Cx43 hemichannels contribute to astrocyte-mediated toxicity in sporadic and familial ALS.

Connexin 43 (Cx43) gap junctions and hemichannels mediate astrocyte intercellular communication in the central nervous system under normal conditions and contribute to astrocyte-mediated neurotoxicity in amyotrophic lateral sclerosis (ALS). Here, we show that astrocyte-specific knockout of Cx43 in a mouse model of ALS slows disease progression both spatially and temporally, provides motor neuron (MN) protection, and improves survival. In addition, Cx43 expression is up-regulated in human postmortem tissue and cerebrospinal fluid from ALS patients. Using human induced pluripotent stem cell­derived astrocytes (hiPSC-A) from both familial and sporadic ALS, we establish that Cx43 is up-regulated and that Cx43-hemichannels are enriched at the astrocyte membrane. We also demonstrate that the pharmacological blockade of Cx43-hemichannels in ALS astrocytes using GAP 19, a mimetic peptide blocker, and tonabersat, a clinically tested small molecule, provides neuroprotection of hiPSC-MN and reduces ALS astrocyte-mediated neuronal hyperexcitability. Extending the in vitro application of tonabersat with chronic administration to SOD1G93A mice results in MN protection with a reduction in reactive astrocytosis and microgliosis. Taking these data together, our studies identify Cx43 hemichannels as conduits of astrocyte-mediated disease progression and a pharmacological target for disease-modifying ALS therapies.

Graft Augmentation of Rotator Cuff Repair Improves Load to Failure But Does Not Affect Stiffness or Gap Formation: A Meta-analysis of Biomechanical Studies.

PURPOSE: To examine the biomechanical properties of rotator cuff repair with graft augmentation (RCR-G) with regard to ultimate load to failure, gap displacement, and stiffness. METHODS: A systematic review was performed by searching PubMed, the Cochrane library, and Embase using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to identify studies that analyzed the biomechanical properties of RCR-G. The search string implemented used the concepts "rotator cuff" and "graft," and "biomechanical" OR "cadaver." Meta-analysis was performed to provide a quantitative comparison of the 2 techniques. Primary outcome measures were ultimate load to failure (N), gap displacement (mm), and stiffness (N/mm). RESULTS: Our initial search yielded 1,493 articles for review. Following screening for inclusion criteria, 8 studies were included in the meta-analysis, including a total of 191 cadaveric specimens (106 RCR-G, 85 RCR). The pooled analysis from 6 studies reporting on ultimate load to failure revealed a statistically significant difference in favor of RCR-G compared with RCR (P < .001). Pooled analysis from 6 studies reporting on gap displacement failed to reveal a difference between RCR-G and RCR (P = .719). Pooled analysis from 4 studies reporting on stiffness failed to reveal a difference between RCR-G and RCR (P = .842). CONCLUSIONS: Graft augmentation of RCR in vitro resulted in significantly increased ultimate load to failure, with no influence on gap formation or stiffness. CLINICAL RELEVANCE: The biomechanical advantage of RCR with graft augmentation demonstrated via increased ultimate load to failure in cadaveric studies may provide an explanation for the decreased RCR retear rates and improved patient reported outcomes reported in the clinical literature regarding graft augmentation.

The statistical fragility of studies on rotator cuff repair with graft augmentation.

BACKGROUND: Clinical decision-making often relies on evidence-based medicine. Our purpose was to determine the fragility index (FI) and fragility quotient (FQ) for studies evaluating rotator cuff repair (RCR) with graft augmentation. A lost to follow-up (LTF) value greater than the FI indicates statistical instability for the reported outcomes and conclusions. METHODS: We performed a systematic review using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines by searching PubMed, the Cochrane library, and Embase in June 2022 to identify studies of RCR with graft augmentation. Comparative studies with at least 1 statistically analyzed dichotomous outcome were included. Seventeen studies published in seven peer-reviewed journals from 2003 to 2019 were subsequently evaluated. The FI was determined by changing each reported outcome event within 2 × 2 contingency tables until statistical significance or nonsignificance was reversed. The associated FQ was determined by dividing the FI by the sample size. LTF values were also extracted from each included study. RESULTS: The included studies had a total of 1098 patients with 36 dichotomous outcomes. The associated median FI was 4 (interquartile range 2-5), indicating that the reversal of 4 patients' outcomes would have reversed the finding of significant difference. The median FQ was 0.08 (interquartile range 0.04-0.15), indicating that in a sample of 100 patients, reversal of 8 patients' outcomes would reverse statistical significance. The median number of patients LTF was 3 (range 0-25), with 56% of reported outcomes having LTF greater than their respective FI. CONCLUSION: Studies of RCR with graft augmentation lack statistical stability, with few altered outcome events required to reverse statistical significance. Larger comparative studies with better follow-up will strengthen the statistical stability of the evidence for RCR with graft augmentation. For future investigations and reports, we recommend including FI and FQ along with traditional statistical significance analyses to provide better context on the strength of conclusions.

Poor evidence is used to support commercial payers' coverage policies for shoulder arthroplasty.

BACKGROUND: The incidence of shoulder arthroplasty has continued to increase over the past decade. In response, commercial payers have implemented strategies to control the medical requirement of these surgeries in attempt to contain the growing costs. For example, most payers require a prolonged trial of conservative management prior to shoulder arthroplasty for patients who may otherwise be surgical candidates. However, little is known regarding the evidence used to support these indications. The purpose of this study was to analyze the references used by commercial payers to substantiate their coverage policies for shoulder arthroplasty. METHODS: Ten of the leading commercial payers for total shoulder arthroplasty were identified. Publicly available coverage policies were searched on the internet or requested directly from the payer via email or telephone. Cited references were reviewed independently by two authors for type of document, level of evidence, and mention of the efficacy of conservative management. RESULTS: A total of 5 coverage policies were obtained with 118 references. The most common reference type was primary journal article (n = 70; 59.3%) followed by review or expert opinion articles (n = 35; 29.7%). Most references were of level IV evidence (n = 60; 52.2%), with only 6 (5.2%) of level I or II evidence. Only 4 (3.5%) references mentioned the efficacy of conservative management in patients who may be candidates for shoulder arthroplasty. CONCLUSION: The majority of references used to substantiate the coverage policies for shoulder arthroplasty among major commercial payers within the United States are of low scientific evidence and fail to demonstrate the success of required nonoperative intervention strategies. Our study underscores the need for high-quality, comparative trials that evaluate the outcomes of conservative management vs. shoulder arthroplasty in end-stage glenohumeral osteoarthritis patients in order to determine the most cost-effective treatment algorithm.

Seasonal Variation of Pediatric Septic Arthritis in the United States: A PHIS Database Study.

BACKGROUND: The presence of seasonal patterns in pediatric septic arthritis cases is a common orthopaedic teaching. Seasonal variation has been seen in centers outside of the United States and with other inflammatory and infectious joint-related conditions within the country, but it is unknown if a seasonal pattern exists among different regions of the United States. The purpose of this study was to examine the seasonal variation of septic arthritis within specific regions across the United States. METHODS: The Pediatric Health Information System database was queried for all patients 19 years or younger who were treated for septic arthritis. Data from 34 pediatric hospitals in the Pediatric Health Information System initiative were included. Centers were organized by geographical region, and season of presentation was determined using equinoxes/solstices. χ 2 tests were performed to detect seasonal differences in septic arthritis for the entire cohort and separated by geographical region. Proportion differences along with 95% CIs were provided. RESULTS: Between 2016 and 2019, there were 5764 cases of septic arthritis. Median age at diagnosis was 6.2 years (range: 0 to 19.0 y). Each season contributed 24% to 25% of the total septic arthritis cases, and there were no significant differences detected between the 4 seasons ( P =0.66). There was no seasonal variation seen in the Midwest, South, or West ( P =0.71, 0.98, 0.36, respectively). However, there was seasonal variation in the Northeast ( P =0.05), with fall and summer having a higher percentage of cases (28%) than the winter (21%). CONCLUSIONS: This study showed no clear seasonal variation in septic arthritis in children across the United States using a national database of pediatric hospital centers. However, there is regional seasonal variation in the Northeast, which may relate to climate differences. With no clear seasonal variation across the United States, continued diligence is needed in diagnosing septic arthritis throughout the year. LEVEL OF EVIDENCE: Prognostic II.

Clinical and Molecular Aspects of Senataxin Mutations in Amyotrophic Lateral Sclerosis 4.

OBJECTIVE: To determine the clinical and molecular features in patients with amyotrophic lateral sclerosis 4 (ALS4) due to mutations in the senataxin (SETX) gene and to develop tools for evaluating SETX variants. METHODS: Our study involved 32 patients, including 31 with mutation in SETX at c.1166 T>C (p.Leu389Ser) and 1 with mutation at c.1153 G>A (p.Glu385Lys). Clinical characterization of the patients included neurological examination, blood tests, magnetic resonance imaging (MRI), and dual-energy x-ray absorptiometry (DEXA). Fibroblasts and motor neurons were obtained to model the disease and characterize the molecular alteration in senataxin function. RESULTS: We report key clinical features of ALS4. Laboratory analysis showed alteration of serum creatine kinase and creatinine in the Leu389Ser ALS4 cohort. MRI showed increased muscle fat fraction in the lower extremities, which correlates with disease duration (thigh fat fraction R2 = 0.35, p = 0.01; lower leg fat fraction R2 = 0.49, p < 0.01). DEXA measurements showed lower extremities are more affected than upper extremities (average fat z scores of 2.1 and 0.6, respectively). A cellular assay for SETX function confirmed that like the Leu389Ser mutation, the Glu385Lys variant leads to a decrease in R loops, likely from a gain of function. INTERPRETATION: We identified clinical laboratory and radiological features of ALS4, and hence they should be monitored for disease progression. The molecular characterization of R-loop levels in patient-derived cells provides insight into the disease pathology and assays to evaluate the pathogenicity of candidate mutations in the SETX gene. ANN NEUROL 2020;87:547-555.

Effects of Postoperative Splinting on Outcomes following Digital Mucous Cyst Excision: A Retrospective Review.

Background: Digital mucous cysts (DMCs) are masses on the fingers that can be definitively managed with surgical excision. Though uncommon, surgical site infections can develop into septic arthritis. We sought to determine whether postoperative splinting decreases rates of postoperative infection and the need for postoperative antibiotics. We also explored the effect of age, gender, obesity, and preoperative antibiotic administration on infectious complications. Methods: Patients who underwent DMC excision between 2011 and 2021 were retrospectively identified. Chi-squared and Fisher's exact tests were used to analyze the complication rates including documented infection, postoperative antibiotic administration, mass recurrence, and return to operating room. Associations were analyzed between both preoperative antibiotic administration and postoperative splinting with respect to postsurgical complications. Results: The database search identified 373 patients who underwent 394 DMC excisions. Postoperative antibiotics were given in splinted patients at lower rates than their nonsplinted counterparts with a small-to-moderate effect size, but the difference was not statistically significant (2.7 vs. 7.5%). Preoperative antibiotic administration was not found to significantly affect the prescription of postoperative antibiotics. Splinting did not reduce rates of DMC recurrence. Patients who were splinted were more likely to have also received preoperative antibiotics. Males were given postoperative antibiotics more frequently than females (12.6 vs. 4.0%). Conclusions: Though not statistically significant, splinted patients were prescribed postoperative antibiotics less frequently. Postoperative antibiotics were utilized more frequently than the rate of infections typically reported following this procedure, possibly indicating overcautious prescription habits or underreported suspected infections.

Pelvic Incidence-Lumbar Lordosis Mismatch Is Not Associated with Early Reoperation for Adjacent Segment Disease After Lumbar Fusion.

OBJECTIVE: To compare the 2-year reoperation rates for adjacent segment disease between patients with pelvic incidence-lumbar lordosis (PI-LL) mismatch postoperatively and patients with normal PI-LL measurements. METHODS: Patients undergoing elective 1- to 2-level lumbar fusion for degenerative conditions between 2016 and 2018 were retrospectively reviewed. Spinopelvic radiographic parameters immediately postoperation were measured, and PI-LL mismatch was determined using the age-adjusted thresholds defined in Lafage et al. After propensity score matching, early reoperation rates were compared between the PI-LL mismatch and normal PI-LL cohorts. Early reoperation was defined as symptomatic adjacent segment disease (ASD) requiring reoperation within 2 years of the index surgery. RESULTS: A total of 219 patients were identified. The average age was 59 years of age, with 59.8% female. The PI-LL mismatch cohort (n = 148) was younger (57.5 vs. 63.5 years, P < 0.001) and had a higher proportion of Black patients (31.8% vs. 11.3%, P = 0.001) than the normal PI-LL cohort, respectively. A total of 100 patients in the PI-LL mismatch cohort were propensity score matched to 66 patients in the normal PI-LL cohort, resulting in no difference in age (P = 0.177), sex (P = 0.302), race (P = 0.727), or body mass index (P = 0.892). Using these matched cohorts, the rate of early reoperation for ASD was 8.0% in the PI-LL mismatch cohort and 9.1% in the normal PI-LL cohort (P = 0.805), with a mean time to reoperation of 1.28 and 1.33 years, respectively. CONCLUSIONS: After propensity score matching, PI-LL mismatch was not associated with early reoperation for ASD in patients undergoing 1- to 2-level lumbar fusions for degenerative conditions.

Psychological Aspects of Adolescent Knee Injuries.

Knee injuries are prevalent in pediatric and adolescent athletes, leading to both physical and psychological disturbances following injury. Various preoperative psychological measures of maladaptive beliefs-including kinesiophobia, fear avoidance, and pain catastrophizing-can predict responses to recovery, such as knee function, knee-related quality of life, and return-to-sport. Treatment recommendations for the psychological aspect of adolescent knee injuries can include screening patients to identify those at high risk for poor recovery. These patients can be targeted with psychologically informed media or cognitive-behavioral therapy models aimed at reducing maladaptive beliefs and supporting individualized motivations and recovery goals.

Evaluation of the National Institutes of Health-supported relative citation ratio among American orthopedic spine surgery faculty: A new bibliometric measure of scientific influence.

Background: Publication metrics have been traditionally used to compare research productivity amongst academic faculty. However, traditional bibliometrics lack field-normalization and are often biased towards time-dependent publication factors. The National Institutes of Health (NIH) has developed a new, field-normalized, article-level metric, known as the "relative citation ratio" (RCR), that can be used to make accurate self, departmental, and cross-specialty comparisons of research productivity. This study evaluates the use of the RCR amongst academic orthopedic spine surgery faculty and analyzes physician factors associated with RCR values. Methods: A retrospective data analysis was performed using the iCite database for all fellowship trained orthopedic spine surgery (OSS) faculty associated with Accreditation Council for Graduate Medical Education (ACGME)-accredited orthopedic surgery residency program. Mean RCR, weighted RCR, and total publication count were compared by sex, career duration, academic rank, and presence of additional degrees. A value of 1.0 is the NIH-funded field-normalized standard. Student t-tests were used for two-group analyses whereas the analysis of variance tests (ANOVA) was used for between-group comparisons of three or more subgroups. Statistical significance was achieved at P < 0.05. Results: A total of 502 academic OSS faculty members from 159 institutions were included in the analysis. Overall, OSS faculty were highly productive, with a median RCR of 1.62 (IQR 1.38-2.32) and a median weighted RCR of 68.98 (IQR 21.06-212.70). Advancing academic rank was associated with weighted RCR, career longevity was associated with mean RCR score, and male sex was associated with having increased mean and weighted RCR scores. All subgroups analyzed had an RCR value above 1.0. Conclusions: Academic orthopedic spine surgery faculty produce impactful research as evidenced by the high median RCR relative to the standard value set by the NIH of 1.0. Our data can be used to evaluate research productivity in the orthopedic spine community.

Single-Stage Bilateral Total Hip Arthroplasty in an Ambulatory Surgical Center: A Report of Three Cases.

In recent years, there has been increased interest in transitioning total joint arthroplasty procedures from inpatient settings to ambulatory surgical centers to decrease costs and eliminate the need for hospital stays. In addition, simultaneous bilateral total hip arthroplasty (THA) has been found to be favorable in certain patient populations when compared with staged bilateral THA. In this study, we report the results of a series of three patients who underwent single-stage bilateral THA in a free-standing ambulatory surgical center with excellent short-term outcomes and no 90-day complications.

Negative Online Ratings of Joint Replacement Surgeons: An Analysis of 6,402 Reviews.

BACKGROUND: With the expanding accessibility of online health-care information, patients frequently report visiting physician rating websites before choosing a surgeon. As such, it is important to analyze patients' perception of arthroplasty surgeons as reflected on physician rating websites. METHODS: A total of 6402 online reviews of arthroplasty surgeons were extracted for analysis. Each review rated less than 5 on a 5-point scale was deemed a "negative" review and was subsequently assigned to an appropriate category. Reviews were stratified by practice type, years in practice, gender, and low (<3) vs high (> 3) ratings. RESULTS: A total of 6402 reviews comprising 315 physicians were included in the analysis. The average rating for all surgeons was 4.35. The average rating for physicians in private practice was 4.3, compared to 4.5 for those in an academic setting. The average rating for physicians in practice for 1-10 years was 4.46, compared to 4.03 for those with >10 years of experience (P < .001). The most common factors contributing to negative reviews were bedside manner, wait time, poor outcome, and surgeon proficiency. Surgeon-dependent factors were more commonly associated with lower rated reviews (P < .001). CONCLUSIONS: Arthroplasty surgeons typically receive high online ratings, with a mean of 4.35 on a 5-point scale. Physicians in academic practice received higher ratings than those in private practice, and physicians who have been in practice for 1-10 years received higher ratings than those with more than 10 years in practice. The most common factors contributing to negative reviews are surgeon-dependent, including bedside manner, poor outcome, and surgeon proficiency.

Patient Perceptions of COVID-19 Precautions and Their Effects on Experiences With Hand Surgery.

PURPOSE: The purpose of this study is to evaluate patient perceptions of COVID-19 precautions and how these precautions have affected their hand and upper extremity surgery experience. METHODS: We sent an 18-item survey to 1,213 patients who underwent elective hand and upper extremity surgery at 1 academic institution from October 2020 to January 2021. The survey consisted of questions related to patient demographics, treatment delays due to COVID-19, and patient perceptions of COVID-19 precautions. Descriptive statistics were performed to analyze the survey responses. Responses for patients aged 18-50 and 51+ were compared using a chi-square analysis for categorical variables and a Student t-test for continuous variables. RESULTS: Out of 1,213 invitations, 384 survey respondents completed the survey (31.6%). Of the respondents, 16.8% reported delaying medical treatment for an average of 123.2 days because of COVID-19. The preventative measures were found to be adequate by 95% of patients. Only 2.6% of patients reported experiencing surgical delays due to preoperative COVID-19 testing or other COVID-19-related precautions. COVID-19 testing was seen as necessary by 88% of patients, and 74% did not find COVID-19 testing to be a barrier to their surgery. Patients aged 51+ were more likely to delay seeking medical treatment than younger patients (19.3% vs 9.1%, respectively). Furthermore, those that did delay seeking treatment waited longer on average than their younger counterparts (136.1 vs 72.9 days, respectively). CONCLUSIONS: In conclusion, patients undergoing hand and upper extremity surgery typically do not find COVID-19 precautions to be a significant barrier to care and understand their importance. Despite this, many patients, particularly older ones, are delaying medical care for extended periods of time. It is important for hand surgeons to acknowledge their patients' perspectives and work to educate patients on evolving surgical safety guidelines. CLINICAL RELEVANCE: Patient perspectives of current COVID-19 precautions can help inform hand surgeons on areas for continued patient education.

Ryanodine Receptor 1-Related Myopathies: Quantification of Intramuscular Fatty Infiltration from T1-Weighted MRI.

BACKGROUND: Ryanodine receptor 1-related myopathy (RYR1-RM) can present with a selective pattern and gradient of intramuscular fatty infiltration (IMFI) on magnetic resonance imaging (MRI). OBJECTIVE: To demonstrate an automated protocol for quantification of IMFI in the lower extremity muscles of individuals with RYR1-RM using T1-weighted MRI and to examine the relationships of IMFI with motor function and clinical severity. METHODS: Axial images of the lower extremity muscles were acquired by T1-weighted fast spin-echo and short tau inversion recovery (STIR) sequences. A modified ImageJ-based program was used for quantification. IMFI data was analyzed by mode of inheritance, motor function, and clinical severity. RESULTS: Upper and lower leg IMFI from 36 genetically confirmed and ambulatory RYR1-RM affected individuals (26 dominant and 10 recessive) were analyzed using Grey-scale quantification. There was no statistically significant difference in IMFI between dominant and recessive cases in upper or lower legs. IMFI in both upper and lower legs was inversely correlated with participant performance on the motor function measure (MFM-32) total score (upper leg: p < 0.001; lower leg: p = 0.003) and the six-minute walk test (6MWT) distance (upper leg: p < 0.001; lower leg: p = 0.010). There was no significant difference in mean IMFI between participants with mild versus severe clinical phenotypes (p = 0.257). CONCLUSION: A modified ImageJ-based algorithm was able to select and quantify fatty infiltration in a cohort of heterogeneously affected individuals with RYR1-RM. IMFI was not predictive of mode of inheritance but showed strong correlation with motor function and capacity tests including MFM-32 and 6MWT, respectively.