Super-enhancer interactomes from single cells link clustering and transcription.

Regulation of gene expression hinges on the interplay between enhancers and promoters, traditionally explored through pairwise analyses. Recent advancements in mapping genome folding, like GAM, SPRITE, and multi-contact Hi-C, have uncovered multi-way interactions among super-enhancers (SEs), spanning megabases, yet have not measured their frequency in single cells or the relationship between clustering and transcription. To close this gap, here we used multiplexed imaging to map the 3D positions of 376 SEs across thousands of mammalian nuclei. Notably, our single-cell images reveal that while SE-SE contacts are rare, SEs often form looser associations we termed "communities". These communities, averaging 4-5 SEs, assemble cooperatively under the combined effects of genomic tethers, Pol2 clustering, and nuclear compartmentalization. Larger communities are associated with more frequent and larger transcriptional bursts. Our work provides insights about the SE interactome in single cells that challenge existing hypotheses on SE clustering in the context of transcriptional regulation.

Socioeconomic Factors Including Patient Income, Education Level, and Health Insurance Influence Postoperative Secondary Surgery and Hospitalization Rates Following Hip Arthroscopy.

PURPOSE: To evaluate a large cross-sectional sample of patients utilizing administrative database records and analyze the effects of income, insurance type, and education level on outcomes after hip arthroscopy, including 2-year revision surgery, conversion to total hip arthroplasty (THA), and 90-day hospitalizations. METHODS: Current Procedural Terminology codes were used to query the PearlDiver Mariner database from October 2015 to January 2020 for patients undergoing hip arthroscopy with a minimum 2-year follow-up. Patients were categorized by mean family income in their zip code of residence (MFIR), health insurance type, and educational attainment in their zip code of residence (EAR). Two-year revision arthroscopy, conversion to THA, and 90-day hospital readmissions or emergency department (ED) visits were analyzed along socioeconomic strata. RESULTS: Multivariate analysis of 33,326 patients revealed that patients with MFIR between $30,000 and $70,000 had lower odds of 2-year revision arthroscopy (odds ratio [OR], 0.63; P < .001), THA conversion (OR, 0.76; P = .050), and 90-day readmission (OR, 0.53; P = .007) compared to MFIR >$100,000. Compared to patients with commercial insurance, patients with Medicare had lower odds of revision arthroscopy (OR, 0.60; P = .035) and THA conversion (OR, 0.46, P < .001) but greater odds of 90-day readmission (OR, 1.74; P = .007). Patients with Medicaid had higher odds of 90-day ED visits (OR, 1.84; P < .001). Patients with low EAR had higher odds of revision arthroscopy (OR, 1.42; P = .005) and THA conversion (OR, 1.58; P = .002) compared to those with high EAR. CONCLUSIONS: Following hip arthroscopy, patients residing in areas with lower mean family income were less likely to undergo reoperations and readmissions. Medicare patients showed lower reoperation but higher readmission odds, while Medicaid patients showed higher odds of ED visits. Additionally, higher educational attainment in the zip code of residence is protective against future reoperation. LEVEL OF EVIDENCE: Level III, retrospective case series.

Assessment of Risk Factors and Rate of Conversion to Total Hip Arthroplasty Within 2 Years After Hip Arthroscopy Utilizing a Large Database of Commercially Insured Patients in the United States.

Background: The conversion rate of hip arthroscopy (HA) to total hip arthroplasty (THA) has been reported to be as high as 10%. Despite identifying factors that increase the risk of conversion, current studies do not stratify patients by type of arthroscopic procedure. Purpose/Hypothesis: To analyze the rate and predictors of conversion to THA within 2 years after HA. It was hypothesized that osteoarthritis (OA) and increased patient age would negatively affect the survivorship of HA. Study Design: Cohort study; Evidence level, 3. Methods: The IBM MarketScan database was utilized to identify patients who underwent HA and converted to THA within 2 years at inpatient and outpatient facilities between 2013 and 2017. Patients were split into 3 procedure cohorts as follows: (1) femoroacetabular osteoplasty (FAO), which included treatment for femoroacetabular impingement; (2) isolated debridement; and (3) isolated labral repair. Cohort characteristics were compared using standardized differences. Conversion rates between the 3 cohorts were compared using chi-square tests. The relationship between age and conversion was assessed using linear regression. Predictors of conversion were analyzed using multivariable logistic regression. The median time to conversion was estimated using Kaplan-Meier tests. Results: A total of 5048 patients were identified, and the rates of conversion to THA were 12.86% for isolated debridement, 8.67% for isolated labral repair, and 6.76% for FAO (standardized difference, 0.138). The isolated labral repair cohort had the shortest median time to conversion (isolated labral repair, 10.88 months; isolated debridement, 10.98 months; and FAO, 11.9 months [P = .034). For patients >50 years, isolated debridement had the highest rate of conversion at 18.8%. The conversion rate increased linearly with age. Factors that increased the odds of conversion to THA were OA, having an isolated debridement procedure, and older patient age (P < .05). Conclusion: Older patients and those with preexisting OA of the hip were at a significantly increased risk of failing HA and requiring a total hip replacement within 2 years of the index procedure. Younger patients were at low risk of requiring a conversion procedure no matter which arthroscopic procedure was performed.

Increased rate of out-of-network surgeon selection for hip arthroscopy compared to more common orthopedic sports procedures.

Background: Demand for hip arthroscopy (HA) has increased, but shortfalls in HA training may create disparities in care access. This analysis aimed to (1) compare out-of-network (OON) surgeon utilization for HA with that of more common orthopedics sports procedures, including rotator cuff repair (RCR), partial meniscectomy (PM), and anterior cruciate ligament reconstruction (ACLR), (2) compare the HA OON surgeon rate with another less commonly performed procedure, meniscus allograft transplant (MAT), and (3) analyze trends and predictors of OON surgeon utilization. Methods: The 2013-2017 IBM MarketScan database identified patients under 65 who underwent HA, RCR, PM, ACLR, or MAT. Demographic differences were determined using standardized differences. Cochran-Armitage tests analyzed trends in OON surgeon utilization. Multivariable logistic regression identified predictors of OON surgeon utilization. Statistical significance was set to p < 0.05 and significant standardized differences were >0.1. Results: 410,487 patients were identified, of which 12,636 patients underwent HA, 87,607 RCR, 233,241 PM, 76,700 ACLR, and 303 MAT. OON surgeon utilization increased for HA, rising from 7.98 % in 2013 to 9.37 % in 2017 (p = 0.026). Compared to RCR, PM, and ACLR, HA was associated with higher likelihood of OON surgeon utilization. Usage of ambulatory surgery centers (ASCs) was predictive of higher OON surgeon rates along with procedure year, insurance plan type, and geographic region. HA performed in an ASC was 13 % less likely to have an OON surgeon (p = 0.047). Conclusion: OON surgeon utilization generally declined but increased for HA. HA was a predictor of OON surgeon status, possibly because HA is a technically complicated procedure with fewer trained in-network providers. Other predictors of OON surgeon status included ASC usage, PPO/EPO plan type, and Northeast geographic region. There is a need to improve access to experienced HA providers-perhaps with prioritization of HA training in residency and fellowship programs-in order to address rising OON surgeon utilization.

The 50 most-cited articles in reverse shoulder arthroplasty.

Background: Citation analyses have been used to understand the impact that a group of publications has on its field. As the techniques and indications of reverse total shoulder arthroplasty (RTSA) continue to expand, it is important to identify articles that can orient readers to the history, evolution, and current status of the body of RTSA literature. The purpose of this study was to identify and analyze the 50 most-cited articles related to RTSA. Methods: Various Boolean queries were searched on the Clarivate Analytics Web of Science. Information collected included author name, publication year, country of origin, journal name, article type, total number of citations, and level of evidence. Results: Top 50 most-cited articles amassed a total of 10,521 citations. The most-cited article was cited a total of 766 times. The most common study designs were case series (28) and cohort studies (9). Authors from the United States (24) contributed the most to included papers, followed by France (19) and Switzerland (8). Discussion: The most-cited articles on RTSA are expert opinions, case studies, and cohort studies published by American authors. As RTSA continues to grow over the next decade, studies with higher levels-of-evidence may overtake articles included in this analysis.

Transcription factor stoichiometry, motif affinity and syntax regulate single-cell chromatin dynamics during fibroblast reprogramming to pluripotency.

Ectopic expression of OCT4, SOX2, KLF4 and MYC (OSKM) transforms differentiated cells into induced pluripotent stem cells. To refine our mechanistic understanding of reprogramming, especially during the early stages, we profiled chromatin accessibility and gene expression at single-cell resolution across a densely sampled time course of human fibroblast reprogramming. Using neural networks that map DNA sequence to ATAC-seq profiles at base-resolution, we annotated cell-state-specific predictive transcription factor (TF) motif syntax in regulatory elements, inferred affinity- and concentration-dependent dynamics of Tn5-bias corrected TF footprints, linked peaks to putative target genes, and elucidated rewiring of TF-to-gene cis-regulatory networks. Our models reveal that early in reprogramming, OSK, at supraphysiological concentrations, rapidly open transient regulatory elements by occupying non-canonical low-affinity binding sites. As OSK concentration falls, the accessibility of these transient elements decays as a function of motif affinity. We find that these OSK-dependent transient elements sequester the somatic TF AP-1. This redistribution is strongly associated with the silencing of fibroblast-specific genes within individual nuclei. Together, our integrated single-cell resource and models reveal insights into the cis-regulatory code of reprogramming at unprecedented resolution, connect TF stoichiometry and motif syntax to diversification of cell fate trajectories, and provide new perspectives on the dynamics and role of transient regulatory elements in somatic silencing.

Impact of tobacco usage on readmission and complication rates following shoulder replacement surgery: A study of 164,527 patients.

Background: Tobacco carcinogens have adverse effects on bone health and are associated with inferior outcomes following orthopedic procedures. The purpose of this study was to assess the impact tobacco use has on readmission and complication rates following shoulder arthroplasty. Methods: The 2016-2018 National Readmissions Database was queried to identify patients who underwent anatomical, reverse, and hemi-shoulder arthroplasty. ICD-10 codes Z72.0 × (tobacco use disorder) and F17.2 × (nicotine dependence) were used to define "tobacco-users." Demographic, 30-/90-day readmission, surgical complication, and medical complication data were collected. Inferential statistics were used to analyze complications for both the cohort as a whole and for each procedure separately (i.e. anatomical, reverse, and hemiarthroplasty). Results: 164,527 patients were identified (92% nontobacco users). Tobacco users necessitated replacement seven years sooner than nonusers (p < 0.01) and were more likely to be male (52% vs. 43%; p < 0.01). Univariate analysis showed that tobacco users had higher rates of readmission, revisions, shoulder complications, and medical complications overall. In the multivariate analysis for the entire cohort, readmission, revision, and complication rates did not differ based on tobacco usage; however, smokers who underwent reverse shoulder arthroplasty in particular were found to have higher 90-day readmission, dislocation, and prosthetic complication rates compared to nonsmokers. Conclusion: Comparatively, tobacco users required surgical correction earlier in life and had higher rates of readmission, revision, and complications in the short term following their shoulder replacement. However, when controlling for tobacco usage as an independent predictor of adverse outcomes, these aforementioned findings were lost for the cohort as a whole. Overall, these findings indicate that shoulder replacement in general is a viable treatment option regardless of patient tobacco usage at short-term follow-up, but this conclusion may vary depending on the replacement type used.

Acetabular Rim Disorders: Epidemiology, Etiology, Management, and Outcomes.

¼ Anatomic disorders of the acetabular rim are a common, correctable source of hip pain in younger patients.¼ Some common conditions of involving abnormal acetabular rim morphology include developmental dysplasia of the hip, pincer-type femoroacetabular impingement, acetabular protrusion, and acetabular retroversion.¼ Treatment option for these conditions were historically limited to open osteotomy and osteoplasty procedures; however, there is increasing use of arthroscopic intervention for these patients.¼ Arthroscopic intervention has demonstrated short-term success in a variety of focal acetabular rim disorders; however, further research is needed to determine the long-term outcomes of these procedures and their utility in more global pathology.

Schizophrenia Risk Mapping and Functional Engineering of the 3D Genome in Three Neuronal Subtypes.

Common variants associated with schizophrenia are concentrated in non-coding regulatory sequences, but their precise target genes are context-dependent and impacted by cell-type-specific three-dimensional spatial chromatin organization. Here, we map long-range chromosomal conformations in isogenic human dopaminergic, GABAergic, and glutamatergic neurons to track developmentally programmed shifts in the regulatory activity of schizophrenia risk loci. Massive repressive compartmentalization, concomitant with the emergence of hundreds of neuron-specific multi-valent chromatin architectural stripes, occurs during neuronal differentiation, with genes interconnected to genetic risk loci through these long-range chromatin structures differing in their biological roles from genes more proximal to sequences conferring heritable risk. Chemically induced CRISPR-guided chromosomal loop-engineering for the proximal risk gene SNAP91 and distal risk gene BHLHE22 profoundly alters synaptic development and functional activity. Our findings highlight the large-scale cell-type-specific reorganization of chromosomal conformations at schizophrenia risk loci during neurodevelopment and establish a causal link between risk-associated gene-regulatory loop structures and neuronal function.

The Impact of COVID-19 on the Timing of Rotator Cuff Repair and Method of Postoperative Follow-up.

Objective Rotator cuff repair (RCR) is one of the most common arthroscopic procedures. Our investigation aims to quantify the impact that the COVID-19 pandemic had on RCR, specifically on patients with acute, traumatic injuries. Methods Institutional records were queried to identify patients who underwent arthroscopic RCR between March 1 st to October 31 st of both 2019 and 2020. Patient demographic, preoperative, perioperative, and postoperative data were collected from electronic medical records. Inferential statistics were used to analyze data. Results Totals of 72 and of 60 patients were identified in 2019 and in 2020, respectively. Patients in 2019 experienced shorter lengths of time from MRI to surgery (62.7 ± 70.5 days versus 115.7 ± 151.0 days; p = 0.01). Magnetic resonance imaging (MRI) scans showed a smaller average degree of retraction in 2019 (2.1 ± 1.3 cm versus 2.6 ± 1.2 cm; p = 0.05) but no difference in anterior to posterior tear size between years (1.6 ± 1.0 cm versus 1.8 ± 1.0 cm; p = 0.17). Less patients in 2019 had a telehealth postoperative consultation with their operating surgeon compared with 2020 (0.0% versus 10.0%; p = 0.009). No significant changes in complications (0.0% versus 0.0%; p > 0.999), readmission (0.0% versus 0.0%; p > 0.999), or revision rates (5.6% versus 0.0%; p = 0.13) were observed. Conclusion From 2019 to 2020, there were no significant differences in patient demographics or major comorbidities. Our data suggests that even though the time from MRI to surgery was delayed in 2020 and telemedicine appointments were necessary, RCR was still performed in a timely manner and with no significant changes in early complications. Level of Evidence III.

The Impact of COVID-19 on the Timing of Rotator Cuff Repair and Method of Postoperative Follow-up / Impacto da COVID-19 no momento de reparo do manguito rotador e método de acompanhamento pós-operatório

Abstract Objective Rotator cuff repair (RCR) is one of the most common arthroscopic procedures. Our investigation aims to quantify the impact that the COVID-19 pandemic had on RCR, specifically on patients with acute, traumatic injuries. Methods Institutional records were queried to identify patients who underwent arthroscopic RCR between March 1st to October 31st of both 2019 and 2020. Patient demographic, preoperative, perioperative, and postoperative data were collected from electronic medical records. Inferential statistics were used to analyze data. Results Totals of 72 and of 60 patients were identified in 2019 and in 2020, respectively. Patients in 2019 experienced shorter lengths of time from MRI to surgery (62.7 ± 70.5 days versus 115.7 ± 151.0 days; p = 0.01). Magnetic resonance imaging (MRI) scans showed a smaller average degree of retraction in 2019 (2.1 ± 1.3 cm versus 2.6 ± 1.2 cm; p = 0.05) butnodifference in anterior toposterior tear size between years (1.6 ± 1.0 cm versus 1.8 ± 1.0 cm; p = 0.17). Less patients in 2019 had a tele-health postoperative consultation with their operating surgeon compared with 2020 (0.0% versus 10.0%; p = 0.009). No significant changes in complications (0.0% versus 0.0%; p > 0.999), readmission (0.0% versus 0.0%; p > 0.999), or revision rates (5.6% versus 0.0%; p = 0.13) were observed. Conclusion From 2019 to 2020, there were no significant differences in patient demographics or major comorbidities. Our data suggests that even though the time from MRI to surgery was delayed in 2020 and telemedicine appointments were necessary, RCR was still performed in a time in early complications. Level of Evidence III.

Resumo Objetivo Oreparodomanguitorotador (RMR) é um dos procedimentos artroscópi-cos maiscomuns. Nossapesquisavisaquantificar o impacto da pandemia de COVID-19 sobre o RMR, especificamente em pacientes com lesões agudas e traumáticas. Métodos Os prontuários institucionais foram consultados para identificação de pacientes submetidos ao RMR artroscópico entre 1° de março e 31 de outubro de 2019 e de 2020. Dados demográficos, pré-operatórios, perioperatórios e pós-operatórios dos pacientes foram coletados de prontuários eletrônicos. Os dados foram analisados por estatística inferencial. Resultados Totais de 72 ede60pacientes foramidentificados em 2019 e 2020, respectivamente. Os pacientes de 2019 apresentaram menor intervalo entre a ressonância magnética (RM) e a cirurgia (62,7 ± 70,5 dias versus 115,7 ± 151,0 dias; p = 0,01). Os exames de RM mostraram menor grau médio de retração em 2019 (2,1 ± 1,3 cm versus 2,6 ± 1,2 cm; p = 0,05), mas nenhuma diferença foi observada na extensão anteroposterior da laceração entre os anos (1,6 ± 1,0 cm versus 1,8 ± 1,0 cm; p = 0,17).Em 2019,o número de pacientes atendidos por seus cirurgiões em consultas pós-operatórias por telemedicina foi menor em comparação com 2020 (0,0% versus 10,0%; p = 0,009). Não foram observadas alterações significativas nas taxas de complicação (0,0% versus 0,0%; p > 0,999), de readmissão (0,0% versus 0,0%; p > 0,999) ou de revisão (5,6% versus 0,0%; p = 0,13). Conclusão Não houve diferenças significativas nos dados demográficos dos pacientes ou nas principais comorbidades entre 2019 e 2020. Nossos dados sugerem que, embora o intervalo entre a RM e a cirurgia tenha sido maior em 2020 e tenha havido necessidade de consultas por telemedicina, o RMR ainda foi realizado em tempo hábil e sem alterações significativas nas complicações precoces. Nível de Evidência III.

Effect of COVID-19 on Shoulder Arthroplasty at a Tertiary Care Medical Center in New York City.

Objective The COVID-19 pandemic led to an unprecedented pause in elective surgeries, including shoulder arthroplasty. We sought to determine whether clinical and/or demographic differences would be seen between patients who presented for shoulder arthroplasty during the pandemic compared with the previous year (2019). Methods Institutional records were queried for patients who underwent shoulder replacement between March 1 and July 1 of 2019 and 2020. Demographics, range of motion, surgical duration, hospitalization time, discharge disposition, and postoperative management were analyzed. Results The mean duration of surgery was 160 ± 50 minutes in 2020 and 179 ± 54 minutes in 2019 ( p = 0.13). The mean hospitalization time was 36 ± 13 hours in 2020 and 51 ± 40 hours in 2019 ( p = 0.04). In 2019, 96% of the patients participated in physical therapy, while 71% did it in 2020 ( p = 0.003). A total of 100% of the 2019 patients and 86% of the 2020 patients participated in an in-person postoperative follow-up ( p = 0.006). The 2019 patients reported for an office visit on average 14 ± 11 days after surgery; the 2020 patients waited 25 ± 25 days to return for a follow-up ( p = 0.10). Range of motion, age, American Society of Anesthesiologists (ASA) scores, and complication rates did not differ between the cohorts. Conclusion Patients presenting for surgery during the initial phase of the pandemic were demographically and clinically similar to 2019 patients. However, the length of stay was significantly reduced during the COVID-19 pandemic. Postoperative follow-up and physical therapy were delayed in 2020, but this did not lead to differences in complication or readmission rates compared with those of the 2019 cohort. Level of Evidence III.

Effect of COVID-19 on Shoulder Arthroplasty at a Tertiary Care Medical Center in New York City / Efeito da COVID-19 na artroplastia de ombro em um centro médico terciário na cidade de Nova York

Abstract Objective The COVID-19 pandemic led to an unprecedented pause in elective surgeries, including shoulder arthroplasty. We sought to determine whether clinical and/or demographic differences would be seen between patients who presented for shoulder arthroplasty during the pandemic compared with the previous year (2019). Methods Institutional records were queried for patients who underwent shoulder replacement between March 1 and July 1 of 2019 and 2020. Demographics, range of motion, surgical duration, hospitalization time, discharge disposition, and postoperative management were analyzed. Results The mean duration of surgery was 160 ± 50 minutes in 2020 and 179 ± 54 minutes in 2019 (p= 0.13). The mean hospitalization time was 36 ± 13 hours in 2020 and 51 ± 40 hours in 2019 (p= 0.04). In 2019, 96% of the patients participated in physical therapy, while 71% did it in 2020 (p= 0.003). A total of 100% of the 2019 patients and 86% of the 2020 patients participated in an in-person postoperative follow-up (p= 0.006). The 2019 patients reported for an office visit on average 14 ± 11 days after surgery; the 2020 patients waited 25 ± 25 days to return for a follow-up (p= 0.10). Range of motion, age, American Society of Anesthesiologists (ASA) scores, and complication rates did not differ between the cohorts. Conclusion Patients presenting for surgery during the initial phase of the pandemic were demographically and clinically similar to 2019 patients. However, the length of stay was significantly reduced during the COVID-19 pandemic. Postoperative follow-up and physical therapy were delayed in 2020, but this did not lead to differences in complication or readmission rates compared with those of the 2019 cohort. Level of EvidenceIII.

Resumo Objetivo A pandemia de COVID-19 causou uma pausa sem precedentes em cirurgias eletivas, inclusive artroplastia de ombro. Procuramos determinar as possíveis diferenças clínicas e/ou demográficas entre os pacientes que realizaram artroplastia de ombro durante a pandemia em comparação com o ano anterior (2019). Métodos Os registros institucionais foram consultados para obtenção de informações sobre pacientes submetidos a artroplastia de ombro entre 1° de março a 1° de julho de 2019 e 2020. Dados demográficos, amplitude de movimento, duração da cirurgia, tempo de hospitalização, condições à alta e manejo pós-operatório foram analisados. Resultados O tempo médio de cirurgia foi de 160 ± 50 minutos em 2020 e de 179 ± 54 minutos em 2019 (p= 0,13). O tempo médio de internação foi de 36 ± 13 horas em 2020 e de 51 ± 40 horas em 2019 (p= 0,04). Em 2019, 96% dos pacientes fizeram fisioterapia, enquanto 71% o fizeram em 2020 (p= 0,003). Todos os pacientes de 2019 e 86% dos pacientes de 2020 participaram do acompanhamento pós-operatório presencial (p= 0,006). Os pacientes de 2019 retornaram para a consulta médica em média 14 ± 11 dias após a cirurgia; os pacientes de 2020 retornaram para o acompanhamento em 25 ± 25 dias (p= 0,10). A amplitude de movimento, a idade, a pontuação da American Society of Anesthesiologists (ASA, na sigla em inglês) e as taxas de complicações não diferiram entre as coortes. Conclusão Os pacientes submetidos a cirurgia na fase inicial da pandemia eram demográfica e clinicamente semelhantes aos pacientes de 2019. No entanto, o tempo de internação diminuiu de forma significativa durante a pandemia de COVID-19. O acompanhamento pós-operatório e a fisioterapia foram adiados em 2020, mas isso não levou a diferenças nas taxas de complicações ou de reinternações em comparação às da coorte de 2019. Nível de EvidênciaIII.

The impact of tobacco use on clinical outcomes and long-term survivorship after anatomic total shoulder arthroplasty.

Introduction: Postoperative outcomes following total shoulder arthroplasty can be affected by preoperative health factors such as tobacco usage. Methods: The charts of patients who underwent anatomic total shoulder arthroplasty were retrospectively analyzed and stratified based on smoking status. The primary data included range of motion and patient reported outcomes. Additionally, demographic, radiographic, and survivorship analyses were conducted. All data were analyzed using statistical inference. Results: There were 78, 49, and 16 non-smoker, former smoker, and current smoker shoulders respectively with no significant differences in sex, American Society of Anesthesiologists status, body mass index, or mean follow-up time (average: 10.7 yrs). Smokers (51.5 ± 10.4 years) were younger than both non-smokers (64.9 ± 8.1 years; p < 0.01) and former smokers (65.1 ± 9.1years; p < 0.01) at the time of surgery. For non-smokers and former smokers, all range of motion and patient reported outcome scores significantly improved. Smokers reported significant improvements in all patient reported outcomes and external and internal rotation. Visual Analog Scale, American Shoulder and Elbow, and Simple Shoulder Test scores were lower for smokers comparatively, but these differences did not reach significance. Forward elevation was higher postoperatively for non-smokers (149.7o ± 17.2o) and former smokers (147.1o ± 26.0o) compared to current smokers (130.9o ± 41.2o; p = 0.017). No differences between the cohorts were found in the radiographic analysis. Revision rates were lower in the non-smoking cohort (7.7%) compared to both former (20.4%; p = 0.036) and current smokers (37.5%; p < 0.01). Survival curves showed that non-smoker implants lasted longer than those of current smokers. Conclusion: After a decade, patients generally had improved shoulder range of motion, functionality, and pain regardless of smoking status. However, current smokers required shoulder replacements sooner and revision surgery more frequently.

Tendon Transfers, Balloon Spacers, and Bursal Acromial Reconstruction for Massive Rotator Cuff Tears.

Several options exist for the management of irreparable rotator cuff tears without advanced arthritic changes. Tendon transfer poses technical challenges and has limited but promising outcomes data. Newer procedures such as balloon spacers and bursal acromial reconstruction are currently being investigated as a reproducible solution to this challenging problem. Ultimately the decision to continue with conservative measures, use one of the aforementioned techniques, or proceed with reverse shoulder arthroplasty remains a decision to be made in the context of patient's unique demands and provider comfort with the various modalities of treatment.

Does body mass index influence long-term outcomes after anatomic total shoulder arthroplasty?

BACKGROUND: As of 2018, upwards of 42% of the US adult population was considered obese based on body mass index (BMI) scales. With the annual number of total joint replacements increasing, this study aimed to evaluate the impact BMI has on anatomic total shoulder arthroplasty (aTSA) outcomes. METHODS: This was a retrospective analysis of 128 shoulders requiring primary aTSA. Patients were stratified into 3 cohorts based on their BMI at surgery: underweight/normal weight (U/NW; BMI ≤25.0), overweight (25.0 < BMI ≤ 30.0), and obese (BMI >30.0). BMI was separately analyzed as a continuous variable. Clinical endpoints were range of motion scores, including forward elevation, external rotation, and internal rotation, and patient-reported outcomes, including visual analog scale (VAS) scores, American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES) scores, and the Simple Shoulder Test (SST). Survivorship curves were calculated using Kaplan-Meier analysis. RESULTS: Forty-four, 50, and 34 patient shoulders were in the U/NW, overweight, and obese cohorts, respectively. The mean follow-up time was 11.4 years. The U/NW cohort had more females (73%) compared with the overweight (34%; P = .0030) and obese (35%; P = .0015) groups; no differences were seen in revision rates. BMI was negatively correlated with age at surgery (r = -0.19, P = .014); it was not correlated with any of the 6 postoperative clinical endpoints. All 3 cohorts saw significant improvements in forward elevation, external rotation, internal rotation and VAS, ASES, and SST scores when compared preoperatively to postoperatively (P < .001). There were no significant differences between the 3 cohorts with respect to postoperative range of motion. Postoperative ASES scores were higher for the overweight cohort (82.6 ± 18.6) compared with both the U/NW (63.0 ± 25.1) and obese cohorts (70.5 ± 26.8) (P < .001). The overweight cohort also had higher SST (P = .0012) postoperative scores compared with the U/NW and obese cohorts; VAS scores were comparable between groups (P = .12). The nonobese (BMI <30) group (n = 94) showed 5-, 10-, and 15-year implant survival of 98.9%, 94.9%, and 83.9%, respectively compared to 97.1%, 93.7%, and 87.0% in the obese (BMI ≥30) group (n = 34). The log rank test revealed no significant difference in survival curves (P = .82). CONCLUSION: To our knowledge, this is the longest follow-up study analyzing clinical endpoints stratified by BMI for aTSA. We saw that patients with a higher BMI required shoulder replacement at a significantly younger age. However, we also report that regardless of BMI, all patients saw significant improvements in patient-reported outcomes and range of motion scores postoperatively.

Integrative single-cell analysis of cardiogenesis identifies developmental trajectories and non-coding mutations in congenital heart disease.

To define the multi-cellular epigenomic and transcriptional landscape of cardiac cellular development, we generated single-cell chromatin accessibility maps of human fetal heart tissues. We identified eight major differentiation trajectories involving primary cardiac cell types, each associated with dynamic transcription factor (TF) activity signatures. We contrasted regulatory landscapes of iPSC-derived cardiac cell types and their in vivo counterparts, which enabled optimization of in vitro differentiation of epicardial cells. Further, we interpreted sequence based deep learning models of cell-type-resolved chromatin accessibility profiles to decipher underlying TF motif lexicons. De novo mutations predicted to affect chromatin accessibility in arterial endothelium were enriched in congenital heart disease (CHD) cases vs. controls. In vitro studies in iPSCs validated the functional impact of identified variation on the predicted developmental cell types. This work thus defines the cell-type-resolved cis-regulatory sequence determinants of heart development and identifies disruption of cell type-specific regulatory elements in CHD.

Increasing Patient Age, Ambulatory Surgery Center Setting, and Surgeon Experience Are Associated With Shorter Operative Duration for Anterior Cruciate Ligament Reconstruction.

Purpose: To identify variables associated with operative duration and intraoperative or perioperative complications after primary anterior cruciate ligament reconstruction (ACLR). Methods: Surgeons who performed a minimum of 20 arthroscopic cases per month were recruited for participation through the Arthroscopy Association of North America from 2011 through 2013. All participants agreed to voluntarily submit data for 6 months of consecutive knee and shoulder arthroscopy cases. Only subjects coded for ACLR were analyzed, whereas revision cases were excluded. ACLRs were subdivided into isolated ACLR, ACLR with minor concomitant procedures, and ACLR with major concomitant procedures. Patient, surgeon, and surgical variables were analyzed for their effect on operative duration and complications. Results: One hundred thirty-five orthopaedic surgeons participated, providing 1,180 primary ACLRs (399 isolated ACLRs, 441 ACLRs plus minor procedures, and 340 ACLRs plus major procedures). Most surgeons were in private practice (72.8%). Most patients were male patients (58.8%), and the mean body mass index (BMI) was 26.2 ± 5.1. The overall mean operative duration was 95.9 ± 42.0 minutes (isolated ACLRs, 88.4 ± 36.8 minutes; ACLRs plus minor concomitant procedures, 90.1 ± 37.6 minutes; and ACLRs plus major concomitant procedures, 118.5 ± 112.4 minutes; P < .001). Patient age was inversely correlated with operative duration (ρ = -0.221, P < .001). Surgical procedures performed in an ambulatory surgery center had a shorter mean operative duration (91.5 ± 40.4 minutes) compared with those performed in a hospital setting (105.0 ± 43.8 minutes, P < .001). There were 22 intraoperative and 47 early postoperative complications, with the most common being deep vein thrombosis (n = 15). Surgical volume (knee arthroscopy cases per month) correlated inversely with operative time (ρ = -0.200, P = .001) and complication rate (ρ = -0.112, P < .001). Patient BMI was associated with increased odds of early postoperative complications on multivariate analysis (odds ratio, 1.060; P = .044; 95% confidence interval, 1.002-1.121). Conclusions: Increasing patient age, private practice, ambulatory surgery center setting, and surgeon experience are associated with a shorter operative duration for ACLR. Although an increasing number of arthroscopic knee procedures performed by surgeons correlated with fewer complications, only increasing patient BMI significantly predicted odds of complications. Level of Evidence: Level IV, prognostic case series.

CLOuD9: CRISPR-Cas9-Mediated Technique for Reversible Manipulation of Chromatin Architecture.

The spatial organization of the genome plays a critical role in cell-specific biological functions such as gene expression. Existing genome-wide technologies reveal a dynamic interplay between chromatin looping and gene regulation, but the mechanisms by which regulatory interactions between genetic elements are established or maintained remain unclear. Here, we present CLOuD9, a CRISPR-based technology that can create de novo, pairwise chromatin interactions in cells. This technique for chromatin loop reorganization employs dCas9-targeting and ABI1-PYL heterodimerization. It is reversible, but can also establish epigenetic memory under certain conditions, which provides a way to dissect gene regulation mechanisms.