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Antibody-drug conjugates (ADCs) are an established modality that allow for targeted delivery of a potent molecule, or payload, to a desired site of action. ADCs, wherein the payload is a targeted protein degrader, are an emerging area in the field. Herein we describe our efforts of delivering a Bruton's tyrosine kinase (BTK) bifunctional degrader 1 via a CD79b mAb (monoclonal antibody) where the degrader is linked at the ligase binding portion of the payload via a cleavable linker to the mAb. The resulting CD79b ADCs, 3 and 4, exhibit in vitro degradation and cytotoxicity comparable with that of 1, and ADC 3 can achieve more sustained in vivo degradation than intravenously administered 1 with markedly reduced systemic exposure of the payload.
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Inmunoconjugados , Inmunoconjugados/química , Agammaglobulinemia Tirosina Quinasa , Anticuerpos Monoclonales/químicaRESUMEN
OBJECTIVE: The goals of this study were (i) to assess the association between hip capsule morphology and pain in patients without any other MRI abnormalities that would correlate with pain and (ii) to investigate whether hip capsule morphology in hip pain patients is different from that of controls. METHODS: In this study, 76 adults with hip pain who did not show any structural abnormalities on MRI and 46 asymptomatic volunteers were included. Manual segmentation of the anterior and posterior hip capsules was performed. Total and mean anterior hip capsule area, posterior capsule area, anterior-to-posterior capsule area ratio, and medial-to-lateral area ratio in the anterior capsule were quantified. Differences between the pain and control groups were evaluated using logistic regression models. RESULTS: Patients with hip pain showed a significantly lower anterior-to-posterior area ratio as compared with the control group (p = 0.002). The pain group's posterior hip capsule area was significantly larger than that of controls (p = 0.001). Additionally, the ratio between the medial and lateral sections of the anterior capsule was significantly lower in the pain group (p = 0.004). CONCLUSIONS: Patients with hip pain are more likely to have thicker posterior capsules and a lower ratio of the anterior-to-posterior capsule area and thinner medial anterior capsules with a lower ratio of the medial-to-lateral anterior hip capsule compartment, compared with controls. CLINICAL RELEVANCE STATEMENT: During MRI evaluations of patients with hip pain, morphology of the hip capsule should be assessed. This study aims to be a foundation for future analyses to identify thresholds distinguishing normal from abnormal hip capsule measurements. KEY POINTS: ⢠Even with modern image modalities such as MRI, one of the biggest challenges in handling hip pain patients is finding a structural link for their pain. ⢠Hip capsule morphologies that correlated with hip pain showed a larger posterior hip capsule area and a lower anterior-to-posterior capsule area ratio, as well as a smaller medial anterior capsule area with a lower medial-to-lateral anterior hip capsule ratio. ⢠The hip capsule morphology is correlated with hip pain in patients who do not show other morphology abnormalities in MRI and should get more attention in clinical practice.
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Articulación de la Cadera , Cápsula Articular , Imagen por Resonancia Magnética , Humanos , Femenino , Masculino , Imagen por Resonancia Magnética/métodos , Cápsula Articular/diagnóstico por imagen , Cápsula Articular/patología , Adulto , Articulación de la Cadera/diagnóstico por imagen , Articulación de la Cadera/patología , Persona de Mediana Edad , Artralgia/diagnóstico por imagen , Artralgia/etiología , Estudios de Casos y Controles , AncianoRESUMEN
The hip capsule consists of the iliofemoral, ischiofemoral, and pubfemoral ligaments. The iliofemoral ligament is an important part of the anterior hip capsule that functions to stabilize the joint but is commonly incised in order to obtain access during hip arthroscopy, as described in techniques such as interportal, T, puncture, and periportal capsulotomy. For the most commonly used interportal capsulotomy, recent literature has advocated for closure of the capsule at the end of the surgery to avoid iatrogenic instability or microinstability. Systematic reviews and cohort studies have reported significantly better patient-reported outcomes after hip arthroscopy for femoroacetabular impingement syndrome with capsule closure compared to without capsule closure. However, recent high-level evidence from a randomized controlled trial demonstrated that in a predominantly male cohort there was no difference in patient-reported outcomes improvements or complications between patients undergoing hip arthroscopy for femoroacetabular impingement syndrome through an interportal capsulotomy who were randomized to receive capsule closure versus no capsule closure. Of note, male patients have inherently tighter and more stable joints than female patients and therefore are at lower risk for postoperative instability or microinstability from an interportal capsulotomy that does not properly heal. Also, if the capsule is not violated below the 3-o'clock position (for a right hip, or 9 o'clock for a left hip), there may be less risk to destabilizing the hip joint. A limited interportal capsulotomy in male patients could lead to healing in an unrepaired state.
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PURPOSE: To evaluate a large cross-sectional sample of patients utilizing administrative database records and analyze the effects of income, insurance type, and education level on outcomes after hip arthroscopy, including 2-year revision surgery, conversion to total hip arthroplasty (THA), and 90-day hospitalizations. METHODS: Current Procedural Terminology codes were used to query the PearlDiver Mariner database from October 2015 to January 2020 for patients undergoing hip arthroscopy with a minimum 2-year follow-up. Patients were categorized by mean family income in their zip code of residence (MFIR), health insurance type, and educational attainment in their zip code of residence (EAR). Two-year revision arthroscopy, conversion to THA, and 90-day hospital readmissions or emergency department (ED) visits were analyzed along socioeconomic strata. RESULTS: Multivariate analysis of 33,326 patients revealed that patients with MFIR between $30,000 and $70,000 had lower odds of 2-year revision arthroscopy (odds ratio [OR], 0.63; P < .001), THA conversion (OR, 0.76; P = .050), and 90-day readmission (OR, 0.53; P = .007) compared to MFIR >$100,000. Compared to patients with commercial insurance, patients with Medicare had lower odds of revision arthroscopy (OR, 0.60; P = .035) and THA conversion (OR, 0.46, P < .001) but greater odds of 90-day readmission (OR, 1.74; P = .007). Patients with Medicaid had higher odds of 90-day ED visits (OR, 1.84; P < .001). Patients with low EAR had higher odds of revision arthroscopy (OR, 1.42; P = .005) and THA conversion (OR, 1.58; P = .002) compared to those with high EAR. CONCLUSIONS: Following hip arthroscopy, patients residing in areas with lower mean family income were less likely to undergo reoperations and readmissions. Medicare patients showed lower reoperation but higher readmission odds, while Medicaid patients showed higher odds of ED visits. Additionally, higher educational attainment in the zip code of residence is protective against future reoperation. LEVEL OF EVIDENCE: Level III, retrospective case series.
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PURPOSE: To investigate reoperation rates after meniscus allograft transplant (MAT), comparing rates with and without concomitant articular cartilage and osteotomy procedures using a national insurance claims database. METHODS: We performed a retrospective cohort study of patients who underwent MAT from 2010 to 2021 with minimum 2 year follow-up using the PearlDiver database. Using Current Procedural Terminology (CPT) and International Classification of Diseases (ICD) codes, we identified patients who underwent concomitant procedures including chondroplasty or microfracture, cartilage restoration defined as osteochondral graft or autologous chondrocyte implantation (ACI), or osteotomy. Univariate logistic regressions identified risk factors for reoperation. Reoperations were classified as knee arthroplasty, interventional procedures, or diagnostic or debridement procedures. RESULTS: 750 patients were included with an average age of 29.6 years (interquartile range 21.0-36.8) and average follow-up time was 5.41 years (SD: 2.51). 90-day, 2-year, and all-time reoperation rates were 1.33%, 14.4%, and 27.6% respectively. MAT with cartilage restoration was associated with increased reoperation rate at 90 days (OR: 4.88; 95% CI: 1.38-19.27; p=.015), however there was no significant difference in reoperation rates at 2 years or to the end of follow-up. ACI had increased reoperation rates at 90 days (OR: 6.95; 95% CI: 1.45-25.96; p=.006), with no difference in reoperation rates 2 years post-operatively or to the end of follow-up. Osteochondral autograft and allograft were not associated with increased reoperation rates. CONCLUSION: 14.4% of patients in our cohort had a reoperation within 2 years of MAT. Nearly one in four patients undergoing MAT had concomitant cartilage restoration, showing that it is commonly performed on patients with articular cartilage damage. Concomitant osteochondral autograft, osteochondral allograft, chondroplasty, microfracture and osteotomy were not associated with any significant difference in reoperation rates. ACI was associated with increased reoperation rates at 90 days, but not later.
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PURPOSE: To determine whether response to preoperative local anesthetic or corticosteroid intra-articular injections can predict 2-year postoperative outcomes in patients undergoing hip arthroscopy for femoroacetabular impingement syndrome (FAIS). METHODS: This was a retrospective analysis of patients undergoing hip arthroscopy for FAIS at a single institution from 2014-2020. Patients who underwent preoperative intra-articular hip injection were classified based on injection type (local anesthetic, corticosteroid) and whether they experienced pain relief following injection (responders, non-responders). Responders were matched 2:1 by age, BMI, and sex with non-responders. Patient reported outcomes (PROs) including Hip Disability and Osteoarthritis Outcome Score (HOOS), 12-item Short-Form Survey mental (SF-12-MCS) and physical component summary (SF-12-PCS) and visual analogue scale (VAS) pain were collected preoperatively and 2-years postoperatively. Mean score change and Minimal Clinically Important Difference (MCID) achievement were calculated and compared between groups. RESULTS: The matched cohort included 126 total patients (42 non-responders, 84 responders; 74.6% female; mean ± SD age: 30.9 ± 9.9 years; BMI: 24.7 ± 3.7 kg/m2) with no differences in demographic or radiographic hip variables. Both groups demonstrated significant 2-year postoperative score improvements across all PROs, except SF-12-MCS, which remained unchanged. There was no difference in mean score change or MCID achievement across all PROs between corticosteroid injection responder and non-responder groups. In the local anesthetic group, MCID achievement was similar across all PROs, except VAS pain which showed greater percentage of MCID achievement among local anesthetic non-responders relative responders (Responders: 55.0%, Non-responders: 89.5%; p = 0.03). Significant ceiling effects were most readily apparent among the injection responders group with greater percentages of patients achieving maximal 2-year postoperative survey scores (36.9% HOOS-ADL, 19.0% HOOS-Pain, 15.5% HOOS-QoL, 32.1% HOOS-Sport). CONCLUSIONS: Response to preoperative injection with either corticosteroid or local anesthetic did not predict 2-year outcomes after hip arthroscopy in patients with FAIS. LEVEL OF EVIDENCE: Level III, retrospective matched cohort study.
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PURPOSE: To compare rates of revisions between patients with isolated anterior cruciate ligament (ACL) reconstruction and those who had concomitant medial collateral ligament (MCL) injuries managed either operatively or nonoperatively at the time of index anterior cruciate ligament reconstruction (ACLR). METHODS: Using laterality-specific International Classification of Diseases, Tenth Revision (ICD-10) and Current Procedural Terminology (CPT) codes, we queried the PearlDiver-Mariner Database for all patients who underwent ACLR between 2016 and 2020. Patients were included if they were ages 15 or older and had a minimum of 2 years of follow-up after index ACLR. Patients were then divided into cohorts by presence or absence of concomitant MCL injury. The cohort of concomitant MCL injuries was further subdivided into those with MCL injuries managed nonoperatively, with MCL repair, or with MCL reconstruction at the time of index ACLR. Multivariate regression was performed between cohorts to evaluate for factors associated with revision ACLR. RESULTS: We identified 47,306 patients with isolated ACL injuries and 10,846 with concomitant MCL and ACL injuries. In total, 93% of patients with concomitant MCL injuries had their MCL treated nonoperatively; however, the annual proportion of patients being surgically managed for their MCL injury increased by 70% from 2016 to 2020. Concomitant MCL injury patients had greater odds of undergoing revision ACLR compared with patients with isolated ACL injuries (odds ratio 1.50, 95% confidence interval 1.36-1.66, P < .001). Among patients with concomitant MCL injuries, surgically managed patients had a greater risk of revision ACLR compared with nonoperatively managed MCL injuries (odds ratio 1.39, 95% confidence interval 1.01-1.86, P = .034). CONCLUSIONS: Despite an increase in operatively managed concomitant MCL injuries, most concomitant MCL injuries were still managed nonoperatively at the time of ACLR. Patients with concomitant MCL injuries, particularly those managed operatively, at the time of ACLR are at increased risk of requiring revision ACLR compared with those with isolated ACL injuries. LEVEL OF EVIDENCE: Level III, retrospective comparative case series.
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Medial patellofemoral ligament (MPFL) reconstruction is a commonly performed procedure to reestablish the checkrein to the lateral patellar translation in patients with recurrent patellofemoral instability. Graft tensioning is one of the most critical aspects of the procedure. Most surgical methods for MPFL reconstruction involve tensioning and securing the graft on the femoral side. In this article, we describe a technique for patellar-sided tensioning of the graft using all-suture anchors, which provides the surgeon with the ability to finely control graft tension with two independent graft limbs, while preserving patellar bone stock.
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Purpose: To evaluate patient-reported outcomes and risk for rerupture after surgical treatment of proximal hamstring tendon ruptures using all-suture anchors and a unique postoperative bracing strategy. Methods: A retrospective review of a prospectively collected database was conducted of patients undergoing proximal hamstring repair or reconstruction from 2020 to 2022 at a tertiary, academic institution. Patients were included if they reached minimum 1-year follow-up and completed postoperative patient-reported outcomes. The surgical protocol for proximal hamstring repairs included all-suture anchors placed either in an open or endoscopic fashion in the ischial tuberosity. After surgery, all patients underwent an accelerated rehabilitation protocol, including 6 weeks touchdown weight-bearing in a hinged knee brace locked in extension for ambulation, allowing passive knee flexion to 90° while seated. Descriptive statistics were used to analyze the data. Results: Twenty-one patients were included (mean age 50.4 ± 9.5 years, body mass index 24.4 ± 3.5, 66.7% female). Lower Extremity Functional Scale score achieved postoperatively was 74.2 ± 7.5 (out of 80). Patients had minimal pain (mean visual analog scale pain score of 0.9 ± 1.2). 61.9% of patients were able to return to the same level of activity after based on Tegner score by 1 year. Postoperative Single Assessment Numeric Evaluation activity of daily living was 94.3 ± 8.3, and Single Assessment Numeric Evaluation Sports was 82.3 ± 19.0. Mean Short Form Survey (SF-12) postoperative scores were 51.6 ± 6.8 for SF-12 Physical Component Score and 53.9 ± 9.7 for Mental Component Score. 95.2% (20 of 21) patients were satisfied with their outcome. There were no reruptures, infections, or reoperations. One patient of 21 (4.8%) incurred a postoperative deep venous thrombosis, which was treated with therapeutic anticoagulation for 3 months. Conclusions: All-suture anchors for proximal hamstring repair with a unique accelerated postoperative rehabilitation and bracing protocol result in good outcomes and patient satisfaction with minimal risk of complications. Level of Evidence: Level IV, case series, therapeutic.
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Introduction: In recent years, the utilization of hip arthroscopy to treat femoroacetabular impingement syndrome (FAIS) has increased due to its low complication rates, positive impact on patient-reported outcomes (PROs), and association with faster rehabilitation. Despite this, there are high rates of revision and conversion to total hip arthroplasty (THA) in some of these patients. It is unclear whether time from initial FAIS diagnosis to surgery is a risk factor for poor outcomes. In this study, we examined the relationship between timing of hip arthroscopy for FAIS and rates of 2-year revision hip procedures, 2-year conversion to total hip arthroplasty (THA), post-operative medical complications, and opioid prescriptions. Methods: This is a retrospective cohort study utilizing the PearlDiver database. Current Procedural Terminology (CPT) and International Classification of Diseases (ICD) codes were used to identify patients who had surgery for FAIS with minimum 2 years follow-up available. Patients were stratified by 3-month intervals into 5 groups based on time from diagnosis of FAIS to hip arthroscopy. Multivariate logistic regression was performed to determine factors independently associated with continued opiate use and subsequent surgeries. Results: A total of 14,677 patients were included in the study. The 2-year rate of revision hip arthroscopy was 4.2%. As time from diagnosis to surgery increased, even in multivariate regression analysis, there was a higher risk of filling an opioid prescription 90 days after surgery (P < 0.001). Regression analysis demonstrated that timing of surgery was not associated with 2-year revision hip arthroscopy or conversion to THA. Age, sex, obesity, and tobacco use were significant predictors of revision hip arthroscopy and conversion to THA (p < 0.001). Conclusion: There is no significant difference between timing of surgery for FAIS and odds of revision or conversion to THA. Prolonged opiate use after hip arthroscopy was significantly higher as duration from initial FAIS diagnosis to surgery increased. Age, sex, obesity, and tobacco use are significant predictors for revision, conversion to THA, and continued opiate prescriptions.
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Background: Anatomic total shoulder arthroplasty (ATSA) and reverse total shoulder arthroplasty (RTSA) reliably alleviate pain and restore shoulder function for a variety of indications. However, these procedures are not well-studied in patients with neurocognitive impairment. Therefore, the purpose of this study was to investigate whether patients with dementia or mild cognitive impairment (MCI) have increased odds of surgical or medical complications following arthroplasty. Methods: The PearlDiver database was queried from 2010 through October 2021 to identify a cohort of patients who underwent either ATSA or RTSA and had a minimum 2-year follow-up. Current Procedural Terminology and International Classification of Diseases codes were used to stratify this cohort into three groups: (1) patients with dementia, (2) patients with MCI, and (3) patients with neither condition. Surgical and medical complication rates were compared among these three groups. Results: The overall prevalence of neurocognitive impairment among patients undergoing total shoulder arthroplasty was 3.0% in a cohort of 92,022 patients. Patients with dementia had increased odds of sustaining a periprosthetic humerus fracture (odds ratio [OR] = 1.46, P < .001), developing prosthesis instability (OR = 1.72, P < .001), and undergoing revision arthroplasty (OR = 1.55, P = .003) after RTSA compared to patients with normal cognition. ATSA patients with dementia did not have an elevated risk of surgical complications or revision. Conversely, RTSA patients with MCI did not have an elevated risk of complications or revision, although ATSA patients with MCI had greater odds of prosthesis instability (OR = 2.51, P = .008). Additionally, patients with neurocognitive impairment had elevated odds of medical complications compared to patients with normal cognition, including acute myocardial infarction and cerebrovascular accident. Conclusion: Compared to patients with normal cognition, RTSA patients with preoperative dementia and ATSA patients with preoperative MCI are at increased risk for surgical complications. Moreover, both ATSA and RTSA patients with either preoperative MCI or dementia are at increased risk for medical complications. As the mean age in the U.S. continues to rise, special attention should be directed towards patients with neurocognitive impairment to minimize postoperative complications aftertotal shoulder arthroplasty, and the risks of this surgery more carefully discussed with patients and their families and caretakers.
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PURPOSE: Older adults with subjective cognitive decline (SCD) experience cognitive difficulties without objectively measurable cognitive impairments but which may affect their everyday functioning. However, everyday functioning in this population has not yet been characterized. We sought to describe the empirical literature on the everyday functioning of community-dwelling older adults with SCD, their recruitment methods, and the measurements used. METHODS: A scoping review was conducted for primary research articles including at least one measure of everyday functioning. Retrieved records were independently screened. Data were extracted then analyzed using descriptive statistics and summative content analysis. RESULTS: 6544 studies were screened; 21 studies were included. All were observational analytic studies. Most compared an SCD group with a group of healthy control (47.6%), mild cognitive impairment (71.5%), and/or dementia (33.3%). Subjective cognition was measured via interview (28.6%) or clinical question(s) (14.3%). Normal cognition was determined by a wide variety of cognitive tests. The most studied everyday functioning domain was instrumental activities of daily living (90.5%). Most studies used questionnaires (81.0%), and measured ability to do an everyday life task (76.2%). CONCLUSIONS: More research is needed on everyday functioning other than IADL, with greater focus on measures that consider an individual's real-life participation.
These is heterogeneity in the operational definitions and reporting of subjective cognitive decline in the empirical literature.Assessment of everyday functioning in the empirical literature on people with subjective cognitive decline is focused on the individual's ability to do instrumental activities of daily living.There is a need for consensus on: (1) standards to assess subjective and objective cognition in determining subjective cognitive decline; and (2) best practice in assessing changes in everyday functioning in people with subjective cognitive decline.Clinical and research assessment of older adults with subjective cognitive decline should be expanded to functional domains other than instrumental activities of daily living.
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Purpose: To analyze the annual use of hip arthroscopy (HA) and Bernese periacetabular osteotomy (PAO) for the treatment of hip dysplasia (HD), as well as postoperative outcomes, including ipsilateral reoperations. Methods: International Classification of Diseases, Ninth and Tenth Revision, codes were used to query the PearlDiver Mariner database from January 2010 through January 2022 to identify patients aged 10 to 59 years who had a presenting diagnosis of HD and subsequently underwent (1) HA; (2) PAO; or (3) combined HA and PAO (HA-PAO, defined as PAO on the same day or within 28 days after HA). We analyzed annual rates for each treatment, as well as rates of postoperative emergency visits, readmissions, and 5-year ipsilateral secondary operations (determined via Kaplan-Meier analysis). Results: There were 32,068 patients who underwent surgical treatment of HD. For HA, PAO, and HA-PAO, there were 29,700, 2,083, and 285 patients, respectively. All operations had the greatest percent-increase from 2015 to 2016. HA and HA-PAO peaked in 2021, whereas PAO peaked in 2019. For HA, PAO, and HA-PAO, most cases were performed in female patients and patients aged 30 to 49 years, 10 to 19 years, and 10 to 29 years, respectively. The 5-year incidence of ipsilateral secondary operations, which include revision HA, PAO, or conversion to total hip arthroplasty, was 9.2% (95% confidence interval 8.6%-9.8%) in the HA group and 6.5% (95% confidence interval 4.1%-8.8%) in the PAO group. Combining HA with PAO resulted in so few secondary operations that Kaplan-Meier analysis was infeasible. The PAO cohort had the greatest 30-day emergency visit and 90-day readmission rates, with infection as the most common cause for readmission. Conclusions: HA is more frequently performed than PAO for hip dysplasia. HA-PAO is increasing at the greatest rate, demonstrating fewer complications and reoperations. Level of Evidence: Level III, retrospective comparative trial.
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OBJECTIVES: This study evaluated the relationship between obesity and postoperative complications in patients undergoing ankle open reduction internal fixation (ORIF). DESIGN: Retrospective cohort study. SETTING: PearlDiver-Mariner All-Payor Database. PATIENT SELECTION CRITERIA: Patients who underwent ankle ORIF from 2010 to 2021 and had a minimum of 2 years of follow-up were identified using Current Procedural Terminology, ICD-9, and ICD-10 codes. OUTCOME MEASURES AND OUTCOMES: Patients were stratified by body mass index into nonobese, obese, morbidly obese, and super-obese groups. Complication rates, including 90-day readmissions, infection, and post-traumatic osteoarthritis, were compared between obesity groups. Patients were additionally compared with a 1:1 matched analysis that controlled for demographics and comorbidities. RESULTS: A total of 160,415 patients undergoing ankle ORIF from 2010 to 2021 were identified. The cohort consisted mostly of females (64.8%) and the average age was 52.5 (SD 18.4) years. There were higher rates of 90-day readmissions, UTIs, DVT/PE, pneumonia, superficial infections, and acute kidney injuries in patients with increasing levels of obesity (P < 0.001). There were increased odds of nonunion and post-traumatic arthritis in the matched analysis at 2 years in the obesity group [OR: 2.36, 95% confidence interval (CI): 1.68-3.31, P < 0.001; OR: 2.18, 95% CI: 1.77-2.68, P < 0.001, respectively]. CONCLUSIONS: Postoperative medical complication rates in patients undergoing ankle ORIF, including infection, are higher in obese patients, even in the 1:1 matched analysis that controlled for demographic and comorbidity factors. Rates of nonunion and post-traumatic arthritis were higher in obese patients, as well. As such, it is important for surgeons to provide appropriate education regarding the risks after ankle ORIF in patients with obesity. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.
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Fracturas de Tobillo , Fijación Interna de Fracturas , Obesidad , Complicaciones Posoperatorias , Humanos , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Fracturas de Tobillo/cirugía , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Obesidad/complicaciones , Adulto , Fijación Interna de Fracturas/efectos adversos , Anciano , Reducción Abierta , Estudios de CohortesRESUMEN
As genome sequencing technologies advance, the accumulation of sequencing data in public databases necessitates more robust and adaptable data analysis workflows. Here, we present Rocketchip, which aims to offer a solution to this problem by allowing researchers to easily compare and swap out different components of ChIP-seq, CUT&RUN, and CUT&Tag data analysis, thereby facilitating the identification of reliable analysis methodologies. Rocketchip enables researchers to efficiently process large datasets while ensuring reproducibility and allowing for the reanalysis of existing data. By supporting comparative analyses across different datasets and methodologies, Rocketchip contributes to the rigor and reproducibility of scientific findings. Furthermore, Rocketchip serves as a platform for benchmarking algorithms, allowing researchers to identify the most accurate and efficient analytical approaches to be applied to their data. In emphasizing reproducibility and adaptability, Rocketchip represents a significant step towards fostering robust scientific research practices.
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Background: Given the complexity of arthroscopic rotator cuff repair (ARCR) and increasing prevalence, there is a need for comprehensive, large-scale studies that investigate potential correlations between surgeon-specific factors and postoperative outcomes after ARCR. This study examines how surgeon-specific factors including case volume, career length, fellowship training, practice setting, and regional practice impact two-year reoperation rates, conversion to total shoulder arthroplasty (anatomic or reverse), and 90-day post-ARCR hospitalization. Methods: The PearlDiver Mariner database was used to collect surgeon-specific variables and query patients who underwent ARCR from 2015 to 2018. Patient outcomes were tracked for two years, including reoperations, hospitalizations, and International Classification of Diseases, Tenth Revision codes for revision rotator cuff repair (RCR) laterality. Hospitalizations were defined as any emergency department (ED) visit or hospital readmission within 90 days after primary ARCR. Surgeon-specific factors including surgeon case volume, career length, fellowship training, practice setting, and regional practice were analyzed in relation to postoperative outcomes using both univariate and multivariate logistic regression. Results: 94,150 patients underwent ARCR by 1489 surgeons. On multivariate analysis, high-volume surgeons demonstrated a higher risk for two-year total reoperation (odds ratio [OR] = 1.06, 95% confidence interval [CI]: 1.01-1.12, P = .03) and revision RCR (OR = 1.06, 95% CI: 1.01-1.12, P = .02) compared to low-volume surgeons. Early-career surgeons showed higher rates of 90-day ED visits (mid-career surgeons: OR = 0.78, 95% CI: 0.73-0.83, P < .001; late-career surgeons: OR = 0.73, 95% CI: 0.68-0.78, P < .001) and hospital readmission (mid-career surgeons: OR = 0.74, 95% CI: 0.63-0.87, P < .001; late-career surgeons: OR = 0.73, 95% CI: 0.61-0.88, P = .006) compared to mid- and late-career surgeons. Sports medicine and/or shoulder and elbow fellowship-trained surgeons demonstrated lower two-year reoperation risk (OR = 0.95, CI: 0.91-0.99, P = .04) and fewer 90-day ED visits (OR = 0.93, 95% CI = 0.88-0.98, P = .002). Academic surgeons experienced higher readmission rates compared to community surgeons (OR = 1.16, 95% CI = 1.01-1.34, P = .03). Surgeons practicing in the Northeast demonstrated lower two-year reoperation (OR = 0.88, 95% CI: 0.83-0.93, P < .001) and revision (OR = 0.88, 95% CI: 0.83-0.94, P < .001) RCR risk compared to surgeons in the Southern United States. Conclusion: High-volume surgeons exhibit higher two-year reoperation rates after ARCR compared to low-volume surgeons. Early-career surgeons demonstrate increased hospitalizations. Sports medicine or shoulder and elbow surgery fellowships correlate with reduced two-year reoperation rates and 90-day ED visits.
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While digital computers rely on software-generated pseudo-random number generators, hardware-based true random number generators (TRNGs), which employ the natural physics of the underlying hardware, provide true stochasticity, and power and area efficiency. Research into TRNGs has extensively relied on the unpredictability in phase transitions, but such phase transitions are difficult to control given their often abrupt and narrow parameter ranges (e.g., occurring in a small temperature window). Here we demonstrate a TRNG based on self-oscillations in LaCoO3 that is electrically biased within its spin crossover regime. The LaCoO3 TRNG passes all standard tests of true stochasticity and uses only half the number of components compared to prior TRNGs. Assisted by phase field modeling, we show how spin crossovers are fundamentally better in producing true stochasticity compared to traditional phase transitions. As a validation, by probabilistically solving the NP-hard max-cut problem in a memristor crossbar array using our TRNG as a source of the required stochasticity, we demonstrate solution quality exceeding that using software-generated randomness.
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Uveal melanoma (UM) is the most common primary intraocular malignancy in the adult eye. Despite the aggressive local management of primary UM, the development of metastases is common with no effective treatment options for metastatic disease. Genetic analysis of UM samples reveals the presence of mutually exclusive activating mutations in the Gq alpha subunits GNAQ and GNA11. One of the key downstream targets of the constitutively active Gq alpha subunits is the protein kinase C (PKC) signaling pathway. Herein, we describe the discovery of darovasertib (NVP-LXS196), a potent pan-PKC inhibitor with high whole kinome selectivity. The lead series was optimized for kinase and off target selectivity to afford a compound that is rapidly absorbed and well tolerated in preclinical species. LXS196 is being investigated in the clinic as a monotherapy and in combination with other agents for the treatment of uveal melanoma (UM), including primary UM and metastatic uveal melanoma (MUM).
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Melanoma , Neoplasias de la Úvea , Adulto , Humanos , Subunidades alfa de la Proteína de Unión al GTP/genética , Subunidades alfa de la Proteína de Unión al GTP/metabolismo , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/metabolismo , Melanoma/tratamiento farmacológico , Melanoma/patología , Neoplasias de la Úvea/tratamiento farmacológico , Neoplasias de la Úvea/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , MutaciónRESUMEN
Spatial super-resolution in thermophotonic imaging was achieved using a combination of spatial second-derivative forming, spatial gradient adaptive filtering, and Richardson-Lucy deconvolution in conjunction with the construction of an experimental point spread function. When implemented through enhanced truncation-correlation photothermal coherence tomography (eTC-PCT), it was possible to restore blurred infrared thermophotonic images to their prediffusion optical resolution state. This modality was tested in various biological applications and proved to be capable of imaging fine axial cracks in human teeth, well-patterned anatomical subsurface structures of a mouse brain, and neovascularization in a mouse thigh due to the rapid proliferation of cancer cells. This modality was found to be immune to optical scattering and could reveal the true spatial extent of biological features at subsurface depths that conventional thermal imaging cannot reach because of limitations imposed by the physics of spreading diffusion.