Therapeutic TNF-alpha Delivery After CRISPR Receptor Modulation in the Intervertebral Disc.

Low back pain (LBP) ranks among the leading causes of disability worldwide and generates a tremendous socioeconomic cost. Disc degeneration, a leading contributor to LBP, can be characterized by the breakdown of the extracellular matrix of the intervertebral disc (IVD), disc height loss, and inflammation. The inflammatory cytokine TNF-α has multiple pathways and has been implicated as a primary mediator of disc degeneration. We tested our ability to regulate the multiple TNF-α inflammatory signaling pathways in vivo utilizing CRISPR receptor modulation to slow the progression of disc degeneration in rats. Sprague-Dawley rats were treated with CRISPRi-based epigenome-editing therapeutics targeting TNFR1 and showed a decrease in behavioral pain in a disc degeneration model. Surprisingly, while treatment with the vectors alone was therapeutic, TNF-α injection itself became therapeutic after TNFR1 modulation. These results suggest direct inflammatory receptor modulation, to harness beneficial inflammatory signaling pathways, as a potent strategy for treating disc degeneration.

Risk of Total Wrist Arthrodesis Following Proximal Row Carpectomy: An Analysis of 1,070 Patients.

PURPOSE: Proximal row carpectomy (PRC) is a motion-sparing procedure with good patient-reported and clinical outcomes. Although some studies have investigated the risk of conversion to total wrist arthrodesis (TWA) after PRC, additional larger studies evaluating the specific risk factors that lead to failure are required. This study aimed to investigate the patient and procedure factors that are associated with increased risk for conversion to TWA in a large cohort of patients who underwent PRC. METHODS: The current procedural technology codes identified patients in a National Veteran's Health database undergoing a PRC over a 26-year period. Risk factors of interest comprised age, posterior interosseous nerve neurectomy, wrist arthritis pattern, bilateral surgery, smoking, comorbidities, and preoperative opioid use. The primary outcome was the rate of conversion to TWA. Cox proportional hazard regression was used to create hazard ratios of selected factors for reoperation. RESULTS: There were 1,070 PRCs performed, with a mean follow-up of 79.8 ± 59.6 months. A total of 5.3% (57/1,070) wrists underwent conversion to TWA. Younger age at the time of PRC (<50 years) significantly increased the risk of TWA (hazard ratio, 3.8; 95% confidence interval, 2.2-6.6). With every 1-year increase in age, there was a reduction of 4% (hazard ratio, 0.96; 95% confidence interval: 0.94-0.98) in the hazard of conversion to TWA. No other factors, including concomitant posterior interosseous nerve neurectomy or bilateral PRC, increased the risk of conversion to TWA. CONCLUSIONS: Proximal row carpectomy is a motion-preserving salvage procedure with a low rate of conversion to wrist arthrodesis. Younger patient age increases the risk of conversion to arthrodesis, whereas posterior interosseous nerve neurectomy, bilateral PRCs, and comorbidity status do not appear to have an impact on the risk of arthrodesis. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic II.

Risk Factors for Postoperative Ileus in Patients Undergoing Spine Surgery.

STUDY DESIGN: Retrospective Cohort Study. OBJECTIVES: Postoperative ileus (POI) is a common complication following elective spinal surgeries. The aim of this study was to determine the incidence of POI and identify demographic and surgical risk factors for developing POI after elective instrumented fusion of the thoracolumbar spine. METHODS: The University of Utah Institutional Review Board (IRB) approved this retrospective study. The study does not require informed consent given the data reviewed was deidentified and collected in accordance with the institution's standard of care. A designated IRB committee determined that study is exempt under exemption category 7. IRB approval number 00069703. Patients undergoing instrumented thoracolumbar fusion for one or more levels were retrospectively identified from an internal spine surgery database. Cases performed for trauma, infection, or tumors were excluded. Demographics, medical comorbidities, surgical variables, and opioid medication administration (morphine milligram equivalents, MME) were abstracted from the electronic medical record. Univariate analysis was used to identify variables associated with POI. These variables were then tested for independent association with POI using multivariate logistic regression. RESULTS: 418 patients were included in the current study. The incidence of POI was 9.3% in this cohort. There was no significant relationship between development of POI and patient age, gender, BMI, diabetes mellitus, thyroid dysfunction, lung disease, CKD, GERD, smoking status, alcohol abuse, anemia, or prior abdominal surgery. Univariate analysis demonstrated significant association between POI and fusion ≥7 levels compared to fusions of fewer levels (P = .001), as well as intraoperative sufentanil compared to other opioids (35.9% vs 20.1%, P = .02). POI was not significantly associated with total intraoperative MME, approach, use of interbody cage, or osteotomy. Multivariate logistic regression confirmed total 24-hour postoperative MME as an independent risk factor for POI (OR 1.004, P = .04), however, intraoperative sufentanil administration was not an independent risk factor for POI when controlling for other variables. CONCLUSIONS: This retrospective cohort study demonstrates that greater postoperative MME is an independent risk factor for POI after thoracolumbar spine fusion when accounting for demographic, medical, and surgical variables with multiple logistic regression. Prospective studies are warranted to evaluate clinical measures to decrease the risk of POI among patients undergoing instrumented thoracolumbar spinal fusions.

Establishing the Substantial Clinical Benefit in a Non-Shoulder Hand and Upper Extremity Population for the QuickDASH and PROMIS Upper Extremity and Physical Function Computer Adaptive Tests.

PURPOSE: It is unclear what score changes on the abbreviated Disabilities of the Arm, Hand, and Shoulder (QuickDASH), Patient-Reported Outcomes Measurement Information System (PROMIS) upper extremity (UE) computer adaptive test (CAT), and PROMIS physical function (PF) CAT represent a substantial improvement. We calculated the substantial clinical benefit (SCB) for these 3 instruments in a non-shoulder hand and upper extremity population. METHODS: Adult patients treated between March 2015 and September 2019 at a single academic tertiary institution were identified. The QuickDASH, PROMIS UE CAT v2.0, and PROMIS PF CAT v2.0 scores were collected using a tablet computer. Responses to the QuickDASH both at baseline and follow-up 6 ± 4 weeks later, and a response to the anchor question "Compared to your first evaluation at the University Orthopaedic Center, how would you describe your physical function level now?" were required for inclusion. A second anchor question querying treatment-related improvement was also used. The SCB was calculated using an anchor-based approach comparing the mean change difference between groups reporting no change and a maximal change for both anchor questions. RESULTS: Of 1,119 included participants, the mean age was 48 ± 17 years, 53% were women, and half were recovering from surgery. Score changes between baseline and follow-up were significantly different between groups reporting no improvement and maximal improvement on both anchor questions. The SCB values ranged between 16.9 and 22.8 on the QuickDASH, 5.9 and 7.1 on the UE CAT, and 3.5 and 6.7 on the PF CAT. CONCLUSIONS: These score improvements for the QuickDASH, UE CAT, and PF CAT represent a substantial clinical improvement in a non-shoulder hand and upper extremity population. CLINICAL RELEVANCE: These SCB estimates may assist with the interpretation of outcome scores at a population level.

Evaluating the Impact of Social Deprivation on Mid-Term Outcomes Following Distal Radius Open Reduction Internal Fixation.

PURPOSE: Although baseline biopsychosocial factors are associated with short-term patient-reported outcomes following distal radius fracture open reduction internal fixation (ORIF), their effect on mid-term outcomes is unclear. We aimed to evaluate the effect of social deprivation, previously established as a surrogate for depression, pain interference, and anxiety, on quick Disabilities of the Arm, Shoulder and Hand (QuickDASH) scores >1 year following distal radius ORIF. METHODS: Adult patients (≥18 years) with an isolated distal radius fracture treated with ORIF by orthopedic trauma and hand surgeons at a single tertiary academic center over a 3-year period were included. Outcomes at ≥1 year postoperatively were evaluated using QuickDASH. Age, follow-up duration, area deprivation index (ADI; a measure of social deprivation), subspecialty (hand vs trauma), and postoperative alignment were assessed using linear regression with 95% confidence intervals after bootstrapping and a permutation test for P values to test for their association with the final QuickDASH score. RESULTS: Follow-up data were obtained for 98 of 220 (44.5%) patients at a mean of 3.1 ± 1.0 years after surgery. Mean age and ADI were 53.2 ± 15.4 years and 26.8 ± 18.7, respectively. Most fractures were intra-articular (67.3%), and 72.4% had acceptable postoperative alignment parameters, as defined by the American Academy of Orthopaedic Surgeons clinical practice guidelines. The mean QuickDASH score was 13.0 ± 16.5. There were no significant associations between the final QuickDASH score and any studied factor, including ADI, as determined using univariable analysis. Multivariable analysis showed no association between ADI and the final QuickDASH score, independent of age, sex, treating service, follow-up duration, and fracture alignment or pattern. CONCLUSIONS: At mid-term follow up after distal radius ORIF, ADI did not correlate with QuickDASH scores, and the QuickDASH scores of the patients did not differ from those of the general population. However, our cohort mostly comprised patients with levels of deprivation below the national median. Although studies have shown that the short-term outcomes of distal radius ORIF are influenced by biopsychosocial factors, outcomes at the time of final recovery may not be associated with social deprivation. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV.

Establishing the Minimal Clinically Important Difference for the PROMIS Upper Extremity Computer Adaptive Test Version 2.0 in a Nonshoulder Hand and Upper Extremity Population.

PURPOSE: Our primary purpose was to calculate the minimal clinically important difference (MCID) for the Patient-Reported Outcomes Measurement Information System (PROMIS) Upper Extremity (UE) Computer Adaptive Test (CAT) version 2.0 (v2.0) for a nonshoulder hand and upper extremity population. Secondarily, we calculated the PROMIS Physical Function (PF) CAT v2.0 and the abbreviated version of the Disabilities of the Arm, Shoulder, and Hand (QuickDASH) MCID. METHODS: Adult patients treated by 1 of 5 fellowship-trained hand surgeons between March 2015 and September 2019 at an academic tertiary institution were identified. The PROMIS UE CAT v2.0, PROMIS PF CAT v2.0, and QuickDASH were collected via tablet computer. Inclusion required response to at least 1 of the instruments at both baseline and follow-up (6 ± 4 weeks), and a response to the anchor question: "Compared to your first evaluation at the University Orthopaedic Center, how would you describe your physical function level now?" An additional anchor question assessing treatment-related improvement was also asked. The MCID was calculated using an anchor-based approach using the mean change difference between groups reporting no change and slight change for both anchor questions, and with the 1/2 SD method. RESULTS: Of 2,106 participants, mean age was 48 ± 17 years, 53% were female, and 53% were recovering from surgery. Of these patients, 381 completed the PROMISE UE CAT v2.0, 497 completed the PROMIS PF CAT v2.0, and 2,018 completed the QuickDASH. The score change between baseline and follow-up was significantly different between anchor groups for both anchor-based MCID calculations. Anchor-based MCID values were 3.0 to 4.0 for the UE CAT, 2.1 to 3.6 for the PF CAT, and 10.3 for the QuickDASH. The MCID values per the 1/2 SD method were 4.1, 4.1, and 10.2, respectively. CONCLUSIONS: We propose MCID ranges of 3.0 to 4.1 for the PROMIS UE CAT v2.0, and 2.1 to 4.1 for the PROMIS PF CAT v2.0. The observed QuickDASH MCID values (10.2-10.3) are within the range of previously published values. CLINICAL RELEVANCE: These MCID estimates will aid in interpreting clinical outcomes and in powering clinical studies.

Evaluation of factors driving cost variation for distal humerus open reduction internal fixation.

BACKGROUND: Distal humerus fracture open reduction and internal fixation (ORIF) represents a substantial cost burden to the health care system. The purpose of this study was to describe surgical encounter cost variation for distal humerus ORIF, and to determine demographic-, injury-, and treatment-specific factors that influence cost. METHODS: We retrospectively identified adult patients (≥18 years) treated for isolated distal humerus fractures between July 2014 and July 2019 at a single tertiary academic referral center. For each case, surgical encounter total direct costs (SETDCs) were obtained via our institution's information technology value tools, which prospectively record granular direct cost data for every health care encounter. Costs were converted to 2019 dollars using the personal consumption expenditure indices for health and summarized with descriptive statistics. Univariate and multivariate linear regression models were used to identify factors influencing SETDC. RESULTS: Surgical costs varied widely for the 47 included patients, with a standard deviation (SD) of 33% and interquartile range of 76%-124% relative to the mean SETDC. Implant and facility costs were responsible for 46.2% and 32.6% of the SETDC, respectively. Implant costs also varied considerably, with an SD of 21% and range from 13%-36% relative to the mean SETDC. Multivariate analysis demonstrated that SETDC increased 24% (P < .001) on performing an olecranon osteotomy, and by 15% for each additional 1 hour of surgical time (P < .001). These findings were independent of age, sex, body mass index, open fracture, need for an additional small plate construct as a reduction aid, and fracture pattern (all insignificant in the multivariate analysis, with P >.05 for each factor). CONCLUSION: Substantial variations in surgical encounter total direct costs for distal humerus ORIF exist, as do wide variations in associated implant costs that comprise nearly half of the entire surgical cost. Performing an olecranon osteotomy, and increased surgical time, significantly increased surgical costs. Although use of an olecranon osteotomy may not be a completely controllable factor as it is confounded by fracture severity and operative time, this may suggest that surgeons should try to use an olecranon osteotomy judiciously. Although complexity of the fracture pattern was statistically insignificant, it is confounded by the need for an olecranon osteotomy and increased surgical time and likely is a clinically relevant and nonmodifiable driver of surgical cost. These findings highlight opportunities to reduce cost variation, and potentially improve the value of care, for distal humerus ORIF patients.

Predictors of Readmission and Prolonged Length of Stay After Cervical Disc Arthroplasty.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: The aim of the study was to assess which factors increase risk of readmission within 30 days of surgery or prolonged length of stay (LOS) (≥2 days) after cervical disc arthroplasty (CDA). SUMMARY OF BACKGROUND DATA: Several studies have shown noninferiority at mid- and long-term outcomes after cervical disc arthroplasty (CDA) compared to anterior cervical discectomy and fusion ACDF, but few have evaluated short-term outcomes regarding risk of readmission or prolonged LOS after surgery. METHODS: Demographics, comorbidities, operative details, postoperative complications, and perioperative outcomes were collected for patients undergoing single level CDA in the National Surgical Quality Improvement Program (NSQIP) database. Patients with prolonged LOS, defined as >2 days, and readmission within 30 days following CDA were identified. Univariable and multivariable logistic regression models were used to identify risk factors for prolonged LOS and readmission. RESULTS: A total of 3221 patients underwent single level CDA. Average age was 45.6 years (range 19-82) and 53% of patients were male. A total of 472 (14.7%) experienced a prolonged LOS and 36 (1.1%) patients were readmitted within 30 days following surgery. Predictors of readmission were postoperative superficial wound infection (odds ratio [OR] = 73.83, P < 0.001), American Society of Anesthesiologists (ASA) classification (OR = 1.98, P = 0.048), and body mass index (BMI) (OR = 1.06, P = 0.02). Female sex (OR = 1.76, P < 0.001), diabetes (OR = 1.50, P = 0.024), postoperative wound dehiscence (OR = 13.11, P = 0.042), ASA class (OR = 1.43, P < 0.01), and operative time (OR = 1.01, P < 0.001) were significantly associated with prolonged LOS. CONCLUSION: From a nationwide database analysis of 3221 patients, wound complications are predictors of both prolonged LOS and readmission. Patient comorbidities, including diabetes, higher ASA classification, female sex, and higher BMI also increased risk of prolonged LOS or readmission.Level of Evidence: 3.

Educational Resource Utilization by Current Orthopaedic Surgical Residents: A Nation-wide Survey.

BACKGROUND: More than 150 accredited orthopaedic residency programs exist in the United States with more than 3,300 residents. Every year, between 600 and 800 orthopaedic surgeons complete board certification. However, little is known about what residents use and prefer of the many resources available to them. The purpose of this study is to understand how orthopaedic residents across the country prioritize educational resources. METHODS: An 18-question survey with subqueries was compiled on the REDCap (Research Electronic Data Capture) platform. Residents were reached through program coordinators, program directors, and word of mouth. There were 374 total respondents. Responses were summarized for the total population and stratified separately by sex, location, and year of training. P values were adjusted for multiple comparisons using the Bonferroni method. RESULTS: Respondents were 83.4% male and 16.6% female. Orthobullets was the single most valued resource and general review articles were the single most valued journal resource. The average time spent studying was 10.7 hr/wk (SD = 7.6), with no notable differences by program location or sex. A significantly larger percentage of female residents placed more importance on specialty-specific journals (32.8% rated as very important versus 19.9% from males, P = 0.016) and research-related journals (P = 0.004). VuMedi use significantly increased until postgraduate year-4 (P < 0.001), whereas residents earlier in training used YouTube more often (P = 0.026). There were differences in journal prioritization by program region, with the Midwest, Northeast, and South preferring primary, focused articles and the Northeast, South, and West emphasizing systematic review articles (P = 0.032). Industry-sponsored events were used by 67.4% of residents as an educational adjunct. CONCLUSIONS: Current residents-regardless of sex, location, and year in training-use Orthobullets and other electronic resources. There continues to be utilization of industry-sponsored resources, although they are not the primary focus for those in training.

Long-term outcomes of antegrade continence enema in children with chronic encopresis and incontinence: what is the optimal flush to use?

PURPOSE: Severe constipation and encopresis are significant problems in the pediatric population. Medical management succeeds in 50-70%; however, surgical considerations are necessary for the remainder such as the antegrade continence enema (ACE). The purpose of this study is to assess the long-term outcomes following the ACE procedure. METHODS: All patients undergoing an ACE over a 14-year period were included. Data on clinical conditions, treatments, and outcomes were collected. A successful outcome was defined as remaining clean with ≤ 1 accident per week. Comparative data were analyzed using the Fisher's exact test, Mann-Whitney U test, or Student's t test. RESULTS: There were 42 ACE patients, and overall, 79% had improvement in their bowel regimens. Encopresis rates decreased from 79 to 5% (P < 0.001). Admissions for cleanouts decreased from 52 to 19% (P = 0.003). All cases of Hirschsprung's, functional constipation and spina bifida were successful. Rates of success varied for other diseases such as slow-transit constipation (60%) and cerebral palsy (33%). A majority (85%) required a change in the enema composition for improvement. CONCLUSION: In our study, ACE reduced soiling, constipation, and need for fecal disimpaction. Higher volume saline flushes used once a day was the optimal solution and most preferred option. LEVEL OF EVIDENCE: Level 4 (retrospective case series or cohort).

Neurodevelopmental outcomes in infants undergoing general anesthesia.

PURPOSE: Preclinical data strongly suggest that all agents used for general anesthesia (GA) have detrimental effects on the developing brain. However, clinical data are unclear. The purpose of this study was to use a cohort of infants who underwent GA and understand their neurodevelopmental outcomes. METHODS: A cohort of infants who underwent GA was selected between 2010 and 2011, and a control group was created. Data regarding GA, procedures, and outcomes were collected in 2015. The cohort was divided into controls, GA without surgery, GA and surgery once, and multiple general anesthetics. Both univariate and multivariate analysis were performed, and a p value of less than 0.05 was considered significant. RESULTS: 457 patients, 121 controls, and 336 cases were included. Median follow-up was 5.1years. While developmental delay and the need for speech therapy were higher with GA, this did not correlate with the duration of GA. Patients having GA for MRI had the poorest outcomes. Multivariate analysis using combined binary outcome measures for psychiatric and neurologic outcomes did not show any significant difference for duration of anesthesia, age at anesthesia, or induction and maintenance agents. CONCLUSIONS: These data suggest that GA during the first year of life may have few significant neurodevelopmental effects compared to controls. Additionally, the duration of GA did not correlate with neurodevelopmental outcomes. TYPE OF STUDY: Retrospective Case Control Cohort Study. LEVEL OF EVIDENCE: 3 b (according to Oxford Center for EBM Levels of Evidence, March 2009, http://www.cebm.net/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/).