Quantifying lesion enhancement on contrast-enhanced mammography: a review of published data.

AIM: To review and discuss the current published data on FUNCTIONAL DATA DERIVED FROM contrast-enhanced spectral mammography (CESM) for investigation of breast lesions. MATERIALS AND METHODS: Literature searches were conducted in MEDLINE and PUBMED. Due to the novel nature of CESM and sparsity of published literature pertaining to associated functional data, the Medical Subject Headings (MeSH) used were intentionally broad. RESULTS: After inclusion and exclusion criteria, 23 papers were included; 13 pertained to assessment of intensity or pattern of lesion enhancement, and 10 considered textural analysis for lesion assessment, including those using computer-aided detection (CAD) software. Meta-analysis of data was not possible due to heterogeneity of methodology. CONCLUSIONS: There is consistent evidence that benign lesions tend to demonstrate different enhancement characteristics to cancers, with benign lesions tending to demonstrate weaker, homogeneous contrast medium uptake. Limited evidence suggests malignant lesions exhibit "wash-out" or decreasing pattern of enhancement, and benign lesions a progressively enhancing one. The application of textural analysis and radiomics to CESM images shows promising results for differentiating benign and malignant lesions, with potential to predict immunohistological features. A large-scale multicentre study, ideally using multivendor CESM equipment, will be needed to confirm this.

Advances in the development of Salmonella-based vaccine strategies for protection against Salmonellosis in humans.

Salmonella spp. are important human pathogens globally causing millions of cases of typhoid fever and non-typhoidal salmonellosis annually. There are only a few vaccines licensed for use in humans which all target Salmonella enterica serovar Typhi. Vaccine development is hampered by antigenic diversity between the thousands of serovars capable of causing infection in humans. However, a number of attenuated candidate vaccine strains are currently being developed. As facultative intracellular pathogens with multiple systems for transporting effector proteins to host cells, attenuated Salmonella strains can also serve as ideal tools for the delivery of foreign antigens to create multivalent live carrier vaccines for simultaneous immunization against several unrelated pathogens. Further, the ease with which Salmonella can be genetically modified and the extensive knowledge of the virulence mechanisms of this pathogen means that this bacterium has often served as a model organism to test new approaches. In this review we focus on (1) recent advances in live attenuated Salmonella vaccine development, (2) improvements in expression of foreign antigens in carrier vaccines and (3) adaptation of attenuated strains as sources of purified antigens and vesicles that can be used for subunit and conjugate vaccines or together with attenuated vaccine strains in heterologous prime-boosting immunization strategies. These advances have led to the development of new vaccines against Salmonella which have or will soon be tested in clinical trials.

Contrast-enhanced spectral mammography (CESM).

Contrast-enhanced spectral mammography (CESM) is a valuable tool in the diagnosis and staging of primary breast cancer. It combines an iodinated contrast agent with conventional mammography to improve diagnostic accuracy, particularly in women with denser parenchymal background patterns. This review describes the CESM technique, reviews performance compared to conventional mammography and magnetic resonance imaging, assesses its role in the diagnosis and staging of primary breast cancer, and investigates its potential as a screening tool.

Posteromedial bowing of the tibia: a benign condition or a case for limb reconstruction?

PURPOSE: To review the initial deformity and subsequent remodelling in posteromedial bowing of the tibia and the outcome of limb reconstruction in this condition. PATIENTS AND METHODS: In all, 38 patients with posteromedial bowing of the tibia presenting between 2000 and 2016 were identified. Mean follow-up from presentation was 78 months. A total of 17 patients underwent lengthening and deformity correction surgery, whilst three further patients are awaiting lengthening and deformity correction procedures. RESULTS: The greatest correction of deformity occurred in the first year of life, but after the age of four years, remodelling was limited. The absolute leg-length discrepancy (LLD) increased throughout growth with a mean 14.3% discrepancy in tibial length. In the lengthening group, mean length gained per episode was 45 mm (35 to 60). Mean duration in frame was 192 days, with a mean healing index of 42.4 days/cm. Significantly higher rates of recurrence in LLD were seen in those undergoing lengthening under the age of ten years (p = 0.046). Four contralateral epiphysiodeses were also performed. CONCLUSION: Posteromedial bowing of the tibia improves spontaneously during the first years of life, but in 20/38 (53%) patients, limb reconstruction was indicated for significant residual deformity and/or worsening LLD. For larger discrepancies and persistent deformity, limb reconstruction with a hexapod external fixator should be considered as part of the treatment options. LEVEL OF EVIDENCE: Level IV (Case series).

Overexpression of O-polysaccharide chain length regulators in Gram-negative bacteria using the Wzx-/Wzy-dependent pathway enhances production of defined modal length O-polysaccharide polymers for use as haptens in glycoconjugate vaccines.

AIMS: O-polysaccharide (OPS) molecules are protective antigens for several bacterial pathogens, and have broad utility as components of glycoconjugate vaccines. Variability in the OPS chain length is one obstacle towards further development of these vaccines. Introduction of sizing steps during purification of OPS molecules of suboptimal or of mixed lengths introduces additional costs and complexity while decreasing the final yield. The overall goal of this study was to demonstrate the utility of engineering Gram-negative bacteria to produce homogenous O-polysaccharide populations that can be used as the basis of carbohydrate vaccines by overexpressing O-polysaccharide chain length regulators of the Wzx-/Wzy-dependent pathway. METHOD AND RESULTS: The O-polysaccharide chain length regulators wzzB and fepE from Salmonella Typhimurium I77 and wzz2 from Pseudomonas aeruginosa PAO1 were cloned and expressed in the homologous organism or in other Gram-negative bacteria. Overexpression of these Wzz proteins in the homologous organism significantly increased the proportion of long or very long chain O-polysaccharides. The same observation was made when wzzB was overexpressed in Salmonella Paratyphi A and Shigella flexneri, and wzz2 was overexpressed in two other strains of P. aeruginosa. CONCLUSIONS: Overexpression of Wzz proteins in Gram-negative bacteria using the Wzx/Wzy-dependant pathway for lipopolysaccharide synthesis provides a genetic method to increase the production of an O-polysaccharide population of a defined size. SIGNIFICANCE AND IMPACT OF THE STUDY: The methods presented herein represent a cost-effective and improved strategy for isolating preferred OPS vaccine haptens, and could facilitate the further use of O-polysaccharides in glycoconjugate vaccine development.

A comparison of functional outcome between amputation and extension prosthesis in the treatment of congenital absence of the fibula with severe limb deformity.

PURPOSE: Complete fibula absence often presents with significant lower-limb deformity. Parental counselling regarding management is paramount in achieving the optimum functional outcome. Amputation offers a single surgical event with minimal complications. This study compares outcomes with an amputation protocol to those using an extension prosthesis. METHOD: Thirty-two patients were identified. Nine patients (2 males, 7 females; median age at assessment of 23.5 years) used an extension prosthesis. Twenty-three patients (16  males, 7 females; median age at assessment of eight years) underwent 25 amputations during childhood. Mobility was assessed using SIGAM and K scores. Quality of life was assessed using the PedsQL inventory questionnaire; pain by a verbal severity score. RESULTS: The 19 Syme and one Boyd amputation in 19 patients were performed early (mean age 15 months). Four Syme and one trans-tibial amputation in four patients took place in older children (mean age 6.6 years). Only two underwent tibial kyphus correction to aid prosthetic fitting. K scores were significantly higher (mean 4 vs 2) and pain scores lower in the amputation group allowing high impact activity compared with community ambulation with an extension prosthesis. The SIGAM and PedsQL scores were all better in the amputation group, but not significantly so. CONCLUSION: Childhood amputation for severe limb length inequality and foot deformity in congenital fibula absence offers excellent short-term functional outcome with prosthetic support. The tibial kyphus does not need routine correction and facilitates prosthetic suspension. Accommodative extension prostheses offer reasonable long-term function but outcome scores are lower.

Phenotype-driven molecular autopsy for sudden cardiac death.

A phenotype-driven approach to molecular autopsy based in a multidisciplinary team comprising clinical and laboratory genetics, forensic medicine and cardiology is described. Over a 13 year period, molecular autopsy was undertaken in 96 sudden cardiac death cases. A total of 46 cases aged 1-40 years had normal hearts and suspected arrhythmic death. Seven (15%) had likely pathogenic variants in ion channelopathy genes [KCNQ1 (1), KCNH2 (4), SCN5A (1), RyR2(1)]. Fifty cases aged between 2 and 67 had a cardiomyopathy. Twenty-five had arrhythmogenic right ventricular cardiomyopathy (ARVC), 10 dilated cardiomyopathy (DCM) and 15 hypertrophic cardiomyopathy (HCM). Likely pathogenic variants were found in three ARVC cases (12%) in PKP2, DSC2 or DSP, two DCM cases (20%) in MYH7, and four HCM cases (27%) in MYBPC3 (3) or MYH7 (1). Uptake of cascade screening in relatives was higher when a molecular diagnosis was made at autopsy. In three families, variants previously published as pathogenic were detected, but clinical investigation revealed no abnormalities in carrier relatives. With a conservative approach to defining pathogenicity of sequence variants incorporating family phenotype information and population genomic data, a molecular diagnosis was made in 15% of sudden arrhythmic deaths and 18% of cardiomyopathy deaths.

A protocol for the use of closed reduction in children with developmental dysplasia of the hip incorporating open psoas and adductor releases and a short-leg cast: Mid-term outcomes in 113 hips.

AIMS: Our aim was to assess the effectiveness of a protocol involving a standardised closed reduction for the treatment of children with developmental dysplasia of the hip (DDH) in maintaining reduction and to report the mid-term results. METHODS: A total of 133 hips in 120 children aged less than two years who underwent closed reduction, with a minimum follow-up of five years or until subsequent surgery, were included in the study. The protocol defines the criteria for an acceptable reduction and the indications for a concomitant soft-tissue release. All children were immobilised in a short- leg cast for three months. Arthrograms were undertaken at the time of closed reduction and six weeks later. Follow-up radiographs were taken at six months and one, two and five years later and at the latest follow-up. The Tönnis grade, acetabular index, Severin grade and signs of osteonecrosis were recorded. RESULTS: A total of 67 hips (51%) were Tönnis grade 3/4 hips. By 12 months, 20 reductions (15%) had not been maintained, and these required open reduction. In all, 55% of these were Severin 1; the others were Severin 2, due to minor acetabular dysplasia. Of the 113 successful closed reductions, 98 hips (87%) were Severin 1. Surgery for residual DDH was offered for ten hips. Osteonecrosis was seen in 32 hips (29%) but was transient in 28. In total, two children (1.5%) had severe osteonecrosis. Bilateral dislocations were significantly more likely to fail and most Tönnis 4 hips failed. CONCLUSION: Closed reduction, with concomitant adductor and psoas release when required and the use of a short leg plaster of Paris cast for three months, can produce good mid-term results in children with DDH aged less than two years. This protocol is not recommended for Tönnis 4 hips. Cite this article: Bone Joint J 2016;98-B:1548-53.

An unusual case of Salmonella Enteritidis causing pneumonia, septic shock and multiple organ failure in an immunocompetent patient.

Salmonella species are facultative intracellular pathogens that most frequently cause self-limiting gastrointestinal disease, often acquired through the ingestion of contaminated food. We report the case of a 33-year-old otherwise healthy, not overtly immunosuppressed, man who was transferred to our facility with the chief complaint of respiratory failure and septic shock. Computed tomography of the chest revealed multifocal pneumonia in both lungs. A bronchial alveolar lavage was performed in the right middle lobe and cultures predominantly grew Salmonella enterica serovar Enteritidis. The patient received a prolonged course of antimicrobials, ultimately changing to oral levofloxacin. The etiology of the salmonella infection likely occurred through an aspiration event. Salmonella species are not a typical respiratory pathogen in immunocompetent hosts; however, clinicians should be aware of the possibility that salmonella species may be a pathogenic source of infection in the lungs; a prolonged course of antimicrobials may be warranted.

Contrast-enhanced spectral mammography improves diagnostic accuracy in the symptomatic setting.

AIM: To assess the diagnostic accuracy of contrast-enhanced spectral mammography (CESM), and gauge its "added value" in the symptomatic setting. MATERIALS AND METHODS: A retrospective multi-reader review of 100 consecutive CESM examinations was performed. Anonymised low-energy (LE) images were reviewed and given a score for malignancy. At least 3 weeks later, the entire examination (LE and recombined images) was reviewed. Histopathology data were obtained for all cases. Differences in performance were assessed using receiver operator characteristic (ROC) analysis. Sensitivity, specificity, and lesion size (versus MRI or histopathology) differences were calculated. RESULTS: Seventy-three percent of cases were malignant at final histology, 27% were benign following standard triple assessment. ROC analysis showed improved overall performance of CESM over LE alone, with area under the curve of 0.93 versus 0.83 (p<0.025). CESM showed increased sensitivity (95% versus 84%, p<0.025) and specificity (81% versus 63%, p<0.025) compared to LE alone, with all five readers showing improved accuracy. Tumour size estimation at CESM was significantly more accurate than LE alone, the latter tending to undersize lesions. In 75% of cases, CESM was deemed a useful or significant aid to diagnosis. CONCLUSION: CESM provides immediately available, clinically useful information in the symptomatic clinic in patients with suspicious palpable abnormalities. Radiologist sensitivity, specificity, and size accuracy for breast cancer detection and staging are all improved using CESM as the primary mammographic investigation.

Adaptation of red blood cell lysis represents a fundamental breakthrough that improves the sensitivity of Salmonella detection in blood.

AIMS: Isolation of Salmonella Typhi from blood culture is the standard diagnostic for confirming typhoid fever but it is unavailable in many developing countries. We previously described a Microwave Accelerated Metal Enhanced Fluorescence (MAMEF)-based assay to detect Salmonella in medium. Attempts to detect Salmonella in blood were unsuccessful, presumably due to the interference of erythrocytes. The objective of this study was to evaluate various blood treatment methods that could be used prior to PCR, real-time PCR or MAMEF to increase sensitivity of detection of Salmonella. METHODS AND RESULTS: We tested ammonium chloride and erythrocyte lysis buffer, water, Lymphocyte Separation Medium, BD Vacutainer(®) CPT(™) Tubes and dextran. Erythrocyte lysis buffer was the best isolation method as it is fast, inexpensive and works with either fresh or stored blood. The sensitivity of PCR- and real-time PCR detection of Salmonella in spiked blood was improved when whole blood was first lysed using erythrocyte lysis buffer prior to DNA extraction. Removal of erythrocytes and clotting factors also enabled reproducible lysis of Salmonella and fragmentation of DNA, which are necessary for MAMEF sensing. CONCLUSIONS: Use of the erythrocyte lysis procedure prior to DNA extraction has enabled improved sensitivity of Salmonella detection by PCR and real-time PCR and has allowed lysis and fragmentation of Salmonella using microwave radiation (for future detection by MAMEF). SIGNIFICANCE AND IMPACT OF THE STUDY: Adaptation of the blood lysis method represents a fundamental breakthrough that improves the sensitivity of DNA-based detection of Salmonella in blood.

CT staging for breast cancer patients with poor prognostic tumours.

The aim of this study was to assess the value of computed tomography (CT) staging of the chest, abdomen and pelvis in patients with poor prognostic tumours and no symptoms of metastatic disease in those who have undergone primary surgical management for the treatment of breast cancer. Patients who had primary operable invasive breast cancer treated by surgery over a 2-year period were retrospectively identified. Pathological data from the surgical resection were used to calculate the Nottingham Prognostic Index. Patients with no symptoms of distant metastases who underwent CT staging of the chest, abdomen and pelvis as a result of being placed in the poor prognostic group were identified. The presence and sites of metastatic disease or any indeterminate finding were documented. Additional investigations generated as a result of the staging CT and the outcome were also recorded. Sixty-seven patients (80%) in the poor prognostic group underwent a staging CT. Forty-seven patients (70%) had no signs of metastatic disease on the staging CT. Two patients (3%) were diagnosed with metastatic disease, on the basis of the initial CT scan. Eighteen patients (27%) had an indeterminate finding requiring further investigation, generating 21 additional imaging tests - following this only one additional patient was diagnosed with metastatic disease. Seventeen patients with an initially indeterminate finding did not have metastatic disease, giving a false-positive rate of 25%. In total, three patients (4%) had a final diagnosis of metastatic disease. The routine use of CT staging in patients with no symptoms of distant metastases with primary operable breast cancer even when in a poor prognostic group is of limited value, with a low pick-up rate of metastatic disease and considerable risk of false-positive findings.

Frequency and patterns of metastatic disease in locally advanced inflammatory and non-inflammatory breast cancer.

AIMS: To determine the frequency and pattern of metastatic disease as detected by staging computed tomography in patients presenting with locally advanced primary breast cancer, comparing non-inflammatory and inflammatory subtypes. MATERIALS AND METHODS: Patients who underwent staging computed tomography for locally advanced breast cancer were identified from the hospital's computerised radiology system. The computed tomography scans, breast imaging and pathology were reviewed. RESULTS: Over a 29 month period, 97 patients underwent staging computed tomography for locally advanced primary breast cancer. Sixteen patients (16%) were found to have metastatic disease at presentation. Thirty-eight patients (39%) presented with the inflammatory subtype and 59 patients (61%) with the non-inflammatory subtype. Metastases were significantly more likely in patients with the inflammatory subtype, with 10 patients (26%) having metastases at presentation compared with six patients (10%) with the non-inflammatory subtype (P=0.034). Metastases to the lung and the pleura were the most commonly encountered sites, with pleural-based metastases more likely in patients with the inflammatory subtype (P=0.05). CONCLUSION: Routine computed tomography staging of patients with locally advanced breast cancer is worthwhile with the inflammatory subtype of locally advanced disease having the higher risk of metastatic disease at presentation. Pleural-based metastatic disease is more likely in patients with the inflammatory subtype.

CT staging of loco-regional breast cancer recurrence. A worthwhile practice?

AIMS: To assess the usefulness of computed tomography of the chest, abdomen, and pelvis (CTCAP) in the detection of metastatic disease in patients presenting with loco-regional recurrence of breast cancer, and to identify subgroups particularly likely to have metastases. MATERIALS AND METHODS: Over a 32-month period, 63 patients with 65 recurrences underwent CTCAP, and were identified from the hospital's computerized radiology system. RESULTS: Twenty-one patients (32%) had metastases, including bony (n=5, 8%), liver (n=7, 11%), and thoracic disease (n=11, 17%). Patients with recurrence in a conserved breast had lower rates of metastasis on CT than those with other sites of recurrence [three of 21 (14%) versus 18 of 44 (41%), p=0.03]. Patients younger than 50 years at primary diagnosis or younger than 60 years at recurrence had statistically significantly higher rates of metastasis than older patients [10 of 16 (63%) versus 11 of 48 (23%), p=0.003, and 13 of 23 (57%) versus eight of 42 (19%), p=0.002, respectively]. CONCLUSION: CT staging of patients presenting with loco-regional recurrence of breast cancer is a worthwhile practice. Younger patients and those with recurrence other than in the conserved breast are particularly likely to have metastatic disease.

Novel POLG1 mutations associated with neuromuscular and liver phenotypes in adults and children.

BACKGROUND: The POLG1 gene encodes the catalytic subunit of DNA polymerase gamma, essential for mitochondrial DNA replication and repair. Mutations in POLG1 have been linked to a spectrum of clinical phenotypes, and may account for up to 25% of all adult presentations of mitochondrial disease. METHODS AND RESULTS: We present 14 patients, with characteristic features of mitochondrial disease including progressive external ophthalmoplegia (PEO) and Alpers-Huttenlocher syndrome and laboratory findings indicative of mitochondrial dysfunction, including cytochrome c oxidase (COX) deficiency and multiple deletions or depletion of the mitochondrial DNA. Four novel POLG1 missense substitutions (p.R597W, p.L605R, p.G746S, p.A862T), are described, together with the first adult patient with a recently described polymerase domain mutation (p.R1047W). All novel changes were rare in a control population and affected highly conserved amino acids. CONCLUSION: The addition of these substitutions-including the first report of a dinucleotide mutation (c.1814_1815TT>GC)-to the growing list of defects further confirms the importance of POLG1 mutations as the underlying abnormality in a range of neurological presentations.

Vacuum-assisted excision of breast lesions of uncertain malignant potential (B3) - an alternative to surgery in selected cases.

To assess whether vacuum-assisted excision (VAE) is a safe alternative to surgery in the treatment of breast lesions of uncertain malignant potential (B3) in which no atypia is present on needle core biopsy (NCB). Forty two VAE procedures were performed for B3 lesions. Twenty four (57%) were papillary lesions. Eighteen (43%) were radial scars. Two patients (4.7%) were upgraded to carcinoma at VAE. Two patients with papillary lesions went on to develop cancer in the same breast (at 24 and 41 months post VAE). No cancer developed in the radial scar group. Eight patients (19%) had surgery - four for carcinoma, two for radial scars missed at VAE excision and two for symptomatic papillomatosis. Follow-up mammography after VAE of radial scars often showed residual distortion. VAE can be a safe alternative to surgery in the treatment of B3 lesions without atypia, providing thorough multidisciplinary discussion has taken place.

Identification of a mutation in synapsin I, a synaptic vesicle protein, in a family with epilepsy.

A four generation family is described in which some men of normal intelligence have epilepsy and others have various combinations of epilepsy, learning difficulties, macrocephaly, and aggressive behaviour. As the phenotype in this family is distinct from other X linked recessive disorders linkage studies were carried out. Linkage analysis was done using X chromosome microsatellite polymorphisms to define the interval containing the causative gene. Genes from within the region were considered possible candidates and one of these, SYN1, was screened for mutations by direct DNA sequencing of amplified products. Microsatellite analysis showed that the region between MAOB (Xp11.3) and DXS1275 (Xq12) segregated with the disease. Two point linkage analysis demonstrated linkage with DXS1039, lod score 4.06 at theta = 0, and DXS991, 3.63 at theta = 0. Candidate gene analysis led to identification of a nonsense mutation in the gene encoding synapsin I that was present in all affected family members and female carriers and was not present in 287 control chromosomes. Synapsin I is a synaptic vesicle associated protein involved in the regulation of synaptogenesis and neurotransmitter release. The SYN1 nonsense mutation that was identified is the likely cause of the phenotype in this family.

Walking problems in young children.

This article attempts to define normal development throughout childhood and provide straightforward advice in the physical assessment of the child in this situation. It also attempts to outline the groups of conditions that lead to walking abnormalities and highlight the salient physical features and special investigations that are required to make these diagnoses with confidence.