Fulminant Myocarditis and Venoarterial Extracorporeal Membrane Oxygenation: A Systematic Review.

This systematic review aimed to look at the effectiveness of venoarterial extracorporeal membrane oxygenation (VA-ECMO) therapy in treating fulminant myocarditis and evaluating the optimal length of time a patient should be placed on VA-ECMO. Fulminant myocarditis is a potentially life-threatening medical condition most commonly brought on by cardiogenic shock, which often progresses to severe circulatory compromise, requiring the patient to be placed on some form of mechanical circulatory assistance to maintain adequate tissue perfusion. Medical centers have multiple mechanical assistive devices available for treatment at their disposal, but our area of focus was placed on one system in particular: VA-ECMO therapy. Although the technology has been around for more than 30 years, there is limited information on how effective VA-ECMO is regarding the treatment of fulminant myocarditis. Due to the lack of data regarding the treatment administration of VA-ECMO for fulminant myocarditis, standard treatment duration guidelines do not exist, resulting in a wide variation of treatment administrations among medical centers. In regard to short-term outcomes, VA-ECMO has shown to be effective in treating fulminant myocarditis, with a one-year post-hospital survival rate ranging from 57.1% to 78% at discharge. For long-term health and survival, the studies that recorded long-term survival ranged from 65% to 94.1%. However, given the small number of studies that pursue this, more research is needed to prove the efficacy of VA-ECMO for the treatment of fulminant myocarditis.

Identification of gene fusions associated with amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Genetics is an important risk factor for amyotrophic lateral sclerosis (ALS), a neurodegenerative disease affecting motor neurons. Recent findings demonstrate that in addition to specific genetic mutations, structural variants caused by genetic instability can also play a causative role in ALS. Genomic instability can lead to deletions, duplications, insertions, inversions, and translocations in the genome, and these changes can sometimes lead to fusion of distinct genes into a single transcript. Gene fusion events have been studied extensively in cancer; however, they have not been thoroughly investigated in ALS. The aim of this study was to determine whether gene fusions are present in ALS. METHODS: Gene fusions were identified using STAR Fusion v1.10.0 software in bulk RNA-Seq data from human postmortem samples from publicly available data sets from Target ALS and the New York Genome Center ALS Consortium. RESULTS: We report the presence of gene fusion events in several brain regions as well as in spinal cord samples in ALS. Although most gene fusions were intra-chromosomal events between neighboring genes and present in both ALS and control samples, there was a significantly greater number of unique gene fusions in ALS compared to controls. Lastly, we identified specific gene fusions with a significant burden in ALS, that were absent from both control samples and known cancer gene fusion databases. DISCUSSION: Collectively, our findings reveal an enrichment of gene fusions in ALS and suggest that these events may be an additional genetic cause linked to ALS pathogenesis.

A functional identification platform reveals frequent, spontaneous neoantigen-specific T cell responses in patients with cancer.

The clinical impact of tumor-specific neoantigens as both immunotherapeutic targets and biomarkers has been impeded by the lack of efficient methods for their identification and validation from routine samples. We have developed a platform that combines bioinformatic analysis of tumor exomes and transcriptional data with functional testing of autologous peripheral blood mononuclear cells (PBMCs) to simultaneously identify and validate neoantigens recognized by naturally primed CD4+ and CD8+ T cell responses across a range of tumor types and mutational burdens. The method features a human leukocyte antigen (HLA)-agnostic bioinformatic algorithm that prioritizes mutations recognized by patient PBMCs at a greater than 40% positive predictive value followed by a short-term in vitro functional assay, which allows interrogation of 50 to 75 expressed mutations from a single 50-ml blood sample. Neoantigens validated by this method include both driver and passenger mutations, and this method identified neoantigens that would not have been otherwise detected using an in silico prediction approach. These findings reveal an efficient approach to systematically validate clinically actionable neoantigens and the T cell receptors that recognize them and demonstrate that patients across a variety of human cancers have a diverse repertoire of neoantigen-specific T cells.

Phase space analysis of two-wavelength interferometry.

Multiple wavelength phase shifting interferometry is widely used to extend the unambiguous range (UR) beyond that of a single wavelength. Towards this end, many algorithms have been developed to calculate the optical path difference (OPD) from the phase measurements of multiple wavelengths. These algorithms fail when phase error exceeds a specific threshold. In this paper, we examine this failure condition. We introduce a "phase-space" view of multi-wavelength algorithms and demonstrate how this view may be used to understand an algorithm's robustness to phase measurement error. In particular, we show that the robustness of the synthetic wavelength algorithm deteriorates near the edges of its UR. We show that the robustness of de Groot's extended range algorithm [Appl. Opt.33, 5948 (1994)APOPAI0003-693510.1364/AO.33.005948] depends on both wavelength and OPD in a non-trivial manner. Further, we demonstrate that the algorithm developed by Houairi and Cassaing (HC) [J. Opt. Soc. Am. A26, 2503 (2009)JOAOD60740-323210.1364/JOSAA.26.002503] results in uniform robustness across the entire UR. Finally, we explore the effect that wavelength error has on the robustness of the HC algorithm.

Cyclic loading induces anabolic gene expression in ACLs in a load-dependent and sex-specific manner.

Anterior cruciate ligament (ACL) injuries are historically thought to be a result of a single acute overload or traumatic event. However, recent studies suggest that ACL failure may be a consequence of fatigue damage. Additionally, the remodeling response of ACLs to fatigue loading is unknown. Therefore, the objective of this study was to investigate the remodeling response of ACLs to cyclic loading. Furthermore, given that women have an increased rate of ACL rupture, we investigated whether this remodeling response is sex specific. ACLs were harvested from male and female New Zealand white rabbits and cyclically loaded in a tensile bioreactor mimicking the full range of physiological loading (2, 4, and 8 MPa). Expression of markers for anabolic and catabolic tissue remodeling, as well as inflammatory cytokines, was quantified using quantitative reverse transcription polymerase chain reaction. We found that the expression of markers for tissue remodeling of the ACL is dependent on the magnitude of loading and is sex specific. Male ACLs activated an anabolic response to cyclic loading at 4 MPa but turned off remodeling at 8 MPa. These data support the hypothesis that noncontact ACL injury may be a consequence of failed tissue remodeling and inadequate repair of microtrauma resulting from elevated loading. Compared to males, female ACLs failed to increase anabolic gene expression with loading and exhibited higher expression of catabolic genes at all loading levels, which may explain the increased rate of ACL tears in women. Together, these data provide insight into load-induced ACL remodeling and potential causes of tissue rupture.

Discovery of MK-1468: A Potent, Kinome-Selective, Brain-Penetrant Amidoisoquinoline LRRK2 Inhibitor for the Potential Treatment of Parkinson's Disease.

Genetic mutation of the leucine-rich repeat kinase 2 (LRRK2) protein has been associated with Parkinson's disease (PD), a disabling and progressive neurodegenerative disorder that is devoid of efficacious disease-modifying therapies. Herein, we describe the invention of an amidoisoquinoline (IQ)-derived LRRK2 inhibitor lead chemical series. Knowledge-, structure-, and property-based drug design in concert with rigorous application of in silico calculations and presynthesis predictions enabled the prioritization of molecules with favorable CNS "drug-like" physicochemical properties. This resulted in the discovery of compound 8, which was profiled extensively before human ether-a-go-go (hERG) ion channel inhibition halted its progression. Strategic reduction of lipophilicity and basicity resulted in attenuation of hERG ion channel inhibition while maintaining a favorable CNS efflux transporter profile. Further structure- and property-based optimizations resulted in the discovery of preclinical candidate MK-1468. This exquisitely selective LRRK2 inhibitor has a projected human dose of 48 mg BID and a preclinical safety profile that supported advancement toward GLP toxicology studies.

Targeted RNAi screen identifies transcriptional mechanisms that prevent premature degeneration of adult photoreceptors.

Aging is associated with a decline in visual function and increased prevalence of ocular disease, correlating with changes in the transcriptome and epigenome of cells in the eye. Here, we sought to identify the transcriptional mechanisms that are necessary to maintain photoreceptor viability and function during aging. To do this, we performed a targeted photoreceptor-specific RNAi screen in Drosophila to identify transcriptional regulators whose knockdown results in premature, age-dependent retinal degeneration. From an initial set of 155 RNAi lines each targeting a unique gene and spanning a diverse set of transcription factors, chromatin remodelers, and histone modifiers, we identified 18 high-confidence target genes whose decreased expression in adult photoreceptors leads to premature and progressive retinal degeneration. These 18 target genes were enriched for factors involved in the regulation of transcription initiation, pausing, and elongation, suggesting that these processes are essential for maintaining the health of aging photoreceptors. To identify the genes regulated by these factors, we profiled the photoreceptor transcriptome in a subset of lines. Strikingly, two of the 18 target genes, Spt5 and domino, show similar changes in gene expression to those observed in photoreceptors with advanced age. Together, our data suggest that dysregulation of factors involved in transcription initiation and elongation plays a key role in shaping the transcriptome of aging photoreceptors. Further, our findings indicate that the age-dependent changes in gene expression not only correlate but might also contribute to an increased risk of retinal degeneration.

Linked CD4+/CD8+ T cell neoantigen vaccination overcomes immune checkpoint blockade resistance and enables tumor regression.

Therapeutic benefit to immune checkpoint blockade (ICB) is currently limited to the subset of cancers thought to possess a sufficient tumor mutational burden (TMB) to allow for the spontaneous recognition of neoantigens (NeoAg) by autologous T cells. We explored whether the response to ICB of an aggressive low-TMB squamous cell tumor could be improved through combination immunotherapy using functionally defined NeoAg as targets for endogenous CD4+ and CD8+ T cells. We found that, whereas vaccination with CD4+ or CD8+ NeoAg alone did not offer prophylactic or therapeutic immunity, vaccines containing NeoAg recognized by both subsets overcame ICB resistance and led to the eradication of large established tumors that contained a subset of PD-L1+ tumor-initiating cancer stem cells (tCSC), provided the relevant epitopes were physically linked. Therapeutic CD4+/CD8+ T cell NeoAg vaccination produced a modified tumor microenvironment (TME) with increased numbers of NeoAg-specific CD8+ T cells existing in progenitor and intermediate exhausted states enabled by combination ICB-mediated intermolecular epitope spreading. We believe that the concepts explored herein should be exploited for the development of more potent personalized cancer vaccines that can expand the range of tumors treatable with ICB.

Age-Dependent Increase in Tau Phosphorylation at Serine 396 in Huntington's Disease Prefrontal Cortex.

BACKGROUND: To date, it is still controversial whether tau phosphorylation plays a role in Huntington's disease (HD), as previous studies demonstrated either no alterations or increases in phosphorylated tau (pTau) in HD postmortem brain and mouse models. OBJECTIVE: The goal of this study was to determine whether total tau and pTau levels are altered in HD. METHODS: Immunohistochemistry, cellular fractionations, and western blots were used to measure total tau and pTau levels in a large cohort of HD and control postmortem prefrontal cortex (PFC). Furthermore, western blots were performed to assess tau, and pTau levels in HD and control isogenic embryonic stem cell (ESC)-derived cortical neurons and neuronal stem cells (NSCs). Similarly, western blots were used to assess tau and pTau levels in HttQ111 and transgenic R6/2 mice. Lastly, total tau levels were assessed in HD and healthy control plasma using Quanterix Simoa assay. RESULTS: Our results revealed that, while there was no difference in total tau or pTau levels in HD PFC compared to controls, the levels of tau phosphorylated at S396 were increased in PFC samples from HD patients 60 years or older at time of death. Additionally, tau and pTau levels were not changed in HD ESC-derived cortical neurons and NSCs. Similarly, total tau or pTau levels were not altered in HttQ111 and transgenic R6/2 mice compared to wild-type littermates. Lastly, tau levels were not changed in plasma from a small cohort of HD patients compared to controls. CONCLUSIONS: Together these findings demonstrate that pTau-S396 levels increase significantly with age in HD PFC.

META-INSTI: metabolic adverse events following integrase strand transfer inhibitor administration in spontaneous adverse event reports.

Background: Metabolic effects of integrase strand transfer inhibitors (INSTIs) have been reported. The FDA Adverse Event Reporting System (FAERS) is a publicly available database that captures spontaneously reported adverse events. The objective of this study was to evaluate the relationship between INSTIs and metabolic adverse events using the FAERS database. Methods: FAERS data were queried from quarter 4 of 2007 through quarter 4 of 2019 and limited to adults. The Standardized MedDRA Query for 'hyperglycaemia/new-onset diabetes mellitus' (H/DM) was used to identify metabolic adverse events of interest. Weight gain was analysed as a separate event. Reporting odds ratios (RORs) and 95% CIs were calculated for the INSTI class and individual agents. Results: Over 10.1 million FAERS reports were identified. Any INSTI was mentioned as a primary and/or secondary suspect agent in 18,400 (0.18%) reports (bictegravir: 1414 [0.01%]; dolutegravir: 7840 [0.08%]; elvitegravir: 4034 [0.04%]; raltegravir: 5551 [0.05%]). RORs (95% CI) for H/DM and weight gain for any INSTI were 1.20 (1.15-1.27) and 2.16 (1.96-2.38). For individual agents, RORs (95% CI) for H/DM and weight gain were as follows: bictegravir, 1.23 (1.10-1.37) and 6.82 (5.50-8.41); dolutegravir, 1.28 (1.19-1.39) and 1.86 (1.58-2.18); elvitegravir, 0.76 (0.56-1.02) and 1.63 (1.37-1.92); and raltegravir, 1.00 (0.90-1.11) and 3.29 (2.77-3.91). H/DM was noted in 159 bictegravir and 712 dolutegravir reports. Conclusion: Overall, H/DM was associated with bictegravir and dolutegravir and weight gain with all INSTIs. Clinicians should know the potential relationship between INSTIs and metabolic effects and institute appropriate monitoring. This paper was previously presented: META-INSTI: Metabolic Adverse Events Following Integrase Strand Transfer Inhibitor Administration in Spontaneous Adverse Event Reports. Platform Presentation. ID Week. Virtual 2020.

Experimental and Theoretical Exploration of the Kinetics and Thermodynamics of the Nucleophile-Induced Fragmentation of Ylidenenorbornadiene Carboxylates.

Ylidenenorbornadienes (YNDs), prepared by [4 + 2] cycloadditions between fulvenes and acetylene carboxylates, react with thiol nucleophiles to yield mixtures of four to eight diastereomers depending on the symmetry of the YND substrate. The mixtures of diastereomers fragment via a retro-[4 + 2] cycloaddition with a large variation in rate, with half-lives ranging from 16 to 11,000 min at 80 °C. The diastereomer-enriched samples of propane thiol adducts [YND-propanethiol (PTs)] were isolated and identified by nuclear Overhauser effect spectroscopy (NOESY) correlations. Simulated kinetics were used to extrapolate the rate constants of individual diastereomers from the observed rate data, and it correlated well with rate constants measured directly and from isolated diastereomer-enriched samples. The individual diastereomers of a model system fragment at differing rates with half-lives ranging from 5 to 44 min in CDCl3. Density functional theory calculations were performed to investigate the mechanism of fragmentation and support an asynchronous retro-[4 + 2] cycloaddition transition state. The computations generally correlated well with the observed free energies of activation for four diastereomers of the model system as a whole, within 2.6 kcal/mol. However, the observed order of the fragmentation rates across the set of diastereomers deviated from the computational results. YNDs display wide variability in the rate of fragmentation, dependent on the stereoelectronics of the ylidene substituents. A Hammett study showed that the electron-rich aromatic rings attached to the ylidene bridge increase the fragmentation rate, while electron-deficient systems slow fragmentation rates.

Neoantigen-specific stem cell memory-like CD4+ T cells mediate CD8+ T cell-dependent immunotherapy of MHC class II-negative solid tumors.

CD4+ T cells play key roles in a range of immune responses, either as direct effectors or through accessory cells, including CD8+ T lymphocytes. In cancer, neoantigen (NeoAg)-specific CD8+ T cells capable of direct tumor recognition have been extensively studied, whereas the role of NeoAg-specific CD4+ T cells is less well understood. We have characterized the murine CD4+ T cell response against a validated NeoAg (CLTCH129>Q) expressed by the MHC-II-deficient squamous cell carcinoma tumor model (SCC VII) at the level of single T cell receptor (TCR) clonotypes and in the setting of adoptive immunotherapy. We find that the natural CLTCH129>Q-specific repertoire is diverse and contains TCRs with distinct avidities as measured by tetramer-binding assays and CD4 dependence. Despite these differences, CD4+ T cells expressing high or moderate avidity TCRs undergo comparable in vivo proliferation to cross-presented antigen from growing tumors and drive similar levels of therapeutic immunity that is dependent on CD8+ T cells and CD40L signaling. Adoptive cellular therapy (ACT) with NeoAg-specific CD4+ T cells is most effective when TCR-engineered cells are differentiated ex vivo with IL-7 and IL-15 rather than IL-2 and this was associated with both increased expansion as well as the acquisition and stable maintenance of a T stem cell memory (TSCM)-like phenotype in tumor-draining lymph nodes (tdLNs). ACT with TSCM-like CD4+ T cells results in lower PD-1 expression by CD8+ T cells in the tumor microenvironment and an increased frequency of PD-1+CD8+ T cells in tdLNs. These findings illuminate the role of NeoAg-specific CD4+ T cells in mediating antitumor immunity via providing help to CD8+ T cells and highlight their therapeutic potential in ACT.

Age-dependent increase in tau phosphorylation at serine 396 in Huntington's disease pre-frontal cortex.

Background: To date, it is still controversial whether tau phosphorylation plays a role in Huntington's disease (HD), as previous studies demonstrated either no alterations or increases in phosphorylated tau (pTau) in HD post-mortem brain and mouse models. Objectives: The goal of this study was to determine whether total tau and pTau levels are altered in HD. Methods: Immunohistochemistry, cellular fractionations, and western blots were used to measure tau and pTau levels in a large cohort of HD and control post-mortem prefrontal cortex (PFC). Furthermore, western blots were performed to assess tau, and pTau levels in HD and control isogenic embryonic stem cell (ESC)-derived cortical neurons and neuronal stem cells (NSCs). Similarly, western blots were used to assess tau and pTau in Htt Q111 and transgenic R6/2 mice. Lastly, total tau levels were assessed in HD and healthy control plasma using Quanterix Simoa assay. Results: Our results revealed that, while there was no difference in tau or pTau levels in HD PFC compared to controls, tau phosphorylated at S396 levels were increased in PFC samples from HD patients 60 years or older at time of death. Additionally, tau and pTau levels were not changed in HD ESC-derived cortical neurons and NSCs. Similarly, tau or pTau levels were not altered in Htt Q111 and transgenic R6/2 mice compared to wild-type littermates. Lastly, tau levels were not changed in plasma from a small cohort of HD patients compared to controls. Conclusion: Together these findings demonstrate that pTau-S396 levels increase significantly with age in HD PFC.

Nanoparticle-Decorated Biomimetic Extracellular Matrix for Cell Nanoencapsulation and Regulation.

Cell encapsulation has been studied for various applications ranging from cell transplantation to biological production. However, current encapsulation technologies focus on cell protection rather than cell regulation that is essential to most if not all cell-based applications. Here we report a method for cell nanoencapsulation and regulation using an ultrathin biomimetic extracellular matrix as a cell nanocapsule to carry nanoparticles (CN2 ). This method allows high-capacity nanoparticle retention at the vicinity of cell surfaces. The encapsulated cells maintain high viability and normal metabolism. When gold nanoparticles (AuNPs) are used as a model to decorate the nanocapsule, light irradiation transiently increases the temperature, leading to the activation of the heat shock protein 70 (HSP70) promoter and the regulation of reporter gene expression. As the biomimetic nanocapsule can be decorated with any or multiple NPs, CN2 is a promising platform for advancing cell-based applications.

Linked CD4 + /CD8 + T cell neoantigen vaccination overcomes immune checkpoint blockade resistance and enables tumor regression.

Therapeutic benefit to immune checkpoint blockade (ICB) is currently limited to the subset of cancers thought to possess a sufficient tumor mutational burden (TMB) to allow for the spontaneous recognition of neoantigens (NeoAg) by autologous T cells. We explored whether the response of an aggressive low TMB squamous cell tumor to ICB could be improved through combination immunotherapy using functionally defined NeoAg as targets for endogenous CD4 + and CD8 + T cells. We found that, whereas vaccination with CD4 + or CD8 + NeoAg alone did not offer prophylactic or therapeutic immunity, vaccines containing NeoAg recognized by both subsets overcame ICB resistance and led to the eradication of large established tumors that contained a subset of PD-L1 + tumor-initiating cancer stem cells (tCSC), provided the relevant epitopes were physically linked. Therapeutic CD4 + /CD8 + T cell NeoAg vaccination produced a modified tumor microenvironment (TME) with increased numbers of NeoAg-specific CD8 + T cells existing in progenitor and intermediate exhausted states enabled by combination ICB-mediated intermolecular epitope spreading. The concepts explored herein should be exploited for the development of more potent personalized cancer vaccines that can expand the range of tumors treatable with ICB.

Systematic Review of Binge Eating Rodent Models for Developing Novel or Repurposing Existing Pharmacotherapies.

Recent advances in developing and screening candidate pharmacotherapies for psychiatric disorders have depended on rodent models. Eating disorders are a set of psychiatric disorders that have traditionally relied on behavioral therapies for effective long-term treatment. However, the clinical use of Lisdexamfatamine for binge eating disorder (BED) has furthered the notion of using pharmacotherapies for treating binge eating pathologies. While there are several binge eating rodent models, there is not a consensus on how to define pharmacological effectiveness within these models. Our purpose is to provide an overview of the potential pharmacotherapies or compounds tested in established rodent models of binge eating behavior. These findings will help provide guidance for determining pharmacological effectiveness for potential novel or repurposed pharmacotherapies.

Dynamic Changes in Lumbar Spine Kinematics During Gait May Explain Improvement in Back Pain and Disability in Patients With Hip-Spine Syndrome.

STUDY DESIGN: Prospective cohort. OBJECTIVE: Determine if total hip arthroplasty (THA) changes lumbar spine kinematics during gait in a manner that explains the improvements in back pain seen in patients with hip-spine syndrome. SUMMARY OF BACKGROUND DATA: For patients with hip-spine syndrome, improvements in both hip and back pain have been demonstrated after THA; however, the exact mechanism of improvement in back pain remains unknown, as no corresponding changes in lumbar spine static radiographic parameters have been identified. METHODS: Thirteen patients with severe, unilateral hip osteoarthritis scheduled to undergo THA with concomitant back pain and disability were tested at baseline and 6 months after THA. Harris Hip Score (HHS) and Oswestry Disability Index questionnaires were completed; the static orientation of the spine and pelvis were measured on standing radiographs, and lumbar spine kinematics were measured during treadmill walking using a validated measurement system that matched subject-specific bone models created from CT scans to dynamic biplane radiographs. RESULTS: After THA, both the Oswestry Disability Index (36.3-11.3, P <0.001) and Harris Hip Score (55.7-77.9, P <0.001) improved; however, there were no changes in static intervertebral or pelvis orientation. During gait after THA, the overall lumbar spine (L1 to L5) was less lordotic from heel strike to contralateral toe off ( P <0.001), the L4 and L5 vertebra were less anteriorly tilted by 3.9° ( P =0.038) from midstance to contralateral heel strike and by 3.9° ( P =0.001) during stance, respectively. CONCLUSION: The decreased anterior tilt of the 2 lowest lumbar vertebrae and the corresponding loss of lumbar lordosis may reduce facet loading during the stance phase of gait after THA. This change in lumbar spine kinematics during gait is a potential mechanism to explain the observed improvements in back pain and disability after THA. LEVEL OF EVIDENCE: 4.

Minimum 10-Year Clinical Outcomes After Arthroscopic Capsulolabral Repair for Isolated Posterior Shoulder Instability.

BACKGROUND: Arthroscopic capsulolabral repair for posterior shoulder instability has been shown to improve patient-reported outcomes and return to sport at short-term and midterm follow-up, but long-term outcomes are unknown. PURPOSE: To determine the objective and subjective clinical outcomes of shoulder function after arthroscopic posterior shoulder stabilization at a minimum 10-year follow-up. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A total of 53 patients (55 shoulders) with unidirectional recurrent posterior shoulder instability who underwent arthroscopic capsulolabral repair were evaluated at a mean follow-up of 15.4 years. Outcomes such as the American Shoulder and Elbow Surgeons (ASES) shoulder score, Kerlan-Jobe Orthopaedic Clinic shoulder and elbow score, and subjective strength, stability, range of motion, and pain were evaluated preoperatively and postoperatively at a minimum 10-year follow-up. Outcomes from the same patient cohort were previously collected at 3.0-year follow-up and were evaluated for longitudinal analysis. Subgroup analyses for sport type (contact vs noncontact), position (thrower vs nonthrower), and revision versus nonrevision were performed. Risk factors for revision surgery based on magnetic resonance imaging findings, patient characteristics, and surgical findings were investigated. RESULTS: Arthroscopic capsulolabral repair for posterior shoulder instability led to a statistically significant improvement on all outcome measures, with similar values at short-term (3.0-year) and long-term (15.4-year) follow-up. Across the total population, patients with 19 of 55 shoulders (35%) returned to sport at the same preinjury level, and patients with 33 of 55 shoulders (60%) returned to sport at some level. At long-term follow-up, patients with only 22% of shoulders were involved in the primary sport in which the injury was sustained, with patients with 28% of shoulders discontinuing sporting participation because of ongoing shoulder issues. Throwers trended toward lower Kerlan-Jobe Orthopaedic Clinic scores than nonthrowers both preoperatively (36.5 ± 22.8 vs 48.7 ± 22.9, respectively; P = .10) and postoperatively (57.4 ± 27.0 vs 73.5 ± 26.8, respectively; P = .09) but had similar improvements. Contact and noncontact athletes had similar preoperative and postoperative values, with equal improvements after surgery. With failure defined as revision surgery, an ASES score <60, or a stability value >5, 19 of 55 shoulders (35%) met failure criteria at final follow-up. Overall, 7 of 55 shoulders (13%) underwent revision surgery. At long-term follow-up, patients who underwent revision surgery had worse outcomes than those who did not undergo revision (ASES score: 53.1 ± 25.9 vs 81.8 ± 19.4, respectively; P < .001). An acute injury in the postoperative period (P < .001) and a smaller glenoid bone width on magnetic resonance imaging (P = .02) were the only identified risk factors for revision surgery. CONCLUSION: Arthroscopic capsulolabral repair for posterior shoulder instability was a durable treatment option that improved long-term shoulder pain and function and facilitated return to sport in the majority of patients at a mean follow-up of 15.4 years, although a notable proportion of patients met various criteria for failure.