Delayed and significant hypercalcaemia due to teriparatide therapy: a case report and review.

INTRODUCTION: Transient hypercalcaemia due to teriparatide occurs in up to 11% of patients though delayed hypercalcaemia (> 24 h post injection) is rare. We report the case of a female who developed significant delayed hypercalcaemia after teriparatide treatment for osteoporosis and review other cases in the literature to date. CASE REPORT: A 72-year-old female on teriparatide for the treatment of osteoporosis was found to have hypercalcaemia (3.30 mmol/l) on routine testing approximately 3 months after starting therapy. Serum calcium pretreatment was normal at 2.39 mmol/l. She was admitted to the hospital for investigations which identified a serum 25-hydroxyvitamin D of 94 nmol/l, a low parathyroid hormone of 6.0 pg/ml, and normal test results for 1,25 dihydroxyvitamin D (115 pmol/l), parathyroid hormone-related peptide (< 1.4 pmol/ml), serum electrophoresis and angiotensin-converting enzyme (39 IU/l). CT abdomen, pelvis, and thorax revealed no evidence of malignancy and an isotope bone scan ruled out skeletal metastases. Serum calcium normalised (2.34 mmol/l) several days after stopping teriparatide and calcium supplements and administering intravenous fluid. On restarting teriparatide, delayed hypercalcaemia reoccurred and treatment was switched to denosumab. DISCUSSION: Delayed moderate to severe hypercalcaemia (serum calcium > 3.0 mmol/l) due to teriparatide is rare but may lead to therapy withdrawal. The underlying predisposing risk factors remain unclear and highlight the importance of a routine serum calcium assessment on therapy.

Neurobiomarker and body temperature responses to recreational marathon running.

OBJECTIVES: To assess how biomarkers indicating central nervous system insult (neurobiomarkers) vary in peripheral blood with exertional-heat stress from prolonged endurance exercise. DESIGN: Observational study of changes in neuron specific enolase (NSE), S100 calcium-binding protein B (S100ß), Glial Fibrillary Acid Protein (GFAP) and Ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1) at Brighton Marathon 2022. METHODS: In 38 marathoners with in-race core temperature (Tc) monitoring, exposure (High, Intermediate or Low) was classified by cumulative hyperthermia - calculated as area under curve of Time × Tc > 38 °C - and also by running duration (finishing time). Blood was sampled for neurobiomarkers, cortisol and fluid-regulatory stress surrogates, including copeptin and creatinine (at rested baseline; within 30 min of finishing; and at 24 h). RESULTS: Finishing in 236 ±â€¯40 min, runners showed stable GFAP and UCH-L1 across the marathon and next-day. Significant (P < 0.05) increases from baseline were shown post-marathon and at 24 h for S100ß (8.52 [3.65, 22.95] vs 39.0 [26.48, 52.33] vs 80.3 [49.1, 99.7] ng·L-1) and post-marathon only for NSE (3.73 [3.30, 4.32] vs 4.85 [4.45, 5.80] µg·L-1, P < 0.0001). Whilst differential response to hyperthermia was observed for cortisol, copeptin and creatinine, neurobiomarker responses did not vary. Post-marathon, only NSE differed by exercise duration (High vs Low, 5.81 ±â€¯1.77 vs. 4.69 ±â€¯0.73 µg·L-1, adjusted P = 0.0358). CONCLUSIONS: Successful marathon performance did not associate with evidence for substantial neuronal insult. To account for variation in neurobiomarkers with prolonged endurance exercise, factors additional to hyperthermia, such as exercise duration and intensity, should be further investigated.

Creation and evaluation of full-text literature-derived, feature-weighted disease models of genetically determined developmental disorders.

There are >2500 different genetically determined developmental disorders (DD), which, as a group, show very high levels of both locus and allelic heterogeneity. This has led to the wide-spread use of evidence-based filtering of genome-wide sequence data as a diagnostic tool in DD. Determining whether the association of a filtered variant at a specific locus is a plausible explanation of the phenotype in the proband is crucial and commonly requires extensive manual literature review by both clinical scientists and clinicians. Access to a database of weighted clinical features extracted from rigorously curated literature would increase the efficiency of this process and facilitate the development of robust phenotypic similarity metrics. However, given the large and rapidly increasing volume of published information, conventional biocuration approaches are becoming impractical. Here, we present a scalable, automated method for the extraction of categorical phenotypic descriptors from the full-text literature. Papers identified through literature review were downloaded and parsed using the Cadmus custom retrieval package. Human Phenotype Ontology terms were extracted using MetaMap, with 76-84% precision and 65-73% recall. Mean terms per paper increased from 9 in title + abstract, to 68 using full text. We demonstrate that these literature-derived disease models plausibly reflect true disease expressivity more accurately than widely used manually curated models, through comparison with prospectively gathered data from the Deciphering Developmental Disorders study. The area under the curve for receiver operating characteristic (ROC) curves increased by 5-10% through the use of literature-derived models. This work shows that scalable automated literature curation increases performance and adds weight to the need for this strategy to be integrated into informatic variant analysis pipelines. Database URL: https://doi.org/10.1093/database/baac038.

Clinically-relevant postzygotic mosaicism in parents and children with developmental disorders in trio exome sequencing data.

Mosaic genetic variants can have major clinical impact. We systematically analyse trio exome sequence data from 4,293 probands from the DDD Study with severe developmental disorders for pathogenic postzygotic mosaicism (PZM) in the child or a clinically-unaffected parent, and use ultrahigh-depth sequencing to validate candidate mosaic variants. We observe that levels of mosaicism for small genetic variants are usually equivalent in both saliva and blood and ~3% of causative de novo mutations exhibit PZM; this is an important observation, as the sibling recurrence risk is extremely low. We identify parental PZM in 21 trios (0.5% of trios), resulting in a substantially increased sibling recurrence risk in future pregnancies. Together, these forms of mosaicism account for 40 (1%) diagnoses in our cohort. Likely child-PZM mutations occur equally on both parental haplotypes, and the penetrance of detectable mosaic pathogenic variants overall is likely to be less than half that of constitutive variants.

Structuring Diabetes Mellitus Care in Long-Term Nursing Home Residents.

Nursing home residents with diabetes have more complex care needs with higher levels of comorbidity, disability and cognitive impairment. We compared current practice in the 44 long-term residents in Peamount hospital with the standards recommended in the Diabetes UK "Good Clinical Practice Guidelines for Care Home Residents with Diabetes". Of 44 residents, 11 were diabetic. Residents did not have specific diabetes care plans. There were some elements of good practice with a low incidence of hypoglycaemia and in-house access to dietetics and chiropody. However, diabetes care was delivered on an ad-hoc basis without individualised care plans, documented glycaemic targets, or scheduled monitoring for complications and no formal screening for diabetes on admission. National and local policy to guide management of diabetes mellitus should be developed. There should be individualised diabetes care plans, clear policies for hypoglycaemia, hyperglycaemia and long-term diabetes complications, screening on admission and increased uptake of the national retinal screening and foot care programmes.

Bicycle helmets are protective against facial injuries, including facial fractures: a meta-analysis.

Cycling is a popular activity. However there are risks associated with cycling, including facial injury. Helmets are often worn to prevent head injury. Evidence for their protection against facial injury is limited. This meta-analysis investigated the effect of bicycle helmets on the incidence of facial injury. The PubMed/MEDLINE, Google Scholar, and Cochrane Library databases were searched. Studies included were observational and involved adult participants. Paediatric studies, studies on helmet legislation, and those combining facial injuries with other injury types were excluded. The studies were evaluated by two reviewers. Risk of bias was assessed using the RevMan bias assessment tool. Odds ratios (OR) were extracted for facial injuries and facial fractures. Two meta-analyses were performed using these categories. Nine of the 102 studies identified were included. Helmets were protective against facial injury (OR 0.69, 95% confidence interval 0.63-0.75, P<0.0001). Five studies reported facial fracture rates; helmets were protective against these also (OR 0.79 95% confidence interval 0.70-0.90, P=0.0003). There are no randomized controlled trials on this topic and the number of studies available is small. Bicycle helmets offer protection against facial injuries and this should be considered by cyclists when deciding whether or not to use one.

Post marathon cardiac troponin T is associated with relative exercise intensity.

OBJECTIVES: This study aimed to investigate whether measures of cardiopulmonary fitness and relative exercise intensity were associated with high sensitivity cardiac troponin T (cTnT) rise after a road marathon. METHODS: Fifty-two marathon runners (age 39±11 years, body mass 76.2±12.9kg, height 1.74±0.09m) attended the laboratory between 2 and 3 weeks prior to attempting the Brighton Marathon, UK. Running economy at 10kmh-1 (RE10) and race pace (RERP), ventilatory threshold (VT) and VO2max tests were completed. CTnT was measured within 48h prior to the marathon and within 10min of completing the marathon, using a high sensitivity assay. Heart rates (HR) were recorded throughout the marathon. RESULTS: Runners demonstrated a significant increase in cTnT over the marathon (pre-race 5.60±3.27ngL-1, post-race 74.52±30.39ngL-1, p<0.001). Markers of endurance performance such as running economy (10kmh-1 223±18mlkg-1km-1; race pace 225±22mlkg-1km-1), VT (38.5±6.4mlkg-1min-1) and V˙O2max (50.9±7.7mlkg-1min-1) were not associated with post-race cTnT. Runners exercise intensity correlated with post-race cTnT (mean HR %VT 104±5%, r=0.50; peak HR %VT 118±8%, r=0.68; peak HR %V˙O2max 96±6, r=0.60, p<0.05) and was different between the low, medium and high cTnT groups (p<0.05). CONCLUSIONS: CTnT increases above reference limits during a marathon. Magnitude of cTnT rise is related to exercise intensity relative to ventilatory threshold and V˙O2max, but not individuals' absolute cardiopulmonary fitness, training state or running history.

A Phase II Toxicity End Point Trial (ICORG 99-09) of Accelerated Dose-escalated Hypofractionated Radiation in Non-small Cell Lung Cancer.

AIMS: The objective of this phase II clinical trial was to prospectively evaluate the safety and efficacy of accelerated hypofractionated three-dimensional conformal radiation therapy (3DCRT) in localised non-resectable/non-operable non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Sixty patients with stage I-III NSCLC were enrolled in a prospective single-arm All Ireland Co-operative Oncology Research Group (ICORG 99-09) toxicity end point phase II trial. The protocol allocated patients between three radiation schedule dose levels (60, 66 or 72 Gy, in 20, 22 and 24 fractions, respectively, 3 Gy daily, five fractions per week) according to combined lung V25Gy (V25Gy ≤ 30%) with built-in early stopping toxicity rules. The primary end point was toxicity with evaluation of dose-limiting toxicity. The secondary objectives included radiological tumour response rate at 3 months after the completion of radiation therapy and the thoracic progression-free survival time. RESULTS: Sixty patients were recruited from August 1999 to June 2009. Forty-nine patients were included in the primary per-protocol analysis. Eleven patients were not evaluable. In the first 30 evaluable patient cohort, severe oesophageal toxicity was reported in two patients (2/49; 4% experiencing grade 5 oesophageal late toxicity, related to the 97% oesophageal length). The trial was temporarily closed and was then reopened to validate an oesophageal dose volume constraint (DVC) of limiting the length of oesophagus fully encompassed by the 97% isodose to less than 1 cm (applied to 21 patients). The trial prospectively showed the safety of the oesophageal DVC, with no oesophageal toxicity above grade 3 thereafter. Thirty-nine per cent of patients had disease progression at 3-4 months after radiotherapy, 22% had stable disease, 20% had a complete response and 14% had a partial response. The median overall survival was 13.6 months (95% confidence interval 10.5-16.7) and overall survival at 1 and 3 years was 57% and 29%, respectively. CONCLUSION: A strategy using accelerated hypofractionated 3DCRT is feasible and reasonably safe for patients with inoperable NSCLC. It is safe to deliver for centrally located tumours if DVCs are applied to the oesophagus, which is the primary dose-limiting toxicity. Further studies are required to assess the efficacy of hypofractionated regimens for centrally located tumours using an oesophageal DVC and monitoring for oesophageal toxicity.

Older Motorcyclists in Ireland.

Older motorcyclists are under-recognised as vulnerable road users. Using Irish data from the Central Statistics Office, the Road Safety Authority and the Healthcare Pricing Office, we explored the trend of ageing riders and factors in older motorcyclist collisions and injuries. In 2005, 17 motorcyclists aged 55 and over were injured compared to 31 in 2012. Motorcyclists aged between 30-49 years and 50 years and over have longer lengths of stay compared to riders <30. The percentage of motorcycles with an engine capacity of 750cc or more increased from 39.6% in 2007 to 46.7% in 2015. Older motorcyclists are less likely to be fatally injured in single vehicle collisions. Older motorcyclists are generally safer than younger riders but the proportion of older motorcyclist injury is rising. Irish road safety strategies and trauma services need to incorporate these findings into planning and development of preventive and treatment approaches.

On the fate of particles liberated from hydroxyapatite coatings in vivo.

PURPOSE: Hydroxyapatite (HA) has been used as a coating for orthopaedic implants for over 30 years to help promote the fixation of orthopaedic implants into the surrounding bone. However, concerns exist about the fate of the hydroxyapatite coating and hydroxyapatite particles in vivo, especially in the wake of recent concerns about particulates from metal-on-metal bearings. METHODS: Here, we assess the mechanisms of particle detachment from coated orthopaedic devices as well as the safety and performance concerns and biomedical implications arising from the liberation of the particles by review of the literature. FINDINGS: The mechanisms that can result in the detachment of the HA coating from the implant can be mechanical or biochemical, or both. Mechanical mechanisms include implant insertion, abrasion, fatigue and micro-motion. Biochemical mechanisms that contribute to the liberation of HA particles include dissolution into extra-cellular fluid, cell-mediated processes and crystallisation of amorphous phases. The form the particles take once liberated is influenced by a number of factors such as coating method, the raw powder morphology, processing parameters, coating thickness and coating structure. CONCLUSIONS: This review summarises and discusses each of these factors and concludes that HA is a safe biomimetic material to use as a coating and does not cause any problems in particulate form if liberated as debris from an orthopaedic implant.

Aspirated bile: a major host trigger modulating respiratory pathogen colonisation in cystic fibrosis patients.

Chronic respiratory infections are a leading global cause of morbidity and mortality. However, the molecular triggers that cause respiratory pathogens to adopt persistent and often untreatable lifestyles during infection remain largely uncharacterised. Recently, bile aspiration caused by gastro-oesophageal reflux (GOR) has emerged as a significant complication associated with respiratory disease, and cystic fibrosis (CF) in particular. Based on our previous finding that the physiological concentrations of bile influence respiratory pathogens towards a chronic lifestyle in vitro, we investigated the impact of bile aspiration on the lung microbiome of respiratory patients. Sputum samples (n = 25) obtained from a cohort of paediatric CF patients were profiled for the presence of bile acids using high-resolution liquid chromatography-mass spectrometry (LC-MS). Pyrosequencing was performed on a set of ten DNA samples that were isolated from bile aspirating (n = 5) and non-bile aspirating (n = 5) patients. Both denaturing gradient gel electrophoresis (DGGE) and pyrosequencing revealed significantly reduced biodiversity and richness in the sputum samples from bile aspirating patients when compared with non-aspirating patients. Families and genera associated with the pervasive CF microbiome dominated aspirating patients, while bacteria associated with the healthy lung were most abundant in non-aspirating patients. Bile aspiration linked to GOR is emerging as a major host trigger of chronic bacterial infections. The markedly reduced biodiversity and increased colonisation by dominant proteobacterial CF-associated pathogens observed in the sputum of bile aspirating patients suggest that bile may play a major role in disease progression in CF and other respiratory diseases.

Development of mapped stress-field boundary conditions based on a Hill-type muscle model.

Forces generated in the muscles and tendons actuate the movement of the skeleton. Accurate estimation and application of these musculotendon forces in a continuum model is not a trivial matter. Frequently, musculotendon attachments are approximated as point forces; however, accurate estimation of local mechanics requires a more realistic application of musculotendon forces. This paper describes the development of mapped Hill-type muscle models as boundary conditions for a finite volume model of the hip joint, where the calculated muscle fibres map continuously between attachment sites. The applied muscle forces are calculated using active Hill-type models, where input electromyography signals are determined from gait analysis. Realistic muscle attachment sites are determined directly from tomography images. The mapped muscle boundary conditions, implemented in a finite volume structural OpenFOAM (ESI-OpenCFD, Bracknell, UK) solver, are employed to simulate the mid-stance phase of gait using a patient-specific natural hip joint, and a comparison is performed with the standard point load muscle approach. It is concluded that physiological joint loading is not accurately represented by simplistic muscle point loading conditions; however, when contact pressures are of sole interest, simplifying assumptions with regard to muscular forces may be valid.

Changes in management and outcome of patients with rectal cancer in Northern Ireland: 1996-2006.

AIM: This study aimed to document developments in rectal cancer services in a UK population and evaluate changes in outcome over a 10-year period. METHOD: Patients diagnosed with primary rectal carcinoma in 1996, 2001 and 2006 were identified by the Northern Ireland Cancer Registry. Data were retrospectively collected on presentation, investigation, treatment and staging. Differences over the period were analysed using the chi-squared test; Kaplan-Meier and Cox regression tests were used for survival analysis. RESULTS: After exclusions there were 636 patients, including 187 presenting in 1996, 203 in 2001 and 246 in 2006. The use of preoperative MRI of the rectum, endorectal ultrasound and abdominal CT increased during the study period. For patients treated by surgery, total mesorectal excision (TME) increased from 19% in 1996 to 64% in 2006 (P < 0.001). The use of radiotherapy (27% in 1996, 47% in 2006) and chemotherapy (21% in 1996, 32% in 2006) increased. The overall 5-year survival improved significantly between 1996 and 2006 from 34% in 1996 to 45% in 2006 (P = 0.02). Among patients having surgery, 5-year survival increased from 43% in 1996 to 63% in 2006 (P < 0.001). Multivariate analysis showed that the improvement in survival was associated with TME and chemotherapy, while radiotherapy was not. CONCLUSION: Survival of patients with rectal cancer in Northern Ireland has improved significantly over the last decade, probably due to the increased use of TME and chemotherapy.

Rapid profiling of enteric coated drug delivery spheres via broadband acoustic resonance dissolution spectroscopy (BARDS).

There is an increased trend towards the use of drug and enteric coated sugar spheres for controlled oral delivery of active pharmaceutical ingredients (API). This trend is driven by increased efficacy and ease of formulation of different dosage levels. However, difficulties exist in determining the thickness of drug and enteric coatings in a time efficient manner during manufacture, quality assurance and stability testing. The thickness of the coating determines the dosage of the API and the thickness of the enteric coating determines the release rate of the drug in the gastro-intestinal tract. Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS) offers a rapid new approach to characterising the enteric coating thickness and the raw materials used in their manufacture. BARDS applications are based on reproducible changes in the compressibility of a solvent during dissolution which is monitored acoustically due to associated changes in the speed of sound in solution. It is demonstrated how core delivery sugar spheres have unique acoustic spectra attributable to the mean size distribution of the spheres. A steady state acoustic lag time is associated with the disintegration of the enteric coating, in basic solution. This lag time can be manipulated by varying the concentration of the base which affects the rate at which the coating dissolves. It is anticipated that the thickness/loading of the spheres can be estimated from the lag time.

Radiography and biomechanics of sixth and seventh cervical vertebrae segments after disc fenestration and after insertion of an intervertebral body spacer. A canine cadaveric study.

OBJECTIVES: To study the radiographic characteristics and the biomechanical properties of the sixth and seventh cervical (C6-C7) vertebral motion unit (VMU) with an intact disc, after disc fenestration, and after placement of an intervertebral body spacer (IVBS). METHODS: Six cadaveric C6-C7 VMU were retrieved from six Greyhound cadavers. Each VMU was loaded at 3 Nm of torque sequentially in flexion, extension, and in right and left lateral bending. The range-of-motion (ROM) was measured with a Zebris 3D® system. The intervertebral disc cross-sectional area was measured on lateral and ventro-dorsal radiographs. Biomechanical testing and radiographic measurements were performed with an intact disc, after disc fenestration, and after IVBS placement. Data were reported as mean±SD. RESULTS: The intervertebral disc cross-sectional area was significantly decreased after disc fenestration and increased after IVBS placement, but remained significantly smaller than the area of intact disc in some of the tested conditions. The ROM with an intact disc, after disc fenestration and after IVBS placement, in flexion were 11.5°±1.0, 15.2°±2.3, and 10.9°±4.7, respectively, and in extension were 15.6°±3.7, 24.7°±6.2, 21.9°±4.0, respectively. There was a significant increase in extension ROM after disc fenestration. Intervertebral body spacer placement significantly decreased ROM in flexion but ROM in extension was not different from disc fenestration. No significant changes in lateral bending ROM were detected. CLINICAL SIGNIFICANCE: The use of an IVBS reduced disc space collapse but did not restore stability of the VMU to normal values in extension after cervical disc fenestration.

Development of a hip joint model for finite volume simulations.

This paper establishes a procedure for numerical analysis of a hip joint using the finite volume method. Patient-specific hip joint geometry is segmented directly from computed tomography and magnetic resonance imaging datasets and the resulting bone surfaces are processed into a form suitable for volume meshing. A high resolution continuum tetrahedral mesh has been generated, where a sandwich model approach is adopted; the bones are represented as a stiffer cortical shells surrounding more flexible cancellous cores. Cartilage is included as a uniform thickness extruded layer and the effect of layer thickness is investigated. To realistically position the bones, gait analysis has been performed giving the 3D positions of the bones for the full gait cycle. Three phases of the gait cycle are examined using a finite volume based custom structural contact solver implemented in open-source software OpenFOAM.

Clinical and mutation data in 12 patients with the clinical diagnosis of Nager syndrome.

Nager syndrome (MIM #154400) is the best-known preaxial acrofacial dysostosis, mainly characterized by craniofacial and preaxial limb anomalies. The craniofacial abnormalities mainly consist of downslanting palpebral fissures, malar hypoplasia, micrognathia, external ear anomalies, and cleft palate. The preaxial limb defects are characterized by radial and thumb hypoplasia or aplasia, duplication of thumbs and proximal radioulnar synostosis. Haploinsufficiency of SF3B4 (MIM *605593), which encodes SAP49, a component of the pre-mRNA spliceosomal complex, has recently been identified as the underlying cause of Nager syndrome. In our study, we performed exome sequencing in two and Sanger sequencing of SF3B4 in further ten previously unreported patients with the clinical diagnosis of Nager syndrome, including one familial case. We identified heterozygous SF3B4 mutations in seven out of twelve patients. Four of the seven mutations were shown to be de novo; in three individuals, DNA of both parents was not available. No familial mutations were discovered. Three mutations were nonsense, three were frameshift mutations and one T > C transition destroyed the translation start signal. In three of four SF3B4 negative families, EFTUD2 was analyzed, but no pathogenic variants were identified. Our results indicate that the SF3B4 gene is mutated in about half of the patients with the clinical diagnosis of Nager syndrome and further support genetic heterogeneity for this condition.