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.

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.

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.

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.

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.

National Trends Show Declining Use of Arthroscopic Subacromial Decompression Without Rotator Cuff Repair.

PURPOSE: The goal of this study was to investigate trends in the United States for arthroscopic subacromial decompression (aSAD) and open SAD (oSAD) with and without rotator cuff repair (RCR) between 2010 and 2018. METHODS: The PearlDiver Mariner claims database was queried using CPT codes for open and arthroscopic subacromial decompression and rotator cuff repair. Patient cohorts were developed for those undergoing aSAD or oSAD between 2010 and 2018, then segmented by whether RCR was performed simultaneously. Annual incidence was analyzed, as were associated diagnosis codes, and concomitant shoulder-associated procedures performed on the same day. RESULTS: The PearlDiver Mariner dataset from 2010 to 2018 included 186,932 patients that underwent aSAD, while 9,263 patients underwent oSAD. The total incidence of aSAD declined from 118.0 to 71.3 per 100,000 (39.6% decrease) (P < .001). This change was due primarily to a decreasing incidence of aSAD performed without RCR, which declined from 66.3 to 25.5 per 100,000 (61.5% decrease) (P < .001). During the same period, the incidence of aSAD combined with RCR remained relatively stable, from 51.7 to 45.8 per 100,000 (11.5% decrease) (P = .27). The overall incidence of oSAD declined from 7.1 to 2.2 per 100,000 (68.1% decrease) (P < .001). CONCLUSIONS: The overall rate of aSAD has declined in recent years, primarily due to a large decrease in the incidence of aSAD without RCR as an isolated treatment for rotator cuff disorders. CLINICAL RELEVANCE: Prior studies have demonstrated a rising incidence of SAD; however, high-level clinical evidence and clinical practice guidelines have challenged its efficacy. It is important for orthopaedic surgeons to understand evolving national trends in management among their peers.

Superior Capsule Reconstruction With Subacromial Allograft Spacer: Biomechanical Cadaveric Study of Subacromial Contact Pressure and Superior Humeral Head Translation.

PURPOSE: To investigate the biomechanical effects of superior capsule reconstruction with subacromial allograft spacer on superior humeral head translation and subacromial contact pressure. METHODS: Eight cadaveric shoulder specimens were tested in 4 conditions: (1) intact rotator cuff, (2) supraspinatus tear and superior capsule excision, (3) superior capsule reconstruction with human dermal allograft, and (4) superior capsule reconstruction with subacromial resurfacing using human dermal allograft. In each condition, specimens were tested at 0, 30, 60, and 90° of shoulder abduction in balanced and unbalanced loaded states for subacromial contact pressure and superior humeral head translation. Statistical comparisons were made using a repeated-measures analysis of variance test, followed by a Tukey post hoc test for pairwise comparisons. A P value <.05 was set as statistically significant. RESULTS: Superior humeral head translation and subacromial contact pressure were increased after irreparable rotator cuff tear (P = .001). There was no significant difference between superior capsule reconstruction and intact cuff in regard to superior humeral head translation and subacromial contact pressure at all abduction angles. Superior capsule reconstruction with subacromial resurfacing decreased superior humeral head translation relative to intact (0°, P = .004; 30°, P = .02; 60°, P = .08; 90°, P = .01), superior capsule reconstruction (0°, P = .001; 30°, P = .003; 60°, P = .019; 90°, P = .001), and cuff-deficient states (P = .001). Superior capsule reconstruction with subacromial resurfacing resulted in nonsignificant increases in subacromial contact pressure relative to intact cuff at 0 to 90° abduction angles. CONCLUSIONS: Superior capsule reconstruction with subacromial resurfacing using human dermal allograft results in decreased superior humeral head translation relative to superior capsule reconstruction with human dermal allograft only, while increasing subacromial contact pressure. CLINICAL RELEVANCE: Superior capsule reconstruction with subacromial resurfacing using human dermal allograft reduces superior humeral head translation while increasing subacromial contact pressure in a cadaveric model.

Suspicious minds: cinematic depiction of distrust during epidemic disease outbreaks.

One key factor that appears to be crucial in the rejection of quarantines, isolation and other social controls during epidemic outbreaks is trust-or rather distrust. Much like news reporting and social media, popular culture such as fictional novels, television shows and films can influence people's trust, especially given that the information provided about an epidemic disease is sometimes seen as grounded in 'scientific fact' by societies. As well as providing information on the 'correct science' behind disease transmission, spread and illness in films and literature, popular culture can also inform societies about how to feel and how to react during epidemics-that is to say create some expectations about the kinds of societal responses that could potentially occur. In this article we closely analyse three films that centre around epidemic diseases-Contagion (Steven Soderbergh, 2011), Blindness (Fernando Meirelles, 2008) and The Painted Veil (John Curran, 2006)-in order to highlight three categories of distrust that have recently been identified and conceptualised in broader discussions regarding trust and health: institutional, social and interpersonal. These films raise two key issues about trust and social responses during epidemics. First, while certain aspects of trust are badly diminished during epidemic disease outbreaks, epidemics can also interact with pre-existing structural inequalities within society-based on race, gender or wealth-to create mixed outcomes of discord, prejudice and fear that coexist with new forms of cohesion. Second, the breakdown in trust seen at certain levels during epidemics, such as at the institutional level between communities and authorities or elites, might be mediated or negotiated, perhaps even compensated for, by heightened solidity of trust at the social level, within or between communities.

Orthopaedic Shoulder Surgery in the Ambulatory Surgical Center: Safety and Outcomes.

PURPOSE: To determine whether the risk of adverse events and readmission after non-arthroplasty shoulder surgery is influenced by the outpatient setting of surgical care and to identify risk factors associated with these adverse events. METHODS: The Humana Claims Database was queried for all patients undergoing arthroscopic shoulder surgery and related open procedures in the hospital-based outpatient department (HOPD) or ambulatory surgical center (ASC) setting, using the PearlDiver supercomputer. Arthroplasty procedures were excluded because they carry a risk profile different from that of other outpatient surgical procedures. Outcome variables included unanticipated admission after surgery, readmission, deep vein thrombosis, pulmonary embolism, and wound infection within 90 days of surgery. The ASC and HOPD cohorts were propensity score matched, and outcomes were compared between them. Finally, logistic regression models were created to identify risk factors associated with unplanned admission after surgery. RESULTS: A total of 84,658 patients met the inclusion criteria for the study: 28,730 in the ASC cohort and 56,819 in the HOPD cohort. The rates of all queried outcomes were greater in the HOPD cohort and achieved statistical significance. Sex, region, race, insurance status, comorbidity burden, anesthesia type, and procedural type were included in the regression analysis of unplanned admission. Factors associated with unplanned admission included increasing Charlson Comorbidity Index (odds ratio [OR], 1.16; 95% confidence interval [CI], 1.12-1.17; P < .001); HOPD service location (OR, 2.37; 95% CI, 2.18-2.58; P < .001); general anesthesia (OR, 1.34; 95% CI, 1.08-1.59; P = .008); male sex (OR, 2.58; 95% CI, 2.17-3.15; P = .007); and open surgery (OR, 2.35; 95% CI, 1.90-2.61; P < .001). CONCLUSIONS: The lower rates of perioperative morbidity in the ASC cohort suggest that proper patient selection is taking place and lends reassurance to surgeons who are practicing or are considering practicing in an ASC. Patients to whom some or all the risk factors for unplanned admission apply (male sex, higher comorbidity burden, open surgery) may be more suitable for HOPDs because admission from an ASC can be difficult and potentially unsafe. LEVEL OF EVIDENCE: Level III, comparative study.

SMN2 splice modulators enhance U1-pre-mRNA association and rescue SMA mice.

Spinal muscular atrophy (SMA), which results from the loss of expression of the survival of motor neuron-1 (SMN1) gene, represents the most common genetic cause of pediatric mortality. A duplicate copy (SMN2) is inefficiently spliced, producing a truncated and unstable protein. We describe herein a potent, orally active, small-molecule enhancer of SMN2 splicing that elevates full-length SMN protein and extends survival in a severe SMA mouse model. We demonstrate that the molecular mechanism of action is via stabilization of the transient double-strand RNA structure formed by the SMN2 pre-mRNA and U1 small nuclear ribonucleic protein (snRNP) complex. The binding affinity of U1 snRNP to the 5' splice site is increased in a sequence-selective manner, discrete from constitutive recognition. This new mechanism demonstrates the feasibility of small molecule-mediated, sequence-selective splice modulation and the potential for leveraging this strategy in other splicing diseases.

The sex-selective impact of the Black Death and recurring plagues in the Southern Netherlands, 1349-1450.

Although recent work has begun to establish that early modern plagues had selective mortality effects, it was generally accepted that the initial outbreak of Black Death in 1347-52 was a "universal killer." Recent bioarchaeological work, however, has argued that the Black Death was also selective with regard to age and pre-plague health status. The issue of the Black Death's potential sex selectivity is less clear. Bioarchaeological research hypothesizes that sex-selection in mortality was possible during the initial Black Death outbreak, and we present evidence from historical sources to test this notion. OBJECTIVE: To determine whether the Black Death and recurring plagues in the period 1349-1450 had a sex-selective mortality effect. MATERIALS AND METHODS: We present a newly compiled database of mortality information taken from mortmain records in Hainaut, Belgium, in the period 1349-1450, which not only is an important new source of information on medieval mortality, but also allows for sex-disaggregation. RESULTS: We find that the Black Death period of 1349-51, as well as recurring plagues in the 100 years up to 1450, often had a sex-selective effect-killing more women than in "non-plague years." DISCUSSION: Although much research tends to suggest that men are more susceptible to a variety of diseases caused by bacteria, viruses and parasites, we cannot assume that the same direction of sex-selection in mortality applied to diseases in the distant past such as Second Pandemic plagues. While the exact reasons for the sex-selective effect of late-medieval plague are unclear in the absence of further data, we suggest that simple inequities between the sexes in exposure to the disease may not have been a key driver.

The Effects of Temperature on Clot Microstructure and Strength in Healthy Volunteers.

BACKGROUND: Anesthesia, critical illness, and trauma are known to alter thermoregulation, which can potentially affect coagulation and clinical outcome. This in vitro preclinical study explores the relationship between temperature change and hemostasis using a recently validated viscoelastic technique. We hypothesize that temperature change will cause significant alterations in the microstructural properties of clot. METHODS: We used a novel viscoelastic technique to identify the gel point of the blood. The gel point identifies the transition of the blood from a viscoelastic liquid to a viscoelastic solid state. Furthermore, identification of the gel point provides 3 related biomarkers: the elastic modulus at the gel point, which is a measure of clot elasticity; the time to the gel point (TGP), which is a measure of the time required to form the clot; and the fractal dimension of the clot at the gel point, df, which quantifies the microstructure of the clot. The gel point measurements were performed in vitro on whole blood samples from 136 healthy volunteers over a temperature range of 27°C to 43°C. RESULTS: There was a significant negative correlation between increases in temperature, from 27°C to 43°C, and TGP (r = -0.641, P < 0.0005). Conversely, significant positive correlations were observed for both the elastic modulus at the gel point (r = 0.513, P = 0.0008) and df (r = 0.777, P < 0.0005) across the range of 27°C to 43°C. When temperature was reduced below 37°C, significant reductions in df and TGP occurred at ≤32°C (Bonferroni-corrected P = 0.0093) and ≤29°C (Bonferroni-corrected P = 0.0317), respectively. No significant changes were observed when temperature was increased to >37°C. CONCLUSIONS: This study demonstrates that the gel point technique can identify alterations in clot microstructure because of changes in temperature. This was demonstrated in slower-forming clots with less structural complexity as temperature is decreased. We also found that significant changes in clot microstructure occurred when the temperature was ≤32°C.

Genetic circuitry of Survival motor neuron, the gene underlying spinal muscular atrophy.

The clinical severity of the neurodegenerative disorder spinal muscular atrophy (SMA) is dependent on the levels of functional Survival Motor Neuron (SMN) protein. Consequently, current strategies for developing treatments for SMA generally focus on augmenting SMN levels. To identify additional potential therapeutic avenues and achieve a greater understanding of SMN, we applied in vivo, in vitro, and in silico approaches to identify genetic and biochemical interactors of the Drosophila SMN homolog. We identified more than 300 candidate genes that alter an Smn-dependent phenotype in vivo. Integrating the results from our genetic screens, large-scale protein interaction studies, and bioinformatic analysis, we define a unique interactome for SMN that provides a knowledge base for a better understanding of SMA.

A new biomarker quantifies differences in clot microstructure in patients with venous thromboembolism.

This study compared patients with venous thromboembolism (VTE) to non-VTE patients using a biomarker of clot microstructure (df ) and clot formation time (TGP ). df was the only marker that identified a significant difference (P < 0·001) between the VTE (n = 60) and non-VTE cohorts (n = 69). The 'abnormal' clot microstructures in the VTE patients suggests either inadequate response to anticoagulant therapy or the presence of a procoagulant state not detected by other markers of coagulation (i.e., International Normalized Ratio). Furthermore, elevated values of df in first time VTE patients who later develop a secondary event indicates that df may identify those at risk of recurrence.

A Slow-Release Substrate Stimulates Groundwater Microbial Communities for Long-Term in Situ Cr(VI) Reduction.

Cr(VI) is a widespread environmental contaminant that is highly toxic and soluble. Previous work indicated that a one-time amendment of polylactate hydrogen-release compound (HRC) reduced groundwater Cr(VI) concentrations for >3.5 years at a contaminated aquifer; however, microbial communities responsible for Cr(VI) reduction are poorly understood. In this study, we hypothesized that HRC amendment would significantly change the composition and structure of groundwater microbial communities, and that the abundance of key functional genes involved in HRC degradation and electron acceptor reduction would increase long-term in response to this slowly degrading, complex substrate. To test these hypotheses, groundwater microbial communities were monitored after HRC amendment for >1 year using a comprehensive functional gene microarray. The results showed that the overall functional composition and structure of groundwater microbial communities underwent sequential shifts after HRC amendment. Particularly, the abundance of functional genes involved in acetate oxidation, denitrification, dissimilatory nitrate reduction, metal reduction, and sulfate reduction significantly increased. The overall community dynamics was significantly correlated with changes in groundwater concentrations of microbial biomass, acetate, NO3-, Cr(VI), Fe(II) and SO4(2-). Our results suggest that HRC amendment primarily stimulated key functional processes associated with HRC degradation and reduction of multiple electron acceptors in the aquifer toward long-term Cr(VI) reduction.

Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling.

The stability of the Wnt pathway transcription factor beta-catenin is tightly regulated by the multi-subunit destruction complex. Deregulated Wnt pathway activity has been implicated in many cancers, making this pathway an attractive target for anticancer therapies. However, the development of targeted Wnt pathway inhibitors has been hampered by the limited number of pathway components that are amenable to small molecule inhibition. Here, we used a chemical genetic screen to identify a small molecule, XAV939, which selectively inhibits beta-catenin-mediated transcription. XAV939 stimulates beta-catenin degradation by stabilizing axin, the concentration-limiting component of the destruction complex. Using a quantitative chemical proteomic approach, we discovered that XAV939 stabilizes axin by inhibiting the poly-ADP-ribosylating enzymes tankyrase 1 and tankyrase 2. Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway. Thus, our study provides new mechanistic insights into the regulation of axin protein homeostasis and presents new avenues for targeted Wnt pathway therapies.

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.

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.