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.

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.

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.

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.

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.

Process evaluation of schistosomiasis control in Uganda, 2003 to 2006: perceptions, attitudes and constraints of a national programme.

Schistosomiasis is widespread in Uganda along large lakes and rivers with approximately 4 million people infected. Hookworm infections also prevalent throughout the country, while infections with Ascaris lumbricoides and Trichuris trichiura are mainly found in south-western Uganda. A national programme aimed at controlling morbidity due to these infections was launched in 2003. This article describes the perceptions, attitudes, constraints and experiences of those implementing the programme and those receiving the treatment. The study used qualitative data collected largely in two districts but also from 18 other districts implementing the programme. Results showed that mass treatment was perceived to be beneficial because the drugs make people feel better. However, side-effects of praziquantel (PZQ), the smell and size of the tablets and the use of height, not weight, to determine dose were raised as major factors discouraging people from taking the drug. Generally, most of the end-users were appreciative of the programme and were beginning to demand regular treatment. Nevertheless, intensive and sustained health education is still vital for improvement of treatment coverage, especially among the non-compliers. It was repeatedly highlighted that there is a need to stock PZQ in all health facilities in endemic areas. Provision of incentives to drug distributors and to involve as many stakeholders as possible in the planning phase were also raised by respondents. Lessons learned for the development and success of a helminth control programme at a national scale are discussed.

Present and future schistosomiasis control activities with support from the Schistosomiasis Control Initiative in West Africa.

Since 2004 the West African countries of Burkina Faso, Mali and Niger have implemented national schistosomiasis and soil-transmitted helminthiasis control programmes with financial and technical support from the Schistosomiasis Control Initiative (SCI). In the first three years of the control programmes, nearly 13.5 million doses of praziquantel and albendazole have been administered against schistosomiasis and soil-transmitted helminthiasis with coverage rates varying between 67.0% and 93.9%. These treatments have resulted in a reduction of the prevalence and intensity of Schistosoma infection in the sentinel cohorts that were set up to monitor and evaluate the national control programmes. The challenges currently faced by these national control programmes are the ability to maintain the reduction in morbidity achieved thus far due to the mass treatment campaigns and ensuring sustainability. For reinforcement of surveillance, the establishment of a geographical information system is suggested in order to contribute towards enhanced sustainability of these programmes. Our new working hypothesis is that targeted control accompanied by periodic mass treatment campaigns (every two to three years) can contribute to maintaining the low levels of morbidity achieved thus far. The implementation of integrated neglected tropical disease control programmes in these countries will provide means to ensure the financial sustainability of control activities for the years to come.

The Schistosomiasis Control Initiative (SCI): rationale, development and implementation from 2002-2008.

Schistosomiasis remains one of the most prevalent parasitic diseases in developing countries. After malaria, schistosomiasis is the most important tropical disease in terms of human morbidity with significant economic and public health consequences. Although schistosomiasis has recently attracted increased focus and funding for control, it has been estimated that less than 20% of the funding needed to control the disease in Africa is currently available. In this article the following issues are discussed: the rationale, development and objectives of the Schistosomiasis Control Initiative (SCI)-supported programmes; the management approaches followed to achieve implementation by each country; mapping, monitoring and evaluation activities with quantifiable impact of control programmes; monitoring for any potential drug resistance; and finally exit strategies within each country. The results have demonstrated that morbidity due to schistosomiasis has been reduced by the control programmes. While challenges remain, the case for the control of schistosomiasis has been strengthened by research by SCI teams and the principle that a national programme using 'preventive chemotherapy' can be successfully implemented in sub-Saharan Africa, whenever the resources are available. SCI and partners are now actively striving to raise further funds to expand the coverage of integrated control of neglected tropical diseases (NTDs) in sub-Saharan Africa.

Evaluation and application of potential schistosome-associated morbidity markers within large-scale mass chemotherapy programmes.

A primary objective of schistosomiasis control programmes is to achieve, and hence also demonstrate, a quantifiable reduction in schistosome-associated morbidity as a consequence of chemotherapeutic intervention. Inherent within such an objective, it is necessary to define and validate direct and indirect indicators of schistosome-related morbidity. However, to define and thereby document such morbidity, and its reduction following treatment, may not be straightforward, particularly for intestinal schistosomiasis-induced morbidity, which is often not apparent in all but the most severe or chronic cases. Within all 'Schistosomiasis Control Initiative' activities, across selected sub-Saharan African countries since 2002, a range of standard and novel potential morbidity markers have been monitored and evaluated. Parasitological intensity measures, combined with haemoglobin/anaemia counts and ultrasonography, proved valuable schistosomiasis-related morbidity indicators, being both logistically practical and informative. Additional measures tested, such as albumin excretion profiles, were promising, and are subject to ongoing research, whilst some measures, such as distended stomach/umbilical circumference, anthropometrics and health questionnaires proved less reliable. These results serve to both illustrate the success of current control activities in reducing schistosome-induced morbidity, and to highlight key tools and techniques for continued application within ongoing and future mass drug administration programmes.

Novel mutations in GJA1 cause oculodentodigital syndrome.

Oculodentodigital syndrome (ODD) is a rare, usually autosomal-dominant disorder that is characterized by developmental abnormalities of the face, eyes, teeth, and limbs. The most common clinical findings include a long, narrow nose, short palpebral fissures, type III syndactyly, and dental abnormalities including generalized microdontia and enamel hypoplasia. Recently, it has been shown that mutations in the gene GJA1, which encodes the gap junction protein connexin 43, underlie oculodentodigital syndrome. Gap junction communication between adjacent cells is known to be vital during embryogenesis and subsequently for normal tissue homeostasis. Here, we report 8 missense mutations in the coding region of GJA1, 6 of which have not been described previously, in ten unrelated families diagnosed with ODD. In addition, immunofluorescence analyses of a developmental series of mouse embryos and adult tissue demonstrates a strong correlation between the sites of connexin 43 expression and the clinical phenotype displayed by individuals affected by ODD.

Multimedia materials for education, training, and advocacy in international health: experiences with the Schistosomiasis Control Initiative CD-ROM

We describe an innovative use of multimedia materials to support training and advocacy within a schistosomiasis control programme. The Schistosomiasis Control Initiative (SCI) at Imperial College London works with selected sub-Saharan African countries to develop schistosomiasis control programmes. Two elements of the SCI programme were supported by multimedia materials developed at the Wellcome Trust in collaboration with the SCI: (1) training of programme managers, district health officers, and those delivering practical elements of the programme; and (2) advocacy targeted at decision-makers and donors. Evaluation of the materials revealed high reported ratings for both user satisfaction and impact from use of the product. From this experience we draw out several general messages about development of multimedia materials and how these will play a growing future role in promoting training within international health.

The WHO dose pole for the administration of praziquantel is also accurate in non-African populations.

In 2001, WHO developed a pole for the administration of praziquantel without the use of weighing scales, with encouraging results in African populations. In the present study, the pole was tested on height/weight data from 9354 individuals from 11 non-African countries. In more than 98% of the individuals (95% CI 97.8-98.4) the pole estimated an acceptable dosage (30-60 mg/kg), a performance statistically similar to that observed in African populations. Reproducing the present pole in the form of a strip of paper and including it in each container of praziquantel would greatly facilitate the administration of the drug in large-scale interventions.

Cyclic ketone inhibitors of the cysteine protease cathepsin K.

Cathepsin K (EC 3.4.22.38), a cysteine protease of the papain superfamily, is predominantly expressed in osteoclasts and has been postulated as a target for the treatment of osteoporosis. Crystallographic and structure--activity studies on a series of acyclic ketone-based inhibitors of cathepsin K have led to the design and identification of two series of cyclic ketone inhibitors. The mode of binding for four of these cyclic and acyclic inhibitors to cathepsin K is discussed and compared. All of the structures are consistent with addition of the active site thiol to the ketone of the inhibitors with the formation of a hemithioketal. Cocrystallization of the C-3 diastereomeric 3-amidotetrahydrofuran-4-one analogue 16 with cathepsin K showed the inhibitor to occupy the unprimed side of the active site with the 3S diastereomer preferred. This C-3 stereochemical preference is in contrast to the X-ray cocrystal structures of the 3-amidopyrrolidin-4-one inhibitors 29 and 33 which show these inhibitors to prefer binding of the 3R diastereomer. The 3-amidopyrrolidin-4-one inhibitors were bound in the active site of the enzyme in two alternate directions. Epimerization issues associated with the labile alpha-amino ketone diastereomeric center contained within these inhibitor classes has proven to limit their utility despite promising pharmacokinetics displayed in both series of compounds.

Solid-phase synthesis of cyclic alkoxyketones, inhibitors of the cysteine protease cathepsin K.

Using solid-phase synthesis, a library of novel cyclic alkoxyketones has been constructed which show strong inhibitory activity against the cysteine protease, cathepsin K (EC 3.4.22.38).