Updating M6 pregnancy of unknown location risk-prediction model including evaluation of clinical factors.

OBJECTIVES: Ectopic pregnancy (EP) is a major high-risk outcome following a pregnancy of unknown location (PUL) classification. Biochemical markers are used to triage PUL as high vs low risk to guide appropriate follow-up. The M6 model is currently the best risk-prediction model. We aimed to update the M6 model and evaluate whether performance can be improved by including clinical factors. METHODS: This prospective cohort study recruited consecutive PUL between January 2015 and January 2017 at eight units (Phase 1), with two centers continuing recruitment between January 2017 and March 2021 (Phase 2). Serum samples were collected routinely and sent for ß-human chorionic gonadotropin (ß-hCG) and progesterone measurement. Clinical factors recorded were maternal age, pain score, bleeding score and history of EP. Based on transvaginal ultrasonography and/or biochemical confirmation during follow-up, PUL were classified subsequently as failed PUL (FPUL), intrauterine pregnancy (IUP) or EP (including persistent PUL (PPUL)). The M6 models with (M6P ) and without (M6NP ) progesterone were refitted and extended with clinical factors. Model validation was performed using internal-external cross-validation (IECV) (Phase 1) and temporal external validation (EV) (Phase 2). Missing values were handled using multiple imputation. RESULTS: Overall, 5473 PUL were recruited over both phases. A total of 709 PUL were excluded because maternal age was < 16 years or initial ß-hCG was ≤ 25 IU/L, leaving 4764 (87%) PUL for analysis (2894 in Phase 1 and 1870 in Phase 2). For the refitted M6P model, the area under the receiver-operating-characteristics curve (AUC) for EP/PPUL vs IUP/FPUL was 0.89 for IECV and 0.84-0.88 for EV, with respective sensitivities of 94% and 92-93%. For the refitted M6NP model, the AUCs were 0.85 for IECV and 0.82-0.86 for EV, with respective sensitivities of 92% and 93-94%. Calibration performance was good overall, but with heterogeneity between centers. Net Benefit confirmed clinical utility. The change in AUC when M6P was extended to include maternal age, bleeding score and history of EP was between -0.02 and 0.01, depending on center and phase. The corresponding change in AUC when M6NP was extended was between -0.01 and 0.03. At the 5% threshold to define high risk of EP/PPUL, extending M6P altered sensitivity by -0.02 to -0.01, specificity by 0.03 to 0.04 and Net Benefit by -0.005 to 0.006. Extending M6NP altered sensitivity by -0.03 to -0.01, specificity by 0.05 to 0.07 and Net Benefit by -0.005 to 0.006. CONCLUSIONS: The updated M6 model offers accurate diagnostic performance, with excellent sensitivity for EP. Adding clinical factors to the model improved performance in some centers, especially when progesterone levels were not suitable or unavailable. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

External validation of models to predict the outcome of pregnancies of unknown location: a multicentre cohort study.

OBJECTIVE: To validate externally five approaches to predict ectopic pregnancy (EP) in pregnancies of unknown location (PUL): the M6P and M6NP risk models, the two-step triage strategy (2ST, which incorporates M6P), the M4 risk model, and beta human chorionic gonadotropin ratio cut-offs (BhCG-RC). DESIGN: Secondary analysis of a prospective cohort study. SETTING: Eight UK early pregnancy assessment units. POPULATION: Women presenting with a PUL and BhCG >25 IU/l. METHODS: Women were managed using the 2ST protocol: PUL were classified as low risk of EP if presenting progesterone ≤2 nmol/l; the remaining cases returned 2 days later for triage based on M6P. EP risk ≥5% was used to classify PUL as high risk. Missing values were imputed, and predictions for the five approaches were calculated post hoc. We meta-analysed centre-specific results. MAIN OUTCOME MEASURES: Discrimination, calibration and clinical utility (decision curve analysis) for predicting EP. RESULTS: Of 2899 eligible women, the primary analysis excluded 297 (10%) women who were lost to follow up. The area under the ROC curve for EP was 0.89 (95% CI 0.86-0.91) for M6P, 0.88 (0.86-0.90) for 2ST, 0.86 (0.83-0.88) for M6NP and 0.82 (0.78-0.85) for M4. Sensitivities for EP were 96% (M6P), 94% (2ST), 92% (N6NP), 80% (M4) and 58% (BhCG-RC); false-positive rates were 35%, 33%, 39%, 24% and 13%. M6P and 2ST had the best clinical utility and good overall calibration, with modest variability between centres. CONCLUSIONS: 2ST and M6P performed best for prediction and triage in PUL. TWEETABLE ABSTRACT: The M6 model, as part of a two-step triage strategy, is the best approach to characterise and triage PULs.

Diagnostic accuracy of functional imaging modalities for chondrosarcoma: A systematic review and meta-analysis.

INTRODUCTION: The distinction between low-grade (grade 1) chondrosarcoma and its benign counterparts can be challenging. This systematic review aims to quantify the diagnostic accuracies of all functional imaging modalities used in the diagnosis of chondrosarcoma. METHODS: Medline and Embase were searched in February 2019. We included studies of either retrospective or prospective design if the results of functional scans were compared with pre-determined reference standards. Studies had to be primary diagnostic reports on patients with chondral tumours at first diagnosis. Two review authors independently performed study selection, extracted data and assessed the methodological quality. We calculated diagnostic accuracy measures for each included study. RESULTS: Four functional imaging modalities were identified across thirteen studies that met the inclusion criteria. 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography (FDG-PET) was a sensitive and specific test. Technetium-99 m with methylene diphosphonate (Tc-99 m MDP) had an overall low specificity of 4%. Thallium-201 scintigraphy demonstrated high positive predictive values across the studies. The negative predictive values of Technetium-99 m pentavalent dimercaptosuccinic acid (Tc-99 m DMSA (V)) were consistently 100%. CONCLUSIONS: Low-grade chondrosarcomas continue to pose a diagnostic dilemma. FDG-PET demonstrated superior diagnostic accuracy compared to Tc-99 m MDP, Thallium-201 and Tc-99 m DMSA (V). Characteristic uptake patterns of Thallium-201 and Tc-99 m DMSA (V) may provide additional metabolic information to guide the diagnosis in this challenging group of tumours.

Photodynamic therapy platform based on localized delivery of photosensitizer by vaterite submicron particles.

The elaboration of biocompatible and biodegradable carriers for photosensitizer targeted delivery is one of the most promising approaches in a modern photodynamic therapy (PDT). This approach is aimed at reducing sides effects connected with incidental toxicity in healthy tissue whilst also enhancing drug accumulation in the tumour area. In the present work, Photosens-loaded calcium carbonate (CaCO3) submicron particles in vaterite modification are proposed as a novel platform for anticancer PDT. Fast penetration of the carriers (0.9±0.2µm in diameter) containing 0.12% (w/w) of the photosensitizer into NIH3T3/EGFP cells is demonstrated. The captured particles provide the dye localization inside the cell increasing its local concentration, compared with "free" Photosens solution which is uniformly distributed throughout the cell. The effect of photosensitizer encapsulation into vaterite submicron particles on cell viability under laser irradiation (670nm, 19mW/cm(2), 10min) is discussed in the work. As determined by a viability assay, the encapsulation renders Photosens more phototoxic. By this means, CaCO3 carriers allow improvement of the photosensitizer effectiveness supposing, therefore, the reduction of therapeutic dose. Summation of these effects with the simplicity, upscalability and cheapness of fabrication, biocompatibility and high payload ability of the vaterite particles hold out the prospect of a novel PDT platform.

The management of cytotoxic chemotherapy extravasation: a systematic review of the literature to evaluate the evidence underpinning contemporary practice.

Management of cytotoxic drug extravasation remains contentious, with differing views on the most effective management strategy. With the increasing drive to provide effective, evidence-based healthcare, while ensuring the patient experience of the treatment provided plays a significant part in the development of clinical practice guidelines, the purpose of this literature review was to both critically analyse the quality of evidence that underpins contemporary practice and to determine if the patient experience is taken into account. A literature search was undertaken sourcing publications from the 1960s to July 2014 identifying all studies detailing strategies aimed at preventing the need for surgical debridement and all studies evaluating extravasation management from the patient's perspective. No conclusive evidence was found to suggest one clinical strategy as more effective than the other. No studies were identified that evaluated outcome from the patient's perspective. It is therefore suggested that outcomes-based research should underpin contemporary extravasation management guidelines to determine what the final outcome or 'end result' is and how this impacts on the patient and that the current lack of research into the patient experience of extravasation management is an area that needs to be addressed.

Renal Autotransplantation in Lynch Syndrome: A Viable Option in a Patient With Contralateral Metachronous Ureteral Cancer.

The success of human kidney allotransplantation was realized over six decades ago. First described 50 years ago, renal autotransplantation has been utilized sparingly as a salvage procedure for patients at risk of losing renal function, either from a benign or malignant condition. While classically associated with colorectal malignancies, Lynch syndrome also carries a small yet significant risk for the development of ureteral carcinoma. For these patients who develop chronic kidney disease, allotransplantation may not be an option due to the lifelong risk of several malignancies. We report the first known case of renal autotransplantation in a patient with metachronous ureteral cancer due to Lynch syndrome.

Interventional radiology virtual simulator for liver biopsy.

PURPOSE: Training in Interventional Radiology currently uses the apprenticeship model, where clinical and technical skills of invasive procedures are learnt during practice in patients. This apprenticeship training method is increasingly limited by regulatory restrictions on working hours, concerns over patient risk through trainees' inexperience and the variable exposure to case mix and emergencies during training. To address this, we have developed a computer-based simulation of visceral needle puncture procedures. METHODS: A real-time framework has been built that includes: segmentation, physically based modelling, haptics rendering, pseudo-ultrasound generation and the concept of a physical mannequin. It is the result of a close collaboration between different universities, involving computer scientists, clinicians, clinical engineers and occupational psychologists. RESULTS: The technical implementation of the framework is a robust and real-time simulation environment combining a physical platform and an immersive computerized virtual environment. The face, content and construct validation have been previously assessed, showing the reliability and effectiveness of this framework, as well as its potential for teaching visceral needle puncture. CONCLUSION: A simulator for ultrasound-guided liver biopsy has been developed. It includes functionalities and metrics extracted from cognitive task analysis. This framework can be useful during training, particularly given the known difficulties in gaining significant practice of core skills in patients.

ImaGiNe Seldinger: first simulator for Seldinger technique and angiography training.

In vascular interventional radiology, procedures generally start with the Seldinger technique to access the vasculature, using a needle through which a guidewire is inserted, followed by navigation of catheters within the vessels. Visual and tactile skills are learnt in a patient apprenticeship which is expensive and risky for patients. We propose a training alternative through a new virtual simulator supporting the Seldinger technique: ImaGiNe (imaging guided interventional needle) Seldinger. It is composed of two workstations: (1) a simulated pulse is palpated, in an immersive environment, to guide needle puncture and (2) two haptic devices provide a novel interface where a needle can direct a guidewire and catheter within the vessel lumen, using virtual fluoroscopy. Different complexities are provided by 28 real patient datasets. The feel of the simulation is enhanced by replicating, with the haptics, real force and flexibility measurements. A preliminary validation study has demonstrated training effectiveness for skills transfer.

The efficacy of saline washout technique in the management of exfoliant and vesicant chemotherapy extravasation: a historical case series report.

This report presents the results from a historical case series of cytotoxic drug extravasations managed by saline washout; its purpose is to assess the efficacy of the procedure based on patient outcome. Eighty-nine patients were identified as having experienced a vesicant or exfoliant extravasation from incident reports filed over a 10-year period, from 1 April 2001 to 31 March 2011. Outcome was measured against the need for further surgical treatment being required. Of the 89 cases assessed for efficacy of saline washout one patient experienced a wound infection, which was treated effectively with oral antibiotics. There were no other complications reported and no patients required further treatment with surgical debridement. The majority of patients had no deferral of treatment as chemotherapy could be continued in their unaffected arm immediately following saline washout procedure. For patients where cannulation in their opposite arm for continuation of treatment was not advisable chemotherapy was delayed between 3 and 7 days. Hospitalisation as a result of the extravasation or subsequent treatment was not required in any of the 89 cases. Results indicate that saline washout technique is a safe and effective management strategy for the treatment of both vesicant and exfoliant chemotherapy extravasation.

A sensor for needle puncture force measurement during interventional radiological procedures.

Computer-based simulation for interventional radiology training has attracted increasing attention in recent years because of its potential to train remotely from patients and to provide objective assessment of proficiency. Yet developing a high fidelity simulator with realistic tactile feedback requires accurate knowledge of forces exerted on medical devices during interventional radiology procedures. This paper presents the development and validation of a force sensor for the measurement of axial forces generated during needle, and combined cannula/trocar, puncture procedures in patients. In order to assess the performance of this sensor, in vitro measurements were obtained using needle penetration of porcine liver, kidney and muscle. The results were compared with forces measured by means of a tensile tester. Calibration results showed that the force sensor has high sensitivity and linearity. Comparison of the force profiles obtained from the sensor and the tensile tester shows that good agreement was achieved in the in vitro studies for all the tissues tested. Preliminary clinical force measurements during arterial puncture and liver biopsy procedures have been performed in patients. An example of force recording for each procedure type is presented.

Survey of ophthalmic abnormalities in the labradoodle in the UK.

One-hundred and seventy-five labradoodles underwent slit-lamp biomicroscopy and direct and indirect ophthalmoscopy between January 2008 and December 2009. These examinations were performed at shows by the first author. In addition, labradoodle eye certificates from the 2008 and 2009 British Veterinary Association/Kennel Club/International Sheep Dog Society (BVA/KC/ISDS) Eye Scheme were analysed (n=260). The results of the examinations were reviewed, and all ophthalmic abnormalities were recorded. The prevalence of any abnormality was compared with that reported by the Eye Scheme and the KC during 2009 for the labrador retriever, miniature, toy and standard poodles. Multifocal retinal dysplasia (MRD) was identified in 20 labradoodles (4.6 per cent), and cataracts were identified in 16 labradoodles (3.7 per cent). The prevalence of MRD in labradoodles was significantly greater than in labrador retrievers (P<0.0001). There was no difference in the prevalence of cataract between labradoodles and labrador retrievers (P=0.4866). The results of this study suggest that MRD is a relatively common finding in the labradoodle population in the UK. Given such an apparent high prevalence of MRD, routine screening for hereditary eye disease before breeding is advised for this increasingly popular new crossbreed.

Virtual reality, ultrasound-guided liver biopsy simulator: development and performance discrimination.

OBJECTIVES: The aim of this article was to identify and prospectively investigate simulated ultrasound-guided targeted liver biopsy performance metrics as differentiators between levels of expertise in interventional radiology. METHODS: Task analysis produced detailed procedural step documentation allowing identification of critical procedure steps and performance metrics for use in a virtual reality ultrasound-guided targeted liver biopsy procedure. Consultant (n=14; male=11, female=3) and trainee (n=26; male=19, female=7) scores on the performance metrics were compared. Ethical approval was granted by the Liverpool Research Ethics Committee (UK). Independent t-tests and analysis of variance (ANOVA) investigated differences between groups. RESULTS: Independent t-tests revealed significant differences between trainees and consultants on three performance metrics: targeting, p=0.018, t=-2.487 (-2.040 to -0.207); probe usage time, p = 0.040, t=2.132 (11.064 to 427.983); mean needle length in beam, p=0.029, t=-2.272 (-0.028 to -0.002). ANOVA reported significant differences across years of experience (0-1, 1-2, 3+ years) on seven performance metrics: no-go area touched, p=0.012; targeting, p=0.025; length of session, p=0.024; probe usage time, p=0.025; total needle distance moved, p=0.038; number of skin contacts, p<0.001; total time in no-go area, p=0.008. More experienced participants consistently received better performance scores on all 19 performance metrics. CONCLUSION: It is possible to measure and monitor performance using simulation, with performance metrics providing feedback on skill level and differentiating levels of expertise. However, a transfer of training study is required.

A prototype percutaneous transhepatic cholangiography training simulator with real-time breathing motion.

PURPOSE: We present here a simulator for interventional radiology focusing on percutaneous transhepatic cholangiography (PTC). This procedure consists of inserting a needle into the biliary tree using fluoroscopy for guidance. METHODS: The requirements of the simulator have been driven by a task analysis. The three main components have been identified: the respiration, the real-time X-ray display (fluoroscopy) and the haptic rendering (sense of touch). The framework for modelling the respiratory motion is based on kinematics laws and on the Chainmail algorithm. The fluoroscopic simulation is performed on the graphic card and makes use of the Beer-Lambert law to compute the X-ray attenuation. Finally, the haptic rendering is integrated to the virtual environment and takes into account the soft-tissue reaction force feedback and maintenance of the initial direction of the needle during the insertion. RESULTS: Five training scenarios have been created using patient-specific data. Each of these provides the user with variable breathing behaviour, fluoroscopic display tuneable to any device parameters and needle force feedback. CONCLUSIONS: A detailed task analysis has been used to design and build the PTC simulator described in this paper. The simulator includes real-time respiratory motion with two independent parameters (rib kinematics and diaphragm action), on-line fluoroscopy implemented on the Graphics Processing Unit and haptic feedback to feel the soft-tissue behaviour of the organs during the needle insertion.

Association of severity of enteric granulomatous inflammation with disseminated Mycobacterium avium subspecies paratuberculosis infection and antemortem test results for paratuberculosis in dairy cows.

Disseminated infection (DI) of Mycobacterium avium subspecies paratuberculosis (MAP) in cattle may impair cow health, potentiate spread of disease, and is a potential food-safety risk. The objectives of this study were to determine the association between severity of histologic enteric lesions and the occurrence of DI, clinical signs, and positive fecal culture and serum ELISA results. Bacteriologic fecal culture and serum ELISA were performed on 40 dairy cows from MAP-infected herds. Cows were classified as having DI if MAP was isolated from any of 11 extra-intestinal tissues collected postmortem. A grade of 0-3, corresponding to the severity of histologically evident granulomatous inflammation was determined for sections of ileum, jejunum, mesenteric lymph node, and ileocolic lymph node. An overall intestinal inflammation (OII) grade of 0-3 was assigned to each cow. The proportion of cows with DI increased with tissue-specific lesion grade and OII grade. All cows with grade 3 inflammation in any single tissue had DI, however, some cows with DI had grade 1 inflammation or no lesions. In general, there was a positive association between OII grade and clinical signs, gross enteric lesions, and positive ELISA and fecal culture results. However, 12% of OII grade 0 cows had clinical signs (explained by other conditions recognized with necropsy), and the proportion of positive ELISA results was lower for OII grade 3 cows relative to grade 2 cows. Although MAP dissemination may occur early in the disease process, histopathology of intestinal tissues may be used to detect a substantial proportion of DI cows.

Physics-based virtual environment for training core skills in vascular interventional radiological procedures.

Recent years have seen a significant increase in the use of Interventional Radiology (IR) as an alternative to open surgery. A large number of IR procedures commences with needle puncture of a vessel to insert guidewires and catheters: these clinical skills are acquired by all radiologists during training on patients, associated with some discomfort and occasionally, complications. While some visual skills can be acquired using models such as the ones used in surgery, these have limitations for IR which relies heavily on a sense of touch. Both patients and trainees would benefit from a virtual environment (VE) conveying touch sensation to realistically mimic procedures. The authors are developing a high fidelity VE providing a validated alternative to the traditional apprenticeship model used for teaching the core skills. The current version of the CRaIVE simulator combines home made software, haptic devices and commercial equipments.

Repopulation of B-lymphocytes with restricted gene expression using haematopoietic stem cells engineered with lentiviral vectors.

B-lymphocytes play a key role in the pathogenesis of many immune-mediated diseases, such as autoimmune and atopic diseases. Therefore, targeting B-lymphocytes provides a rationale for refining strategies to treat such diseases for long-term clinical benefits and minimal side effects. In this study we describe a protocol for repopulating irradiated mice with B-lymphocytes engineered for restricted expression of transgenes using haematopoietic stem cells. A self-inactivating lentiviral vector, which encodes enhanced green fluorescence protein (EGFP) from the spleen focus-forming virus (SFFV) promoter, was used to generate new vectors that permit restricted EGFP expression in B-lymphocytes. To achieve this, the SFFV promoter was replaced with the B-lymphocyte-restricted CD19 promoter. Further, an immunoglobulin heavy chain enhancer (Emu) flanked by the associated matrix attachment regions (MARs) was inserted upstream of the CD19 promoter. Incorporation of the Emu-MAR elements upstream of the CD19 promoter resulted in enhanced, stable and selective transgene expression in human and murine B-cell lines. In addition, this modification permitted enhanced selective EGFP expression in B-lymphocytes in vivo in irradiated mice repopulated with transduced bone marrow haematopoietic stem cells (BMHSCs). The study provides evidence for the feasibility of targeting B-lymphocytes for therapeutic restoration of normal B-lymphocyte functions in patients with B-cell-related diseases.

Inflammation-inducible anti-TNF gene expression mediated by intra-articular injection of serotype 5 adeno-associated virus reduces arthritis.

BACKGROUND: The tumor necrosis factor (TNF)-alpha plays a central role in rheumatoid arthritis (RA) and current biotherapies targeting TNF-alpha have a major impact on RA treatment. The long-term safety concerns associated with the repetitive TNF blockade prompt optimization of therapeutic anti-TNF approaches. Since we recently demonstrated that intra-articular gene transfer using a recombinant adeno-associated virus serotype 5 (rAAV5) efficiently transduces arthritic joints, we evaluate its effect on collagen-induced arthritis (CIA) when encoding TNF antagonists. METHODS: Recombinant AAV5 vectors encoding the human TNFRp55 extracellular domain fused to the Fc region of mice IgG1 (TR1) or a small molecular weight dimeric human TNFRp75 extracellular domain (TR2), under two different promoters, the CMV or a chimeric NF-kappaB-based promoter inducible by inflammation, were injected into mouse CIA joints. RESULTS: Best protection against arthritis was obtained with the rAAV5 encoding the TR1, as reflected by delayed disease onset, decreased incidence and severity of joint damage. This effect was associated with a transient expression of the anti-TNF agent when expressed under a NF-kappaB-responsive promoter, only detectable during disease flare, while the antagonist expression was rapidly increased and stable when expressed from a CMV promoter. Importantly, using the intra-articular administration of the rAAV5-NF-kappaB-TR1 vector, we observed a striking correlation between local TR1 expression and inflammation. CONCLUSIONS: These findings strongly support the feasibility of improving the safety of anti-TNF approaches for the treatment of arthritis by local rAAV5-mediated gene expression under an inflammation-responsive promoter, able to provide a limited, transient and therapeutically relevant expression of anti-TNF compounds.