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1.  Integrative “Omic” Analysis of Experimental Bacteremia Identifies a Metabolic Signature That Distinguishes Human Sepsis from Systemic Inflammatory Response Syndromes 
Rationale: Sepsis is a leading cause of morbidity and mortality. Currently, early diagnosis and the progression of the disease are difficult to make. The integration of metabolomic and transcriptomic data in a primate model of sepsis may provide a novel molecular signature of clinical sepsis.
Objectives: To develop a biomarker panel to characterize sepsis in primates and ascertain its relevance to early diagnosis and progression of human sepsis.
Methods: Intravenous inoculation of Macaca fascicularis with Escherichia coli produced mild to severe sepsis, lung injury, and death. Plasma samples were obtained before and after 1, 3, and 5 days of E. coli challenge and at the time of killing. At necropsy, blood, lung, kidney, and spleen samples were collected. An integrative analysis of the metabolomic and transcriptomic datasets was performed to identify a panel of sepsis biomarkers.
Measurements and Main Results: The extent of E. coli invasion, respiratory distress, lethargy, and mortality was dependent on the bacterial dose. Metabolomic and transcriptomic changes characterized severe infections and death, and indicated impaired mitochondrial, peroxisomal, and liver functions. Analysis of the pulmonary transcriptome and plasma metabolome suggested impaired fatty acid catabolism regulated by peroxisome-proliferator activated receptor signaling. A representative four-metabolite model effectively diagnosed sepsis in primates (area under the curve, 0.966) and in two human sepsis cohorts (area under the curve, 0.78 and 0.82).
Conclusions: A model of sepsis based on reciprocal metabolomic and transcriptomic data was developed in primates and validated in two human patient cohorts. It is anticipated that the identified parameters will facilitate early diagnosis and management of sepsis.
PMCID: PMC4214130  PMID: 25054455
metabolomics; transcriptomics; bacteremia; nonhuman primates; mitochondrial dysfunction
2.  Advancing our understanding of the human microbiome using QIIME 
Methods in enzymology  2013;531:371-444.
High-throughput DNA sequencing technologies, coupled with advanced bioinformatics tools, have enabled rapid advances in microbial ecology and our understanding of the human microbiome. QIIME (Quantitative Insights Into Microbial Ecology) is an open-source bioinformatics software package designed for microbial community analysis based on DNA sequence data, which provides a single analysis framework for analysis of raw sequence data through publication quality statistical analyses and interactive visualizations. In this paper, we demonstrate the use of the QIIME pipeline to analyze microbial communities obtained from several sites on the bodies of transgenic and wild-type mice, as assessed using 16S rRNA gene sequences generated on the Illumina MiSeq platform. We present our recommended pipeline for performing microbial community analysis, and provide guidelines for making critical choices in the process. We present examples of some of the types of analyses that are enabled by QIIME, and discuss how other tools, such as phyloseq and R, can be applied to expand upon these analyses.
PMCID: PMC4517945  PMID: 24060131
3.  Monteggia type IV fracture in a child with radial head dislocation irreducible by closed means: a case report 
BMC Research Notes  2014;7:539.
Fractures of the proximal third of the ulna and radius with associated anterior radial head dislocation are uncommon in children. Early recognition and appropriate management are essential to prevent long-term consequences of loss of forearm rotation, cubitus valgus, elbow instability and chronic pain.
Case presentation
We present the case of a 3-year-old Caucasian boy who attended the emergency department following an un-witnessed fall, resulting in right elbow and forearm pain, swelling and deformity. Clinical and radiological examination revealed a Monteggia type IV fracture-dislocation.
The patient was treated with closed manipulation and percutaneous fixation of both bone forearm fractures with intra-medullary wires. After failed attempts at closed reduction, open reduction of the radial head was required.
The block to reduction was due to a buttonholing of the radial head through the anterior joint capsule, with interposition of the capsule in the radiocapitellar joint. Subsequently, alignment was maintained with fracture healing. Follow-up at five months showed a full range of elbow movement with no adverse symptoms.
Monteggia lesions of the paediatric elbow, albeit uncommon, should be considered in all forearm fractures. Accurate reduction of the radiocapitellar joint is crucial to prevent significant long-term consequences and failed closed reduction requires open reduction. Here we have described the management of a rare type IV lesion in which there was buttonholing of the radial head through the anterior capsule, causing the radiocapitellar dislocation to be irreducible (even after fixation of the radial and ulnar fractures).
PMCID: PMC4150939  PMID: 25129627
Paediatric; Monteggia fracture-dislocation; Irreducible radial head
4.  Paediatric fracture clinic design – current practice and implications for change 
BMC Research Notes  2014;7:96.
In our region there has been considerable success in the redesign of adult fracture clinics. The aim of this study was to define our paediatric fracture clinic load, to assess the feasibility of increasing efficiency by decreasing inappropriate attendance.
Prospective case notes review of all attendees at 6 serial fracture clinics at the Royal Hospital for Sick Children (Glasgow) which has both local and tertiary referrals. Of 234 consecutive attendances across 6 fracture clinics, 34 (15%) were judged inappropriate: 13 had fractures not requiring orthopaedic follow-up (radial torus/clavicle/undisplaced metacarpal), and 21 had diagnoses or situations that were not appropriate. Of the 200 attendances deemed appropriate (172 fractures, 11 soft-tissue injuries, 9 infections and 8 acute atraumatic limps), there were 33 new referrals from the emergency department, and a further 39 were first-time attenders at the fracture clinic after an acute admission (37 were post-operative and 2 were non-operative). Of these 200, the treatment plan was changed for 67 (34%), a cast removed or exchanged for 92 (46%), and radiographs taken for 153 (77%). The overall discharge to return ratio was 76:158 (1:2.1), and for appropriate attenders 61:139 (1:2.3).
Tighter discipline can be applied to indications for fracture clinic appointments, including certain fracture types being discharged from the emergency department without unnecessary review - our particular fracture clinic numbers can be decreased by 15%. In the remaining attendances there are high radiograph and intervention rates, such that it seems unlikely that further reductions in attendance would be feasible.
PMCID: PMC3933002  PMID: 24555762
Fracture clinic; Paediatric; Efficiency; Torus; Buckle
5.  Growth arrest lines and intra-epiphyseal silhouettes: a case series 
BMC Research Notes  2014;7:27.
Growth arrest lines can develop within the skeleton after physiological stress or trauma. They are usually evident on radiographs as transverse lines in the metaphyses and have been used in fields from palaeontology to orthopaedics. This report consists of three cases, two of which describe growth arrest lines in an intra-epiphyseal site hitherto rarely documented, and a third demonstrating their clinical application.
Case presentation
Case 1 describes a 9-year-old who suffered a knee hyperflexion injury requiring anterior cruciate ligament and posterior cruciate ligament reattachments. She subsequently developed a marked distal femoral intra-epiphyseal arrest silhouette, as well as metaphyseal arrest lines in the femur, tibia and fibula. Case 2 describes an 8-year-old who sustained a tibial spine fracture and underwent open reduction and internal fixation. Subsequent imaging shows a further example of femoral intra-epiphyseal arrest silhouette as well as tibia and fibula metaphyseal arrest lines. Case 3 describes a 10-year-old who sustained a distal tibia fracture which was managed with open reduction and internal fixation. Subsequently the metaphyseal growth arrest line was parallel to the physis, suggesting no growth arrest (a danger with such a fracture).
This case series describes two examples of rarely described intra-epiphyseal growth arrest silhouettes and demonstrates the usefulness of arrest lines when assessing for growth plate damage.
PMCID: PMC3927262  PMID: 24410952
Growth arrest lines; Orthopaedics; Physis
6.  Congenital vertical talus in Cri du Chat Syndrome: a case report 
BMC Research Notes  2013;6:270.
Congenital vertical talus is a rare deformity of the foot which can cause substantial pain and disability. Its incidence is approximately 1 in 100,000 live births. It has an association with other neuromuscular abnormalities and identified genetic syndromes in 50% of cases [1-5]. This report presents a case of congenital vertical talus in an infant with Cri du Chat Syndrome (CdCS) which - to our knowledge - has not been previously reported.
Case presentation
A 2 week-old Caucasian, male infant was referred for congenital feet abnormalities and a “clicky” hip at the post-natal baby check. The diagnosis was vertical talus of the right foot and oblique talus of the left foot. Treatment involved serial plaster casts in the “reverse-Ponseti” position until surgery 16 weeks later. The correction was maintained and the feet remain in good position at follow-up. General concern over the infant’s development, failing to reach appropriate milestones, prompted paediatric referral. Genetic analysis was finally carried out, giving a diagnosis of Cri du Chat syndrome at two and a half years of age.
In light of other reports of chromosomal anomalies causing congenital vertical talus, the learning point from this case is to investigate early for possible aetiologies, not only spinal/neuromuscular, but also those of a genetic basis.
PMCID: PMC3722027  PMID: 23849392
Congenital vertical talus; Cri du chat syndrome; Flat foot
7.  Ultra-high-throughput microbial community analysis on the Illumina HiSeq and MiSeq platforms 
The ISME Journal  2012;6(8):1621-1624.
DNA sequencing continues to decrease in cost with the Illumina HiSeq2000 generating up to 600 Gb of paired-end 100 base reads in a ten-day run. Here we present a protocol for community amplicon sequencing on the HiSeq2000 and MiSeq Illumina platforms, and apply that protocol to sequence 24 microbial communities from host-associated and free-living environments. A critical question as more sequencing platforms become available is whether biological conclusions derived on one platform are consistent with what would be derived on a different platform. We show that the protocol developed for these instruments successfully recaptures known biological results, and additionally that biological conclusions are consistent across sequencing platforms (the HiSeq2000 versus the MiSeq) and across the sequenced regions of amplicons.
PMCID: PMC3400413  PMID: 22402401
illumine; barcoded sequencing; QIIME
8.  Neurological status in paediatric upper limb injuries in the emergency department – current practice 
BMC Research Notes  2012;5:324.
In upper limb injuries it is important to assess associated neurological injury. The aim of this study was to assess the initial (Emergency Department (ED)) documentation of neurological status in paediatric patients presenting with upper limb injuries.
Case notes of paediatric patients admitted to the orthopaedic ward with upper limb injuries were retrospectively collected over a three month period. Initial ED documentation was recorded and case notes examined for any neurological deficit on admission. Of the 121 patients, 107 (88.4%) of case notes had some form of neurological documentation. The remaining case notes (n = 14, 11.6%) had no mention of neurological examination. There were 10 (8.2%) patients with pre-operative neurological deficits identified; none of these had been previously identified by the ED.
There are failings of neurological documentation on the part of ED staff. It is likely that these reflect a knowledge deficit in the examination of the injured upper limb in paediatric patients.
PMCID: PMC3408341  PMID: 22726384
Trauma; Paediatric Injury; Paediatric Emergency Medicine; Clinical Assessment; Musculoskeletal
9.  Rapid Prototyping in Orthopaedic Surgery: A User's Guide 
The Scientific World Journal  2012;2012:838575.
Rapid prototyping (RP) is applicable to orthopaedic problems involving three dimensions, particularly fractures, deformities, and reconstruction. In the past, RP has been hampered by cost and difficulties accessing the appropriate expertise. Here we outline the history of rapid prototyping and furthermore a process using open-source software to produce a high fidelity physical model from CT data. This greatly mitigates the expense associated with the technique, allowing surgeons to produce precise models for preoperative planning and procedure rehearsal. We describe the method with an illustrative case.
PMCID: PMC3361341  PMID: 22666160
10.  Profiles of Biomarkers of Excess Alcohol Consumption in Patients Undergoing Total Hip Replacement: Correlation with Function 
TheScientificWorldJournal  2011;11:1804-1811.
Aims. Patients who misuse alcohol may be at increased risk of surgical complications and poorer function following hip replacement. Identification and intervention may lead to harm reduction and improve the outcomes of surgery. The aim of this study was to determine the prevalence of biomarker elevation in patients undergoing hip replacement and to investigate any correlation with functional scores and complications. Methods. We performed a retrospective study that examined the profile of biomarkers of alcohol misuse in 1049 patients undergoing hip replacement. Results. Gamma-glutamyltransferase was elevated in 150 (17.6%), and mean corpuscular volume was elevated in 23 (4%). At one year general physical health was poorer where there was elevation of γGT, and the mental health and hip function was poorer with elevation of MCV. There were no differences in complications. Discussion. Raised biomarkers can alert clinicians to potential problems. They also provide an opportunity to perform further investigation and offer intervention. Future research should focus on the use in orthopaedic practice of validated screening questionnaires and more sensitive biomarkers of alcohol misuse. Conclusion. This study demonstrates a potential substantial proportion of unrecognised alcohol misuse that is associated with poorer functional scores in patients after total hip replacement.
PMCID: PMC3201696  PMID: 22125438
Total hip replacement; total hip arthroplasty; hip replacement; alcohol misuse; patient reported outcome measure
11.  Use of intra-medullary stacked nailing in the reduction of proximal plastic deformity in a pediatric Monteggia fracture: a case report 
In a Monteggia fracture dislocation, it is important to reduce the ulnar fracture completely. Extensive plastic deformation of the proximal ulna may make reduction by closed manipulation impossible.
Case presentation
We report the case of a four-year-old Caucasian boy in whom the plastic deformation of the proximal ulna was reduced, and this reduction was maintained, using intra-medullary stacked nailing.
The technique of stacked nailing is a useful addition to the armamentarium in the management of the potentially awkward Monteggia fracture.
PMCID: PMC3084165  PMID: 21496290
12.  Increasing the Osmolarity of Joint Irrigation Solutions May Avoid Injury to Cartilage: A Pilot Study 
Saline (0.9%, 285 mOsm) and Hartmann’s solution (255 mOsm) are two commonly used joint irrigation solutions that alter the extracellular osmolarity of in situ chondrocytes during articular surgery. We asked whether varying the osmolarity of these solutions influences in situ chondrocyte death in mechanically injured articular cartilage. We initially exposed osteochondral tissue harvested from the metacarpophalangeal joints of 3-year-old cows to solutions of 0.9% saline and Hartmann’s solution of different osmolarity (100–600 mOsm) for 2 minutes to allow in situ chondrocytes to respond to the altered osmotic environment. The full thickness of articular cartilage then was “injured” with a fresh scalpel. Using confocal laser scanning microscopy, in situ chondrocyte death at the injured cartilage edge was quantified spatially as a function of osmolarity at 2.5 hours. Increasing the osmolarity of 0.9% saline and Hartmann’s solution to 600 mOsm decreased in situ chondrocyte death in the superficial zone of injured cartilage. Compared with 0.9% saline, Hartmann’s solution was associated with greater chondrocyte death in the superficial zone of injured cartilage, but not when the osmolarity of both solutions was increased to 600 mOsm. These experiments may have implications for the design of irrigation solutions used during arthroscopic and open articular surgery.
PMCID: PMC2816775  PMID: 19641975
13.  Meiosis-specific gene discovery in plants: RNA-Seq applied to isolated Arabidopsis male meiocytes 
BMC Plant Biology  2010;10:280.
Meiosis is a critical process in the reproduction and life cycle of flowering plants in which homologous chromosomes pair, synapse, recombine and segregate. Understanding meiosis will not only advance our knowledge of the mechanisms of genetic recombination, but also has substantial applications in crop improvement. Despite the tremendous progress in the past decade in other model organisms (e.g., Saccharomyces cerevisiae and Drosophila melanogaster), the global identification of meiotic genes in flowering plants has remained a challenge due to the lack of efficient methods to collect pure meiocytes for analyzing the temporal and spatial gene expression patterns during meiosis, and for the sensitive identification and quantitation of novel genes.
A high-throughput approach to identify meiosis-specific genes by combining isolated meiocytes, RNA-Seq, bioinformatic and statistical analysis pipelines was developed. By analyzing the studied genes that have a meiosis function, a pipeline for identifying meiosis-specific genes has been defined. More than 1,000 genes that are specifically or preferentially expressed in meiocytes have been identified as candidate meiosis-specific genes. A group of 55 genes that have mitochondrial genome origins and a significant number of transposable element (TE) genes (1,036) were also found to have up-regulated expression levels in meiocytes.
These findings advance our understanding of meiotic genes, gene expression and regulation, especially the transcript profiles of MGI genes and TE genes, and provide a framework for functional analysis of genes in meiosis.
PMCID: PMC3018465  PMID: 21167045
14.  Attitudes towards alcohol of emergency department doctors trained in the detection of alcohol misuse. 
INTRODUCTION: Alcohol misuse creates an immense burden for society, with problem drinkers too often constituting a neglected group. The Paddington Alcohol Test (PAT) is a useful screening tool in emergency departments. METHODS: Using a questionnaire, we assessed the attitudes of 127 emergency department junior doctors over 5 years to misuse detection using the PAT, in a centre with a well-defined protocol for detection and referral. RESULTS: The majority (99%) thought early detection important, and the emergency department an appropriate place for screening (98%). Most thought that treatment could be successful (98%), and the PAT a useful instrument for early detection (87%). However, 63% reported that they misuse alcohol at least once a month and 30% once or more a week. DISCUSSION and CONCLUSIONS: Junior doctors trained in the detection of alcohol misuse have a very positive view of this work. However, this professional insight is in marked contrast to their personal misuse of alcohol. This paradox reflects the entrenched culture of alcohol use in the medical profession, perhaps learnt at medical school.
PMCID: PMC1964257  PMID: 15333166

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