Determination of the Terbium-152 half-life from mass-separated samples from CERN-ISOLDE and assessment of the radionuclide purity.

Terbium-152 is one of four terbium radioisotopes that together form a potential theranostic toolbox for the personalised treatment of tumours. As 152 Tb decay by positron emission it can be utilised for diagnostics by positron emission tomography. For use in radiopharmaceuticals and for activity measurements by an activity calibrator a high radionuclide purity of the material and an accurate and precise knowledge of the half-life is required. Mass-separation and radiochemical purification provide a production route of high purity 152Tb. In the current work, two mass-separated samples from the CERN-ISOLDE facility have been assayed at the National Physical Laboratory to investigate the radionuclide purity. These samples have been used to perform four measurements of the half-life by three independent techniques: high-purity germanium gamma-ray spectrometry, ionisation chamber measurements and liquid scintillation counting. From the four measurement campaigns a half-life of 17.8784(95) h has been determined. The reported half-life shows a significant difference to the currently evaluated half-life (ζ-score = 3.77), with a relative difference of 2.2 % and an order of magnitude improvement in the precision. This work also shows that under controlled conditions the combination of mass-separation and radiochemical separation can provide high-purity 152Tb.

Does tranexamic acid reliably reduce blood loss in proximal femur fracture surgery?

PURPOSE: The aim of our study was to investigate the use of tranexamic acid in patients with proximal femoral fractures and compare the total blood loss, transfusion rates, complications, and the application method. METHODS: A retrospective single center cohort study (level I trauma center) with 1479 patients treated operatively for a proximal femoral fracture between January 2016 and June 2020 was performed. 1 g of tranexamic acid was applied (systemic, topic or combined application). Patient data, surgical procedure, complications, and mortality were assessed. Hemoglobin levels, blood loss and transfusion rates for patients with and without tranexamic acid and the application methods were compared. RESULTS: 667 femoral neck fractures, 701 pertrochanteric and 109 subtrochanteric fractures were included. Mean age was 80.8 years. 274 patients received tranexamic acid. At admission average hemoglobin was 12.2 g/l. Hemoglobin drop postoperatively was less after tranexamic acid (9.72 vs. 9.35 g/dl). Transfusion rates were lowered significantly by 17.1% after tranexamic acid. Blood loss was reduced for all patients after tranexamic acid independent of fracture morphology. The combination of 1 g i.v. and 1 g topical-applied tranexamic acid seems to be more effective. Complication rates did not differ. CONCLUSION: Tranexamic acid is effective in reducing blood loss and transfusion rates, without increasing the risk of thromboembolic events after proximal femoral fractures. For open reduction and nailing and arthroplasty in fracture setting combined topical and single i.v. application seems most effective and closed reduction with nailing can be treated by single dose i.v. application of 1 g tranexamic acid.

Half-life determination of 155Tb from mass-separated samples produced at CERN-MEDICIS.

Terbium-155 has been identified for its potential for single-photon emission computed tomography (SPECT) in nuclear medicine. For activity measurements, an accurate and precise half-life of this radionuclide is required. However, the currently evaluated half-life of 5.32(6) d with a relative standard uncertainty of 1.1% determines the precision possible. Limited literature for the half-life measurements of this radionuclide is available and all reported investigations are prior to 1970. Further measurements are therefore needed to confirm the accuracy and improve the precision of the half-life for its use in the clinical setting. Two samples produced and mass separated at the CERN-MEDICIS facility have been measured at the National Physical Laboratory by two independent techniques: liquid scintillation counting and high-purity germanium gamma-ray spectrometry. A half-life of 5.2346(36) d has been determined from the weighted mean of the half-lives determined by the two techniques. The half-life reported in this work has shown a relative difference of 1.6% to the currently evaluated half-life and has vastly improved the precision.

Pedobarography shows no differences in gait after talar fractures.

BACKGROUND: Fractures of the talus often lead to permanent restrictions of the affected limb. Possible alterations after these fractures in gait have not been evaluated yet. OBJECTIVE: To evaluate possible alterations of gait by pedybarography after talar fractures. METHODS: We conducted a retrospective single-centre study at a level I trauma center. Twenty patients with operatively treated talar fractures were followed up. Objective and subjective function of the ankle was measured using range of motion, clinical scores and dynamic pedobarography (emed-M; Novel, Germany). RESULTS: There were 11 talar neck and 9 talar body fractures. All patients received screw fixation. There was a significant reduction in range of motion. The outcome was moderate to satisfying and the severity of the injury correlated with the clinical outcome and the range of motion. The presence of posttraumatic arthritis and joint incongruity lead to a decreased function of ankle and subtalar joint and resulted in a worse clinical outcome. AVN rate was associated to initial displacement. Dynamic pedobarography showed no significant changes in gait pattern. CONCLUSIONS: Fractures of the talus lead to dissatisfaction, pain and malfunction. However, a change in gait pattern could not be proved.

The first official measurement of 11C in the SIRTI.

In the summer of 2017, the Système International de Référence Transfer Instrument (SIRTI) of the Bureau International des Poids et Mesures (BIPM) was hosted by the National Research Council of Canada (NRC) in Ottawa, Canada. This SIRTI visit was unique in many aspects. It was the first visit of the SIRTI to Canada. NRC was the first National Metrological Institute (NMI) to perform comparisons of four isotopes (99mTc, 18F, 64Cu and 11C) during a single two-week period. Finally, this was the first official measurement of 11C in the SIRTI. The NRC had performed a primary standardization of 11C in February of 2017 and calibrated its Secondary Standard Ionizing Radiation Chamber System (SSIRCS) in preparation for the SIRTI comparison. Two primary Liquid Scintillation methods (CIEMAT/NIST and TDCR) were employed and the results agreed. The stock material was received from a local cyclotron in the form of a 11C-labelled sodium acetate (NaC2H3O2). Three ampoules were prepared for the purposes of comparison; one concentrated from the bulk material and two derived from a single dilution. Some inconsistency was evident due to a weighing problem for one of the ampoules containing the diluted solution, whose measurements were excluded from the analysis. The other two ampoules' results were consistent within their respective uncertainties. The SIRTI was very stable and the final BIPM report will detail the stability checks, performance and behaviour of the SIRTI during its measurement campaign in Canada. There is still no Key Comparison Reference Value (KCRV) for 11C as NRC is the first participant. However, during a test of the SIRTI at NPL in 2014, an equivalent SIRTI activity was measured as 9.87(5) kBq which was consistent with MonteCarlo predictions for 11C in the SIRTI of 9.867(15) kBq. The NRC SIRTI equivalent activity for 11C agrees within uncertainty with these results. This offers encouragement to other NMIs to request a 11C comparison given the consistency of experimental results from NRC and test results from the National Physical Laboratory, UK (NPL) and the BIPM. Finally a half-life measurement was determined from the NRC measurement of multiple half-lives of a 11C ampoule and was found to be 20.332(40)min. From the SIRTI measurements at NRC, the half-life was derived as 20.328(13) min. This is smaller but consistent with the DDEP recommended value of 20.361(23)min.

Activity measurements and determination of nuclear decay data of 166Ho in the MRTDosimetry project.

Holmium-166 is a high-energy ß--emitter radionuclide (~ 1.8 MeV) with a short half-life (~26.8h) that offers great potential as an alternative to 90Y for the treatment of liver cancer based on radioembolization. The possibility of quantitative Single Photon Emission Computed Tomography (SPECT) imaging of the main γ-ray emission at 80.6 keV, in addition to strong paramagnetic properties suitable for Magnetic Resonance Imaging (MRI), complement this therapeutic potential. The present paper describes the measurements carried out in three European radionuclide metrology laboratories for primary standardization of 166Ho and new determinations of X- and γ-ray photon-emission intensities in the framework of the European EMPIR project MRTDosimetry. New half-life measurements were also performed.

The potential radio-immunotherapeutic α-emitter 227Th - part II: Absolute γ-ray emission intensities from the excited levels of 223Ra.

At the time of publication, radiopharmaceuticals labelled with thorium-227 are in clinical trials in Europe for the treatment of various types of cancer. In part I of this two-part series the primary standardisation of an aqueous solution of 227Th was reported. In part II, the activity derived from the recommended absolute γ-ray emission intensities have been compared to that from the primary standardisation techniques. This comparison showed a negative bias of 4% in the determined activity per unit mass with an 11% spread in the activities determined for the eight most intense γ-ray emissions (Iγ > 1%) from the 227Th α decay. Using the standardised 227Th, measurements of the characteristic γ-ray emissions from the 223Ra excited states were made using a calibrated HPGe γ-ray spectrometer. This has enabled the absolute intensities of 70 γ ray emissions from the 227Th α-decay to be experimentally determined. A significant improvement over the precision of the recommended normalisation scaling factor has been made, with a value of 12.470 (35) % determined. Typically, the precision of the intensities has been improved by an order of magnitude or greater than current recommended values. The correlation matrices for pairs of the most intense γ-ray emission intensities are presented.

The potential radio-immunotherapeutic α-emitter 227Th - part I: Standardisation via primary liquid scintillation techniques and decay progeny ingrowth measurements.

Thorium-227 is a potential therapeutic radionuclide for applications in targeted α-radioimmunotherapy for the treatment of various types of cancer. To provide nuclear medicine departments involved in Phase I clinical trials traceability to the SI unit of radioactivity (Bq), a standardisation of a radiochemically pure 227Th aqueous solution has been performed at the National Physical Laboratory. This was achieved via two primary liquid scintillation (LS) techniques -4π(LS)-γ digital coincidence counting (DCC) and 4π LS counting. These absolute techniques were supported by the indirect determination of the 227Th activity via the measurement of the ingrowth and decay rate of the decay progeny by both ionisations chambers and high purity germanium (HPGe) gamma-ray spectrometry. The results of the primary techniques were found to be consistent, both with each other (zeta score = 1.1) and to the decay progeny ingrowth measurements. An activity per unit mass of 20.726 (51) kBq g-1 was determined for the solution. A procedure has been developed that provided an effective separation of the 227Th from its decay progeny, which was shown by the effective time zero of the 227Th-223Ra nuclear chronometer measured by HPGe gamma-ray spectrometry.

Quantitative imaging, dosimetry and metrology; Where do National Metrology Institutes fit in?

In External Beam Radiotherapy, National Metrology Institutes (NMIs) play a critical role in the delivery of accurate absorbed doses to patients undergoing treatment. In contrast for nuclear medicine the role of the NMI is less clear and although significant work has been done in order to establish links for activity measurement, the calculation of administered absorbed doses is not traceable in the same manner as EBRT. Over recent decades the use of novel radiolabelled pharmaceuticals has increased dramatically. The limitation of secondary complications due to radiation damage to non-target tissue has historically been achieved by the use of activity escalation studies during clinical trials and this in turn has led to a chronic under dosing of the majority of patients. This paper looks to address the difficulties in combining clinical everyday practice with the grand challenges laid out by national metrology institutes to improve measurement capability in all walks of life. In the life sciences it can often be difficult to find the correct balance between pure research and practical solutions to measurement problems, and this paper is a discussion regarding these difficulties and how some NMIs have chosen to tackle these issues. The necessity of establishing strong links to underlying standards in the field of quantitative nuclear medicine imaging is highlighted. The difficulties and successes of current methods for providing traceability in nuclear medicine are discussed.

Activity measurements of the radionuclides 18F and 64Cu for the NIST, USA in the ongoing comparisons BIPM.RI(II)-K4.F-18 and BIPM.RI(II)-K4.Cu-64.

In 2016, comparisons of activity measurements of 18F and 64Cu using the Transfer Instrument of the International Reference System (SIRTI) took place at the National Institute of Standards and Technology (NIST, USA). This is the first SIRTI comparison for 64Cu. Ampoules containing about 27 kBq of 18F and 100 kBq of 64Cu solutions were measured in the SIRTI for about 5 and 1.5 half-lives, respectively. The NIST standardized the activity in the ampoules by ionization chamber measurements traceable to 4π(LS)ß-γ anticoincidence measurements. The comparisons, identifiers BIPM.RI(II)-K4.F-18 and BIPM.RI(II)-K4.Cu-64, are linked to the corresponding BIPM.RI(II)-K1.F-18 and BIPM.RI(II)-K1.Cu-64 comparisons and degrees of equivalence with the respective key comparison reference values have been evaluated. The NIST replaces its earlier degree of equivalence for 18F obtained in the frame of the CCRI(II)-K3.F-18 comparison in 2001.

Gamma camera calibration and validation for quantitative SPECT imaging with (177)Lu.

Over the last years (177)Lu has received considerable attention from the clinical nuclear medicine community thanks to its wide range of applications in molecular radiotherapy, especially in peptide-receptor radionuclide therapy (PRRT). In addition to short-range beta particles, (177)Lu emits low energy gamma radiation of 113keV and 208keV that allows gamma camera quantitative imaging. Despite quantitative cancer imaging in molecular radiotherapy having been proven to be a key instrument for the assessment of therapeutic response, at present no general clinically accepted quantitative imaging protocol exists and absolute quantification studies are usually based on individual initiatives. The aim of this work was to develop and evaluate an approach to gamma camera calibration for absolute quantification in tomographic imaging with (177)Lu. We assessed the gamma camera calibration factors for a Philips IRIX and Philips AXIS gamma camera system using various reference geometries, both in air and in water. Images were corrected for the major effects that contribute to image degradation, i.e. attenuation, scatter and dead- time. We validated our method in non-reference geometry using an anthropomorphic torso phantom provided with the liver cavity uniformly filled with (177)LuCl3. Our results showed that calibration factors depend on the particular reference condition. In general, acquisitions performed with the IRIX gamma camera provided good results at 208keV, with agreement within 5% for all geometries. The use of a Jaszczak 16mL hollow sphere in water provided calibration factors capable of recovering the activity in anthropomorphic geometry within 1% for the 208keV peak, for both gamma cameras. The point source provided the poorest results, most likely because scatter and attenuation correction are not incorporated in the calibration factor. However, for both gamma cameras all geometries provided calibration factors capable of recovering the activity in anthropomorphic geometry within about 10% (range -11.6% to +7.3%) for acquisitions at the 208keV photopeak. As a general rule, scatter and attenuation play a much larger role at 113keV compared to 208keV and are likely to hinder an accurate absolute quantification. Acquisitions of only the (177)Lu main photopeak (208keV) are therefore recommended in clinical practice. Preliminary results suggest that the gamma camera calibration factor can be assessed with a standard uncertainty below (or of the order of) 3% if activity is determined with equipment traceable to primary standards, accurate volume measurements are made, and an appropriate chemical carrier is used to allow a homogeneous and stable solution to be used during the measurements.

Comparison of (18)F activity measurements at the VNIIM, NPL and the ENEA-INMRI using the SIRTI of the BIPM.

In 2014, the first three comparisons of activity measurements of (18)F were carried out at the VNIIM, NPL and the ENEA-INMRI using the BIPM's Transfer Instrument of the International Reference System. The transfer instrument and the NMIs primary measurement methods are briefly described. The degrees of equivalence with the key comparison reference value defined in the frame of the corresponding SIR comparison have been evaluated. World-wide consistency of activity measurements of (18)F is demonstrated.

Measurement of the (109)Cd half-life.

A new determination of the (109)Cd half-life was made by a time series of measurements of an aqueous sample using a re-entrant type ionisation chamber. The measurement campaign covered a period of 6 years or approximately 4.7 half-lives of (109)Cd. The resulting value of 462.1 (3) days is in good agreement with the recently published values of 462.29 (30) days and 462.3 (8) days. This new half-life determination will allow evaluators to specify a recommended value of the (109)Cd half-life making it more accurate and precise.

Direct measurement of the half-life of (223)Ra.

Radioactive decay half-life measurements of (223)Ra, a member of the (235)U naturally occurring radioactive decay series, have been performed of a radiochemically pure solution with an ionisation chamber. The radioactive decay of (223)Ra was followed for 50 days, approximately 4.4 half-lives. The deduced half-life of (223)Ra was found to be 11.4358 (28) days, supporting the other published direct measurements. A detailed uncertainty budget is presented. A new evaluation of the published half-life values was performed, indicating significant variation across the existing published values, suggesting that further measurements of the half-life of (223)Ra are required. A new evaluated half-life has been calculated using a power moderated weighted mean of selected experimental values, with a new value of the recommended half-life for (223)Ra of 11.4354 (17) days.

Evaluation of circulating cathodic antigen (CCA) urine-cassette assay as a survey tool for Schistosoma mansoni in different transmission settings within Bugiri District, Uganda.

Diagnosis of schistosomiasis at the point-of-care (POC) is a growing topic in neglected tropical disease research. There is a need for diagnostic tests which are affordable, sensitive, specific, user-friendly, rapid, equipment-free and delivered to those who need it, and POC is an important tool for disease mapping and guiding mass deworming. The aim of present study was to evaluate the relative diagnostic performance of two urine-circulating cathodic antigen (CCA) cassette assays, one commercially available and the other in experimental production, against results obtained using the standard Kato-Katz faecal smear method (six thick smears from three consecutive days), as a 'gold-standard', for Schistosoma mansoni infection in different transmission settings in Uganda. Our study was conducted among 500 school children randomly selected across 5 schools within Bugiri district, adjacent to Lake Victoria in Uganda. Considering results from the 469 pupils who provided three stool samples for the six Kato-Katz smears, 293 (76%) children had no infection, 109 (23%) were in the light intensity category, while 42 (9%) and 25 (5%) were in the moderate and heavy intensity categories respectively. Following performance analysis of CCA tests in terms of sensitivity, specificity, negative and positive predictive values, overall performance of the commercially available CCA test was more informative than single Kato-Katz faecal smear microscopy, the current operational field standard for disease mapping. The current CCA assay is therefore a satisfactory method for surveillance of S. mansoni in an area where disease endemicity is declining due to control interventions. With the recent resolution on schistosomiasis elimination by the 65th World Health Assembly, the urine POC CCA test is an attractive tool to augment and perhaps replace the Kato-Katz sampling within ongoing control programmes.

Migration to new ampoule types for the NPL secondary standard ionisation chambers.

As the pre-calibrated sample containers used for activity assay in the two NPL secondary standards ionisation chambers are being phased out, suitable replacements have been identified. Characterisation checks have been carried out on the new ISO ampoules and a long-term recalibration schedule has been devised. Around 40 calibration factors have been determined so far and comparison of ion chamber responses for the two ampoule types showed variations of up to 7% for low energy photon emitting radionuclides.

Notes on the use of urine-CCA dipsticks for detection of intestinal schistosomiasis in preschool children.

Urine-dipstick diagnostic tests that detect schistosome circulating cathodic antigen (CCA) have the potential to provide more sensitive and rapid testing for intestinal schistosomiasis in field-based surveys; this is especially so when examining preschool children, from whom it may be difficult to obtain consecutive stool samples. To assess the performance of urine dipsticks, 569 preschool children from four villages along the shore of Lake Albert, Uganda, were screened for Schistosoma mansoni by Kato-Katz (K-K) examination of a single stool sample and CCA urine dipsticks. The prevalence of infection was 32.2% by K-K and 40.0% by CCA tests. Sensitivity and specificity were influenced by whether 'trace' results from the CCA test were characterised as positive or negative for infection with S. mansoni; ambiguities around this issue need to be resolved. Nevertheless, the CCA test showed particular promise for routine epidemiological screening in this setting.

Efficacy of praziquantel syrup versus crushed praziquantel tablets in the treatment of intestinal schistosomiasis in Ugandan preschool children, with observation on compliance and safety.

Preschool children (aged ≤5 years) have so far been overlooked by mass treatment campaigns targeting schistosomiasis, even though praziquantel (PZQ) has been shown to be well tolerated and effective within this age group. The WHO provided the Ugandan Ministry of Health with a syrup formulation of PZQ with the aim of assessing its safety and efficacy in comparison with crushed PZQ tablets for the treatment of intestinal schistosomiasis in preschool children. This study included 1144 preschool children randomly assigned to two treatment arms (PZQ syrup or crushed PZQ tablet) regardless of infection status for direct comparison. Diagnosis of intestinal schistosomiasis was assessed using single stool sample, double Kato-Katz smear examinations. Parasitological cure was assessed 3 weeks after treatment. The observed cure rate was 80.9% for the PZQ syrup arm and 81.7% for the crushed PZQ tablet arm, with egg reduction rates of 86.1% and 89.0%, respectively. Pre-treatment infection intensity was observed to influence cure rates significantly, with cure rates of 88.6% for light infections, 74.5% for moderate infections and 67.4% for heavy infections. No significant difference was found in non-compliance between the PZQ syrup (11.1%) and crushed PZQ tablet (14.7%) arms. PZQ syrup and crushed PZQ tablets have very similar efficacies in the treatment of intestinal schistosomiasis in preschool children.

The global burden of neglected tropical diseases.

The first comprehensive study on the global burden of disease and risk factors was commissioned by the World Bank in 1992. A follow-up study was performed in 2005, and another iteration was commissioned by the World Health Organization in 2010, due for publication in 2011. The author suggests that the global burden of neglected tropical diseases (NTDs) has been seriously underestimated. The way forward is the integration of control efforts, with programmes coming together to deliver a package of drugs against NTDs. Barriers to continent-wide coverage of drugs against NTDs are political will (missing in those countries with poor governance), funding (approximately half of the $1.5-2 billion is needed) and human resources. However, if the donors who give so much to malaria, tuberculosis and human immunodeficiency virus would share just 10% of the amount allocated to the big three, the most common NTDs could become diseases of the past. This could well happen within 7 years, and the targets of GET2020 (Global Elimination of Trachoma by 2020) to eliminate trachoma and GAELF (the Global Alliance to Eliminate Lymphatic Filariasis) to eliminate lymphatic filariasis by 2020 are achievable.

Mirazid shows insignificant activity against ovine fascioliasis.

In a recent study, the fasciolicidal activity of Mirazid (a myrrh-derived drug) and its effect on the function and histopathology of host liver were investigated in Egyptian sheep, with triclabendazole (TCBZ) used as the positive control. Sheep were infected with metacercariae (150/animal) and treated 3 months later, either with Mirazid (10 mg/kg/day for six consecutive days) or TCBZ (a single dose of 10 mg/kg), or left untreated, as controls. When the animals were killed 4 weeks after the end of treatment, no Fasciola flukes or eggs could be found in the animals given TCBZ but the number of flukes found in the Mirazid-treated animals was only 6% lower than that recorded in the untreated sheep (a statistically insignificant difference). In terms of their Fasciola egg loads, serum concentrations of hepatic enzymes and hepatic histopathological changes, the Mirazid-treated sheep appeared very similar to the untreated, infected animals. The TCBZ-treated animals, in contrast, showed remarkably little evidence of hepatic pathology. It therefore appears that, in the treatment of ovine fascioliasis, at least some batches of Mirazid have little, if any, value.