A comprehensive MRI investigation to identify potential biomarkers of Osgood Schlatter disease in adolescents: A cross sectional study comparing Osgood Schlatter disease with controls.

BACKGROUND: Osgood-Schlatter disease (OSD) is the most common knee pain complaint among adolescents playing sports. Despite this, there remains controversy over the pathophysiology and whether specific anatomical characteristics are associated with OSD. PURPOSE: This study aimed to systematically and comprehensively characterize adolescents with OSD using magnetic resonance imaging (MRI) compared to pain-free controls, including both tissue abnormalities that may be associated with OSD, as well as anatomical characteristics. A secondary objective was to identify potential imaging biomarkers associated with pain. STUDY DESIGN: Cross-sectional study. METHODS: Adolescents with OSD and controls were recruited from 2020 to 2022. Following a clinical exam, demographics, pain, sports participation, and Tanner stage were collected. Knee MRI was conducted on the participants' most symptomatic knee (OSD) or the dominant leg (controls). RESULTS: Sixty-seven adolescents (46 with OSD and 30 controls) were included. 80% of participants with OSD had at least one tissue alteration compared to 54% of controls. Compared to controls, OSD had 36.3 (95%CI 4.5 to 289.7) higher odds of bony oedema at the tibial tuberosity, and 32.7 (95%CI 4.1 to 260.6) and 5.3 (95%CI 0.6 to 46.2) higher odds of bony oedema at the  tibial epiphysis and metaphysis respectively. Participants with OSD also had higher odds of fluid/oedema at the patellar tendon (12.3 95%CI 3.3 to 46.6), and superficial infrapatellar bursitis (7.2).  Participants with OSD had a more proximal tendon attachment (mean tibial attachment portion difference, -0.05, 95% CI: -0.1 to 0.0, p = 0.02), tendon thickness (proximal mean difference, -0.09, 95% CI: -0.4 to 0.2, p = 0.04; distal mean difference, -0.6, 95% CI: -0.9 to -0.2, p = 0.01). Those with bony/tendon oedema had 1.8 points (95% CI: 0.3 to 3.2) higher pain on palpation than those without (t = -2.5, df = 26.6, p = 0.019), but there was no difference between these groups in a functional single leg pain provocation. CONCLUSION: Adolescents with OSD present with tissue and structural abnormalities on MRI that differed from age-matched controls. The majority had findings in the patellar tendon and bone, which often co-occurred. However, a small proportion of OSD also presents without alterations. It appears these findings may be associated with clinical OSD-related pain on palpation of the tibial tuberosity. CLINICAL RELEVANCE: Our highlight the pathophysiology on imaging, which has implications for understanding the mechanism and treatment of OSD.

Exercise therapy with or without other physical therapy interventions versus placebo interventions for osteoarthritis -Systematic review.

Objective: To evaluate whether exercise therapy, with or without other physical therapy interventions, is superior to placebo intervention for osteoarthritis (OA). Design: Systematic review and meta-analysis. Data sources: MEDLINE and EMBASE via OVID, CINAHL and SPORTDiscus via EBSCO were searched from inception to February 2021. Study selection: Randomised controlled trials (RCTs) of adults with OA investigating an intervention involving exercise therapy with a placebo comparator. Data extraction and analysis: Data were extracted and checked for accuracy and completeness by pairs of reviewers. Primary outcomes were self-reported pain, function and quality of life (QoL). Comparative treatment effects were analysed by random effects model for short- and longer-term follow up. Methodological quality was evaluated using the Cochrane risk of bias tool, and the Grading of Recommendations Assessment system was used to evaluate the certainty of evidence. Results: 13 RCTs involving 1079 patients were identified and included. Meta-analysis demonstrated improved pain (10 studies (GRADE low certainty), SMD -1.1 (95%CI -1.7 to -0.4)) and function (8 studies (GRADE low certainty), SMD -0.8 (95%CI -1.5 to -0.2)) in the short-term with exercise versus placebo, but no significant difference in the longer-term (pain 3 studies; function 3 studies). Conclusion: Current evidence demonstrates that exercise therapy is superior to placebo in the short-term for pain and function in OA. The certainty of this evidence is low to very low and further research is very likely to have an important impact on our confidence in the estimate of effects.

Management and outcome of acral soft-tissue sarcomas.

AIMS: The aim of this study was to evaluate the surgical management and outcome of patients with an acral soft-tissue sarcoma of the hand or foot. PATIENTS AND METHODS: We identified 63 patients with an acral soft-tissue sarcoma who presented to our tertiary referral sarcoma service between 2000 and 2016. There were 35 men and 28 women with a mean age of 49 years (sd 21). Of the 63 sarcomas, 27 were in the hands and 36 in the feet. The commonest subtypes were epithelioid sarcoma in the hand (n = 8) and synovial sarcoma in the foot (n = 11). RESULTS: In 41 patients (65%), the tumour measured less than 5 cm in its largest dimension (median size 3 cm (2 to 6)); 27 patients (43%) were diagnosed after inadvertent excision prior to their referral to the specialist sarcoma unit. After biopsy and staging, primary surgical intervention at the sarcoma unit was excision and limb salvage in 43 (68%), partial (digit or ray) amputation in 14 (22%), and more proximal amputation in six (10%). At final follow up, local recurrence had been treated by one partial amputation and six amputations, resulting in a partial amputation rate of 24% and a proximal amputation rate of 19%. The five-year survival rate was 82%. Patients who underwent inadvertent excision showed no statistically significant difference in survival or local recurrence, but were more likely to undergo amputation (p = 0.008). Large tumour size (> 5 cm) was associated with lower survival (p = 0.04) and a higher risk of local recurrence (p = 0.009;). CONCLUSION: Most acral soft-tissue sarcomas measure less than 5 cm at presentation, indicating that while size can be a useful prognostic factor, it should not be used as a diagnostic threshold for referral. Increased tumour size is associated with a higher rate of local recurrence and reduced survival. Sarcoma excision with limb preservation does not result in an increased risk of local recurrence. Cite this article: Bone Joint J 2018;100-B:1518-23.

Academic requirements for Certificate of Completion of Training in surgical training: Consensus recommendations from the Association of Surgeons in Training/National Research Collaborative Consensus Group.

BACKGROUND: Surgical trainees are expected to demonstrate academic achievement in order to obtain their certificate of completion of training (CCT). These standards are set by the Joint Committee on Surgical Training (JCST) and specialty advisory committees (SAC). The standards are not equivalent across all surgical specialties and recognise different achievements as evidence. They do not recognise changes in models of research and focus on outcomes rather than process. The Association of Surgeons in Training (ASiT) and National Research Collaborative (NRC) set out to develop progressive, consistent and flexible evidence set for academic requirements at CCT. METHODS: A modified-Delphi approach was used. An expert group consisting of representatives from the ASiT and the NRC undertook iterative review of a document proposing changes to requirements. This was circulated amongst wider stakeholders. After ten iterations, an open meeting was held to discuss these proposals. Voting on statements was performed using a 5-point Likert Scale. Each statement was voted on twice, with ≥80% of votes in agreement meaning the statement was approved. The results of this vote were used to propose core and optional academic requirements for CCT. RESULTS: Online discussion concluded after ten rounds. At the consensus meeting, statements were voted on by 25 delegates from across surgical specialties and training-grades. The group strongly favoured acquisition of 'Good Clinical Practice' training and research methodology training as CCT requirements. The group agreed that higher degrees, publications in any author position (including collaborative authorship), recruiting patients to a study or multicentre audit and presentation at a national or international meeting could be used as evidence for the purpose of CCT. The group agreed on two essential 'core' requirements (GCP and methodology training) and two of a menu of four 'additional' requirements (publication with any authorship position, presentation, recruitment of patients to a multicentre study and completion of a higher degree), which should be completed in order to attain CCT. CONCLUSION: This approach has engaged stakeholders to produce a progressive set of academic requirements for CCT, which are applicable across surgical specialties. Flexibility in requirements whilst retaining a high standard of evidence is desirable.

A review of current surgical practice in the operative treatment of proximal humeral fractures: Does the PROFHER trial demonstrate a need for change?

OBJECTIVES: The PROximal Fracture of the Humerus: Evaluation by Randomisation (PROFHER) trial has recently demonstrated that surgery is non-superior to non-operative treatment in the management of displaced proximal humeral fractures. The objective of this study was to assess current surgical practice in the context of the PROFHER trial in terms of patient demographics, injury characteristics and the nature of the surgical treatment. METHODS: A total of ten consecutive patients undergoing surgery for the treatment of a proximal humeral fracture from each of 11 United Kingdom hospitals were retrospectively identified over a 15 month period between January 2014 and March 2015. Data gathered for the 110 patients included patient demographics, injury characteristics, mode of surgical fixation, the grade of operating surgeon and the cost of the surgical implants. RESULTS: A majority of the patients were female (66%, 73 of 110). The mean patient age was 62 years (range 18 to 89). A majority of patients met the inclusion criteria for the PROFHER trial (75%, 83 of 110). Plate fixation was the most common mode of surgery (68%, 75 patients), followed by intramedullary fixation (12%, 13 patients), reverse shoulder arthroplasty (10%, 11 patients) and hemiarthroplasty (7%, eight patients). The consultant was either the primary operating surgeon or supervising the operating surgeon in a large majority of cases (91%, 100 patients). Implant costs for plate fixation were significantly less than both hemiarthroplasty (p < 0.05) and reverse shoulder arthroplasty (p < 0.0001). Implant costs for intramedullary fixation were significantly less than plate fixation (p < 0.01), hemiarthroplasty (p < 0.0001) and reverse shoulder arthroplasty (p < 0.0001). CONCLUSIONS: Our study has shown that the majority of a representative sample of patients currently undergoing surgical treatment for a proximal humeral fracture in these United Kingdom centres met the inclusion criteria for the PROFHER trial and that a proportion of these patients may, therefore, have been effectively managed non-operatively.Cite this article: Mr B. J. F. Dean. A review of current surgical practice in the operative treatment of proximal humeral fractures: Does the PROFHER trial demonstrate a need for change? Bone Joint Res 2016;5:178-184. DOI: 10.1302/2046-3758.55.2000596.

A systematic review of the histological and molecular changes in rotator cuff disease.

INTRODUCTION: The pathogenesis of rotator cuff disease (RCD) is complex and not fully understood. This systematic review set out to summarise the histological and molecular changes that occur throughout the spectrum of RCD. METHODS: We conducted a systematic review of the scientific literature with specific inclusion and exclusion criteria. RESULTS: A total of 101 studies met the inclusion criteria: 92 studies used human subjects exclusively, seven used animal overuse models, and the remaining two studies involved both humans and an animal overuse model. A total of 58 studies analysed supraspinatus tendon exclusively, 16 analysed subacromial bursal tissue exclusively, while the other studies analysed other tissue or varying combinations of tissue types including joint fluid and muscle. The molecular biomarkers that were altered in RCD included matrix substances, growth factors, enzymes and other proteins including certain neuropeptides. CONCLUSIONS: The pathogenesis of RCD is being slowly unravelled as a result of the significant recent advances in molecular medicine. Future research aimed at further unlocking these key molecular processes will be pivotal in developing new surgical interventions both in terms of the diagnosis and treatment of RCD.

The management of solitary tumours of Hoffa's fat pad.

Hoffa's fat pad (HFP) of the knee is affected by a variety of tumours and tumour-like conditions. HFP can be affected by diffuse or solitary, focal disease. This paper reports a consecutive series of 19 cases of solitary symptomatic HFP tumours. The commonest presenting symptom was anterior knee pain. All patients underwent open excision after diagnostic magnetic resonance imaging (MRI). Histology revealed varied diagnoses with the commonest being pigmented villonodular synovitis (PVNS) and ganglia. American Knee Society scores improved from 76 pre-operatively to 96 post-operatively with an improvement in functional scores from 92 to 100. In conclusion the majority of solitary HFP tumours are benign and may be either cystic or solid. MRI and plain radiographs are the imaging of choice. The definitive treatments of both cystic and solid tumours should be selective arthrotomy and excision biopsy. All patients in this series reported substantial improvement in symptoms following surgery.

The advantages gained by the use of modern materials in the post operative casting procedure for foot and ankle surgery.

BACKGROUND: In June 2006, the post operative plaster immobilisation protocol for patients undergoing hindfoot and ankle surgery, at our institution, changed from multiple plaster changes to the immediate application of a definitive removable and reusable split synthetic cast. This study aims to assess the savings to the hospital and patient, following this change in practice. METHODS: A retrospective analysis of plaster room records from June 2005 to June 2007 was performed. The difference in cost to the hospital of the two different post operative journeys was then calculated. RESULTS: Two-hundred and twenty-two patients from 2005 to 2006 were managed at a total cost of 97,125 euro. From 2006 to 2007, 203 patients were managed with the new technique at a total cost of 37,860 euro. The net saving to the hospital of this change in practice was 251 euro per patient and 50,953 euro in total, while 203 patient visits and costs associated therewith were also saved. CONCLUSIONS: This study demonstrates how small changes in local practice can result in significant financial and temporal savings for hospitals and patients.

The pharmacokinetics and disposition of MK-0524, a Prosglandin D2 Receptor 1 antagonist, in rats, dogs and monkeys.

MK-0524 is a potent, selective and orally active Prosglandin D(2) Receptor 1 (DP(1)) antagonist currently under clinical development for the treatment of niacin-induced flushing. Experiments to study the pharmacokinetics, metabolism and excretion of MK-0524 were conducted in rats, dogs and monkeys. MK-0524 displayed linear kinetics and rapid absorption following an oral dose. Following intravenous (i.v.) administration of MK-0524 to rats and dogs (1 and 5 mg/kg), the mean Cl(p) was approximately 2 and approximately 6 ml/min/kg, the T(1/2) was approximately 7 and approximately 13 h and the Vd(ss) was approximately 1 and approximately 5 L/kg, respectively. In monkeys dosed i.v. at 3 mg/kg, the corresponding values were 8 ml/min/kg, 3 h and 1 L/kg, respectively. Following oral dosing of MK-0524 to rats (5, 25 and 100 mg/kg), dogs (5 mg/kg) and monkeys (3 mg/kg), the absorption was rapid with the mean C(max) occurring between 1 and 4 h. Absolute oral bioavailability values in rats, dogs and monkeys were 50, 70 and 8%, respectively. The major circulating metabolite was the acyl glucuronide of MK-0524 (M2), with ratios of glucuronide to the parent aglycone being highest in the monkey followed by dog and rat. In bile duct-cannulated rats and dogs, MK-0524 was eliminated primarily via acyl glucuronidation followed by biliary excretion of the acyl glucuronide, M2, the major drug-related entity in bile.

Say Yes First: follow up of a five-year rural drug prevention program.

Say Yes First--To Rural Youth and Family Alcohol/Drug Prevention (SYF) was a 5-year, federally-funded U.S.D.H.H.S. Center for Substance Abuse Prevention (CSAP) project that involved 859 children in the class of the year 2000. The children in four rural school districts were followed from Grade 4 to Grade 8 from 1991 to 1996. Initial results in a previous publication showed significant lower drug usage in this cohort than comparison students. A follow-up of 120 SYF participants and 136 comparison students in high schools using the National Youth Survey (Follow Up Questionnaire) indicated lower usage of alcohol, tobacco and other drugs for the program students and lower lifetime prevalence of marijuana use for program vs. comparison students. SYF students had higher course grades, lower school absenteeism, more positive attitudes toward school, less trouble in school and less negative self-appraisal. Program students also reported greater participation in sports, more family communication and fewer disagreements or arguments with their parents.

Phosphorylated morpholine acetal human neurokinin-1 receptor antagonists as water-soluble prodrugs.

The regioselective dibenzylphosphorylation of 2 followed by catalytic reduction in the presence of N-methyl-D-glucamine afforded 2-(S)-(1-(R)-(3, 5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(5-(2- phosphoryl-3-oxo-4H,-1,2,4-triazolo)methylmorpholine, bis(N-methyl-D-glucamine) salt, 11. Incubation of 11 in rat, dog, and human plasma and in human hepatic subcellular fractions in vitro indicated that conversion to 2 would be expected to occur in vivo most readily in humans during hepatic circulation. Conversion of 11 to 2 occurred rapidly in vivo in the rat and dog with the levels of 11 being undetectable within 5 min after 1 and 8 mg/kg doses iv in the rat and within 15 min after 0.5, 2, and 32 mg/kg doses iv in the dog. Compound 11 has a 10-fold lower affinity for the human NK-1 receptor as compared to 2, but it is functionally equivalent to 2 in preclinical models of NK-1-mediated inflammation in the guinea pig and cisplatin-induced emesis in the ferret, indicating that 11 acts as a prodrug of 2. Based in part on these data, 11 was identified as a novel, water-soluble prodrug of the clinical candidate 2 suitable for intravenous administration in humans.

Substance P receptor antagonist I: conversion of phosphoramidate prodrug after i.v. administration to rats and dogs.

A water-soluble phosphoramidate prodrug (L-758,298, compound I) of the potent and selective human Substance P receptor antagonist L-754, 030 (compound II) is under development as an i.v. drug for treatment of emesis, migraine, and chronic pain. Compound I undergoes hydrolysis readily to II under acidic conditions. In the studies reported herein, we investigated the stability of I in blood and hepatic subcellular fractions from rats, dogs, and humans as well as the conversion of I to II in rats and dogs after i.v. dosing. Compound I was converted to II rapidly in rat blood but was stable in dog and human blood. However, the conversion was rapid in liver microsomes prepared from dogs and humans. As expected from the results of in vitro studies, the in vivo conversion of I to II was rapid after i.v. dosing of I to rats and dogs. The relative extent of exposure of II after i.v. dosing of I was estimated by comparing the dose-adjusted area under the plasma concentration versus time curve values of II after i.v. dosing of I with those after i.v. dosing of II. In rats, the extent of exposure was estimated to be approximately 90 and approximately 100% at 1 and 8 mg/kg, respectively; in dogs, that was approximately 59% at 0.5 mg/kg. A nonproportional increase in the area under the concentration versus time curve value of II with dose was observed after i.v. administration of I in dogs from 0.5 to 32 mg/kg, suggesting that the elimination of II might have been saturated at higher doses.

Hydroxamic acid-based bisubstrate analog inhibitors of Ras farnesyl protein transferase.

The rational design, synthesis, and activity of novel, hydroxamic acid-based, collective bisubstrate analog inhibitors of farnesyl protein transferase (FPT) is described. This class of compounds differ structurally from the conventional FPT inhibitors by being non-sulfhydryl and by being bisubstrate based rather than peptide or FPP derived inhibitors. Whereas replacement of the sulfhydryl group of tetrapeptide CVLS (I50 = 1 microM) by an N-methylhydroxamic acid had a deleterious effect (10, I50 > 360 microM), moderate inhibition was realized with 16 (I50 = 42.5 microM), a bisubstrate analog involving anchorage of farnesyl and tripeptide groups by a hydroxamic acid-embedded linker. Starting from 16, a 1 order of magnitude improvement in in vitro potency was obtained by optimization of the linker (20, I50 = 4.35 microM). An additional 13-fold enhancement was achieved by substituting the tripeptide moiety VLS in 20 by VVM (23, I50 = 0.33 microM). The dependence of these inhibitors on their peptide and farnesyl subunits is suggestive of their bisubstrate nature. Compound 23 (I50 = 0.33 microM) is 2 orders of magnitude better in activity compared to the initial lead 16 [I50 = 42.5 microM) and is effective in blocking prenylation of protein in whole cells including p21ras.

Inhibition of antibacterial activity of himastatin, a new antitumor antibiotic from Streptomyces hygroscopicus, by fatty acid sodium salts.

Himastatin, a cyclohexadepsipeptide antibiotic, had in vivo antitumor activity against localized P388 leukemia and B16 melanoma but had no distal site antitumor activity. An in vitro Bacillus subtilis well-agar diffusion assay was employed to test the hypothesis that himastatin was enzymatically inactivated. The activity of himastatin against B. subtilis was inhibited when himastatin was mixed with mouse liver S9 fraction and microsomes. However, subsequent investigations demonstrated that the markedly decreased antibacterial activity was not enzymatic in nature but was related to the presence of certain fatty acid salts. Saturated fatty acid sodium salts with a carbon chain number of 8 or more reduced the antimicrobial activity of himastatin 50 to 100 times. If antibiotics such as ampicillin, bacitracin, chloramphenicol, and tunicamycin were used in place of himastatin, no meaningful reduction in antibacterial activity occurred. However, the antibacterial activity of the membrane-active peptide antibiotic polymyxin B, but not that of polymyxin E (colistin), was reduced in a manner similar to that of himastatin. Importantly, the activity of himastatin against HCT-116 colon adenocarcinoma cells in soft agar was markedly reduced in the presence of sodium palmitate as the reference fatty acid salt. The data indicate that himastatin may be trapped in micelles in vitro. It may be speculated that the lack of distal site antitumor activity resulted from similar complex formation between himastatin and lipids in vivo. The results also suggest that the cancer cytotoxic and antimicrobial effects of himastatin may result from interactions with the cell membrane.

Chromosome analysis of lymphocytes from workers at an ethylene oxide plant.

Samples of peripheral blood were collected from 33 men who had been employed in the manufacture of ethylene oxide for between 1 and 14 years, and from 32 men from other parts of the same plant who were used as controls. Their lymphocytes were analysed for chromosome damage. There were low frequencies of polyploidy, chromatid aberrations and chromosome breaks in the cells of the 65 men. A slightly higher frequency of chromatid aberrations was observed in the cells of the ethylene oxide workers than in those of the controls, but the difference between the two groups was not statistically significant. There was a positive correlation between length of employment in the ethylene oxide group and the numbers of aberrations in the cultures of each individual. This trend was not solely attributable to the age of the men. The levels of chromatid and chromosome damage observed in this study are consistent with those in humans who have not recently been exposed to known chromosome-breaking agents.

Cytogenetic, immunological, and haematological effects in workers in an ethylene oxide manufacturing plant.

Samples of blood were collected from a group of plant workers engaged in the manufacture of ethylene oxide (EO) for periods of up to 14 years and also from a group of control personnel matched by age and smoking habits. Peripheral blood lymphocytes were cultured for cytogenetic analysis. Selected immune and haematological parameters were also investigated. The results of these studies showed no statistically significant difference between the group of plant workers and the control group in respect of any of the biological parameters investigated in this study. Nevertheless, duration of employment in EO manufacturing was positively correlated (p less than 0.05) with the frequency of chromosome breaks and with the percentage of neutrophils in a differential white blood cell count and negatively correlated (p less than 0.05) with the percentage of lymphocytes. As the values of these parameters remained within the normal limits of control populations, the correlations were considered to have no significance for health. Atmospheric concentrations of EO were determined using personnel air samplers and were generally below the detection limit (less than 0.05 ppm) during stable plant operations, although transient concentrations of up to 8 ppm were occasionally recorded. The amount of alkylation (2-hydroxyethyl groups) of the Nt atom of histidinyl residues in haemoglobin was also measured in an attempt to gauge recent individual exposures to EO. Variable but, in most instances, readily measurable amounts of Nt-(2'-hydroxyethyl)-L-histidine (Nt represents the N3 atom of histidine) were found in the haemoglobin of plant workers and in the control group who had not knowingly been exposed to an exogenous source of EO. There was no statistically significant difference between the results obtained in the control group and in the group of plant workers.

Genetic toxicology testing of 41 industrial chemicals.

41 compounds or mixtures of diverse structure and application have been tested for genotoxic activity. The materials were tested in bacterial mutation assays, in Saccharomyces cerevisiae JD1 for mitotic gene conversion and in a cultured rat-liver cell line for structural chromosome damage. 11 compounds were bacterial mutagens, 4 induced mitotic gene conversion in yeast and 5 were positive in the chromosome assay. 5 of the materials were positive in bacteria only and 2 compounds induced chromosome damage in cultured cells in the absence of mutation in bacteria or gene conversion in yeast. The materials were tested over a 5-year period and the performance and evolution of the 3 assays during this time is evaluated. The results are considered in relation to the structure of the chemicals and the genotoxicity of related compounds.