Plantar flexion, dorsiflexion, range of movement and hindfoot deviation are important determinants of foot function in children.

PURPOSE: Paediatric foot surgery is often performed to restore anatomical shape or range of movement (ROM). The purpose of this study was to determine how foot morphology and ROM are associated with foot function in children aged five to 16 years of age. METHODS: Participants included 89 patients with foot disorders and 58 healthy controls. In addition to measuring children's foot alignment and ankle ROM, children and parents completed the Oxford Ankle and Foot Questionnaire (OxAFQ). RESULTS: Mean age was 10.3 years for patients and 10.6 years for controls; 53 of 89 patients had clubfoot. All foot measurements and scores on the OxAFQ significantly differed (p < 0.001) between patients and controls. Patients and their parents significantly differed on the physical (p = 0.03) and emotional (p = 0.02) domains of the OxAFQ, with parents' ratings being lower than their children. Moderate correlations (r = 0.54 to 0.059; p < 0.001) were found between physical domain (reported by parents on the OxAFQ) and dorsiflexion-knee flexed, and foot- arc-of-movement. Moderate correlations were found between physical domain (reported by children on OxAFQ) and foot-arc-of-movement (r = 0.56; p < 0.001). Patients in the surgical group showed moderate correlations (r = 0.57;, p < 0.001) between physical domain (reported by children on OxAFQ) and plantar flexion, and foot arc-of-movement. The control group and the patients in non-surgical subgroup showed no significant correlations. CONCLUSION: Plantar flexion, arc of ankle ROM and hindfoot alignment impact foot function in children with foot deformities. Parents report significantly lower scores on the OxAFQ when judging foot functioning. LEVEL OF EVIDENCE: Level II. Prognostic Studies.

Inter-rater reliability of the radiographic assessment of simple bone cysts.

PURPOSE: To develop and evaluate the reliability of an explicit set of parameters and criteria for simple bone cysts (SBCs) and evaluate the reliability of single versus serial chronological reading methods. METHODS: Radiographic criteria were developed based on the literature and expert consensus. A single anteroposterior/lateral radiograph from 32 subjects with SBC were evaluated by three radiologists. A second reading was then conducted using revised criteria including a visual schematic. In the third reading the same images were assessed but radiologists had access to images from two additional time points. Inter-rater reliability was assessed after each reading using kappa (κ) and percentage agreement for categorical and binary parameters and intra-class correlation coefficient (ICC) for continuous parameters. RESULTS: Parameters that were revised with more explicit definitions including the visual schematic demonstrated consistent or improved inter-rater reliability with the exception of continuous cortical rim present and cyst location in the metaphysis and mid-diaphysis. Cortical rim displayed only slight reliability throughout (κ= -0.008 to 0.16). All other categorical parameters had a percentage agreement above 0.8 or a moderate (κ= 0.41 to 0.60), substantial (κ = 0.61 to 0.80) or almost perfect inter-rater reliability (κ = 0.81 to 1.0) in at least one reading. All continuous parameters demonstrated excellent inter-rater reliability (ICC > 0.75) in at least one reading with the exception of scalloping (ICC = 0.37 to 0.70). Inter-rater reliability values did not indicate an obviously superior method of assessment between single and serial chronological readings. CONCLUSION: Explicit criteria for SBC parameters used in their assessment demonstrated improved and substantial inter-rater reliability. Inter-rater reliability did not differ between single and serial chronological readings. LEVEL OF EVIDENCE: Not Applicable.

A consensus exercise identifying priorities for research into clinical effectiveness among children's orthopaedic surgeons in the United Kingdom.

Aims: High-quality clinical research in children's orthopaedic surgery has lagged behind other surgical subspecialties. This study used a consensus-based approach to identify research priorities for clinical trials in children's orthopaedics. Methods: A modified Delphi technique was used, which involved an initial scoping survey, a two-round Delphi process and an expert panel formed of members of the British Society of Children's Orthopaedic Surgery. The survey was conducted amongst orthopaedic surgeons treating children in the United Kingdom and Ireland. Results: A total of 86 clinicians contributed to both rounds of the Delphi process, scoring priorities from one (low priority) to five (high priority). Elective topics were ranked higher than those relating to trauma, with the top ten elective research questions scoring higher than the top question for trauma. Ten elective, and five trauma research priorities were identified, with the three highest ranked questions relating to the treatment of slipped capital femoral epiphysis (mean score 4.6/ 5), Perthes' disease (4.5) and bone infection (4.5). Conclusion: This consensus-based research agenda will guide surgeons, academics and funders to improve the evidence in children's orthopaedic surgery and encourage the development of multicentre clinical trials. Cite this article: Bone Joint J 2018;100-B:680-4.

A thermodynamic study of the trp repressor-operator interaction.

We have measured the heats of formation of the trp repressor/operator complex by direct titration calorimetry over the temperature range 10 degrees C to 40 degrees C. A primary strong mode of binding displays the characteristic large negative heat capacity change observed by other methods in the formation of specific protein/DNA complexes. Unlike most such reactions, however, the formation of the trp repressor/operator complex is enthalpically driven throughout the physiological temperature range. After saturation of this principal mode, we also detected a secondary weaker binding mode, which we ascribe to a now well documented interaction called "half-site" binding. Although weak, this mode also exhibits an unusually large negative heat capacity change. Since the interface of the proposed secondary half-site binding mode has the same complementary stereochemistry as the primary one (due to internal symmetry), we correlate the negative heat capacity change with the formation of a stereospecific interface and not with high affinity. As in similar cases, the empirical correlation between buried non-polar surfaces and reduction of heat capacity does not account for the large negative delta Cp, nor do crystal structures reveal any further reduction in solvent excluded surfaces within the reactants upon complex formation. We attribute the "unaccounted for" decrement in the heat capacity of the complex to the stereospecific restriction of the hydrated polar elements that form the specific interface. We suggest that the "tightening of soft internal modes" at and near the polar interface of the complex is more important than previously recognized because previous considerations did not take into account the highly hydrated nature of these polar elements and the concomitant reduction in the degrees of freedom of the water structure.

Specialist integrated haematological malignancy diagnostic services: an Activity Based Cost (ABC) analysis of a networked laboratory service model.

AIMS: Specialist Integrated Haematological Malignancy Diagnostic Services (SIHMDS) were introduced as a standard of care within the UK National Health Service to reduce diagnostic error and improve clinical outcomes. Two broad models of service delivery have become established: 'co-located' services operating from a single-site and 'networked' services, with geographically separated laboratories linked by common management and information systems. Detailed systematic cost analysis has never been published on any established SIHMDS model. METHODS: We used Activity Based Costing (ABC) to construct a cost model for our regional 'networked' SIHMDS covering a two-million population based on activity in 2011. RESULTS: Overall estimated annual running costs were £1 056 260 per annum (£733 400 excluding consultant costs), with individual running costs for diagnosis, staging, disease monitoring and end of treatment assessment components of £723 138, £55 302, £184 152 and £94 134 per annum, respectively. The cost distribution by department was 28.5% for haematology, 29.5% for histopathology and 42% for genetics laboratories. Costs of the diagnostic pathways varied considerably; pathways for myelodysplastic syndromes and lymphoma were the most expensive and the pathways for essential thrombocythaemia and polycythaemia vera being the least. CONCLUSIONS: ABC analysis enables estimation of running costs of a SIHMDS model comprised of 'networked' laboratories. Similar cost analyses for other SIHMDS models covering varying populations are warranted to optimise quality and cost-effectiveness in delivery of modern haemato-oncology diagnostic services in the UK as well as internationally.

Population pharmacokinetics of adjuvant cyclophosphamide, methotrexate and 5-fluorouracil (CMF).

Despite the success of adjuvant cyclophosphamide, methotrexate (MTX), 5-fluouracil (5-FU) (CMF) treatment for early stage breast cancer, more than 35% of patients die within 5 years of diagnosis. Optimisation of the dose of each component drug may improve survival and reduce toxicity. In this study, the pharmacokinetics of intravenous (i.v.) cyclophosphamide (600 mg/m(2)), MTX (40 mg/m(2)) and 5-FU (600 mg/m(2)) were determined in 46 women, with data on two consecutive courses available for 41 patients. A population analysis using NONMEM was performed to investigate the effect of patient covariates on pharmacokinetics (PK), and to estimate the relative magnitude of interindividual and interoccasion variability. Patient weight had a significant influence on the clearance of cyclophosphamide and on the volume of central compartment for MTX, whose clearance was dependent on renal function. For all three drugs, interoccasion variability was of the same order (20-40%) as that between individuals, suggesting a limited potential for dose-optimisation of this regimen.

All half-lives are wrong, but some half-lives are useful.

The half-life of a drug, which expresses a change in concentration in units of time, is perhaps the most easily understood pharmacokinetic parameter and provides a succinct description of many concentration-time profiles. The calculation of a half-life implies a linear, first-order, time-invariant process. No drug perfectly obeys such assumptions, although in practise this is often a valid approximation and provides invaluable quantitative information. Nevertheless, the physiological processes underlying half-life should not be forgotten. The concept of clearance facilitates the interpretation of factors affecting drug elimination, such as enzyme inhibition or renal impairment. Relating clearance to the observed concentration-time profile is not as naturally intuitive as is the case with half-life. As such, these 2 approaches to parameterising a linear pharmacokinetic model should be viewed as complementary rather than alternatives. The interpretation of pharmacokinetic parameters when there are multiple disposition phases is more challenging. Indeed, in any pharmacokinetic model, the half-lives are only one component of the parameters required to specify the concentration-time profile. Furthermore, pharmacokinetic parameters are of little use without a dose history. Other factors influencing the relevance of each disposition phase to clinical end-points must also be considered. In summarising the pharmacokinetics of a drug, statistical aspects of the estimation of a half-life are often overlooked. Half-lives are rarely reported with confidence intervals or measures of variability in the population, and some approaches to this problem are suggested. Half-life is an important summary statistic in pharmacokinetics, but care must be taken to employ it appropriately in the context of dose history and clinically relevant pharmacodynamic end-points.

Early repolarization: an electrocardiographic predictor of enhanced aerobic fitness.

The presence or absence of early repolarization on the electrocardiogram at rest was correlated with aerobic exercise capacity in healthy volunteers from the Baltimore Longitudinal Study of Aging. Patients with early repolarization had both longer treadmill exercise duration and higher peak oxygen consumption than age-and gender-matched control subjects.

Evaluating the outcome of treatment. Shouldn't We be asking patients if they are better?

Increasingly clinicians and investigators are recognizing the need to include patients in the assessment of therapy. Patient-based assessments, such as measures of health status or health-related quality-of-life, require patients to rate themselves on a fixed number of questions. Because patients come to their doctors with unique, different, and individual concerns, the concern is that commonly used scales with a fixed number of questions might be excluding important individual concerns or including issues irrelevant to individual patients. Clinicians usually do not rely on health status questionnaires in routine practice to judge the success of therapy, but ask patients directly if they are better. Despite this fundamental interchange between patients and clinicians, relatively little attention has been directed towards the specification, measurement, and quantification of patients' individual concerns. Patient-specific measures are a particular type of measure which allow patients to state their individual concerns, and weight their relative importance. Because we are often trying to address with treatment the concerns of individual patients, patient-specific outcomes would provide us a standardized method useful in research and clinical practice of asking patients whether they are better.

A comparison of different indices of responsiveness.

The first purpose of this study was to determine if different indices of responsiveness provided similar rank orderings of scales in terms of responsiveness. The second purpose was to compare the responsiveness of patient-specific, disease-specific, and generic health status measures for patients undergoing total hip arthroplasty. All patients of one surgeon at a single institution were eligible for the study. Patients who did not speak English or did not return for post-operative evaluations were excluded. Patients completed two disease-specific scales (the Harris Hip Scale and the Western Ontario and McMaster osteoarthritis scale or WOMAC), one generic health status scale (the SF-36), and two patient-specific scales (the McMaster-Toronto Arthritis questionnaire or MACTAR and the Patient Specific Index or PASI). All scales were administered on two occasions: before and 6 months after total hip arthroplasty. Responsiveness was measured using: (1) the responsiveness statistic; (2) standardized response mean; (3) relative efficiency statistic; (4) effect size; and also by (5) correlating each scale's change score with the change in patients' global ratings of their "hip function." Seventy-eight sequential patients completed the study. The mean age was 62 years (range 25-87), 55% were male, and 71% had osteoarthritis. Test-retest reliability of the scales ranged from 0.31 to 0.93. The correlation among scales was consistent with a priori hypotheses confirming construct validity of the scales. Although the disease-specific scales were generally rated as the most responsive scales, the different indices provided different rank orderings by up to 5 levels (p = 0.04). In conclusion, disease-specific scales are the most responsive scales. However, choosing among scales based on responsiveness must be done with caution because different indices of responsiveness provide different rank ordering.

A taxonomy for responsiveness.

Responsiveness is quickly becoming a critical criterion for the selection of outcomes measures in studies of treatment effectiveness, economic appraisals, and other program evaluations. Statistical characteristics, specifically "large effect sizes," are often felt to indicate the relative worth of one instrument over another. However, debates about their meaning led the present authors to propose a taxonomy for responsiveness based on the context of the study concerned. The three axes underlying the classification system relate to: who is this being analyzed for (individuals or groups); which scores are being contrasted (over time/at one point in time); and the type of change being quantified (for example, observed change or important change). It is concluded that responsiveness should be considered a highly contextualized attribute of an instrument, rather than a static property and should be described only in that way. A questionnaire could thus be described as being "responsive to" a given category in the new taxonomy.

Changing rates of cancer. The hazards of using a single definition.

Changing cancer rates, abstracted from tumor registries, are used to make inferences about the effect of carcinogens and cancer treatments on a population-wide basis. We compared the annual age-standardized incidence rates of extremity soft tissue sarcomas from two large tumor registries using different case definitions. We identified all limb soft tissue sarcoma cases diagnosed 1973-1993 in the Ontario Cancer Registry (OCR) and the Surveillance, Epidemiology, and End Results (SEER) databases. Two case definitions for limb soft tissue sarcoma were used based on missing data, incomplete diagnostic methods and ICD-9 codes; an upper limit estimate of the rates which included all possible cases of limb soft tissue sarcoma and a lower limit estimate of the rates which included all definite cases of limb soft tissue sarcoma (with the true rates lying in between). The upper limit OCR rates showed a statistically significant decreasing linear trend (slope = -0.021, P < 0.01). Whereas the slope of the OCR lower limit regression line showed a statistically significant increase in rates (slope = 0.01, P = 0.04). Neither the upper or lower limit SEER rates had a statistically significant linear trend (slope = 0.002, P = 0.60 and slope = 0.001, P = 0.18, respectively). Case definition affects incidence rates and changing rates of cancer. Thus the use of a single case definition along with changing coding practices may alone explain changing cancer rates.

How should importance and severity ratings be combined for item reduction in the development of health status instruments?

Patients' ratings of the severity and importance of items are often used to select items for health status instruments. The purpose of this study was to compare six different methods of combining severity-importance ratings. Two different patient groups separately rated the importance and severity of their complaints; (i) 76 patients with upper-extremity disorders rated 70 upper-extremity-related questions; and (ii) 86 patients with hip arthrosis rated 22 questions relating to their hip problem. The rank ordering of the items using the six different methods in the two populations were very similar (tau(bi) = 0.91 and 0.87, respectively). Furthermore, the six methods when used to choose 30 upper-extremity items shared 25 items in common and shared 9 (of 10) hip items in the second group. In conclusion, the results of item reduction were not affected by the method of creating importance-severity ratings.

Clinimetric and psychometric strategies for development of a health measurement scale.

Clinimetrics and psychometrics, two accepted methods for developing multiitem health measurement scales, have fundamentally different aims and methods that have seldom been compared and never prospectively. The purpose of this study was to determine whether these two methodologies provided comparable scales in the development of an upper extremity disability measure. Psychometric analysis involved field testing a 70-item questionnaire on 407 patients. Equidiscriminatory item total correlation (EITC) was used to select the top 30 items. Clinimetric testing used the mean importance and severity ratings of the 70 items by 76 patients to select the top 30 items. Clinimetric and psychometric analyses were performed independently. Cronbach's alpha was 0.97 for the top 30 items selected by EITC and 0.96 for the items selected based on patient's ratings. The two scales (after clinician modification to improve face validity) shared 16 items in common (P=0.10). The intraclass correlation coefficient of the patient scores on the two 30-item scales was 0.93 before clinician input and 0.97 after. The mean (and standard deviation) difference between scales was 9.1 (8.8) before and 1.7 (5.2) after clinician input. A scale developed with a clinimetric strategy can measure a complex (so-called heterogeneous) clinical phenomenon (thought to be composed of several patient attributes) but still fulfill psychometric criteria for "homogeneity." Thus, these strategies for the development of health measurement scales, which have been considered potentially opposite or conflicting, may be complementary.

Accuracy of administrative data for assessing outcomes after knee replacement surgery.

OBJECTIVE: To assess the accuracy of information in an administrative database (Canadian Institute for Health Information; CIHI) compared with the hospital record for patients undergoing knee replacement (KR). METHODS: A stratified random sample of 185 KR recipients from 5 Ontario hospitals were chosen. Their hospital records and corresponding CIHI files were compared to assess percent complete agreement, false negative (FN) and false positive (FP) rates for demographic data, procedures, and diagnoses. RESULTS: Of 185 records, 175 (95%) were reviewed. Percent complete agreement was greater than 94% for each of patient demographics and procedures (mean FN rates: 0%; mean FP rates: 0-5%). For comorbidities and complications, although mean percent complete agreement was high, and FP rates were low, mean FN rates were 63% for specific comorbid conditions and 70% for organ systems. CONCLUSIONS: High FN rates have been found in documentation of comorbidities and in-hospital complications for CIHI data compared with the hospital record. Under-coding of comorbidities and in-hospital complications has potential implications for researchers using administrative databases.

The context of measuring disability: does it matter whether capability or performance is measured?

This study assesses the differences between two methods of conceptually framing physical disability questions, using two scenarios (capability and performance). The relationship between capability and performance was explored on the basis of the literature and empirically tested by administering two versions of the Activities Scale for Kids (ASK) to 28 physically disabled children. The capability version asked children what they "could do," whereas the performance version asked what they "did do." Capability was found to exceed performance (p < 0.001) by approximately 18%. The difference may relate to a difference in environmental contexts between the two versions, with performance reflecting abilities in usual (or real life) circumstances and capability reflecting abilities in a defined situation apart from real life. Researchers must, therefore, consider carefully the environmental circumstances in which they wish to evaluate outcomes, and use this information to decide whether to measure capability, performance, or both.

Measurement properties of the activities scale for kids.

The Activities Scale for Kids (ASK) is a self-report measure of childhood physical disability, that has excellent reliability (ICC = 0.97). The purpose of this study was to assess further the ASK's measurement properties. ASK questionnaires were completed by 200 children with musculoskeletal limitations (mean age, 10.1 years). Rasch analyses confirmed that all items measured the same construct and supported aggregation of a summary score. Validity of the ASK was demonstrated by a correlation of 0.81 (P<0.0001) with parent-reported Childhood Health Assessment Questionnaire scores; a significant difference in scores according to clinicians' global ratings of disability (P<0.0001), and a correlation of 0.92 (P<0.0001) with clinician-observation. The ASK showed minimal ceiling effects, no floor effects, and changed by 1.73 standard deviation units after clinically important change. The ASK is a valid and responsive outcome measure that permits 5- to 15-year-old children physical functioning in the community to be assessed accurately by mail. The quality of this measure will enable clinical studies to measure outcome not only in a way that is relevant to patients, but also in a way that is sensitive to small amounts of change and is practical and inexpensive.

Rasch analysis of the Western Ontario McMaster (WOMAC) Osteoarthritis Index: results from community and arthroplasty samples.

BACKGROUND AND OBJECTIVE: This study is based on secondary analysis of Western Ontario McMaster Osteoarthritis Index (WOMAC) data from a community sample over 55 years and total hip or knee arthroplasty samples presurgery and 1-year postoperative. METHODS: The WOMAC data were evaluated by Rasch analysis. Data were considered to fit the Rasch mathematical model for the pain and physical dimensions of the WOMAC if unidimensionality was confirmed by principle component analysis of the subscale and the residuals from the Rasch analysis, infit and outfit statistics were in the range of 0.80 to 1.20; if there was no differential item functioning based on gender or hip vs. knee subjects; and, if there was stability of the item logits across the three data samples. RESULTS: A three-item pain dimension (excluding night pain and pain on standing) and a 14-item physical dimension (excluding heavy domestic duties, getting in and out of the bath and getting on and off the toilet) fit the Rasch model based on these criteria. CONCLUSION: In evaluating existing health status questionnaires using Rasch methodology, it is important to evaluate relevant patient samples and longitudinal data when the measure is intended to evaluate change in status. By these criteria, a modified WOMAC questionnaire fits the Rasch model and has interval-level scaling properties.

A comparison of patients' responses about their disability with and without attribution to their affected area.

The purpose of this study was to determine whether individual items in a disability questionnaire were answered differently depending on whether or not the questions were attributed to the upper limb (i.e., "do you have difficulty eating due to your arm or hand problem?" or "do you have difficulty eating?", respectively). The a priori hypothesis was that the same or more disability would be detected by nonattributed items. Four hundred sixty-seven patients with upper extremity disorders completed the SF-36 general health survey, which does not attribute health problems to affected areas. Patients also completed six additional questions, modified from the SF-36, regarding work (four questions) and social function with friends and family (two questions), which attributed their disability to their affected upper extremity. Of 467 patients, 419-431 (89-92%) responded to both versions of the questions. Although we demonstrated a significant order effect (Generalized Estimating Equation; P=.003), comparison of the responses to the six questions showed that for five of the six questions (Generalized Estimating Equation; P< or = .001) patients reported more disability when the questions were worded with attribution to the upper extremity. Even considering the order effect, patients demonstrated a counterintuitive result by reporting more disability when questions were attributed to their affected area. Thus, both the wording of questions and order of questions can significantly affect patients' responses about their disability and raises questions about the validity of patients' reports of their disability.

Multivariate discriminant analysis of risk factors for operative mortality following isolated coronary artery bypass graft. Loyola University Medical Center experience, 1970 to 1984.

The Loyola Open-Heart Registry is a fully operational database that contains detailed data on approximately 9,000 patients who have undergone coronary bypass or cardiac valve replacement from January 1970 to December 1984. We analyzed the registry data using multivariate discriminant analysis to identify and quantitate those factors that might predict operative mortality (OM) for patients undergoing coronary artery bypass grafts at Loyola University Medical Center: Operative mortality was defined as death within 30 days following surgery. A total of 50 clinical and angiographic variables were analyzed for possible univariate association with operative mortality. Twenty-two variables were found to have significant univariate association with OM, and these 22 variables were subjected to multivariate discriminant analysis. For patients undergoing isolated, elective coronary artery bypass, the factors found to be predictive of OM are age (greater than 70) (F = 11.57), severe (more than six stenoses) coronary artery disease (F = 5.81), diffuse disease (F = 5.54), positive family history (F = 5.17), and number of coronary arteries bypassed (F = 4.78).