Psychological Impact and Posttraumatic Stress Disorder Symptomatology After Ulnar Collateral Ligament Injuries in Baseball Players.

Background: Significant psychological impact and prevalence of posttraumatic stress disorder (PTSD) have been well documented in patients sustaining anterior cruciate ligament injury. Purpose: To examine PTSD symptomatology in baseball players after sustaining elbow ulnar collateral ligament (UCL) injury. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Male baseball players of various competition levels (high school through Minor League Baseball [MiLB]) who underwent surgery for a UCL injury between April 2019 and June 2022 participated in the study. Before surgery, patients completed the Impact of Event Scale-Revised (IES-R) to assess PTSD symptomatology. Subgroup analysis was conducted according to level of play and player position. Results: A total of 104 male baseball players with a mean age of 19.4 years (range, 15-29 years) were included in the study; 32 players (30.8%) were in high school, 65 (62.5%) were in college, and 7 (6.7%) were in MiLB. There were 64 (61.5%) pitchers, 18 (17.3%) position players, and 22 (21.2%) 2-way players (both pitching and playing on the field). A total of 30 (28.8%) patients scored high enough on the IES-R to support PTSD as a probable diagnosis, and another 22 patients (21.2%) scored high enough to support PTSD as a clinical concern. Nineteen patients (18.3%) had potentially severe PTSD. Only 4 players (3.8%) were completely asymptomatic. Subgroup analysis revealed college players as significantly more symptomatic than high school players (P = .02), and 2-way players were found to be significantly less susceptible to developing symptoms of PTSD compared with pitchers (P = .04). Conclusion: Nearly 30% of baseball players who sustained a UCL injury qualified for a probable diagnosis of PTSD based on the IES-R. Pitchers and college athletes were at increased risk for PTSD after UCL injury compared with 2-way players and high school athletes, respectively.

Molecular landscape of proliferative verrucous leukoplakia: a systematic review.

Proliferative verrucous leukoplakia (PVL) is a rare oral potentially malignant disorder characterised by multifocal origin and unpredictable long-term evolution to oral squamous cell carcinoma (OSCC) or oral verrucous carcinoma (OVC). Currently no predictive biomarkers are in clinical use. We aimed to explore the genomic profile of PVL. A total of 685 cases in 26 studies were included in this review. Genomic data were presented in 15% of studies and biomarker analysis was reported in 85% of studies. At first clinical presentation, PVL is characterised by a high loss of heterozygosity (LOH), similar to OSCC, and low copy number alterations (CNA). As these progress, more CNAs and mutations in CDKN2A and alterations to ELAVL1 expression are noted, but no TP53 mutations are identified. There is significantly lower LOH at 17p in early PVL compared with OSCC (p = 0.037). Deletions in chromosomal loci 17q12, 5q31.1 and amplifications in 7q11.2, 7q22 are shared between early lesions and OVC. PVL shows CNAs at 11q31. WNT signalling pathway genes (SUZ12, CTTN and FOLR3) are enriched in CN-altered regions. PVL stroma shows significantly lower α-SMA and higher CD34 expression than OVC and OSCC. The exact genomic landscape is currently unclear, and further studies are necessary to unravel this mystery.

Determining the True Incidence of Glenohumeral Instability Among Players in the National Football League: An Epidemiological Study of Non-Missed Time Shoulder Instability Injuries.

Background: Shoulder instability encompasses a spectrum of glenohumeral pathology ranging from subluxation to dislocation. While dislocation frequently leads to removal from play, athletes are often able to play through subluxation. Previous research on glenohumeral instability among athletes has largely focused on missed-time injuries, which has likely disproportionately excluded subluxation injuries and underestimated the overall incidence of shoulder instability. Purpose: To describe the epidemiology of shoulder instability injuries resulting in no missed time beyond the date of injury (non-missed time injuries) among athletes in the National Football League (NFL). Study Design: Descriptive epidemiology study. Methods: The NFL's electronic medical record was retrospectively reviewed to identify non-missed time shoulder instability injuries during the 2015 through 2019 seasons. For each injury, player age, player position, shoulder laterality, instability type, instability direction, injury timing, injury setting, and injury mechanism were recorded. For injuries that occurred during games, incidence rates were calculated based on time during the season as well as player position. The influence of player position on instability direction was also investigated. Results: Of the 546 shoulder instability injuries documented during the study period, 162 were non-missed time injuries. The majority of non-missed time injuries were subluxations (97.4%), occurred during games (70.7%), and resulted from a contact mechanism (91.2%). The overall incidence rate of game-related instability was 1.6 injuries per 100,000 player-plays and was highest during the postseason (3.5 per 100,000 player-plays). The greatest proportion of non-missed time injuries occurred in defensive secondary players (28.4%) and offensive linemen (19.8%), while kickers/punters and defensive secondary players had the highest game incidence rates (5.5 and 2.1 per 100,000 player-plays, respectively). In terms of direction, 54.3% of instability events were posterior, 31.9% anterior, 8.5% multidirectional, and 5.3% inferior. Instability events were most often anterior among linebackers and wide receivers (50% and 100%, respectively), while posterior instability was most common in defensive linemen (66.7%), defensive secondary players (58.6%), quarterbacks (100.0%), running backs (55.6%), and tight ends (75.0%). Conclusion: The majority of non-missed time shoulder instability injuries (97.4%) were subluxations, which were likely excluded from or underreported in previous shoulder instability studies due to the inherent difficulty of detecting and diagnosing shoulder subluxation.

Single-cell analysis reveals prognostic fibroblast subpopulations linked to molecular and immunological subtypes of lung cancer.

Fibroblasts are poorly characterised cells that variably impact tumour progression. Here, we use single cell RNA-sequencing, multiplexed immunohistochemistry and digital cytometry (CIBERSORTx) to identify and characterise three major fibroblast subpopulations in human non-small cell lung cancer: adventitial, alveolar and myofibroblasts. Alveolar and adventitial fibroblasts (enriched in control tissue samples) localise to discrete spatial niches in histologically normal lung tissue and indicate improved overall survival rates when present in lung adenocarcinomas (LUAD). Trajectory inference identifies three phases of control tissue fibroblast activation, leading to myofibroblast enrichment in tumour samples: initial upregulation of inflammatory cytokines, followed by stress-response signalling and ultimately increased expression of fibrillar collagens. Myofibroblasts correlate with poor overall survival rates in LUAD, associated with loss of epithelial differentiation, TP53 mutations, proximal molecular subtypes and myeloid cell recruitment. In squamous carcinomas myofibroblasts were not prognostic despite being transcriptomically equivalent. These findings have important implications for developing fibroblast-targeting strategies for cancer therapy.

The spatiotemporal dynamics of microglia across the human lifespan.

Microglia, the brain's resident macrophages, shape neural development and are key neuroimmune hubs in the pathological signatures of neurodevelopmental disorders. Despite the importance of microglia, their development has not been carefully examined in the human brain, and most of our knowledge derives from rodents. We aimed to address this gap in knowledge by establishing an extensive collection of 97 post-mortem tissues in order to enable quantitative, sex-matched, detailed analysis of microglia across the human lifespan. We identify the dynamics of these cells in the human telencephalon, describing waves in microglial density across gestation, infancy, and childhood, controlled by a balance of proliferation and apoptosis, which track key neurodevelopmental milestones. These profound changes in microglia are also observed in bulk RNA-seq and single-cell RNA-seq datasets. This study provides a detailed insight into the spatiotemporal dynamics of microglia across the human lifespan and serves as a foundation for elucidating how microglia contribute to shaping neurodevelopment in humans.

Evaluating Bone Loss in Anterior Shoulder Instability.

Anterior shoulder instability is a common orthopaedic condition that often involves damage to the bony architecture of the glenohumeral joint in addition to the capsulolabral complex. Patients with recurrent shoulder dislocations are at increased risk for glenohumeral bone loss, as each instability event leads to the accumulation of additional glenoid and/or humeral head bone defects. Depending on the degree of bone loss, successful treatment may need to address bony lesions in addition to injured soft-tissue structures. As such, a thorough understanding of methods for evaluating bone loss preoperatively, in terms of location, size, and significance, is essential. Although numerous imaging modalities can be used, three-dimensional imaging has proven particularly useful and is now an integral component of preoperative planning.

Return-to-Competition Criteria After Ulnar Collateral Ligament Reconstruction: A Systematic Review and Meta-analysis.

BACKGROUND: Injury to the ulnar collateral ligament of the elbow is common among overhead throwing athletes and can result in significant functional limitations. While surgical reconstruction offers high rates of return to competition, there are no validated or universally accepted guidelines for determining when an athlete can safely resume play. PURPOSE: To assess the existing scientific literature for return-to-competition criteria utilized after ulnar collateral ligament reconstruction. STUDY DESIGN: Systematic review and meta-analysis; Level of evidence, 4. METHODS: The PubMed database was searched for clinical investigations of ulnar collateral ligament reconstruction in overhead throwing athletes published between January 2000 and June 2020. Only studies that had a minimum follow-up of 1 year and included at least 1 specific return-to-competition criterion were considered. RESULTS: A total of 15 studies were included in the final analysis, encompassing 1156 patients with an average age of 20.7 years (SD, 2.0 years). Baseball players composed 96.3% of patients for whom sport was specified, and 92.4% of baseball players were pitchers. The most common return-to-competition criterion, identified in 87% of studies, was completion of a return-to-throwing program, which started on average 16.7 weeks (range, 12-18 weeks) after surgery. A return-to-mound program was utilized in 53% of studies, starting on average 7.4 months (range, 6-9 months) postoperatively. Minimum time from surgery was used in 73% studies, with players waiting 7 to 12 months (mean, 9.7; SD, 1.4 months) after surgery before return-to-competition consideration. The overall rate of return to competition at the preinjury level or higher was 85.7% (SD, 8.5%) at an average of 12.2 months (SD, 0.6 months). CONCLUSION: In general, we observed a paucity of literature describing the return-to-competition process after ulnar collateral ligament reconstruction in overhead throwing athletes. Only 3 explicit return-to-competition criteria were identified across all studies: completion of a return-to-throwing program, completion of a return-to-mound program for pitchers, and minimum time from surgery. Increased transparency regarding postoperative rehabilitation protocols and further research are necessary to identify and validate sport-specific return-to-competition criteria, which will ultimately help athletes return to play in a safe and timely fashion after ulnar collateral ligament reconstruction.

Using machine learning methods to predict nonhome discharge after elective total shoulder arthroplasty.

BACKGROUND: Machine learning has shown potential in accurately predicting outcomes after orthopedic surgery, thereby allowing for improved patient selection, risk stratification, and preoperative planning. This study sought to develop machine learning models to predict nonhome discharge after total shoulder arthroplasty (TSA). METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was queried for patients who underwent elective TSA from 2012 to 2018. Boosted decision tree and artificial neural networks (ANN) machine learning models were developed to predict non-home discharge and 30-day postoperative complications. Model performance was measured using the area under the receiver operating characteristic curve (AUC) and overall accuracy (%). Multivariate binary logistic regression analyses were used to identify variables that were significantly associated with the predicted outcomes. RESULTS: There were 21,544 elective TSA cases identified in the National Surgical Quality Improvement Program registry from 2012 to 2018 that met inclusion criteria. Multivariate logistic regression identified several variables associated with increased risk of nonhome discharge including female sex (odds ratio [OR] = 2.83; 95% confidence interval [CI] = 2.53-3.17; P < .001), age older than 70 years (OR = 3.19; 95% CI = 2.86-3.57; P < .001), American Society of Anesthesiologists classification 3 or greater (OR = 2.70; 95% CI = 2.41-2.03; P < .001), prolonged operative time (OR = 1.38; 95% CI = 1.20-1.58; P < .001), as well as history of diabetes (OR = 1.56; 95% CI = 1.38-1.75; P < .001), chronic obstructive pulmonary disease (OR = 1.71; 95% CI = 1.46-2.01; P < .001), congestive heart failure (OR = 2.65; 95% CI = 1.72-4.01; P < .001), hypertension (OR = 1.35; 95% CI = 1.20-1.52; P = .004), dialysis (OR = 3.58; 95% CI = 2.01-6.39; P = .002), wound infection (OR = 5.67; 95% CI = 3.46-9.29; P < .001), steroid use (OR = 1.43; 95% CI = 1.18-1.74; P = .010), and bleeding disorder (OR = 1.84; 95% CI = 1.45-2.34; P < .001). The boosted decision tree model for predicting nonhome discharge had an AUC of 0.788 and an overall accuracy of 90.3%. The ANN model for predicting nonhome discharge had an AUC of 0.851 and an overall accuracy of 89.9%. For predicting the occurrence of 1 or more postoperative complications, the boosted decision tree model had an AUC of 0.795 and an overall accuracy of 95.5%. The ANN model yielded an AUC of 0.788 and an overall accuracy of 92.5%. CONCLUSIONS: Both the boosted decision tree and ANN models performed well in predicting nonhome discharge with similar overall accuracy, but the ANN had higher discriminative ability. Based on the findings of this study, machine learning has the potential to accurately predict nonhome discharge after elective TSA. Surgeons can use such tools to guide patient expectations and to improve preoperative discharge planning, with the ultimate goal of decreasing hospital length of stay and improving cost-efficiency.

Dual dean entrainment with volume ratio modulation for efficient droplet co-encapsulation: extreme single-cell indexing.

The future of single cell diversity screens involves ever-larger sample sizes, dictating the need for higher throughput methods with low analytical noise to accurately describe the nature of the cellular system. Current approaches are limited by the Poisson statistic, requiring dilute cell suspensions and associated losses in throughput. In this contribution, we apply Dean entrainment to both cell and bead inputs, defining different volume packets to effect efficient co-encapsulation. Volume ratio scaling was explored to identify optimal conditions. This enabled the co-encapsulation of single cells with reporter beads at rates of ∼1 million cells per hour, while increasing assay signal-to-noise with cell multiplet rates of ∼2.5% and capturing ∼70% of cells. The method, called Pirouette coupling, extends our capacity to investigate biological systems.

Single-nucleotide Fcγ receptor polymorphisms do not impact obinutuzumab/rituximab outcome in patients with lymphoma.

Single-nucleotide polymorphisms (SNPs) have been shown to influence Fcγ receptor (FcγR) affinity and activity, but their effect on treatment response is unclear. We assessed their importance in the efficacy of obinutuzumab or rituximab combined with chemotherapy in untreated advanced follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) in the GALLIUM (www.clinicaltrials.gov #NCT01332968) and GOYA (#NCT01287741) trials, respectively. Genomic DNA was extracted from patients enrolled in GALLIUM (n = 1202) and GOYA (n = 1418). Key germline SNPs, FCGR2A R131H (rs1801274), FCGR3A F158V (rs396991), and FCGR2B I232T (rs1050501), were genotyped and assessed for their impact on investigator-assessed progression-free survival (PFS). In both cohorts there was no prognostic effect of FCGR2A or FCGR3A. In FL, FCGR2B was associated with favorable PFS in univariate and multivariate analyses comparing I232T with I232I, with a more modest association for rituximab-treated (univariate: hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.54-1.14; P = .21) vs obinutuzumab-treated patients (HR, 0.56; 95% CI, 0.34-0.91; P = .02). Comparing T232T with I232I, an association was found for obinutuzumab (univariate: HR, 2.76; 95% CI, 1.02-7.5; P = .0459). Neither observation retained significance after multiple-test adjustment. FCGR2B was associated with poorer PFS in multivariate analyses comparing T232T with I232I in rituximab- but not obinutuzumab-treated patients with DLBCL (HR, 4.40; 95% CI, 1.71-11.32; P = .002; multiple-test-adjusted P = .03); however, this genotype was rare (n = 13). This study shows that FcγR genotype is not associated with response to rituximab/obinutuzumab plus chemotherapy in treatment-naive patients with advanced FL or DLBCL.

Genomic Analysis of Response to Neoadjuvant Chemotherapy in Esophageal Adenocarcinoma.

Neoadjuvant therapy followed by surgery is the standard of care for locally advanced esophageal adenocarcinoma (EAC). Unfortunately, response to neoadjuvant chemotherapy (NAC) is poor (20-37%), as is the overall survival benefit at five years (9%). The EAC genome is complex and heterogeneous between patients, and it is not yet understood whether specific mutational patterns may result in chemotherapy sensitivity or resistance. To identify associations between genomic events and response to NAC in EAC, a comparative genomic analysis was performed in 65 patients with extensive clinical and pathological annotation using whole-genome sequencing (WGS). We defined response using Mandard Tumor Regression Grade (TRG), with responders classified as TRG1-2 (n = 27) and non-responders classified as TRG4-5 (n =38). We report a higher non-synonymous mutation burden in responders (median 2.08/Mb vs. 1.70/Mb, p = 0.036) and elevated copy number variation in non-responders (282 vs. 136/patient, p < 0.001). We identified copy number variants unique to each group in our cohort, with cell cycle (CDKN2A, CCND1), c-Myc (MYC), RTK/PIK3 (KRAS, EGFR) and gastrointestinal differentiation (GATA6) pathway genes being specifically altered in non-responders. Of note, NAV3 mutations were exclusively present in the non-responder group with a frequency of 22%. Thus, lower mutation burden, higher chromosomal instability and specific copy number alterations are associated with resistance to NAC.

Epidemiology of Shoulder Instability in the National Football League.

BACKGROUND: Shoulder instability is a common and potentially debilitating injury among collision sport athletes that can lead to long-term damage of the glenohumeral joint. Limited data exist regarding instability among elite athletes in the National Football League (NFL). PURPOSE: To describe the epidemiology of shoulder instability in the NFL from 2012 through 2017. STUDY DESIGN: Descriptive epidemiology study. METHODS: The NFL's injury database was reviewed for shoulder instability injuries resulting in missed time during the study inclusion dates. Injuries were classified by type and direction, as well as timing, setting, and mechanism. Median missed time was determined for the different types and directions of instability. Incidence rates for game-related injuries were calculated based on timing during the season and player position. Finally, the relationship between player position and instability direction was assessed. RESULTS: During the 6-year study period, 355 players sustained 403 missed-time shoulder instability injuries. Most injuries occurred during games (65%) via a contact mechanism (85%). The overall incidence rate of game-related instability was 3.6 injuries per 100,000 player-plays and was highest during the preseason (4.9 per 100,000 player-plays). The defensive secondary position accounted for the most injuries, but quarterbacks had the highest incidence rate in games (5.5 per 100,000 player-plays). Excluding unspecified events (n = 128; 32%), 70% (n = 192) of injuries were subluxations and 30% (n = 83) were dislocations; 75% of dislocations were anterior, while subluxations were more evenly distributed between the anterior and posterior directions (45% vs 52%, respectively). Players missed substantially more time after dislocation compared with subluxation (median, 47 days vs 13 days, respectively). When instability direction was known, the majority of instability events among quarterbacks and offensive linemen were posterior (73% and 53%, respectively), while anterior instability was most common for all other positions. CONCLUSION: Shoulder instability is a common injury in the NFL and can result in considerable missed time. Dislocations occur less frequently than subluxations but lead to greater time lost. While most dislocations are anterior, more than half of subluxations are posterior, which is likely the result of repetitive microtrauma to the posterior capsulolabral complex sustained during sport-specific motions such as blocking. The risk of instability varies by player position, and position may also influence instability direction.

Debate Update: Surgery After 48 Hours of Admission for Geriatric Hip Fracture Patients Is Associated With Increase in Mortality and Complication Rate: A Study of 27,058 Patients Using the National Trauma Data Bank.

OBJECTIVE: To determine the association between surgical timing and short-term morbidity and mortality in elderly patients who sustain hip fractures using a national trauma database (OTA/AO 31A1-3, 31B1-3). DESIGN: Retrospective cohort study. SETTING: Level I-IV trauma centers in the United States. PATIENTS/PARTICIPANTS: All patients ≥65 years of age who underwent surgery for hip fracture from 2011 to 2013. INTERVENTION: Time to surgery of <24, 24-48, and >48 hours from admission. MAIN OUTCOME MEASUREMENTS: Primary outcome was mortality by hospital discharge. Secondary outcomes were complications of myocardial infarction, cardiac arrest, acute respiratory distress syndrome (ARDS), unplanned reintubation, pneumonia, stroke, severe sepsis, and intensive care unit length of stay. RESULTS: Twenty-seven thousand fifty-eight patients were included in the study. Relative to the <24 hours cohort, patients in the >48 hours cohort were at increased risk for mortality (OR 1.89, 95% CI 1.52-2.33, P < 0.001), ARDS (OR 2.57, 95% CI 1.94-3.39, P < 0.001 for ARDS), myocardial infarction (OR 2.19, 95% CI 1.64-2.94, P < 0.0001), pneumonia (OR 2.04, 95% CI 1.71-2.44, P < 0.001), severe sepsis (OR 2.34, 95% CI 1.52-3.58, P = 0.003), and intensive care unit stay (OR 2.48, 95% CI 2.25-2.74, P < 0.0001). A subgroup analysis showed that healthier patients (modified Charlson Comorbidity Index less than 5) who had surgery >48 hours were not at increased risk of mortality. CONCLUSIONS: For elderly patients with hip fractures, delaying surgery for more than 48 hours may be associated with increased short-term morbidity and mortality. This association may be pronounced for patients with more medical comorbidities. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Cognitive Training in Orthopaedic Surgery.

INTRODUCTION: Over the past two decades, various factors have led to fewer opportunities for hands-on learning in the operating room among orthopaedic surgery trainees. Innovative training platforms using anatomic models, cadaveric specimens, and augmented reality have been devised to address this deficiency in surgical training, but such training tools are often costly with limited accessibility. Cognitive training is a low-cost training technique that improves physical performance by refining the way in which information is mentally processed and has long been used by professional athletes and world-class musicians. More recently, cognitive training tools have been developed for several orthopaedic surgery procedures, but the overall utility of cognitive training in orthopaedic surgery remains unknown. METHODS: The purpose of this study was to review the existing literature regarding the use of cognitive training in orthopaedic surgery and to summarize the results of investigations comparing cognitive training tools with other methods of learning. To that effect, the PubMed and Embase databases were systematically reviewed for articles related to cognitive training in orthopaedic surgery. RESULTS: Eleven publications met the inclusion criteria, including six randomized controlled trials. Cognitive task analysis and mental rehearsal were the most common forms of cognitive training identified. All 11 publications supported the use of cognitive training in orthopaedic surgery training. In the six randomized controlled trials, the utilization of cognitive training was associated with notably improved surgical performance and increased knowledge compared with traditional methods of learning. DISCUSSION: Based on the limited evidence presented in this review, cognitive training represents a promising, low-cost adjunct to traditional orthopaedic surgery training. Further efforts should be directed at developing and evaluating additional cognitive training tools for orthopaedic surgery trainees.

Recent trends in Medicare utilization and surgeon reimbursement for shoulder arthroplasty.

BACKGROUND: Recent efforts to contain health care costs and move toward value-based health care have intensified, with a continued focus on Medicare expenditures, especially for high-volume procedures. As total shoulder arthroplasty (TSA) volume continues to increase, especially within the Medicare population, it is important for orthopedic surgeons to understand recent trends in the allocation of health care expenditures and potential effects on reimbursements. The purpose of this study was to evaluate trends in annual Medicare utilization and provider reimbursement rates for shoulder arthroplasty procedures between 2012 and 2017. METHODS: This study tracked annual Medicare claims and payments to shoulder arthroplasty surgeons via publicly available databases and aggregated data at the county level. Descriptive statistics were used to evaluate trends in procedure volume, utilization rate (per 10,000 Medicare beneficiaries), and reimbursement rate. We used adjusted multiple linear regression models to examine associations between county-specific variables (ie, urban or rural, average household income, poverty rate, percentage Medicare population, and race and ethnicity demographics) and procedure volume, utilization rate, and reimbursement rate. RESULTS: Between 2012 and 2017, there was an 81.3% increase in primary TSA volume and 55.5% increase in primary TSA utilization. The Midwest and South had higher utilization rates than the Northeast and West (P < .001). TSA utilization rates in metropolitan areas were significantly higher than in rural areas (P < .001). Utilization rates for primary TSA procedures also had a significant negative association with poverty rate (P < .001). Regarding reimbursements, the Medicare payment per TSA case decreased from 2012 to 2017, with overall inflation-adjusted decreases of 7.1% and 11.8% for primary and revision cases, respectively. TSAs performed in metropolitan areas received significantly higher reimbursements per case than TSAs performed in rural areas ($1108.05 and $1066.40, respectively; P = .002). Furthermore, reimbursements per case were on average higher in the Northeast and West than in the South and Midwest (P < .001). CONCLUSIONS: Our study confirms that although TSA volume and per capita utilization have increased dramatically since 2012, Medicare Part B reimbursements to surgeons have continued to fall even after the adoption of bundled-payment models for orthopedic procedures. Cost-containment efforts continue to focus on Medicare reimbursements to surgeons, although other expenditures such as hospital payments and operational and implant costs must also be evaluated as part of an overall transition to value-based health care.

Trends in total shoulder arthroplasty from 2005 to 2018: lower complications rates and shorter lengths of stay despite patients with more comorbidities.

BACKGROUND: Total shoulder arthroplasty (TSA) is an increasingly common procedure. This study looked at trends in TSA using a nationwide registry, with a focus on patient demographics, comorbidities, and complications. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was queried for patients who underwent TSA from 2005 to 2018. Cohorts were created based on year of surgery: 2005-2010 (N = 1116), 2011-2014 (N = 5920), and 2015-2018 (N = 16,717). Patient demographics, comorbidities, operative time, hospital length of stay, discharge location, and complications within 30 days of surgery were compared between cohorts using bivariate and multivariate analysis. RESULTS: Bivariate analysis revealed significantly more comorbidities among patients in the 2015-2018 cohort compared with the 2005-2010 cohort, specifically American Society of Anesthesiologist class III or IV (57.0% vs. 44.3%, P < .001), morbid obesity (10.8% vs. 7.8%, P < .001), diabetes (17.8% vs. 12.1%, P < .001), and chronic obstructive pulmonary disease (6.7% vs. 4.1%, P = .003). The use of regional anesthesia has decreased (5.6% in 2005-2010 vs. 2.8% in 2015-2018, P < .001), as has operative time (▵: -16 minutes, P < .001) and length of stay (▵: -0.6 days, P < .001). There were also significant decreased rates of perioperative blood transfusion (OR [odds ratio], 0.46), non-home discharge (OR, 0.79), urinary tract infection (OR, 0.47), and sepsis (OR, 0.17), (P < .001 for all comparisons) between the 2005-2010 and 2015-2018 cohorts. CONCLUSIONS: Between 2005 and 2018, patients undergoing TSA had increasingly more comorbidities but experienced lower rates of short-term complications, in the context of shorter hospitalizations and more frequent discharge to home.

p53 is regulated by aerobic glycolysis in cancer cells by the CtBP family of NADH-dependent transcriptional regulators.

High rates of glycolysis in cancer cells are a well-established characteristic of many human tumors, providing rapidly proliferating cancer cells with metabolites that can be used as precursors for anabolic pathways. Maintenance of high glycolytic rates depends on the lactate dehydrogenase-catalyzed regeneration of NAD+ from GAPDH-generated NADH because an increased NADH:NAD+ ratio inhibits GAPDH. Here, using human breast cancer cell models, we identified a pathway in which changes in the extramitochondrial-free NADH:NAD+ ratio signaled through the CtBP family of NADH-sensitive transcriptional regulators to control the abundance and activity of p53. NADH-free forms of CtBPs cooperated with the p53-binding partner HDM2 to suppress p53 function, and loss of these forms in highly glycolytic cells resulted in p53 accumulation. We propose that this pathway represents a "glycolytic stress response" in which the initiation of a protective p53 response by an increased NADH:NAD+ ratio enables cells to avoid cellular damage caused by mismatches between metabolic supply and demand.

Clinical significance of TP53, BIRC3, ATM and MAPK-ERK genes in chronic lymphocytic leukaemia: data from the randomised UK LRF CLL4 trial.

Despite advances in chronic lymphocytic leukaemia (CLL) treatment, globally chemotherapy remains a central treatment modality, with chemotherapy trials representing an invaluable resource to explore disease-related/genetic features contributing to long-term outcomes. In 499 LRF CLL4 cases, a trial with >12 years follow-up, we employed targeted resequencing of 22 genes, identifying 623 mutations. After background mutation rate correction, 11/22 genes were recurrently mutated at frequencies between 3.6% (NFKBIE) and 24% (SF3B1). Mutations beyond Sanger resolution (<12% VAF) were observed in all genes, with KRAS mutations principally composed of these low VAF variants. Firstly, employing orthogonal approaches to confirm <12% VAF TP53 mutations, we assessed the clinical impact of TP53 clonal architecture. Whilst ≥ 12% VAF TP53mut cases were associated with reduced PFS and OS, we could not demonstrate a difference between <12% VAF TP53 mutations and either wild type or ≥12% VAF TP53mut cases. Secondly, we identified biallelic BIRC3 lesions (mutation and deletion) as an independent marker of inferior PFS and OS. Finally, we observed that mutated MAPK-ERK genes were independent markers of poor OS in multivariate survival analysis. In conclusion, our study supports using targeted resequencing of expanded gene panels to elucidate the prognostic impact of gene mutations.

Single-cell analysis based dissection of clonality in myelofibrosis.

Cancer development is an evolutionary genomic process with parallels to Darwinian selection. It requires acquisition of multiple somatic mutations that collectively cause a malignant phenotype and continuous clonal evolution is often linked to tumor progression. Here, we show the clonal evolution structure in 15 myelofibrosis (MF) patients while receiving treatment with JAK inhibitors (mean follow-up 3.9 years). Whole-exome sequencing at multiple time points reveal acquisition of somatic mutations and copy number aberrations over time. While JAK inhibition therapy does not seem to create a clear evolutionary bottleneck, we observe a more complex clonal architecture over time, and appearance of unrelated clones. Disease progression associates with increased genetic heterogeneity and gain of RAS/RTK pathway mutations. Clonal diversity results in clone-specific expansion within different myeloid cell lineages. Single-cell genotyping of circulating CD34 + progenitor cells allows the reconstruction of MF phylogeny demonstrating loss of heterozygosity and parallel evolution as recurrent events.