The objective was to describe the causes of initial and overall AIDS-defining disease episodes among HIV patients in Singapore.A retrospective observational cohort study was performed of all adult patients seen at the national HIV referral center between 1985 and 2001. Data were extracted from the patients' records by ten trained healthcare workers. AIDS-defining conditions were established using predefined criteria.Pneumocystis carinii pneumonia (35.7%), Mycobacterium tuberculosis (22.7%) and herpes simplex (7.4%). In total 1742 AIDS-defining episodes occurred. The most frequent causes were Pneumocystis carinii pneumonia (25.1%), Mycobacterium tuberculosis (16.2%) and cytomegalovirus retinitis (9.5%).Among 1504 patients, 834 had experienced one or more AIDS-defining diseases. The most frequent causes of the initial AIDS-defining episode were The most frequent causes of AIDS-defining illnesses in Singapore are similar to those reported in the West, prior to the introduction of anti-retroviral therapy. Opportunistic infections remain the most frequent AIDS-defining illnesses. Mycobacterium avium have decreased from 9% to 2% and 8% to 3% respectively [Pneumocystis carinii, Mycobacterium avium and other opportunistic infections have also been observed in the United States [Cohort studies have provided valuable information on the clinical course of HIV infection in patients from Europe -16, Nortectively . The proectively . Substand States ,21.Pneumocystis carinii pneumonia (7.0%) and cryptococcal meningitis (10.9%) [Relatively few data are available on the course of HIV infection in Asian populations. In Bangkok between 1987 and 1993 the most frequent AIDS-defining diagnoses were extrapulmonary tuberculosis (22.8%),  (10.9%) . Little The Communicable Diseases Centre (CDC) in Singapore is the national reference centre for adult patients with HIV and AIDS and nationwide 94.9% of all Singaporean adult residents, who have ever been diagnosed, have been referred there. Underreporting of HIV does not occur as reporting occurs automatically from the reference laboratory. Records have been kept since the first case was identified in Singapore in 1985. Therefore the Singapore HIV Observational Cohort Study (SHOCS) contains almost the entire country's HIV experience. Nucleoside analogues have been available in Singapore since the early 1990s and protease inhibitors and non-nucleoside reverse transcriptase inhibitors since 1997. The usage of these drugs has been increasing annually and during 2000 and 2001 approximately 70–80% of patients regularly attending CDC were taking some form of anti-retroviral therapy.st December 2001, by ten trained healthcare workers. Probable and confirmed criteria were developed for the diagnosis of category C [The details of the SHOCS cohort have been described previously . The stutegory C  and catetegory C .All disease episodes were initially determined by the data extractors and then checked by an infectious disease physician (RB). Diagnoses were not included if they did not fulfill the specified criteria even if there was a strong clinical suspicion of a particular condition. If there was insufficient evidence to satisfy the criteria for a specific diagnosis, a more general diagnosis was assigned, for example cerebral lesion (cause unknown) would be used if there was insufficient evidence to support a diagnosis of toxoplasmosis of the brain or primary cerebral lymphoma.Pneumocystis carinii pneumonia, Mycobacterium tuberculosis and cytomegalovirus retinitis), comparisons were made between the pre-HAART era (1986 to 1995) and the established HAART era (2000 to 2001) using χ2 tests.Median CD4 counts were calculated based on the sample taken nearest the time of diagnosis of the initial AIDS-defining condition. CD4 counts from 893 patients were used, as in 37 (4.0%) cases no suitable count was available. Data were entered into a computer database (Microsoft Access™) and checked for errors and inconsistencies. Statistical analyses were performed using Stata 7.0™. Each new or recurrent AIDS-defining condition counted as one event (i.e. a patient with three diagnoses would contribute three events). An AIDS-defining condition was counted as a separate additional event if it recurred six or more months after the initial diagnosis or in the case of tuberculosis, six or more months after treatment completion. To examine the effects of highly active anti-retroviral therapy (HAART) on the proportions of AIDS-defining illnesses due to each of the three most common infections , M. tuberculosis (22.7%), herpes simplex (chronic mucocutaneous) (7.4%) and candidiasis  (6.9%) (table M. tuberculosis infection (52, IQR = 18 – 110) and Kaposi's sarcoma (46.5, IQR = 23.5 – 227.5) than for Pneumocystis carinii pneumonia (16.5, IQR = 9 – 40), herpes simplex (25, IQR = 9 – 63) and extrapulmonary cryptococcosis (13, IQR = 6.5 – 39) , M. tuberculosis (16.2%), cytomegalovirus retinitis (9.5%), candidiasis (7.8%), chronic mucocutaneous herpes simplex (8.2%) and disseminated M. avium (8.2%) , but that due to M. tuberculosis had increased to 18.0% (Yates' χ2 = 8.10, 2df, P = 0.004). There was no significant change in the percentage of episodes due to cytomegalovirus retinitis   [Pneumocystis carinii pneumonia (4.8%) [Pneumocystis carinii pneumonia caused a much higher proportion of AIDS-defining diseases in Singapore than in Bangkok and cryptococcal meningitis occurred less frequently in Singapore.In the SHOCS cohort the proportion of conditions which were of infectious etiology remained very high throughout the study period. The distribution of conditions was similar to that seen in Western countries prior to the introduction of anti-retroviral therapy . Howevernia (7%) . Betweena (4.8%) . PneumocThe SHOCS cohort provides data on the experience of 94.9% of Singaporean residents who have been diagnosed with HIV since the epidemic began. There are good diagnostic facilities in Singapore and patients with HIV-related illness receive extensive investigations. Therefore Singapore offers an ideal location for collecting information on the causes of morbidity and mortality in persons with HIV in Asia. Medical record keeping is of a high standard in our hospital and this allowed accurate diagnoses to be assigned for AIDS-defining conditions which occurred throughout the AIDS era. To ensure consistency, data was extracted by carefully trained healthcare workers and diagnoses were assigned using predefined criteria. All AIDS-defining diagnoses and all causes of death were reviewed by the same infectious diseases physician (RB). Follow-up rates in our cohort are very high with only 5.8% of patients lost to follow-up at 12 months and 9.3% after 3 years. The SHOCS cohort therefore provides a unique source of information on HIV infection in an Asian country since the start of the epidemic.Mycobacterium tuberculosis". However if a patient receives a successful trial of treatment for disseminated M. avium, the diagnosis is "probable mycobacteriosis (species unidentified)".In a retrospective study it is impossible to ensure that all patients received a full series of investigations in order to satisfy the study criteria for diagnosis of HIV-related conditions. As a consequence the criteria for making a probable diagnosis are unavoidably biased against certain conditions. For example if a patient undergoes a therapeutic trial of tuberculosis treatment he or she can be given the diagnosis of "probable M. avium and M. tuberculosis may also have been affected by improvements in mycobacterial culture techniques.Differences in physicians' awareness of the link between HIV and opportunistic infections can influence diagnosis rates. For example, the increase in the proportion of AIDS-defining disease episodes caused by tuberculosis between 1986–1995 and 2000–2001 may have been due to greater awareness of the link between HIV and tuberculosis. Diagnosis rates for Despite the availability of anti-retroviral medication, opportunistic infections remain a common problem among HIV patients in Singapore. This may partly be explained by the high proportion of Singaporean patients, who present with advanced disease and very low CD4 counts. These patients often already have one or more AIDS-defining opportunistic infections at first presentation. Opportunistic infections may also occur before adequate immune-reconstitution can occur when HAART is commenced when the patient has a very low CD4 count. Studies in the West have shown that AIDS-defining illnesses occur more frequently among patients who have a CD4 count below 50 when anti-retroviral therapy is commenced than among those with higher CD4 counts ,38. ImmuThe current reductions in the cost of anti-retroviral therapy (Eg. due to generic manufacture) may enable high levels of anti-retroviral use to be achieved in many Asian countries. The experiences of the SHOCS cohort are likely to be repeated throughout Asia. Our results suggest that avoidable opportunistic infections may continue to occur even when high levels of anti-retroviral use are achieved. To reduce the burden of morbidity and mortality caused by these infections, efforts must be made to diagnose HIV infection earlier and to make the treatment of HIV and its associated opportunistic infections more affordable.SHOCS = Singapore HIV observational cohort study, CDC = Communicable Diseases Centre, AIDS = acquired immunodeficiency syndrome, HIV = human immunodeficiency virus, HAART = highly active anti-retroviral therapy.The authors declare that they have no competing interests.RB participated in the design of the study, supervised data extraction, performed the statistical analysis and wrote the manuscript. SS designed the database and supervised data extraction. NP participated in the design of the study and contributed to the statistical analysis and production of the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


Depression and anxiety in patients with coronary heart disease (CHD) are associated with a poorer prognosis. Therefore the screening for psychological distress is strongly recommended in cardiac rehabilitation. The Hospital Anxiety and Depression Scale (HADS) is a widely used screening tool that has demonstrated good sensitivity and specificity for mental disorders.We assessed mental distress in in-patient cardiac rehabilitation in Germany. The factor structure of the German language version of the HADS was investigated in 1320 patients with CHD. Exploratory factor analysis and confirmatory factor analysis were used to determine the underlying factor structure of the instrument.Three-factor models were found to offer a superior fit to the data compared to two-factor (anxiety and depression) models. The German language HADS performs similarly to the English language version of the instrument in CHD patients. The German language HADS fundamentally comprises a tri-dimensional underlying factor structure .Despite of clinical usefulness in screening for mental disturbances the construct validity of the HADS is not clear. The resulting scores of the tri-dimensional model can be interpreted as psychomotor agitation, psychic anxiety, and depression in individual patient data or clinical investigations. Coronary heart disease (CHD) is of profound interest to health and clinical psychology due to the high levels of anxiety and depression observed in patients following the occurrence of a coronary event -5. CHD wA candidate screening tool that has been widely and increasingly used with CHD patients is the Hospital Anxiety and Depression Scale (HADS: ), an easOn the other hand, recent psychometric evaluations of the HADS in a range of clinical populations have suggested that the proposed factor structure of the instrument may indeed be compromised by the physiological aspects of the disease or by changes in health status ,29,30. CDunbar et al.  found a There has been little systematic investigation of the factor structure of the translated HADS in German cardiac patients, though interestingly a German language version of the instrument has been developed in Germany using cardiac patients within the context of the original assumed two-dimensional (anxiety and depression) structure . To dateIdentification of a coherent three-factor underlying structure of the HADS has a number of significant implications in terms of the validity of the tool as a screening instrument. Firstly, referral to mental health services could be undermined based on a two-dimensional (anxiety and depression) interpretation of HADS scores in cardiac patients. Secondly, further replication of a three-factor structure of the HADS in a German cardiac population would be valuable in determining if the HADS should be more effectively used as a screening instrument when comprised of three sub-scales in this group. Thirdly, replication of a consistent three-factor structure in the German-translated version of the HADS would provide strong evidence that the three-dimensional structure is implicit to the instrument and not a language-based artifact. Finally, the widespread international use of the HADS provides a compelling rationale to establish the psychometric properties of the instrument not only in broad diagnostic categories, but also across culturally-diverse groups.The purpose of the present study was to determine whether the three-factor structure of the HADS identified by Martin and colleagues  in myoca1) Do exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) techniques concord to the proposed bi-dimensional structure of the HADS in German CHD patients?2) Does a three-dimensional factor structure provide a superior fit compared to competing bi-dimensional factor structures?The study used a cross-sectional design with all measures taken at one observation. The dependent variables were sum scores obtained on the HADS , and the anxiety (HADS-A) and depression (HADS-D) sub-scales. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) methods were used to address the research questions using a pooled HADS data set from all patients. Ethical approval for the study was given by the local ethical committee of the University Hospital of Freiburg. Written informed consent was obtained from all participants prior to the commencement of the study.The study was conducted in three German cardiac rehabilitation hospitals. The patients stay in these hospitals for three to four weeks for a comprehensive cardiac rehabilitation program consisting of medical advice, exercise, patient education, relaxation and psychosocial interventions. All cardiac patients who agreed to take part in the PROTeCD-study (Psychotherapeutic Resource-Orientated Treatment for Cardiac Patients with Depression) were screened for mental distress with the German version of the HADS  at admisExploratory factor analysis was performed on the full 14-item HADS using SPSS 12.0 statistical software. The criterion chosen to determine that an extracted factor accounted for a reasonably large proportion of the total variance was based on an eigenvalue greater than 1. A maximum likelihood factor extraction procedure was chosen since this method of factor condensation is consistent with our previous research  and is p2 indicates a significant proportion of variance remains unexplained by the model [Confirmatory factor analysis was conducted using the Analysis of Moment Structures (AMOS) version 4  statistihe model .t(401.14) = 4.14, p < 0.001) than male patients .1320 patients  enrolled in an in-patient cardiac rehabilitation programme in three hospitals in Germany provided complete HADS data sets for analysis. Inclusion criteria for participation in the study was a confirmed diagnosis of CHD; for details see . The patpossible clinically relevant levels of anxiety and 373 participants (28%) possible clinically relevant levels of depression. Adopting Snaith and Zigmond's [probable clinically relevant levels of anxiety and 161 participants (12%) probable clinically relevant levels of depression.The mean HADS-A sub-scale score was 6.14 (SD = 4.15, range 0–20) and the mean HADS-D sub-scale score was 5.41 (SD = 4.00, range 0–20). Using Snaith and Zigmond's  cut-off icipants % possibl2 = 7758.34, df = 91, p < 0.001) was highly significant indicating the data satisfied the psychometric criteria for the factor analysis to be performed based on data distribution characteristics. Examination of individual item skew and kurtosis characteristics confirmed the suitability of the maximum likelihood factor extraction procedure [r = 0.82, p < 0.001, explaining 67% of the common variance between factors.The Kaiser-Meyer-Olkin (KMO) measure of sampling adequacy and the Bartlett Test of Sphericity (BTS) were conducted on the data prior to factor extraction to ensure that the characteristics of the data set were suitable for the EFA to be conducted. KMO analysis yielded an index of 0.94, and BTS  indicating that a proportion of the total variance was unexplained by each model. Examination of the fit indices revealed that the best fit to the data was offered by Friedman et al.'s [The factor models tested and accompanying fit indices are shown in Table et al.'s  three-fa p < 0.00 indicatiet al.'s  three-faet al.'s  'tripartet al.'s  three-faet al.'s  and Mooret al.'s  offered et al.'s  was obseThe findings of the current study offer a further important contribution to the evidence base regarding the underlying factor structure of the widely used HADS. It is worthy of note that high levels of HADS assessed anxiety and depression were observed in the study. This finding is consistent with investigators using this instrument in cardiac populations in other parts of the world ,24,26 anThe findings from the factor analyses conducted on the HADS data are of pertinent methodological as well as clinical interest. EFA of the HADS revealed two factors, the loadings of individual items being consistent with the anxiety and depression sub-scale domains. However, it was also observed that the HADS-A item-7 'I can sit at ease and feel relaxed' was jointly loading on both anxiety and depression factors, this split-loading slightly in favour of the depression factor. A recent EFA of the HADS conducted with patients with significant facial disfigurement  also revtri-dimensional instrument, consistent with contemporary research with this instrument across diverse clinical presentations [The findings from the CFA revealed the best model fit to be provided by Friedman et al.'s  three-fantations ,31,33,35In conclusion, the current study found the German language version of the HADS to have an underlying three-dimensional factor structure following CFA in CHD patients, an observation consistent with UK  and ChinJB designed the study, carried out the data collection and clinical assessment. JB drafted part of the manuscript and was involved in the interpretation of the findings. CRM developed the statistical framework, carried out the statistical analysis and drafted part of the manuscript. Both authors have no competing financial or other interest in relation to this manuscript.The study was funded by the Federal Ministry of Education and Research, Germany; Regional Pension Insurance Institute, Baden-Wuerttemberg, Germany, LVA 02 804 and is part of the Rehabilitation Research Network South-West (Germany).


Limb-salvage is a primary objective in the management of extremity soft-tissue sarcoma in adults and children. Wide-local excision combined with radiation therapy is effective in achieving local tumor control with acceptable morbidity and good functional outcomes for most patients.Two cases of deformity after wide-local excision, brachytherapy and external beam irradiation for lower-extremity synovial cell sarcoma are presented and discussed to highlight contributing factors, time course of radiation effects and orthopedic management. In an effort to spare normal tissues from the long-term effects of radiation therapy, more focal irradiation techniques have been applied to patients with musculoskeletal tumors including brachytherapy and conformal radiation therapy. As illustrated in this report, the use of these techniques results in the asymmetric irradiation of growth plates and contributes to the development of valgus or varus deformity and leg-length discrepancies.Despite good functional outcomes, progressive deformity in both patients required epiphysiodesis more than 3 years after initial management. There is a dearth of information related to the effects of radiation therapy on the musculoskeletal system in children. Because limb-sparing approaches are to be highlighted in the next generation of cooperative group protocols for children with musculoskeletal tumors, documentation of the effects of surgery and radiation therapy will lead to improved decision making in the selection of the best treatment approach and in the follow-up of these patients. Limb-salvage is an important treatment objective for adults and children with extremity soft tissue sarcoma and often requires the use of limited surgery and irradiation . LimitinSurgery and radiation therapy both have the potential to cause significant morbidity including loss of function and deformity ,11-15. TIndividual cases of valgus and varus deformity after limited surgery and irradiation for extremity soft-tissue sarcoma are presented and discussed to identify factors that may be responsible for these treatment complications. Pre-existing orthopedic problems, multiple attempts at resection, post-operative infection, the use of chemotherapy and the addition of brachytherapy to external beam radiation therapy appear to be contributory. Because limb-sparing approaches will be an important component of the next generation of cooperative group studies for extremity soft tissue sarcoma in children, the incidence and severity of this and other treatment-related complications should be documented as well as efforts to limit the effects of these treatments and identify solutions for established problems.At the time of diagnosis, this patient was an 8 year-old male with an approximate 12–24 month history of mild pain and swelling in the left popliteal region. There was no complaint of fever or decreased range of motion. He presented to a local orthopedist (April 1995) and was found to have a palpable abnormality on the posterior aspect of the knee consistent with a Baker's cyst. Aspiration was unsuccessful and the patient was treated with ibuprofen for a 10-day course. Nearly one year later (April 1996) the family sought a second opinion and an MR study was ordered that revealed a cystic structure [Figure At the time of his evaluation after referral, he had strong popliteal pulses. There was a 7.0 × 4.5 cm area of swelling and numbness in the left popliteal region. The deep-tendon reflexes were brisk and the motor exam and gait were normal. MR showed residual abnormality consistent with tumor lateral to the joint capsule. Metastatic work-up including nuclear bone scan and CT scan of the chest was negative. Tumor bed re-excision with placement of afterloading catheters was performed in December 1996. All visible residual abnormality was removed without significant disruption of underlying ligaments and tendons. The walls of the tumor bed were biopsied to map the extent of microscopic residual disease. Microscopic residual disease was anticipated given the site of involvement and the limited ability to operate beyond the extent of the abnormal appearing tissues. Eleven afterloading catheters were placed in a parallel array to cover the tumor bed Figure . Radio-o125. The dwell time of the implant was 64 hours and the patient received a total implant dose of 2560 cGy delivered at 40 cGy/hr. Three weeks later, the patient began external beam irradiation at 180 cGy per day and received a total external beam dose of 4860 cGy using 6 MV photons with treatment delivered in a parallel-opposed beam arrangement using a CT based treatment plan [Figure Five days after surgery, the 11 catheters were loaded with a total of 135 seeds representing 408 millicuries of IA decision was made to initiate chemotherapy three weeks into the course of external beam irradiation based on the perceived high-risk nature of his case – longstanding history of symptoms, known residual tumor and size of tumor at presentation. Chemotherapy included vincristine, ifosfamide, and adriamycin was eventually administered for a total of four cycles. There was central dehiscence of the wound prior to the completion of radiation therapy. The wound was colonized with Enterococci sensitive to ampicillin and managed with antibiotics, whirlpool treatment and daily dressing changes. There was a one-week treatment break during the external beam portion of the treatment.At the completion of chemotherapy (June 1997) the patient underwent excision of scar tissue with rotation flap of gastrocnemius and skin and Z-plasty of the semi-membranous and semi-tendinous tendon for a non-healing ulcer in the operative region. There was also contracture of the knee joint without signs of abscess or cellulitis. One month later, a second procedure was required to debride and irrigate the left popliteal fossa wound at the site of previously irradiated tissue and contracture release with muscle and fasciocutaneous flap closure. One year after the completion of all therapy (June 1998) the patient reported full range of motion and softening of previously fibrotic tissue. He was actively playing baseball and had no imposed limitations.Nearly two years after completion of treatment (March 1999), the patient was noted to have Trendelenburg gait after prolonged walking ascribed to poor endurance of weakened hip abductors bilaterally. Hip hiking was also noted on the contralateral side due to leg length and ASIS height discrepancy. A difference of 2.5 cm was noted when measured from the umbilicus to the medial malleolus. He had grown 7.0 cm since the time of diagnosis. He was instructed to stretch the heel cord and strengthening his weak hip abductors. Arrangements were made to provide a shoe lift to accommodate the leg length difference. The discrepancy improved to less than 1 cm over a three month period of time (March-June 1999). He was carefully monitored for growth discrepancy and 6 months later, nearly 3 years after the initiation of treatment, the discrepancy returned to its original value of greater than 2 cm. He also had difficulty with ambulation with slight left-sided limp. Orthopedic surgery was re-consulted. The discrepancy was followed and treated with additional shoe lift. The patient continued to engage in normal activities including sports and reported full range of motion and normal strength. More than four and a half years after initiating treatment (August 2001) Figure , x-ray sAt the time of diagnosis this patient was a 9 year-old female with a one year history of pain and swelling about her left knee. She had experienced a fall and related all symptoms to the fall. She was seen in her local emergency room by her family physician; there was no diagnosis or treatment. Approximately one month prior to her representation, she was struck in the left knee by a basketball and developed worsening pain. She was seen by an orthopedic surgeon (December 1999) and was noted to have a valgus posture of both lower extremities, exaggerated on the left by external rotation and she walked with a mild limp. The left knee had no effusion but was hypersensitive to light touch over the lateral aspect where there was soft tissue swelling just below the knee. There was no obvious mass in the area, although firm palpation was difficult because of patient discomfort. Plain films were normal and an MR was ordered that revealed an apparent meniscal cyst in the lateral aspect of the left knee Figure . Biopsy 125 . The dwell time of the implant was 62 hours and the patient received a total implant dose of 2480 cGy delivered at 40 cGy/hr. Two weeks later the patient began external beam irradiation at 180 cGy/day and received a course of treatment and total external beam dose of 5040 cGy using 6 MV photons with treatment delivered with two beams using a CT based treatment plan [Figure At the time of her evaluation after referral (January 2000), there was a well healed scar with no excessive swelling. There was mild tenderness on the lateral aspect of her left knee. Additional imaging studies showed abnormality at the site of prior surgery equivocal for residual tumor. There was no evidence of abnormality in the joint space. The tumor bed was explored. There was no physical evidence of compromise at the level of the joint space. She underwent wide local excision with placement of afterloading catheters. Six catheters were placed in a parallel array with 1 cm spacing. Radio-opaque clips were placed to delineate the tumor bed and assist in brachytherapy planning Figure . The marn Figure . RadiatiThe patient suffered moist desquamation corresponding to the radiation therapy portal that was predicted based on the treatment and the use of a tissue equivalent bolus material which was placed on the wound on alternating days during her course of external beam irradiation. She was able to return home on the last day of treatment. On routine follow-up, only 4 months after treatment, left leg appearing to be slightly longer than her right leg by less than 1 cm. No corresponding gait problems were reported. Nearly one year after treatment (January 2000) physical examination showed good range of motion at the left knee; however, there was significant valgus angulation. An MR study was reviewed by Orthopedic Surgery and was noted to show growth arrest laterally and predominantly involving the distal femoral physis Figure . Based oDue to its high propensity for local recurrence and metastasis, aggressive treatment of synovial sarcoma is imperative. While many different methods have been used in the treatment of these high-grade tumors, including mono-bloc soft part resection and amputation, the current standard includes local excision and radiation therapy when feasible . Wide loBoth patients in our study underwent two surgical procedures and were treated with brachytherapy and external beam irradiation. Brachytherapy was used to confine the highest doses to the region at risk and minimize the dose received by normal tissues. The use of brachytherapy shortens the overall treatment time and increases the rate of local control in the setting of involved margins of resection. CT-based treatment planning was used to define the volume of irradiation and to spare normal tissue structures. By reducing the amount of radiation dose delivered to normal tissues, the probability of growth deformity, radio-chemotherapy interactions, and even the hypothetical risk of second tumor formation may be lowered. No effort was made to symmetrically irradiate the physes, which would hypothetically lead to symmetrically diminished growth without the added effect of angular deformity. Because of concerns about the effects of total joint irradiation and its possible effects on functional outcome, the inhomogeneous and asymmetric approach was taken. Despite the valgus and varus deformity experienced by these children and the need for intervention, both children and parents were completely satisfied with their functional outcome and indicated that they would chose the same course of treatment if presented again with the same options.The importance of achieving local control with aggressive surgery and high-dose irradiation cannot be overemphasized. Local control is crucial to long-term survival and avoiding the morbidity of local tumor progression. Local control, even in the setting of metastatic disease, is an important endpoint. Radiation therapy is highly successful in achieving local control in soft tissue sarcoma and is standard in the care of children with high-grade tumors such as those reviewed in this report. At our institution high-grade tumors with resection margins of 1 cm has an observed local control rate of 72% (5 of 7 patients) in the absence of radiation therapy and 100% (7 of 7 patients) when radiation therapy was given postoperatively. Among 20 unirradiated high-grade tumors that were completely resected with margins > 1 cm only 15 (75%) were locally controlled for an extended period . Our polDespite efforts to achieve local control and minimize the effects of treatment on normal tissues, damage to bone and soft tissues may be unavoidable. Synovial cell sarcoma commonly arises near tendon sheaths and joint capsules of adolescents and young adults and may be in close proximity to an epiphyseal growth plate during a time of rapid growth. The situation is made worse if the tumor is located around the distal femur or proximal tibia. Among the four epiphyseal plates in the lower extremity that contribute to the growth of the limb, those around the knee make the most significant contribution, with the distal femur and proximal tibia accounting for 50–90% and 57% of limb growth, respectively depending on age . In our There are two non-congenital mechanisms that are known to interfere with growth of the physis: direct trauma and environmental change around the plate. Trauma includes acute injury to the growth plate in manner that affects all or partial growth and results in premature closure or the formation of a physeal bar. Even if the region has retained its ability to grow it is hampered by solid bone formation across the plate . EnvironParalysis is also known to cause of growth inhibition, although the mechanism is poorly understood. Proposed contributors include reduced muscle activity, which indirectly alters the blood supply, and abnormal vasomotor control . AvasculRogalski et al.  observedIt is also conceivable that repeated surgeries to the lateral aspect of the knee in both patients played a contributive role. A change in the environment surrounding the physis, such as muscle atrophy following prolonged bed rest, paralysis, or limb-sparing surgery with muscle loss, is known to cause a significant slowing of growth . AlthougThe patients included in this report had many of the above noted contributions to abnormal growth and development including a pre-existing condition, vascular compromise due to multiple surgeries, loss of muscle mass, limited use of the extremity for a defined period of time, infection and chemotherapy. Chemotherapy may temporarily reduce bone growth through systemic effects that include the direct effects of specific agents or the indirect effects resulting from systemic infections and abnormalities in metabolism and nutrition.It has been known for almost a century that radiation therapy at sufficient levels can affect growing bone. Several factors contributing to the severity of effect including the total dose, dose per fraction, dosimetry (asymmetry and inhomogeneity) and age at the time of irradiation ,30,31. PThe conclusions of Gonzalez and Breur  were sliThe epiphyseal growth plate is the area of the developing skeleton most sensitive to the effect of radiation due in part to its rapidly proliferating stem cell population. Even low doses of radiation have been shown to cause histologic changes including temporary swelling, fragmentation, and degeneration of chondrocytes . When hiCreating a treatment plan for patients with leg deformities who have undergone radiation therapy with or without chemotherapy can pose a difficult challenge. Because the osteocytes of neighboring bone are also destroyed, it may take years for the bone to revascularize and repopulate with healthy osteocytes . The absHistorically, there have been two primary treatments for patients with angular limb deformities: epiphysiodesis and stapling. Both methods seek to achieve the same result while offering different sets of advantages and disadvantages. Partial epiphysiodesis of the knee to correct angular deformity was first described by Phemister in 1933 . It has Newer radiation delivery techniques including high-dose rate brachytherapy, intraoperative radiation therapy ,40 and tLimited surgery and irradiation may result in growth abnormalities and deformity. These effects may have minimal or significant impact depending on functional outcome and the value attached to limb preservation for a particular patient. As mentioned in this report, both patients and families were queried about their decisions regarding treatment and both reported satisfaction with outcome recognizing that side effects were anticipated. Both families attached a high value to limb preservation.None declared.DTF reviewed the patient records and drafted the manuscript. WCW contributed to drafting the manuscript. MDN contributed to drafting the manuscript. TEM conceived of the study, participated in the review of the data, and helped draft the manuscript. All authors read and approved the final manuscriptThe pre-publication history for this paper can be accessed here:


It is commonly held that "a calorie is a calorie", i.e. that diets of equal caloric content will result in identical weight change independent of macronutrient composition, and appeal is frequently made to the laws of thermodynamics. We have previously shown that thermodynamics does not support such a view and that diets of different macronutrient content may be expected to induce different changes in body mass. Low carbohydrate diets in particular have claimed a "metabolic advantage" meaning more weight loss than in isocaloric diets of higher carbohydrate content. In this review, for pedagogic clarity, we reframe the theoretical discussion to directly link thermodynamic inefficiency to weight change. The problem in outline: Is metabolic advantage theoretically possible? If so, what biochemical mechanisms might plausibly explain it? Finally, what experimental evidence exists to determine whether it does or does not occur?Reduced thermodynamic efficiency will result in increased weight loss. The laws of thermodynamics are silent on the existence of variable thermodynamic efficiency in metabolic processes. Therefore such variability is permitted and can be related to differences in weight lost. The existence of variable efficiency and metabolic advantage is therefore an empiric question rather than a theoretical one, confirmed by many experimental isocaloric studies, pending a properly performed meta-analysis. Mechanisms are as yet unknown, but plausible mechanisms at the metabolic level are proposed.Variable thermodynamic efficiency due to dietary manipulation is permitted by physical laws, is supported by much experimental data, and may be reasonably explained by plausible mechanisms. Carbohydrate restriction as a general strategy for weight loss continues to gain in popularity and its utility and generally protective effect in lipid profile and glycemic control continues to be demonstrated, at least in an experimental setting -4. The sWe have previously presented arguments that there is no violation of physical principles ,7 and, iThe misunderstanding that continues to be repeated in the expression "a calorie is a calorie" appears to be exclusive reference to the first law of thermodynamics. The difficulty with this theoretical approach is that it is only part of the relevant physics and its relationship to biologic systems. The first law says that in any transformation the total energy in the system can be accounted for by the heat added to the system, the work done by the system on its environment and the change in energy content of all the components of the system. It is important to understand, however, that the first law does not say what the relative distribution between these effects will be for any process. In fact, the first law does not even allow us to say whether the process will occur at all. To understand the progress of a physical change it is necessary to understand the second law which introduces an entity known as the entropy, S, a measure of disorder in all processes. In all real (irreversible) processes, entropy increases, usually written ΔS > 0. The most common marker of increasing entropy is heat, although it is by no means the only evidence for increased entropy.maximum useful work that can be performed by the process. The actual process however, in general derives less useful work than permitted by the theoretically available ΔG due to inefficiency in energy capture. A proper accounting of entropy and efficiency must be included if we are to understand energy utilization in biological and biochemical systems.In systems at constant temperature and pressure (i.e. biologic systems)), the first and second law are combined in the Gibbs Free Energy, ΔG, which represents the It is also important in the discussion of biological systems to understand that they are open systems, i.e. they take in nutrients and oxygen and excrete carbon dioxide, water, urea and other waste products, as well as heat. The importance with respect to weight considerations is that mass and energy are conserved , but they are not conserved entirely within the organism.To illustrate the proper interpretation of the first law of thermodynamics consider a subject whose resting energy expenditure is met by the production of 95 moles of ATP. Since oxidation of a single mole of glucose provides 38 moles of ATP, 2.5 moles of glucose will be needed to meet this individual's resting energy requirements. It is important to note that the resultant carbon dioxide, water, and heat are not retained within the organism. The useful retained energy is in the 95 moles of ATP Figure . . This value approximates the efficiency for oxidation of carbohydrate as well as lipid, whereas proteins are generally oxidized at a lower value of approximately 30–35%  value for glucose obtained in the calorimeter is approximately 4 kilocalories of energy per gram Figure . By cont% Figure .1. The second law of thermodynamics dictates that there is an inevitable metabolic inefficiency in all biological and biochemical processes with heat and high entropy molecules (carbon dioxide, water, urea) as the most common products.excreted and the heat radiated and exported in high entropy molecules.2. The first law of thermodynamics is satisfied in living (open) systems by properly accounting for the mass The most common example of weight loss is reduction of caloric intake. At the risk of oversimplification, if our subject ingests fewer than 2.5 moles of glucose and produces, for example, only 90 moles of ATP from food, then homeostasis would require enlisting endogenous body stores for further oxidation. This oxidation would then provide the additional 5 moles of ATP required. Oxidation of body stores (lipid or lean body mass) will result in production of additional carbon dioxide, urea, water and heat. The excretion of these products will result in weight loss. Figure .uncoupling in mitochondria. ATP is produced in a variety of cellular locations. Glycolysis produces a net of two ATP's per molecule of glucose, in the cell cytoplasm. On the other hand, we recall that 36 additional molecules of ATP are produced from glucose as a result of the mitochondrial TCA cycle and electron transport. A critical part of the process involves the development of a hydrogen ion gradient across the mitochondrial membrane. This concentration gradient provides the energy that is converted into ATP as hydrogen ions pass down the gradient through the ATP synthase particle, entirely analogous to the energy in a high-pressure gas in a cylinder with a movable piston. (The expansion of the gas is like diffusion down a gradient: It does work against the piston). In the mitochondrion the energy of moving down the gradient is captured in ATP, the medium of exchange for the performance of work within cells. This capture of energy, referred to as coupling the energy to the formation of ATP, is the essential process permitting work to be done by living systems.The implication of the first and second laws of thermodynamics is that reduced efficiency has precisely the same result as reduced caloric intake. One conceptually simple means of reducing efficiency involves the process of There are known endogenous and pharmacologic agents, which result in uncoupling the formation of ATP from the dissipation of the gradient. Uncouplers such as 2, 4-dinitrophenol bypass ATP synthase and cause hydrogen ion gradient dissipation without ATP formation that can result in organ dysfunction causing death. More modest degrees of uncoupling may be caused by the class of endogenous compounds we know as uncoupling proteins (UCP's). Three different isoforms, UCP1, UCP2 and UCP3 have been identified thus far in mammalian tissues. While the overall and relative physiologic importance of these proteins remains incompletely understood in human tissues, UCP1 has been shown in mice  to resulguarantees inefficiency in all metabolic processes. However, variation of efficiency is not excluded. In fact, the laws of thermodynamics are silent on the existence of variable efficiency. If efficiency can vary (as in the example of oxidative uncoupling) then "a calorie is a calorie" is no longer a true statement. The role of uncoupling proteins in humans, as indicated, is as yet incompletely defined [The essence of the second law of thermodynamics is that it  defined . HoweverIt is possible that metabolic efficiency may be decreased by oxidative uncoupling as described above. Polymorphisms connecting uncoupling proteins with obesity or propensity to gain weight have been identified in humans ,12 altho2 and water generates 38 moles of ATP with an overall efficiency of about 38.5%. On the other hand, if glucose is first incorporated into glycogen, followed by hydrolysis of the glucose and subsequent oxidation, 2 moles of ATP are lost per mole in this cycle with overall efficiency reduced to 35%. Similarly an amino acid from an "average" protein, when directly oxidized to CO2, produces ATP with an efficiency of about 33%. If the amino acid is first incorporated into a protein and later hydrolyzed and oxidized, four ATP's per molecule are used for synthesis of the peptide bond. This reduces the efficiency to 27%. Smaller degrees of inefficiency are seen for lipid cycles  . If indeth binomial coefficient shows this probability to be p < 0.01.Having established that there is no theoretical barrier to metabolic advantage and that there are plausible mechanisms that could account for such an effect, we must ask whether it can be demonstrated experimentally, that is, whether the proposed effects are of sufficient magnitude to be a practical feature of weight reduction strategies, in particular very low carbohydrate diets. If so there will be increased weight loss for the same caloric intake, or metabolic advantage. A recent animal model provides support for greater metabolic inefficiency in rats fed carbohydrate restricted diets compared with higher carbohydrate, leading to excess weight loss . Human dWhile the above suggests the possibility of metabolic advantage, it does not prove it, nor do we know the magnitude of the effect, or the factors that control it. The studies above were chosen from among those quoted by many of the authors who have disputed the existence of metabolic advantage. Nonetheless, a formal meta-analysis would be necessary to avoid the possibility of conscious or unconscious bias in their selection. Further, it would be necessary to establish evidence that energetically costly metabolic processes are more prevalent in low carbohydrate diets than in diets of higher carbohydrate content. Whereas the proposed mechanisms are plausible, they need to be proven.guarantees inefficiency in all metabolic processes and is silent on the possibility that inefficiency may be augmented in some instances. A familiar example of inefficiency is thyrotoxicosis, with attendant weight loss and heat generation despite unchanged or increased caloric consumption. The theoretical possibility of inefficiency and metabolic advantage due to macronutrient compositional change exists, but demonstration of the phenomenon can only be resolved experimentally. Isocaloric dietary studies with a low vs. a higher carbohydrate arm support the experimental possibility of metabolic advantage. A formal meta-analysis would be required to evaluate this more objectively. Further studies, including tracer methods, would be required to establish mechanisms. The presence of high quantities of dietary protein (often a feature of low carbohydrate diets) is known to stimulate protein turnover, an energetically costly process. However, it is unclear whether this is the only factor, or whether it is necessary for metabolic advantage to occur. In particular, obligate gluconeogenesis from endogenous sources may also contribute to induction of protein turnover.Thermodynamics is not the limiting factor behind the concept of metabolic advantage. On the contrary, thermodynamics The author(s) declare that they have no competing interests.


Cholecystokinin (CCK) concentrations in plasma have been shown to be significantly higher in colectomised subjects compared to healthy controls. This has been ascribed to reduced inhibition of CCK release from colon. In an earlier study CCK in all but one woman who was colectomised, induced release of oxytocin, a peptide present throughout the gastrointestinal (GI) tract. The aim of this study was thus to examine if colectomised women had a different oxytocin response to CCK compared to healthy controls.Eleven women, mean age 34.4 ± 2.3 years, who had undergone colectomy because of ulcerative colitis or constipation were studied. Eleven age-matched healthy women served as controls. All subjects were fasted overnight and given 0.2 μg/kg body weight of CCK-8 i.v. in the morning. Samples were taken ten minutes and immediately before the injection, and 10, 20, 30, 45, 60, 90 and 120 min afterwards. Plasma was collected for measurement of CCK and oxytocin concentrations.The basal oxytocin and CCK concentrations in plasma were similar in the two groups. Intravenous injection of CCK increased the release of oxytocin from 1.31 ± 0.12 and 1.64 ± 0.19 pmol/l to 2.82 ± 0.35 and 3.26 ± 0.50 pmol/l in controls and colectomised women, respectively (p < 0.001). Given the short half-life of CCK-8 in plasma, the increased concentration following injection could not be demonstrated in the controls. On the other hand, in colectomised women, an increase of CCK in plasma was observed for up to 20 minutes after the injection, concentrations increasing from 1.00 ± 0.21 to a maximum of 1.81 ± 0.26 pmol/l (p < 0.002).CCK stimulates the release of oxytocin in women. There is no difference in plasma concentrations between colectomised and controls. However, colectomy seems to reduce the metabolic clearance of CCK. The hyperCCKemia in patients who had undergone colectomy is consequently not only dependent on CCK release, but may also depend on reduced clearance. The gut hormone cholecystokinin (CCK) is synthesised in endocrine I cells in the mucosa of the upper small intestine  and is rOxytocin is synthesised in the supraoptic and paraventricular nuclei of the hypothalamus as part of a larger precursor polypeptide . While tWe have recently found that CCK also leads to oxytocin release in healthy women . HoweverEleven women from the Departments of Medicine and Surgery at Malmö University Hospital (mean age 34.4 ± 2.3 years, range 22–42 years) were studied. They had all a history of colectomy. Two were colectomised because of slow transit constipation (STC) and had undergone a subtotal colectomy with the creation of ileo-rectal anastomosis. Proctocolectomy with ileal pouch-anal anastomosis had been performed in seven of them because of ulcerative colitis, and one because of familial multiple polyposis. The last patient has an ileostomy after subtotal colectomy, saving the rectum, because of ulcerative colitis. Thus, the subjects were cured from their original conditions. The time interval between the proctocolectomy/colectomy and this study was 10–149 months, with a mean of 48.5 ± 12.6 months. Eleven age-matched healthy women with preserved GI tract served as controls. Physical examination and laboratory routine screening were all within normal limits in both groups. The body weight was 68.7 ± 5.8 kg in the patients and 73.8 ± 6.1 kg in the controls. No drugs and no oral contraceptives or other hormonal treatments were allowed in either group. The experiments were performed at no specific stage of the menstrual cycle. None of the included subjects had participated in our former study [The protocols were approved by the local Ethics committee at the University of Lund, and written informed consent was obtained from all subjects before the study was started. The possibility of pregnancy was excluded in all women.All subjects were fasted overnight. In the morning they were given 0.2 μg/kg body weight of cholecystokinin octapeptide (CCK-8)  as an intravenous injection. This bolus was chosen as it was the only dose giving raise to a weak, but not significant, oxytocin release in an earlier study . Blood sAll blood samples consisted of 8.0 ml whole blood drawn into iced heparinised tubes. The plasma was separated and frozen at -20°C immediately after the experiment. Oxytocin was measured as described by Balment et al . The limThe values are expressed as mean ± standard error of the mean (SEM). The basal value is the mean of the two fasting values. The peak value is the mean of the highest concentration in every subject after the injection. The total plasma CCK and oxytocin response was assessed by calculating the area under the plasma concentration time curve (AUC). The Kruskal-Wallis followed by Wilcoxon signed ranks test were used for assessment of the significance of the differences within and between the two groups. The Spearman rank test was used for calculating the correlation between CCK and oxytocin concentrations in plasma. Probabilities of less than 0.05 were considered significant.The basal oxytocin concentration in plasma was similar in the two groups. The concentration was stable before the start of the experiments. Injection of CCK-8 led to an increase of the oxytocin secretion compared to basal values in both groups p < 0.001) . Neither was there any difference in CCK and oxytocin concentrations between patients with different diagnosis and those who had rectum saved or resected (data not shown).This study shows for the first time that CCK-8 increases the secretion of oxytocin in women. We have previously shown that exogenous CCK-33 and -39, and a fatty meal with endogenous CCK release, led to enhanced concentrations of oxytocin in plasma . One patCCK has been shown to stimulate oxytocin secretion in mammals in many studies -14. HoweOxytocin is present in plasma in men, although at lower concentrations ,25, and Several studies have reported that after colectomy in different species there are higher concentrations of CCK in plasma, both basal and postprandial, compared to healthy controls -17. It hCCK has a wide range of effects on the GI tract. Three physiological effects on gut motility have been identified; contraction of the gallbladder , relaxatCCK stimulates the release of oxytocin in women, probably via an effect on the neurohypophysial system. There is no difference in plasma concentrations between colectomised women and women with intact GI tract. The hyperCCKemia observed in patients who have undergone colectomy is dependent not only on an increase in CCK release, but may also depend on a reduced degradation. It was beyond the aim of our study to determine the clearance of CCK. However, this should be evaluated further.AUC = area under the curveCCK = cholecystokininGI = gastrointestinalPYY = peptide YYSEM = standard error of the meanBO designed the study, included patients, paid for the most, performed the statistical analysis and drafted the manuscriptJR carried out the radioimmunoassay for CCK and participated in the writing processMF carried out the radioimmunoassay for oxytocin and participated in the writing processAll authors read and approved the final manuscript.The authors declare that they have no competing interests.The pre-publication history for this paper can be accessed here:


Physical performance measures play an important role in the measurement of outcome in patients undergoing hip and knee arthroplasty. However, many of the commonly used measures lack information on their psychometric properties in this population. The purposes of this study were to examine the reliability and sensitivity to change of the six minute walk test (6MWT), timed up and go test (TUG), stair measure (ST), and a fast self-paced walk test (SPWT) in patients with hip or knee osteoarthritis (OA) who subsequently underwent total joint arthroplasty.A sample of convenience of 150 eligible patients, part of an ongoing, larger observational study, was selected. This included 69 subjects who had a diagnosis of hip OA and 81 diagnosed with knee OA with an overall mean age of 63.7 ± 10.7 years. Test-retest reliability, using Shrout and Fleiss Type 2,1 intraclass correlations (ICCs), was assessed preoperatively in a sub-sample of 21 patients at 3 time points during the waiting period prior to surgery. Error associated with the measures' scores and the minimal detectable change at the 90% confidence level was determined. A construct validation process was applied to evaluate the measures' abilities to detect deterioration and improvement at two different time points post-operatively. The standardized response mean (SRM) was used to quantify change for all measures for the two change intervals. Bootstrapping was used to estimate the 95% confidence intervals (CI) for the SRMs.The ICCs (95% CI) were as follows: 6MWT 0.94 (0.88,0.98), TUG 0.75 (0.51, 0.89), ST 0.90 (0.79, 0.96), and the SPWT 0.91 (0.81, 0.97). Standardized response means varied from .79 to 1.98, being greatest for the ST and 6MWT over the studied time intervals.The test-retest estimates of the 6MWT, ST, and the SPWT met the requisite standards for making decisions at the individual patient level. All measures were responsive to detecting deterioration and improvement in the early postoperative period. Osteoarthritis, the most common reason for total hip (THA) and knee arthroplasty (TKA), accounts for more difficulty with climbing stairs and walking than any other disease ,2. PhysiInformation about customary or normal values often exists for performances measures, however, information concerning sensitivity to change and clinically important change are rarely available . This gaA few studies have examined the responsiveness of the 6MWT and STs in patients following arthroplasty. Kreibich et al  investigResponsiveness statistics such as the standardized response mean (SRM) and effect size (ES) are important for making relative comparisons between measures. However, clinicians still require estimates to quantify the error in patients' scores and to determine if change has truly occurred. In the absence of population specific benchmarks, clinicians and researchers apply the results available from other populations. For example, Mahon et al  used theThe importance of determining THA and TKA population specific benchmarks is further underlined when one considers the growing number of North Americans requiring total joint arthroplasty ,24. In CThe sample consisted of patients with a diagnosis of OA who were scheduled to undergo primary, unilateral THA or TKA and was part of a larger, observational, longitudinal study. A sample of convenience was chosen and included one hundred fifty consecutive, eligible patients (69 hips, 81 knees) investigated over the one-year period, November 2001 to 2002. Eligibility criteria included the following: diagnosis of OA, scheduled for primary total joint arthroplasty; sufficient language skills to communicate in written and spoken English; and absence of neurological, cardiac, psychiatric disorders or other medical conditions that would significantly compromise physical function. Patients were excluded if they were scheduled for revision, bilateral or staged arthroplasties. All of the surgeries took place at a specialized, orthopaedic tertiary care hospital in Toronto.The characteristics of the patients with respect to age, height, weight, and body mass index (BMI) are reported in Table As noted earlier, patients completed four timed performance measures; the fast SPWT, TUG, ST, and 6MWT, at each assessment point. Time was measured on a stopwatch to the nearest 1/100 of a second. The order of testing was as follows: SPWT, TUG, ST, and 6MWT with a 10 minute rest between the ST and 6MWT. Standardized guidelines for performing the SPWT, TUG, and ST have been reported previously for a similar patient population ,11. In tAs noted previously, the data for this study represent a subset from a larger ongoing study that examines recovery profiles using a number of self-report and physical performance measures. The study has two arms, in Phase 1 patients are recruited from the caseload of two orthopaedic surgeons with high volumes and long waiting lists to examine the impact of waiting time on recovery profiles. In phase 2, patients are recruited from all of the orthopaedic surgeons' lists at their preoperative visit to the hospital's standardized patient orientation program, which is scheduled one to two weeks prior to surgery. There are no differences in the postoperative follow-up for both of the Phases and all patients receive standardized treatment, following either a primary total hip or knee care pathway. To provide an accurate model of change over time, patients' follow-up measurements are scheduled at different intervals. The format is that of an observational repeated measures' design  and between the first and third assessments was 178 days (1st, 3rd quartiles: 140, 204 days), there is evidence to suggest that the amount of change in function while on the waiting list is minimal [90) to be 9 LEFS points [Test-retest reliability was assessed preoperatively in a sub-sample of 21 patients from Phase 1. These 21 patients represented individuals who had progressed to surgery and follow-up by the time of this analysis. Data from patients' initial consultations with the surgeon, an intermediate assessment, and then again at patients' preoperative orientation visits contributed to the reliability analysis. Although the median interval between the first and second assessments was 91 days . It was theorized that patients' lower extremity functional status, as represented by either the time to complete a task or the distance covered in the case of the 6-minute walk test, would demonstrate deterioration compared to their preoperative values [st, 3rd quartiles: 32, 46 days).It is important when assessing responsiveness that a research design be employed in a period where change is expected. Based on the results of prior work , it was 90) was calculated [90, the value obtained from the error calculation was multiplied by the square root of two (i.e. MDC90 = SEM × 1.65 × ). The interpretation of MDC90 is that 90% of truly stable patients will demonstrate random variation of less than this magnitude when assessed on multiple occasions. A change greater than MDC90 is often interpreted as a true change.Descriptive statistics including the mean, standard deviation, and quartiles were applied to summarize the data. Shrout and Fleiss Type 2,1 intraclass correlation coefficients (ICC) were used to describe the measures' test-retest reliabilities . Standarlculated . The errth and 975th observations from the bootstrap samples represented the 95% confidence limits. This method provides a distribution free estimate of the confidence limits.The standardized response mean (SRM) was used to quantify change  and SRMs90. There was no systematic difference between the test and retest assessments for any of the measures (p > 0.05). All of the estimates were greater or equal to 0.90 with the exception of the TUG. Table Figures s p > 0.0. All of 90 was applied to further define a stable patient sample. The reliability coefficients  declare that they have no competing interests.DMK conceived and designed the study, assisted with the statistical analysis and prepared the manuscript.PWS assisted with the design, performed the statistical analysis and assisted with the manuscript preparation.JW consulted in the conception and design of the study and assisted with the manuscript preparation.JDG assisted with the design and execution of the study and manuscript preparation.DP assisted in the coordination of the study, data collection and assisted with the manuscript preparation.All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


In the present study we address the role of calcineurin in mediating adaptations in myosin heavy chain (MHC) isoform expression and muscle mass using 3-month old wild-type (WT) and transgenic mice displaying high-level expression of a constitutively active form of calcineurin (MCK-CN* mice).The calcium activated protein phosphatase 2B, also known as calcineurin, has been implicated as a cell signaling molecule involved with transduction of physiological signals (free cytosolic CaSlow muscles, e.g., soleus, were significantly larger (by ~24%), whereas fast muscles, e.g., medial gastrocnemius (MG) and tibialis anterior were significantly smaller (by ~26 and ~16%, respectively) in MCK-CN* mice compared to WT. The masses of mixed phenotype muscles, such as the plantaris and the extensor digitorum longus, were not significantly changed from WT. The soleus, plantaris, MG and diaphragm displayed shifts toward slower MHC isoforms, e.g., soleus from WT mice contained ~52% MHC-I, ~39% MHC-IIa, and ~9% MHC-IIx, whereas MCK-CN* mice had ~67% MHC-I, ~26% MHC-IIa, and ~7% MHC-IIx. The specific isoforms that were either up or down-regulated were muscle-specific. For instance, the proportion of MHC-IIa was decreased in the soleus and diaphragm, but increased in the plantaris and MG of MCK-CN* mice. Also, the proportion of MHC-IIx was unchanged in the soleus, decreased in the diaphragm and increased in the plantaris and MG of MCK-CN* relative to WT mice. Fast to slow shifts in fiber type proportions were evident for the plantaris, but not the soleus. Fast, but not slow, plantaris fibers of MCK-CN* mice had higher oxidative and lower glycolytic properties than WT.These data suggest that calcineurin activation can influence muscle phenotype and that the specific influence of calcineurin activation on the phenotypic and mass characteristics of a muscle is dependent upon the original phenotypic state of the muscle. Calciphocytes ,16. Subsphocytes . Upon dephocytes -17.2+ could potentially result in altered phenotype-specific gene expression via calcineurin [It has been proposed that in skeletal muscle nuclear NFAT can activate the expression of slow muscle phenotypic genes ,8,11,14.cineurin , and procineurin .The MCK-CN* transgenic mice expressed the transgene in all muscles tested as shown in Figure As shown in Figure 2+-ATPase (SERCA), and troponin I plasmic reticulum CaI Figure . PlantarI Figure . HoweverTo ascertain if other phenotypic properties of muscle fibers were influenced by calcineurin activation, plantaris fibers of MCK-CN* and WT mice were analyzed for marker enzymes of oxidative (succinate dehydrogenase, SDH) and glycolytic (α-glycerophosphate dehydrogenase, GPD) capacity. Fast plantaris fibers of MCK-CN* mice showed a significant increase in SDH staining intensity, indicative of elevated mitochondrial content, and a decrease in glycolytic staining intensity, indicative of reduced glycolytic capacity Figure . In contAs shown in Table As expected, based on the overall differences in muscle mass between MCK-CN* and WT mice, the soleus contained fibers with CSAs greater than WT, whereas the MG contained fibers with CSAs smaller than WT Figure . The plaElevated calcineurin activity altered the phenotypic profile and mass of both fast and slow muscles and muscle fibers. The phenotypic changes were indicated by the general fast to slow adaptation in MHC isoform expression in MCK-CN* versus WT mice. The changes in phenotype were apparently not restricted to MHC isoforms since the plantaris of MCK-CN* mice had higher proportions of fibers that stained positive for the slow isoforms of MHC, SERCA and troponin I, suggesting a coordinated increase in the expression of slow phenotypic proteins upon calcineurin activation. Fast plantaris fibers also had elevated oxidative and reduced glycolytic profiles, suggesting that calcineurin activation influenced the metabolic profile of fibers promoting a more oxidative phenotype. These data suggest that fibers that did not show adaptations in MHC, SERCA or troponin I isoforms and remained fast were still influenced by calcineurin activation to acquire an oxidative phenotype. These changes are consistent with the proposed role of calcineurin as a sensor of contractile activity and transducer of contractile signals into molecular signals that induce the expression of a slow oxidative phenotype .The overall changes in MHC isoform composition for some muscles, such as the soleus, were apparently aided by fiber type-specific changes in the CSA of the fibers, such that type I fibers were increased and type II fibers decreased (or increased only slightly in the soleus) in CSA as a result of elevated calcineurin activity. These data are consistent with the hypothesis that elevated calcineurin activity induces increased expression of slow muscle phenotypic genes resulting in elevated mass of slow muscles and muscle fibers. In addition, fibers from fast muscles may attain a smaller CSA in MCK-CN* mice relative to WT as a result of the change in phenotype from a fast glycolytic type of fiber  towards a slow or fast oxidative type of fiber , see Rivero et al. ,22.In vitro data suggest that MHC-IIa is highly (100 fold) and MHC-IIx and -IIb moderately (~5 – 10 fold) stimulated by calcineurin activation in mouse C2C12 cells [in vivo state to modulate the ultimate response to calcineurin activation. Since the diaphragm showed the greatest response to calcineurin activation and the diaphragm is a chronically active muscle it is tempting to speculate that the chronic motor activity of this muscle results in an up-regulation of parallel signaling pathways that may support a more pronounced calcineurin activity-induced shift in fiber phenotype.Although the general adaptations in phenotype were in the direction of faster to slower isoforms, the actual transitions in MHC isoform content were muscle-specific. This is reminiscent of the muscle-specific influence of thyroid hormone treatment on muscle phenotype . Of the 12 cells . BecauseThe observation that MHC-IIa and MHC-IIx were up-regulated in fast muscles and MHC-I was up-regulated in slow muscles of MCK-CN* mice is in agreement with the idea of a limited adaptive range for muscles of varying phenotype. The limited adaptive range theory essentially states that muscles from a slow developmental lineage have the capacity to adapt in the range of I ↔ IIa ↔ IIx, whereas muscles from a fast developmental lineage can adapt in the range of IIa ↔ IIx ↔ IIb . Thus, MAnother potential explanation for the muscle-specific response to chronic calcineurin activation is a possible obligatory step-wise transition from MHC-IIb ↔ IIx ↔ IIa ↔ I . FollowiThe molecular mechanisms involved in directing the muscle-specific response are unknown, but could involve parallel signaling pathways, perhaps involving CAMKinase, MEF2, PGC-1, or altered histone acetylation at specific sites. It is also possible that variability in inherent motor-neuron activity influences the expression of specific sets of parallel signaling pathways which in turn allows for alteration of only specific sets of phenotypic proteins in muscles of differing phenotype. Our data showing that the diaphragm, a chronically active muscle, had the greatest absolute increase in MHC-I protein lends support to this idea.2+-calmodulin stimulation of calcineurin can be as great as 100-fold [in vivo calcium-induced activation of endogenous calcineurin would result in a much greater elevation in calcineurin activity and a greater degree of fiber type transformation.Ultimately, these data support the idea that calcineurin activity plays a role in the regulation of muscle phenotype. Since the expression level of the transgene in these mice results in basal calcineurin activity levels that are ~10 times the activity in WT mice , and sin100-fold , it is pSeveral studies have suggested that calcineurin activation does not influence muscle mass ,34-36 orCuriously, our data suggest that chronic calcineurin activation results in elevated mass of slow muscle and reduced mass of fast muscle. This suggests that the changes in mass and fiber CSA may be secondary to the changes in phenotype. The differential effect of chronic calcineurin activation on slow vs. fast muscle mass may be explained as follows. Elevated expression of slow phenotypic genes in a slow muscle could theoretically result in an increased accretion of slow phenotypic proteins and elevated size of slow fibers. Fast muscle fibers showed an elevation in oxidative enzyme activity, i.e., transitioned from a fast glycolytic (FG) to a fast oxidative glycolytic (FOG) phenotype. Typically, FG fibers are larger than FOG fibers in mammalian muscle. A strong inverse correlation exists between oxidative capacity and fiber CSA ,40. ThusCollectively, the data support the hypothesis that calcineurin activation plays an important role in the modulation of skeletal muscle phenotype. The responses to calcineurin activation were muscle specific, suggesting that inherent differences in signaling mechanisms within distinct muscles likely modulate the response to calcineurin activation. The observation that a 10-fold increase in basal calcineurin activity results in alterations in the expression of fast versus slow phenotypic proteins and alterations in the metabolic capacities of fibers that do not show a transition to slow fiber type isoforms suggests that the activation of this pathway can modulate multiple aspects of fiber phenotype. However, parallel pathways likely need to be invoked to completely alter the phenotype of all fibers in a muscle.Breeding pairs of MCK-CN* transgenic mice were obtained from the primary colony at the University of Texas Southwestern Medical Center  and housMCK-CN* (n = 10) and WT littermate controls (n = 6) were sacrificed by pentobarbital injection at 3 months of age. Animals from two independent litters were used. The diaphragm, soleus, medial gastrocnemius (MG), plantaris, tibialis anterior, and extensor digitorum longus muscles were dissected free, trimmed of excess connective tissue, and weighed (diaphragm weights were not obtained). The muscles  were then rapidly frozen in melting isopentane cooled with liquid nitrogen and stored at -70°C.260) light absorbance. All RNA samples had A260:A280 ratios of greater than 1.8. Two μg of the isolated RNA were reverse transcribed to cDNA with Superscript II (Invitrogen Corp.) in a final volume of 20 μl. The same PCR primers used for genotyping were used to amplify the specific cDNA fragment from transgenic mice expressing the MCK-CN* transgene. The PCR reaction included: 1 μl of cDNA, 1X Platinum Taq PCR buffer (Invitrogen Corp.), 1.5 mM MgCl2, 0.2 mM dNTPs, 1 μM each primer, and 1 unit Platinum Taq (Invitrogen Corp.) in a final volume of 25 μl. The PCR cycle conditions were 94°C for 4 min and then 40 cycles of 94°C for 30 sec, 61°C for 30 sec, and 72°C for 30 sec, followed by a final step at 72°C for 5 min. The PCR products were separated on 1.5% agarose gels, stained with SYBR® green I (Molecular Probes Inc., Eugene, OR, USA) and quantified using a ChemiImager 5500 (Alpha Innotech, San Leandro, CA, USA).Total RNA was isolated from frozen muscle (soleus, MG, plantaris, and diaphragm) samples using Trizol reagent according to the manufacturer's instructions (Invitrogen Corp., Carlsbad, CA, USA). The final RNA pellet was dissolved in nuclease-free water, treated with DNA-free™ (Ambion Inc, Austin, TX, USA) to remove potential contaminating genomic DNA, and then quantified by UV (A2+ ATPase (SERCA, Novocastra Laboratories, Inc.) isoforms using similar techniques. The sections treated for immunohistochemistry were used to measure the cross-sectional area (CSA) of fifty individual muscle fibers per muscle using a calibrated microscopy-based image analysis system consisting of a GMS-300 grayscale microscopy system (Scion, Frederick, MD) and a Nikon Eclipse E400 microscope.One MG, plantaris and soleus muscle from each animal were serially sectioned perpendicular to the fiber axis using a Microm cryostat, stained imuunohistochemically for fast or slow myosin heavy chain (MHC) isoforms using either anti-fast or anti-slow MHC monoclonal antibodies (mAb, Novocastra Laboratories, Inc.) according to Talmadge et al., . Soleus The MG, plantaris and soleus from the opposite limb and the whole diaphragm  were subjected to high resolution SDS-PAGE for analysis of myosin heavy chain isoforms as detailed in Talmadge and Roy . These m2.Quantitative histochemical analyses of oxidative and glycolytic enzyme activities were measured on 50 plantaris fibers per muscle that were immunohistochemically typed for fast or slow MHC isoform content in serial sections. According to Rivero et al., ,22, succStudent's t-tests were used for comparing mean data between transgenic and WT mice at each age. Statistical differences were significant at p ≤ 0.05.RJT: conception, design, data collection and analysis, manuscript preparation, research funds collection.JSO: quantitative histochemical analyses, genotyping, statistical analysis, figure preparation.MRR: electrophoretic analyses, statistical analysis, figure preparation.NDG: mRNA and electrophoretic analyses, figure preparation.SRS: western blotting, figure preparation.SJL: muscle sample collection.FJN: supplied transgenic mice, provided genotyping expertise.


There is now good evidence about the management options for pregnant women with a breech presentation (buttocks or feet rather than head-first) at term; external cephalic version (ECV) – the turning of a breech baby to a head-down position and/or planned caesarean section (CS). Each of these options has benefits and risks and the relative importance of these vary for each woman, subject to her personal values and preferences, a situation where a decision aid may be helpful.Decision aids are designed to assist patients and their doctors in making informed decisions using information that is unbiased and based on high quality research evidence. Decision aids are non-directive in the sense that they do not aim to steer the user towards any one option, but rather to support decision making which is informed and consistent with personal values.The ECV decision aid was developed using the Ottawa Decision Support Framework, including a systematic review of the evidence about the benefits and risks of the options for breech pregnancy. It comprises an audiotape with a supplementary booklet and worksheet, a format that can be taken home and discussed with a partner. This project aims to evaluate the ECV decision aid for women with a breech presenting baby in late pregnancy.We aim to evaluate the effectiveness of the decision aid compared with usual care in a randomised controlled trial in maternity hospitals that offer ECV. The study group will receive the decision aid in addition to usual care and the control group will receive standard information on management options for breech presentation from their usual pregnancy care provider. Approximately 184 women with a single breech-presenting baby at greater than 34 weeks gestation and who are clinically eligible for ECV will be recruited for the trial.The primary outcomes of the study are knowledge, decisional conflict, anxiety and satisfaction with decision-making that will be assessed using self-administered questionnaires. The decision aid is not intended to influence either the uptake of either ECV or planned CS, however we will monitor health service utilisation rates and maternal and perinatal outcomes. Breech presentation occurs when a baby presents with the buttocks or feet rather than head first . As breech presentation is related to both fetal size and gestational age, the incidence decreases as pregnancy progresses to 3–4% by full-term,2. DecadThese results have dramatically altered a woman's options if she has a breech presentation at term, as CS is now offered as the safest and in many institutions the only, management option. This change has occurred rapidly: The TBT was published in October 2000 and the rate of vaginal breech birth in NSW declined from 17% in 1999 to 14% in 2000 and 4.5% in 2001,7. ComplExternal cephalic version (ECV) is the turning of a breech baby to a cephalic presentation. Systematic review of six well designed randomised controlled trials demonstrates that among women with breech presentation in late pregnancy, ECV reduces both breech presentations in labour (RR = 0.42, 95%CI 0.35–0.50) and caesarean sections (RR = 0.52. 95%CI 0.39–0.71).Despite clear evidence of effectiveness and potential benefit, many women decline ECV for a variety of reasons. Both breech presentation and ECV success rates are strongly influenced by parity, with success rates reported as low as 25% for women having their first baby. For othTo obtain data on Australian women's views and information needs about ECV we undertook a cross-sectional study of women's knowledge, attitudes and decision-making preferences for the management of breech presentation. Of 174 It is now recognised that many consumers want to participate in clinical decisions about their health -31. NHMRnon-directive in the sense that they do not aim to steer the user towards any one option, but rather to support decision making which is informed, consistent with personal values and acted upon[To help patients take a more active role in important clinical decisions, decision aids based on latest research evidence are being developed by several centres . Decision aids are defined by the Cochrane Collaboration as "intected upon. Decisiocted upon.Currently only 38 decision aids worldwide have been developed and carefully evaluated in randomised controlled trials,35. ExamThe management of breech presentation is a clinical decision that fulfils Eddy's criteria for a decision in which patients' values and preferences should be included. The outIn 2002 we developed an evidence-based decision aid for women with a breech presentation in late pregnancy. In developing the decision aid we utilised the NHMRC guideline "How to prepare and present information for consumers of health services" , were developed and each subjected to pilot testing and revision as we obtained feedback. The process of testing and revising started with the project group. The next phase included a review by a group of national and international content experts, including decision aid experts, obstetricians, midwives, perinatal epidemiologists and psychologists. Once we were convinced that the content was accurate the decision aid was pilot-tested amongst consumers. There were several rounds of consumer review and refinement. We pilot-tested with members of consumer organisation (Maternity Alliance) and in a convenience sample of pregnant and recently pregnant women. The next draft was pilot-tested amongst pregnant women attending the antenatal clinic, who may or may not have had a breech presentation. And finally we formally pilot tested the decision aid with women who had a breech presentation in late pregnancy and were at the point of decision making. Pilot-testing results included: 95% of participants found the decision aid clear and easy to understand and 80% thought there was enough information for them to make a decision. Over 90% found it very helpful and nearly all women would recommend it to others. After reviewing the decision aid, women experienced a significant increase in their knowledge scores, less anxiety, had no difficulty making decisions and were satisfied with their decision.This study aims to evaluate the ECV Decision Aid for women with a breech-presenting baby in late pregnancy. The decision aid is based on the most recently available evidence and will be evaluated to assess the impact on women's satisfaction with decision-making, knowledge, anxiety and pregnancy outcomes. If successful, the results could be applied to a improve consumer information and participation in clinical decisions across a wide spectrum of pregnancy care issues.To compare the relative effectiveness of the decision aid with standard care in relation to women's knowledge, expectations, satisfaction with and participation in decision making, anxiety and decisional conflict. Secondary outcomes will include service utilisation and perinatal outcomes.The primary hypotheses of the study are:Use of the ECV decision aid by women with a singleton breech-presenting infant in late pregnancy1. increases knowledge about breech presentation and the management options2. reduces decisional conflict (uncertainty about the course of action)3. increases satisfaction with decision making4. reduces anxietyThe secondary hypotheses of the study are:Use of the ECV decision aid by women with a singleton breech-presenting infant in late pregnancy does not influence1. uptake of ECV2. the proportion of women having a planned caesarean section for breech presentation at term3. maternal and infant outcomesWe will use a randomised trial with the following study groups to assess the impact of the decision aid:Group 1: Usual care Group 2: Usual care + Decision aid with review by a research midwifeAs randomisation will be done at the individual level, there is a risk of contamination of the usual care group if the usual care provider also reviews the decision aid with women in the study group. Therefore the decision aid will be reviewed with a research midwife and the usual antenatal care providers will be blinded to the exact content and format of the decision aid.Australian obstetric hospitals that offer external cephalic version.Women with a single breech-presenting baby at ≥ 34 weeks gestation and who are clinically eligible for ECV will be invited to participate in the trial.Exclusion criteria are therefore those for ECV and include women presenting with a breech in labour, multiple pregnancies, previous CS, severe fetal anomaly, ruptured membranes and indications for CS anyway. The decision aid will be produced in English and will be designed to be simple and accessible for women with low levels of literacy. The use of audiotapes and graphics will further aid comprehension and ensure that, as far as possible, women with low English literacy need not be excluded.The study procedure will draw upon the usual schedule of antenatal visits becoming weekly in late pregnancy and the usual management of a breech-presentation in the late pregnancy Figure . Women dThe study group will receive the decision aid (workbook, tape or CD, and worksheet) and the control group will receive standard information on management options for breech presentation from their usual carer. The study group will be given the opportunity to work through the decision aid while in the antenatal clinic and/or to take home, which ever is most convenient. Many women will also want to discuss the decision with their partner. This pragmatic approach aims to assess the decision aid under the conditions most likely to be applied in real practice. At the next antenatal visit, women in the study group will review their decision aid worksheet and any questions with the research nurse.All women will be given a follow-up questionnaire to complete prior to their next antenatal clinic visit (see Outcome Measures below for more detail). All women choosing ECV will be given the opportunity to discuss the procedure with the obstetrician providing the service. This discussion is likely to include some of the probabilistic information in the decision aid but will occur after the follow-up questionnaire and will not influence the outcome measures.At 12–16 weeks post-partum all participants will be mailed a second follow-up questionnaire. This will assess women's satisfaction with their decision and the decision making process when the events are past and the outcomes known. (See Outcome Measures below for more detail). Questionnaires will be mailed with reply paid envelopes, with up to two reminder telephone prompts to non-responders.As in many obstetric interventions double blinding is virtually impossible. The main outcomes of this study are self-reported and the women are clearly not blinded to their treatment allocation. However, we will institute a number of measures aimed at keeping antenatal staff blind to the treatment allocation and preventing contamination of the control group:• Women will review the decision aid with the research midwife and complete the first questionnaire (primary outcome measures) prior to their next antenatal consultation• Usual antenatal care providers will be blinded to the content and format of the decision aid• Regular in-service  for the antenatal care providers to explain the trial protocol and to make clear the potential effect of unmasking or contamination.• Monitoring decision aid distribution and keeping them locked up and only accessible by the research midwife• Asking participants not to reveal their treatment allocation, or share their decision aid material with antenatal staff or other women. If participants do not want to keep their decision aid they will be asked to return it.st follow-up questionnaire. Thus we will have a baseline record of knowledge about ECV, anxiety and decisional conflict about the decision and satisfaction with the decision before the DA is in use. Comparison of the data obtained from this run-in period and the control arm will allow us to judge whether, and to what extent, contamination has occurred.• Monitoring the "usual care" (control) arm by conducting a run-in period in which women found to have a breech presentation will be asked to complete the 1Brief baseline data will be collected to assess comparability of the study groups. The baseline assessment will include age, parity, brief socio-demographic data, highest level of education achieved, knowledge and anxiety as assessed by the state component of the short Spielberger anxiety scale.The effectiveness of risk communication to aid patient decision making is best assessed by a combination of cognitive, affective and behavioural outcomes. Thus th• cognitive: change in knowledge and realistic expectations of the management options and possible benefits and risks of each option• affective: anxiety, satisfaction with the decision, participation in decision-making and the amount of decisional conflict (uncertainty about which course of action to choose) experienced• behavioural: actual decision taken and acted upon (see secondary outcomes)Measures of knowledge and realistic expectations about options for the management of breech presentation and the benefits and risks of ECV will be specific to this project. Thus we will need to develop, and test these measures as part of the project.Anxiety will be measured by the state component of the short Spielberger anxiety scale which has been extensively used and validated. We do nSatisfaction with the decision will be assessed using the Satisfaction with Decision Scale. Satisfaction with Decision Scale  was developed specifically to assess satisfaction with health care decisions.Participation in decision-making will be ascertained using the five-item Degner Control Preferences Scale. This alDecisional conflict will be assessed by the Decisional Conflict Scale which has established reliability, good psychometric properties and is short (16 items)[46]. It has been used to evaluate a range of decision aids.st follow-up).Because the decision about ECV must be made within a short timeframe, the outcomes will be measured as soon as practical after the consultation in which the ECV decision was made – prior to the next antenatal visit. For the primary outcomes this will be within one week of the decision being made .Satisfaction with the decision and anxiety will be measured again at 12–16 weeks postpartum as the last weeks of pregnancy and the week after birth are associated with a reduction in state anxiety. We are The aim of the decision aid is to assist patient decision making, and not to influence the direction of the decision taken. Nevertheless, we think it is important to collect service utilisation and pregnancy outcome data so we will record and compare the numbers of ECVs undergone and ECV success rate in both arms of the study, as well as recording and comparing rates of pregnancy complications and perinatal outcomes. Data on ECVs are already prospectively collected for quality assurance, these include fetal lie, parity, success rates and complications. Other perinatal outcomes will be obtained (with informed consent) from the existing computerised obstetric database. These outcomes include mode of delivery , enrolment to delivery interval, gestational age, birthweight, Apgar scores, perinatal deaths, Neonatal Intensive Care Unit admission, maternal haemorrhage (antepartum or postpartum) and length of stay.Sample size calculations for the trial (significance 0.05, power 0.8) were determined using the mean difference we would like to detect in women's decisional conflict scores and knowledge of options and outcomes. Compared with usual care, decisional conflict was shown in the most current systematic review to be significantly reduced by decision aids; the meta-analysed mean difference was -5.75, 95%CI -8.63, -2.87 . AssuminAnalyses will be by intention to treat, including withdrawals and losses to follow-up. Study groups will be compared in terms of baseline characteristics. As this is a randomised trial, we would anticipate minimal differences in baseline characteristics. If however, important differences are found, these potential confounders will be adjusted for in the analysis of outcomes. For the primary outcomes, the mean score for each measure for each group will be compared using t-tests. If adjustment for confounders is needed a multiple linear regression model will be used. The secondary outcomes will be compared using chi-square tests of significance for categorical data and t-tests for continuous data. If adjustment for confounding is necessary logistic regression and multiple linear regression will be used respectively.An interim analysis will be conducted part way through the study and the results will be reviewed by an independent Data Monitoring Committee. Specifically the incidence of anxiety and decisional conflict in the two randomised groups will be determined after the first 150 women have been enrolled and data have been collected. If there is a significant increase in either of these outcomes at p < 0.01 (1-tailed) with the decision aid, the trial will be stopped. The trial will also be stopped of it is evident that no clear outcome will be obtained.We expect the project to provide ethical benefit. It is possible that some women may experience heightened anxiety as a result of receiving the decision aid during its evaluation by randomised trial. However, a systematic review of decision aids found they improved knowledge without increasing anxiety. NeverthThe study has been approved by the Central Sydney Area Health Service Ethics Review Committee (Protocol no. X01-0067) and the University of Sydney Human Ethics Committee (Ref No. 3806).Participants in the trial will be identified by a study number only, with a master code sheet linking names with numbers being held securely and separately from the study data.To ensure that all information is secure, data records will be kept in a secure location at the University of Sydney and accessible only to research staff. As soon as all follow-up is completed the data records will be de-identified. De-identified data will be used for the statistical analysis and all publications will include only aggregated data.The electronic version of the data will be maintained on a computer protected by password. All hard copy patient identifiable data and electronic backup files will be kept in locked cabinets, which are held in a locked room accessed only by security code and limited staff.Data files will be stored for 7 (seven) years after completion of the project as recommended by the NHMRC. Disposal of identifiable information will be done through the use of designated bags and/or a shredding machine.This project will make an important contribution to a largely neglected aspect of pregnancy care, assisting informed participation by women in clinical decisions that affect their pregnancy. Involvement in decision making is a strong predictor of satisfaction with care in pregnancy and childbirth, yet there are only a few published decision aids for maternity care. A decision aid for the management of breech presentation is both timely and practical as there is new evidence supporting planned CS, dramatically altering the management options. Further, the randomised trial will provide high quality evidence about the effectiveness of the decision aid in supporting shared clinical decision making during pregnancy. If successful, the results of this project could be applied to improve consumer information and participation in clinical decisions across a wide spectrum of pregnancy care. Finally, if the decision aid increases the utilisation of ECV, in addition to reducing breech presentation and CS for breech presentation , some women may have more choice of where they give birth as breech presentation precludes birth in birth centres and small rural hospitals.The author(s) declare that they have no competing interests.CR, AB, CRG, BP, DHS were involved in the conception and design of the study. CR, NN and CRG were responsible for the drafting of the protocol and NN and CR were involved in the development and implementation of the study. All authors have read and given final approval of the final manuscript.The pre-publication history for this paper can be accessed here: