decrease in accuracy in such tasks. In two experiments, we explored the nature of PI on dog working memory. First, we manipulated the size of the set of odors (2, 6, trial-unique) used to construct each session to maximize (2-odor set) and minimize (trial-unique) within-session proactive interference during an olfactory MTS task. Matching-to-sample accuracy decreased with greater PI. Second, we adapted procedures originally designed for pigeons and rhesus macaques to determine the locus of PI in dogs. To test for proactive interference, probe trials were inserted into MTS sessions where sample odors from earlier trials reappeared as incorrect comparisons. Incorrect responses on these probe trials indicated proactive interference. These probe tests were conducted with a 0-s or 20-s retention interval in separate sessions. We found that dogs performed worse on the matching task when the source of interference (odor stimulus) was from the immediately preceding trial compared with when they were from trials further back in the session but only for the 0-s retention interval. These results are compared with previous work examining the effects of proactive interference on working memory in other species.

Thriving from Work Questionnaire: Dimensionality, reliability, and validity of the long and short form questionnaires.

INTRODUCTION: Thriving from Work is defined as the state of positive mental, physical, and social functioning in which workers' experiences of their work and working conditions enable them to thrive in their overall lives, contributing to their ability to achieve their full potential at work, at home, and in the community. The purpose of this study was to develop a psychometrically-sound questionnaire measuring the positive contribution that work can have on one's well-being both at, and outside of, their work. METHODS: We used both a qualitative and quantitative approach of item reduction, domain mapping dimensionality testing, development of "long-" and "short-" versions of the questionnaire, reliability, and construct and criterion validity testing. This was established in two independent online samples of US based workers (n = 1550, n = 500). RESULTS: We developed a bi-factor model 30-item long-form and a uni-factorial 8-item short-version. The long-form measures both the latent construct of Thriving from Work and six domains (psychological/emotional; work-life integration; social; experience of work; basic needs; health). Both long- and short- forms were found to have high empirical reliability (0.93  and 0.87 respectively). The short-form captures 94% of variance of the long-form. Construct and criterion validity were supported. Test-retest reliability was high. CONCLUSIONS: The Thriving from Work Questionnaire appears to be a valid and reliable measure of work-related well-being in United States workers. Further testing is needed to refine and test the instrument in specific industries, unique worker populations, and across geographic regions.

The influence of meniscal pathology in the incidence of knee osteoarthritis: a review.

IMPORTANCE: Knee osteoarthritis (OA) is a common cause of pain and disability in older persons, affecting approximately 14 million individuals in the USA. Meniscal damage is also common in this age group with a prevalence of 35% in a middle-aged and older community sample and 82% in persons with evidence of radiographic knee osteoarthritis. This paper systematically reviews evidence on the association of meniscal pathology and incident radiographic knee OA. OBSERVATIONS: We included 15 articles, published between 2013 and 2021, assessing the relationship between meniscal pathology and OA incidence (Fig. 1). The menisci are crucial load-bearing structures, and the resulting increase in biomechanical stress due to meniscal damage increases the risk for OA development. While some discrepancies are present in the literature, a clinically meaningful association has been generally established between the presence of a meniscal tear or meniscal extrusion and subsequent development of incident OA. Of note, larger radial tears as well as complex and more severe tears exhibit the strongest association with the development of incident OA. The relationship between other features of meniscal morphology-such as meniscal volume and meniscal coverage-and incident OA is less clearly documented. CONCLUSIONS AND RELEVANCE: The early detection of meniscal pathology can be used to trigger preventative and therapeutic strategies designed to avert or delay knee OA in this at-risk population.

Grinding, Clicking, and Pivot Pain Resolve in Most Patients After Knee Arthroscopy.

PURPOSE: To determine whether knee arthroscopy alleviates the symptom constellation of knee grinding/clicking, catching/locking, and pivot pain. METHODS: One-year follow-up data from 584 consecutive subjects who underwent knee arthroscopy from August 2012 to December 2019 were collected prospectively. Subjects reported frequency of knee grinding/clicking, catching/locking, and/or pivot pain preoperatively and 1 and 2 years postoperatively. A single surgeon performed each procedure and documented all intraoperative pathology. We measured the postoperative resolution or persistence of these symptoms and used multivariable regression models to identify preoperative demographic and clinical variables that predicted symptom persistence. We also assessed changes in the Pain, Activities of Daily Living, and Quality of Life subscales of the Knee Injury and Osteoarthritis Outcome Score (KOOS). RESULTS: Postoperative symptom resolution was more likely for grinding/clicking (65.6%) and pivot pain (67.8%) than for catching/locking (44.1%). Smoking status, overweight/obesity, absence of meniscal tear, and number of compartments with focal cartilage lesions predicted persistence of 1 or more patient-reported knee symptoms. KOOS subscale scores consistently improved by at least one standard deviation. Individuals who had resolution of patient-reported knee symptoms exhibited roughly 2-fold improvements in KOOS Pain, ADL and Quality of Life scores compared with those whose symptoms persisted. Persistence of pivot pain was associated with the least improvement of the 3 KOOS subscales. CONCLUSIONS: Two in three patients with grinding/clicking or pivot pain experience symptom resolution after knee arthroscopy, although catching/locking is more likely to persist. Smoking status, overweight/obesity, absence of meniscal tear, and number of compartments with focal cartilage lesions predict symptom persistence after knee arthroscopy. LEVEL OF EVIDENCE: Therapeutic Level IV, retrospective cohort analysis of prospective data.

The Association of Sacro-Femoro-Pubic Angle and Postoperative Dislocation Following Total Hip Arthroplasty.

BACKGROUND: Spino-pelvic orientation may affect dislocation risk following total hip arthroplasty (THA). It can be measured on lateral lumbo-pelvic radiographs. The sacro-femoro-pubic (SFP) angle, measured on an antero-posterior (AP) pelvis radiograph, is a reliable proxy for pelvic tilt, a measurement of spino-pelvic orientation measured on a lateral lumbo-pelvic radiograph. The purpose of this study was to investigate the relationship between SFP angle and dislocation following THA. METHODS: An Institutional Review Board-approved retrospective case-control study was conducted at a single academic center. We matched 71 dislocators (cases) to 71 nondislocators (controls) following THA performed by 1 of 10 surgeons between September 2001 and December 2010. Two authors (readers) independently calculated SFP angle from single preoperative AP pelvis radiographs. Readers were blinded to cases and controls. Conditional logistic regressions were used to identify factors differentiating cases and controls. RESULTS: The data did not show a clinically relevant or statistically significant difference in SFP angles after adjusting for gender, American Society of Anesthesiologists classification, prosthetic head size, age at time of THA, measurement laterality, and surgeon. CONCLUSION: We did not find an association between preoperative SFP angle and dislocation following THA in our cohort. Based on our data, SFP angle as measured on a single AP pelvis radiograph should not be used to assess dislocation risk prior to THA.

Comparative outcomes of the treatment of unruptured paraophthalmic aneurysms in the era of flow diversion.

BACKGROUND: Paraophthalmic aneurysms present a challenge to surgeons and their ideal management remains up for debate. We studied recent outcomes of these lesions in a single center. METHODS: A retrospective chart review of all patients undergoing treatment for paraophthalmic aneurysms from 2017-2019 was performed. Factors including patient demographics, aneurysm characteristics, treatment modality, radiographic treatment outcome, clinical outcome, and length of stay were collected, and bivariate analysis was performed. RESULTS: In total 84.5% (82/97) of aneurysms were treated endovascularly and 15.5% (15/97) surgically. In the surgery cohort, there were three transient perioperative complications (20%) and one minor postoperative complication (6.7%). Complete aneurysm occlusion or near complete (<2mm residual) was achieved in 100% (15/15). All but one patient had mRS ≤1 at the last follow-up. In the endovascular group, 78.1% (64/82) underwent flow diversion alone. Endovascular treatment was associated with a 4.9% (4/82) rate of periprocedural complications: 3 transient events, and 1 death, and a 3.7% (3/82) rate of delayed complications: 2 transient vision changes, and one death. Rate of total occlusion was 87.8% (72/82). 76 patients (92.7%) had mRS ≤1 at the last follow-up. Length of stay was significantly shorter in the endovascular group (3.4 days vs. 7.0 days) [p < 0.001]. CONCLUSIONS: This series demonstrates similar safety to previously reported series as well as the efficacy of both surgical clipping and endovascular embolization of paraophthalmic aneurysms. Rate of complications and treatment efficacy were similar in both groups although this represents a single institution series not generalizable to all centers.

Hyperperfusion syndrome after superficial temporal artery-middle cerebral artery bypass for non-moyamoya steno-occlusive disease.

BACKGROUND AND OBJECTIVES: Stroke is a major cause of morbidity and mortality worldwide, and intracranial stenoses increase the risk for stroke. Superficial temporal artery to middle cerebral artery bypass can be beneficial in selected patients with non-moyamoya steno-occlusive disease, however data is limited regarding the postoperative occurrence of hyperperfusion syndrome in this population. This case series describes the outcomes and complications, including hyperperfusion, in these patients who underwent bypass. METHODS: This is a retrospective review of bypass procedures done for medically refractory intracranial stenosis at a single institution by a single surgeon between 2014 and 2021. RESULTS: 30 patients underwent 33 bypass procedures for unequivocal non-moyamoya steno-occlusive disease. All patients had immediate bypass patency on post-operative day one. Major perioperative complications (9%) included one stroke and two cases of hyperperfusion syndrome. Minor perioperative complications (12%) included two seizures, one superficial wound infection and one deep vein thrombosis. Modified Rankin Score improved in 20 patients (74%), worsened in one patient (4%), and remained stable in seven patients (22%) at the last follow up. Twenty-three patients (85%) had scores ≤ 2. The recurrent stroke rate was 3% at 30 days and 7% at two years. The bypass patency rate at one year was 87.5%. CONCLUSION: In this series, bypass for patients with medically refractory non-moyamoya steno-occlusive disease was well tolerated and effective, with overall favorable outcomes. The occurrence of hyperperfusion syndrome is rare but significant and should be considered in post-operative management of this population.

Stroke mechanisms in adult moyamoya disease: The association between infarction patterns and quantitative magnetic resonance angiography flow state.

INTRODUCTION: Flow augmentation is the mainstay treatment for moyamoya disease as hemodynamic failure is believed to be the dominant mechanism. We aimed to investigate the mechanisms of stroke in moyamoya disease by assessing the relationship between infarction patterns and quantitative magnetic resonance angiography flow state. METHODS: A retrospective study of adult patients with suspected MMD who presented with MRI confirmed acute ischemic stroke predating or following QMRA by a maximum of six months between 2009 and 2021 was conducted. Of the 177 consecutive patients with MMD who received QMRA, 35 patients, consisting of 41 hemispheres, met inclusion criteria. Flow-status was dichotomized into low-flow and normal-flow state based on previously established criteria. RESULTS: Mixed infarction pattern was the most frequent finding (70.7 %), followed by embolic (17.1 %), perforator (7.3 %), and internal borderzone (IBZ) (4.9 %). Infarction patterns were further dichotomized into IBZ+ (internal borderzone alone or mixed) and IBZ- (no internal borderzone constituent). Low-flow states were not significantly more frequent in the IBZ+ compared to IBZ- population (48.4 % vs. 20.0 %, p = 0.14). Ipsilateral posterior cerebral artery fractional flow was significantly higher with IBZ+ compared to IBZ- (345.0 % vs. 214.7 %, p = 0.04). CONCLUSION: Mixed infarction pattern was the most common pattern of infarction in patients with moyamoya disease, implying hypoperfusion and thromboembolism are codominant stroke mechanisms. An association between ICA flow status and infarction pattern was not found, although QMRA evidence of more robust posterior cerebral artery leptomeningeal collaterals was found in patients with a hypoperfusion contribution to their stroke mechanism.

Endovascular Treatment of Acute Ischemic Stroke With the Penumbra System in Routine Practice: COMPLETE Registry Results.

BACKGROUND AND PURPOSE: The purpose of the COMPLETE (International Acute Ischemic Stroke Registry With the Penumbra System Aspiration Including the 3D Revascularization Device) registry was to evaluate the generalizability of the safety and efficacy of the Penumbra System (Penumbra, Inc, Alameda) in a real-world setting. METHODS: COMPLETE was a global, prospective, postmarket, multicenter registry. Patients with large vessel occlusion-acute ischemic stroke who underwent mechanical thrombectomy using the Penumbra System with or without the 3D Revascularization Device as frontline approach were enrolled at 42 centers (29 United States, 13 Europe) from July 2018 to October 2019. Primary efficacy end points were successful postprocedure angiographic revascularization (modified Thrombolysis in Cerebral Infarction ≥2b) and 90-day functional outcome (modified Rankin Scale score 0-2). The primary safety end point was 90-day all-cause mortality. An imaging core lab determined modified Thrombolysis in Cerebral Infarction scores, Alberta Stroke Program Early CT Scores, clot location, and occurrence of intracranial hemorrhage at 24 hours. Independent medical reviewers adjudicated safety end points. RESULTS: Six hundred fifty patients were enrolled (median age 70 years, 54.0% female, 49.2% given intravenous recombinant tissue-type plasminogen activator before thrombectomy). Rate of modified Thrombolysis in Cerebral Infarction 2b to 3 postprocedure was 87.8% (95% CI, 85.3%-90.4%). First pass and postprocedure rates of modified Thrombolysis in Cerebral Infarction 2c to 3 were 41.5% and 66.2%, respectively. At 90 days, 55.8% (95% CI, 51.9%-59.7%) had modified Rankin Scale score 0 to 2, and all-cause mortality was 15.5% (95% CI, 12.8%-18.3%). CONCLUSIONS: Using Penumbra System for frontline mechanical thrombectomy treatment of patients with large vessel occlusion-acute ischemic stroke in a real-world setting was associated with angiographic, clinical, and safety outcomes that were comparable to prior randomized clinical trials with stringent site and operator selection criteria. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03464565.

The Value of Total Knee Replacement in Patients With Knee Osteoarthritis and a Body Mass Index of 40 kg/m2 or Greater : A Cost-Effectiveness Analysis.

BACKGROUND: Total knee replacement (TKR) is an effective and cost-effective strategy for treating end-stage knee osteoarthritis. Greater risk for complications among TKR recipients with a body mass index (BMI) of 40 kg/m2 or greater has raised concerns about the value of TKR in this population. OBJECTIVE: To assess the value of TKR in recipients with a BMI of 40 kg/m2 or greater using a cost-effectiveness analysis. DESIGN: Osteoarthritis Policy Model to assess long-term clinical benefits, costs, and cost-effectiveness of TKR in patients with a BMI of 40 kg/m2 or greater. DATA SOURCES: Total knee replacement parameters from longitudinal studies and published literature, and costs from Medicare Physician Fee Schedules, the Healthcare Cost and Utilization Project, and published data. TARGET POPULATION: Recipients of TKR with a BMI of 40 kg/m2 or greater in the United States. TIME HORIZON: Lifetime. PERSPECTIVE: Health care sector. INTERVENTION: Total knee replacement. OUTCOME MEASURES: Cost, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs), discounted at 3% annually. RESULTS OF BASE-CASE ANALYSIS: Total knee replacement increased QALYs by 0.71 year and lifetime medical costs by $25 200 among patients aged 50 to 65 years with a BMI of 40 kg/m2 or greater, resulting in an ICER of $35 200. Total knee replacement in patients older than 65 years with a BMI of 40 kg/m2 or greater increased QALYs by 0.39 year and costs by $21 100, resulting in an ICER of $54 100. RESULTS OF SENSITIVITY ANALYSIS: In TKR recipients with a BMI of 40 kg/m2 or greater and diabetes and cardiovascular disease, ICERs were below $75 000 per QALY. Results were most sensitive to complication rates and preoperative pain levels. In the probabilistic sensitivity analysis, at a $55 000-per-QALY willingness-to-pay threshold, TKR had a 100% and 90% likelihood of being a cost-effective strategy for patients aged 50 to 65 years and patients older than 65 years, respectively. LIMITATION: Data are derived from several sources. CONCLUSION: From a cost-effectiveness perspective, TKR offers good value in patients with a BMI of 40 kg/m2 or greater, including those with multiple comorbidities. PRIMARY FUNDING SOURCE: National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health.

Multimodal prediction of pain and functional outcomes 6 months following total knee replacement: a prospective cohort study.

BACKGROUND: Knee osteoarthritis (OA) is among the most common and disabling persistent pain conditions, with increasing prevalence and impact around the globe. In the U.S., the rising prevalence of knee OA has been paralleled by an increase in annual rates of total knee arthroplasty (TKA), a surgical treatment option for late-stage knee OA. While TKA outcomes are generally good, post-operative trajectories of pain and functional status vary substantially; a significant minority of patients report ongoing pain and impaired function following TKA. A number of studies have identified sets of biopsychosocial risk factors for poor post-TKA outcomes (e.g., comorbidities, negative affect, sensory sensitivity), but few prospective studies have systematically evaluated the unique and combined influence of a broad array of factors. METHODS: This multi-site longitudinal cohort study investigated predictors of 6-month pain and functional outcomes following TKA. A wide spectrum of relevant biopsychosocial predictors was assessed preoperatively by medical history, patient-reported questionnaire, functional testing, and quantitative sensory testing in 248 patients undergoing TKA, and subsequently examined for their predictive capacity. RESULTS: The majority of patients had mild or no pain at 6 months, and minimal pain-related impairment, but approximately 30% reported pain intensity ratings of 3/10 or higher. Reporting greater pain severity and dysfunction at 6 months post-TKA was predicted by higher preoperative levels of negative affect, prior pain history, opioid use, and disrupted sleep. Interestingly, lower levels of resilience-related "positive" psychosocial characteristics (i.e., lower agreeableness, lower social support) were among the strongest, most consistent predictors of poor outcomes in multivariable linear regression models. Maladaptive profiles of pain modulation (e.g., elevated temporal summation of pain), while not robust unique predictors, interacted with psychosocial risk factors such that the TKA patients with the most pain and dysfunction exhibited lower resilience and enhanced temporal summation of pain. CONCLUSIONS: This study underscores the importance of considering psychosocial (particularly positively-oriented resilience variables) and sensory profiles, as well as their interaction, in understanding post-surgical pain trajectories.

A Provider Perspective of Psychosocial Predictors of Upper-Extremity Vascularized Composite Allotransplantation Success.

PURPOSE: We performed a qualitative study to understand the psychosocial factors associated with success in upper-extremity vascularized composite allotransplantation from the perspective of transplant providers. METHODS: We recruited 13 providers actively involved in upper-extremity vascularized composite allotransplantation. Participants included physicians, nurses, social workers, occupational therapists, and research administrators. We conducted semistructured face-to-face focus group interviews using a guide that explored providers' perceptions of qualities contributing to transplant outcome. Topics included social support networks and their influence on recovery, barriers to treatment compliance and successful posttransplant rehabilitation, and the process of setting patients' expectations. We performed a thematic analysis that produced a list of themes, subthemes, and proposed hypotheses explaining how the themes related to the study's guiding questions. RESULTS: The analysis identified numerous factors that contribute to transplant success: (1) recipients' prior experiences modify their ability to cope and adapt after transplantation, (2) behaviors and characteristics such as positivity influence candidacy and may be predictive of successful outcomes, and (3) social support is essential for improved function and compliance. The provider care team cited difficulty in predicting recipient compliance and in setting realistic expectations. CONCLUSIONS: Motivated recipients with developed coping and resiliency, a positive attitude, and stable, physically-able caregivers are perceived by providers to have greater success after transplantation. CLINICAL RELEVANCE: Findings from this work may help providers determine optimal candidates for upper-extremity vascularized composite allotransplantation.