Terbium-149 production: a focus on yield and quality improvement towards preclinical application.

Terbium-149 (T1/2 = 4.1 h, Eα = 3.98 MeV (16.7%), 28 µm range in tissue) is a radionuclide with potential for targeted alpha therapy. Due to the negligible emission of α-emitting daughter nuclides, toxicity to healthy tissue may be reduced in comparison with other α-particle emitters. In this study, terbium-149 was produced via 1.4 GeV proton irradiation of a tantalum target at the CERN-ISOLDE facility. The spallation products were mass separated and implanted on zinc-coated foils and, later, radiochemically processed. Terbium-149 was separated from the co-produced isobaric radioisotopes and the zinc coating from the implantation foil, using cation-exchange and extraction chromatographic techniques, respectively. At the end of separation, up to 260 MBq terbium-149 were obtained with > 99% radionuclidic purity. Radiolabeling experiments were performed with DOTATATE, achieving 50 MBq/nmol apparent molar activity with radiochemical purity > 99%. The chemical purity was determined by inductively coupled plasma-mass spectrometry measurements, which showed lead, copper, iron and zinc only at ppb level. The radiolabeling of the somatostatin analogue DOTATATE with [149Tb]TbCl3 and the subsequent in vivo PET/CT scans conducted in xenografted mice, showing good tumor uptake, further demonstrated product quality and its ability to be used in a preclinical setting.

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.

Growth and Nutritional Outcomes in Children Post-Haematopoietic Stem Cell Transplant without Exposure to Total Body Irradiation.

AIMS: Poor growth in childhood cancer survivors who undergo haematopoietic stem cell transplant (HSCT) without exposure to radiation is reported anecdotally, although literature to support this is limited. The aims of this study were to assess the change in height standard deviation score (SDS) and the final adult height (FAH) in children who underwent chemotherapy-only conditioned HSCT and to identify predictors of poor growth. MATERIALS AND METHODS: We conducted a retrospective hospital medical record review (1984-2010) of children (1-10 years) who underwent chemotherapy-only conditioned HSCT, noting anthropology measurements at cancer diagnosis, HSCT, 10 years old and FAH. RESULTS: The median age at HSCT of the 53 patients was 4.5 years, 75% had a haematological malignancy and 25% a solid tumour. Half of the cohort underwent allogenic HSCT and most (89%) conditioned with busulphan. The mean change in height SDS from primary cancer diagnosis to FAH was -1.21 (±1.18 SD), equivalent to 7-8.5 cm loss, with a mean FAH of -0.91 SDS (±1.10 SD). The greatest height loss occurred between diagnosis and HSCT (-0.77 SDS, 95% confidence interval -1.42, -0.12, P = 0.01), with no catch-up growth seen by FAH. Patients with solid tumours had the greatest height loss. Overall body mass index SDS did not change significantly over time, or by cancer type. CONCLUSIONS: Chemotherapy-only conditioned HSCT during childhood can impact FAH, with the greatest height loss occurring prior to HSCT and no catch-up growth after treatment finishes. Children transplanted for a solid tumour malignancy seem to be more at risk, possibly due to intensive treatment regimens, both pre-transplant and during conditioning.

PET in vivo generators 134Ce and 140Nd on an internalizing monoclonal antibody probe.

The in vivo-generator radionuclides 140Nd (t1/2 = 3.4 d) and 134Ce (t1/2 = 3.2 d) were used to trace a urokinase-type plasminogen activator (uPA)-targeting mouse monoclonal antibody, ATN-291, in U87 MG xenograft tumor-bearing mice. ATN-291 is known to internalize on the uPA/uPA-receptor pair, making it an appropriate targeting vector for investigating the fate of in vivo generator daughters on internalizing probes. Ante-mortem and post-mortem PET imaging at 120 h post-injection gave no indication of redistribution of the positron emitting daughter nuclides 134La and 140Pr from tumor tissue (p > 0.5). The lack of redistribution indicates that the parent radionuclides 134Ce and 140Nd could be considered as long-lived PET-diagnostic matches to therapeutic radionuclides like 177Lu, 161Tb and 225Ac when internalizing bioconjugates are employed.

Comparative efficacy, safety, and cost-effectiveness of abobotulinumtoxinA and onabotulinumtoxinA in children with upper limb spasticity: a systematic literature review, indirect treatment comparison, and economic evaluation.

OBJECTIVE: The objective of this study was to compare clinical- and cost-effectiveness of type A botulinum toxin (BoNT-A) therapies for management of pediatric upper limb spasticity, including AbobotulinumtoxinA (aboBoNT-A) and Onabotulinumtoxin A (onaBoNT-A). METHODS: Systematic literature review and indirect treatment comparisons were conducted of randomized controlled trials reporting efficacy and safety outcomes. Efficacy was characterized by Modified Ashworth Scale (MAS) and Ashworth Scale (AS) up to 16-weeks post-injection. Results were used to inform a cost-effectiveness model with a 1-year time horizon, linking response rates with health-related quality-of-life (HRQoL) outcomes and costs from a UK perspective. Other data sources included in the cost-effectiveness model were drug unit costs, health care resource utilization based on UK physician survey, and HRQoL impacts of adverse events associated with oral anti-spasticity therapies. Results were characterized as cost per quality-adjusted life year and cost per responder. RESULTS: Six studies were included in evidence syntheses. There was a trend towards greater response rate for aboBoNT-A which resulted in improved HRQoL and lower annual costs compared with onaBoNT-A. Safety outcomes were similar across BoNT-A therapies. In cost-effectiveness analysis, aboBoNT-A was an economically dominant therapy with respect to cost per quality-adjusted life year. The cost per responder at 1 year was estimated to be £39,056 for aboBoNT-A vs. £54,831 for onaBoNT-A. LIMITATIONS AND CONCLUSIONS: Based on observed safety and efficacy data, aboBoNT-A is estimated to result in higher treatment response and consequently increased quality-of-life and reduced costs, vs. onaBoNT-A in children with upper limb spasticity. Limitations to the study include study heterogeneity limited details available for onaBoNT-A studies (e.g. use of physical therapy), and limited availability of responder data. Where assumptions were required, they were made to be conservative towards aboBoN-A.

Annealing studies combined with low temperature emission Mössbauer spectroscopy of short-lived parent isotopes: Determination of local Debye-Waller factors.

An extension of the online implantation chamber used for emission Mössbauer Spectroscopy (eMS) at ISOLDE/CERN that allows for quick removal of samples for offline low temperature studies is briefly described. We demonstrate how online eMS data obtained during implantation at temperatures between 300 K and 650 K of short-lived parent isotopes combined with rapid cooling and offline eMS measurements during the decay of the parent isotope can give detailed information on the binding properties of the Mössbauer probe in the lattice. This approach has been applied to study the properties of Sn impurities in ZnO following implantation of 119In (T½ = 2.4 min). Sn in the 4+ and 2+ charge states is observed. Above T > 600 K, Sn2+ is observed and is ascribed to Sn on regular Zn sites, while Sn2+ detected at T < 600 K is due to Sn in local amorphous regions. A new annealing stage is reported at T ≈ 550 K, characterized by changes in the Sn4+ emission profile, and is attributed to the annihilation of close Frenkel pairs.

Vascular injury-related in-hospital mortality in Ontario between 1991 and 2009.

OBJECTIVE: Trauma-related vascular injuries are major contributors to morbidity and mortality worldwide. We conducted a retrospective, population-based, cross-sectional study to examine temporal trends and factors associated with traumatic vascular injury-related in-hospital mortality in Ontario, Canada from 1991 to 2009. METHODS: We obtained data on Ontario hospital admissions for traumatic vascular injury, including injury mechanism and body region; and patient age, sex, socioeconomic status, and residence from the Canadian Institute for Health Information Discharge Abstract Database and Registered Persons Database from fiscal years 1991 to 2009. We performed time series analysis of vascular injury-related in-hospital mortality rates and multivariable logistic regression analysis to identify significant mortality-associated factors. RESULTS: The overall in-hospital mortality rate for trauma-related vascular injury was 5.5%. A slight but non-significant decline in mortality occurred over time. The likelihood of vascular injury-related in-hospital mortality was significantly higher for patients involved in transport-related accidents (odds ratio [OR[=2.21, 95% confidence interval [CI], 1.76-2.76), age ≥65 years (OR = 4.34, 95% CI, 2.25-8.38), or with thoracic (OR = 2.24, 95% CI, 1.56-3.20) or abdominal (OR = 2.45, 95% CI, 1.75-3.42) injuries. CONCLUSIONS: In-hospital mortality from traumatic vascular injury in Ontario was low and stable from 1991 to 2009.

Systematic approach to delivering prolonged field care in a prehospital care environment.

BACKGROUND: This article describes a novel patient care algorithm which provides a Role 1 (R1) medic with a structured approach to delivering prolonged field care (PFC) in a resource-limited environment. PFC is a vital component of the operational patient care pathway providing the continuum of care from completion of a primary survey to the delivery to hospital care. Future operational environments are likely to have more fragile or extended lines of communication, potentially delaying evacuation to hospital care. This delay may lead to increases in patient morbidity and mortality. Effective PFC offers an opportunity to improve patient outcomes and help mitigate against this risk. METHODS: An initial prototype model of a PFC care process was developed using existing hospital-based guidance. A series of medical and trauma vignettes and best available evidence were used to refine the algorithm. RESULTS: The algorithm has been designed be used in conjunction with patient specific clinical guidance making the approach generalisable for all patient groups. For UK military, clinical guidance is provided by clinical guidelines for operations. The algorithm can be downloaded into a convenient format to be used on mobile devices or printed as an aide memoire.

Comprehensive genomic profiling for non-small-cell lung cancer: health and budget impact.

Background: Single-gene tests and hotspot panels targeting specific subsets of biomarkers constitute the Canadian genomic testing landscape for non-small-cell lung cancer (nsclc). However, newer testing options such as comprehensive genomic profiling (cgp) offer improved detection rates and identification of multiple classes of genomic alterations in a single assay, minimizing tissue requirements and turnaround time. The objective of the present analysis was to assess the health and budget impacts of adopting cgp testing for nsclc in Canada. Methods: This study assessed the impact of funding the cgp tests FoundationOne CDx and FoundationOne Liquid (Foundation Medicine, Cambridge, MA, U.S.A.) over a 3-year time horizon using a Canadian societal perspective for Ontario. Conventional testing strategies were summarized into two reference scenarios: a series of single-gene tests only, and reflex single-gene testing followed by a hotspot panel for negative results. Four adoption scenarios for cgp testing were considered: replacing all single-gene and hotspot panel testing, replacing hotspot panel testing only, use after negative single-gene and hotspot testing, and use of FoundationOne Liquid in individuals with insufficient tissue for conventional testing. Results: When cgp testing was assumed to replace all conventional testing with 50% uptake, the budget impact per person per year ranged from $0.71 to $0.87, depending on the reference scenario, with a 3-year gain of 680.9 life-years and 3831 working days over the full cohort. Conclusions: Given the present testing landscape for patients with nsclc in Canada, listing cgp testing could optimize the selection of appropriately targeted treatments, and thus add life-years and productivity for this population, with a minimal budget impact.

Publisher Correction: The observation of vibrating pear-shapes in radon nuclei.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The effect of laboratory requisition modification, audit and feedback with academic detailing or both on utilization of blood urea testing in family practice in Newfoundland, Canada.

OBJECTIVES: Measuring blood urea at the same time as serum creatinine in stable ambulatory patients in family practice is largely unnecessary. The objective was to assess the relative impact of changing the laboratory requisition versus audit and feedback and academic detailing on the volume of orders for blood urea. DESIGN AND METHODS: A natural experiment was observed over the period April 2015 to March 2018 in the Canadian province of Newfoundland where three health regions had different approaches to trying to reduce such urea testing. The Eastern and Western regions removed urea from the standard laboratory requisition but the test could still be ordered by writing it on the requisition. Central region requisitions continued to list urea. Audit and feedback was undertaken with family doctors in Eastern region after the requisition change and that was followed by academic detailing. A nephrologist gave presentations to groups of family doctors on one occasion in Central region. RESULTS: The volume of serum creatinine testing was largely unchanged over time in each region. The volume of urea testing reduced by 73%, 48% and 28% in Eastern, Western and central regions. Interrupted time series analysis showed significant changes in test volume after requisition change in Eastern and Western regions as well as after audit and feedback in Eastern and the presentations in Central region. The incremental impact of academic detailing was not statistically significant. CONCLUSION: We conclude that removing urea from standard test order menus was the most effective in reducing test volumes, but combination with audit and feedback augmented the impact.

Local increase of the Curie temperature in Mn/Fe implanted Y3Fe5O12 (YIG).

The change in the Curie temperature of single crystalline garnet Y3Fe5O12 (YIG) sample due to lattice damage induced by ion implantation has been investigated in 57Fe emission Mössbauer Spectroscopy (eMS) following implantation of 57Mn (T½ = 1.5 min). The Mössbauer spectra analysis reveal high spin Fe3+ ions substituted on both the octahedral and the tetrahedral sites. Measurements in the temperature range 298 K-798 K show that average values of the magnetic hyperfine field are decreased by the implantation-induced damage on the local lattice structure of the YIG. The Curie temperature, however, is determined to be 651 ± 5 K, considerably higher than the value of bulk YIG (559 K). This is most likely due to lattice damage-induced changes on the spin configurations of YIG through a FeA-O-FeD distortion scheme.

Changes in long term peripheral nerve biophysical properties in childhood cancer survivors following neurotoxic chemotherapy.

OBJECTIVE: In the context of increasing numbers of childhood cancer survivors (CCS), this study aimed to enhance understanding of the biophysical basis for long term chemotherapy induced peripheral neuropathy from different chemotherapy agents in CCS. METHODS: Detailed cross-sectional neurophysiological examination, using median nerve axonal excitability studies, alongside clinical assessments, in 103 long term CCS (10.5 ± 0.6 years post-treatment). RESULTS: Cisplatin treated CCS (n = 16) demonstrated multiple sensory axonal excitability changes including increased threshold (P < 0.05), alterations in depolarising and hyperpolarising threshold electrotonus (P < 0.05) and reduction in resting and minimum IV slope (P < 0.01). Vincristine treated CCS (n = 73) were comparable to controls, except for prolonged distal motor latency (P = 0.001). No differences were seen in the non-neurotoxic chemotherapy group (n = 14). Abnormalities were more evident in the cisplatin subgroup with greater clinical neuropathy manifestations. CONCLUSION: Persistent long term changes in axonal biophysical properties vary with different chemotherapy agents, most evident after cisplatin exposure. Longitudinal studies of nerve function during chemotherapy treatment are required to further evaluate these differences and their mechanistic basis. SIGNIFICANCE: This study provides a unique biophysical perspective for persistent cisplatin related neurotoxicity in children, previously under recognised.

Evolution of Octupole Deformation in Radium Nuclei from Coulomb Excitation of Radioactive

There is sparse direct experimental evidence that atomic nuclei can exhibit stable "pear" shapes arising from strong octupole correlations. In order to investigate the nature of octupole collectivity in radium isotopes, electric octupole (E3) matrix elements have been determined for transitions in ^{222,228}Ra nuclei using the method of sub-barrier, multistep Coulomb excitation. Beams of the radioactive radium isotopes were provided by the HIE-ISOLDE facility at CERN. The observed pattern of E3 matrix elements for different nuclear transitions is explained by describing ^{222}Ra as pear shaped with stable octupole deformation, while ^{228}Ra behaves like an octupole vibrator.

Outcomes of femoral de-rotation osteotomy for treatment of femoroacetabular impingement in adults with decreased femoral anteversion.

Decreased femoral anteversion is an often overlooked factor in femoroacetabular impingement (FAI), with potential to exacerbate both cam and pincer type impingement, or itself be the primary cause. Femoral de-rotation osteotomy (FDO) is a surgical option for symptomatic patients with such underlying bony deformity. This study aimed to investigate outcomes of FDO for management of symptomatic FAI in the presence of decreased (<5°) femoral anteversion. Secondary aims were to describe the surgical technique and assess complications. This study included 33 cases (29 patients) with average pre-operative anteversion measuring -3.1° (true retroversion). At an average follow-up of 1.5 years (19.8 months), 97% reported significant improvement. The overall average post-operative International Hip Outcome Tool (iHOT-33) score of 70.6 points (r: 23-98) compared to the average pre-operative score of 42.8 points (r: 0-56) for the 11 patients with available pre-operative scores suggests an overall improvement. The minimal clinically important difference for the iHOT-33 is 6.1 points. Patients with both pre- and post-operative iHOT-33 scores available demonstrated a statistically and clinically significant improvement of 37.7 (r: 13-70) points. There were three cases (9%) of delayed union and two cases (6%) of non-union early in the series which prompted evolution of the technique. Locking screw removal was performed in 33% of patients for a resultant overall re-operation rate of 45%. The findings suggest improvement in patient-reported outcomes can be achieved with FDO for symptomatic FAI in the setting of decreased femoral anteversion (<5°).

Efficacy of an intermittent energy restriction diet in a primary care setting.

PURPOSE: Intermittent energy restriction (IER) is a popular weight loss (WL) strategy; however, its efficacy in clinical practice remains unknown. The present study compared the effects of IER compared to continuous energy restriction (CER) on WL and cardiometabolic risk factors in primary care. METHODS: A (self-selected) cohort study was conducted at the Rotherham Institute for Obesity (RIO), a primary care-based weight management service. 197(24% male) obese patients volunteered to participate and selected their diet group. IER participants (n = 99) consumed ~ 2600 kJ for two days/week. CER participants (n = 98) restricted their diet by ~ 2100 kJ/day below estimated requirements. Both interventions were delivered alongside RIO standard care. Changes in anthropometry and cardiometabolic disease risk markers (fasting biochemistry and blood pressure) were assessed after a 6-month intervention period and then participants were followed up again 6 months later (month 12). RESULTS: 27 IER patients (27%) and 39 CER patients (40%) completed the 6-month weight loss phase. Among completers, mean (SEM) WL was greater in the IER group at 6 months (5.4 ± 1.1% versus 2.8 ± 0.6%; p = 0.01), as were reductions in fat mass (p < 0.001) and improvements in systolic blood pressure (p < 0.001). Fasting insulin (p = 0.873) and diastolic blood pressure (p = 0.701) were reduced similarly in both groups. However, in the IER group, changes in anthropometry and blood pressure in the IER group had reverted to baseline by 12-month follow-up, whilst the CER group maintained weight loss but showed an increase in blood pressure. CONCLUSIONS: Among completers, IER resulted in superior short-term changes in anthropometry and some cardiometabolic risk factors. However, rates of attrition and weight regain were higher compared with standard care, providing important insights in the implementations of IER within a "real-life" NHS setting. TRIAL REGISTRATION NUMBER: ISRCTN31465600.