Lack of racial and ethnic diversity in pediatric ophthalmology clinical trials from 2000 to 2022.

PURPOSE: To examine the prevalence of and factors associated with racial and ethnic reporting and trends in such reporting and to assess whether categories of race and ethnicity have been under- or over-represented in pediatric ophthalmology randomized control trials (RCTs) in the United States. METHODS: We systematically searched the literature on pediatric ophthalmology RCTs in high-impact factor ophthalmology journals published between 2000 and 2022. Logistic regression was used to assess parameters linked to race/ethnicity reporting; linear regression, to gauge the relationship between publication year and race/ethnicity reporting. The racial and ethnic composition of RCTs was contrasted with 2010 US census data by calculating percentage difference. RESULTS: Of 170 eligible articles, 89 (52.4%) included race/ethnicity data. Multivariable analysis showed that academic (OR = 12.19; 95% CI, 3.34-44.44) and government (OR = 3.91; 95% CI, 1.20-12.72) funding was linked to data reporting. During the study period, publication year and race/ethnicity reporting had a nonstatistically significant 1.0% annual increase (r = 0.29, P = 0.18). White participants were over-represented, with a percentage difference of 16.7% (95% CI, 11.8%-21.7%), whereas Hispanic individuals were under-represented, with a percentage difference of -7.6% (95% CI, -11.2% to -4.1%) compared to the 2010 US census data. CONCLUSIONS: Our results indicate a gradual rise in reported race and/or ethnicity in published pediatric ophthalmology RCTs, though not statistically significant, both in the United States and globally. Notably, under-representation of Hispanic, over-representation of White, and proportional representation of Black and Asian individuals were observed in US-based studies.

Market resilience of orthopaedic hip/knee arthroplasty sales during COVID-19.

INTRODUCTION: The coronavirus 2019 (COVID-19) pandemic led to a marked decrease in elective surgical volume and orthopaedic device sales. The aim of this paper was to quantify this decrease and the related financial impact on the largest hip/knee arthroplasty companies by: (1) tracking individual hip/knee company valuations; (2) calculating aggregate changes in overall hip/knee arthroplasty market valuations; and (3) quantifying quarterly hip/knee revenues relative to prior years. MATERIALS AND METHODS: Financial data on the top five hip/knee arthroplasty companies by size between January 1, 2019, and October 1, 2020, was collected from a Wall Street financial database, S&P Capital IQ. Changes in valuation of these companies were compared against benchmark market indices, the S&P500 and Vanguard Healthcare ETF. U.S. hip/knee arthroplasty-specific revenue for Q1 and Q2 of 2019 and 2020 was collected from Securities Exchange Commission 10-Q forms. Quarterly revenue changes were calculated using 1-2Q19 revenues as baselines and aggregate to approximate the overall hip/knee arthroplasty market. RESULTS: The top five hip/knee companies lost $179.2 billion (32.7% loss) in market value from pre COVID-19 market highs to COVID-19 market lows (March 2020), while S&P500 and Vanguard Healthcare ETF decreased 36.1 and 33.2%, respectively. From market lows to October 2020, arthroplasty companies rallied 38.6% while the S&P500 and Vanguard Healthcare ETF regained 43.5 and 56.4% respectively. Notably, this occurred while aggregate 1Q/2Q20 revenue lagged 7.1/41.8% relative to 2019, with an overall decrease of $1.58B (24.8%). CONCLUSIONS: Similar to the overall market and healthcare sector, the top five hip/knee arthroplasty companies have recovered from their COVID market lows. Our results reveal that the valuations of hip/knee companies remained robust during COVID, even as revenues fell, likely due to strong investor confidence in the industry outlook and the greater overall healthcare system utilization.

Factors Predisposing Patients to Non-Home Discharge After Surgery for Degenerative Cervical Myelopathy: A Retrospective Analysis.

OBJECTIVE: The objective of this study is to evaluate factors associated with discharge to subacute care after surgery for degenerative cervical myelopathy (DCM). DESIGN: This is a retrospective chart review of adults who underwent cervical spine surgery at a for DCM between 2014 and 2020 (n = 135). RESULTS: Patients discharged to a subacute setting were older (68.1 +/- 8.6 vs. 64.1 years +/- 8.8; p = 0.01); more likely to be unmarried (55.8% vs. 33.7% married; p = 0.01); and more likely to have Medicare or Medicaid (83.7% vs. 65.9% private insurance; p = 0.03). than patients discharged home. A posterior surgical approach was associated with discharge to a subacute setting (62.8% vs. 43.5% anterior approach; p = 0.04). 87.8% of patients discharged to a subacute setting required moderate or maximum assistance for bed mobility vs. 26.6% of patients discharged home (p < 0.0001).Compared to patients discharged home, patients discharged to a subacute setting ambulated a shorter distance in their first Physical Therapy Evaluation after surgery (8.9 meters +/- 35.8 vs. 53.7 meters +/- 61.78 in the home discharge group; p < 0.0001). CONCLUSION: Analysis of these factors may guide discussions about patient expectations for postoperative discharge placement.

seco-1-Azacubane-2-carboxylic Acid: Derivative Scope and Comparative Biological Evaluation.

The unusual and sterically constrained amino acid, seco-1-azacubane-2-carboxylic acid, was incorporated into a range of bioactive chemical templates, including enalaprilat, perindoprilat, endomorphin-2 and isoniazid, and subjected to biological testing. The endomorphin-2 derivative displayed increased activity at the δ opioid receptor, but a loss in activity was observed in the other cases, although human normal cell line evaluation suggests limited cytotoxic effects.

Periorbital Necrotizing Sweet's Syndrome: A Case Report.

Sweet's syndrome (acute febrile neutrophilic dermatosis) is an uncommon inflammatory condition most often associated with painful skin lesions of the head, neck, and upper extremities. To the authors' knowledge, this case report is the only published record of the necrotizing clinical variant of Sweet's syndrome in the periorbital space. This case follows a 91-year-old female who presented with generalized cutaneous eruptions of tender erythematous plaques, including a necrotic plaque of the left upper eyelid, and pancytopenia. A biopsy of an inner thigh lesion was consistent with Sweet's syndrome. Initially diagnosed with preseptal cellulitis, the patient experienced marked clinical improvement with corticosteroids. This, coupled with the histopathologic findings of her thigh biopsy and the absence of eyelid margins, led to the diagnosis of periorbital necrotizing Sweet's syndrome. Although cases of Sweet's syndrome in the periorbital region are rare, these diagnoses should not be overlooked and may be critical to patient care.

Aggressive thoracic vertebral hemangioma: case report and literature review.

INTRODUCTION: Vertebral hemangiomas are common and typically benign vascular lesions, with a prevalence of 10-12% in the general population and 2-3% in all spine tumors. A small subset of vertebral hemangiomas can be categorized as "aggressive" if they exhibit extraosseous expansion that compress the spinal cord, causing pain and various neurologic symptoms. This report details a case of aggressive thoracic hemangioma resulting in worsening pain and paraplegia to draw attention to this rare condition, including identification and treatment. CASE PRESENTATION: In this case, we present a 39 year-old female with a history of progressively worsening pain and paraplegia caused by compression of the spinal cord from an aggressive thoracic vertebral hemangioma. Clinical presentation, imaging, and biopsies, confirmed the diagnosis. A combined surgical and endovascular treatment strategy was implemented, and the patient's symptoms improved. DISCUSSION: Aggressive vertebral hemangioma is a rare condition that may cause symptoms that diminishes the quality of life, including pain and various neurological symptoms. Given the low number of such cases, and significant impact on lifestyle, it is beneficial to identify cases of aggressive thoracic hemangiomas to ensure timely and accurate diagnosis and help development of treatment guidelines. This case highlights the importance of identifying and diagnosing this rare but serious disease.

Applicability of Shoulder, Olecranon, and Wrist-based Skeletal Maturity Estimation Systems to the Modern Pediatric Population.

BACKGROUND: The proximal humerus ossification system (PHOS), olecranon apophyseal ossification system (OAOS), and modified Fels wrist skeletal maturity system (mFWS) were recently developed or updated using a historical, mostly White, pediatric population. These upper extremity skeletal maturity systems have demonstrated skeletal age estimation performance superior or equivalent to Greulich and Pyle in historical patients. Their applicability to modern pediatric populations has not yet been evaluated. METHODS: We reviewed anteroposterior shoulder, lateral elbow, and anteroposterior hand and wrist x-rays of 4 pediatric cohorts: White males, Black males, White females, and Black females. Peripubertal x-rays were evaluated: males 9 to17 years and females 7 to 15 years. Five nonpathologic radiographs for each age and joint were randomly selected from each group. Skeletal age estimates made by each of the 3 skeletal maturity systems were plotted against the chronological age associated with each radiograph and compared between cohorts, and with the historical patients. RESULTS: Five hundred forty modern radiographs were evaluated (180 shoulders, 180 elbows, and 180 wrists). All radiographic parameters had inter- and intra-rater reliability coefficients at or above 0.79, indicating very good reliability. For PHOS, White males had delayed skeletal age compared with Black males (Δ-0.12 y, P =0.02) and historical males (Δ-0.17 y, P <0.001). Black females were skeletally advanced compared with historical females (Δ0.11 y, P =0.01). For OAOS, White males (Δ-0.31 y, P <0.001) and Black males (Δ-0.24 y, P <0.001) had delayed skeletal age compared with historical males. For mFWS, White males (Δ0.29 y, P =0.024), Black males (Δ0.58 y, P <0.001), and Black females (Δ0.44 y, P <0.001) had advanced skeletal age compared with historical counterparts of the same sex. All other comparisons were not significant ( P >0.05). CONCLUSIONS: The PHOS, OAOS, and mFWS have mild discrepancies in skeletal age estimates when applied to modern pediatric populations depending on the race and sex of the patient. LEVEL OF EVIDENCE: Level III - retrospective chart review.

Multitargeted Opioid Ligand Discovery as a Strategy to Retain Analgesia and Reduce Opioid-Related Adverse Effects.

The global "opioid crisis" has placed enormous pressure on the opioid ligand discovery community to produce novel opioid analgesics with superior opioid-related adverse-effect profiles compared with morphine. In this Perspective, the multitargeted opioid ligand strategy for the discovery of opioid analgesics with superior preclinical therapeutic indices relative to morphine is reviewed and discussed. Dual-targeted µ-opioid (MOP)/δ-opioid (DOP) ligands in which the in vitro DOP antagonist potency at least equals that of the MOP agonist activity, and are devoid of DOP or κ-opioid (KOP) agonist activity, are sufficiently promising candidates to warrant further investigation. Dual-targeted MOP/NOP partial agonists have superior preclinical therapeutic indices to morphine and/or fentanyl in nonhuman primates and are also considered promising. Based on the poor preclinical and clinical therapeutic indices of cebranopadol, which is a full agonist at MOP, DOP, and NOP receptors and a partial agonist at the KOP receptor, this pharmacologic template should be avoided.

CYX-5, a G-protein biassed MOP receptor agonist, DOP receptor antagonist and KOP receptor agonist, evokes constipation but not respiratory depression relative to morphine in rats.

BACKGROUND: Strong opioid analgesics such as morphine alleviate moderate to severe acute nociceptive pain (e.g. post-surgical or post-trauma pain) as well as chronic cancer pain. However, they evoke many adverse effects and so there is an unmet need for opioid analgesics with improved tolerability. Recently, a prominent hypothesis has been that opioid-related adverse effects are mediated by ß-arrestin2 recruitment at the µ-opioid (MOP) receptor and this stimulated research on discovery of G-protein biassed opioid analgesics. In other efforts, opioids with MOP agonist and δ-opioid (DOP) receptor antagonist profiles are promising for reducing side effects c.f. morphine. Herein, we report on the in vivo pharmacology of a novel opioid peptide (CYX-5) that is a G-protein biassed MOP receptor agonist, DOP receptor antagonist and kappa opioid (KOP) receptor agonist. METHODS: Male Sprague-Dawley received intracerebroventricular bolus doses of CYX-5 (3, 10, 20 nmol), morphine (100 nmol) or vehicle, and antinociception (tail flick) was assessed relative to constipation (charcoal meal and castor oil-induced diarrhoea tests) and respiratory depression (whole body plethysmography). RESULTS: CYX-5 evoked naloxone-sensitive, moderate antinociception, at the highest dose tested. Although CYX-5 did not inhibit gastrointestinal motility, it reduced stool output markedly in the castor oil-induced diarrhoea test. In contrast to morphine that evoked respiratory depression, CYX-5 increased tidal volume, thereby stimulating respiration. CONCLUSION: Despite its lack of recruitment of ß-arrestin2 at MOP, DOP and KOP receptors, CYX-5 evoked constipation, implicating a mechanism other than ß-arrestin2 recruitment at MOP, DOP and KOP receptors, mediating constipation evoked by CYX-5 and potentially other opioid ligands.

Applicability of the Modified Fels and Optimized Oxford Skeletal Maturity Estimation Systems to the Modern Pediatric Population.

BACKGROUND: The recently developed modified Fels knee and optimized Oxford hip skeletal maturity systems (SMS) have demonstrated impressive performance compared with the Greulich and Pyle skeletal age atlas when applied to the same historical, mostly white, pediatric population. We sought to determine whether these 2 systems require modification before being used in modern children. METHODS: We collected knee and hip radiographs between January 2015 and September 2020 from our electronic medical record from 4 groups of children: (1) white males, (2) black males, (3) white females, and (4) black females. Males between 9 and 17 years and females between 7 and 15 years were included. After reliability analyses, 5 nonpathologic radiographs for each age and joint were randomly selected from each group and evaluated with the appropriate SMS. The mean discrepancy between each group's chronological age at the time of radiograph and estimated skeletal age was compared between our modern cohort and the historical Bolton-Brush children. After normality testing, paired t tests or Wilcoxon signed-rank tests were performed, as appropriate. A Bonferroni correction was applied to address multiple testing. RESULTS: Three hundred sixty modern radiographs were evaluated (180 knees and 180 hips). All 7 modified Fels knee parameters and all 5 optimized Oxford hip parameters had inter and intrarater reliability coefficients ≥0.7, indicating good to very good reliability. For the modified Fels knee SMS, white males (Δ0.74 y, P <0.001), black males (Δ0.69 y, P <0.001), and black females (Δ0.4 y, P =0.04) had advanced skeletal age compared with their historical counterparts of the same sex. No differences were found between historical and modern patients for the optimized Oxford hip SMS. No differences were found for either SMS comparing modern patients along racial lines ( P >0.05 for all). CONCLUSIONS: Discrepancies in skeletal age estimates made by the modified Fels knee SMS exist between modern pediatric white males, black males, and black females and their historic counterparts. No differences were found when using optimized Oxford hip SMS. Future studies should evaluate how these translate to clinical decision-making. LEVEL OF EVIDENCE: Level III; retrospective chart review.

Anterior and superior plate positions in diaphyseal clavicle fractures produce similar patient outcomes.

PURPOSE: While diaphyseal clavicle fractures can be treated with plate fixation on either the superior or anteroinferior aspect of the clavicle, the optimal plate position remains controversial. The purpose of this study was to determine if anteroinferior vs. superior plating for clavicle fracture fixation leads to better patient outcomes. METHODS: A retrospective review of patients who sustained clavicle fractures (OTA/AO 15.2) treated with superior or anteroinferior plating at a tertiary Level I trauma center from 2015 to 2021 was performed. The clinical outcomes of clavicle fractures were compared between groups treated with an anterior versus a superior approach via Mann-Whitney U and Chi-squared tests as appropriate to evaluate for differences in outcomes between the two plate positions. RESULTS: A total of 315 diaphyseal clavicle fractures were identified. One hundred and forty patients were excluded due to inadequate follow-up. Of the remaining 175 patients, 25 were treated with an anteroinferior approach (14%) and 150 were treated with a superior approach (86%). There were no differences in age, BMI, tobacco use, or substance use between the two groups (p > 0.05 for all). On univariate analysis, there was no difference in rate of union (p = 0.60), nerve injury (p = 0.60), infection (p = 1.0), implant-related irritation (p = 0.42), implant removal (p = 0.26), or revision (p = 1.0) based on approach. Contoured plates had an association with risk of nerve injury (p = 0.04). CONCLUSION: There are no differences in union, nerve injury, infection, symptomatic implant, or revision rate between anteroinferior and superior clavicle approaches. Plate positioning during diaphyseal clavicle fracture fixation can reasonably be dictated based on surgeon preference and ideal reduction quality.

The association between perioperative blood transfusions and venous thromboembolism risk following surgical management of hip fractures.

Introduction: Despite high rates of transfusion reported among hip fracture patients in the perioperative period, the relationship between perioperative transfusions and VTE has not been thoroughly explored. Therefore, we used a national database to evaluate how perioperative transfusions among patients undergoing surgical management of hip fractures impacted 1) deep vein thrombosis (DVT) and 2) pulmonary embolism (PE) risk. Methods: The Targeted Hip Fracture Database of the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) was queried for patients undergoing surgical management of hip fractures from 2016 to 2019. A multivariate logistic regression was conducted using various patient-specific variables to identify risk factors for DVT and PE. A nearest-neighbor propensity score matched (PSM) comparison between patients receiving and not receiving perioperative blood transfusions (1:1) was additionally conducted. Results: Prior to our PSM, preoperative transfusions were not associated with DVT incidence (OR: 1.48, 95% CI: 0.80-2.50; p = 0.2). However, intra-operative/post-operative transfusions (OR: 1.26, 95% CI: 1.02-1.56; p = 0.00.30) as well as the receipt of both transfusion types (OR: 1.81, 95% CI: 1.10-2.81; p = 0.012) were associated with an increased risk of DVT. The latter of these findings remained significant following PSM (OR: 1.73, 95% CI: 1.04-2.73; p = 0.025). No relationship was demonstrated between PE risk and perioperative transfusion receipt. Conclusion: Our findings emphasize the importance of perioperative blood management strategies among patients undergoing surgical repair of hip fracture. Specifically, orthopaedic surgeons should aim to optimize hip fracture patients prior to surgical intervention as well as intra-operatively to reduce transfusion incidence.

Outcomes in surgical treatment for tandem spinal stenosis: systematic literature review.

BACKGROUND CONTEXT: Tandem spinal stenosis (TSS) refers to a narrowing of the spinal canal in distinct, noncontiguous regions. TSS most commonly occurs in the cervical and lumbar regions. Decompressive surgery is indicated for those with cervical myelopathy or persistent symptoms from lumbar stenosis despite conservative management. Surgical management typically involves staged procedures, with cervical decompression taking precedence in most cases, followed by lumbar decompression at a later time. However, several studies have shown favorable outcomes in simultaneous decompression. PURPOSE: The aim of this study is to provide a literature review and compare surgical outcomes in patients undergoing staged vs simultaneous surgery for TSS. STUDY DESIGN/SETTING: Systematic literature review. METHODS: A systematic review using PRISMA guidelines to identify original research articles for tandem spinal stenosis. PubMed, Cochrane, Ovid, Scopus, and Web of Science were used for electronic literature search. Original articles from 2005 to 2021 with more than eight adult patients treated surgically for cervical and lumbar TSS in staged or simultaneous procedures were included. Articles including pediatric patients, primarily thoracic stenosis, stenosis secondary to neoplasm or infectious disease, minimally invasive surgery, and non-English language were excluded. Demographic, perioperative, complications, functional outcome, and neurologic outcome data including mJOA (modified Japanese Orthopaedic Association), Nurick grade (NG), and ODI (Oswestry disability index), were extracted and summarized. RESULTS: A total of 667 articles were initially identified. After preliminary screening, 21 articles underwent full-text screening. Ten articles met our inclusion criteria. A total of 831 patients were included, 571 (68%) of them underwent staged procedures, and 260 (32%) underwent simultaneous procedures for TSS. Mean follow-ups ranged from 12 to 85 months. There was no difference in estimated blood loss (EBL) between staged and simultaneous groups (p=.639). Simultaneous surgeries had shorter surgical time than staged surgeries (p<.001). Mean changes in mJOA, NG, and ODI was comparable between staged and simultaneous groups. Complications were similar between the groups. There were more major complications reported in simultaneous operations, although this was not statistically significant (p=.301). CONCLUSION: Staged and simultaneous surgery for TSS have comparable perioperative, functional, and neurologic outcomes, as well as complication rates. Careful selection of candidates for simultaneous surgery may reduce the length of stay and consolidate rehabilitation, thereby reducing hospital-associated costs.

Analgesic Opioid Ligand Discovery Based on Nonmorphinan Scaffolds Derived from Natural Sources.

Strong opioid analgesics, including morphine, are the mainstays for treating moderate to severe acute pain and alleviating chronic cancer pain. However, opioid-related adverse effects, including nausea or vomiting, sedation, respiratory depression, constipation, pruritus (itch), analgesic tolerance, and addiction and abuse liability, are problematic. In addition, the use of opioids to relieve chronic noncancer pain is controversial due to the "opioid crisis" characterized by opioid misuse or abuse and escalating unintentional death rates due to respiratory depression. Hence, considerable research internationally has been aimed at the "Holy Grail" of the opioid analgesic field, namely the discovery of novel and safer opioid analgesics with improved opioid-related adverse effects. In this Perspective, medicinal chemistry strategies are addressed, where structurally diverse nonmorphinan-based opioid ligands derived from natural sources were deployed as lead molecules. The current state of play, clinical or experimental status, and novel opioid ligand discovery approaches are elaborated in the context of retaining analgesia with improved safety and reduced adverse effects, especially addiction liability.

Is Our Science Representative? A Systematic Review of Racial and Ethnic Diversity in Orthopaedic Clinical Trials from 2000 to 2020.

BACKGROUND: A lack of racial and ethnic representation in clinical trials may limit the generalizability of the orthopaedic evidence base as it applies to patients in underrepresented minority populations and perpetuate existing disparities in use, complications, or functional outcomes. Although some commentators have implied the need for mandatory race or ethnicity reporting across all orthopaedic trials, the usefulness of race or ethnic reporting likely depends on the specific topic, prior evidence of disparities, and individualized study hypotheses. QUESTIONS/PURPOSES: In a systematic review, we asked: (1) What proportion of orthopaedic clinical trials report race or ethnicity data, and of studies that do, how many report data regarding social covariates or genomic testing? (2) What trends and associations exist for racial and ethnic reporting among these trials between 2000 and 2020? (3) What is the racial or ethnic representation of United States trial participants compared with that reported in the United States Census? METHODS: We performed a systematic review of randomized controlled trials with human participants published in three leading general-interest orthopaedic journals that focus on clinical research: The Journal of Bone and Joint Surgery, American Volume; Clinical Orthopaedics and Related Research; and Osteoarthritis and Cartilage. We searched the PubMed and Embase databases using the following inclusion criteria: English-language studies, human studies, randomized controlled trials, publication date from 2000 to 2020, and published in Clinical Orthopaedics and Related Research; The Journal of Bone and Joint Surgery, American Volume; or Osteoarthritis and Cartilage. Primary outcome measures included whether studies reported participant race or ethnicity, other social covariates (insurance status, housing or homelessness, education and literacy, transportation, income and employment, and food security and nutrition), and genomic testing. The secondary outcome measure was the racial and ethnic categorical distribution of the trial participants included in the studies reporting race or ethnicity. From our search, 1043 randomized controlled trials with 184,643 enrolled patients met the inclusion criteria. Among these studies, 21% (223 of 1043) had a small (< 50) sample size, 56% (581 of 1043) had a medium (50 to 200) sample size, and 23% (239 of 1043) had a large (> 200) sample size. Fourteen percent (141 of 1043) were based in the Northeast United States, 9.2% (96 of 1043) were in the Midwest, 4.7% (49 of 1043) were in the West, 7.2% (75 of 1043) were in the South, and 65% (682 of 1043) were outside the United States. We calculated the overall proportion of studies meeting the inclusion criteria that reported race or ethnicity. Then among the subset of studies reporting race or ethnicity, we determined the overall rate and distribution of social covariates and genomic testing reporting. We calculated the proportion of studies reporting race or ethnicity that also reported a difference in outcome by race or ethnicity. We calculated the proportion of studies reporting race or ethnicity by each year in the study period. We also calculated the proportions and 95% CIs of individual patients in each racial or ethnic category of the studies meeting the inclusion criteria. RESULTS: During the study period (2000 to 2020), 8.5% (89 of 1043) of studies reported race or ethnicity. Of the trials reporting this factor, 4.5% (four of 89) reported insurance status, 15% (13 of 89) reported income, 4.5% (four of 89) reported housing or homelessness, 18% (16 of 89) reported education and literacy, 0% (0 of 89) reported transportation, and 2.2% (two of 89) reported food security or nutrition of trial participants. Seventy-eight percent (69 of 89) of trials reported no social covariates, while 22% (20 of 89) reported at least one. However, 0% (0 of 89) of trials reported genomic testing. Additionally, 5.6% (five of 89) of these trials reported a difference in outcomes by race or ethnicity. The proportion of studies reporting race or ethnicity increased, on average, by 0.6% annually (95% CI 0.2% to 1.0%; p = 0.02). After controlling for potentially confounding variables such as funding source, we found that studies with an increased sample size were more likely to report data by race or ethnicity; location in North America overall, Europe, Asia, and Australia or New Zealand (compared with the Northeast United States) were less likely to; and specialty-topic studies (compared with general orthopaedics research) were less likely to. Our sample of United States trials contained 18.9% more white participants than that reported in the United States Census (95% CI 18.4% to 19.4%; p < 0.001), 5.0% fewer Black participants (95% CI 4.6% to 5.3%; p < 0.001), 17.0% fewer Hispanic participants (95% CI 16.8% to 17.1%; p < 0.001), 5.3% fewer Asian participants (95% CI 5.2% to 5.4%; p < 0.001), and 7.5% more participants from other groups (95% CI 7.2% to 7.9%; p < 0.001). CONCLUSION: Reporting of race or ethnicity data in orthopaedic clinical trials is low compared with other medical fields, although the proportion of diseases warranting this reporting might be lower in orthopaedics. CLINICAL RELEVANCE: Investigators should initiate discussions about race and ethnicity reporting in the early stages of clinical trial development by surveying available published evidence for relevant health disparities, social determinants, and, when warranted, genomic risk factors. The decision to include or exclude race and ethnicity data in study protocols should be based on specific hypotheses, necessary statistical power, and an appreciation for unmeasured confounding. Future studies should evaluate cost-efficient mechanisms for obtaining baseline social covariate data and investigate researcher perspectives on current administrative workflows and decision-making algorithms for race and ethnicity reporting.

Robotic-arm assisted versus manual total hip arthroplasty: Systematic review and meta-analysis of radiographic accuracy.

BACKGROUND: We systematically reviewed the radiological outcomes of studies comparing robotic-assisted (RA-THA) and manual total hip arthroplasty (mTHA). METHODS: The PubMed, Embase, and Cochrane databases were queried from 1994-2021 for articles comparing radiographic outcomes between RA-THA and mTHA cohorts. A meta-analysis was conducted whenever sufficient data was present for common outcomes. RESULTS: Our analysis included 20 articles reporting on 4140 patients (RA-THA: n = 1228; mTHA: n = 2912). No differences were demonstrated for acetabular inclination or anteversion. However, RA-THA demonstrated higher rates of cup orientation within the Lewinnek and Callanan safe zones, improved femoral stem alignment, and lower global offset difference (GOD) and limb length discrepancy (all p-values <0.05). Superior femoral canal fill and combined offset were seen among RA-THA patients. CONCLUSION: Our review found that the use of RA-THA yields superior radiographic outcomes compared to mTHA counterparts. This information can inform healthcare systems considering investing in and implementing these technologies.

Assessment of the Anti-Allodynic and Anti-Hyperalgesic Efficacy of a Glycine Transporter 2 Inhibitor Relative to Pregabalin, Duloxetine and Indomethacin in a Rat Model of Cisplatin-Induced Peripheral Neuropathy.

Cisplatin, which is a chemotherapy drug listed on the World Health Organisation's List of Essential Medicines, commonly induces dose-limiting side effects including chemotherapy-induced peripheral neuropathy (CIPN) that has a major negative impact on quality of life in cancer survivors. Although adjuvant drugs including anticonvulsants and antidepressants are used for the relief of CIPN, analgesia is often unsatisfactory. Herein, we used a rat model of CIPN (cisplatin) to assess the effect of a glycine transporter 2 (GlyT2) inhibitor, relative to pregabalin, duloxetine, indomethacin and vehicle. Male Sprague-Dawley rats with cisplatin-induced mechanical allodynia and mechanical hyperalgesia in the bilateral hindpaws received oral bolus doses of the GlyT2 inhibitor (3-30 mg/kg), pregabalin (3-100 mg/kg), duloxetine (3-100 mg/kg), indomethacin (1-10 mg/kg) or vehicle. The GlyT2 inhibitor alleviated both mechanical allodynia and hyperalgesia in the bilateral hindpaws at a dose of 10 mg/kg, but not at higher or lower doses. Pregabalin and indomethacin induced dose-dependent relief of mechanical allodynia but duloxetine lacked efficacy. Pregabalin and duloxetine alleviated mechanical hyperalgesia in the bilateral hindpaws while indomethacin lacked efficacy. The mechanism underpinning pain relief induced by the GlyT2 inhibitor at 10 mg/kg is likely due to increased glycinergic inhibition in the lumbar spinal cord, although the bell-shaped dose-response curve warrants further translational considerations.

Characterisation of a rat model of mechanical low back pain at an advanced stage using immunohistochemical methods.

Chronic low back pain (LBP) has high prevalence in the adult population which is associated with enormous disability. Hence, our aim was to further characterise our LBP rat model by using immunohistological and immunohistochemical methods at an advanced stage (day 49) of the model. Male Sprague-Dawley rats were anaesthetised and their lumbar L4/L5 and L5/L6 intervertebral discs (IVDs) were punctured (0.5 mm outer diameter, 2 mm-deep) 10 times per disc. Sham-rats underwent similar surgery, but no discs were punctured. For LBP- but not sham-rats, noxious pressure hyperalgesia was fully developed in the lumbar axial deep tissues on day 21 post-surgery, which was maintained until at least day 49. In the lumbar (L4-L6) dorsal root ganglia (DRGs), somatostatin (SRIF) and the somatostatin receptor type 4 (SST4 receptor) were co-localised with substance P and IB4, markers of small diameter unmyelinated peptidergic and non-peptidergic C-fibres respectively as well as with NF200, a marker of medium to large diameter neurons. On day 49, there was increased expression of SRIF but not the somatostatin receptor type 4 (SST4 receptor) in the lumbar DRGs and the spinal dorsal horns. There were increased DRG expression levels of the putative pro-nociceptive mediators: phosphorylated p38 (pp38) mitogen-activated protein kinase (MAPK) and phosphorylated p44/p42 MAPK (pp44/pp42 MAPK) as well as pp38 MAPK expression levels in the lumbar spinal cord. Taken together, the increased expression of SRIF in the lumbar DRGs and spinal cord and its co-localisation with nociceptive fibres in DRG sections suggest a potential role of SRIF in modulating chronic mechanical LBP.

Herbicides That Target Acetohydroxyacid Synthase Are Potent Inhibitors of the Growth of Drug-Resistant Candida auris.

Acetohydroxyacid synthase (AHAS, EC 2.2.1.6), the first enzyme in the branched chain amino acid biosynthesis pathway, is the target for more than 50 commercially available herbicides, and is a promising target for antimicrobial drug discovery. Herein, we have expressed and purified AHAS from Candida auris, a newly identified human invasive fungal pathogen. Thirteen AHAS inhibiting herbicides have Ki values of <2 µM for this enzyme, with the most potent having Ki values of <32 nM. Six of these compounds exhibited MIC50 values of <1 µM against C. auris (CBS10913 strain) grown in culture, with bensulfuron methyl (BSM) being fungicidal and the most potent (MIC50 of 0.090 µM) in defined minimal media. The MIC50 value increases to 0.90 µM in media enriched by the addition of branched-chain amino acids at the expected concentration in the blood serum. The sessile MIC50 for BSM is 0.6 µM. Thus, it is also an excellent inhibitor of the growth of C. auris biofilms. BSM is nontoxic in HEK-293 cells at concentrations >100 µM and thus possesses a therapeutic index of >100. These data suggest that targeting AHAS is a viable strategy for treating C. auris infections.