Mosaic vaccine-induced antibody-dependent cellular phagocytosis associated with delayed HIV-1 viral load rebound post treatment interruption.

A heterologous Ad26/MVA vaccine was given prior to an analytic treatment interruption (ATI) in people living with HIV-1 (mainly CRF01_AE) who initiated antiretroviral treatment (ART) during acute HIV-1. We investigate the impact of Ad26/MVA vaccination on antibody (Ab)-mediated immune responses and their effect on time to viral rebound. The vaccine mainly triggers vaccine-matched binding Abs while, upon viral rebound post ATI, infection-specific CRF01_AE binding Abs increase in all participants. Binding Abs are not associated with time to viral rebound. The Ad26/MVA mosaic vaccine profile consists of correlated non-CRF01_AE binding Ab and Fc effector features, with strong Ab-dependent cellular phagocytosis (ADCP) responses. CRF01_AE-specific ADCP responses (measured either prior to or post ATI) are significantly higher in individuals with delayed viral rebound. Our results suggest that vaccines eliciting cross-reactive responses with circulating viruses in a target population could be beneficial and that ADCP responses may play a role in viral control post treatment interruption.

High accuracy of intra-articular needle position during anterior landmark guided glenohumeral injections.

OBJECTIVES: Image-guided ultrasound or fluoroscopic glenohumeral injections have high accuracy rates but require training, equipment, cost, and radiation exposure (fluoroscopy). In contrast, landmark-guided glenohumeral injections do not require additional subspecialist referrals or equipment. An optimal technique would be safe and accurate and have few barriers to implementation. The purpose of this study was to define the accuracy of glenohumeral needle placement via an anterior landmark-guided approach as assessed by direct arthroscopic visualization. METHODS: A consecutive series of adult patients undergoing shoulder arthroscopy in the beach chair position were included in this study. Demographic and procedural data were collected. The time required to perform the injection, the precise location of the needle tip, and factors that affected the accuracy of the injection were also assessed. RESULTS: A standardized anterior landmark-guided glenohumeral joint injection was performed in the operating room prior to surgery, and the location of the needle tip was documented by arthroscopic visualization with a low complication profile and few barriers to implementation. A total of 81 patients were enrolled. Successful intra-articular glenohumeral needle placement by sports medicine and shoulder/elbow fellowship-trained orthopedic surgeons was confirmed in 93.8% (76/81) of patients. The average time to complete the procedure was 24.8 â€‹s. There were no patient-related variables associated with nonintra-articular injections in the cohort. CONCLUSIONS: This study demonstrated that the technique of anterior landmark-guided glenohumeral injection has an accuracy of 93.8% and requires less than 30 â€‹s to perform. This method is safe, yields similar accuracy to image-guided procedures, has improved cost and time efficiency, and requires less radiation exposure. No patient-related factors were associated with inaccurate needle placement. Anterior landmark-guided glenohumeral injections may be utilized with confidence by providers in the clinical setting. LEVEL OF EVIDENCE: Level 5. IRB: Approved under Stanford IRB-56323.

Biodistribution of Radioactively Labeled Splice Modulating Antisense Oligonucleotides After Intracerebroventricular and Intrathecal Injection in Mice.

Antisense oligonucleotides (AONs) are promising therapeutic candidates, especially for neurological diseases. Intracerebroventricular (ICV) injection is the predominant route of administration in mouse studies, while in clinical trials, intrathecal (IT) administration is mostly used. There is little knowledge on the differences in distribution of these injection methods within the same species over time. In this study, we compared the distribution of splice-switching AONs targeting exon 15 of amyloid precursor protein pre-mRNA injected via the ICV and IT route in mice. The AON was labeled with radioactive indium-111 and mice were imaged using single-photon emission computed tomography (SPECT) 0, 4, 24, 48, 72, and 96 h after injection. In vivo SPECT imaging showed 111In-AON activity diffused throughout the central nervous system (CNS) in the first hours after injection. The 111In-AON activity in the CNS persisted over the course of 4 days, while signal in the kidneys rapidly decreased. Postmortem counting in different organs and tissues showed very similar distribution of 111In-AON activity throughout the body, while the signal in the different brain regions was higher with ICV injection. Overall, IT and ICV injection have very similar distribution patterns in the mouse, but ICV injection is much more effective in reaching the brain.

Environmental stress mediates groundwater microbial community assembly.

Community assembly describes how different ecological processes shape microbial community composition and structure. How environmental factors impact community assembly remains elusive. Here we sampled microbial communities and >200 biogeochemical variables in groundwater at the Oak Ridge Field Research Center, a former nuclear waste disposal site, and developed a theoretical framework to conceptualize the relationships between community assembly processes and environmental stresses. We found that stochastic assembly processes were critical (>60% on average) in shaping community structure, but their relative importance decreased as stress increased. Dispersal limitation and 'drift' related to random birth and death had negative correlations with stresses, whereas the selection processes leading to dissimilar communities increased with stresses, primarily related to pH, cobalt and molybdenum. Assembly mechanisms also varied greatly among different phylogenetic groups. Our findings highlight the importance of microbial dispersal limitation and environmental heterogeneity in ecosystem restoration and management.

Priming with Japanese encephalitis virus or yellow fever virus vaccination led to the recognition of multiple flaviviruses without boosting antibody responses induced by an inactivated Zika virus vaccine.

BACKGROUND: Complex patterns of cross-reactivity exist between flaviviruses, yet there is no precise understanding of how sequential exposures due to flavivirus infections or vaccinations impact subsequent antibody responses. METHODS: We investigated whether B cell priming from Japanese encephalitis virus (JEV) or yellow fever virus (YFV) vaccination impacted binding and functional antibody responses to flaviviruses following vaccination with a Zika virus (ZIKV) purified inactivated virus (ZPIV) vaccine. Binding antibody responses and Fc gamma receptor engagement against 23 flavivirus antigens were characterized along with neutralization titres and Fc effector responses in 75 participants at six time points. FINDINGS: We found no evidence that priming with JEV or YFV vaccines improved the magnitude of ZPIV induced antibody responses to ZIKV. Binding antibodies and Fc gamma receptor engagement to ZIKV antigens did not differ significantly across groups, while antibody-dependent cellular phagocytosis (ADCP) and neutralizing responses were higher in the naïve group than in the JEV and YFV primed groups following the second ZPIV immunization (p ≤ 0.02). After a third dose of ZPIV, ADCP responses remained higher in the naïve group than in the primed groups. However, priming affected the quality of the response following ZPIV vaccination, as primed individuals recognized a broader array of flavivirus antigens than individuals in the naïve group. INTERPRETATION: While a priming vaccination to either JEV or YFV did not boost ZIKV-specific responses upon ZIKV vaccination, the qualitatively different responses elicited in the primed groups highlight the complexity in the cross-reactive antibody responses to flaviviruses. FUNDING: This work was supported by a cooperative agreement between The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., and the U.S. Department of the Army [W81XWH-18-2-0040]. The work was also funded in part by the National Institute of Allergy and Infectious Diseases (NIAID) R01AI155983 to SJK and KM.

Seizure reduction in TSC2-mutant mouse model by an mTOR catalytic inhibitor.

OBJECTIVE: Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder caused by autosomal-dominant pathogenic variants in either the TSC1 or TSC2 gene, and it is characterized by hamartomas in multiple organs, such as skin, kidney, lung, and brain. These changes can result in epilepsy, learning disabilities, and behavioral complications, among others. The mechanistic link between TSC and the mechanistic target of the rapamycin (mTOR) pathway is well established, thus mTOR inhibitors can potentially be used to treat the clinical manifestations of the disorder, including epilepsy. METHODS: In this study, we tested the efficacy of a novel mTOR catalytic inhibitor (here named Tool Compound 1 or TC1) previously reported to be more brain-penetrant compared with other mTOR inhibitors. Using a well-characterized hypomorphic Tsc2 mouse model, which displays a translationally relevant seizure phenotype, we tested the efficacy of TC1. RESULTS: Our results show that chronic treatment with this novel mTOR catalytic inhibitor (TC1), which affects both the mTORC1 and mTORC2 signaling complexes, reduces seizure burden, and extends the survival of Tsc2 hypomorphic mice, restoring species typical weight gain over development. INTERPRETATION: Novel mTOR catalytic inhibitor TC1 exhibits a promising therapeutic option in the treatment of TSC.

Identification of Brain-Penetrant ATP-Competitive mTOR Inhibitors for CNS Syndromes.

The allosteric inhibitor of the mechanistic target of rapamycin (mTOR) everolimus reduces seizures in tuberous sclerosis complex (TSC) patients through partial inhibition of mTOR functions. Due to its limited brain permeability, we sought to develop a catalytic mTOR inhibitor optimized for central nervous system (CNS) indications. We recently reported an mTOR inhibitor (1) that is able to block mTOR functions in the mouse brain and extend the survival of mice with neuronal-specific ablation of the Tsc1 gene. However, 1 showed the risk of genotoxicity in vitro. Through structure-activity relationship (SAR) optimization, we identified compounds 9 and 11 without genotoxicity risk. In neuronal cell-based models of mTOR hyperactivity, both corrected aberrant mTOR activity and significantly improved the survival rate of mice in the Tsc1 gene knockout model. Unfortunately, 9 and 11 showed limited oral exposures in higher species and dose-limiting toxicities in cynomolgus macaque, respectively. However, they remain optimal tools to explore mTOR hyperactivity in CNS disease models.

No significant difference in risk of prolonged opioid use following outpatient versus inpatient total shoulder arthroplasty: A propensity matched analysis.

Background: The purpose of this investigation was to compare rates of filled opioid prescriptions and prolonged opioid use in opioid naïve patients undergoing total shoulder arthroplasty (TSA) in inpatient versus outpatient settings. Methods: A retrospective cohort study was conducted using a national insurance claims database. Inpatient and outpatient cohorts were created by identifying continuously enrolled, opioid naïve TSA patients. A greedy nearest-neighbor algorithm was used to match baseline demographic characteristics between cohorts with a 1:1 inpatient to outpatient ratio to compare the primary outcomes of filled opioid prescriptions and prolonged opioid use following surgery between cohorts. Results: A total of 11,703 opioid naïve patients (mean age 72.5 ± 8.5 years, 54.5% female, 87.6% inpatient) were included for analysis. After propensity score matching (n = 1447 inpatients; n = 1447 outpatients), outpatient TSA patients were significantly more likely to fill an opioid prescription in the perioperative window compared to inpatients (82.9% versus 71.5%, p < 0.001). No significant differences in prolonged opioid use were detected (5.74% inpatient versus 6.77% outpatient; p = 0.25). Conclusions: Outpatient TSA patients were more likely to fill opioid prescriptions compared to inpatient TSA patients. The quantity of opioids prescribed and rates of prolonged opioid use were similar between the cohorts. Level of evidence: Therapeutic Level III.

Can Hip Passive Range of Motion Predict Hip Microinstability? A Comparative Study.

Background: Hip microinstability is an increasingly recognized cause of pain and disability in young adults. It is unknown whether differences in passive hip range of motion (ROM) exist between patients with versus without hip microinstability. Hypothesis: Underlying ligamentous and capsular laxity will result in differences in clinically detectable passive ROM between patients with femoroacetabular impingement (FAI), patients with microinstability, and asymptomatic controls. Study Design: Cross-sectional study; Level of evidence, 3. Methods: A retrospective review of all patients undergoing hip arthroscopy between 2012 and 2018 was conducted. Patients with a diagnosis of isolated microinstability based on intraoperative findings were identified and classified as having isolated FAI, instability, or FAI + instability. Patients without a history of hip injury were included as controls. Range of motion was recorded in the supine position for flexion, internal rotation, and external rotation. Univariate and multivariate analysis was performed on each measurement in isolation as well as combinations of motion to include total rotation arc, flexion + rotation arc, and flexion + 2× rotation arc Models were then created and tested to predict instability status. Results: In total, 263 hips were included: 69 with isolated instability, 50 with FAI, 50 with FAI + instability, and 94 control hips. A higher proportion of patients in the instability and FAI + instability groups were female compared with the FAI and control groups (P < .001). On univariate analysis, differences were found in all groups in all planes of motion (P < .001). Multivariable analysis demonstrated differences in all groups in flexion and flexion + rotation arc. In symptomatic patients, the best performing predictive model for hip microinstability was flexion + rotation arc ≥200° (Akaike information criterion, 132.3; P < .001) with a sensitivity of 68.9%, specificity of 80.0%, positive predictive value of 89.1%, and negative predictive value of 51.9%. Conclusion: Patients with hip microinstability had significantly greater ROM than symptomatic and asymptomatic cohorts without hip microinstability. Symptomatic patients with hip flexion + rotation arc ≥200° were highly likely to have positive intraoperative findings for hip microinstability, whereas instability status was difficult to predict in patients with a flexion + rotation arc of <200°.

Gadolinium injected concurrently with anesthetic can result in false-negative diagnostic intra-articular hip injections.

PURPOSE: The purpose of this paper was to evaluate the response to intra-articular hip injections with and without concurrent gadolinium administration. Our secondary outcome was to compare post-operative outcomes between patients with an initial false-negative gadolinium-containing injection and a matched control group. METHODS: Patients receiving a series of two hip diagnostic intra-articular injections (DIAI), the first with gadolinium for concurrent MRA and the second without gadolinium, were retrospectively identified. Pain response to DIAI, injectate volume, local anesthetic volume, inclusion of corticosteroids, and method of injection were compared between injections. False-negative injection was defined as < 50% pain relief with concurrent gadolinium, but ≥ 50% pain relief with subsequent anesthetic injection without gadolinium. False-negative injections in patients that ultimately underwent primary hip arthroscopy were identified from this cohort and matched in a 3:1 ratio to a control cohort to compare short-term post-operative single assessment numerical evaluation (SANE) outcomes. RESULTS: Forty-three patients underwent a series of anesthetic injections with and without gadolinium and met inclusion and exclusion criteria. Pain response was significantly different in injections performed with and without gadolinium (18% vs. 81%; p < 0.001). There were significant differences in total injectate volume, local anesthetic volume, corticosteroid use, and method of injection between injections, but these variables were not correlated with pain response. Fifteen patients with false-negative responses to injection underwent primary hip arthroscopy and were matched in a 3:1 ratio to a control cohort. There was no difference in short-term post-operative SANE scores between the gadolinium-sensitive and control groups (81.6 vs. 80.0, n.s.). CONCLUSION: Concurrent administration of intra-articular gadolinium with DIAI may result in a false-negative response to anesthetic. Additionally, in patients with initial false-negative DIAI with gadolinium, short-term post-operative outcomes after hip arthroscopy are similar to a matched cohort. LEVEL OF EVIDENCE: Level III.

The diagnosis of hip microinstability is correlated with ease of intra-operative hip distraction.

PURPOSE: Hip microinstability has emerged as a contributor to young adult, non-arthritic hip pain. There is a paucity of objective clinical data to identify patients with hip microinstability and guide surgical treatment. The purpose of this study was to identify the degree of distractibility in patients with and without microinstability undergoing hip arthroscopy. METHODS: A single-surgeon series of hip arthroscopies were retrospectively reviewed from 2014-2020. All procedures were performed with paralysis on a fracture table with a perineal post where 1 turn of fine traction equates to 4 mm of axial traction. Diagnosis was recorded as isolated instability, instability plus femoroacetabular impingement (FAI), and isolated FAI. Operative reports were reviewed to collect patient demographic data, number of turns of traction required for adequate distraction of the femoral head relative to the acetabulum (10 mm), and the presence of residual subluxation after initial traction was released. RESULTS: A total of 464 patients were identified, 26 (5.6%) with isolated microinstability, 183 (39.4%) with microinstability with FAI anatomy, and 255 (55.0%) with FAI. The concurrent diagnosis of microinstability was associated with decreased turns required to adequately distract the hip. Isolated microinstability patients required 6.9 turns (IQR 4.6-8.8) while those with instability plus FAI required 8.8 turns (IQR 6.5-11) and isolated FAI required 19.1 turns (IQR 15-22). Residual subluxation after removal of negative intra-articular pressure but before performing the hip arthroscopy was more commonly associated with instability, occurring in 84.6% of isolated instability and 86.9% of instability plus FAI as compared with 29.8% in the isolated FAI cohort. CONCLUSION: A diagnosis of hip microinstability, with or without features of FAI, is associated with decreased axial traction required to distract the hip. These data support the use of intra-operative ease of distraction as a method of identifying patients with hip microinstability. LEVEL OF EVIDENCE: Level III.

Are Oblique Views Necessary? A Review of the Clinical Value of Oblique Knee Radiographs in the Acute Setting.

INTRODUCTION: The purpose of this study was to assess the added clinical value of oblique knee radiographs four-view (4V) compared to orthogonal anteroposterior (AP) and lateral radiographs in a two-view (2V) series. METHODS: We obtained 200 adult, 4V knee radiographs in 200 patients in the ED and randomly divided them into two groups with 100 series in each group. Ten reviewers - three musculoskeletal radiologists and seven orthopedic surgeons - performed radiograph analyses. These reviewers were randomly divided evenly into group one and group two. Reviewers were blinded to patient data and first reviewed 2V radiographs (AP/lateral) only, and then reviewed 4V radiographs, including AP/lateral, and two additional oblique views for the same patients at least four weeks later. Acute pathology identification and the need for further imaging was assessed for all reviewers, and clinical decision-making (operative vs nonoperative treatment, need for admission, need for additional imaging) was assessed only by the seven orthopaedic surgeon reviewers. RESULTS: Mean sensitivity for pathology identification was 79% with 2V and 81% with 4V (P =0.25). Intra-observer kappa value was 0.81 (range 0.54-1.00). Additional oblique radiographs led orthopaedic reviewers to change their treatment recommendations in 62/329 patients (18.84%) (P <0.001). Eight of 329 radiographic series were identified as "critical misses." (2.43%) (P =0.004), when pathology was reported as normal or reviewers recommended nonoperative treatment on 2V radiographs but changed their recommendation to operative management after the addition of oblique radiographs. The number needed to treat (NNT) for any treatment change and for "critical misses" was 83 and 643, respectively. CONCLUSION: Although the addition of oblique radiographs may improve a clinician's ability to identify subtle pathologic findings not identified on 2V, it rarely leads to significant changes in treatment recommendations. Given the high NNT, limiting the usage of these oblique radiographs in the general patient population may reduce costs without significantly affecting patient care.

Transfer of Metals to the Aerosol Generated by an Electronic Cigarette: Influence of Number of Puffs and Power.

Electronic cigarettes (e-cigarettes) are increasing in popularity despite uncertainties about their health hazards. Literature studies have shown that e-cigarettes may be a source of toxic heavy metal exposure to the user, but the mechanism by which metals are transferred from the e-cigarette parts into the aerosol plume that is inhaled by the user is poorly understood. The goal of this study was to quantify the potentially harmful heavy metals chromium, nickel, copper, and lead systematically during the simulated use of a mod-type e-cigarette in order to better understand the mechanism of metal transfer from the e-cigarette parts into the aerosol plume and into the liquid in the storage tank. Aerosol was collected and aliquots of the remaining liquid in the storage tank were collected from 0 to 40 puffs in 10 puff increments and analyzed with atomic absorption spectroscopy. It was found that the concentration of metals increased in both the aerosol and tank liquid the more times the e-cigarette was puffed, but at varying rates for each element and depending on the power applied to the heating coil. For copper, lead, and nickel, the concentrations of metals in the aerosol and tank increased with increasing power but for chromium, the concentration varied with power. Additionally, it was observed that chromium and nickel concentrations were greater in the aerosol than in tank liquid, consistent with the direct transfer of those metals to the aerosol from heating of the nichrome coil element used in this study. For copper and lead, the concentrations were similar or greater in the tank compared to the aerosol, consistent with transfer first into the storage tank liquid, followed by vaporization into the aerosol.

Central Femoral Head Chondromalacia Is Associated with a Diagnosis of Hip Instability.

Purpose: To compare the locations and patterns of femoral head chondral damage in patients with instability in contrast to those with femoroacetabular impingement (FAI) without instability. Methods: All consecutive hip arthroscopies were reviewed from 2013 to 2020 from a single surgeon. Intraoperative records were reviewed on all patients identified to have femoral head chondromalacia. Data were collected to include laterality, location of femoral head chondromalacia, intraoperative diagnosis (instability and/or FAI subtype), and ease of distractibility. The location of the femoral head chondromalacia was defined on the basis of intraoperative description. Chi-squared and Fisher's exact tests were used for categorical variables, and a two-sample t test was used for continuous variables. Statistical significance was set at P < .05. Results: A total of 64 patients were in the study cohort, with 32 patients identified as having non-central head chondromalacia and 32 patients identified as having central head chondromalacia. Of the patients with central head chondromalacia, 81% were diagnosed with instability. Central head chondromalacia was associated with a sensitivity of 84% (71%-97%), specificity of 82% (69%-95%), and positive predictive value of 81% (67%-95%). Conclusions: A high percentage of patients with central femoral head chondromalacia were found to have hip microinstability. These results suggest that there is a pattern of femoral head chondral damage in patients with hip microinstability. Level of Evidence: Level III, case-control study.

Female gender, decreased lateral center edge angle and a positive hyperextension-external rotation test are associated with ease of hip distractability at time of hip arthroscopy.

PURPOSE: To identify factors associated with ease of hip distraction at the time of hip arthroscopy. METHODS: A retrospective review of patients 17-50 years old undergoing hip arthroscopy with a single high-volume hip arthroscopist was performed from 2014 to 2020. Demographics, clinical history, examination, and imaging findings were collected. Distractibility was quantified using turns of fine traction (1 turn = 4 mm axial distraction) with the patient paralyzed on a fracture table with a well-padded perineal post Fine axial traction was applied after the patient's perineum contacted the post. Demographic and clinical predictors of ease of distractibility were analyzed with simple linear regression models. Significant predictors were subsequently added to a multivariable linear regression model, estimating the effect of each variable. RESULTS: In total, 453 patients were included, with an average age of 31.6 years (± 9.2) and 45.9% females. In univariate analysis, gender, race, BMI, range of motion, hyperextension-external rotation (HEER) test, the abduction-extension-external rotation test, and lateral center edge angle (LCEA) were associated with the number of fine traction turns required to distract the hip. On multivariable analysis, lower LCEA (p = 0.002), female gender (p < 0.001), and a positive HEER test (p = 0.045) were associated with decreased turns required for adequate hip distraction. CONCLUSION: Female gender, decreased LCEA, and a positive HEER test are associated with decreased axial traction required for adequate hip distraction at the time of hip arthroscopy. As ease of distractibility has been associated with hip microinstability, these findings may allow pre-operative identification of hip instability patients and aid in pre-operative counseling, risk stratification and capsular management planning. LEVEL OF EVIDENCE: IV. CLINICAL RELEVANCE: Preoperative identification of risk factors for ease of hip distraction may raise pre-surgical suspicion and, when coupled with other intraoperative findings, may aid in the diagnosis and management of hip microinstability.

Hip Microinstability: Understanding a Newly Defined Hip Pathology in Young Athletes.

Microinstability is an increasingly recognized diagnosis in young athletes presenting with hip pain. Causes of microinstability may include abnormality of the hip bony anatomy, acetabular labral tears, joint capsule laxity or injury, and muscle dysfunction. Borderline hip dysplasia is an increasingly recognized factor predisposing to microinstability. The capsuloligamentous structures of the hip, particularly the iliofemoral ligament, provide important restraints to femoral head motion, and iatrogenic defects can predispose patients to instability after surgery. Injury to the acetabular labrum may disrupt its important hip-stabilizing properties including the suction seal and improved acetabular depth. Hip muscle weakness or imbalance may result in increased femoral head motion within the acetabulum. The diagnosis of hip microinstability can be challenging, and the history is often nonspecific. Physical examination maneuvers include the anterior apprehension, prone instability, axial distraction, and abduction-hyperextension-external rotation tests. Radiographic features may include borderline hip dysplasia, femoral head-neck junction cliff sign, and an elevated femoral-epiphyseal acetabular roof index. Magnetic resonance arthrography may demonstrate a capsular defect, capsular thinning, or labral pathology. Diagnostic intra-articular injection of anesthetic can confirm the intra-articular nature of the pathology. Management of hip microinstability focuses on strengthening the dynamic stabilizers of the hip through focused physical therapy. Surgery may be considered in recalcitrant cases where symptoms persist despite optimization of hip stabilizer strength. In such cases, addressing the primary source of instability through labral repair or reconstruction and capsular repair or plication can be considered. In highly selected cases, surgery can result in excellent outcomes.

Editorial Commentary: Identifying the Problem Is Only the First Step in Fixing Disparities in Anterior Cruciate Ligament Injury Care.

Anterior cruciate ligament reconstruction (ACL-R) is one of the most commonly performed orthopaedic surgeries. Social determinants of health, including race, ethnicity, income, education, insurance, and employment status, are major nonmodifiable risk factors for worse outcomes and higher complication rates after ACL-R. Improved understanding of these variables can help surgeons assess risk and counsel their patients, but evidence-based solutions to improving access to care and outcomes after ACL-R in at-risk patients are needed.

Editorial Commentary: Is the Pendulum "Swinging" Away From Patellar Fixation in Medial Patellofemoral Ligament Reconstruction?

Medial patellofemoral ligament (MPFL) reconstruction is the "workhorse" for surgical stabilization of recurrent patella instability. Complications of patella fixation (i.e., patella fracture) are rare but potentially catastrophic. Modifications to traditional MPFL reconstruction that avoid patella fixation are promising. These alternatives may be favored in high-risk scenarios such as revision, smaller pediatric cases, and patellofemoral arthroplasty with concomitant instability. Large-scale prospective and/or randomized studies are needed to differentiate between MPFL reconstruction techniques.

Antisense Oligonucleotide-Induced Amyloid Precursor Protein Splicing Modulation as a Therapeutic Approach for Dutch-Type Cerebral Amyloid Angiopathy.

Dutch-type cerebral amyloid angiopathy (D-CAA) is a monogenic form of cerebral amyloid angiopathy and is inherited in an autosomal dominant manner. The disease is caused by a point mutation in exon 17 of the amyloid precursor protein (APP) gene that leads to an amino acid substitution at codon 693. The mutation is located within the amyloid beta (Aß) domain of APP, and leads to accumulation of toxic Aß peptide in and around the cerebral vasculature. We have designed an antisense oligonucleotide (AON) approach that results in skipping of exon 17, generating a shorter APP isoform that lacks part of the Aß domain and the D-CAA mutation. We demonstrate efficient AON-induced skipping of exon 17 at RNA level and the occurrence of a shorter APP protein isoform in three different cell types. This resulted in a reduction of Aß40 in neuronally differentiated, patient-derived induced pluripotent stem cells. AON-treated wild-type mice showed successful exon skipping on RNA and protein levels throughout the brain. These results illustrate APP splice modulation as a promising therapeutic approach for D-CAA.