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The human ataxia telangiectasia mutated and Rad3-related (ATR) kinase functions in the nucleus to protect genomic integrity. Micronuclei (MN) arise from genomic and chromosomal instability and cause aneuploidy and chromothripsis, but how MN are removed is poorly understood. Here, we show that ATR is active in MN and promotes their rupture in S phase by phosphorylating Lamin A/C at Ser395, which primes Ser392 for CDK1 phosphorylation and destabilizes the MN envelope. In cells harboring MN, ATR or CDK1 inhibition reduces MN rupture. Consequently, ATR inhibitor (ATRi) diminishes activation of the cytoplasmic DNA sensor cGAS and compromises cGAS-dependent autophagosome accumulation in MN and clearance of micronuclear DNA. Furthermore, ATRi reduces cGAS-mediated senescence and killing of MN-bearing cancer cells by natural killer cells. Thus, in addition to the canonical ATR signaling pathway, an ATR-CDK1-Lamin A/C axis promotes MN rupture to clear damaged DNA and cells, protecting the genome in cell populations through unexpected cell-autonomous and cell-non-autonomous mechanisms., Competing Interests: Declaration of interests L.Z. is a member of the advisory board of Molecular Cell., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The hypocretins/orexins (HCRT) have been demonstrated to influence motivation for cocaine through actions on dopamine (DA) transmission. Pharmacological or genetic disruption of the hypocretin receptor 1 (Hcrtr1) reduces cocaine self-administration, blocks reinstatement of cocaine seeking, and decreases conditioned place preference for cocaine. These effects are likely mediated through actions in the ventral tegmental area (VTA) and resulting alterations in DA transmission. For example, HCRT drives VTA DA neuron activity and enhances the effects of cocaine on DA transmission, while disrupting Hcrtr1 attenuates DA responses to cocaine. These findings have led to the perspective that HCRT exerts its effects through Hcrtr1 actions in VTA DA neurons. However, this assumption is complicated by the observation that Hcrtr1 are present on both DA and GABA neurons in the VTA and HCRT drives the activity of both neuronal populations. To address this issue, we selectively knocked down Hcrtr1 on either DA or GABA neurons in the VTA and examined alterations in DA transmission and cocaine self-administration in female and male rats. We found that Hcrtr1 knockdown in DA neurons decreased DA responses to cocaine, increased days to acquire cocaine self-administration, and reduced motivation for cocaine. Although, Hcrtr1 knockdown in GABA neurons enhanced DA responses to cocaine, this manipulation did not affect cocaine self-administration. These observations indicate that while Hcrtr1 on DA versus GABA neurons exert opposing effects on DA transmission, only Hcrtr1 on DA neurons affected acquisition or motivation for cocaine - suggesting a complex interplay between DA transmission and behavior.

Centromere protein A (CENP-A) defines centromere identity and nucleates kinetochore formation for mitotic chromosome segregation. Here, we show that ataxia telangiectasia and Rad3-related (ATR) kinase, a master regulator of the DNA damage response, protects CENP-A occupancy at interphase centromeres in a DNA damage-independent manner. In unperturbed cells, ATR localizes to promyelocytic leukemia nuclear bodies (PML NBs), which house the histone H3.3 chaperone DAXX (death domain-associated protein 6). We find that ATR inhibition reduces DAXX association with PML NBs, resulting in the DAXX-dependent loss of CENP-A and an aberrant increase in H3.3 at interphase centromeres. Additionally, we show that ATR-dependent phosphorylation within the C terminus of DAXX regulates CENP-A occupancy at centromeres and DAXX localization. Lastly, we demonstrate that acute ATR inhibition during interphase leads to kinetochore formation defects and an increased rate of lagging chromosomes. These findings highlight a mechanism by which ATR protects centromere identity and genome stability., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Chk1 is a member of the DNA damage response pathway, whose loss leads to replication stress and genome instability. Because of its protective role against lethal levels of DNA replication stress, Chk1 has been studied as a valuable and intriguing target for cancer therapy. However, one of the most prominent challenges with this strategy is development of resistance to Chk1 inhibitors, rendering the treatment ineffective. In their recent papers, Hunter and colleagues demonstrate multiple mechanisms by which Chk1 inhibitor resistance can arise in lymphomas. Specifically, this series of papers identify the relationship between dysfunction in NF-κB and the development of Chk1 inhibitor resistance through a loss of Chk1 activity in mouse models of lymphoma. They identify that cells lacking Chk1 activity can compensate for this loss through up-regulation of alternative pathways, such as PI3K/AKT. Finally, this work also identifies a novel role for Claspin, an important Chk1 activator, in female fertility and cancer development, furthering our understanding of how dysfunction in the Claspin/Chk1 signaling pathway affects disease states. These findings improve our understanding of drug resistance in cancer therapy, which has important implications for clinical use of Chk1 inhibitors., (© 2022 The Author(s).)

Context: Several heterozygous loss-of-function mutations in the calcium-sensing receptor gene (CASR) leading to elevated ionized serum calcium and familial hypocalciuric hypercalcemia 1 (FHH1) have been characterized. Few mutations are not pathogenic, and previous studies suggested that the Q459R mutation does not result in an FHH1 phenotype., Objective: We identified a family with a heterozygous CASR Q459R mutation and characterized their calcium homeostasis and the pathophysiological mechanisms of a homozygous and heterozygous Q459R mutation in vitro., Design: The index patient and her family had clinical, biochemical, and genetic analyses performed. In vitro functional characterization of homozygous and heterozygous (Q459R) mutations was conducted by determining CaSR cell-surface expression and inositol monophosphate (IP1) signaling in transiently transfected human embryonic kidney 293A (HEK293A) cells., Results: All 3 heterozygous carriers had mild asymptomatic hypercalcemia, hypocalciuria, and 2 had elevated serum parathyroid hormone (PTH). In vitro characterization in HEK293A cells revealed that CASR Q459R is a loss-of-function mutation with no impact on cell-surface expression. Cells with the homozygous Q459R genotype had significantly reduced calcium potency of IP1 signaling compared to wild type, whereas the heterozygous Q459R also had lower calcium potency albeit not significantly different from wild type., Conclusion: A loss-of-function Q459R mutation in CASR in a family caused FHH1 characterized by elevated ionized calcium and PTH and low calcium excretion. The marked presence of CaSR at the membrane and inhibition of IP1 signaling in vitro suggest that calcimimetics may be functional in patients with this mutation, which seems to be a mild loss-of-function mutation associated with autosomal dominant transmission of FHH1., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Post-traumatic stress disorder and cocaine use disorder are highly co-morbid psychiatric conditions. The onset of post-traumatic stress disorder generally occurs prior to the development of cocaine use disorder, and thus it appears that the development of post-traumatic stress disorder drives cocaine use vulnerability. We recently characterized a rat model of post-traumatic stress disorder with segregation of rats as susceptible and resilient based on anxiety-like behavior in the elevated plus maze and context avoidance. We paired this model with in vivo fast scan cyclic voltammetry in freely moving rats to test for differences in dopamine signaling in the nucleus accumbens core at baseline, in response to a single dose of cocaine, and in response to cocaine-paired cues. Further, we examined differences in the acquisition of cocaine self-administration across groups. Results indicate that susceptibility to traumatic stress is associated with alterations in phasic dopamine signaling architecture that increase the rate at which dopamine signals entrain to cocaine-associated cues and increase the magnitude of persistent cue-evoked dopamine signals following training. These changes in phasic dopamine signaling correspond with increases in the rate at which susceptible rats develop excessive cocaine-taking behavior. Together, our studies demonstrate that susceptibility to traumatic stress is associated with a cocaine use-vulnerable phenotype and suggests that differences in phasic dopamine signaling architecture may contribute to the process by which this vulnerability occurs.

We investigated the impact of native freshwater mussel assemblages (order Unionoida) on the abundance and composition of nitrogen-cycling genes in sediment of an upper Mississippi river habitat. We hypothesized that the genomic potential for ammonia and nitrite oxidation would be greater in the sediment with mussel assemblages, presumably due to mussel biodeposition products, namely ammonia and organic carbon. Regardless of the presence of mussels, upper Mississippi river sediment microbial communities had the largest genomic potential for nitrogen fixation followed by urea catabolism, nitrate metabolism, and nitrate assimilation, as evidenced by analysis of nitrogen cycling pathway abundances. However, genes encoding nitrate and nitrite redox reactions, narGHI and nxrAB, were the most abundant functional genes of the nitrogen cycling gene families. Using linear discriminant analysis (LDA), we found nitrification genes were the most important biomarkers for nitrogen cycling genomic potential when mussels were present, and this presented an opposing effect on the abundance of genes encoding nitric oxide reduction. The genes involved in nitrification that increased the most were amoA associated with comammox Nitrospira and nxr homologs associated with Nitrospira. On the other hand, the most distinctive biomarkers of microbial communities without mussels were norB and nrfA, as part of denitrification and dissimilatory nitrate reduction to ammonium pathways, respectively. Ultimately, this research demonstrates the impact of native mollusks on microbial nitrogen cycling in an aquatic agroecosystem., (© 2018 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd.)

Maintenance of an intact genome is essential for cellular and organismal homeostasis. The centromere is a specialized chromosomal locus required for faithful genome inheritance at each round of cell division. Human centromeres are composed of large tandem arrays of repetitive alpha-satellite DNA, which are often sites of aberrant rearrangements that may lead to chromosome fusions and genetic abnormalities. While the centromere has an essential role in chromosome segregation during mitosis, the long and repetitive nature of the highly identical repeats has greatly hindered in-depth genetic studies, and complete annotation of all human centromeres is still lacking. Here, we review our current understanding of human centromere genetics and epigenetics as well as recent investigations into the role of centromere DNA in disease, with a special focus on cancer, aging, and human immunodeficiency⁻centromeric instability⁻facial anomalies (ICF) syndrome. We also highlight the causes and consequences of genomic instability at these large repetitive arrays and describe the possible sources of centromere fragility. The novel connection between alpha-satellite DNA instability and human pathological conditions emphasizes the importance of obtaining a truly complete human genome assembly and accelerating our understanding of centromere repeats' role in physiology and beyond., Competing Interests: The authors declare no conflicts of interest.

Freshwater mussel assemblages of the Upper Mississippi River (UMR) sequester tons of ammonia- and urea-based biodeposits each day and aerate sediment through burrowing activities, thus creating a unique niche for nitrogen (N) cycling microorganisms. This study explored how mussels impact the abundance of N-cycling species with an emphasis on Candidatus Nitrospira inopinata, the first microorganism known to completely oxidize ammonia (comammox) to nitrate. This study used metagenomic shotgun sequencing of genomic DNA to compare nitrogen cycling species in sediment under a well-established mussel assemblage and in nearby sediment without mussels. Metagenomic reads were aligned to the prokaryotic RefSeq non-redundant protein database using BLASTx, taxonomic binning was performed using the weighted lowest common ancestor algorithm, and protein-coding genes were categorized by metabolic function using the SEED subsystem. Linear discriminant analysis (LDA) effect sizes were used to determine which metagenomes and metabolic features explained the most differences between the mussel habitat sediment and sediment without mussels. Of the N-cycling species deemed differentially abundant, Nitrospira moscoviensis and " Candidatus Nitrospira inopinata" were responsible for creating a distinctive N-cycling microbiome in the mussel habitat sediment. Further investigation revealed that comammox Nitrospira had a large metabolic potential to degrade mussel biodeposits, as evidenced the top ten percent of protein-coding genes including the cytochrome c-type biogenesis protein required for hydroxylamine oxidation, ammonia monooxygenase, and urea decomposition SEED subsystems. Genetic marker analysis of these two Nitrospira taxons suggested that N. moscoviensis was most impacted by diverse carbon metabolic processes while " Candidatus Nitrospira inopinata" was most distinguished by multidrug efflux proteins (AcrB), NiFe hydrogenase (HypF) used in hydrogen oxidation and sulfur reduction coupled reactions, and a heme chaperone (CcmE). Furthermore, our research suggests that comammox and NOB Nitrospira likely coexisted by utilizing mixotrophic metabolisms. For example, " Candidatus Nitrospira inopinata" had the largest potentials for ammonia oxidation, nitrite reduction with NirK, and hydrogen oxidation, while NOB Nitrospira had the greatest potential for nitrite oxidation, and nitrate reduction possibly coupled with formate oxidation. Overall, our results suggest that this mussel habitat sediment harbors a niche for NOB and comammox Nitrospira , and ultimately impacts N-cycling in backwaters of the UMR.

Introduction: We examined practice patterns and surgical indications in the management of common shoulder procedures by surgeons practicing at physician-owned facilities., Methods: This study was a retrospective analysis of 501 patients who underwent arthroscopic shoulder procedures performed by five surgeons in our practice at one of five facilities during an 18-month period. Two of the facilities were physician-owned, and three of the five surgeons were shareholders. Demographics, insurance status, symptom duration, time from injury/symptom onset to the decision to perform surgery (at which time surgical consent is obtained), and time to schedule surgery were studied to determine the influence of facility type and physician shareholder status., Results: Median duration of symptoms before surgery was significantly shorter in workers' compensation patients than in non-workers' compensation patients (47% less; P < 0.0001) and in men than in women (31% less; P < 0.001), but was not influenced by shareholder status or facility ownership (P > 0.05). Time between presentation and surgical consent was not influenced by facility ownership (P = 0.39) or shareholder status (P = 0.50). Time from consent to procedure was 13% faster in physician-owned facilities than in non-physician-owned facilities (P = 0.03) and 35% slower with shareholder physicians than with nonshareholder physicians (P < 0.0001)., Discussion: The role of physician investment in private healthcare facilities has caused considerable debate in the orthopaedic surgery field. To our knowledge, this study is the first to examine the effects of shareholder status and facility ownership on surgeons' practice patterns, surgical timing, and measures of nonsurgical treatment before shoulder surgery., Conclusions: Neither shareholder status nor facility ownership characteristics influenced the speed with which surgeons determined that shoulder surgery was indicated or surgeons' use of preoperative nonsurgical treatment. After the need for surgery was determined, patients underwent surgery sooner at physician-owned facilities than at non-physician-owned facilities and with nonshareholder physicians than with shareholder physicians., Level of Evidence: Level III.

Patients with post-traumatic stress disorder have a heightened vulnerability to developing substance use disorders; however, the biological underpinnings of this vulnerability remain unresolved. We used the predator odor stress model of post-traumatic stress disorder with segregation of subjects as susceptible or resilient based on elevated plus maze behavior and context avoidance. We then determined behavioral and neurochemical differences across susceptible, resilient, and control populations using a panel of behavioral and neurochemical assays. Susceptible subjects showed a significant increase in the motoric and dopaminergic effects of cocaine, and this corresponded with heightened motivation to self-administer cocaine. Resilient subjects did not show differences in the motoric effects of cocaine, in dopamine signaling in vivo, or in any measure of cocaine self-administration. Nonetheless, we found that these animals displayed elevations in both the dopamine release-promoting effects of cocaine and dopamine autoreceptor sensitivity ex vivo. Our results suggest that the experience of traumatic stress may produce alterations in dopamine systems that drive elevations in cocaine self-administration behavior in susceptible subjects, but may also produce both active and passive forms of resilience that function to prevent gross changes in cocaine's reinforcing efficacy in resilient subjects., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Targeted qPCR and non-targeted amplicon sequencing of 16S rRNA genes within sediment layers identified the anaerobic ammonium oxidation (anammox) niche and characterized microbial community changes attributable to freshwater mussels. Anammox bacteria were normally distributed (Shapiro-Wilk normality test, W -statistic =0.954, p  = 0.773) between 1 and 15 cm depth and were increased by a factor of 2.2 ( p  < 0.001) at 3 cm below the water-sediment interface when mussels were present. Amplicon sequencing of sediment at depths relevant to mussel burrowing (3 and 5 cm) showed that mussel presence reduced observed species richness ( p  = 0.005), Chao1 diversity ( p  = 0.005), and Shannon diversity ( p  < 0.001), with more pronounced decreases at 5 cm depth. A non-metric, multidimensional scaling model showed that intersample microbial species diversity varied as a function of mussel presence, indicating that sediment below mussels harbored distinct microbial communities. Mussel presence corresponded with a 4-fold decrease in a majority of operational taxonomic units (OTUs) classified in the phyla Gemmatimonadetes, Actinobacteria, Acidobacteria, Plantomycetes, Chloroflexi, Firmicutes, Crenarcheota, and Verrucomicrobia. 38 OTUs in the phylum Nitrospirae were differentially abundant ( p  < 0.001) with mussels, resulting in an overall increase from 25% to 35%. Nitrogen (N)-cycle OTUs significantly impacted by mussels belonged to anammmox genus Candidatus Brocadia, ammonium oxidizing bacteria family Nitrosomonadaceae, ammonium oxidizing archaea genus Candidatus Nitrososphaera, nitrite oxidizing bacteria in genus Nitrospira , and nitrate- and nitrite-dependent anaerobic methane oxidizing organisms in the archaeal family "ANME-2d" and bacterial phylum "NC10", respectively. Nitrosomonadaceae (0.9-fold ( p  < 0.001)) increased with mussels, while NC10 (2.1-fold ( p  < 0.001)), ANME-2d (1.8-fold ( p  < 0.001)), and Candidatus Nitrososphaera (1.5-fold ( p  < 0.001)) decreased with mussels. Co-occurrence of 2-fold increases in Candidatus Brocadia and Nitrospira in shallow sediments suggests that mussels may enhance microbial niches at the interface of oxic-anoxic conditions, presumably through biodeposition and burrowing. Furthermore, it is likely that the niches of Candidatus Nitrososphaera and nitrite- and nitrate-dependent anaerobic methane oxidizers were suppressed by mussel biodeposition and sediment aeration, as these phylotypes require low ammonium concentrations and anoxic conditions, respectively. As far as we know, this is the first study to characterize freshwater mussel impacts on microbial diversity and the vertical distribution of N-cycle microorganisms in upper Mississippi river sediment. These findings advance our understanding of ecosystem services provided by mussels and their impact on aquatic biogeochemical N-cycling., Competing Interests: The authors declare there are no competing interests.

Although the results of arthroscopic management of posterior labral pathology in young athletes have been reported extensively in the literature, the clinical outcomes in older patients are unknown. This retrospective review included patients older than 35 years who underwent arthroscopic posterior labral repair. Functional outcome scores were collected, and subgroup analyses were performed to evaluate the impact of patient-specific factors. Forty-three patients met the inclusion criteria; average follow-up was 36.9 months (range, 24-54 months). Mean patient age at the time of surgery was 40.9 years (range, 35-57 years). Average outcome scores at final follow-up were Quick Disabilities of the Arm, Shoulder and Hand Scale (QuickDASH), 19±22; Simple Shoulder Test (SST), 9.9±3; Western Ontario Shoulder Instability Index (WOSI), 601±546; and Single Assessment Numeric Evaluation (SANE), 79.6%±23.4%. No significant differences in outcomes were observed in patients with preoperative symptomatic instability, active workers' compensation claims, or traumatic injury (P>.05). The presence of intraoperatively definable chondral damage (Outerbridge grade III or higher) was associated with significantly worse final functional outcomes (QuickDASH: 29 vs 11.9, P=.03; SST: 8.5 vs 10.9, P=.02; WOSI: 875 vs 407, P=.01; and SANE: 70.6% vs 86%, P=.05). One patient (2%) experienced a minor postoperative complication, and 3 patients (7%) required subsequent procedures: 2 total shoulder arthroplasties and 1 revision labral repair. The results of arthroscopic posterior labral repair in patients older than 35 years were variable and worse than those previously reported in younger patients. The presence of chondral damage at the time of the index procedure was a negative predictive factor. [Orthopedics. 2017; 40(2):e305-e311.]., (Copyright 2016, SLACK Incorporated.)

The incidence of arthroscopic rotator cuff repair (RCR) continues to rise. Given the changing healthcare climate, it is becoming increasingly important to critically evaluate current practice and attempt to make modifications that decrease costs without compromising patient outcomes. We conducted a study of the costs associated with arthroscopic anchorless (transosseous [TO]) RCR and those associated with the more commonly performed anchor-based TO-equivalent (TOE) method to determine whether there are any cost savings with the TO-RCR method. Twenty-one consecutive patients who underwent arthroscopic TO-RCR were prospectively enrolled in the study and matched on tear size and concomitant procedures with patients who underwent arthroscopic TOE-RCR. The groups' implant costs and operative times were obtained and compared. Outcome measures, including scores on the VAS (visual analog scale) for pain, the SANE (Single Assessment Numeric Evaluation), and the SST (Simple Shoulder Test), recorded at 3, 6, and >12 months after surgery, were compared between the TO and TOE groups. Mean implant cost was $946.91 less for the TO group than the TOE group-a significant difference. Mean operative time was not significantly different between the TO and TOE groups. There was significant improvement on all outcomes measures (VAS, SANE, SST) at >12 months, and this improvement was not significantly different between the groups. Arthroscopic TO-RCR provides significant cost savings over TOE-RCR with no significant difference in operative time or short-term outcomes.

Background: Heterotopic ossification (HO) around shoulder arthroplasty is a frequent finding with unclear clinical relevance. This study evaluated the incidence, relevance, and predisposing factors of HO in the long head of the triceps tendon after reverse shoulder arthroplasty., Methods: Retrospective chart review was conducted to identify patients who had a reverse shoulder arthroplasty performed between 2008 and 2012. Patient demographics, implant types, and diagnoses were noted. Three fellowship-trained shoulder/elbow surgeons independently evaluated postoperative Grashey radiographs using a novel classification system., Results: Within a 164-patient cohort, the overall HO rate in the long head of the triceps tendon was 61.6%; 23.2% of osteophytes were considered impinging, 14.6% had notching, 14.0% were free-floating, and 3.0% appeared ankylosed. Although not statistically significant, revision surgery had a higher rate of HO (68.3%) compared with primary surgery (59.4%). There was no difference in HO rates between diagnoses or implant types. Male and female HO rates were 74.0% and 56.1%, respectively (P = .0304). Between patients with and without HO, forward elevation was 121° compared with 133° (P = .0087) and external rotation was 19° compared with 25° (P = .0266); however, HO size did not significantly affect motion., Conclusions: Using our novel classification scheme, HO was a common finding in this series. Men had a higher rate of HO formation, and HO formation was associated with worse postoperative motion. Further study is needed to fully characterize the clinical implications of HO involving the long head of the triceps tendon and to explore potential preventive measures., (Copyright © 2016 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Background: We investigated the cost savings associated with arthroscopic transosseous (anchorless) double-row rotator cuff repair compared with double-row anchored (transosseous-equivalent [TOE]) repair., Methods: All patients undergoing double-row arthroscopic rotator cuff repair from 2009 to 2012 by a single surgeon were eligible for inclusion. The study included 2 consecutive series of patients undergoing anchorless or TOE repair. Excluded from the study were revision repairs, subscapularis repairs, patients with poor tendon quality or excursion requiring medialized repair, and partial repairs. Rotator cuff implant costs (paid by the institution) and surgical times were compared between the 2 groups, controlling for rotator cuff tear size and additional procedures performed., Results: The study included 344 patients, 178 with TOE repairs and 166 with anchorless repairs. Average implant cost for TOE repairs was $1014.10 ($813.00 for small, $946.67 for medium, $1104.56 for large, and $1507.29 for massive tears). This was significantly more expensive compared with anchorless repairs, which averaged $678.05 ($659.75 for small, $671.39 for medium, $695.55 for large, and $716.00 for massive tears). Average total operative time in TOE and anchorless groups was not significantly different (99 vs. 98 minutes). There was larger (although not statistically significant) case time variation in the TOE group., Conclusions: Compared with TOE repair, anchorless rotator cuff repair provides substantial implant-related cost savings, with no significant differences in surgical time for medium and large rotator cuff tears. Case time for TOE repair varied more with extremes in tear size., (Copyright © 2016 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Background: Complication rates remain high after reverse total shoulder arthroplasty (RTSA). Salvage options after implant failure have not been well defined. This study examines the role of reimplantation and revision RTSA after failed RTSA, reporting outcomes and complications of this salvage technique., Methods: Sixteen patients underwent component revision and reimplantation after a prior failed RTSA from 2004 to 2011. Indications included baseplate failure (7 patients, 43.8%), instability (6 patients, 37.5%), infection (2 patients, 12.5%), and humeral loosening (1 patient, 6.3%). The average age of the patient during revision surgery was 68.6 years. Outcomes information at follow-up was recorded, including visual analog scale score for pain, subjective shoulder value, American Shoulder and Elbow Surgeons score, and Simple Shoulder Test score, and these were compared with pre-revision values. Repeated surgeries and complications were noted., Results: Average time to follow-up from revision was 58.9 months (minimum, 2 years; range, 24-103 months). The average postoperative visual analog scale score for pain was 1.7/10 (7.5/10 preoperatively; P < .0001), and the subjective shoulder value was 62% (17% preoperatively; P < .0001). The average postoperative American Shoulder and Elbow Surgeons score was 66.7, and the Simple Shoulder Test score was 52.6. Fourteen patients (88%) noted that they felt "better" postoperatively than before their original RTSA and would go through the procedure again if given the option. Nine patients suffered major complications (56%), and 6 of these ultimately underwent further procedures (38% of cohort)., Discussion: Salvage options after failure of RTSA remain limited. Component revision and reimplantation can effectively relieve pain and improve function compared with baseline values, and patient satisfaction levels are moderately high. However, complication rates and reoperation rates are significant., (Copyright © 2015 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

The goal of this study was to review the authors' initial experience with arthroscopic transosseous rotator cuff repair. Thirty-one patients with full-thickness rotator cuff tears underwent arthroscopic transosseous rotator cuff repair over a 15-month period. Preoperatively, demographics and subjective scores were recorded. Postoperatively, pain levels, subjective shoulder values, satisfaction scores, American Shoulder and Elbow Surgeons (ASES) scores, complications, and reoperations were noted with a minimum 2-year follow-up. The relationships between pre- and intraoperative variables and outcome scores were determined with univariate analysis. Average patient age was 56 years, and 23 patients (74%) were men. Twenty patients (65%) underwent primary rotator cuff repair, and 11 patients (35%) underwent revision repair. Average time to follow-up was 26 months. Average preoperative pain level and subjective shoulder value were 5.1 of 10 and 35%, respectively. Average postoperative scores included pain level of 0.9 of 10, subjective shoulder value of 84%, satisfaction score of 90.6 of 100, and ASES score of 86.3 of 100. There were 3 (9.7%) major and 2 (6%) minor complications. Patients undergoing revision rotator cuff repair had significantly worse outcomes (pain level, subjective shoulder value, ASES score; P<.05) compared with those undergoing primary repair, and cortical augmentation did not significantly affect outcome. Overall, outcomes after arthroscopic transosseous rotator cuff repair are good, although patients undergoing revision repair do not have the same outcomes as those undergoing primary cuff repair. The procedure is not without complications (9.7% major, 6% minor complications). Cortical augmentation may be used to supplement fixation, although it does not necessarily affect outcomes. Patients without such augmentation may be at increased risk for suture cutout through the bone., (Copyright 2015, SLACK Incorporated.)

Background: This study examined outcomes and complications in young patients undergoing revision reverse total shoulder arthroplasty (RTSA) for failed prior total shoulder arthroplasty or hemiarthroplasty and compared them with those of an age-matched cohort undergoing primary RTSA., Methods: RTSA as a revision for failed shoulder arthroplasty was performed on 36 patients younger than 65 years. Follow-up was available for 32 patients at an average of 55.3 months. Results were compared with those of an age-matched cohort of 37 patients (33 available for follow-up; average, 54.7 months) undergoing primary RTSA. Average age for both groups was 59.3 years. Outcomes were compared before and after revision surgery and between cohorts., Results: Preoperative visual analog scale (VAS) for pain and subjective shoulder value (SSV) scores were similar in both groups, 7.3 of 10 and 24%, respectively, before revision, and 7.0 of 10 and 19% before primary RTSA (P = .3). Postrevision VAS and SSV scores improved to 1.4 of 10 and 60% (P < .0001). Average American Shoulder and Elbow Surgeons and Simple Shoulder Test scores after revision were 69.7 and 58.8, with 9 complications (28.1%; 6 major and 3 minor). VAS and SSV scores improved to 2.1 of 10 and 76% after primary RTSA (P < .0001). American Shoulder and Elbow Surgeons and Simple Shoulder Test scores after primary RTSA were 74 and 67.3, with 6 complications (18.2%; 5 major and 1 minor). Only the postoperative SSV score was statistically different in comparing primary and revision RTSA (P < .05)., Conclusion: RTSA is effective in reducing pain and improving function after failed arthroplasty in young patients, but complication rates are high and expectations should be managed appropriately. Subjective outcome scores are worse than those for age-matched patients undergoing primary RTSA, but pain, functional scores, and complication rates are similar., (Copyright © 2014 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Mosby, Inc. All rights reserved.)

Background: Posterior injuries to the sternoclavicular (SC) joint are uncommon. In the skeletally immature (SI) population, these injuries have been described as either dislocations of the SC joint or fractures of the medial clavicular physis. The current literature and standardized test questions state that a posterior SC injury, in a SI patient, is more likely a physeal fracture than a SC joint dislocation. However, this injury characterization is based on case reports or small case series. The purpose of this study is to characterize posterior SC injuries in SI patients in terms of the prevalence of dislocation versus medial clavicle physeal fracture., Methods: A retrospective review was performed of 48 SI patients treated for posterior SC joint injuries over a 20-year period with a mean age of 15.4 years (range, 13 to 18 y). Forty patients underwent open reduction and internal fixation as their definitive treatment and 8 patients were treated exclusively with closed reduction. Patients treated operatively were utilized in determining the prevalence of SC joint dislocation versus physeal fracture., Results: All patients treated operatively underwent primary repair without reconstruction. Twenty (50%), of the 40 patients treated operatively had a true SC joint dislocation and 20 patients (50%) had a medial clavicle physeal fracture. Twenty-two (46%) of the 48 total patients had an attempted closed reduction of which only 8 (36%) were successful. Among the 14 unsuccessful closed reductions, 12 (86%) were true dislocations (P<0.001). All successful closed reductions occurred in patients within 24 hours from injury. Eleven of the 48 (23%) patients' injuries were missed on initial presentation., Conclusions: Posterior SC joint dislocation and medial clavicular physeal fracture both occur with roughly equivalent prevalence in patients with an open medial physis. An attempted closed reduction may be more successful if performed within 24 hours after injury. Patients who fail attempts at closed reduction are more likely to have a posterior SC joint dislocation than a physeal fracture. Posterior SC joint injury may be missed in nearly 25% of patients on initial presentation., Level of Evidence: Level IV-retrospective case series.

Background: Pathology of the shoulder contributes significantly to the increasing burden of musculoskeletal disease. Currently, there exists high variability in the nature and quality of shoulder care, and outcomes and cost reporting are not uniform. Value-based practice aims to simultaneously maximize outcomes and minimize costs for given disease processes., Methods: The current state of the shoulder care literature was examined with regards to cost and outcomes data, initiatives in streamlining care delivery, and evidence-based practice improvements. This was synthesized with value-based care theory to propose new avenues to improve shoulder care in the future., Conclusion: The treatment of shoulder disorders is ideal for the value-based model but has been slow to adopt its principles thus far. We can begin to advance value-based practices through (1) the universal reporting of outcomes and costs, (2) integrating shoulder care across provider specialties, and (3) critically analyzing data to formulate best practices., (Copyright © 2013 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Mosby, Inc. All rights reserved.)

Background: There is little research on the long-term outcomes of open carpal tunnel release. The purpose of this retrospective study was to determine the functional and symptomatic outcomes of patients at a minimum of ten years postoperatively., Methods: Two hundred and eleven patients underwent open carpal tunnel release from 1996 to 2000 performed by the same hand fellowship-trained surgeon. Follow-up with validated self-administered questionnaire instruments was conducted an average of thirteen years after surgery. The principal outcomes included the Levine-Katz symptom and function scores, ranging from 1 point (best) to 5 points (worst), and satisfaction with the results of surgery. The patients self-reported current comorbidities., Results: After a mean follow-up of thirteen years (range, eleven to seventeen years), 92% (194) of 211 patients were located. They included 140 who were still living and fifty-four who had died. Seventy-two percent (113) of the 157 located, surviving patients responded to the questionnaire. The mean Levine-Katz symptom score (and standard deviation) was 1.3 ± 0.5 points, and 13% of patients had a poor symptom score (≥2 points). The mean Levine-Katz function score was 1.6 ± 0.8 points, and 26% had a poor function score (≥2 points). The most common symptom-related complaint was weakness in the hand, followed by diurnal pain, numbness, and tingling. The least common symptoms were nocturnal pain and tenderness at the incision. Eighty-eight percent of the patients were either completely satisfied or very satisfied with the surgery. Seventy-four percent reported their symptoms to be completely resolved. Thirty-three percent of men were classified as having poor function compared with 23% of women. Two (1.8%) of 113 patients underwent repeat surgery., Conclusions: At an average of thirteen years after open carpal tunnel release, the majority of patients are satisfied and free of symptoms of carpal tunnel syndrome.

Background: There remains no consensus regarding the role of computed tomography (CT) scans in preoperative planning for malleolar ankle fractures. The aim of this study was to determine the role of preoperative CT scans on operative planning in these fractures., Methods: A retrospective analysis was performed on 100 consecutive patients treated at our institution for malleolar ankle fractures (AO type 44) with both preoperative radiographs and CT scans. Six study participants reviewed available radiographs and formulated an operative (or nonoperative) plan including positioning, operative approach, and fixation. Participants then analyzed CT scans of the same fractures, deciding whether (and how) they would alter operative strategy. Characteristics of fractures and radiographs were correlated with changes in operative strategy., Results: Operative strategy was notably changed in 24% of cases after CT review, with strong intraclass correlation (0.733). Common changes included alterations in medial malleolar (21%) or posterior malleolar (15%) fixation and fixation of an occult anterolateral plafond fracture (9%). Notable predictors of changes in operative strategy included trimalleolar over unimalleolar fractures (29% vs 10% rate of change), preoperative dislocation over no dislocation (31% vs 20%), the presence of only radiographs with overlying plaster versus fractures with at least 1 set of radiographs without plaster (25% vs 14%), and suprasyndesmotic versus trans- and infra-syndesmotic fractures (40% vs 20% and 4%, respectively)., Conclusions: CT scans may be useful adjuncts in preoperative planning for malleolar ankle fractures, most notably in fracture dislocations, cases in which all available radiographs are obscured by plaster, trimalleolar fractures, and suprasyndesmotic fractures., Level of Evidence: Level III, retrospective comparative study.

Vasospasm is a major cause of morbidity and mortality after aneurysmal subarachnoid hemorrhage (aSAH). Studies have shown a link between single-nucleotide polymorphisms (SNPs) in the endothelial nitric oxide synthase (eNOS) gene and the incidence of coronary spasm and aneurysms. Alterations in the eNOS T-786 SNP may lead to an increased risk of post-aSAH cerebral vasospasm. In this prospective clinical study, 77 aSAH patients provided genetic material and were followed for the occurrence of vasospasm. In multivariate logistic regression analysis, genotype was the only factor predictive of vasospasm. The odds ratio (OR) for symptomatic vasospasm in patients with one T allele was 3.3 (95% confidence interval (CI): 1.1 to 10.0, P=0.034) and 10.9 for TT. Patients with angiographic spasm were 3.6 times more likely to have a T allele (95% CI: 1.3 to 9.6, P=0.013; for TT: OR 12.6). Patients with severe vasospasm requiring endovascular therapy were more likely to have a T allele (OR 3.5, 95% CI: 1.3 to 9.5, P=0.016; for TT: OR 12.0). Patients with the T allele of the eNOS gene are more likely to have severe vasospasm. Presence of this genotype may allow the identification of individuals at high risk for post-aSAH vasospasm and lead to early treatment and improved outcome.

A rapid and sensitive reverse transcriptase-polymerase chain reaction (RT-PCR) assay incorporating TaqMan probes has been developed that can distinguish among the six established rabies and rabies-related virus genotypes. TaqMan probes were designed and validated against 106 rabies and rabies-related virus isolates, one isolate of the Australian bat Lyssaviruses (genotype 7), and 18 other non-rabies viruses important in the veterinary field. The N gene was used as the target for the probes as it is well conserved and has been intensively used to genotype rabies isolates. Additionally, it was found to contain regions specific to each genotype conducive to probe design. The RT-PCR assay described amplifies a portion of the nucleoprotein gene of all 107 rabies and rabies-related viruses, but none of the other viruses tested. Inclusion of TaqMan-genotype-specific probes in the RT-PCR assay permits rapid identification of the virus present. By combining RT-PCR with TaqMan genotyping probes suspect rabies virus isolates can be identified in a single closed tube system that prevents potential PCR-product carry over contamination.

On May 30, 1996, a sick Daubenton's bat (Myotis daubentonii) was recovered from the cellar of a public house in Newhaven, East Sussex. Its condition deteriorated rapidly, and it was euthanased and examined. Positive results, establishing the presence of a rabies or rabies-related virus in its brain, were obtained from the fluorescent antibody test, the rabies tissue culture isolation test, and a hemi-nested reverse-transcription PCR. The complete sequence of the nucleoprotein gene was determined and a phylogenetic analysis, based on the 470 nucleotide bases of the amino terminus of the nucleoprotein, established the genotype of the virus as European bat lyssavirus 2. Bat rabies had not previously been recorded in the UK but does occur in mainland Europe. A study of the back-trajectories of the wind on May 29 and 30, established that the infected bat possibly came from near the Franco-Swiss border.

A rapid and sensitive reverse transcriptase-polymerase chain reaction (RT-PCR) assay for the detection of classical rabies virus (genotype 1) and the rabies related European bat lyssaviruses (EBLs) (genotypes 5 and 6) was developed. When combined with specific oligonucleotide probes and a PCR-enzyme linked immunosorbent assay (PCR-ELISA), genotype 5 and 6 viruses can be distinguished from each other and from genotype 1 viruses. Ninety-two isolates from the six established genotypes of rabies and rabies-related viruses were screened by RT-PCR and PCR-ELISA to determine the specificity of the assays. All genotype 1, 5 and 6 viruses were detected by RT-PCR while none of the genotype 2, 3 and 4 viruses were detected. All the genotype 5 and 6 viruses were detected by the two PCR-ELISA probes when used in combination while none of the genotype 1-4 viruses were detected. When used individually, the PCR-ELISA probes also distinguished between the genotype 5 and 6 viruses. This new discriminatory test should allow the rapid genotyping of all lyssaviruses likely to be encountered in Europe and as such could provide useful epidemiological information in the event of an outbreak.

A method is described to assess RNA template quality by the incorporation of a ribosomal RNA (rRNA) internal (in tube) control into a standard rabies and rabies-related virus specific RT-PCR. Specific virus and rRNA templates were co-amplified in a duplex reaction from RNA extracts derived from 60 isolates representing all six of the established lyssavirus genotypes. To ensure a wide species applicability of this technique we demonstrated that the rRNA assay was capable of functioning using the cells or tissues of 14 different mammals. Parallel studies between the duplex and the unlinked lyssavirus assay demonstrated only a minor reduction in the sensitivity of the former test. The ribosomal and viral targets (unlike beta-actin RNA) were shown to have similar degradation kinetics making rRNA amplification a good control for viral target integrity. As a consequence, the use of this system would reduce the likelihood of obtaining false negative RT-PCR results from lyssavirus infected material.

The authors studied 44 outpatients with unipolar depression to determine the association among social support systems, life events, social adjustment, and depressive symptoms. Social support had a reasonably high correlation with outcome measures. Patients with high social support had significantly better scores than those with low social support on the Hamilton Rating Scale for Depression and the Social Adjustment Rating Scale Self-Report. These data corroborate the hypothesis that social support systems play a critical role in the ongoing functioning of a defined group of depressed patients.