There is currently conflicting evidence surrounding the effects of obesity on postoperative outcomes. Previous studies have found obesity to be associated with adverse events, but others have found no association. The aim of this study was to determine whether increasing body mass index (BMI) is an independent risk factor for development of major postoperative complications.
This was a multicentre prospective cohort study across the UK and Republic of Ireland. Consecutive patients undergoing elective or emergency gastrointestinal surgery over a 4‐month interval (October–December 2014) were eligible for inclusion. The primary outcome was the 30‐day major complication rate (Clavien–Dindo grade III–V). BMI was grouped according to the World Health Organization classification. Multilevel logistic regression models were used to adjust for patient, operative and hospital‐level effects, creating odds ratios (ORs) and 95 per cent confidence intervals (c.i.).
Of 7965 patients, 2545 (32·0 per cent) were of normal weight, 2673 (33·6 per cent) were overweight and 2747 (34·5 per cent) were obese. Overall, 4925 (61·8 per cent) underwent elective and 3038 (38·1 per cent) emergency operations. The 30‐day major complication rate was 11·4 per cent (908 of 7965). In adjusted models, a significant interaction was found between BMI and diagnosis, with an association seen between BMI and major complications for patients with malignancy (overweight: OR 1·59, 95 per cent c.i. 1·12 to 2·29, P = 0·008; obese: OR 1·91, 1·31 to 2·83, P = 0·002; compared with normal weight) but not benign disease (overweight: OR 0·89, 0·71 to 1·12, P = 0·329; obese: OR 0·84, 0·66 to 1·06, P = 0·147).
Overweight and obese patients undergoing surgery for gastrointestinal malignancy are at increased risk of major postoperative complications compared with those of normal weight.
High BMI increases risk of complications
Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all‐cause mortality may guide interventions.
Methods and Results
In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose‐adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all‐cause mortality in the 14 171 participants in the intention‐to‐treat population. The median age was 73 years, and the mean CHADS
2 score was 3.5. Over 1.9 years of median follow‐up, 1214 (8.6%) patients died. Kaplan–Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all‐cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33–1.70, P<0.0001) and age ≥75 years (hazard ratio 1.69, 95% CI 1.51–1.90, P<0.0001) were associated with higher all‐cause mortality. Multiple additional characteristics were independently associated with higher mortality, with decreasing creatinine clearance, chronic obstructive pulmonary disease, male sex, peripheral vascular disease, and diabetes being among the most strongly associated (model C‐index 0.677).
In a large population of patients anticoagulated for nonvalvular atrial fibrillation, ≈7 in 10 deaths were cardiovascular, whereas <1 in 10 deaths were caused by nonhemorrhagic stroke or systemic embolism. Optimal prevention and treatment of heart failure, renal impairment, chronic obstructive pulmonary disease, and diabetes may improve survival.
Clinical Trial Registration
URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00403767.
atrial fibrillation; mortality; rivaroxaban; stroke; warfarin; Atrial Fibrillation; Sudden Cardiac Death; Heart Failure; Ischemic Stroke; Intracranial Hemorrhage
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.
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
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.
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.
Anatomic plates; Intramedullary splints; Rib fracture; Flail chest
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.
Flail chest; Rib fracture; Surgical stabilization; Rib plate; Rib splint
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.
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.
Report by Dr Alma-Victoria Rittner and Dr Kevin Fitzpatrick, Senior House Officers
Checked by Dr Alasdair Corfield, Registrar
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.
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.
Barrett’s oesophagus; mortality; cancer; stroke
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.
Testisin; methylation; serine protease; tumour suppressor
iris coloboma; microdeletion syndrome; chromosome 22
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.
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.
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.
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.
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.
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.