Establishing weight-based diagnostic reference levels for neonatal chest X-rays.

INTRODUCTION: As weights among neonates can vary from <900 g to >2.5 kg, weight-based Diagnostic Reference Levels (DRLs) specific to the neonatal intensive care unit (NICU) are essential. Repeated radiation exposure to this sensitive patient group raises concerns regarding high cumulative radiation doses and the potential for long-term health detriment. This study aimed to establish weight-based DRLs for neonates undergoing mobile chest radiography (CXR) in the NICU. METHODS: Neonates were classified into three discrete groups; <1000, 1000-2500 and >2500 g. Data were collected prospectively over three months; 95 DAP values were collected, and five were excluded due to poor technique, leaving 90 patients that met the inclusion criteria for mobile CXR in the NICU. Dose-area-product (DAP) in mGycm2, the peak kilovoltage (kVp) and the product of tube current and exposure time (mAs) were retrieved from the Picture Archiving and Communication System (PACS). Images and radiological reports were also analysed to confirm diagnostic image quality (IQ). Local DRLs (LDRLs) were derived using the median DAP, and national DRLs were suggested using the 3rd quartile value. RESULTS: The proposed LDRLs for neonates weighing <1000 g was 2.7 mGycm2, for neonates weighing between 1000 g and 2500 g, it was 3.7 mGycm2, and for neonates weighing >2500 g it was 6.6 mGycm2. The radiation dose received by the 90 (100%) neonates included in the study fell below 11.4 mGycm2; of these, 82% of the DAP values fell below the study institution's existing LDRL of 7.25 mGycm2. CONCLUSION: Weight-based DRLs provide crucial information on doses to this specific radiation-sensitive group. This work recommends using weight-based categories for DRLs and serves as a benchmark for neonatal CXR standardisation and optimisation. IMPLICATIONS FOR PRACTICE: The proposed weight-based DRLs can be adopted for neonates' locally, nationally and internationally.

Foot and ankle service adaptation in response to COVID-19 and beyond.

The disruption to healthcare provision as a result of the COVID-19 pandemic has compelled us to streamline healthcare delivery. This has given us an opportunity to implement healthcare technology, reform inter-disciplinary collaboration and ultimately enhance patient care. We discuss some of the advances made by the foot and ankle department at our hospital. These innovations have broad applicability and will hopefully ignite discussion amoung a number of healthcare teams about improving the future care of their patients.

Is there an interaction between socioeconomic status and FRAX 10-year fracture probability determined with and without bone density measures? Data from the Geelong Osteoporosis Study of female cohort.

FRAX(©) evaluates 10-year fracture probabilities and can be calculated with and without bone mineral density (BMD). Low socioeconomic status (SES) may affect BMD, and is associated with increased fracture risk. Clinical risk factors differ by SES; however, it is unknown whether aninteraction exists between SES and FRAX determined with and without the BMD. From the Geelong Osteoporosis Study, we drew 819 females aged ≥50 years. Clinical data were collected during 1993-1997. SES was determined by cross-referencing residential addresses with Australian Bureau of Statistics census data and categorized in quintiles. BMD was measured by dual energy X-ray absorptiometry at the same time as other clinical data were collected. Ten-year fracture probabilities were calculated using FRAX (Australia). Using multivariable regression analyses, we examined whether interactions existed between SES and 10-year probability for hip and any major osteoporotic fracture (MOF) defined by use of FRAX with and without BMD. We observed a trend for a SES * FRAX(no-BMD) interaction term for 10-year hip fracture probability (p = 0.09); however, not for MOF (p = 0.42). In women without prior fracture (n = 518), we observed a significant SES * FRAX(no-BMD) interaction term for hip fracture (p = 0.03) and MOF (p = 0.04). SES does not appear to have an interaction with 10-year fracture probabilities determined by FRAX with and without BMD in women with previous fracture; however, it does appear to exist for those without previous fracture.

The social gradient of fractures at any skeletal site in men and women: data from the Geelong Osteoporosis Study Fracture Grid.

UNLABELLED: Age-specific and age-standardized associations between socioeconomic status (SES) and fractures in adults showed a social gradient of fracture, irrespective of fracture site. Compared to the highest SES, males in the lowest SES group had a sixfold increased odds for any fracture, whilst females had a twofold increased odds. INTRODUCTION: The effective identification of predisposing risk factors for fracture requires understanding any association with SES. These investigations should consider both sexes, span the adult age range and include any fractures. We investigated age- and sex-specific and age-standardized associations between SES and fractures at any skeletal site in Australians aged ≥ 50 years. METHODS: Incident fractures that occurred 2006-2007 for adults aged ≥ 50 years were identified from radiological reports extracted for the Barwon Statistical Division, in south-eastern Australia. SES was determined by cross-referencing residential addresses with Australian Bureau of Statistics census data and then categorized in quintiles. We compared frequencies of observed vs. expected fractures for SES quintiles using χ (2) comparison, calculated age-specific fracture incidence across SES and compared age-standardized fracture rates in SES quintile 1 to quintile 5. RESULTS: We identified 3943 incident fractures (69.4 % female); 47.4 % had occurred at major osteoporotic fracture (MOF) sites (hip, humerus, spine and forearm/wrist). Differences existed in observed vs. expected fractures across SES quintiles (p ≤ 0.001, sexes combined); all fractures showed an inverse association with SES (p ≤ 0.001, sexes combined). Compared to the highest SES quintile, individuals from the lowest SES quintile had between two to six times greater standardized fracture rates. CONCLUSIONS: Disadvantaged men and women have an increased fracture incidence compared to their less disadvantaged counterparts. The large differences in fracture rates between SES groups warrant further research into designing appropriate, targeted interventions for those demographics at most risk.

Anti-platelet agents and surgical delay in elderly patients with hip fractures.

PURPOSE: To assess the risk of surgical delay in elderly hip fracture patients on anti-platelet agents. METHODS: Records of 180 patients aged over 65 years with either an intertrochanteric or femoral neck fracture were reviewed. The clopidogrel group included 10 patients on clopidogrel alone and 11 others on clopidogrel and aspirin, whereas the control group included 69 on aspirin alone and the remaining 90 not on any anti-coagulants. The 2 groups were compared with regard to time to surgery, preoperative American Society of Anesthesiologists (ASA) score, pre- and post-operative haemoglobin levels, in-patient complication rates, duration of hospital stay, and 30-day mortality. RESULTS: In the clopidogrel and control groups respectively, the mean times to surgery were 7.2 and 2.1 days (p=0.03, t-test), the mean preoperative ASA scores were 3.35 and 2.8 (p=0.29, t-test), the mean preoperative haemoglobin levels were 119 and 115 g/l (p=0.5, t-test), the mean postoperative haemoglobin levels were 98 and 96 g/l (p=0.68, t-test), the mean durations of hospital stay were 7.4 and 3.1 days (p=0.02, t-test). The 30-day mortalities were 6/21 (29%) and 6/159 (4%) [p=0.0003, Fisher's exact test]. CONCLUSION: Surgical delay in elderly patients on anti-platelet agents with hip fracture was associated with higher mortality. Despite the risk of increased blood loss, we suggest early surgery be carried out by an experienced surgeon to expedite the operating time. Pooled platelets should be given intravenously one to 2 hours preoperatively.

The H-flap: a useful flap for forehead reconstruction.

We have found that double opposing rectangular advancement flaps in the forehead may be easily performed under either local or general anaesthesia, and are associated with high patient satisfaction and low morbidity. We claim no originality for the mode of reconstruction, but highlight its broad spectrum of application and its popularity with junior plastic surgeons passing through our unit. We have found that the term 'H-flap' provides a readily communicated alternative to 'double opposing rectangular advancement flaps'.

Fringe modulation of Jagged1-induced Notch signaling requires the action of beta 4galactosyltransferase-1.

Fringe modulates Notch signaling resulting in the establishment of compartmental boundaries in developing organisms. Fringe is a beta 3N-acetylglucosaminyltransferase (beta 3GlcNAcT) that transfers GlcNAc to O-fucose in epidermal growth factor-like repeats of Notch. Here we use five different Chinese hamster ovary cell glycosylation mutants to identify a key aspect of the mechanism of fringe action. Although the beta 3GlcNAcT activity of manic or lunatic fringe is shown to be necessary for inhibition of Jagged1-induced Notch signaling in a coculture assay, it is not sufficient. Fringe fails to inhibit Notch signaling if the disaccharide generated by fringe action, GlcNAc beta 3Fuc, is not elongated. The trisaccharide, Gal beta 4GlcNAc beta 3Fuc, is the minimal O-fucose glycan to support fringe modulation of Notch signaling. Of six beta 4galactosyltransferases (beta 4GalT) in Chinese hamster ovary cells, only beta 4GalT-1 is required to add Gal to GlcNAc beta 3Fuc, identifying beta 4GalT-1 as a new modulator of Notch signaling.

An aberrant lymph node containing metastatic melanoma detected by sentinel node biopsy.

The use of sentinel node biopsy in the staging of malignant melanoma has led to the identification of lymph nodes outside the described regional basins, so-called aberrant nodes. We present a case in which such an aberrant sentinel node was found to be positive for metastatic disease, and discuss our surgical management.

A conservative surgical approach to the treatment of 'locally invasive' lentigo maligna melanoma of the face.

Lentigo maligna has the potential for malignant change, and is managed in many cases by wide local excision. However, there are clinical situations in which aggressive surgical management is inappropriate or unsuccessful. We present three such cases, in which a more conservative surgical approach was adopted and maintained over several decades.

Iminopropadienethiones, Ar=N=C=C=C=S.

Aryliminopropadienethiones 9 have been generated by flash vacuum thermolysis of isoxazolones of the type 5 and characterized by mass spectrometry and matrix isolation IR spectroscopy in conjunction with DFT calculations and chemical trapping.

Hunterian Lecture. What can we learn about mechanisms of mutation from a study of craniosynostosis?

Mutation may be defined simply as structural change affecting the genetic material. The generation of genetic variety by spontaneous mutational events has been the driving force behind evolution--without such mutation our complex human genome could not have evolved. However, as doctors, we more frequently encounter mutation in the context of human disease, whether in somatic cells as a cause of cancer, or in the germline as a cause of inheritable disease. In these contexts, the processes of mutagenesis are relevant to every field of medicine. Scientific study of mutational mechanisms has logically been founded in the relatively simple genetic systems of the prokaryotes and such lowly eukaryotes as the fruit-fly. The study of human clinical genetics approaches the problem from quite the opposite direction--from that of the most highly evolved genetic system. Whilst this approach may be dependent less on logical progression and more on phenomenology, it nevertheless provides a complementary avenue for the observation and study of mutational mechanisms. The genetic research described in this article is firmly rooted in such phenomenology, based as it is on rare craniosynostosis syndromes. Over the past decade, there has been a deluge of molecular discoveries in the field of craniosynostosis. This promises improvements in classification, prognostication, pre-natal diagnosis, and perhaps ultimately for potential avenues for cure. However, exciting as these clinical prospects are, the research presented here has a different focus: it investigates the mechanistic basis underlying the craniosynostosis mutations, in the hope that such study may lead to insights applicable generally to the field of mutagenesis.

Patients with acute skin loss: are they best managed on a burns unit?

Patients who are critically ill and have large areas of skin loss or breakdown present a difficult management problem. They require the combination of intensive therapy facilities to support failing organs and specialized skin care, sometimes including extensive debridement and reconstruction. The expertise required for both aspects of treatment are found uniquely on a burns unit. We present five patients with large areas of cutaneous loss or damage secondary to a variety of non-burn aetiologies who were managed on a burns unit. We suggest that a burns unit may be the most appropriate place for such patients to be treated during both the acute phase of their illness and the later stages of surgical reconstruction and physical rehabilitation.

Fringe is a glycosyltransferase that modifies Notch.

Notch receptors function in highly conserved intercellular signalling pathways that direct cell-fate decisions, proliferation and apoptosis in metazoans. Fringe proteins can positively and negatively modulate the ability of Notch ligands to activate the Notch receptor. Here we establish the biochemical mechanism of Fringe action. Drosophila and mammalian Fringe proteins possess a fucose-specific beta1,3 N-acetylglucosaminyltransferase activity that initiates elongation of O-linked fucose residues attached to epidermal growth factor-like sequence repeats of Notch. We obtained biological evidence that Fringe-dependent elongation of O-linked fucose on Notch modulates Notch signalling by using co-culture assays in mammalian cells and by expression of an enzymatically inactive Fringe mutant in Drosophila. The post-translational modification of Notch by Fringe represents a striking example of modulation of a signalling event by differential receptor glycosylation and identifies a mechanism that is likely to be relevant to other signalling pathways.

Rehabilitation of a person with severe traumatic brain injury.

A case study report of a long and intensive rehabilitation programme for a young woman after she sustained a severe diffuse axonal injury in a motor vehicle accident is described in detail. The purpose of this paper is to encourage specialist brain injury rehabilitation services to offer extended rehabilitation programmes to patients, even with very severe injuries. Significant functional improvements and enhanced quality of life frequently reward the high cost and hard work involved.

Mammalian Notch1 is modified with two unusual forms of O-linked glycosylation found on epidermal growth factor-like modules.

Notch is a large cell-surface receptor known to be an essential player in a wide variety of developmental cascades. Here we show that Notch1 endogenously expressed in Chinese hamster ovary cells is modified with O-linked fucose and O-linked glucose saccharides, two unusual forms of O-linked glycosylation found on epidermal growth factor-like (EGF) modules. Interestingly, both modifications occur as monosaccharide and oligosaccharide species. Through exoglycosidase digestions we determined that the O-linked fucose oligosaccharide is a tetrasaccharide with a structure identical to that found on human clotting factor IX: Sia-alpha2,3-Gal-beta1, 4-GlcNAc-beta1,3-Fuc-alpha1-O-Ser/Thr. The elongated form of O-linked glucose appears to be a trisaccharide. Notch1 is the first membrane-associated protein identified with either O-linked fucose or O-linked glucose modifications. It also represents the second protein discovered with an elongated form of O-linked fucose. The sites of glycosylation, which fall within the multiple EGF modules of Notch, are highly conserved across species and within Notch homologs. Since Notch is known to interact with its ligands through subsets of EGF modules, these results suggest that the O-linked carbohydrate modifications of these modules may influence receptor-ligand interactions.

The O-linked fucose glycosylation pathway: identification and characterization of a uridine diphosphoglucose: fucose-beta1,3-glucosyltransferase activity from Chinese hamster ovary cells.

O-Linked fucose is an unusual carbohydrate modification in which fucose is linked directly to the hydroxyl groups of serines or threonines. It has been found on the epidermal growth factor-like modules of several secreted proteins involved in blood coagulation and fibrinolysis. We have recently reported the existence of an elongated form of O-linked fucose in Chinese hamster ovary cells consisting of a glucose linked to the 3'-hydroxyl of fucose (Glcbeta1,3Fuc- O-Ser/Thr). This structure is highly unusual for two reasons. First, in mammalian systems fucose is usually a terminal modification of N - and O-linked oligosaccharides. Here the fucose is internal. Secondly, terminal beta-linked glucose is extremely rare on mammalian glycoconjugates. Thus, the Glcbeta1,3Fuc structure is a very unique mammalian carbohydrate structure. Here we report the identification and initial characterization of a novel enzyme activity capable of forming this unique linkage: UDP-glucose: O-linked fucose beta1,3 glucosyltransferase. The enzyme utilizes UDP-glucose as the high energy donor and transfers glucose to alpha-linked fucose residues. The activity is linearly dependent on time, enzyme, and substrate concentrations and is enhanced in the presence of manganese ions. Activity is present in extracts of cultured cells from a variety of species (hamster, human, mouse, rat, chicken) and is enriched in brain and spleen of a normal adult rat. Thus, while this glycosyltransferase appears to be widespread in biology, it forms a very unique linkage, and it represents the first mammalian enzyme identified capable of elongating fucose.

A comprehensive screen for TWIST mutations in patients with craniosynostosis identifies a new microdeletion syndrome of chromosome band 7p21.1.

Mutations in the coding region of the TWIST gene (encoding a basic helix-loop-helix transcription factor) have been identified in some cases of Saethre-Chotzen syndrome. Haploinsufficiency appears to be the pathogenic mechanism involved. To investigate the possibility that complete deletions of the TWIST gene also contribute to this disorder, we have developed a comprehensive strategy to screen for coding-region mutations and for complete gene deletions. Heterozygous TWIST mutations were identified in 8 of 10 patients with Saethre-Chotzen syndrome and in 2 of 43 craniosynostosis patients with no clear diagnosis. In addition to six coding-region mutations, our strategy revealed four complete TWIST deletions, only one of which associated with a translocation was suspected on the basis of conventional cytogenetic analysis. This case and two interstitial deletions were detectable by analysis of polymorphic microsatellite loci, including a novel (CA)n locus 7.9 kb away from TWIST, combined with FISH; these deletions ranged in size from 3.5 Mb to >11.6 Mb. The remaining, much smaller deletion was detected by Southern blot analysis and removed 2,924 bp, with a 2-bp orphan sequence at the breakpoint. Significant learning difficulties were present in the three patients with megabase-sized deletions, which suggests that haploinsufficiency of genes neighboring TWIST contributes to developmental delay. Our results identify a new microdeletion disorder that maps to chromosome band 7p21.1 and that causes a significant proportion of Saethre-Chotzen syndrome.