The global transcriptomic signature in sinonasal tissues reveals roles for tissue type and chronic rhinosinusitis disease phenotype.

BACKGROUND: RNA sequencing (RNA-Seq) allows the characterization of a global transcriptomic signature in a least-biased fashion, but few studies have applied this method to investigate the pathophysiology of CRS. METHODS: We collected mucosal tissue samples from 6 CRS without nasal polyps (CRSsNP), 6 CRS with nasal polyps (CRSwNP), and 6 control patients. Additional matched polyp samples were collected from the 6 CRSwNP patients. RNA was extracted and sequenced on the Illumina HiSeq-2500. Differential gene expression and pathway analyses were performed. RESULTS: CRSsNP showed evidence of upregulated interferon-mediated immunity, MHC-class-I mediated antigen presentation, CXCR3 binding, neutrophil chemotaxis and degranulation, and potential downregulation of genes related to cilia movement and production. CRSwNP polyp tissue showed upregulation of B-cell mediated immune responses, but reduced expression of genes related to epithelial morphogenesis and haemostasis. Polyps also showed a generalized reduction of positive gene regulation. The sinonasal transcriptomic signature was largely determined by tissue type (polyp versus mucosa) and disease phenotype, with minimal signal originating from the individual patient. CONCLUSION: RNA-Seq is a useful tool to explore the complex pathophysiology of CRS. Our findings stress the importance of tissue selection in molecular research utilizing sinonasal tissue, and demonstrate the limitation of the sNP/wNP paradigm (and the importance of endotyping). On the other hand, classical CRSsNP/wNP disease phenotypes played some role in determining the global transcriptomic signature, and should not be hastily discarded. The value of RNA-Seq-described transcriptomic signatures in exploring endotypes is yet to be explored in future studies.

The widespread use of topical antimicrobials enriches for resistance in Staphylococcus aureus isolated from patients with atopic dermatitis.

BACKGROUND: Carriage rates of Staphylococcus aureus on affected skin in atopic dermatitis (AD) are approximately 70%. Increasing disease severity during flares and overall disease severity correlate with increased burden of S. aureus. Treatment in AD therefore often targets S. aureus with topical and systemic antimicrobials. OBJECTIVES: To determine whether antimicrobial sensitivities and genetic determinants of resistance differed in S. aureus isolates from the skin of children with AD and healthy child nasal carriers. METHODS: In this case-control study, we compared S. aureus isolates from children with AD (n = 50) attending a hospital dermatology department against nasal carriage isolates from children without skin disease (n = 49) attending a hospital emergency department for noninfective conditions. Using whole genome sequencing we generated a phylogenetic framework for the isolates based on variation in the core genome, then compared antimicrobial resistance phenotypes and genotypes between disease groups. RESULTS: Staphylococcus aureus from cases and controls had on average similar numbers of phenotypic resistances per isolate. Case isolates differed in their resistance patterns, with fusidic acid resistance (FusR ) being significantly more frequent in AD (P = 0·009). The genetic basis of FusR also differentiated the populations, with chromosomal mutations in fusA predominating in AD (P = 0·049). Analysis revealed that FusR evolved multiple times and via multiple mechanism in the population. Carriage of plasmid-derived qac genes, which have been associated with reduced susceptibility to antiseptics, was eight times more frequent in AD (P = 0·016). CONCLUSIONS: The results suggest that strong selective pressure drives the emergence and maintenance of specific resistances in AD.

Caecal diverticulitis: a rare cause of right iliac fossa pain.

We present a case of a young boy with an unusual cause of right iliac fossa pain. His history, examination and laboratory investigations suggested a diagnosis of acute appendicitis. However preoperative abdominal CT revealed an inflamed solitary caecal diverticulum and a normal appendix. He was subsequently treated conservatively and recovered well, saving him from undergoing a general anaesthetic and abdominal surgery.

Clinical and Survival Outcomes Using Percutaneous Cholecystostomy Tube Alone or Subsequent Interval Cholecystectomy to Treat Acute Cholecystitis.

BACKGROUND: Percutaneous cholecystostomy (PCT) is a safe method of gallbladder drainage in the setting of severe or complicated acute cholecystitis (AC), particularly in patients who are high-risk surgical candidates. Small case series suggest that PCT aids resolution of acute cholecystitis in up to 90% of patients. However, reluctance is observed in utilising PCT more frequently, due to concerns that we are committing comorbid patients to an interval surgical procedure for which they may not be suitable. AIM: The aim of this study was to assess the clinical and survival outcomes of PCT use, with particular emphasis on a subgroup of patients who did not proceed to cholecystectomy. METHODS: A retrospective analysis was performed of all patients with severe acute cholecystitis who required PCT insertion in a tertiary referral hospital from 2010 to 2015. Patient demographics and clinical data including systemic inflammatory response (SIRS) scores at presentation, readmissions and clinical and survival outcomes were analysed. Statistical analysis was performed using SPSS v.22 and GraphPad Prism v.7. RESULTS: In total, 157 patients (59% males) with AC underwent PCT insertion during the study period. Median age at presentation was 71 years (range 29-94). A median SIRS score of 3 was noted at presentation. Patients required a median of two cholecystostomy tube changes/replacements (range 1-10) during treatment. Transhepatic tube placement was the preferred approach (69%) with 31% of tubes being placed via transabdominal approach. Only 55% proceeded to interval cholecystectomy. Of the 70 patients treated with PCT alone, their median age was 75 years. In this subgroup, only 12.9% (n = 9) developed recurrent biliary sepsis necessitating readmission following initial resolution of symptoms and tube removal. All episodes of recurrent biliary sepsis presented within 6 months of index presentation, and definitive PCT removal in this group was performed at a median of 3 months. No difference in survival was observed between both groups. CONCLUSION: Almost 90% of patients with AC who are managed definitively with a PCT will recover uneventfully without recurrent sepsis following PCT removal. This is a viable option for older, comorbid patients who are unfit for surgical intervention and is not associated with significantly increased mortality.

Cell salvage at caesarean section: the need for an evidence-based approach.

Haemorrhage, a leading cause of maternal morbidity and mortality, is frequently associated with caesarean section. Allogeneic blood is an increasingly rare and scare resource. Intraoperative Cell Salvage (IOCS) offers the possibility of improving outcome and reducing allogeneic blood transfusion in cases of haemorrhage at caesarean section. The available literature on the use of IOCS in obstetrics demonstrates that there is limited evidence to support or refute the use of IOCS at caesarean section. However, this procedure has been introduced into obstetric practice. Before opinions about its use become solidified, there is a window of opportunity to launch a large multicentre randomised controlled trial to address the current equipoise.

Radical pancreaticoduodenectomy for benign disease.

Whipple's procedure is the treatment of choice for pancreatic and periampullary malignancies. Preoperative histological confirmation of malignancy is frequently unavailable and some patients will subsequently be found to have benign disease. Here, we review our experience with Whipple's procedure for patients ultimately proven to have benign disease. The medical records of all patients who underwent Whipple's procedure during a 15-year period (1987-2002) were reviewed; 112 patients underwent the procedure for suspected malignancy. In eight cases, the final histology was benign (7.1%). One additional patient was known to have benign disease at resection. The mean age was 50 years (range: 30-75). The major presenting features included jaundice (five), pain (two), gastric outlet obstruction (one), and recurrent gastrointestinal haemorrhage (one). Investigations included ultrasound (eight), computerised tomography (eight), endoscopic retrograde cholangiopancreatography (seven; of these, four patients had a stent inserted and three patients had sampling for cytology), and endoscopic ultrasound (two). The pathological diagnosis included benign biliary stricture (two), chronic pancreatitis (two), choledochal cyst (one), inflammatory pseudotumour (one), cystic duodenal wall dysplasia (one), duodenal angiodysplasia (one), and granular cell neoplasm (one). There was no operative mortality. Morbidity included intra-abdominal collection (one), anastomotic leak (one), liver abscess (one), and myocardial infarction (one). All patients remain alive and well at mean follow-up of 41 months. Despite recent advances in diagnostic imaging, 8% of the patients undergoing Whipple's procedure had benign disease. A range of unusual pathological entities can mimic malignancy. Accurate preoperative histological diagnosis may have allowed a less radical operation to be performed. Endoscopic ultrasound-guided fine needle aspirate (EUS-FNA) may reduce the need for Whipple's operation in benign pancreaticobiliary disease in the future.

Implications of altered gastrointestinal motility in obesity.

The onset of obesity occurs as a result of an imbalance between nutrient consumption/absorption and energy expenditure. Gastrointestinal (GI) motility plays a critical role in the rate of consumption of foods, digestion, and absorption of nutrients. Various segments of the GI tract coordinate in a complex yet precise way, to control the process of food consumption, digestion, and absorption of nutrients. GI motility not only regulates the rates at which nutrients are processed and absorbed in the gut, but also, via mechanical and neurohormonal methods, participates in the control of appetite and satiety. Altered GI motility has frequently been observed in obese patients, the significance of which is incompletely understood. However, these alterations can be considered as potential contributing factors in the development and maintenance of obesity and changed eating behavior. Therapies aimed at regulating or counteracting the observed changes in GI motility are being actively explored and applied clinically in the management of obese patients.

Improved survival outcomes for liver transplantation.

UNLABELLED: Liver transplantation is the treatment of choice for end stage liver disease and fulminant hepatic failure. Outcome of the procedure may be dependent on multiple factors including patient selection, donor selection, and centre experience. AIM: To determine whether the outcome for liver transplantation has improved over the time for the Irish National Liver Transplant Unit since its initial set up in 1993. METHODS: All patients who underwent liver transplantation between Jan 1993 to Oct 2004 were included. Patients were sub-divided into three sequential cohorts of 90 patients each. Survival outcomes were compared between the groups. RESULTS: 270 patients (male = 137) underwent 323 liver transplants (median age 49 yrs, range 16-68 yrs). Indications included primary biliary cirrhosis (14.1%), alcohol related liver disease (6.2%), fulminant hepatic failure (14.2%), primary sclerosing cholangitis (10.1%), chronic active hepatitis (9.5%), viral hepatitis (9.5%) and cryptogenic cirrhosis (7.1%). Most procedures (85.8%) were elective. Re-transplantation rates within the first 3 months of primary procedure were 9%, 5%, and 5% for the three chronological groups. Overall calculated 3-month, 1-year and 3 year survival rates for group 1 were 87%, 82% and 77%. For the groups 2 and 3 the figures were 86%, 81%, 77% and 89%, 89%, and 81% respectively. One- and 3-year survival rates were significantly better for group 3 compared to group 1 (p < 0.05). CONCLUSIONS: Survival outcome has improved significantly over the past 12 years and is likely attributed to increasing experience of the transplant centre.

MELD score as a prognostic model for listing acute liver failure patients for liver transplantation.

OBJECTIVES: The King's College Hospital (KCH) criteria are widely used for listing patients with acute liver failure (ALF) for liver transplantation (LT). Recent reports have suggested that the Model for End-Stage Liver Disease (MELD) score may be useful in assessing prognosis in ALF (nonparacetamol). This study compares prognostic accuracy of the two systems in patients with paracetamol (POD)-induced ALF treated in this unit. METHODS: Seventy-two patients (average age 38 years; F:M ratio 2:1) admitted from 1994 to 2005 with POD-related ALF were studied. Clinical and biochemical parameters were recorded. The effect of applying a MELD score of greater than 30 as listing criteria for LT was calculated and compared with the KCH criteria. Outcomes were defined as LT, death, or full recovery. RESULTS: Thirty-one patients (43%) recovered with medical therapy, 29 (40%) patients died, and 12 (17%) underwent LT. Sixty five percent of patients had a MELD > 30 and therefore could potentially be listed on admission; however, using KCH criteria only 24% patients were listed immediately. Sensitivity and negative predictive value of MELD was higher then KCH; however, we found KCH to have much higher specificity and positive predictive value. CONCLUSION: MELD has higher sensitivity and negative predictive value for POD-induced ALF than the KCH criteria. However, the high false-positive rate associated with MELD limits its clinical utility. The high negative predictive value of MELD score may allow it to be used in conjunction with KCH criteria to avoid unneeded LT in patients who will likely recover spontaneously.

Human papillomavirus type 16 E6 and E7 proteins inhibit differentiation-dependent expression of transforming growth factor-beta2 in cervical keratinocytes.

Infection with high-risk human papillomaviruses (HPVs) represents a major risk factor for the development of cervical cancer. The HPV-16 E6 and E7 proteins are highly expressed in differentiating keratinocytes, where they inactivate the p53 and retinoblastoma (pRb) proteins, two important transcriptional regulators. We have used cDNA expression arrays to identify global alterations in gene expression induced by E6 and E7 in differentiating cultures of human cervical keratinocytes. We show that E6 and E7 decrease expression of TGF-beta2 mRNA and alter expression of multiple TGF-beta-responsive genes involved in cell cycle regulation, apoptosis, and tissue remodeling. E6 and E7 inhibited expression of TGF-beta2 RNA 7-fold (relative effectiveness, E6/ E7 > E6 > E7 > control) and decreased secretion of biologically active TGF-beta2 by 70-80% (reduced from 70 to 10 pg/10(6) cells/24 h). Downregulation occurred through p53- and pRb-dependent pathways. In contrast, E6 and E7 did not alter expression of TGF-beta1 and TGF-beta3. Down-regulation of TGF-beta2 was biologically relevant because the addition of recombinant cytokine (10-200 pg/ml) to E6/E7-expressing cells restored expression of TGF-P-responsive genes, inhibited growth of keratinocytes, and decreased immortalization by E6 and E7. These results suggest that TGF-32- and TGF-3-responsive genes are important targets for the HPV-16 E6 and E7 oncoproteins in differentiating cervical keratinocytes.

Iatrogenic common bile duct injuries: Increasing complexity in the laparoscopic era: A prospective cohort study.

PURPOSE: Iatrogenic bile duct injury (BDI) is the most significant associated complication to laparoscopic cholecystectomy (LC). Little is known about the evolution of the pattern of BDI in the era of laparoscopy. The aim of the study is to assess the pattern of post-LC BDIs managed in a tertiary referral centre. METHODS: Post-LC BDI referred over two decades were studied. Demographic data, type of BDI (classified using the Strasberg System), clinical symptoms, diagnostic investigations, timing of referral, post-referral management and morbidity were analysed. The pattern of injury, associated vascular injuries rate and their management were compared over two time periods (1992-2004,2005-2014). RESULTS: 78 BDIs were referred. During the second time period Strasberg A injuries decreased from 14% to 0 and Strasberg E1increased from 4% to 23%, the rate of associated vascular injury was six time higher (3.6% versus 22.7%), more patients had an attempted repair at the index hospital (16% versus 35%) sand fewer patients could be managed without surgical intervention at the referral hospital (28% versus 4%). CONCLUSION: Complexity of referred BDIs and rate of associated vascular injuries have increased over time. These findings led to more patients managed requiring surgical intervention at the referral hospital.

Characterization of moxidectin resistant Trichostrongylus colubriformis and Haemonchus contortus.

The development of moxidectin resistance (MOX-R) in sheep parasitic gastrointestinal nematodes already carrying multiple resistances to other anthelmintic groups has made control of these strains very difficult. The anthelmintic resistance patterns of MOX-R strains of Trichostrongylus colubriformis and Haemonchus contortus were characterized to provide an insight into the remaining role of anthelmintics in the control of such strains. Homozygous MOX-R individuals of both genera were unaffected by moxidectin. For MOX-R heterozygotes a dose rate of 200 microg/kg abamectin (ABA) given orally removed 25% of H. contortus while 200 microg/kg MOX given orally achieved a 72% reduction. Doubling the dose rate of ABA improved the mean efficacy to 37%. Consequently, in H. contortus, the degree of dominance differs markedly between the two anthelmintics. A dose rate of 8 mg/kg levamisole and 185 mg/kg napthalophos achieved >95% reduction in worm count of the MOX-R homozygous H. contortus but only 85 and 7%, respectively against the MOX-R homozygous T. colubriformis.

Shortcomings of the National Joint Registry: a survey of consultants' views.

INTRODUCTION: The National Joint Registry (NJR) for England and Wales was launched in April 2003. The UK Department of Health (DoH) awarded the contract to run the NJR to Atomic Energy Authority (AEA) Technology in September 2002. The aim was to etablish the views of a large group of orthopaedic consultants on the new NJR. METHODS: A questionnaire was sent by post to 405 orthopaedic consultants in the Midlands and South West. RESULTS: Overwhelming support was found for the idea of a national joint replacement register that is used for peer-run audit. However, there was wide-spread concern about the lack of orthopaedic representation on the steering committee. The majority of surgeons have concerns about the possible use of NJR data for the production of league tables.

A randomized controlled trial comparing polyethylene glycol + ascorbic acid with sodium picosulphate + magnesium citrate solution for bowel cleansing prior to colonoscopy.

INTRODUCTION: Adequate bowel cleansing which is acceptable to the patient is a prerequisite for safe and effective colonoscopy. A 2-L polyethylene glycol solution containing ascorbic acid and electrolytes (PEG-Asc) is an alternative to sodium picosulphate + magnesium citrate (SPS-Mg) for bowel preparation. The aim of the current study is to compare PEG-Asc to SPS-Mg in terms of tolerability and efficacy. METHODS: This was a single blind, randomized controlled trial. A blinded assessment of bowel cleansing was made by the attending endoscopist. Patients completed a questionnaire on the acceptability of the preparation. RESULTS: One hundred and thirty (130) consecutive patients attending for day case colonoscopy were randomly allocated to bowel preparation with PEG-Asc (n = 66) or SPS-Mg (n = 64). More patients found PEG-Asc to taste unpleasant (37.9 vs. 10.9%, P < 0.001) and more patients found PEG-Asc to be a more distressing preparation than SPS-Mg (15.1 vs. 4.7%, P = 0.043). However, there was no difference in the proportion of patients being able to complete bowel preparation (PEG-Asc vs. SPS-Mg, 92.4 vs. 93.8%, P = 0.520). There was no detectable difference between PEG-Asc and SPS-Mg in the quality of cleansing with a good or very good preparation being reported by the endoscopist in 46.9 and 54.5% of cases, respectively (P = 0.242). CONCLUSIONS: More patients find PEG-Asc to taste unpleasant and to be a more distressing preparation than SPS-Mg. However, there was no detectable difference between PEG-Asc and SPS-Mg in bowel cleansing prior to colonoscopy.

Segmental duodenal resection: indications, surgical techniques and postoperative outcomes.

INTRODUCTION: Segmental duodenal resections (DR) have been increasingly performed for the treatment of primary duodenal tumours. The aim of the study is to review the indications for, clinical and operative details, and outcomes of patients undergoing elective DR. MATERIAL AND METHODS: We retrospectively reviewed all patients who underwent elective segmental DR for the treatment of primary duodenal tumours, at a single institution between January 2007 and December 2013. Demographic data, clinical presentation, preoperative investigations, operative details, postoperative complications/mortality and histopathological results were recorded. RESULTS: In the study period, 11 duodenal resections were performed (7 male, median age 61 years). Thirty-six percent of the patients presented with anaemia. Surgical resection included two or more segments in seven patients. The most frequently resected part of the duodenum was segment 3 (n = 7). Median operative time was 191 min and blood loss was 675 ml. End-to-end and end-to-side anastomoses were performed in equal numbers. The pathology of resected specimens included adenocarcinoma (n = 4), gastrointestinal stromal tumour (GIST) (n = 1), adenoma (n = 5) and lymphoma (n = 1). Median hospital stay was 14 days. Overall, 30-day morbidity rate was 82% (78% Clavien 2 or less). CONCLUSIONS: Segmental duodenal resection is a safe and effective surgical technique for the resection of primary duodenal tumours.