Quantitative 3D imaging parameters improve prediction of hip osteoarthritis outcome.

Osteoarthritis is an increasingly important health problem for which the main treatment remains joint replacement. Therapy developments have been hampered by a lack of biomarkers that can reliably predict disease, while 2D radiographs interpreted by human observers are still the gold standard for clinical trial imaging assessment. We propose a 3D approach using computed tomography-a fast, readily available clinical technique-that can be applied in the assessment of osteoarthritis using a new quantitative 3D analysis technique called joint space mapping (JSM). We demonstrate the application of JSM at the hip in 263 healthy older adults from the AGES-Reykjavík cohort, examining relationships between 3D joint space width, 3D joint shape, and future joint replacement. Using JSM, statistical shape modelling, and statistical parametric mapping, we show an 18% improvement in prediction of joint replacement using 3D metrics combined with radiographic Kellgren & Lawrence grade (AUC 0.86) over the existing 2D FDA-approved gold standard of minimum 2D joint space width (AUC 0.73). We also show that assessment of joint asymmetry can reveal significant differences between individuals destined for joint replacement versus controls at regions of the joint that are not captured by radiographs. This technique is immediately implementable with standard imaging technologies.

Flavin Binding Allosteric Aptamer with Noncovalent Labeling for miR Sensing.

Modular allosteric aptamers with discrete recognition and signaling regions provide a facile method of carrying out label-free detection by forgoing complex target labeling requirements. Herein, we describe the design and function of an aptamer scaffold capable of forming a hairpin loop in the presence of FAD (the signaling trigger). The aptamer includes a recognition region for the microRNA (miR) Let-7i. Upon selective miR hybridization, the aptamer undergoes a conformational shift to release FAD and thus produce a measurable response. As a result, the described method can sensitively and selectively detect miR Let-7i with a wide linear range of 0.1 pM to 1 µM and a detection limit of 150 fM. Additionally, this strategy was able to selectively discriminate between sequences with 1- and 2-nucleotide (nt) differences.

A new quantitative 3D approach to imaging of structural joint disease.

Imaging of joints with 2D radiography has not been able to detect therapeutic success in research trials while 3D imaging, used regularly in the clinic, has not been approved for this purpose. We present a new 3D approach to this challenge called joint space mapping (JSM) that measures joint space width in 3D from standard clinical computed tomography (CT) data, demonstrating its analysis steps, technical validation, and reproducibility. Using high resolution peripheral quantitative CT as gold standard, we show a marginal over-estimation in accuracy of +0.13 mm and precision of ±0.32 mm. Inter-operator reproducibility bias was near-zero at -0.03 mm with limits of agreement ±0.29 mm and a root mean square coefficient of variation 7.5%. In a technical advance, we present results from across the hip joint in 3D with optimum validation and reproducibility metrics shown at inner joint regions. We also show JSM versatility using different imaging data sets and discuss potential applications. This 3D mapping approach provides information with greater sensitivity than reported for current radiographic methods that could result in improved patient stratification and treatment monitoring.

How does the femoral cortex depend on bone shape? A methodology for the joint analysis of surface texture and shape.

In humans, there is clear evidence of an association between hip fracture risk and femoral neck bone mineral density, and some evidence of an association between fracture risk and the shape of the proximal femur. Here, we investigate whether the femoral cortex plays a role in these associations: do particular morphologies predispose to weaker cortices? To answer this question, we used cortical bone mapping to measure the distribution of cortical mass surface density (CMSD, mg/cm2) in a cohort of 125 females. Principal component analysis of the femoral surfaces identified three modes of shape variation accounting for 65% of the population variance. We then used statistical parametric mapping (SPM) to locate regions of the cortex where CMSD depends on shape, allowing for age. Our principal findings were increased CMSD with increased gracility over much of the proximal femur; and decreased CMSD at the superior femoral neck, coupled with increased CMSD at the calcar femorale, with increasing neck-shaft angle. In obtaining these results, we studied the role of spatial normalization in SPM, identifying systematic misregistration as a major impediment to the joint analysis of CMSD and shape. Through a series of experiments on synthetic data, we evaluated a number of registration methods for spatial normalization, concluding that only those predicated on an explicit set of homologous landmarks are suitable for this kind of analysis. The emergent methodology amounts to an extension of Geometric Morphometric Image Analysis to the domain of textured surfaces, alongside a protocol for labelling homologous landmarks in clinical CT scans of the human proximal femur.

From [11C]CO2 to [11C]amides: a rapid one-pot synthesis via the Mitsunobu reaction.

A novel amide synthesis methodology is described using amines, CO2 and Grignard reagents and Mitsunobu reagents. The method was applied to carbon-11 radiochemistry to label amides using cyclotron-produced [11C]CO2. The synthetic utility of the one-pot labelling methodology was demonstrated by producing [11C]melatonin. The incorporation of [11C]CO2 into [11C]melatonin was 36% - determined by radioHPLC 2 min post [11C]CO2 delivery.

Intervention improves assisted conception intracytoplasmic sperm injection outcomes for patients with high levels of sperm DNA fragmentation: a retrospective analysis.

Sperm DNA fragmentation (SDF) is used in assisted reproductive technology (ART) programs as an indicator for sperm quality, although there is still a lack of consensus as to its clinical utility. In this retrospective study, we examined intracytoplasmic sperm injection (ICSI) outcomes of 1924 infertile patients who underwent SDF analysis using the sperm chromatin integrity test. ART patients were classified as having low [DNA fragmentation index (DFI) <29%] or high SDF (DFI ≥29%) and by whether or not an intervention [physiological intracytoplasmic sperm injection (PICSI), intracytoplasmic morphologically selected sperm injection (IMSI), testicular sperm extraction (TESE)/testicular sperm aspiration (TESA), frequent ejaculation] was performed. High SDF patients who did not have an intervention had a lower fertilization rate and poorer clinical outcomes from blastocyst transfers as compared with low SDF patients; the fertilization rate was 66.0% vs. 70.2% (p = 0.042), single embryo transfer (SET) fetal heart pregnancy rate was 28.5% vs. 45.2% (p = 0.042), and SET live birth rate was 24.9% vs. 40.6% (p = 0.060), respectively. Furthermore, high SDF patients who had an intervention had significantly improved blastocyst transfer outcomes, similar to those of low SDF patients; the SET live birth rate for high SDF intervention patients was 43.8% as compared with 24.9% for high SDF no intervention patients (p = 0.037) and 40.6% for low SDF patients (p = 0.446). Analysis of the three main intervention subgroups for high SDF patients revealed that TESE/TESA patients had the highest SET live birth rate; in comparison with 24.2% for high SDF patients who did not have an intervention, PICSI patients had 38.3% (p = 0.151), IMSI patients had 28.7% (p = 0.680), and TESE/TESA patients had 49.8% (p = 0.020). Our data suggest that SDF results indicate ICSI outcomes and that patients who have high SDF benefit from an intervention.

Recurrence rate after Delorme's procedure with simultaneous placement of a Thiersch suture.

Introduction Rectal prolapse is a debilitating condition usually affecting elderly women. The management is generally surgical but the optimal operation remains unclear. The recurrence rate after Delorme's procedure has been found to be similar to that for an abdominal approach. Thiersch sutures have been associated with high rates of complications and recurrence. The aim of this study was to compare the outcomes of Delorme's procedure with those of a combined Delorme-Thiersch procedure. Methods A retrospective case note review was performed of all patients who underwent Delorme's procedure for rectal prolapse between 2008 and 2014 in a single centre. Results Sixty-seven patients (63 women) underwent Delorme's procedure during the study period. The majority (85%) of patients were over 75 years old. Twelve patients had a Thiersch suture placed at the time of the procedure. The median length of stay was 3 days (range: 0-19 days). Postoperative bleeding requiring either transfusion or readmission occurred in five patients (7.5%) and two patients (3.0%) were readmitted with pain. There was no difference in the rate of complications regardless of whether a Thiersch suture had been placed. Recurrence occurred in 8.3% of those who had a Thiersch suture compared with 21.8% of those who did not (p=0.26). There was no difference in the median time to recurrence between the groups. Conclusions There was no increase in complications after placement of a Thiersch suture with Delorme's procedure. The rate of recurrence could potentially be decreased with this combined technique. Additional studies are required to investigate this further.

Estimation of clinical and economic effects of prophylaxis against venous thromboembolism in medical patients, including the effect of targeting patients at high-risk.

BACKGROUND: The clinical and economic effects of medical thromboprophylaxis (MT) using low molecular weight heparin in Australia are unknown. AIM: To estimate the effects of MT in Australia. METHODS: A decision tree model of MT was populated with national data for medical admissions. The Prevention of Recurrent Venous Thromboembolism (PREVENT) trial was chosen as the primary data source because its design uniquely avoided bias caused by treatment of sub-clinical events. Clinical efficacy and costs were estimated compared with no prophylaxis, assuming full compliance and according to three definitions of eligibility. Effectiveness was estimated as thrombotic events saved, mortality from bleeding or pulmonary embolus (PE), cost and $/year of life saved. Model outputs were subjected to sensitivity analysis. RESULTS: MT decreased thrombotic events, and the numbers avoided increased as eligibility broadened (deep vein thrombosis (DVT): 2597, 2771 and 3232 at restricted, intermediate and broad eligibility; PE: 454, 484 and 565 respectively). The annual cost of no prophylaxis was $88.7 m. Costs were reduced at most restricted eligibility (-$7.9 m), but increased by $3.0 and $32.1 m at broader eligibility. PE deaths declined, but this was offset by deaths from haemorrhage, causing a net increase (158, 299 and 672 respectively). Estimates were sensitive to the incidence of venous thromboembolic event (VTE), case-fatality rates for PE and bleeds and the relative risk reduction for PE with prophylaxis. CONCLUSIONS: Under PREVENT trial conditions, MT avoids up to 3200 DVT and 565 PE events annually, but may increase mortality.

Association between femur size and a focal defect of the superior femoral neck.

Within each sex, there is an association between hip fracture risk and the size of the proximal femur, with larger femurs apparently more susceptible to fracture. Here, we investigate whether the thickness and density of the femoral cortex play a role in this association: might larger femurs harbour focal, cortical defects? To answer this question, we used cortical bone mapping to measure the distribution of cortical mass surface density (CMSD, mg/cm(2)) in cohorts of 308 males and 125 females. Principal component analysis of the various femoral surfaces led to a measure of size that is linearly independent from shape. After mapping the data onto a canonical femur surface, we used statistical parametric mapping to identify any regions where CMSD depends on size, allowing for other confounding covariates including shape. Our principal finding was a focal patch on the superior femoral neck, where CMSD is reduced by around 1% for each 1% increase in proximal-distal size (p<0.000005 in the males, p<0.001 in the females). This finding appears to be consistent with models of functional adaptation, and may help with the design of interventional strategies for reducing fracture risk.

Manufacturing genetically modified T cells for clinical trials.

Compliance with Food and Drug Administration regulations relating to initiating early phase clinical trials of new cellular therapy products often presents a hurdle to new investigators. One of the biggest obstacles is the requirement to manufacture the therapeutic products under current Good Manufacturing Practices-a system that is usually poorly understood by both basic researchers and clinicians. This article reviews the major points that must be addressed when manufacturing genetically modified T cells for therapeutic use.

Altered regional loading patterns on articular cartilage following meniscectomy are not fully restored by autograft meniscal transplantation.

OBJECTIVE: To quantify the changes in regional dynamic loading patterns on tibial articular cartilage during simulated walking following medial meniscectomy and meniscal transplantation. METHODS: Seven fresh frozen human cadaveric knees were tested under multidirectional loads mimicking the activity of walking, while the contact stresses on the tibial plateau were synchronously recorded using an electronic sensor. Each knee was tested for three conditions: intact meniscus, medial meniscectomy, and meniscal transplantation. The loading profiles at different locations were assessed and common loading patterns were identified at different sites of the tibial plateau using an established numerical algorithm. RESULTS: Three regional patterns were found on the tibial plateau of intact knees. Following medial meniscectomy, the area of the first pattern which was located at the posterior aspect of the medial plateau was significantly reduced, while the magnitude of peak load was significantly increased by 120%. The second pattern which was located at the central-posterior aspects of the lateral plateau shifted anteriorly and laterally without changing its magnitude. The third pattern in the cartilage-to-cartilage contact region of the medial plateau was absent following meniscectomy. Meniscal transplantation largely restored the first pattern, but it did not restore the other two patterns. CONCLUSION: There are site-dependent changes in regional loading patterns on both the medial and lateral tibial plateau following medial meniscectomy. Even when a meniscal autograft is used where the geometry and material properties are kept constant, the only region in which the loading pattern is restored is at posterior aspect of the medial plateau.

Independent measurement of femoral cortical thickness and cortical bone density using clinical CT.

The local structure of the proximal femoral cortex is of interest since both fracture risk, and the effects of various interventions aimed at reducing that risk, are associated with cortical properties focused in particular regions rather than dispersed over the whole bone. Much of the femoral cortex is less than 3mm thick, appearing so blurred in clinical CT that its actual density is not apparent in the data, and neither thresholding nor full-width half-maximum techniques are capable of determining its width. Our previous work on cortical bone mapping showed how to produce more accurate estimates of cortical thickness by assuming a fixed value of the cortical density for each hip. However, although cortical density varies much less over the proximal femur than thickness, what little variation there is leads to errors in thickness measurement. In this paper, we develop the cortical bone mapping technique by exploiting local estimates of imaging blur to correct the global density estimate, thus providing a local density estimate as well as more accurate estimates of thickness. We also consider measurement of cortical mass surface density and the density of trabecular bone immediately adjacent to the cortex. Performance is assessed with ex vivo clinical QCT scans of proximal femurs, with true values derived from high resolution HRpQCT scans of the same bones. We demonstrate superior estimation of thickness than is possible with alternative techniques (accuracy 0.12 ± 0.39 mm for cortices in the range 1-3mm), and that local cortical density estimation is feasible for densities >800 mg/cm(3).

A clinical system for three-dimensional extended-field-of-view ultrasound.

OBJECTIVE: This work is concerned with the creation of three-dimensional (3D) extended-field-of-view ultrasound from a set of volumes acquired using a mechanically swept 3D probe. 3D volumes of ultrasound data can be registered by attaching a position sensor to the probe; this can be an inconvenience in a clinical setting. A position sensor can also cause some misalignment due to patient movement and respiratory motion. We propose a combination of three-degrees-of-freedom image registration and an unobtrusively integrated inertial sensor for measuring orientation. The aim of this research is to produce a reliable and portable ultrasound system that is able to register 3D volumes quickly, making it suitable for clinical use. METHOD: As part of a feasibility study we recruited 28 pregnant females attending for routine obstetric scans to undergo 3D extended-field-of-view ultrasound. A total of 49 data sets were recorded. Each registered data set was assessed for correct alignment of each volume by two independent observers. RESULTS: In 77-83% of the data sets more than four consecutive volumes registered. The successful registration relies on good overlap between volumes and is adversely affected by advancing gestational age and foetal movement. CONCLUSION: The development of reliable 3D extended-field-of-view ultrasound may help ultrasound practitioners to demonstrate the anatomical relation of pathology and provide a convenient way to store data.

Imaging the femoral cortex: thickness, density and mass from clinical CT.

There is growing evidence that focal thinning of cortical bone in the proximal femur may predispose a hip to fracture. Detecting such defects in clinical CT is challenging, since cortices may be significantly thinner than the imaging system's point spread function. We recently proposed a model-fitting technique to measure sub-millimetre cortices, an ill-posed problem which was regularized by assuming a specific, fixed value for the cortical density. In this paper, we develop the work further by proposing and evaluating a more rigorous method for estimating the constant cortical density, and extend the paradigm to encompass the mapping of cortical mass (mineral mg/cm(2)) in addition to thickness. Density, thickness and mass estimates are evaluated on sixteen cadaveric femurs, with high resolution measurements from a micro-CT scanner providing the gold standard. The results demonstrate robust, accurate measurement of peak cortical density and cortical mass. Cortical thickness errors are confined to regions of thin cortex and are bounded by the extent to which the local density deviates from the peak, averaging 20% for 0.5mm cortex.

A single-centre experience of chemoradiotherapy for rectal cancer: is there potential for nonoperative management?

AIM: The aim of the study was to assess the outcome of patients who received chemoradiotherapy (CRT) for locally advanced rectal cancer, specifically those with complete clinical response (CCR) and who were then managed nonoperatively with a 'Watch and Wait' follow-up protocol. METHOD: A retrospective study was carried out of patients undergoing preoperative CRT for rectal cancer, conducted in a district general hospital managing rectal cancer through the multidisciplinary team process. RESULTS: Forty-nine patients received preoperative CRT over a 5-year period (2004-2009). Twelve (24%) were considered potentially to have had a complete response on MRI. Of these, six subsequently had clinical evidence of residual disease, leading to surgery (mean time to surgery, 24 weeks; range, 12-36 weeks). The remaining six had CCR, avoiding surgery (mean follow up, 26 months; range, 12-45 months), with all six patients disease free to date. A further six patients had complete pathological response (CPR) following surgery after comprehensive histopathological assessment of the specimen. CONCLUSION: In this consecutive series of patients with locally advanced rectal cancer treated with CRT, 12% demonstrated a CCR and have been actively managed conservatively, thereby avoiding surgery. With further improvements in diagnostic assessment of response to CRT, this figure may rise.

Influence of Salvadora persica (miswak) extract on physical and antimicrobial properties of glass ionomer cement.

AIM: To investigate physical and antimicrobial properties of Glass Ionomer Cement (GIC) combined with Salvadora Persica Extract (SPE). METHODS: SPE was added to GIC (Fuji IX) in concentrations of 1%, 2% and 4% w/w. The compressive strength and diametral tensile strength were measured at 1 h, 24 h and 7 days. The antimicrobial effect was tested in agar dilution assay in blood agar plates with Candida albicans, Streptococcus mutans, Streptococcus sanguis, Streptococcus mitis, Streptococcus salivarius and Actinomyces naeslundii as test organisms. GIC containing 5% chlorhexidine served as positive control. RESULTS: Significant differences were found for the compressive strength and diametral tensile strength as a result of adding SPE to GIC (p<0.05). GIC with 2 or 4 % SPE was significantly weaker than the GIC control, while GIC with 1% SPE was not different from the control. The mean values for the 4% SPE-containing specimens and the GIC control group ranged from 108.7MPa to 141.1MPa for CS and from 8.2MPa to 12.5MPa for DTS. The 1% SPE-containing specimens were not different in physical properties compared to the control GIC specimens; the 2% SPE-containing specimens were statistically slightly less strong (p<0.05), but within an acceptable range. As compared with pure GIC the antimicrobial properties of the SPE-containing specimens were increased significantly (p<0.01). It has been found up to a 2-fold increased inhibition compared to the GIC with increasing concentrations of SPE. For most microorganisms tested the SPE group inhibited less than Chlorhexidine, but significantly better than pure GIC (p<0.01). CONCLUSION: SPE could be a promising natural material as an additive to GICs. Further studies should include in vivo tests and other antimicrobial and physical properties of this combination.