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.

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.

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.

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.

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.

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.

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.

Assessment of the anti-hyperalgesic efficacy of J-2156, relative to clinically available analgesic/adjuvant agents in a rat model of mild to moderate chronic mechanical low back pain (LBP).

Chronic mechanical low back pain (cLBP) is a leading cause of disability and a major socio-economic burden internationally. The lifetime prevalence of non-specific LBP is approximately 84%, with the prevalence of cLBP at about 23%. Clinically available analgesic/adjuvant medications often provide inadequate pain relief in patients experiencing cLBP. Hence, the urgency for discovery of effective and better tolerated medications. Fourteen days after the induction of five shallow annular punctures (5X) in the lumbar intervertebral discs at L4/L5 and L5/L6 in male Sprague-Dawley rats, mechanical hyperalgesia was fully developed in the lumbar axial deep tissues at L4/L5 (primary) and L1 (secondary). Importantly, mechanical allodynia in the hindpaws was absent. From day 28, we assessed the face validity of our mild to moderate LBP-5X rat model using four clinically available analgesic/adjuvant drugs, namely gabapentin, morphine, meloxicam and amitriptyline relative to vehicle. Additionally, the anti-hyperalgesic effects of J-2156, a highly selective small molecule somatostatin type 4 receptor agonist was assessed. Single i.p. bolus doses of gabapentin and meloxicam at the highest doses tested (100 and 30 mg/kg, respectively) alleviated secondary hyperalgesia (L1) but not primary hyperalgesia (L4/5). Morphine at 1 mg/kg alleviated both primary and secondary hyperalgesia in these tissues, whereas amitriptyline at the doses tested, lacked efficacy. These findings attest to the face validity of our model. J-2156 at 10 and 30 mg/kg alleviated secondary hyperalgesia in the lumbar axial deep tissues at L1 with a non-significant trend for relief of primary hyperalgesia in the corresponding tissues at L4/L5 in these animals.

Cyclooctatetraene: A Bioactive Cubane Paradigm Complement.

Cubane was recently validated as a phenyl ring (bio)isostere, but highly strained caged carbocyclic systems lack π character, which is often critical for mediating key biological interactions. This electronic property restriction associated with cubane has been addressed herein with cyclooctatetraene (COT), using known pharmaceutical and agrochemical compounds as templates. COT either outperformed or matched cubane in multiple cases suggesting that versatile complementarity exists between the two systems for enhanced bioactive molecule discovery.

Transcriptomic characterisation of the optimised rat model of Walker 256 breast cancer cell-induced bone pain.

In patients with breast cancer, metastases of cancer cells to the axial skeleton may cause excruciating pain, particularly in the advanced stages. The current drug treatments available to alleviate this debilitating pain condition often lack efficacy and/or produce undesirable side effects. Preclinical animal models of cancer-induced bone pain are key to studying the mechanisms that cause this pain and for the success of drug discovery programs. In a previous study conducted in our laboratory, we validated and characterised the rat model of Walker 256 cell-induced bone pain, which displayed several key resemblances to the human pain condition. However, gene level changes that occur in the pathophysiology of cancer-induced bone pain in this preclinical model are unknown. Hence, in this study, we performed the transcriptomic characterisation of the Walker 256 cell line cultured in vitro to predict the molecular genetic profile of this cell line. We also performed transcriptomic characterisation of the Walker 256 cell-induced bone pain model in rats using the lumbar spinal cord and lumbar dorsal root ganglia tissues. Here we show that the Walker 256 cell line resembles the basal-B molecular subtype of human breast cancer cell lines. We also identify several genes that may underpin the progression of pain hypersensitivities in this condition, however, this needs further confirmatory studies. These transcriptomic insights have the potential to direct future studies aimed at identifying various mechanisms underpinning pain hypersensitivities in this model that may also assist in discovery of novel pain therapeutics for breast cancer-induced bone pain.

Establishment and characterisation of a stavudine (d4T)-induced rat model of antiretroviral toxic neuropathy (ATN) using behavioural and pharmacological methods.

Human immuno-deficiency virus (HIV) associated sensory neuropathy (SN) is a frequent complication of HIV infection. It is extremely difficult to alleviate and hence the quality of life of affected individuals is severely and adversely impacted. Stavudine (d4T) is an antiretroviral drug that was widely used globally prior to 2010 and that is still used today in resource-limited settings. Its low cost and relatively good efficacy when included in antiretroviral dosing regimens means that there is a large population of patients with d4T-induced antiretroviral toxic neuropathy (ATN). As there are no FDA approved drugs for alleviating ATN, it is important to establish rodent models to probe the pathobiology and to identify potentially efficacious new drug treatments. In the model establishment phase, d4T administered intravenously at a cumulative dose of 375 mg/kg in male Wistar Han rats evoked temporal development of sustained mechanical allodynia in the hindpaws from day 10 to day 30 after initiation of d4T treatment. As this d4T dosing regimen was also well tolerated, it was used for ATN model induction for subsequent pharmacological profiling. Both gabapentin at 30-100 mg/kg and morphine at 0.3-2 mg/kg given subcutaneously produced dose-dependent relief of mechanical allodynia with estimated ED50's of 19 mg/kg and 0.4 mg/kg, respectively. In contrast, intraperitoneal administration of meloxicam or amitriptyline up to 30 mg/kg and 7 mg/kg, respectively, lacked efficacy. Our rat model of ATN is suitable for investigation of the pathophysiology of d4T-induced SN as well as for profiling novel molecules from analgesic drug discovery programs.

In vivo profiling of four centrally administered opioids for antinociception, constipation and respiratory depression: Between-colony differences in Sprague Dawley rats.

Outbred rodent stocks including Sprague Dawley rats, are known for their genetic diversity and so they are often used to develop animal models of human disease. Although between-colony differences in pharmaco-behavioural studies have been published previously, a direct head-to-head comparison study, whereby all research was performed in the same laboratory by the same experimenter utilising the supraspinal route of drug administration in the same strain of rat, is lacking. Herein, we report our head-to-head comparison study, involving assessment of antinociception, constipation and respiratory depression evoked by single bolus intracerebroventricular (ICV) doses of morphine, buprenorphine, DPDPE and U69,593 using male Sprague Dawley rats sourced from a different breeding colony (BC2) from that (BC1) used by us previously. Our data show that there are marked differences in the potency rank order for morphine and buprenorphine between rats sourced from BC2 and BC1. Although ICV morphine evoked a bell-shaped dose-response curve in the constipation test for rats from both colonies, this occurred at higher doses for rats from BC2. In conclusion, our head-to-head comparison shows considerable between-colony differences for the same rat strain, in the potency rank order of two clinically important strong opioid analgesics given by the ICV route.

Comparative analgesic efficacy of pregabalin administered according to either a prevention protocol or an intervention protocol in rats with cisplatin-induced peripheral neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a type of peripheral neuropathic pain that may be dose-limiting in patients administered potentially curative cancer chemotherapy dosing regimens. In cancer survivors, persistent CIPN adversely affects patient quality of life and so adjuvant drugs (anticonvulsants eg pregabalin or antidepressants eg amitriptyline) are recommended for the relief of CIPN. However, most studies in rodent models of CIPN involve administration of single bolus doses of adjuvant drugs to assess pain-relieving efficacy. Hence this study was designed to assess the efficacy of pregabalin administered to CIPN-rats according to either a prevention or an intervention protocol. Groups of male Sprague-Dawley rats received four single intraperitoneal bolus doses of cisplatin at 3 mg/kg at once-weekly intervals to induce CIPN. For the prevention protocol, oral pregabalin (or vehicle) was administered to CIPN-rats once-daily for 21 consecutive days from day 0 to day 20 inclusive. For the intervention protocol, oral pregabalin was administered once-daily for 21 consecutive days from day 28 to day 48, inclusive. Mechanical allodynia and mechanical hyperalgesia in the bilateral hindpaws were assessed just prior to each dose of cisplatin and at least once weekly until study completion (day 27, prevention protocol; or day 48, intervention protocol). Mechanical allodynia and mechanical hyperalgesia were also determined at the time of peak effect at about 2 hours post pregabalin/vehicle administration, once weekly until study completion. For the prevention protocol in CIPN-rats, pregabalin alleviated mechanical hyperalgesia but not mechanical allodynia. For the intervention protocol, pregabalin alleviated both mechanical allodynia and mechanical hyperalgesia in the hindpaws.

Chronic low back pain: a mini-review on pharmacological management and pathophysiological insights from clinical and pre-clinical data.

Globally, low back pain (LBP) is one of the most common health problems affecting humans. The lifetime prevalence of non-specific LBP is approximately 84%, with the chronic prevalence at about 23%. Chronic LBP in humans is defined as LBP that persists for more than 12 weeks without a significant pain improvement. Although there are numerous evidence-based guidelines on the management of acute LBP, this is not the case for chronic LBP, which is regarded as particularly difficult to treat. Research aimed at discovering new drug treatments for alleviation of chronic mechanical LBP is lacking due to the paucity of knowledge on the pathobiology of this condition, despite its high morbidity in the affected adult population. For a debilitating condition such as chronic LBP, it is necessary to assess the sustained effects of pharmacotherapy of various agents spanning months to years. Although many rodent models of mechanical LBP have been developed to mimic the human condition, some of the major shortcomings of many of these models are (1) the presence of a concurrent neuropathic component that develops secondary to posterior intervertebral disc puncture, (2) severe model phenotype, and/or (3) use of behavioural endpoints that have yet to be validated for pain. Hence, there is a great, unmet need for research aimed at discovering new biological targets in rodent models of chronic mechanical LBP for use in drug discovery programs as a means to potentially produce new highly effective and well-tolerated analgesic agents to improve relief of chronic LBP. On a cautionary note, it must be borne in mind that because humans and rats display orthograde and pronograde postures, respectively, the different mechanical forces on their spines add to the difficulty in translation of promising rodent data to humans.

Pharmacological inhibition of the NLRP3 inflammasome as a potential target for multiple sclerosis induced central neuropathic pain.

The NOD-like receptor (NLR) family pyrin domain-containing protein 3 (NLRP3) inflammasome is implicated in the pathogenesis of multiple diseases including neuroinflammation associated with multiple sclerosis (MS). However, the extent to which NLRP3 has a pathobiological role in MS-associated central neuropathic pain (CNP) is unknown. Hence, the present study was designed to address this issue using an optimised relapsing-remitting experimental encephalomyelitis (RR-EAE)-mouse model of MS-associated neuropathic pain. RR-EAE mice with fully developed mechanical allodynia in the bilateral hindpaws (paw withdrawal thresholds (PWTs) ≤ 1 g) at day 16 post-immunisation (p.i.) were administered single oral bolus doses of MCC950, a selective and potent small-molecule inhibitor of NLRP3, once daily for 21 consecutive days. Following administration of the first dose of MCC950 at 50 mg kg-1, the mean (± SEM) peak anti-allodynic effect was observed at ~ 1 h post-dosing with a duration of action of ~ 2 h. Following chronic dosing with MCC950, mechanical allodynia in the bilateral hindpaws was progressively reversed by oral treatment with MCC950 (50 mg kg-1 day-1), but not vehicle. Specifically, by day 25 p.i. and continuing until study completion on day 36 p.i., bilateral hindpaw PWTs of RR-EAE mice treated with MCC950 (50 mg kg-1 day-1) did not differ significantly (P > 0.05) from the corresponding hindpaw PWTs for the sham (control) group. In addition, MCC950 at 50 mg kg-1 day-1 attenuated disease relapses in RR-EAE mice indicated by tail limpness as well as hindlimb weakness. Together, our findings suggest that inhibition of NLRP3 inflammasome activation may be a potential therapeutic approach to alleviate MS-associated CNP and disease relapses in patients with RR-MS.

Validating Eaton's Hypothesis: Cubane as a Benzene Bioisostere.

Pharmaceutical and agrochemical discovery programs are under considerable pressure to meet increasing global demand and thus require constant innovation. Classical hydrocarbon scaffolds have long assisted in bringing new molecules to the market place, but an obvious omission is that of the Platonic solid cubane. Eaton, however, suggested that this molecule has the potential to act as a benzene bioisostere. Herein, we report the validation of Eaton's hypothesis with cubane derivatives of five molecules that are used clinically or as agrochemicals. Two cubane analogues showed increased bioactivity compared to their benzene counterparts whereas two further analogues displayed equal bioactivity, and the fifth one demonstrated only partial efficacy. Ramifications from this study are best realized by reflecting on the number of bioactive molecules that contain a benzene ring. Substitution with the cubane scaffold where possible could revitalize these systems, and thus expedite much needed lead candidate identification.

Factors Predisposing Patients to Nonhome 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. DESIGN: This is a retrospective chart review of adults who underwent cervical spine surgery for degenerative cervical myelopathy between 2014 and 2020 ( N = 135). RESULTS: Patients discharged to a subacute setting were older (68.1 ± 8.6 vs. 64.1 yrs ± 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). A total of 87.8% of patients discharged to a subacute setting required moderate or maximum assistance for bed mobility versus 26.6% of patients discharged home ( P < 0.0001). Compared with patients discharged home, patients discharged to a subacute setting ambulated a shorter distance in their first physical therapy evaluation after surgery (8.9 ± 35.8 vs. 53.7 ± 61.78 m in the home discharge group, P < 0.0001). CONCLUSIONS: Analysis of these factors may guide discussions about patient expectations for postoperative discharge placement.

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.