Towards optimized methodological parameters for maximizing the behavioral effects of transcranial direct current stimulation.

Introduction: Transcranial direct current stimulation (tDCS) administers low-intensity direct current electrical stimulation to brain regions via electrodes arranged on the surface of the scalp. The core promise of tDCS is its ability to modulate brain activity and affect performance on diverse cognitive functions (affording causal inferences regarding regional brain activity and behavior), but the optimal methodological parameters for maximizing behavioral effects remain to be elucidated. Here we sought to examine the effects of 10 stimulation and experimental design factors across a series of five cognitive domains: motor performance, visual search, working memory, vigilance, and response inhibition. The objective was to identify a set of optimal parameter settings that consistently and reliably maximized the behavioral effects of tDCS within each cognitive domain. Methods: We surveyed tDCS effects on these various cognitive functions in healthy young adults, ultimately resulting in 721 effects across 106 published reports. Hierarchical Bayesian meta-regression models were fit to characterize how (and to what extent) these design parameters differentially predict the likelihood of positive/negative behavioral outcomes. Results: Consistent with many previous meta-analyses of tDCS effects, extensive variability was observed across tasks and measured outcomes. Consequently, most design parameters did not confer consistent advantages or disadvantages to behavioral effects-a domain-general model suggested an advantage to using within-subjects designs (versus between-subjects) and the tendency for cathodal stimulation (relative to anodal stimulation) to produce reduced behavioral effects, but these associations were scarcely-evident in domain-specific models. Discussion: These findings highlight the urgent need for tDCS studies to more systematically probe the effects of these parameters on behavior to fulfill the promise of identifying causal links between brain function and cognition.

Revisiting the infrageneric classification of Garcinia L. (Clusiaceae): an updated sectional name and new, legitimate names in Garcinia for Allanblackiagabonensis (Pellegr.) Bamps and A.parviflora A.Chev.

In a recent publication dealing with the sectional-level taxonomy of Garcinia, an illegitimate superfluous sectional name and two illegitimate homonyms were published. Herein we choose a legitimate sectional name, GarciniasectionRheediopsis Pierre, for the superfluous name GarciniasectionRheedia (L.) S.W.Jones ex P.W.Sweeney; and create two new legitimate names in Garcinia for Allanblackiagabonensis (Pellegr.) Bamps and A.parviflora A.Chev.

Subthreshold activation of the melanocortin system causes generalized sensitization to anorectic agents in mice.

The melanocortin-3 receptor (MC3R) regulates GABA release from agouti-related protein (AgRP) nerve terminals and thus tonically suppresses multiple circuits involved in feeding behavior and energy homeostasis. Here, we examined the role of the MC3R and the melanocortin system in regulating the response to various anorexigenic agents. The genetic deletion or pharmacological inhibition of the MC3R, or subthreshold doses of an MC4R agonist, improved the dose responsiveness to glucagon-like peptide 1 (GLP1) agonists, as assayed by inhibition of food intake and weight loss. An enhanced anorectic response to the acute satiety factors peptide YY (PYY3-36) and cholecystokinin (CCK) and the long-term adipostatic factor leptin demonstrated that increased sensitivity to anorectic agents was a generalized result of MC3R antagonism. We observed enhanced neuronal activation in multiple hypothalamic nuclei using Fos IHC following low-dose liraglutide in MC3R-KO mice (Mc3r-/-), supporting the hypothesis that the MC3R is a negative regulator of circuits that control multiple aspects of feeding behavior. The enhanced anorectic response in Mc3r-/- mice after administration of GLP1 analogs was also independent of the incretin effects and malaise induced by GLP1 receptor (GLP1R) analogs, suggesting that MC3R antagonists or MC4R agonists may have value in enhancing the dose-response range of obesity therapeutics.

Stereotactic Body Proton Therapy Versus Conventionally Fractionated Proton Therapy for Early Prostate Cancer: A Randomized, Controlled, Phase 3 Trial.

PURPOSE: We aimed to determine if ultra-hypofractionated proton therapy delivered via stereotactic body proton therapy (SBPT) is non-inferior to conventionally fractionated proton therapy (CFPT) in patients with early prostate cancer. MATERIALS AND METHODS: This study was a multicenter, randomized, controlled, non-inferiority phase 3 trial that included patients with histologically confirmed low-risk prostate adenocarcinoma defined by Gleason score grouping 1, PSA <10 ng/mL, and clinical stage T1-2a N0 M0 according to AJCC 7th ed. Eligible participants were randomly assigned initially at a 1:1 ratio and later at a 2:1 ratio to SBPT (38 Gy in 5 fractions) or CFPT (79.2 Gy in 44 fractions). The primary endpoint was freedom from failure (FFF) at 2 years from the date of randomization. Non-inferiority for FFF was determined based on one-sided confidence intervals. Toxicities were compared at different time points using Fisher's Exact test. Health-related quality-of-life (HRQoL) was analyzed at different time points using a mixed-effects linear model. This trial is registered with ClinicalTrials.gov, NCT01230866, and is closed to accrual. RESULTS: Between December 10, 2010, and September 29, 2020, 144 patients were enrolled and 135 were randomly assigned (90 to the SBPT group and 45 to the CFPT group). The median follow-up was 5 years (IQR 3.9-5.2). The 2-year FFF was 100% for both groups, with the one-sided 5-year risk difference in FFF between groups reported as 2.63% (90% CI: -1.70%-6.96%), favoring the SBRT arm, thus fulfilling the pre-specified criteria for non-inferiority of SBPT compared to CFPT. Rates of gastrointestinal (GI) and genitourinary (GU) G2 and G3 toxicities did not differ significantly between groups but the the study was not powered to detect significant toxicity differences. Also, HRQoL metrics did not differ significantly between groups over the study median follow up. CONCLUSIONS: SBPT is non-inferior to CFPT regarding FFF, with similar long-term GU and GI toxicity rates and minimal impact in patient reported HRQoL over time.

Hypothalamic AgRP neurons regulate the hyperphagia of lactation.

OBJECTIVE: The lactational period is associated with profound hyperphagia to accommodate the energy demands of nursing. These changes are important for the long-term metabolic health of the mother and children as altered feeding during lactation increases the risk of mothers and offspring developing metabolic disorders later in life. However, the specific behavioral mechanisms and neural circuitry mediating the hyperphagia of lactation are incompletely understood. METHODS: Here, we utilized home cage feeding devices to characterize the dynamics of feeding behavior in lactating mice. A combination of pharmacological and behavioral assays were utilized to determine how lactation alters meal structure, circadian aspects of feeding, hedonic feeding, and sensitivity to hunger and satiety signals in lactating mice. Finally, we utilized chemogenetic, immunohistochemical, and in vivo imaging approaches to characterize the role of hypothalamic agouti-related peptide (AgRP) neurons in lactational-hyperphagia. RESULTS: The lactational period is associated with increased meal size, altered circadian patterns of feeding, reduced sensitivity to gut-brain satiety signals, and enhanced sensitivity to negative energy balance. Hypothalamic AgRP neurons display increased sensitivity to negative energy balance and altered in vivo activity during the lactational state. Further, using in vivo imaging approaches we demonstrate that AgRP neurons are directly activated by lactation. Chemogenetic inhibition of AgRP neurons acutely reduces feeding in lactating mice, demonstrating an important role for these neurons in lactational-hyperphagia. CONCLUSIONS: Together, these results show that lactation collectively alters multiple components of feeding behavior and position AgRP neurons as an important cellular substrate mediating the hyperphagia of lactation.

Caught in the Act: Incipient Speciation at the Southern limit of Viburnum in the Central Andes.

A fundamental objective of evolutionary biology is to understand the origin of independently evolving species. Phylogenetic studies of species radiations rarely are able to document ongoing speciation; instead, modes of speciation, entailing geographic separation and/or ecological differentiation, are posited retrospectively. The Oreinotinus clade of Viburnum has radiated recently from north to south through the cloud forests of Mexico and Central America to the Central Andes. Our analyses support a hypothesis of incipient speciation in Oreinotinus at the southern edge of its geographic range, from central Peru to northern Argentina. Although several species and infraspecific taxa of have been recognized in this area, multiple lines of evidence and analytical approaches (including analyses of phylogenetic relationships, genetic structure, leaf morphology, and climatic envelopes) favor the recognition of just a single species, V. seemenii. We show that what has previously been recognized as V. seemenii f. minor has recently occupied the drier Tucuman-Bolivian forest region from Samaipata in Bolivia to Salta in northern Argentina. Plants in these populations form a well-supported clade with a distinctive genetic signature and they have evolved smaller, narrower leaves. We interpret this as the beginning of a within-species divergence process that has elsewhere in the neotropics resulted repeatedly in Viburnum species with a particular set of leaf ecomorphs. Specifically, the southern populations are in the process of evolving the small, glabrous, and entire leaf ecomorph that has evolved in four other montane areas of endemism. As predicted based on our studies of leaf ecomorphs in Chiapas, Mexico, these southern populations experience generally drier conditions, with large diurnal temperature fluctuations. In a central portion of the range of V. seemenii, characterized by wetter climatic conditions, we also document what may be the initial differentiation of the leaf ecomorph with larger, pubescent, and toothy leaves. The emergence of these ecomorphs thus appears to be driven by adaptation to subtly different climatic conditions in separate geographic regions, as opposed to parapatric differentiation along elevational gradients as suggested by Viburnum species distributions in other parts of the neotropics.

Neuroanatomical dissection of the MC3R circuitry regulating energy rheostasis.

Although mammals resist both acute weight loss and weight gain, the neural circuitry mediating bi-directional defense against weight change is incompletely understood. Global constitutive deletion of the melanocortin-3-receptor (MC3R) impairs the behavioral response to both anorexic and orexigenic stimuli, with MC3R knockout mice demonstrating increased weight gain following anabolic challenges and increased weight loss following anorexic challenges (i.e. impaired energy rheostasis). However, the brain regions mediating this phenotype remain incompletely understood. Here, we utilized MC3R floxed mice and viral injections of Cre-recombinase to selectively delete MC3R from medial hypothalamus (MH) in adult mice. Behavioral assays were performed on these animals to test the role of MC3R in MH in the acute response to orexigenic and anorexic challenges. Complementary chemogenetic approaches were used in MC3R-Cre mice to localize and characterize the specific medial hypothalamic brain regions mediating the role of MC3R in energy homeostasis. Finally, we performed RNAscope in situ hybridization to map changes in the mRNA expression of MC3R, POMC, and AgRP following energy rheostatic challenges. Our results demonstrate that MC3R deletion in MH increased feeding and weight gain following acute high fat diet feeding in males, and enhanced the anorexic effects of semaglutide, in a sexually dimorphic manner. Additionally, activation of DMH MC3R neurons increased energy expenditure and locomotion. Together, these results demonstrate that MC3R mediated effects on energy rheostasis result from the loss of MC3R signaling in the medial hypothalamus of adult animals and suggest an important role for DMH MC3R signaling in energy rheostasis.

Repeat Next-Generation Sequencing Testing on Progression in Men With Metastatic Prostate Cancer Can Identify New Actionable Alterations.

PURPOSE: There are limited data available on the real-world patterns of molecular testing in men with advanced prostate cancer. We thus sought to evaluate next-generation sequencing (NGS) testing in the United States, focused on single versus serial NGS testing, the different disease states of testing (hormone-sensitive v castration-resistant, metastatic vs nonmetastatic), tissue versus plasma circulating tumor DNA (ctDNA) assays, and how often actionable data were found on each NGS test. METHODS: The Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort clinical-genomic database was used for this retrospective analysis, including 1,597 patients across 15 institutions. Actionable NGS data were defined as including somatic alterations in homologous recombination repair genes, mismatch repair deficiency, microsatellite instability (MSI-high), or a high tumor mutational burden ≥10 mut/MB. RESULTS: Serial NGS testing (two or more NGS tests with specimens collected more than 60 days apart) was performed in 9% (n = 144) of patients with a median of 182 days in between test results. For the second NGS test and beyond, 82.1% (225 of 274) of tests were from ctDNA assays and 76.1% (217 of 285) were collected in the metastatic castration-resistant setting. New actionable data were found on 11.1% (16 of 144) of second NGS tests, with 3.5% (5 of 144) of tests detecting a new BRCA2 alteration or MSI-high. A targeted therapy (poly (ADP-ribose) polymerase inhibitor or immunotherapy) was given after an actionable result on the second NGS test in 31.3% (5 of 16) of patients. CONCLUSION: Repeat somatic NGS testing in men with prostate cancer is infrequently performed in practice and can identify new actionable alterations not present with initial testing, suggesting the utility of repeat molecular profiling with tissue or blood of men with metastatic castration-resistant prostate cancer to guide therapy choices.

An updated infrageneric classification of the pantropical species-rich genus Garcinia L. (Clusiaceae) and some insights into the systematics of New Caledonian species, based on molecular and morphological evidence.

Garcinia L. is a pantropically distributed genus comprised of at least 250 species of shrubs and trees and has centers of diversity located in Africa/Madagascar, Australasia, and Southeast Asia. The genus is notable due to its extreme diversity of floral form, common presence in lowland tropical rainforests worldwide, and potential pharmacological value. Across its entire geographic range, Garcinia lacks a recent taxonomic revision, with the last genus-level taxonomic treatment of Garcinia conducted over 40 years ago. In order to provide an evolutionary-based framework for a revised infrageneric classification of the genus and to investigate in more detail the systematics of New Caledonian species, we conducted molecular phylogenetic analyses using DNA sequence data for the nuclear ITS region on all samples, and for three chloroplast intergenic spacers (psbM-trnD, trnQ-rps16 and rps16-trnK) on a subset of our overall sampling. Our phylogenetic analyses are the most comprehensive to date for the genus, containing 111 biogeographically and morphologically diverse Garcinia species. The analyses support a broad circumscription of Garcinia, including several previously segregated genera (e.g. Allanblackia, Clusianthemum, Ochrocarpos p.p., Pentaphalangium, Rheedia, and Tripetalum). We recovered nine major clades falling within two major lineages, and we delimit 11 sections. We discuss each of the clades, assign them sectional names, discuss their distinguishing morphological features, compare our taxonomic treatment with the most recent sectional treatment, list representative species, note geographic distribution, and highlight some questions that deserve future investigations. We propose nine new nomenclatural combinations, four new names, and three new lectotypes. In New Caledonia (NC), a total of ten, all endemic, species are recognized and were included in our phylogenetic analyses, with several replicates per species (with the exception of G.virgata and G.urceolata, represented by a single accession each). New Caledonian species were retrieved within three separate clades, respectively including 1) G.balansae; 2) G.comptonii, G.neglecta, G.urceolata, G.virgata; and 3) G.amplexicaulis, G.densiflora, G.pedicellata, G.puat, G.vieillardii. Within NC, the phylogenies did not support the distinction between a putative undescribed species and G.balansae. However, it confirmed the distinction between NC species and both G.vitiensis (found in Fiji and Vanuatu) and G.adinantha (found in Fiji), suggesting that all NC species should be considered as endemics.

Inhibition of the melanocortin-3 receptor (MC3R) causes generalized sensitization to anorectic agents.

The melanocortin-3 receptor (MC3R) acts presynaptically to regulate GABA release from agouti-related protein (AgRP) nerve terminals and thus may be a negative regulator of multiple circuits involved in feeding behavior and energy homeostasis. Here, we examined the role of MC3R in regulating the response to various anorexigenic agents. Our findings reveal that genetic deletion or pharmacological inhibition of MC3R improves the dose responsiveness to Glucagon-like peptide 1 (GLP1) agonists, as assayed by inhibition of food intake and weight loss. An enhanced anorectic response to other agents, including the acute satiety factors peptide YY (PYY3-36) and cholecystokinin (CCK) and the long-term adipostatic factor, leptin, demonstrated that increased sensitivity to anorectic agents is a generalized result of MC3R antagonism. Enhanced neuronal activation in multiple nuclei, including ARH, VMH, and DMH, was observed using Fos immunohistochemistry following low-dose liraglutide in MC3R knockout mice (Mc3r-/-), supporting the hypothesis that the MC3R is a negative regulator of circuits regulating multiple aspects of feeding behavior. The enhanced anorectic response in Mc3r -/- mice after administration of GLP1 analogs was also independent of the incretin effects and malaise induced by GLP1R analogs, suggesting that MC3R antagonists may have value in enhancing the dose-response range of obesity therapeutics.

Melanocortin-3 receptor expression in AgRP neurons is required for normal activation of the neurons in response to energy deficiency.

The melanocortin-3 receptor (MC3R) is a negative regulator of the central melanocortin circuitry via presynaptic expression on agouti-related protein (AgRP) nerve terminals, from where it regulates GABA release onto secondary MC4R-expressing neurons. However, MC3R knockout (KO) mice also exhibit defective behavioral and neuroendocrine responses to fasting. Here, we demonstrate that MC3R KO mice exhibit defective activation of AgRP neurons in response to fasting, cold exposure, or ghrelin while exhibiting normal inhibition of AgRP neurons by sensory detection of food in the ad libitum-fed state. Using a conditional MC3R KO model, we show that the control of AgRP neuron activation by fasting and ghrelin requires the specific presence of MC3R within AgRP neurons. Thus, MC3R is a crucial player in the responsiveness of the AgRP soma to both hormonal and neuronal signals of energy need.

Paraventricular Thalamic MC3R Circuits Link Energy Homeostasis with Anxiety-Related Behavior.

The hypothalamic melanocortin system is critically involved in sensing stored energy and communicating this information throughout the brain, including to brain regions controlling motivation and emotion. This system consists of first-order agouti-related peptide (AgRP) and pro-opiomelanocortin (POMC) neurons located in the hypothalamic arcuate nucleus and downstream neurons containing the melanocortin-3 (MC3R) and melanocortin-4 receptor (MC4R). Although extensive work has characterized the function of downstream MC4R neurons, the identity and function of MC3R-containing neurons are poorly understood. Here, we used neuroanatomical and circuit manipulation approaches in mice to identify a novel pathway linking hypothalamic melanocortin neurons to melanocortin-3 receptor neurons located in the paraventricular thalamus (PVT) in male and female mice. MC3R neurons in PVT are innervated by hypothalamic AgRP and POMC neurons and are activated by anorexigenic and aversive stimuli. Consistently, chemogenetic activation of PVT MC3R neurons increases anxiety-related behavior and reduces feeding in hungry mice, whereas inhibition of PVT MC3R neurons reduces anxiety-related behavior. These studies position PVT MC3R neurons as important cellular substrates linking energy status with neural circuitry regulating anxiety-related behavior and represent a promising potential target for diseases at the intersection of metabolism and anxiety-related behavior such as anorexia nervosa.SIGNIFICANCE STATEMENT Animals must constantly adapt their behavior to changing internal and external challenges, and impairments in appropriately responding to these challenges are a hallmark of many neuropsychiatric disorders. Here, we demonstrate that paraventricular thalamic neurons containing the melanocortin-3 receptor respond to energy-state-related information and external challenges to regulate anxiety-related behavior in mice. Thus, these neurons represent a potential target for understanding the neurobiology of disorders at the intersection of metabolism and psychiatry such as anorexia nervosa.

Cell autonomous regulation of the activation of AgRP neurons by the melanocortin-3 receptor.

The melanocortin-3 receptor (MC3R) is a negative regulator of the central melanocortin circuitry via presynaptic expression on AgRP nerve terminals, from where it regulates GABA release onto secondary MC4R-expressing neurons. Hence, animals lacking MC3R (MC3R KO) exhibit hypersensitivity to MC4R agonists. However, MC3R KO mice also exhibit defective behavioral and neuroendocrine responses to fasting. Here, we demonstrate that MC3R KO mice exhibit defective activation of AgRP neurons in response to fasting and cold exposure, while exhibiting normal inhibition of AgRP neurons by sensory detection of food. Further, using an AgRP-specific MC3R knockout model, we show that the control of AgRP neuron activation by MC3R is cell-autonomous. One mechanism underlying this involves the response to ghrelin, which is also blunted in mice with AgRP-specific deletion of the MC3R. Thus, MC3R is a crucial player in the control of energy homeostasis by the central melanocortin system, not only acting presynaptically on AgRP neurons, but via AgRP cell-autonomous regulation of fasting- and cold-induced neuronal activation as well.

Targeting the central melanocortin system for the treatment of metabolic disorders.

A large body of preclinical and clinical data shows that the central melanocortin system is a promising therapeutic target for treating various metabolic disorders such as obesity and cachexia, as well as anorexia nervosa. Setmelanotide, which functions by engaging the central melanocortin circuitry, was approved by the FDA in 2020 for use in certain forms of syndromic obesity. Furthermore, the FDA approvals in 2019 of two peptide drugs targeting melanocortin receptors for the treatment of generalized hypoactive sexual desire disorder (bremelanotide) and erythropoietic protoporphyria-associated phototoxicity (afamelanotide) demonstrate the safety of this class of peptides. These approvals have also renewed excitement in the development of therapeutics targeting the melanocortin system. Here, we review the anatomy and function of the melanocortin system, discuss progress and challenges in developing melanocortin receptor-based therapeutics, and outline potential metabolic and behavioural disorders that could be addressed using pharmacological agents targeting these receptors.

Comparison of circulating tumor DNA between African American and Caucasian patients with metastatic castrate-resistant prostate cancer post-abiraterone and/or enzalutamide.

BACKGROUND: African American men are much more likely than Caucasian men to be diagnosed with and to die of prostate cancer. Genetic differences likely play a role. The cBioPortal database reveals that African American men with prostate cancer have higher rates of CDK12 somatic mutations compared to Caucasian men. However, this does not account for prior prostate cancer treatments, which are particularly important in the castrate-resistant setting. We aimed to compare somatic mutations based on circulating tumor DNA (ctDNA) in metastatic castration-resistant prostate cancer (mCRPC) between African American and Caucasian men after exposure to abiraterone and/or enzalutamide. METHODS: This single-institution retrospective study characterizes the somatic mutations detected on ctDNA for African American and Caucasian men with mCRPC who had progressed after abiraterone and/or enzalutamide from 2015 through 2022. We evaluated the gene mutations and types of mutations in this mCRPC cohort. RESULTS: There were 50 African American and 200 Caucasian men with CRPC with available ctDNA data. African American men were younger at the time of diagnosis (p = 0.008) and development of castration resistance (p = 0.006). African American men were more likely than Caucasian men to have pathogenic/likely pathogenic (P/LP) mutations in CDK12 (12% vs. 1.5%; p = 0.003) and copy number amplifications and P/LP mutations in KIT (8.0% vs. 1.5%; p = 0.031). African American men were also significantly more likely to have frameshift mutations (28% vs. 14%; p = 0.035). CONCLUSIONS: Compared to Caucasian men, African American men with mCRPC after exposure to abiraterone and/or enzalutamide had a higher incidence of somatic CDK12 P/LP mutations and KIT amplifications and P/LP mutations based on ctDNA. African American men also had more frameshift mutations. We hypothesize that these findings have potential implications for tumor immunogenicity.

Enabling Medical Leaders Through Mentoring.

Mentoring is important to the development and enhancement of the medical profession and to organizational performance. The challenge is to implement a mentoring program within your organization. Leaders can use this article to assist in training both mentors and mentees. This article reminds people that the mindsets and skills necessary to become good mentor and mentee improve with practice, thus engage, learn, and improve. The time invested in mentoring relationships enhances patient care, creates positive work environment within organizations, improves individual and organizational performance, and creates a brighter future for the medical profession.

Establishment of Restraint Stress-induced Anorexia and Social Isolation-induced Anorexia Mouse Models.

Anorexia nervosa (AN) is a devastating neuropsychiatric disease with a prevalence rate of approximately 0.3%-1% among women and morbidity and mortality rates among the highest of all neuropsychiatric disorders. The disease etiology is complex but primarily characterized by reduced food intake and body weight, and intense anxiety and fear associated with gaining weight. Existing rodent models of AN are useful and capture features of the disease, but either require specialized genetic mouse models or are difficult to implement in mice. Here, we describe two simple mouse models of stress-induced anorexia that are easy to implement in basic research labs, and capture core features associated with AN, such as reduced food intake in the context of social/physical stress and increased anxiety-related behavior. These protocols provide reproducible and robust assays for stress-induced anorexia and may be implemented with additional assays to probe the neural circuitry mediating the effects of psychological stress on feeding in mice. Graphical abstract.

Total shoulder arthroplasty in patients with a B2 glenoid addressed with corrective reaming: mean 8-year follow-up.

BACKGROUND: The management of Walch B2 glenoid deformities in primary glenohumeral osteoarthritis is frequently debated. Previous literature has shown that the treatment of B2 glenoids with high-side reaming and anatomic total shoulder arthroplasty (aTSA) perform well in the short-term but is associated with an increased glenoid component failure rate in severe deformities. Therefore, many have explored alternative options, including augmented anatomic glenoid components and reverse shoulder arthroplasty. Our goal in this study is to provide mid-term radiographic and clinical outcomes after high-side reaming and aTSA for B2 glenoids. METHODS: Patients were followed both clinically and radiographically. Preoperative computed tomography scans were used for retrospective analysis of deformity. Both preoperative and postoperative visual analog scale pain, American Shoulder and Elbow Surgeons score, and Simple Shoulder Test scores were collected. Radiographs were analyzed preoperatively and postoperatively for humeral head decentering relative to the glenoid vault, immediate glenoid seating, and final glenoid peg radiolucency. RESULTS: Of the original cohort of 59 patients (6 now deceased) reported at a mean radiographic follow-up of 3.4 years, 34 shoulders in 33 patients with B2 glenoids (mean retroversion 18.9°, range 4°-32°) were available for follow-up at a mean of 8.6 years (range 5.5-11.2) after high-side glenoid reaming with aTSA. Three (5.1%) of the original 59 shoulder were revised. At final follow-up, 3 of 30 (10.0%) shoulders had radiographic glenoid component failure, but were unrevised. Glenoid component failure was associated with worse initial glenoid component seating (mean Lazarus score 1.2 vs. 2.0, P = .002). Glenoid failure was also associated with increased posterior humeral head subluxation at 2-4 year follow-up (mean 5.6% vs. 12.6%, P = .045) and at final follow-up (mean 7.0% vs. 21%, P = .002). There was no association between glenoid component failure and preoperative retroversion, inclination, or humeral head subluxation (all P > .05). Glenoid component failure was associated with worse American Shoulder and Elbow Surgeons (88 vs. 73) and visual analog scale pain (0.8 vs. 2.1) scores (both P = .03). CONCLUSIONS: At a mean of 8.6 years, 88% of shoulders available for follow-up had well-fixed glenoid components. Glenoid component failure was associated with poor initial glenoid component seating, with failed components having an average of 25% of the glenoid component not seated. Preoperative deformity such as glenoid retroversion, inclination, or humeral head subluxation did not predict glenoid component failure. This study supports that initial glenoid component seating and recurrence of posterior humeral head subluxation may be the most important factors for mid-term glenoid component survival in aTSA in patients with B2 glenoids.