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1.  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.
Electronic supplementary material
The online version of this article (doi:10.1007/s10096-014-2133-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4182646  PMID: 24816901
2.  A clinical review of treatment outcomes in glioblastoma multiforme—the validation in a non-trial population of the results of a randomised Phase III clinical trial: has a more radical approach improved survival? 
The British Journal of Radiology  2012;85(1017):e729-e733.
Glioblastoma multiforme (GBM) accounts for up to 60% of all malignant primary brain tumours in adults, occurring in 2–3 cases per 100 000 in Europe and North America. In 2005, a Phase III clinical trial demonstrated a significant improvement in survival over 2, and subsequently 5, years with the addition of concurrent and adjuvant temozolomide (TMZ) to radical radiotherapy (RT). The aim of this study was to investigate if the demonstrated improved survival in the literature translated to clinical practice.
This was a retrospective study including all patients with histologically proven GBM diagnosed from 1999 to 2008 and treated with adjuvant RT at our institution. A total of 273 patients were identified. Statistical analysis was carried out using SPSS® v.18 (SPSS, Chicago, IL).
The median survival for the whole group (n=273) over the 10-year period was 7.6 months (95% confidence interval 6.7–8.4 months). Overall, the cumulative probability of survival at 1 and 2 years was 31.5% and 9.4%, respectively. In total, 146 patients received radical RT. 103 patients were treated with radical RT and TMZ and 43 patients received radical RT alone. The median survival for patients receiving radical RT with TMZ was 13.4 months (95% CI 10.9–15.8 months) vs 8.8 months for radical RT alone (95% CI 6.9–10.7 months, p=0.006). 2-year survival figures were 21.2% vs 4.7%, respectively. On multivariate analysis, independent predictors of survival included Karnofsky Performance Status, RT dose, TMZ and extent of surgery. The strongest predictors of poorer outcome based on the hazard ratio were palliative RT, followed by not receiving TMZ chemotherapy, then KPS <90 and a biopsy only surgical approach.
This paper demonstrates improved survival outcomes consistent with those published in the literature for the addition of concurrent and adjuvant TMZ to radical RT for the treatment of GBM. Although 63% of patients seen in the clinic were suitable for a combined modality approach, the prognosis for the lower Radiation Therapy Oncology Group classes still remains poor.
PMCID: PMC3487092  PMID: 22215883
3.  Biomechanical rationale and evaluation of an implant system for rib fracture fixation 
Biomechanical research directed at developing customized implant solutions for rib fracture fixation is essential to reduce the complexity and to increase the reliability of rib osteosynthesis. Without a simple and reliable implant solution, surgical stabilization of rib fractures will remain underutilized despite proven benefits for select indications. This article summarizes the research, development, and testing of a specialized and comprehensive implant solution for rib fracture fixation.
An implant system for rib fracture fixation was developed in three phases: first, research on rib biomechanics was conducted to better define the form and function of ribs. Second, research results were implemented to derive an implant system comprising anatomical plates and intramedullary rib splints. Third, the functionality of anatomic plates and rib splints was evaluated in a series of biomechanical tests.
Geometric analysis of the rib surface yielded a set of anatomical rib plates that traced the rib surface over a distance of 13–15 cm without the need for plate contouring. Structurally, the flexible design of anatomic plates did not increase the native stiffness of ribs while restoring 77% of the native rib strength. Intramedullary rib splints with a rectangular cross-section provided 48% stronger fracture fixation than traditional intramedullary fixation with Kirschner wires.
The anatomic plate set can simplify rib fracture fixation by minimizing the need for plate contouring. Intramedullary fixation with rib splints provides a less-invasive fixation alternative for posterior rib fracture, where access for plating is limited. The combination of anatomic plates and intramedullary splints provides a comprehensive system to manage the wide range of fractures encountered in flail chest injuries.
PMCID: PMC3150823  PMID: 21841953
Anatomic plates; Intramedullary splints; Rib fracture; Flail chest
4.  Operative stabilization of flail chest injuries: review of literature and fixation options 
Flail chest injuries cause significant morbidity, especially in multiply injured patients. Standard treatment is typically focused on the underlying lung injury and involves pain control and positive pressure ventilation. Several studies suggest improved short- and long-term outcomes following operative stabilization of the flail segments. Despite these studies, flail chest fixation remains a largely underutilized procedure.
This article reviews the relevant literature concerning flail chest fixation and describes the different implants and techniques available for fixation. Additionally, an illustrative case example is provided for description of the surgical approach.
Two prospective randomized studies, five comparative studies, and a number of case series documented benefits of operative treatment of flail chest injuries, including a decreased in ventilation duration, ICU stay, rates of pneumonia, mortality, residual chest wall deformity, and total cost of care. Historically, rib fractures have been stabilized with external plates or intramedullary implants. The use of contemporary, anatomically contoured rib plates reduced the need for intraoperative plate bending. Intramedullary rib splints allowed less-invasive fixation of posterior fractures where access for plating was limited.
Operative treatment can provide substantial benefits to patients with flail chest injuries and respiratory compromise requiring mechanical ventilation. The use of anatomically contoured rib plates and intramedullary splints greatly simplifies the procedure of flail chest fixation.
PMCID: PMC3150812  PMID: 21841954
Flail chest; Rib fracture; Surgical stabilization; Rib plate; Rib splint
5.  Molecular and clinical characterization of de novo and familial cases with microduplication 3q29: guidelines for copy number variation case reporting 
Cytogenetic and Genome Research  2009;123(1-4):65-78.
Microdeletions of 3q29 have previously been reported, but the postulated reciprocal microduplication has only recently been observed. Here, cases from four families, two ascertained in Toronto (Canada) and one each from Edinburgh (UK) and Leiden (Netherlands), carrying microduplications of 3q29 are presented. These families have been characterized by cytogenetic and molecular techniques, and all individuals have been further characterized with genome-wide, high density single nucleotide polymorphism (SNP) arrays run at a single centre (The Centre for Applied Genomics, Toronto). In addition to polymorphic copy-number variants (CNV), all carry duplications of 3q29 ranging in size from 1.9 to 2.4 Mb, encompassing multiple genes and defining a minimum region of overlap of about 1.6 Mb bounded by clusters of segmental duplications that is remarkably similar in location to previously reported 3q29 microdeletions. Consistent with other reports, the phenotype is variable, although developmental delay and significant ophthalmological findings were recurrent, suggesting that dosage sensitivity of genes located within 3q29 is important for eye and CNS development. We also consider CNVs found elsewhere in the genome for their contribution to the phenotype. We conclude by providing preliminary guidelines for management and anticipatory care of families with this microduplication, thereby establishing a standard for CNV reporting.
PMCID: PMC2920184  PMID: 19287140
6.  Chromosome analysis: what and when to request 
Archives of Disease in Childhood  2005;90(12):1264-1269.
PMCID: PMC1720203  PMID: 16301555
7.  Partial NSD1 deletions cause 5% of Sotos syndrome and are readily identifiable by multiplex ligation dependent probe amplification 
Journal of Medical Genetics  2005;42(9):e56.
Background: Most cases of Sotos syndrome are caused by intragenic NSD1 mutations or 5q35 microdeletions. It is uncertain whether allelic or genetic heterogeneity underlies the residual cases and it has been proposed that other mechanisms, such as 11p15 defects, might be responsible for Sotos cases without NSD1 mutations or 5q35 microdeletions.
Objective: To develop a multiplex ligation dependent probe amplification (MLPA) assay to screen NSD1 for exonic deletions/duplications.
Methods: Analysis was undertaken of 18 classic Sotos syndrome cases in which NSD1 mutations and 5q35 microdeletions were excluded. Long range polymerase chain reaction (PCR) was used to characterise the mechanism of generation of the partial NSD1 deletions.
Results: Eight unique partial NSD1 deletions were identified: exons 1–2 (n = 4), exons 3–5, exons 9–13, exons 19–21, and exon 22. Using long range PCR six of the deletions were confirmed and the precise breakpoints in five cases characterised. This showed that three had arisen through Alu-Alu recombination and two from non-homologous end joining.
Conclusions: MLPA is a robust, inexpensive, simple technique that reliably detects both 5q35 microdeletions and partial NSD1 deletions that together account for ∼15% of Sotos syndrome.
PMCID: PMC1736125  PMID: 16140999
8.  Are antibiotics indicated following human bites? 
Report by Dr Alma-Victoria Rittner and Dr Kevin Fitzpatrick, Senior House Officers 
Checked by Dr Alasdair Corfield, Registrar
PMCID: PMC1726930  PMID: 16113192
9.  P157-S Understanding Cisplatin Drug Resistance in Human Ovarian Cancer 
Ovarian Cancer is the fifth leading cause of death from all cancers in women. Platinum-based chemotherapy is the primary treatment for ovarian cancer. Most patients with the disease are initially very responsive to chemotherapeutic treatment. However, the majority of ovarian cancer patients eventually relapses and becomes refractory to additional treatment. This drug-resistance is a major impediment to the successful treatment of ovarian cancer. To date the mechanisms of drug-resistance are poorly understood. To elucidate the underlying mechanisms in which drug-resistance is developed in ovarian cancer cells, global protein expression pattern changes in drug-sensitive and -resistant ovarian cancer cells need to be established.
In this study, we approached ovarian cancer resistance using proteomics technology to quantitatively profile the global protein expression levels of two pairs of ovarian cancer cell lines, with cisplatin drug treatment. A2780 and 2008 human ovarian cancer cell lines were chosen as cisplatin-sensitive and A2780/CP and 2008/C13*5.25 were their resistant counterpart. Statistical analysis was carried out by ANOVA models and these were fit using Proc_Mixed in SAS. Through our efforts to identify those protein changes associated with cisplatin drug-resistance, we identified and quantified over ~2000 proteins where 855 proteins were identified with high confidence (Priority 1) and 760 of them showed significant expression changes (False Discovery Rate is less than 0.05). Based on the data that we obtained, we were able to select a panel of potential proteins that could play a role in cisplatin drug resistance. Inhibition assays targeting select proteins from our panel were carried out, to determine whether down-regulation of these proteins would be successful in reversing cisplatin resistance. Preliminary data showed a very promising effect in reversing the cisplatin resistance in the resistant cells when the combination of cisplatin and TETA, an inhibitor of antioxidant Superoxide dismutase (SOD1) protein, were used.
PMCID: PMC2292054
10.  Mortality in Barrett’s oesophagus: results from a population based study 
Gut  2003;52(8):1081-1084.
Background: Patients with Barrett’s oesophagus have an increased risk of oesophageal adenocarcinoma but this cancer only accounts for a small proportion of deaths in these patients. Other causes of death are reportedly raised in this group. We examined cause specific mortality among individuals in a population based Barrett’s oesophagus register.
Methods: We constructed a register of all patients diagnosed with columnar mucosa (including specialised intestinal metaplasia) of the oesophagus within Northern Ireland between 1993 and 1999. Deaths occurring within this cohort until 31 December 2000 were identified and mortality rates were compared with the general population.
Results: Overall mortality was not raised in Barrett’s patients. During 7413 person years of follow up in 2373 patients there were 253 deaths (standardised mortality ratio (SMR) 96 (95% confidence interval (CI) 84–107)). Mortality from oesophageal cancer was raised in patients with specialised intestinal metaplasia (SMR 774 (95% CI 317–1231)) but only 4.7% of patients died from this cancer. Mortality from stroke (SMR 65 (95% CI 37–93)) was significantly lower than the general population while mortality from non-cancerous digestive system diseases was significantly higher (SMR 211 (95% CI 111–311)). Mortality rates from all other causes were similar to those of the general population.
Conclusions: This study demonstrates that the overall mortality rate in patients with Barrett’s oesophagus is closely similar to that of the general population. Oesophageal cancer mortality was raised but is an uncommon cause of death in these patients who also appear to have a reduced risk of death from stroke.
PMCID: PMC1773743  PMID: 12865262
Barrett’s oesophagus; mortality; cancer; stroke
11.  Hypermethylation of the 5′ CpG island of the gene encoding the serine protease Testisin promotes its loss in testicular tumorigenesis 
British Journal of Cancer  2005;92(4):760-769.
The Testisin gene (PRSS21) encodes a glycosylphosphatidylinositol (GPI)-linked serine protease that exhibits testis tissue-specific expression. Loss of Testisin has been implicated in testicular tumorigenesis, but its role in testis biology and tumorigenesis is not known. Here we have investigated the role of CpG methylation in Testisin gene inactivation and tested the hypothesis that Testisin may act as a tumour suppressor for testicular tumorigenesis. Using sequence analysis of bisulphite-treated genomic DNA, we find a strong relationship between hypermethylation of a 385 bp 5′ CpG rich island of the Testisin gene, and silencing of the Testisin gene in a range of human tumour cell lines and in 100% (eight/eight) of testicular germ cell tumours. We show that treatment of Testisin-negative cell lines with demethylating agents and/or a histone deacetylase inhibitor results in reactivation of Testisin gene expression, implicating hypermethylation in Testisin gene silencing. Stable expression of Testisin in the Testisin-negative Tera-2 testicular cancer line suppressed tumorigenicity as revealed by inhibition of both anchorage-dependent cell growth and tumour formation in an SCID mouse model of testicular tumorigenesis. Together, these data show that loss of Testisin is caused, at least in part, by DNA hypermethylation and histone deacetylation, and suggest a tumour suppressor role for Testisin in testicular tumorigenesis.
PMCID: PMC2361880  PMID: 15685234
Testisin; methylation; serine protease; tumour suppressor
12.  Iris coloboma and a microdeletion of chromosome 22: del(22)(q11.22) 
PMCID: PMC1771353  PMID: 12386101
iris coloboma; microdeletion syndrome; chromosome 22
15.  National study of microphthalmia, anophthalmia, and coloboma (MAC) in Scotland: investigation of genetic aetiology 
Journal of Medical Genetics  2002;39(1):16-22.
We report an epidemiological and genetic study attempting complete ascertainment of subjects with microphthalmia, anophthalmia, and coloboma (MAC) born in Scotland during a 16 year period beginning on 1 January 1981. A total of 198 cases were confirmed giving a minimum live birth prevalence of 19 per 100 000. One hundred and twenty-two MAC cases (61.6%) from 115 different families were clinically examined and detailed pregnancy, medical, and family histories obtained. A simple, rational, and apparently robust classification of the eye phenotype was developed based on the presence or absence of a defect in closure of the optic (choroidal) fissure. A total of 85/122 (69.7%) of cases had optic fissure closure defects (OFCD), 12/122 (9.8%) had non-OFCD, and 25/122 (20.5%) had defects that were unclassifiable owing to the severity of the corneal or anterior chamber abnormality. Segregation analysis assuming single and multiple incomplete ascertainment, respectively, returned a sib recurrence risk of 6% and 10% in the whole group and 8.1% and 13.3% in the OFCD subgroup. Significant recurrence risks were found in both unilateral and bilateral disease. In four families, one parent had an OFCD, two of which were new diagnoses in asymptomatic subjects. All recurrences in first degree relatives occurred in the OFCD group with a single first cousin recurrence seen in the non-OFCD group. A total of 84/122 of the MAC cases were screened for mutations in the coding regions of PAX6, CHX10, and SIX3. No pathogenic mutations were identified in the OFCD cases. A single PAX6 homeodomain missense mutation was identified in a subject with partial aniridia that had been initially misclassified as coloboma.
PMCID: PMC1734963  PMID: 11826019
16.  Knowledge, attitudes and behaviour in the sun: the barriers to behavioural change in Northern Ireland. 
The Ulster Medical Journal  2004;73(2):96-104.
To inform future health promotion programmes, we studied the knowledge, attitudes and behaviour of the Northern Ireland population to sun care. An interviewer-administered questionnaire was applied to one adult per household from a random sample of 1242 addresses. Lower levels of knowledge were found among respondents who were male, aged under 25 years or over 65 years, in a manual occupation or living in the west where health promotion activity on this topic was less active than in the east. Younger adults, females and professional groups were more likely to indicate that a suntan was important, healthy or attractive. Use of high factor sunscreen was inversely proportional to perceived importance of a suntan. Sunburn was more common in younger adults but more men reported multiple episodes of burning. Regular skin checks were uncommon and self-assessment of skin type was unrealistic indicating that sun care advice based on self assessment should be avoided in this population. Future campaigns should target appropriate messages at specific population subgroups. The study highlights the importance of collecting baseline information before implementing health promotion programmes and suggests that repeat monitoring is essential to ensure that key messages remain relevant. This study also indicates that Care in the Sun campaigns here impacted on general awareness in the population even with limited resources. There is, therefore, potential for greater impact with high funding levels.
PMCID: PMC2475461  PMID: 15651769
17.  Ovarian cancer--the need for change in service delivery in Northern Ireland. 
The Ulster Medical Journal  2003;72(2):93-97.
This paper provides local data on the provision of services for patients diagnosed with ovarian cancer in 1996 prior to the reorganisation of cancer services. It documents a service for 140 patients provided by 80 consultant teams and illustrates the need for reorganisation to meet the evidence base already in existence for improvement in survival and will serve as a baseline for future audits in this area.
PMCID: PMC2475416  PMID: 14696819
20.  Beckwith-Wiedemann syndrome in a child with chromosome 18q deletion. 
Journal of Medical Genetics  1998;35(2):162-164.
Molecular genetic investigation of a female infant with Beckwith-Wiedemann syndrome (BWS) showed loss of IGF2 imprinting but no evidence of uniparental disomy. In addition, a deletion of chromosome 18q22.1 was identified in this infant without clinical features of 18q-syndrome (microcephaly, short stature, hypotonia). The association of a chromosome 18 deletion and BWS may be coincidental or may indicate the location of a trans activating regulator element for maintenance of IGF2 imprinting.
PMCID: PMC1051225  PMID: 9507400
21.  Neurogenic chronic idiopathic intestinal pseudo-obstruction, patent ductus arteriosus, and thrombocytopenia segregating as an X linked recessive disorder. 
Journal of Medical Genetics  1997;34(8):666-669.
We present a family with three affected males in two generations with congenital neurogenic chronic idiopathic intestinal pseudo-obstruction (CIIP), patent ductus arteriosus, and large platelet thrombocytopenia apparently segregating as an X linked recessive disorder. The pattern of segregation of DNA markers within the family is consistent with linkage to the previously described neurogenic CIIP (CIIPX) locus at Xq28. This combination may represent a new contiguous gene disorder and appears to have a good prognosis with supportive therapy.
PMCID: PMC1051029  PMID: 9279759
22.  Mutilating neuropathic ulcerations in a chromosome 3q13-q22 linked Charcot-Marie-Tooth disease type 2B family. 
BACKGROUND: Charcot-Marie-Tooth disease type 2 (CMT2) or hereditary motor and sensory neuropathy type II (HMSN II) is an inherited axonal neuropathy of the peripheral nervous system. Three autosomal dominant CMT2 loci have been located on chromosomes 1p35-p36 (CMT2A), 3q13-q22 (CMT2B), and 7p14 (CMT2D) indicating that CMT2 is a genetically heterogeneous disorder. METHODS: A CMT2 family was examined for linkage to the CMT2A, CMT2B, and CMT2D loci using short tandem repeat polymorphisms. RESULTS: Suggestive evidence for linkage to 3q13-q22 was found. Recombinations occurred with markers D3S1769 and D3S1267 indicating that the CMT2B locus is located distal to D3S1267 and resides in an interval of 25 cM. Some patients in this family have pronounced sensory disturbances leading to poorly healing ulcerations. CONCLUSIONS: These unusual sensory signs for CMT were also noted in the only other CMT2B family reported so far, suggesting a distinct clinical phenotype for CMT2B. Exclusion of the locus for hereditary sensory neuropathy type I (HSN I) on chromosome 9q22 indicates that HSN I with mild motor symptoms and CMT2 with prominent sensory abnormalities are not allelic.
PMCID: PMC1074138  PMID: 9219740
23.  BRCA1 5382insC mutation in sporadic and familial breast and ovarian carcinoma in Scotland. 
British Journal of Cancer  1997;75(9):1377-1380.
A restriction site-generating polymerase chain reaction (RG-PCR) assay was developed to detect the BRCA1 5382insC mutation that has been reported in multiple, apparently unrelated breast/ovarian carcinoma families. The assay has been used to screen tumour DNA from 250 breast cancer patients (aged 19-86 years) and from 80 ovarian cancer patients (aged 25-90 years) in a local population of patients with no known family history. Altogether, 0/80 (0%) ovarian and 1/250 (0.4%) breast tumour DNAs were found to have the 5382insC mutation. The sole positive case was a 26-year-old woman (BC185) with no known family history. One of the reasons for carrying out this analysis was that the 5382insC mutation had previously been shown to segregate with the disease in a very large Scottish 'West Lothian' kindred having breast/ovarian carcinoma. To investigate whether this apparently isolated case and the known family might be related, haplotypes for the markers D17S855, D17S1322, D17S1323 and D17S1327 were analysed. The mutant haplotype in the large kindred was identical to that reported in all other 5382insC mutation families for all markers with the exception of D17S1327. This implies that there has been a recombination event at the telomeric end of common ancestral haplotype in this family. Since the isolated case we identified carries the 'complete' common haplotype, it is unlikely that she is closely related to the West Lothian family.
PMCID: PMC2228233  PMID: 9155062
24.  A general method for the detection of large CAG repeat expansions by fluorescent PCR. 
Journal of Medical Genetics  1996;33(12):1022-1026.
The expansion of a tandemly repeated trinucleotide sequence, CAG, is the mutational mechanism for several human genetic diseases. We present a generally applicable PCR amplification method using a fluorescently labelled locus specific primer flanking the CAG repeat together with paired primers amplifying from multiple priming sites within the CAG repeat. Triplet repeat primed PCR (TP PCR) gives a characteristic ladder on the fluorescence trace enabling the rapid identification of large pathogenetic CAG repeats that cannot be amplified using flanking primers. We used our method to test a cohort of 183 people from myotonic dystrophy families including unaffected subjects and spouses. Eighty five clinically affected subjects with expanded alleles on Southern blot analysis were all correctly identified by TP PCR. This method is applicable for any human diseases involving CAG repeat expansions.
PMCID: PMC1050815  PMID: 9004136
25.  Zellweger syndrome and associated phenotypes. 
Journal of Medical Genetics  1996;33(10):863-868.
Until recently, the peroxisome was considered a "reactor chamber" for H2O2 producing oxidases, and it is now recognised as a versatile organelle performing complex catabolic and biosynthetic roles in the cell. Zellweger syndrome (ZS), the paradigm of human peroxisomal disorders, is characterised by neonatal hypotonia, severe neuro-developmental delay, hepatomegaly, renal cysts, senorineural deafness, retinal dysfunction, and facial dysmorphism. It is now clear that ZS is at the severe end of a phenotypic spectrum of Zellweger-like syndromes which may present for diagnosis later in childhood and even in adult life. It is important that clinical geneticists are aware of these milder clinical variants as the availability of sensitive and specific biochemical assays of peroxisomal function (for example, serum VLCFA ratios, platelet DHAP-AT activity) makes their diagnosis relatively straightforward.
PMCID: PMC1050768  PMID: 8933342

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