Publications by authors named "Richard Friedman"

265 Publications

Effects of Increased Retroversion Angle on Glenoid Baseplate Fixation in Reverse Total Shoulder Arthroplasty: A Finite Element Analysis.

Semin Arthroplasty 2021 Jul 2;31(2):209-216. Epub 2021 Jan 2.

Department of Bioengineering, Clemson University, Clemson, SC, USA.

Background: Increased glenoid retroversion occurs in patients with severe arthritis but its effect on baseplate fixation of a reverse total shoulder arthroplasty (rTSA) is not clear. The purpose of this study is to determine the effects of increasing glenoid retroversion on baseplate fixation in rTSA using finite element analysis (FEA) modelling.

Methods: Five sets of computerized tomographic (CT) images of healthy normal shoulders were selected and segmented with Amira (Thermo Fisher Scientific) to obtain the solid geometries. Scapula FEA models with 5°, 10°, 15°, 20° and 25° retroversion angles were generated for each healthy scapula geometry and a rTSA glenoid baseplate was implanted on each model. Maximum stress at the anterior and posterior portions of the glenoid and the micromotion between the bone and baseplate were recorded. After simulation with normal scapular bone material properties (Young's modulus 4GPa and Poisson's ratio 0.3), another set of simulations was run on each subject with a 25° retroversion angle and poor bone quality (Young's modulus 500 MPa and Poisson's ratio 0.3) to study a worst-case scenario. Micromotions in each model were also recorded. All statistical analysis was done with SPSS.

Results: Simulation results of models generated from the same subject but with different retroversion angles showed a clear pattern: as retroversion angle increased, the stresses increased posteriorly and decreased anteriorly. Also, micromotion between the bone and the baseplate increased with the increase of retroversion angle. With analysis of variance (ANOVA), we found that all three values change significantly as the retroversion angle increases (p < 0.001). The simulation results also showed that micromotion was large in shoulders with small glenoid size and poor bone quality. However, even in the model with the worst-case scenario (smallest glenoid size, poorest bone quality and 25° retroversion angle), the maximum micromotion and the maximum stresses are still within the safe range.

Discussion: In all cases with both normal and poor bone quality, the stresses and micromotion stayed below the threshold to allow for bone ingrowth of the glenoid baseplate to occur. Based on these results, for glenoid baseplates with a central peg/post and 4 screws for fixation, rTSA baseplate retroversion does not need to be corrected to less than 10° to provide good initial fixation as has been recommended for a cemented glenoid component and can withstand the initial stresses and micromotion up to 25° of retroversion.

Level Of Evidence: Basic Science Study; Computer Modeling.
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http://dx.doi.org/10.1053/j.sart.2020.11.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323535PMC
July 2021

Six Month Follow-up of Patients With Multisystem Inflammatory Syndrome in Children.

Pediatrics 2021 Jul 29. Epub 2021 Jul 29.

Division of Pediatric Cardiology, Cohen Children's Medical Center, Northwell Health, 269-01 76th Avenue, New Hyde Park, New York 11040.

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http://dx.doi.org/10.1542/peds.2021-050973DOI Listing
July 2021

Effects of Obesity on Clinical and Functional Outcomes Following Anatomic and Reverse Total Shoulder Arthroplasty.

J Shoulder Elbow Surg 2021 Jul 20. Epub 2021 Jul 20.

Department of Orthopaedics and Physical Medicine, Medical University of South Carolina, Charleston, SC, USA. Electronic address:

Background: Limited data exists regarding the clinical and functional outcomes following primary total shoulder arthroplasty (TSA) in obese patients. The purpose of this study is to determine the effects of obesity on the clinical and functional outcomes following primary anatomic (aTSA) and reverse total shoulder arthroplasty (rTSA) in a large patient population with mid-term follow-up.

Methods: Patients in a multi-institutional shoulder registry receiving either a primary aTSA (n=1520) or rTSA (n=2054) from 2004 to 2018 with a minimum follow-up of 2 years were studied. All patients received the same platform shoulder prosthesis. Study groups were assigned based on implant type (anatomic or reverse), and further stratification was based on patient BMI, with obese patients having a BMI ≥ 30 kg/m and non-obese patients with a BMI <30 kg/m. Patients were evaluated and scored preoperatively and at latest follow-up using five scoring metrics and range of motion (ROM).

Results: Mean follow-up was 5 years (range, 2-14 years). 41% of aTSA and 35% of rTSA were obese. Significant postoperative improvements in VAS pain scores, ROM, and all 5 scoring metrics occurred in both obese and non-obese patients (P<0.05). Obese patients in both groups reported higher preoperative and postoperative visual analog scale (VAS) pain scores and less preoperative and postoperative ROM compared to non-obese patients. Compared to non-obese patients, obese patients receiving an aTSA reported significantly worse postoperative SST, Constant, ASES, UCLA, and SPADI scores compared to non-obese patients, and those receiving rTSA reported significantly worse ASES and SPADI scores (all P<0.05). However, these differences did not exceed the minimal clinical important difference (MCID) or substantial clinical benefit (SCB) criteria. Radiographic analysis showed that in rTSA, obese patients had significantly less postoperative scapular notching and a lower scapular notching grade when compared to non-obese patients (P<0.05).

Discussion: Both non-obese and obese patients can expect clinically significant improvements in pain, motion and functional outcome scores following both aTSA and rTSA. Obese patients reported significantly more postoperative pain, lower outcome scores and less ROM compared to non-obese patients for both aTSA and rTSA at a mean follow-up of 5 years. However, statistically significant differences were not found to be clinically significant with respect to established MCID and SCB criteria. Therefore, obese and non-obese patients experience similar clinical outcomes following TSA, regardless of BMI. However, obese patients have more comorbidities, greater intraoperative blood loss and less scapular notching compared to non-obese patients.
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http://dx.doi.org/10.1016/j.jse.2021.06.011DOI Listing
July 2021

Effects of the Obesity Epidemic on Total Hip and Knee Arthroplasty Demographics.

J Arthroplasty 2021 Apr 22. Epub 2021 Apr 22.

Department of Orthopaedics, Medical University of South Carolina, Charleston, SC.

Background: Higher body mass index (BMI) is a well-known risk factor for the development of hip and knee osteoarthritis and predicts total hip arthroplasty (THA) and total knee arthroplasty (TKA) at an earlier age. The purpose of this study is to document the nationwide trends in age and obesity in primary THA and TKA throughout the obesity epidemic.

Methods: A retrospective analysis of the National Inpatient Sample database was conducted on patients undergoing primary THA and TKA for primary OA between 2002 and 2017. Analysis of variance and chi-square tests were performed to examine changes in age and obesity percentage over time, respectively. Pearson correlations were used to assess the relationship between patient age, BMI, and year of surgery.

Results: A total of 688,371 THA and 1,556,651 TKA were identified over the sixteen-year period. Between 2002 and 2017, the proportion of obese patients increased for both THA (7.0% to 22.7%, P < .001) and TKA (10.7% to 30.4%, P < .001). Mean age significantly decreased for both THA (66.7 to 65.9 years, P < .001) and TKA (67.6 to 66.8 years; P < .001). Over time, BMI significantly increased (THA: r = 0.221 vs. TKA: r = 0.272) and patient age decreased (THA: r = -0.031 vs. TKA: r = -0.137) for both procedures (P < .001 for all).

Conclusion: THA and TKA patients have become younger and increasingly more obese throughout the obesity epidemic, as obesity rates have tripled over this time period. The current investigation is the first to demonstrate significant trends in both age and obesity in the THA and TKA populations on a national level.

Level Of Evidence: III.
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http://dx.doi.org/10.1016/j.arth.2021.04.017DOI Listing
April 2021

Randomized Controlled Trial of the Gastrin/CCK Receptor Antagonist Netazepide in Patients with Barrett's Esophagus.

Cancer Prev Res (Phila) 2021 Jun 29;14(6):675-682. Epub 2021 Mar 29.

Department of Medicine, Columbia University Irving Medical Center, New York, New York.

Hypergastrinemia has been associated with high-grade dysplasia and adenocarcinoma in patients with Barrett's esophagus, and experimental studies suggest proinflammatory and proneoplastic effects of gastrin on Barrett's esophagus. This is of potential concern, as patients with Barrett's esophagus are treated with medications that suppress gastric acid production, resulting in increased physiologic levels of gastrin. We aimed to determine whether treatment with the novel gastrin/CCK receptor antagonist netazepide reduces expression of markers associated with inflammation and neoplasia in Barrett's esophagus. This was a randomized, double-blind, placebo-controlled trial of netazepide in patients with Barrett's esophagus without dysplasia. Subjects were treated for 12 weeks, with endoscopic assessment at baseline and at end of treatment. The primary outcome was within-individual change in cellular proliferation as assessed by Ki67. Secondary analyses included changes in gene expression, assessed by RNA-sequencing, and safety and tolerability. A total of 20 subjects completed the study and were included in the analyses. There was no difference between arms in mean change in cellular proliferation (netazepide: +35.6 Ki67+ cells/mm, SD 620.7; placebo: +307.8 Ki67+ cells/mm, SD 640.3; = 0.35). Netazepide treatment resulted in increased expression of genes related to gastric phenotype () and certain cancer-associated markers (), and decreased expression of intestinal markers , and No serious adverse events related to study drug occurred. The gastrin/CCK receptor antagonist netazepide did not reduce cellular proliferation in patients with nondysplastic Barrett's esophagus. Further research should focus on the biological effects of gastrin in Barrett's esophagus. Treatment of patients with Barrett's esophagus with a gastrin/CCK receptor antagonist did not have obvious chemopreventive effects.
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http://dx.doi.org/10.1158/1940-6207.CAPR-21-0050DOI Listing
June 2021

Increased perioperative complication rates in patients with solid organ transplants following rotator cuff repair.

J Shoulder Elbow Surg 2021 Feb 8. Epub 2021 Feb 8.

Department of Orthopaedics, Medical University of South Carolina, Charleston, SC, USA. Electronic address:

Background: Rotator cuff repair is the second most common soft tissue procedure performed in orthopedics. Additionally, an increasing percentage of the population has received a solid organ transplant (SOT). The chronic use of immunosuppressants as well as a high prevalence of medical comorbidities in this population are both important risk factors when considering surgical intervention. The purpose of this study is to determine the demographic profile, comorbidity profile, and perioperative complication rate of SOT patients undergoing inpatient rotator cuff repair surgery compared to nontransplanted patients.

Methods: The Nationwide Inpatient Sample (NIS) database was queried from years 2002-2017 to identify all patients who underwent inpatient rotator cuff repair (n = 144,528 weighted). This group was further divided into SOT (n = 286 weighted) and nontransplant (n = 144,242 weighted) cohorts. Demographic and comorbidity analyses were performed between these groups. Additionally, a matched cohort of nontransplanted patients controlled for the year of procedure, age, sex, race, income, and hospital region was created in a 1:1 ratio to the SOT group (n = 286 each) for perioperative complication rate analysis.

Results: Compared to nontransplanted patients, SOT patients were more likely to have at least 1 significant medical comorbidity (98% vs. 69%, P < .001), had a higher number of total comorbidities (3.1 vs. 1.4, P < .001), and had a higher Charlson-Deyo Comorbidity Index (2.6 vs. 0.54, P < .001). Compared to the matched cohort, SOT patients experienced longer hospital stays (2.9 vs. 1.8 days, P < .001), higher surgery costs ($12,031 vs. $8476, P < .001), and were more likely to experience a perioperative complication (24% vs. 3%, P < .001) with an odds ratio of 7.7 (95% confidence interval: 3.9-15.1).

Conclusion: Compared with nontransplanted patients, SOT patients undergoing rotator cuff repair had a significantly higher comorbidity index, longer hospital stays, costlier surgeries, and were >7 times more likely to experience a perioperative complication. With nearly a quarter of all SOT patients experiencing a perioperative complication following rotator cuff repair, careful consideration for surgery as well as increased postoperative surveillance should be considered in this unique population.
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http://dx.doi.org/10.1016/j.jse.2020.12.024DOI Listing
February 2021

The modern reverse shoulder arthroplasty and an updated systematic review for each complication: part II.

JSES Int 2021 Jan 10;5(1):121-137. Epub 2020 Sep 10.

ASES Multicenter Taskforce for RSA Complications, Rosemont, IL, USA.

Background: Globally, reverse shoulder arthroplasty (RSA) has moved away from the Grammont design to modern prosthesis designs. The purpose of this study was to provide a focused, updated systematic review for each of the most common complications of RSA by limiting each search to publications after 2010. In this part II, the following were examined: (1) instability, (2) humerus/glenoid fracture, (3) acromial/scapular spine fractures (AF/SSF), and (4) problems/miscellaneous.

Methods: Four separate PubMed database searches were performed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Overall, 137 studies for instability, 94 for humerus/glenoid fracture, 120 for AF/SSF, and 74 for problems/miscellaneous were included in each review, respectively. Univariate analysis was performed with chi-square and Fisher exact tests.

Results: The Grammont design had a higher instability rate vs. all other designs combined (4.0%, 1.3%; < .001), and the onlay humerus design had a lower rate than the lateralized glenoid design (0.9%, 2.0%;  = .02). The rate for intraoperative humerus fracture was 1.8%; intraoperative glenoid fracture, 0.3%; postoperative humerus fracture, 1.2%; and postoperative glenoid fracture, 0.1%. The rate of AF/SSF was 2.6% (371/14235). The rate for complex regional pain syndrome was 0.4%; deltoid injury, 0.1%; hematoma, 0.3%; and heterotopic ossification, 0.8%.

Conclusions: Focused systematic reviews of recent literature with a large volume of shoulders demonstrate that using non-Grammont modern prosthesis designs, complications including instability, intraoperative humerus and glenoid fractures, and hematoma are significantly reduced compared with previous studies. As the indications continue to expand for RSA, it is imperative to accurately track the rate and types of complications in order to justify its cost and increased indications.
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http://dx.doi.org/10.1016/j.jseint.2020.07.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846704PMC
January 2021

Orthopaedic Application of Cryotherapy: A Comprehensive Review of the History, Basic Science, Methods, and Clinical Effectiveness.

JBJS Rev 2021 Jan 26;9(1):e20.00016. Epub 2021 Jan 26.

Department of Orthopaedics, Medical University of South Carolina, Charleston, South Carolina.

»: Cold therapy, also known as cryotherapy, includes the use of bagged ice, ice packs, compressive cryotherapy devices, or whole-body cryotherapy chambers. Cryotherapy is commonly used in postoperative care for both arthroscopic and open orthopaedic procedures.

»: Cryotherapy is associated with an analgesic effect caused by microvasculature alterations that decrease the production of inflammatory mediators, decrease local edema, disrupt the overall inflammatory response, and reduce nerve conduction velocity.

»: Postoperative cryotherapy using bagged ice, ice packs, or continuous cryotherapy devices reduced visual analog scale pain scores and analgesic consumption in approximately half of research studies in which these outcomes were compared with no cryotherapy (11 [44%] of 25 studies on pain and 11 [48%] of 23 studies on opioids). However, an effect was less frequently reported for increasing range of motion (3 [19%] of 16) or decreasing swelling (2 [22%] of 9).

»: Continuous cryotherapy devices demonstrated the best outcome in orthopaedic patients after knee arthroscopy procedures, compared with all other procedures and body locations, in terms of showing a significant reduction in pain, swelling, and analgesic consumption and increase in range of motion, compared with bagged ice or ice packs.

»: There is no consensus as to whether the use of continuous cryotherapy devices leads to superior outcomes when compared with treatment with bagged ice or ice packs. However, complications from cryotherapy, including skin irritation, frostbite, perniosis, and peripheral nerve injuries, can be avoided through patient education and reducing the duration of application.

»: Future Level-I or II studies are needed to compare both the clinical and cost benefits of continuous cryotherapy devices to bagged ice or ice pack treatment before continuous cryotherapy devices can be recommended as a standard of care in orthopaedic surgery following injury or surgery.
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http://dx.doi.org/10.2106/JBJS.RVW.20.00016DOI Listing
January 2021

The modern reverse shoulder arthroplasty and an updated systematic review for each complication: part I.

JSES Int 2020 Dec 7;4(4):929-943. Epub 2020 Sep 7.

American Shoulder and Elbow Surgeons Multicenter Task Force on Reverse Total Shoulder Arthroplasty Complications, Rosemont, IL, USA.

Background: Globally, reverse shoulder arthroplasty (RSA) has moved away from the Grammont design to modern prosthesis designs. The purpose of this 2-part study was to systematically review each of the most common complications of RSA, limiting each search to publications in 2010 or later. In this part (part I), we examined (1) scapular notching (SN), (2) periprosthetic infection (PJI), (3) mechanical failure (glenoid or humeral component), and (4) neurologic injury (NI).

Methods: Four separate PubMed database searches were performed following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Overall, 113 studies on SN, 62 on PJI, 34 on mechanical failure, and 48 on NI were included in our reviews. Univariate analysis was performed with the χ or Fisher exact test.

Results: The Grammont design had a higher SN rate vs. all other designs combined (42.5% vs. 12.3%, < .001). The onlay humeral design had a lower rate than the lateralized glenoid design (10.5% vs. 14.8%, < .001). The PJI rate was 2.4% for primary RSA and 2.6% for revision RSA. The incidence of glenoid and humeral component loosening was 2.3% and 1.4%, respectively. The Grammont design had an increased NI rate vs. all other designs combined (0.9% vs. 0.1%,  = .04).

Conclusions: Focused systematic reviews of the recent literature with a large volume of RSAs demonstrate that with the use of non-Grammont modern prosthesis designs, complications including SN, PJI, glenoid component loosening, and NI are significantly reduced compared with previous studies. As the indications for RSA continue to expand, it is imperative to accurately track the rates and types of complications to justify its cost and increased indications.
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http://dx.doi.org/10.1016/j.jseint.2020.07.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738599PMC
December 2020

Frailty subtypes and recovery in older survivors of acute respiratory failure: a pilot study.

Thorax 2021 04 9;76(4):350-359. Epub 2020 Dec 9.

Pulmonary, Allergy, and Critical Care, Columbia University Irving Medical Center, New York, New York, USA.

Background: Identifying subtypes of acute respiratory failure survivors may facilitate patient selection for post-intensive care unit (ICU) follow-up clinics and trials.

Methods: We conducted a single-centre prospective cohort study of 185 acute respiratory failure survivors, aged ≥ 65 years. We applied latent class modelling to identify frailty subtypes using frailty phenotype and cognitive impairment measurements made during the week before hospital discharge. We used Fine-Gray competing risks survival regression to test associations between frailty subtypes and recovery, defined as returning to a basic Activities of Daily Living disability count less than or equal to the pre-hospitalisation count within 6 months. We characterised subtypes by pre-ICU frailty (Clinical Frailty Scale score ≥ 5), the post-ICU frailty phenotype, and serum inflammatory cytokines, hormones and exosome proteomics during the week before hospital discharge.

Results: We identified five frailty subtypes. The recovery rate decreased 49% across each subtype independent of age, sex, pre-existing disability, comorbidity and Acute Physiology and Chronic Health Evaluation II score (recovery rate ratio: 0.51, 95% CI 0.41 to 0.63). Post-ICU frailty phenotype prevalence increased across subtypes, but pre-ICU frailty prevalence did not. In the subtype with the slowest recovery, all had cognitive impairment. The three subtypes with the slowest recovery had higher interleukin-6 levels (p=0.03) and a higher prevalence of ≥ 2 deficiencies in insulin growth factor-1, dehydroepiandrostersone-sulfate, or free-testosterone (p=0.02). Exosome proteomics revealed impaired innate immunity in subtypes with slower recovery.

Conclusions: Frailty subtypes varied by prehospitalisation frailty and cognitive impairment at hospital discharge. Subtypes with the slowest recovery were similarly characterised by greater systemic inflammation and more anabolic hormone deficiencies at hospital discharge.
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http://dx.doi.org/10.1136/thoraxjnl-2020-214998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187474PMC
April 2021

Anatomical and reverse shoulder arthroplasty utilizing a single implant system with a platform stem: A prospective observational study with midterm follow-up.

Shoulder Elbow 2020 Oct 10;12(5):330-337. Epub 2019 Apr 10.

Department of Orthopaedics and Rehabilitation, University of Florida, Gainesville, USA.

Background: No studies compare outcomes of anatomic total shoulder arthroplasty to reverse total shoulder arthroplasty with more than five-year follow-up.

Methods: A multicenter prospectively collected shoulder registry was utilized to review all patients undergoing primary anatomic total shoulder arthroplasty or primary reverse total shoulder arthroplasty with a minimum five-year follow-up utilizing a single platform stem implant system. One-hundred-ninety-one patients received an anatomic total shoulder arthroplasty and 139 patients received a reverse total shoulder arthroplasty. Patients were scored preoperatively and at latest follow-up using the simple shoulder test (SST), University of California Los Angeles (UCLA), American shoulder and elbow surgeons (ASES), Constant, and shoulder pain and disability index (SADI) scores as well as range of motion. Radiographs were evaluated for implant loosening or notching. Complications were reviewed. A Student's two-tailed, unpaired t-test identified differences in preoperative, postoperative, and pre-to-postoperative improvements.

Results: Reverse total shoulder arthroplasty patients were significantly older than anatomic total shoulder arthroplasty patients. All patients demonstrated significant improvement in functional metric scores and range of motion following anatomic total shoulder arthroplasty or reverse total shoulder arthroplasty. There was no difference in final outcome scores between anatomic total shoulder arthroplasty and reverse total shoulder arthroplasty patients at midterm follow-up; however, reverse total shoulder arthroplasty patients demonstrated significantly less motion.

Discussion: We demonstrate equivalent outcomes with five scoring metrics at mean follow-up of 71.3 ± 14.1 months. Although postoperative scores were significantly greater than preoperative scores for both anatomic total shoulder arthroplasty and reverse total shoulder arthroplasty patients, significant differences in outcome scores between cohorts were not observed.
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http://dx.doi.org/10.1177/1758573219840675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545527PMC
October 2020

Anatomic total shoulder arthroplasty after healed rotator cuff repair: a matched cohort.

J Shoulder Elbow Surg 2020 Nov 9;29(11):2221-2228. Epub 2020 Jun 9.

Department of Orthopaedics, Medical University of South Carolina, College of Medicine, Charleston, SC, USA.

Background: Rotator cuff tears are a common cause of failure after anatomic total shoulder arthroplasty (TSA). The purpose of this study was to evaluate the effect of a healed prior rotator cuff repair (RCR) on outcomes and complications after primary TSA. We hypothesized that patients with a prior healed RCR would have equivalent outcomes and complication rates compared with patients without prior surgery.

Methods: A retrospective review of all primary TSAs with a prior RCR was performed using a multicenter database between 2005 and 2017. Thirty shoulders with prior RCR were case matched on a 3:1 ratio with a minimum 2-year follow-up. Range of motion, strength, patient-reported outcome measures, complications, and reoperations were compared.

Results: Thirty shoulders with a prior RCR were compared with 90 control patients without prior surgery at a mean follow-up of 43 months (range, 24-109 months). Groups demonstrated similar preoperative range of motion and patient-reported outcome measures. Postoperatively, TSAs with a prior healed RCR demonstrated less forward flexion (132° vs. 143°, P = .14) and strength (5.7 vs. 6.4 kg, P = .55) compared with control shoulders with no prior surgery; however, these did not meet statistical significance. Complications were significantly more common in patients with a prior RCR (17% vs. 7%, P = .01). Postoperative rotator cuff tears were significantly more common in TSA with a healed prior RCR (13% vs. 1%, P = .014).

Conclusions: TSA after RCR results in similar functional improvements compared with shoulders without prior surgery. However, the risk of a postoperative rotator cuff tear is significantly higher after prior successful RCR. Surgeons should consider this potential complication when indicating these patients for primary TSA.
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http://dx.doi.org/10.1016/j.jse.2020.03.029DOI Listing
November 2020

Analysis of 16S rRNA genes reveals reduced Fusobacterial community diversity when translocating from saliva to GI sites.

Gut Microbes 2020 11;12(1):1-13

Division of Periodontics, College of Dental Medicine, Columbia University Irving Medical Center , New York, NY, USA.

is a Gram-negative oral commensal anaerobe which has been increasingly implicated in various gastrointestinal (GI) disorders, including inflammatory bowel disease, appendicitis, GI cancers. The oral cavity harbors a diverse group of , and it is postulated that in the GI tract originate from the mouth. It is not known, however, if all oral translocate to the GI sites with equal efficiencies. Therefore, we amplified 16S rRNA genes of and , two closely related oral species from matched saliva, gastric aspirates, and colon or ileal pouch aspirates of three patients with inflammatory bowel disease (IBD) and three healthy controls, and saliva alone from seven patients with either active IBD or IBD in remission. The 16S rRNA gene amplicons were cloned, and the DNA sequences determined by Sanger sequencing. The results demonstrate that fusobacterial community composition differs more significantly between the oral and GI sites than between different individuals. The oral communities demonstrate the highest level of variation and have the richest pool of unique sequences, with certain nodes/strains enriched in the GI tract and others diminished during translocation. The gastric and colon/pouch communities exhibit reduced diversity and are more closely related, possibly due to selective pressure in the GI tract. This study elucidates selective translocation of oral fusobacteria to the GI tract. Identification of specific transmissible clones will facilitate risk assessment for developing -implicated GI disorders.
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http://dx.doi.org/10.1080/19490976.2020.1814120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577115PMC
November 2020

NIMH's Straight and Neural Path: The Road to Killing Clinical Psychiatric Research.

Psychiatr Serv 2020 11 23;71(11):1096-1097. Epub 2020 Sep 23.

Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York (Markowitz); Department of Clinical Therapeutics, New York State Psychiatric Institute, New York (Markowitz); Department of Psychiatry, Weill Cornell Medical College, New York (Friedman).

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http://dx.doi.org/10.1176/appi.ps.202000057DOI Listing
November 2020

Shoulder Position During Magnetic Resonance Arthrogram Significantly Affects Capsular Measurements.

Arthroscopy 2021 01 19;37(1):17-25. Epub 2020 Sep 19.

Department of Orthopaedics and Physical Medicine, Medical University of South Carolina, Charleston, South Carolina, U.S.A.. Electronic address:

Purpose: To determine whether change in shoulder position between internal rotation (IR) and external rotation (ER) during magnetic resonance arthrography (MRA) affects previously defined capsular measurements and to determine the utility of rotation in the diagnosis of instability.

Methods: A retrospective study was conducted of patients who received a shoulder MRA with humeral IR and ER views. Patients with an arthroscopically confirmed diagnosis of instability and those with clinically stable shoulders, no history of instability, and no MRA findings of instability were identified and compared. Humeral rotation, glenoid retroversion, humeral head subluxation, capsular length, and capsular area using axial sequences of IR and ER views were recorded. Analysis compared IR, ER, and Δ capsular measurements between groups using independent t tests and univariate and multivariate regression.

Results: Thirty-one subjects who were diagnosed with instability were included, along with 28 control subjects. Capsular length, capsular area, and humeral subluxations were significantly greater with ER compared with IR views (P < .001, P < .001, P < .001). Patients with instability displayed greater ER capsular length (P = .0006) and ER capsular area (P = .005) relative to controls. Multivariate logistic regression identified age, weight, sex, ER capsular length, and retroversion to be significant predictors of instability. ER capsular length independently predicts instability with 86% sensitivity and 84% specificity. Interobserver reliability using the intraclass correlation coefficient was rated good or excellent on all measurements.

Conclusion: Variance in humeral rotation during shoulder MRA significantly affects capsular measurements. Rotational views increase the utility of capsular measurements when assessing for instability, particularly capsular length and capsular area. The implementation of ER positioning enhances the ability to examine capsular changes of the shoulder joint and can assist in the diagnosis of instability.

Level Of Evidence: III, retrospective comparative study.
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http://dx.doi.org/10.1016/j.arthro.2020.09.014DOI Listing
January 2021

Shoulder motion decreases as body mass increases in patients with asymptomatic shoulders.

JSES Int 2020 Sep 27;4(3):438-442. Epub 2020 Jun 27.

Medical University of South Carolina, Charleston, SC, USA.

Background: Higher complication rates are reported after shoulder arthroplasty in obese patients. Understanding the effect of body mass index (BMI) on range of motion (ROM) in asymptomatic shoulders may be useful in evaluating clinical outcomes for patients of varying BMIs presenting with shoulder pathology. The purpose of this study is to investigate patient characteristics, in particular BMI, that may affect ROM outcomes after shoulder arthroplasty.

Methods: Individuals aged 18 years or older (mean 57.21 ± 16.27 years) were recruited with asymptomatic shoulder presentation and without history of shoulder injury. A total of 224 shoulders were grouped into 4 BMI categories, and ROM was measured with a goniometer. Analysis was performed between patient demographics and ROM.

Results: Analyzed continuously, BMI negatively correlated with ROM for internal rotation (IR;  = -0.511, < .01), forward elevation (FE;  = -0.418, < .01), and external rotation (ER;  = -0.328, < .01). ROM analyzed by BMI category revealed a dose effect of BMI vs ROM. Obese patients demonstrated a significant decrease in IR whereas morbidly obese patients had significant decreases for all ranges: IR ( = -0.469, < .01), FE ( = -0.452, < .01), and ER ( = -0.33, < .01). Normal- and overweight patients revealed no significant correlations with ROM.

Conclusion: As BMI is negatively correlated with ROM of the asymptomatic shoulder, patients with higher BMIs may be predisposed to diminished outcomes postoperatively. These baseline correlations will allow surgeons to make postoperative expectations and anticipate poorer outcomes of shoulder ROM in obese patients.
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http://dx.doi.org/10.1016/j.jseint.2020.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479022PMC
September 2020

Preoperative external rotation deficit does not predict poor outcomes or lack of improvement after reverse total shoulder arthroplasty.

J Orthop 2020 Sep-Oct;21:379-383. Epub 2020 Aug 22.

Medical University of South Carolina, Charleston, SC, USA.

Introduction: The purpose was to compare postoperative outcomes and functional improvement between patients with preoperative aER deficits vs. preserved aER function.

Results: There were 115 patients in the <0° aER group and 314 in the ≥30° aER group. Preoperative patients in the <0° group were worse for all measures except subjective pain while post-operatively, they had significantly greater improvement for all measures of motion. Postoperatively, both groups achieved comparable scores for forward elevation, pain, SST and ASES.

Conclusion: This study demonstrates that patients with a complete aER deficit can recover substantial and comparable function after RTSA.
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http://dx.doi.org/10.1016/j.jor.2020.08.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475072PMC
August 2020

Quality Testing of Difficult-to-Make Prescription Pharmaceutical Products Marketed in the US.

JAMA Netw Open 2020 08 3;3(8):e2013920. Epub 2020 Aug 3.

Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland.

Importance: Health care practitioners and patients must have information to support their confidence in the quality of prescription pharmaceuticals.

Objective: To determine whether there were clear and substantive differences in major quality attributes between difficult-to-make solid oral dosage form pharmaceutical products marketed in the US.

Design, Setting, And Participants: This quality improvement study analyzed US Food and Drug Administration-collected samples of 252 drug products marketed in the US and manufactured in the US, Canada, Europe, India, and the rest of Asia. These drug products were immediate-release solid oral dosage forms considered difficult to make on the basis of product quality history. This sampling included 35 innovator and 217 generic drug samples manufactured by 46 different firms containing 17 different active ingredients. Statistical analysis was performed from February to November 2019.

Main Outcomes And Measures: All products were tested within their shelf life on the basis of the legally recognized tests of the US Pharmacopeia for the major quality attributes of dosage unit uniformity and dissolution. These tests measure dosage consistency and drug release, respectively. The consistency of either attribute was used to calculate a process performance index to describe the variability in manufacturing.

Results: All 252 drug product samples met the US market standards for dosage unit uniformity and dissolution, although the process performance index (Ppk) for dissolution fell below the level of 4-sigma capability (ie, <1 error per 1600) for 11 different manufacturers and for generics in 4 of 5 regions, including the US. As part of a retrospective analysis, manufacturers performing above the median Ppk for either dissolution or dosage unit uniformity submitted fewer product quality defect reports (mean field alert reports of 0.22 and 0.63, respectively) than those falling at or below the median Ppk for these attributes (mean field alert reports of 2.1 and 1.7, respectively).

Conclusions And Relevance: All samples met the US market standards for dosage unit uniformity and dissolution, indicating acceptability for use by patients regardless of manufacturer or region. To our knowledge, this is the largest sampling study of pharmaceutical manufacturers for the US market and these data provide objective insight into the quality of prescription drugs with high manufacturing risks.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.13920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445591PMC
August 2020

DNMT1 and DNMT3B regulate tumorigenicity of human prostate cancer cells by controlling RAD9 expression through targeted methylation.

Carcinogenesis 2021 02;42(2):220-231

Center for Radiological Research, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.

Prostate cancer is the second most common type of cancer and the second leading cause of cancer death in American men. RAD9 stabilizes the genome, but prostate cancer cells and tumors often have high quantities of the protein. Reduction of RAD9 level within prostate cancer cells decreases tumorigenicity of nude mouse xenographs and metastasis phenotypes in culture, indicating that RAD9 overproduction is essential for the disease. In prostate cancer DU145 cells, CpG hypermethylation in a transcription suppressor site of RAD9 intron 2 causes high-level gene expression. Herein, we demonstrate that DNA methyltransferases DNMT1 and DNMT3B are highly abundant in prostate cancer cells DU145, CWR22, LNCaP and PC-3; yet, these DNMTs bind primarily to the transcription suppressor in DU145, the only cells where methylation is critical for RAD9 regulation. For DU145 cells, DNMT1 or DNMT3B shRNA reduced RAD9 level and tumorigenicity, and RAD9 ectopic expression restored this latter activity in the DNMT knockdown cells. High levels of RAD9, DNMT1, DNMT3B and RAD9 transcription suppressor hypermethylation were significantly correlated in prostate tumors, and not in normal prostate tissues. Based on these results, we propose a novel model where RAD9 is regulated epigenetically by DNMT1 and DNMT3B, via targeted hypermethylation, and that consequent RAD9 overproduction promotes prostate tumorigenesis.
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http://dx.doi.org/10.1093/carcin/bgaa088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905840PMC
February 2021

Comparison of complication types and rates associated with anatomic and reverse total shoulder arthroplasty.

J Shoulder Elbow Surg 2021 Apr 4;30(4):811-818. Epub 2020 Aug 4.

Medical University of South Carolina, Charleston, SC, USA.

Background: Complications after anatomic (aTSA) and reverse (rTSA) total shoulder arthroplasty can be devastating to a patient's quality of life and require revisions that are costly to both the patient and the health care system. The purpose of this study is to determine the types, incidence, and timing of complications following aTSA and rTSA using an international database of patients who received a single-platform total shoulder arthroplasty system, in order to quantify the types of failure modes and the differences that occur between aTSA and rTSA.

Methods: A total of 2224 aTSA (male-female, 1090:1134) and 4158 rTSA (male-female, 1478:2680) patients were enrolled in an international database of primary shoulder arthroplasty performed by 40 different surgeons in the United States and Europe. Adverse events and revisions reported for these 6382 patients were analyzed to identify the most common failure modes associated for both aTSA and rTSA.

Results: For the 2224 aTSA patients, 239 adverse events were reported for a complication rate of 10.7% and 124 revisions for a revision rate of 5.6%. The top 3 complications for aTSA were rotator cuff tear/subscapularis failure (n = 69; complication rate = 3.1%, revision rate = 1.9%), aseptic glenoid loosening (n = 55; complication rate = 2.5%, revision rate = 1.9%), and infection (n = 28; complication rate = 1.3%, revision rate = 0.8%). For the 4158 rTSA patients, 372 adverse events were reported for a complication rate of 8.9% and 104 revisions for a revision rate of 2.5%. The top 3 complications for rTSA were acromial/scapular fracture/pain (n = 102; complication rate = 2.5%, revision rate = 0.0%), instability (n = 60; complication rate = 1.4%, revision rate = 1.0%), and pain (n = 49; complication rate = 1.2%, revision rate = 0.2%).

Conclusions: This large database analysis quantified complication and revision rates for aTSA and rTSA. We found aTSA and rTSA complication rates of 10.7% and 8.9%, respectively; with revision surgery rates of 5.6% and 2.5%, respectively. The 2 most common complications for each prosthesis type (aTSA: subscapularis/rotator cuff tears, aseptic glenoid loosening; rTSA: acromial/scapular fractures, instability) were unique to each device. The rate of infection was similar for both. Future prosthesis and technique development should work to mitigate these common complication types in order to reduce their rate of occurrence.
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http://dx.doi.org/10.1016/j.jse.2020.07.028DOI Listing
April 2021

Reliability of the modified Walch classification for advanced glenohumeral osteoarthritis using 3-dimensional computed tomography analysis: a study of the ASES B2 Glenoid Multicenter Research Group.

J Shoulder Elbow Surg 2021 Apr 23;30(4):736-746. Epub 2020 Jul 23.

ASES B2 Glenoid Multicenter Research Group.

Background: Variations in glenoid morphology affect surgical treatment and outcome of advanced glenohumeral osteoarthritis (OA). The purpose of this study was to assess the inter- and intraobserver reliability of the modified Walch classification using 3-dimensional (3D) computed tomography (CT) imaging in a multicenter research group.

Methods: Deidentified preoperative CTs of patients with primary glenohumeral OA undergoing anatomic or reverse total shoulder arthroplasty (TSA) were reviewed with 3D imaging software by 23 experienced shoulder surgeons across 19 institutions. CTs were separated into 2 groups for review: group 1 (96 cases involving all modified Walch classification categories evaluated by 12 readers) and group 2 (98 cases involving posterior glenoid deformity categories [B2, B3, C1, C2] evaluated by 11 readers other than the first 12). Each case group was reviewed by the same set of readers 4 different times (with and without the glenoid vault model present), blindly and in random order. Inter- and intraobserver reliabilities were calculated to assess agreement (slight, fair, moderate, substantial, almost perfect) within groups and by modified Walch classification categories.

Results: Interobserver reliability showed fair to moderate agreement for both groups. Group 1 had a kappa of 0.43 (95% confidence interval [CI]: 0.38, 0.48) with the glenoid vault model absent and 0.41 (95% CI: 0.37, 0.46) with it present. Group 2 had a kappa of 0.38 (95% CI: 0.33, 0.43) with the glenoid vault model absent and 0.37 (95% CI: 0.32, 0.43) with it present. Intraobserver reliability showed substantial agreement for group 1 with (0.63, range 0.47-0.71) and without (0.61, range 0.52-0.69) the glenoid vault model present. For group 2, intraobserver reliability showed moderate agreement with the glenoid vault model absent (0.51, range 0.30-0.72), which improved to substantial agreement with the glenoid vault model present (0.61, range 0.34-0.87).

Discussion: Inter- and intraobserver reliability of the modified Walch classification were fair to moderate and moderate to substantial, respectively, using standardized 3D CT imaging analysis in a large multicenter study. The findings potentially suggest that cases with a spectrum of posterior glenoid bone loss and/or dysplasia can be harder to distinguish by modified Walch type because of a lack of defined thresholds, and the glenoid vault model may be beneficial in determining Walch type in certain scenarios. The ability to reproducibly separate patients into groups based on preoperative pathology, including Walch type, is important for future studies to accurately evaluate postoperative outcomes in TSA patient cohorts.
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http://dx.doi.org/10.1016/j.jse.2020.07.013DOI Listing
April 2021

Why Humans Are Vulnerable to Conspiracy Theories.

Psychiatr Serv 2021 01 24;72(1):3-4. Epub 2020 Jul 24.

Department of Psychiatry, Weill Cornell Medical College, New York.

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http://dx.doi.org/10.1176/appi.ps.202000348DOI Listing
January 2021

RAGE impairs murine diabetic atherosclerosis regression and implicates IRF7 in macrophage inflammation and cholesterol metabolism.

JCI Insight 2020 07 9;5(13). Epub 2020 Jul 9.

Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine.

Despite advances in lipid-lowering therapies, people with diabetes continue to experience more limited cardiovascular benefits. In diabetes, hyperglycemia sustains inflammation and preempts vascular repair. We tested the hypothesis that the receptor for advanced glycation end-products (RAGE) contributes to these maladaptive processes. We report that transplantation of aortic arches from diabetic, Western diet-fed Ldlr-/- mice into diabetic Ager-/- (Ager, the gene encoding RAGE) versus WT diabetic recipient mice accelerated regression of atherosclerosis. RNA-sequencing experiments traced RAGE-dependent mechanisms principally to the recipient macrophages and linked RAGE to interferon signaling. Specifically, deletion of Ager in the regressing diabetic plaques downregulated interferon regulatory factor 7 (Irf7) in macrophages. Immunohistochemistry studies colocalized IRF7 and macrophages in both murine and human atherosclerotic plaques. In bone marrow-derived macrophages (BMDMs), RAGE ligands upregulated expression of Irf7, and in BMDMs immersed in a cholesterol-rich environment, knockdown of Irf7 triggered a switch from pro- to antiinflammatory gene expression and regulated a host of genes linked to cholesterol efflux and homeostasis. Collectively, this work adds a new dimension to the immunometabolic sphere of perturbations that impair regression of established diabetic atherosclerosis and suggests that targeting RAGE and IRF7 may facilitate vascular repair in diabetes.
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http://dx.doi.org/10.1172/jci.insight.137289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406264PMC
July 2020

Incidence of arrhythmias and electrocardiographic abnormalities in symptomatic pediatric patients with PCR-positive SARS-CoV-2 infection, including drug-induced changes in the corrected QT interval.

Heart Rhythm 2020 11 1;17(11):1960-1966. Epub 2020 Jul 1.

Section of Pediatric Cardiology and; Department of Pediatrics, Cohen Children's Medical Center, Northwell Health System, Donald and Barbara Zucker School of Medicine at Hofstra University, New Hyde Park, New York.

Background: There is limited data regarding the electrophysiological abnormalities and arrhythmias in children with COVID-19, including those associated with treatment using potentially proarrhythmic hydroxychloroquine (HCQ) and azithromycin (AZN).

Objectives: To describe the electrophysiologic findings and arrhythmias associated with pediatric COVID-19 and its treatment.

Methods: A single-center retrospective chart review was undertaken and included all patients with (1) symptoms of COVID-19 and (2) PCR-positive nasopharyngeal swabs for SARS-CoV-2 who were placed on continuous telemetry for the duration of their hospitalization during March through May, 2020.

Results: Thirty-six patients were included in the study. Significant arrhythmias were found in 6 (nonsustained ventricular tachycardia in 5 and sustained atrial tachycardia in 1). All were self-resolving and half prompted prophylactic antiarrhythmic therapy. Patients with significant arrhythmias were likely to have noncardiac comorbidities (4/6), but these were not more common than in patients without arrhythmias (20/30, P = 1). The use of HCQ was associated with statistically significant QTc prolongation (413 ± 19 ms vs 425 ± 16 ms, P =.005). QTc was not statistically different in patients with and without arrhythmias (425 ± 15 ms vs 425 ± 15 ms, P = 1).

Conclusions: In pediatric patients with PCR-positive active COVID-19 infection, significant arrhythmias are infrequent, but are more common than expected in a general pediatric population. Comorbidities are not more common in patients with arrhythmias than in patients without arrhythmias. COVID-19 treatment using HCQ is associated with QTc prolongation but was not associated with arrhythmias in pediatric patients.
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http://dx.doi.org/10.1016/j.hrthm.2020.06.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328618PMC
November 2020

The effect of body mass index on internal rotation and function following anatomic and reverse total shoulder arthroplasty.

J Shoulder Elbow Surg 2021 Feb 30;30(2):265-272. Epub 2020 Jun 30.

Medical University of South Carolina, Department of Orthopaedics, Charleston, SC, USA.

Background: The exact relationship between body mass index (BMI) and internal rotation (IR) before and after total shoulder arthroplasty has not been studied to date. The purpose of this study was to determine the effects of BMI on the preoperative and postoperative shoulder range of motion and function in anatomic (aTSA) and reverse total shoulder arthroplasty (rTSA), and specifically how IR affects patient ability to perform IR-related activities of daily living (ADLs).

Methods: Patients from a prospective multicenter international shoulder arthroplasty registry who underwent primary rTSA (n=1171) and primary aTSA (n=883) were scored preoperatively and at latest follow-up (2-10 years, mean = 3 years) using the Simple Shoulder Test, University of California-Los Angeles shoulder score, American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form, Constant score, and Shoulder Pain and Disability Index patient-reported outcome measures (PROMs). Measured active abduction, forward flexion, IR, and active and passive external rotation were recorded, and BMI was evaluated as a predictor of motion and patient-reported outcomes. Patient responses to questions regarding the difficulty level of IR-related ADLs were studied. The relationships between BMI, IR, and ability to perform IR-related ADLs were quantified through analysis of variance with post hoc comparisons by Tukey honestly significant difference tests, where significance was denoted as P < .05.

Results: BMI was found to be inversely correlated with IR in patients undergoing both aTSA and rTSA, both preoperatively (P < .001 and P = .002) and postoperatively (P < .001 and P < .001). BMI affected the range of motion parameters of forward flexion abduction and external rotation but to a lesser extent than that of IR. Nonobese patients demonstrated significantly greater IR than overweight, obese, and morbidly obese patients postoperatively for aTSA (P < .001). For rTSA, nonobese patients had a significantly greater postoperative IR than obese and morbidly obese patients (P < .001 and P = .011, respectively). For both aTSA and rTSA patients, mean IR scores significantly differed between patients reporting normal function vs. patients reporting slight difficulty, considerable difficulty, or inability to perform IR-related ADLs. Increasing IR demonstrated a significant, positive correlation with all PROMs for both aTSA and rTSA patients (Pearson correlation, P < .001).

Conclusions: BMI is an independent predictor of IR, even when controlling for age, gender, glenosphere size, and subscapularis repair. BMI was inversely correlated with the degree of IR, and decreased IR significantly negatively affected the ability to perform IR-related ADLs.

Clinical Relevance: Increasing BMI adversely affects shoulder ROM, particularly IR. IR is correlated with the ability to perform ADLs requiring IR in both aTSA and rTSA patients.
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http://dx.doi.org/10.1016/j.jse.2020.06.008DOI Listing
February 2021

Intraoperative Identification of Clavicle Fracture Patterns: Do Clavicles Fail in a Predictable Pattern?

J Orthop Trauma 2020 12;34(12):675-678

Department of Orthopaedic Surgery, Medical University of South Carolina, Charleston, SC.

Objectives: To characterize the fracture pattern and pattern of fragmentation for displaced, midshaft clavicle fractures undergoing operative management.

Design: Prospective observational study.

Setting: Two institutions. Level 1 and Level 2 Trauma Centers.

Patients/participants: Fifty-three patients who underwent operative repair of midshaft clavicle fracture.

Intervention: All clavicles were treated by operative open reduction internal fixation.

Main Outcome Measurements: All clavicles were categorized by the Robinson classification based on injury plain film bilateral upright clavicle radiographs. In addition, intraoperative fracture characteristics of fragment length and location were measured and recorded to evaluate the fracture pattern. All fractures were analyzed to determine the frequency of segmental comminution versus length-stable patterns, analyze characteristics of butterfly fragment size, number and location as well as the location of the cortical read for those length-stable fractures.

Results: Analysis revealed 55% were Robinson 2B2 based on preoperative radiographs. Length-stable, anatomic reduction was achievable in 83%. For those in which an anatomic cortical read was achievable, 97.7% had a read present in the posterior-superior aspect of the clavicle.

Conclusions: Midshaft clavicle fractures that meet conventional criteria for operative repair occur in a predictable manner with butterfly fragments generated from anterior-inferior compression and simple fracture line generated from tension along the posterior-superior aspect of the clavicle. Understanding this pattern can assist in the in surgical planning.
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http://dx.doi.org/10.1097/BOT.0000000000001801DOI Listing
December 2020

Notch Signaling Mediates Differentiation in Barrett's Esophagus and Promotes Progression to Adenocarcinoma.

Gastroenterology 2020 08 20;159(2):575-590. Epub 2020 Apr 20.

Department of Medicine, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York.

Background & Aims: Studies are needed to determine the mechanism by which Barrett's esophagus (BE) progresses to esophageal adenocarcinoma (EAC). Notch signaling maintains stem cells in the gastrointestinal tract and is dysregulated during carcinogenesis. We explored the relationship between Notch signaling and goblet cell maturation, a feature of BE, during EAC pathogenesis.

Methods: We measured goblet cell density and levels of Notch messenger RNAs in BE tissues from 164 patients, with and without dysplasia or EAC, enrolled in a multicenter study. We analyzed the effects of conditional expression of an activated form of NOTCH2 (pL2.Lgr5.N2IC), conditional deletion of NOTCH2 (pL2.Lgr5.N2fl/fl), or loss of nuclear factor κB (NF-κB) (pL2.Lgr5.p65fl/fl), in Lgr5 (progenitor) cells in L2-IL1B mice (which overexpress interleukin 1 beta in esophagus and squamous forestomach and are used as a model of BE). We collected esophageal and stomach tissues and performed histology, immunohistochemistry, flow cytometry, transcriptome, and real-time polymerase chain reaction analyses. Cardia and forestomach tissues from mice were cultured as organoids and incubated with inhibitors of Notch or NF-kB.

Results: Progression of BE to EAC was associated with a significant reduction in goblet cell density comparing nondysplastic regions of tissues from patients; there was an inverse correlation between goblet cell density and levels of NOTCH3 and JAG2 messenger RNA. In mice, expression of the activated intracellular form of NOTCH2 in Lgr5 cells reduced goblet-like cell maturation, increased crypt fission, and accelerated the development of tumors in the squamocolumnar junction. Mice with deletion of NOTCH2 from Lgr5 cells had increased maturation of goblet-like cells, reduced crypt fission, and developed fewer tumors. Esophageal tissues from in pL2.Lgr5.N2IC mice had increased levels of RelA (which encodes the p65 unit of NF-κB) compared to tissues from L2-IL1B mice, and we found evidence of increased NF-κB activity in Lgr5 cells. Esophageal tissues from pL2.Lgr5.p65fl/fl mice had lower inflammation and metaplasia scores than pL2.Lgr5.N2IC mice. In organoids derived from pL2-IL1B mice, the NF-κB inhibitor JSH-23 reduced cell survival and proliferation.

Conclusions: Notch signaling contributes to activation of NF-κB and regulates differentiation of gastric cardia progenitor cells in a mouse model of BE. In human esophageal tissues, progression of BE to EAC was associated with reduced goblet cell density and increased levels of Notch expression. Strategies to block this pathway might be developed to prevent EAC in patients with BE.
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http://dx.doi.org/10.1053/j.gastro.2020.04.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484392PMC
August 2020

and Mutations Promote 4NQO-Initated Head and Neck Tumor Progression and Metastasis in Mice.

Mol Cancer Res 2020 06 9;18(6):822-834. Epub 2020 Mar 9.

Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York.

The PI3K signaling pathway is frequently mutated in head and neck squamous cell carcinoma (HNSCC), often via gain-of-function (GOF) mutations in the gene. Here, we present novel genetically engineered mouse models (GEMM) carrying a GOF allele (E20) alone or in combination with heterozygous - (p53) mutation with tissue-specific expression to interrogate the role of oncogenic in transformation of upper aerodigestive track epithelium. We demonstrated that the GOF mutation promoted progression of 4-nitroquinoline 1-oxide-induced oral squamous cell carcinoma (OSCC) in both E20 single mutant and E20/p53 double mutant mice, with frequent distal metastasis detected only in E20/p53 GEMM. Similar to in human OSCC, loss of p16 was associated with progression of OSCC in these mice. RNA-seq analyses revealed that among the common genes differentially expressed in primary OSCC cell lines derived from E20, p53, and E20/p53 GEMMs compared with those from the wild-type mice, genes associated with proliferation and cell cycle were predominantly represented, which is consistent with the progressive loss of p16 detected in these GEMMs. Importantly, all of these OSCC primary cell lines exhibited enhanced sensitivity to BYL719 and cisplatin combination treatment in comparison with cisplatin alone and , regardless of p53 and/or p16 status. Given the prevalence of mutations in and the PI3K pathways in HNSCC in conjunction with loss of p16 genetically or epigenetically, this universal increased sensitivity to cisplatin and BYL719 combination therapy in cancer cells with mutation represents an opportunity to a subset of patients with HNSCC. IMPLICATIONS: Our results suggest that combination therapy of cisplatin and PI3K inhibitor may be worthy of consideration in patients with HNSCC with mutation.
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http://dx.doi.org/10.1158/1541-7786.MCR-19-0549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272268PMC
June 2020

Pitch count adherence and injury assessment of youth baseball in South Carolina.

J Orthop 2020 Sep-Oct;21:62-68. Epub 2020 Feb 5.

Medical University of South Carolina, Department of Orthopaedic Surgery and Physical Rehabilitation, Department of Pediatrics, USA.

Introduction: Overuse injury in youth overhead athletes remains a concern. The introduction of pitch count guidelines was designed to limit the number of pitches per game. South Carolina is considered a warm weather climate which has been proven to expose overhead athletes to higher risk for injury. The purpose of this study was to detect baseline rates of arm pain and sequelae (injury, surgery, impact on participation) among southern youth baseball/softball players to better counsel players, parents, coaches and league administration on the prevention of arm injury.

Methods: A survey was distributed to 14 pediatric practices within the South Carolina Pediatric Practice Research Network. The 2-page survey included 28 closed-ended and descriptive questions that investigated physical and psychosocial responses during and after play. Additional questions were conducted on adherence and understanding of USA Baseball guidelines and pitch counting behavior.

Results: Two hundred and seventy three surveys were completed by parents of baseball/softball players. The players' average age was 11.6 years, who played on an average of 1.78 teams/leagues for 5.2 months each year. Only 26% of baseball players answered "Sometimes", "Often" or "Always" to their arm hurting. Arm fatigue, older age, parent/coach frustration with play, and months played were statistically significantly associated with arm pain. The survey revealed 58.9% of families were familiar with pitch count guidelines.

Discussion: Arm pain is relatively prevalent among the South Carolina youth baseball community and worse in older players and experience fatigue. This survey found lower percentage of youth overhead athletes experiencing arm discomfort when compared to prior studies. It is important for warm weather climate athletes to abide by guidelines, as they are more susceptible to arm injury. Increased recognition, education and compliance with pitch count guidelines will help protect these youth athletes from overuse injury.

Level Of Evidence: IV, Descriptive Epidemiology Study.
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http://dx.doi.org/10.1016/j.jor.2020.01.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036446PMC
February 2020

Targeting MEK5 impairs nonhomologous end-joining repair and sensitizes prostate cancer to DNA damaging agents.

Oncogene 2020 03 24;39(12):2467-2477. Epub 2020 Jan 24.

Center for Radiological Research, Columbia University Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.

Radiotherapy is commonly used to treat a variety of solid human tumors, including localized prostate cancer. However, treatment failure often ensues due to tumor intrinsic or acquired radioresistance. Here we find that the MEK5/ERK5 signaling pathway is associated with resistance to genotoxic stress in aggressive prostate cancer cells. MEK5 knockdown by RNA interference sensitizes prostate cancer cells to ionizing radiation (IR) and etoposide treatment, as assessed by clonogenic survival and short-term proliferation assays. Mechanistically, MEK5 downregulation impairs phosphorylation of the catalytic subunit of DNA-PK at serine 2056 in response to IR or etoposide treatment. Although MEK5 knockdown does not influence the initial appearance of radiation- and etoposide-induced γH2AX and 53BP1 foci, it markedly delays their resolution, indicating a DNA repair defect. A cell-based assay shows that nonhomologous end joining (NHEJ) is compromised in cells with ablated MEK5 protein expression. Finally, MEK5 silencing combined with focal irradiation causes strong inhibition of tumor growth in mouse xenografts, compared with MEK5 depletion or radiation alone. These findings reveal a convergence between MEK5 signaling and DNA repair by NHEJ in conferring resistance to genotoxic stress in advanced prostate cancer and suggest targeting MEK5 as an effective therapeutic intervention in the management of this disease.
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http://dx.doi.org/10.1038/s41388-020-1163-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085449PMC
March 2020
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