Benchtop Zone Refinement of Simulated Future Spent Nuclear Fuel Pyroprocessing Waste.

The UK's adoption of pyroprocessing of spent nuclear fuel as an alternative to the current aqueous processing routes requires a robust scientific underpinning of all relevant processes. One key process is the clean-up of the contaminated salt from the electroreducing and electrorefining processes. A proposed method for this clean-up is zone refining, whereby the tendency of the contaminants to remain in the liquid phase during melting and freezing is exploited to 'sweep' the contaminants to one end of the sample. Experiments were performed, utilising off-the-shelf laboratory equipment, to demonstrate the feasibility of zone refining for clean-up of electroreducing and electrorefining wastes. This was successful for the electrorefining simulant samples, with effective segregation coefficient, keff, values, which provide a measure of the degree of separation in the sample, between 0 and 1. Lower values indicate greater separation, with values of as low as 0.542 achieved here, corresponding to a reduction in RECl3 content from 10.0 wt.% to 8.4 wt.% (for 80% salt reuse). Due to difficulties in obtaining a fully homogeneous electroreducing simulant waste, it was not possible to demonstrate the feasibility of zone refining using the current experimental setup. Further research is required to elucidate the correct preparation conditions for production of homogeneous electroreducing waste simulants.

Clinical, genetic, epidemiologic, evolutionary, and functional delineation of TSPEAR-related autosomal recessive ectodermal dysplasia 14.

TSPEAR variants cause autosomal recessive ectodermal dysplasia (ARED) 14. The function of TSPEAR is unknown. The clinical features, the mutation spectrum, and the underlying mechanisms of ARED14 are poorly understood. Combining data from new and previously published individuals established that ARED14 is primarily characterized by dental anomalies such as conical tooth cusps and hypodontia, like those seen in individuals with WNT10A-related odontoonychodermal dysplasia. AlphaFold-predicted structure-based analysis showed that most of the pathogenic TSPEAR missense variants likely destabilize the ß-propeller of the protein. Analysis of 100000 Genomes Project (100KGP) data revealed multiple founder TSPEAR variants across different populations. Mutational and recombination clock analyses demonstrated that non-Finnish European founder variants likely originated around the end of the last ice age, a period of major climatic transition. Analysis of gnomAD data showed that the non-Finnish European population TSPEAR gene-carrier rate is ∼1/140, making it one of the commonest AREDs. Phylogenetic and AlphaFold structural analyses showed that TSPEAR is an ortholog of drosophila Closca, an extracellular matrix-dependent signaling regulator. We, therefore, hypothesized that TSPEAR could have a role in enamel knot, a structure that coordinates patterning of developing tooth cusps. Analysis of mouse single-cell RNA sequencing (scRNA-seq) data revealed highly restricted expression of Tspear in clusters representing enamel knots. A tspeara -/-;tspearb -/- double-knockout zebrafish model recapitulated the clinical features of ARED14 and fin regeneration abnormalities of wnt10a knockout fish, thus suggesting interaction between tspear and wnt10a. In summary, we provide insights into the role of TSPEAR in ectodermal development and the evolutionary history, epidemiology, mechanisms, and consequences of its loss of function variants.

Macrodontia and double teeth: a review and case series.

Macrodontia is a dental anomaly pertaining to the increased size of a tooth or multiple teeth. Double teeth are dental abnormalities concerning tooth morphology and the term traditionally refers to geminated or fused teeth. These anomalies may manifest in both primary and permanent dentitions and usually become apparent in childhood. They may cause a variety of clinical sequelae, including orthodontic complications, such as crowding, ectopic eruption of adjacent teeth and periodontal concerns. Double teeth are also at a higher risk of developing caries. The aesthetic implications of these dental anomalies can affect the psychosocial development of a patient. This, together with the range of functional repercussions, can often need dental treatment to improve quality of life. The functional and aesthetic complexities that may arise in the affected patients can require endodontic, restorative, surgical and/or orthodontic input as part of the management strategy and execution. We present four clinical cases of paediatric patients where a range of management approaches were employed for both macrodontia and double teeth.

A three-generation family with metaphyseal dysplasia, maxillary hypoplasia and brachydactyly (MDMHB) due to intragenic RUNX2 duplication.

Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly (MDMHB) is an autosomal-dominant skeletal dysplasia characterised by metaphyseal flaring of the long bones, enlargement of the medial halves of the clavicles, maxillary hypoplasia, brachydactyly, dental anomalies and mild osteoporosis. To date, only one large French Canadian family and a Finnish woman have been reported with the condition. In both, intragenic duplication encompassing exons 3-5 of the RUNX2 gene was identified. We describe a new, three-generation family with clinical features of MDMHB and an intragenic tandem duplication of RUNX2 exons 3-6. Dental problems were the primary presenting feature in all four affected individuals. We compare the features in our family to those previously reported in MDMHB, review the natural history of this condition and highlight the importance of considering an underlying skeletal dysplasia in patients presenting with significant dental problems and other suggestive features, including disproportionate short stature and/or digital anomalies.

The BRICS (Bronchiectasis Radiologically Indexed CT Score): A Multicenter Study Score for Use in Idiopathic and Postinfective Bronchiectasis.

OBJECTIVES: The goal of this study was to develop a simplified radiological score that could assess clinical disease severity in bronchiectasis. METHODS: The Bronchiectasis Radiologically Indexed CT Score (BRICS) was devised based on a multivariable analysis of the Bhalla score and its ability in predicting clinical parameters of severity. The score was then externally validated in six centers in 302 patients. RESULTS: A total of 184 high-resolution CT scans were scored for the validation cohort. In a multiple logistic regression model, disease severity markers significantly associated with the Bhalla score were percent predicted FEV1, sputum purulence, and exacerbations requiring hospital admission. Components of the Bhalla score that were significantly associated with the disease severity markers were bronchial dilatation and number of bronchopulmonary segments with emphysema. The BRICS was developed with these two parameters. The receiver operating-characteristic curve values for BRICS in the derivation cohort were 0.79 for percent predicted FEV1, 0.71 for sputum purulence, and 0.75 for hospital admissions per year; these values were 0.81, 0.70, and 0.70, respectively, in the validation cohort. Sputum free neutrophil elastase activity was significantly elevated in the group with emphysema on CT imaging. CONCLUSIONS: A simplified CT scoring system can be used as an adjunct to clinical parameters to predict disease severity in patients with idiopathic and postinfective bronchiectasis.

Oral health-related quality of life following dental treatment under general anaesthesia for early childhood caries - a UK-based study.

OBJECTIVE: To assess parental reports of changes in oral health-related quality of life (OHRQoL) of young children in the UK with early childhood caries (ECC) following dental treatment under general anaesthesia (DGA). To compare the impact of oral rehabilitation (OR) and extraction-only (Exo) treatment approaches on this. METHODS: Data were collected using the proxy reported components of the Child Oral Health-Related Quality of Life (COHRQoL® ) questionnaire: the Parent-Caregivers Perceptions questionnaire (P-CPQ) and Family Impact Scale (FIS), from a convenience sample of parents of children receiving DGA at a UK Paediatric Dental Department. Mean scores and prevalence impacts were compared pre- and postoperatively with mean change score and effect sizes calculations. RESULTS: Seventy-eight parents were recruited (51 children undergoing OR, 27 Exo) with 6 lost to follow-up (92.3%). Following treatment, changes in mean P-CPQ and FIS scores were statistically significant (P < 0.0001) with medium to large effect sizes (0.45-1.39). The differences in change scores between the two treatment approaches were not statistically different. CONCLUSION: DGA for young children with early childhood caries resulted in substantial improvements in parent's ratings of their child's OHRQoL and of the impact on their families. Larger cohort studies are needed to validate these preliminary findings.

Congenital Heart Disease and Primary Ciliary Dyskinesia.

Through the better understanding of the genetics and clinical associations of Primary Ciliary Dyskinesia (PCD), an autosomal recessive disorder of ciliary motility and mucociliary clearance, the association between PCD and heterotaxic congenital heart disease (CHD) has been established. In parallel, research into the cause of CHD has elucidated further the role of ciliary function on the development of normal cardiovascular structure. Increased awareness by clinicians regarding this elevated risk of PCD in patients with CHD will allow for more comprehensive screening and identification of cases in this high-risk group with earlier diagnosis leading to improved health outcomes.

Is there a relationship between increased tooth number and increased tooth size? A case report.

UNLABELLED: A unifying theory has been proposed that links anomalies of tooth size and number. Application of this theory suggests that anomalies of tooth size and number may share a common aetiology but could also be predicted. This article highlights an association between macrodontia and hyperdontia as demonstrated by two clinical cases. These cases demonstrate a localized association and effect on the dentition and highlight the possible predictive application of this theory. CLINICAL RELEVANCE: Clinicians should be made aware of the possibility of supernumeraries associated with macrodont teeth.

Prospective Changes in Health-Related Quality of Life and Emotional Outcomes in Kidney Transplantation over 6 Years.

Little is known on long-term outcomes in kidney transplantation. This study evaluated changes and predictors of generic and transplantation-specific health-related quality of life (HQoL) over six years in N = 102 kidney transplant survivors using the Short-form Health Survey-36 and the Transplant Effects questionnaire. Mixed models analysis was used to determine long-term outcomes. Emotional HQoL improved over time: Mental Component score, Mental Health, Energy (Ps = .000). Physical HQoL deteriorated: Physical Component Score (P = .001), Pain (P = .002). LRD transplant recipients had greater decline in physical functioning (P = .003) and PCS (P = .000) compared to cadaver recipients. Worry about the transplant (P = .036) and feelings of responsibility (P = .008) increased significantly over time. Worry about the transplant and perceived ability to work predicted 12.7% and 31.1% in variance in MCS and PCS, respectively. Efforts should be made to maintain HQoL and emotional outcomes with ongoing monitoring and support programs throughout the course of posttransplant care.

Nebulized hypertonic saline via positive expiratory pressure versus via jet nebulizer in patients with severe cystic fibrosis.

BACKGROUND: Nebulized hypertonic saline is a highly effective therapy for patients with cystic fibrosis (CF), yet 10% of patients are intolerant of hypertonic saline administered via jet nebulizer. Positive expiratory pressure (PEP) nebulizers splint open the airways and offers a more controlled rate of nebulization. METHODS: In 4 consecutive adult CF patients who were intolerant of hypertonic saline via jet nebulizer, we nebulized 6% hypertonic saline via a PEP nebulizer. We measured the number of days the patients required intravenous antibiotics from enrollment to study end, compared to an equal period before PEP, and the mean time between the patients' 3 most recent infective pulmonary exacerbation episodes before PEP to their next exacerbation after PEP. Patients also completed a Likert-scale adverse-effects questionnaire on hypertonic saline via PEP versus jet nebulizer. RESULTS: The 4 patients had severe CF pulmonary disease and all fully tolerated hypertonic saline via PEP, for 77, 92, 128, and 137 days, respectively until the study end date. There were fewer days of antibiotics in 3 of the 4 patients, from 45 to 20 days, 66 to 14 days, and 28 to 0 days (mean relative risk reduction 53%, P = .11). The other patient had 63 days of antibiotics during both the PEP and the jet nebulizer periods. There was a mean 3.6-fold longer time to next infective pulmonary exacerbation during the PEP period (P = .07). Adverse effects were less with PEP: chest tightness 68% (P = .04), bad taste 62% (P = .06), cough 47% (P = .10), and sore throat 50% (P = .20). CONCLUSIONS: Hypertonic saline via PEP nebulizer benefits CF patients who do not tolerate hypertonic saline via jet nebulizer.

In vitro hepatic metabolism of cediranib, a potent vascular endothelial growth factor tyrosine kinase inhibitor: interspecies comparison and human enzymology.

The in vitro metabolism of cediranib (4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[3-(1-pyrrolidinyl)propoxy]quinazoline), a vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) of all three VEGF receptors in late-stage development for the treatment of colorectal cancer and recurrent glioblastoma was investigated in hepatic proteins from preclinical species and humans using radiolabeled material. In human hepatocyte cultures, oxidative and conjugative metabolic pathways were identified, with pyrrolidine N(+)-glucuronidation being the major route. The primary oxidative pathways were di-and trioxidations and pyrrolidine N-oxidation. All metabolites with the exception of the N(+)-glucuronide metabolite were observed in rat and cynomolgus monkey hepatocyte preparations. Additional metabolism studies in liver microsomes from these or other preclinical species (CD-1 mouse, Han Wistar rat, Dunkin Hartley guinea pig, Göttingen mini-pig, New Zealand White rabbit, beagle dog, and cynomolgus and rhesus monkey) indicated that the N(+)-glucuronide metabolite was not formed in these additional species. Incubations with recombinant flavin-containing monooxygenase (FMO) and UDP-glucuronosyltransferase (UGT) enzymes and inhibition studies using the nonselective cytochrome P450 (P450) chemical inhibitor 1-aminobenzotriazole in human hepatocytes indicated that FMO1 and FMO3 contributed to cediranib N-oxidation, whereas UGT1A4 had a major role in cediranib N(+)-glucuronidation. P450 enzymes had only a minor role in the metabolism of cediranib. In conclusion, species differences in the formation of the N(+)-glucuronide metabolite of cediranib were observed. All other metabolites of cediranib found in humans were also detected in rat and cynomolgus monkey. Non-P450 enzymes are predominantly involved in the metabolism of cediranib, and this suggests that clinical drug interactions involving other coadministered drugs are unlikely.

Characterisation and identification of the human N+-glucuronide metabolite of cediranib.

Cediranib (4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[3-(1-pyrrolidinyl)propoxy]quinazoline; RECENTIN), a vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) of all three VEGF receptors, is currently in Phase III clinical trials for the first-line treatment of colorectal cancer and the treatment of recurrent glioblastoma. During its clinical development a unique human metabolite, an N(+)-glucuronide, was identified as a major circulating metabolite and one of the major metabolites excreted into faeces. Given the possibility of four sites for the conjugation of the glucuronic acid moiety, determination of the location of the conjugation site on cediranib was warranted. A small quantity of the N(+)-glucuronide metabolite of cediranib was initially generated using recombinant human uridine glucuronosyltransferase 1A4 (UGT1A4) enzymes. The metabolite generated was characterised by HPLC-UV and mass spectrometric (HPLC-MS(n)) detection and confirmed by (1)H NMR spectroscopy. However, the exact site of conjugation could not be determined without generating more of the metabolite. Hence a subsequent biosynthetic scale-up experiment was devised to generate a sufficiently large quantity for full structural characterisation by (1)H NMR spectroscopy. The identity of the N(+)-glucuronide metabolite generated in the UGT1A4 scale-up experiment was confirmed by HPLC-MS(n) and displayed the same retention time, molecular mass and mass fragmentation data as the metabolite generated in previous human liver microsomal and hepatocyte incubations. (1)H NMR spectroscopy clearly showed the characteristic anomeric doublet at approximately 4.7 ppm, which, following irradiation during selective Rotating frame Overhauser Effect Spectroscopy (ROESY) experiments, enabled the site of glucuronidation to be confirmed on the pyrrolidine nitrogen. With the exception of the N(+)-glucuronide metabolite, all other human metabolites of cediranib were observed following incubation with hepatocytes from rat and cynomolgus monkey, the species used for toxicology testing of the drug [6]. As the N(+)-glucuronide was not detected in the preclinical species, it is suggested that its formation is more likely in human and higher primates (great apes), a finding widely supported in the literature.

A distinct autosomal recessive disorder of limb development with preaxial brachydactyly, phalangeal duplication, symphalangism and hyperphalangism.

We describe four children from two consanguineous families with distinctive hand and foot anomalies including preaxial brachydactyly, together with phalangeal duplication, symphalangism and hyperphalangism of fingers I-III. These anomalies are remarkably similar to those described in a previous case report. Additional features were noted both in this case and, to variable degrees, in the four children reported here. These included sensorineural deafness, optic atrophy, mild facial dysmorphism, orodental anomalies and developmental delay. Autosomal recessive inheritance was previously suggested as the patient had a similarly affected brother and his parents were consanguineous. These four cases provide additional evidence for a novel, autosomal recessive disorder involving limb and other associated anomalies.

Pharmacokinetic profile of intramuscular fulvestrant in advanced breast cancer.

OBJECTIVE: To characterise the pharmacokinetics of a long-acting formulation of fulvestrant following intramuscular administration of single and multiple doses. STUDY DESIGN: Pharmacokinetic investigations of single and multiple doses of fulvestrant were conducted within two global phase III efficacy studies that compared intramuscular fulvestrant with oral anastrozole in postmenopausal women with hormone-sensitive advanced breast cancer (study 0020, conducted in Europe, Australia and South Africa, and study 0021, conducted in North America). METHODS: Patients received once-monthly intramuscular injections of fulvestrant 250 mg (1 x 5 mL for < or =21 months in study 0020; 2 x 2.5 mL for < or =30 months in study 0021). Serial blood samples were collected for the first 28 days after the initial dose and immediately prior to all subsequent monthly doses. Plasma fulvestrant concentrations were determined by high-performance liquid chromatography-tandem mass spectrometry. PATIENTS: Twenty-six (study 0020) and 193 (study 0021) postmenopausal women, comprising the pharmacokinetic subgroups of the phase III efficacy trials, were studied. Patients had shown disease progression or recurrence following previous hormonal therapy for advanced disease or had relapsed after adjuvant endocrine therapy with a nonsteroidal antiestrogen. OUTCOME MEASURES AND RESULTS: For single-dose fulvestrant 250 mg, area under the concentration-time curve from time zero to 28 days (AUC(28)), maximum observed plasma concentration (C(max)), minimum observed plasma concentration at 28 days (C(min)) and time to maximum plasma concentration (t(max)) were determined. For multiple-dose fulvestrant 250 mg once monthly, steady-state trough concentrations (C(trough)) were determined. Plasma fulvestrant concentrations reached a peak at a median of 7 days (range 2-8 days) postdose, and declined biexponentially with a slower phase commencing approximately 2-3 weeks postdose. Intersubject variability in C(max) and AUC(28) was approximately 6-fold and 4-fold, respectively. Mean parameters for single-dose fulvestrant were: AUC(28), 148 microg. day/L; C(max), 8.2 microg/L; C(min), 2.6 microg/L; t(max), 7.0 days. Geometric mean C(trough) increased from 2.57 to 6.15 microg/L (study 0020) and from 2.38 to 6.52 microg/L (study 0021) over the first 6 months, reaching steady-state concentrations of approximately 6-7 microg/L (study 0020) or 9 microg/L (study 0021). Preliminary pharmacokinetic analysis, using a naive pooled data approach, suggests that observed single- and multiple-dose plasma profiles can be adequately described with a two-compartment kinetic model. Model-generated steady-state AUC(28) values were approximately 300 microg. day/L. CONCLUSIONS: The intramuscular formulation of fulvestrant displays predictable kinetics and approximately 2-fold accumulation on administration once monthly. At the proposed therapeutic dosage (250 mg once monthly), plasma fulvestrant concentrations are maintained within a narrow range throughout the administration interval, thus ensuring stable systemic drug exposure during long-term treatment.

Pharmacokinetics of a single dose of fulvestrant prolonged-release intramuscular injection in postmenopausal women awaiting surgery for primary breast cancer.

OBJECTIVE: The aim of this study was to describe the pharmacokinetics of 3 different single doses of fulvestrant-a new estrogen receptor (ER) antagonist that downregulates the ER with no known agonist effects-administered as a prolonged-release IM formulation. METHODS: Pharmacokinetic data were obtained in a randomized, partially blinded, placebo-controlled, parallel-group, Phase I/II multicenter trial involving postmenopausal women with primary breast cancer (clinical stages T1-T3, with tumors that were ER positive or of unknown ER status) awaiting curative-intent surgery. Patients received either IM fulvestrant (50, 125, or 250 mg), oral tamoxifen (20 mg, once daily), or oral placebo (once daily). Treatment started 2 to 3 weeks before surgery and blood was taken at various times up to 12 weeks after fulvestrant administration to assess pharmacokinetic variables. RESULTS: A total of 200 patients entered the trial, of whom 58 took part in the pharmacokinetic analysis (50 mg, n = 20; 125 mg, n = 16; 250 mg, n = 22). Following single IM injections of fulvestrant, the median time to maximum concentration was 6.98, 6.98, and 6.96 days in the 50-, 125,- and 250-mg dose groups, respectively, with an overall range of 2 to 19 days). The plasma concentration-time profiles were primarily controlled by the rate of absorption from the injection site; post-peak plasma concentrations declined over time and were measurable up to 84 days after administration of fulvestrant 125 and 250 mg. Plasma concentrations at 28 days were 2- to 5-fold lower than the maximum value. Plasma concentration data for the 250-mg dose were best described by a 2-compartment pharmacokinetic model, with an apparent terminal phase half-life of approximately 49 days, beginning approximately 3 weeks after administration. Mean area under the plasma concentration-time curve for days 0 through 28 (AUC 0-28) was proportional for fulvestrant 50, 125, and 250 mg. For a doubling of the dose, an analysis of covariance model of the pharmacokinetic data projected an estimated increase in AUC 0-28 of a factor of 1.84 (95% CI, 1.67 to 2.04). CONCLUSIONS: The IM formulation of fulvestrant used in this study had predictable, dose-linear pharmacokinetics. The prolonged-release properties of this formulation suggested that it may be well suited for the once-monthly dosing schedule intended for clinical use.

Putting nanocrystals to work: from solutions to devices.

The colloidal route to semiconductor nanocrystals is extremely flexible, with a high degree of control over size, size distribution, surface passivation and internal structure of the nanoparticles. Simple chemically controlled techniques can be used to assemble these particles into dense films or other microscopic structures, suitable for photonic devices. Working with semiconductors or semi-metals which in the bulk form have low or inverted bandgaps, and taking advantage of the blue shift in the quantum confinement regime, nanocrystals can readily be tuned to the infrared wavelengths of interest for telecommunications. Design flexibility is far greater than with conventional compound semiconductors or rare-earth-doped glasses. Preliminary results demonstrating optical gain from II-VI nanocrystal films at room temperature are reported.