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Purpose The use of laparoscopy for paediatric inguinal hernia repairs has increased significantly over the past 2 decades. However, there is significant variation in the reported recurrence rates in the literature, with many studies reporting higher rates than the open operation. This may be explained by the range of different techniques currently included under the term laparoscopic inguinal hernia repair. The purpose of this study is to determine whether dividing the hernia sac before ligation improves surgical outcomes following a paediatric laparoscopic inguinal hernia repair compared to ligation alone. Methods A systematic review of the literature was performed following PRISMA guidelines of all studies reporting the outcomes following paediatric laparoscopic inguinal hernia repair where the technique was recorded as laparoscopic suture ligation alone (LS) or laparoscopic sac division and suture ligation (LSDS). Studies were assessed for risk of bias and exclusion criteria included reported follow-up of less than 6 months. Results A total of 8518 LS repairs and 6272 LSDS repairs were included in the final analysis. LSDS repair was associated with a significantly lower recurrence rate (odds ratio 0.51, 95% CI 0.36–0.71, p = 0.001). There was no significant difference in the rates of testicular ascent or atrophy. Conclusion Recreating the open operation by hernia sac division followed by suture ligation significantly reduces the risk of hernia recurrence.

Congenital oesophageal stenosis (COS) is characterised by an intrinsic oesophageal narrowing that is present, but not necessarily symptomatic at birth. Small studies report an association of COS with oesophageal atresia (OA) in up to 14% of OA cases. Although OA is usually appreciated shortly after birth, the diagnosis of a concomitant COS is frequently delayed. This risk may be increased with the current movement away from routine postoperative upper gastrointestinal (GI) contrast study following OA repair. We performed a systematic review of the literature to assess the timing of diagnosis of COS in patients with COS and OA and how this impacted on patient outcomes. A systematic review in accordance with PRISMA guidelines was undertaken. Only patients with OA associated with COS were included. Delayed diagnosis was defined as presentation > 1 month of age. 14 full-text studies with a total of 131 patients were included. Diagnosis of COS was delayed in 62/131 (47%) patients. These children presented with symptoms of dysphagia and aspiration at a median age of 13.5 months (IQR 7–30 months). In total, 18/131 patients were identified at the initial operation, due to difficulty passing a tube distally into the stomach. The data on timing of contrast studies were provided in 60/131 (46%) patients. A routine postoperative contrast study was performed in 39/60 (65%) of these, of which COS was identified immediately in 28/39 (72%). A diagnosis of COS could also be made on retrospective review of the early contrast study in a further 6/39 patients, giving an overall sensitivity of 87%. The association of COS and OA may be underrecognised and diagnosis delayed if routine contrast study is not performed. Contrast studies, performed in the neonatal period are effective at detecting a concomitant COS (sensitivity > 87%). This review supports routine early contrast study after OA repair with specific consideration of the presence of COS.

Background : Gastrostomy insertion is a common procedure for paediatric surgeons, with the percutaneous endoscopic gastrostomy (PEG) technique long favoured for its simplicity and speed. However, there is growing evidence to suggest that primary laparoscopic balloon gastrostomy (LBG) insertions may have lower complication rates. This study aimed to determine the relative safety and healthcare resource burden of PEG and LBG. Methods : A retrospective review of all primary gastrostomy insertions (2011–2019). Primary outcome measures included return to theatre for emergency laparotomy and healthcare burden (total gastrostomy-related admissions, length of stay and total theatre utilisation). Results : 338 PEGs and 277 LBGs were inserted with a minimum follow-up period of six months. Following PEG insertion 12/338(3.6%) children required an emergency laparotomy for gastrostomy-related complications. This compared to 2/277(0.7%) following LBG insertion (ARR2.8% (95%CI0.6–5.0), p When considering all gastrostomy related admissions, there was no significant difference in total theatre utilisation (PEG = 85 [IQR58–117] minutes, LBG = 86 [IQR75–105] minutes, p = 0.12). However, PEGs were found to have an overall longer length of stay 4 [IQR3–7] vs 3 [IQR2–4] days. Conclusions : LBGs carry a significantly lower rate of major complications and are not associated with an increased healthcare burden. LBG should be considered as the first line method of gastrostomy insertion in children.

Matrix metalloproteinase-13 (MMP-13) is a uniquely important collagenase that promotes the irreversible destruction of cartilage collagen in osteoarthritis (OA). Collagenase activation is a key control point for cartilage breakdown to occur, yet our understanding of the proteinases involved in this process is limited. Neutrophil elastase (NE) is a well-described proteoglycan-degrading enzyme which is historically associated with inflammatory arthritis, but more recent evidence suggests a potential role in OA. In this study, we investigated the effect of neutrophil elastase on OA cartilage collagen destruction and collagenase activation. Neutrophil elastase induced significant collagen destruction from human OA cartilage ex vivo, in an MMP-dependent manner. In vitro, neutrophil elastase directly and robustly activated pro-MMP-13, and N-terminal sequencing identified cleavage close to the cysteine switch at 72 MKKPR, ultimately resulting in the fully active form with the neo-N terminus of 85 YNVFP. Mole-per-mole, activation was more potent than by MMP-3, a classical collagenase activator. Elastase was detectable in human OA synovial fluid and OA synovia which displayed histologically graded evidence of synovitis. Bioinformatic analyses demonstrated that, compared with other tissues, control cartilage exhibited remarkably high transcript levels of the major elastase inhibitor, (AAT) alpha-1 antitrypsin (gene name SERPINA1), but these were reduced in OA. AAT was located predominantly in superficial cartilage zones, and staining enhanced in regions of cartilage damage. Finally, active MMP-13 specifically inactivated AAT by removal of the serine proteinase cleavage/inhibition site. Taken together, this study identifies elastase as a novel activator of pro-MMP-13 that has relevance for cartilage collagen destruction in OA patients with synovitis.

PurposeThe challenge of endoscopic large vessel control has brought sweat to the brow of many a surgeon, yet the optimal method for use in a small working space remains unknown. Reports of delayed, major haemorrhage with exclusive energy device use have raised significant concerns. We, therefore, report outcomes of an alternative sealing device (Weck Hem-o-Lok polymer clips) in laparoscopic and thoracoscopic surgery.MethodsA retrospective review of all patients (ResultsThirty-three patients were identified (16 female); 16 underwent laparoscopic splenectomy and 17 thoracoscopic lobectomy/excision of congenital pulmonary airway malformation (CPAM) or resection of pulmonary sequestration. Age at surgery was 7 years 7 months (6 years 2 months–9 years 9 months) and weight 23.0 kg (20.2–37.4 kg) in the splenectomy group: it was 16 months (13–19 months) and 12.0 kg (10.4–13.2 kg) in the thoracic group. Hem-o-Lok clips (medium–large) were used to individually clip: (1) the main splenic artery and vein; or (2) pulmonary arterial branches and vein; or (3) systemic sequestration vessels, using a 5 mm endoscopic applicator. In most cases, two clips were placed proximally and one distally: the vessel then divided without energy. There were no incidences of clip failure during application or migration. There was no significant intra-operative or post-operative bleeding.ConclusionHem-o-Lok polymer clips are a safe and reliable method for major vascular control during endoscopic surgery in small children.

Introduction Management of blunt splenic injury has changed drastically with non-operative management increasingly used in paediatric and adult patients. Studies from America and Australia demonstrate disparities in care of patients treated at paediatric and adult centres. This study assessed management of splenic injuries in UK adolescents. Materials and methods Data were acquired from the Trauma Audit and Research Network on isolated blunt splenic injuries reported 2006–2015. Adolescents were divided into age groups of 11–15 years and 16–20 years, and injuries classified as minor (grades 1/2) or major (3+). Primary outcomes were needed for splenectomy and blood transfusion. Results A total of 445 adolescents suffered isolated blunt splenic injuries. Road traffic collisions were the most common mechanism. There were no deaths as a result of isolated blunt splenic injuries, but 49 (11%) adolescents needed transfusions and 105 (23.6%) underwent splenectomies. There was no significant difference observed in the management of adolescents with minor trauma. In major trauma, 11–15-year-olds were more likely to have splenectomies when managed at local trauma units compared with major trauma centres (31% vs 4%, odds ratio 11.5; 95% confidence interval 3.82–34.38, p < 0.0001). Within major trauma centres, older adolescents were more likely to have splenectomies than younger adolescents (35.5% vs 3.8%, odds ratio 14; 95% confidence interval 4.55–43.26, p < 0.0001). There were no significant differences in haemodynamic status, transfusion requirement or embolisation rates. Conclusions There appears to be a large variation in the management of isolated blunt splenic injuries in the UK. The reasons for this remain unclear however non-operative management is safe and should be first line management in the haemodynamically stable adolescent, even with major splenic injuries.

Laparoscopic cholecystectomy (LC) case volume is low for paediatric surgeons relative to the adult sector; coupled with service differences, internationally accepted standards may be more challenging to meet. This study sought to determine (i) the outcomes of LC in children, and (ii) whether recognised care pathways (e.g. acute LC, access to cholangiogram/ERCP and day-case LC provision) can be delivered. Patients who underwent LC were identified retrospectively in a single institution between January 2009 and January 2019. Data are presented as median [IQR] and continuous variables compared using a t test. 101 cases were included (age 12.9 years [10.2–15]; female 65/101). Indications for LC were symptomatic gallstones (98/101) and polyps (2/101). ERCP and/or endoscopic ultrasound were performed in 23/101. For acute presentations, 7/24 (29%) had LC during the same admission. Trainees performed LC in 33/101. 4/101 required intra-operative cholangiogram. Operative time was 109.5 min [90.8–139.5]: consultant vs. trainee times were similar (114 [93.3–149.5] vs. 99.5 [81.5–125.3], p = 0.06). Length of stay was one day [1–1] with 10/101 being day-cases. There were no major complications or re-operations. We report good outcomes from LC. Furthermore, we have demonstrated the capacity to deliver recognised standards of care within a paediatric setting.

Recent evidence suggests simple laparoscopic inguinal herniorrhaphy is associated with higher rates of recurrence and testicular ascent. We instigated a standardised approach to laparoscopic inguinal herniotomy (LIH), with circumferential sac division and 'purse-string' closure (4/0 monofilament polypropylene). An active follow-up programme was pursued. We reviewed our outcomes of this technique and compared them to an open herniotomy (OIH) cohort.LIH patients were identified prospectively (2017-2021): OIH retrospectively from 2016. Risk factors for complications were defined: extremely to very preterm ( 32 weeks), emergency presentation with incarceration, and redo surgery for recurrence. Data are presented as median [IQR]. Comparisons used Fisher's exact and Mann-Whitney U tests: significance defined as p 0.05.192 inguinal herniae in 140 patients were included in the LIH group and 214 herniae in 179 patients in the OIH group. Groups were similar in age and gender. The LIH group had a significantly larger proportion of cases that were premature, had emergency surgery, or had redo surgery after previous OIH. Follow-up was 24.4 months [10.8-33.6] vs. 66.4 [64.5-68.5] (LIH vs. OIH). Hernia recurrence occurred in 2/192 (1.0%) vs. 4/214 (1.9%) (LIH vs. OIH), p = 0.69. There was one known case of testicular ascent after OIH but none in the LIH group.Recreation of the open herniotomy laparoscopically appears to confer excellent outcomes, with low rates of recurrence despite a high proportion of patients having known risk factors. Further long-term data on rates of testicular ascent after active follow-up are required.

Laparoscopy is the gold standard to assess for presence of an intra-abdominal testis. However, techniques for the subsequent orchidopexy vary, and include the recently described staged laparoscopic traction orchidopexy (SLTO) (Shehata in Pediatr Surg 51(2):211–215, 2016). SLTO enables elongation of the testicular vessels without division, with initial success rates reportedly superior to Fowler–Stephens. We present the first UK data following a preliminary study using SLTO. 19 boys prospectively presenting with 22 intra-abdominal testes (IAT) underwent STLO in a single centre, with a median age of 2.5 years (IQR 1.4–5.2) at first stage. 3/19 (16%) boys had bilateral IAT and nine (41%) were left-sided. Pneumoperitoneum was established using 5 mm umbilical and 3 mm accessory ports in bilateral iliac fossae. The gubernaculum and lateral peritoneal attachments were divided prior to securing the intra-abdominal testis to the contralateral anterior abdominal wall with 2/0 Ti-cron™. Second-stage procedures were planned for 3–6 months later. The securing stitch was cut; an 11 mm STEP port was placed trans-scrotally to retrieve the testis and secured in a sub-dartos pouch. Outcome measures included palpable testes in the scrotum and surgical complications. 13/22 IAT have undergone follow-up. Twelve (92%) IAT were palpable in the scrotum following SLTO. There was one diathermy-related bladder injury necessitating laparoscopic repair, and 3/22 (13.6%) slipped sutures, requiring repeat first-stage procedures. Staged laparoscopic traction orchidopexy is a feasible technique, which can be performed as an alternative to Fowler–Stephens procedure, with potentially better outcomes for the testis. The complications described should be preventable as the technique evolves.

Serpins (serine proteinase inhibitors) are an ancient superfamily of structurally similar proteins, the majority of which use an elegant suicide inhibition mechanism to target serine proteinases. Despite likely evolving from a single common ancestor, the 36 human serpins have established roles regulating diverse biological processes, such as blood coagulation, embryonic development and extracellular matrix (ECM) turnover. Genetic mutations in serpin genes underpin a host of monogenic disorders — collectively termed the ‘serpinopathies’ — but serpin dysregulation has also been shown to drive pathological mechanisms in many common diseases. Osteoarthritis is a degenerative joint disorder, characterised by the progressive destruction of articular cartilage. This breakdown of the cartilage is driven by the metalloproteinases, and it has long been established that an imbalance of metalloproteinases to their inhibitors is of critical importance. More recently, a role for serine proteinases in cartilage destruction is emerging; including the activation of latent matrix metalloproteinases and cell-surface receptors, or direct proteolysis of the ECM. Serpins likely regulate these processes, as well as having roles beyond serine proteinase inhibition. Indeed, serpins are routinely observed to be highly modulated in osteoarthritic tissues and fluids by ‘omic analysis, but despite this, they are largely ignored. Confusing nomenclature and an underappreciation for the role of serine proteinases in osteoarthritis (OA) being the likely causes. In this narrative review, serpin structure, biochemistry and nomenclature are introduced, and for the first time, their putative importance in maintaining joint tissues — as well as their dysregulation in OA — are explored.

The administration of chloroform by John Snow to Queen Victoria to provide analgesia for the delivery of her children was a pivotal moment in the development of anaesthesia. It has long been thought that this was the only occasion she had experienced anaesthesia but examination of her diaries shows this to be untrue.

A 32-month-old girl required tunnelled central venous catheter (CVC) insertion prior to stem cell transplantation. After routine internal jugular vein puncture and guidewire insertion under fluoroscopy, resistance was felt as the peel-apart percutaneous introducer was passed over the wire. The

Metalloproteinases were first identified as collagen cleaving enzymes and are now appreciated to play important roles in a wide variety of biological processes. The aberrant activity and dysregulation of the metalloproteinase family are linked to numerous diseases including cardiovascular and pulmonary diseases, chronic wounds, cancer, fibrosis and arthritis. Osteoarthritis (OA) is the most prevalent age-related joint disorder that causes pain and disability, but there are no disease-modifying drugs available. The hallmark of OA is loss of articular cartilage and elevated activities of matrix-degrading metalloproteinases are responsible. These enzymes do not exist in isolation and their activity is tightly regulated by a number of processes, such as transcription, proteolytic activation, interaction with their inhibitors, cell surface and extracellular matrix molecules, and endocytic clearance from the extracellular milieu. Here, we describe the functions and roles of metalloproteinase family in OA pathogenesis. We highlight recent studies that have illustrated novel mechanisms regulating their extracellular activity and impairment of such regulations that lead to the development of OA. We also discuss how to stop or slow down the degenerative processes by targeting aberrant metalloproteinase activity, which may in future become therapeutic interventions for the disease.

Dr. Richard Gill published a textbook in London in 1906 titled The CHCl3 - Problem. Gill was the Chief Chloroformist at St Bartholomew's Hospital, London, and was recognized as an excellent clinical anesthetist and was of an intelligent but reclusive and eccentric personality. This textbook is rarely found and has not been appreciated in the history of anesthesia for several reasons including that it was generally ignored at publication and few copies exist in libraries around the world. The CHCl3Problem is written in a verbose, archaic, and convoluted fashion and is rarely quoted. It has no references whatsoever. Gill was extensively quoted by one of his students who returned to Australia, Dr. John W Bean, which brought the book to the authors' attention. It was found on the Internet, and a copy from the Boston Medical Library had been scanned and was available as a print-on-demand.

Cartilage destruction is a key characteristic of arthritic disease, a process now widely established to be mediated by metzincins such as MMPs. Despite showing promise in preclinical trials during the 1990s, MMP inhibitors for the blockade of extracellular matrix turnover in the treatment of cancer and arthritis failed clinically, primarily due to poor selectivity for target MMPs. In recent years, roles for serine proteinases in the proteolytic cascades leading to cartilage destruction have become increasingly apparent, renewing interest in the potential for new therapeutic strategies that utilize pharmacological inhibitors against this class of proteinases. Herein, we describe key serine proteinases with likely importance in arthritic disease and highlight recent advances in this field. LINKED ARTICLES: This article is part of a themed section on Translating the Matrix. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.1/issuetoc.

The collagenase subfamily of matrix metalloproteinases (MMPs) have important roles in the remodeling of collagenous matrices. The proteinase-activated receptor (PAR) family has a unique mechanism of activation requiring proteolysis of an extracellular domain forming a neo-N terminus that acts as a tethered ligand, a process that has been associated with the development of arthritis. Canonical PAR2 activation typically occurs via a serine proteinase at Arg(36)-Ser(37), but other proteinases can cleave PARs downstream of the tethered ligand and “disarm” the receptor. To identify additional cleavage sites within PAR2, we synthesized a 42-amino-acid peptide corresponding to the extracellular region. We observed that all three soluble MMP collagenases, MMP-1, MMP-8, and MMP-13, cleave PAR2 and discovered a novel cleavage site (Ser(37)-Leu(38)). Metalloproteinases from resorbing bovine nasal cartilage and recombinant human collagenases could cleave a quenched fluorescent peptide mimicking the canonical PAR2 activation region, and kinetic constants were determined. In PAR2-overexpressing SW1353 chondrocytes, we demonstrated that the activator peptide SLIGKV-NH(2) induces rapid calcium flux, inflammatory gene expression (including MMP1 and MMP13), and the phosphorylation of extracellular signal-regulated kinase (ERK) and p38 kinase. The corresponding MMP cleavage-derived peptide (LIGKVD-NH(2)) exhibited no canonical activation; however, we observed phosphorylation of ERK, providing evidence of biased agonism. Importantly, we demonstrated that preincubation with active MMP-1 reduced downstream PAR2 activation by a canonical activator, matriptase, but not SLIGKV-NH(2). These results support a role for collagenases as proteinases capable of disarming PAR2, revealing a mechanism that suppresses PAR2-mediated inflammatory responses.

The CXCR2 antagonist AZD5069 has been synthesized in tritium and carbon-14-labelled forms. [(3) H]AZD5069 was prepared via reductive dehalogenation of an iodinated precursor with tritium gas to provide material with a specific activity of 25.1 Ci/mmol. [(14) C]AZD5069 was labelled in the pyrimidine ring from [(14) C]thiourea in an overall radiochemical yield of 18%. In addition, a synthetic route to the major metabolite of AZD5069 was developed. The synthesis of this metabolite was achieved from AZD5069 using a chemoselective Lindgren-Pinnick reaction in order to minimize oxidation of the sulphide group.

AZD5122, N-(2-(2,3-difluorobenzylthio)-6-((2R,3R)-3,4-dihydroxybutan-2-ylamino)pyrimidin-4-yl)azetidine-1-sulfonamide was under investigation as a potential chemokine receptor CXCR2 antagonist for the treatment for inflammatory diseases. To gain a better understanding of the human pharmacokinetic profile, an exploratory phase I IV microtracer study was conducted using carbon-14 radiolabelled AZD5122. [(14) C]AZD5122 was carbon-14 labelled in the pyrimidine ring in five steps in an overall radiochemical yield of 19% from [(14) C]thiourea. The absolute oral bioavailability of AZD5122 was assessed in healthy subjects by an oral administration of AZD5122, followed by a concomitant intravenous [(14) C]AZD5122 microdose.

A term baby was admitted to the neonatal intensive care unit with respiratory distress. A presumed diagnosis of oesophageal atresia was made following failure to pass an orogastric tube. A thoracic ultrasound was performed, due to persistent right lower lobe changes on chest x-ray and worsening distress without abdominal distention. This identified a soft-tissue mass within the right thorax, prompting a CT (figure 1). This demonstrated an oesophageal atresia and …

Many catabolic stimuli, including interleukin-1 (IL-1) in combination with oncostatin M (OSM), promote cartilage breakdown via the induction of collagen-degrading collagenases such as matrix metalloproteinase 1 (MMP1) and MMP13 in human articular chondrocytes. Indeed, joint diseases with an inflammatory component are characterised by excessive extracellular matrix (ECM) catabolism. Importantly, protein kinase C (PKC) signalling has a primary role in cytokine-induced MMP1/13 expression, and is known to regulate cellular functions associated with pathologies involving ECM remodelling. At present, substrates downstream of PKC remain undefined. Herein, we show that both IL-1- and OSM-induced phosphorylation of protein kinase D (PKD) in human chondrocytes is strongly associated with signalling via the atypical PKCι isoform. Consequently, inhibiting PKD activation with a pan-PKD inhibitor significantly reduced the expression of MMP1/13. Specific gene silencing of the PKD isoforms revealed that only PKD3 (PRKD3) depletion mirrored the observed MMP repression, indicative of the pharmacological inhibitor specifically affecting only this isoform. PRKD3 silencing was also shown to reduce serine phosphorylation of signal transducer and activator of transcription 3 (STAT3) as well as phosphorylation of all three mitogen-activated protein kinase groups. This altered signalling following PRKD3 silencing led to a significant reduction in the expression of the activator protein-1 (AP-1) genes FOS and JUN, critical for the induction of many MMPs including MMP1/13. Furthermore, the AP-1 factor activating transcription factor 3 (ATF3) was also reduced concomitant with the observed reduction in MMP13 expression. Taken together, we highlight an important role for PKD3 in the pro-inflammatory signalling that promotes cartilage destruction.

Introduction Infantile hypertrophic pyloric stenosis (IHPS) is a common surgical condition, but there are no guidelines regarding preoperative fluid resuscitation. Our aim was to evaluate a novel consensus care pathway for IHPS, incorporating a standardized fluid and electrolyte replacement regime. Methods One hundred patients were initially reviewed and compared to thirty-three patients following the introduction of a clinical pathway, whereby infants requiring electrolyte correction received 150 ml/kg/24 h of 0.45% saline, 5% dextrose and 10 mmol KCl, with systematic blood sampling until correction was achieved. We measured time to electrolyte correction, time to surgery and total length of hospitalization. Data were described using the median and interquartile range, and differences between the groups’ categorical and continuous data were described using Chi-squared and the Mann–Whitney U–tests, respectively. Results Time in hours taken to correct electrolytes was reduced: 25(16.5–42) versus 9.5(4.5–24.75) p = 0.004. Time to surgery from admission in uncorrected patients decreased from 50(40.25–66.75) to 39(28.75–41.75) p = 0.018. Subsequently, there was a reduction in total length of stay: 94(71–93.5) versus 75(64.5–93.5) p = 0.025. Parental satisfaction increased from 77% in the pre-pathway group to 83% in the pathway group. Conclusion A consensus care pathway for IHPS reduces the time taken to correct preoperative electrolyte abnormalities, decreases length of hospitalization and improves parental satisfaction.

Haemolytic uraemic syndrome (HUS) is the commonest childhood cause of acute renal failure. Peritoneal dialysis peritonitis (PDP) is a well-recognised complication, with some children requiring surgical intervention (SI). The aim of this study is to determine whether the presence of enteric organisms in cases of PDP might predict the need for SI. Retrospective, 5-year (2009–2014) case note review of all HUS cases requiring PD presenting to a single centre. Mann–Whitney U test was used for continuous non-parametric data and χ 2 for categorical data. 48 children required PD for HUS, 18/48 (38 %) developed PDP and of these 5/18 (28 %) required SI (subtotal colectomy n = 4, small bowel resection n = 1). Peritoneal fluid was cultured as part of the work-up for PDP. The presence of enteric organisms was associated with a 10.4 fold relative risk of requiring surgery (p = 0.02, 95 % CI 1.5–71.9), with 4/5 of these patients requiring surgery (median 17 days post-culture result). Only 1/13 patients not requiring surgery grew gram-negative bacteria. The presence of enteric bacteria in patients with PDP significantly decreases the chances of successful conservative management. In these patients early involvement of the surgical team is essential with a low threshold for SI.

Objective Intestinal malrotation classically presents in the neonatal period with bilious vomiting. However, population studies suggest that up to two-thirds of these patients are diagnosed later in childhood or in adulthood. Increased morbidity in the adult population has been reported. Local experience suggested that surgery was technically more difficult in older children and led to the hypothesis that it would be associated with increased morbidity. Methods A retrospective case note analysis was performed on all children presenting with intestinal malrotation to a tertiary referral center between January 2002 and November 2014. Case notes and operation records were reviewed and those who underwent laparotomy for confirmed malrotation were included. Children were grouped as infants ( 1 year). The primary outcome was total emergency reoperation rate. Secondary outcomes were requirement for a bypass at reoperation and mortality. Results A total of 131 children with malrotation were identified (104 infants, 27 older children; 78 males; age range, 0–16 years). Overall, 13 patients had emergency reoperation following initial Ladd procedure (6 infants and 7 older children). Risk for reoperation was significantly higher in older children ( p = 0.005) and additionally a bypass procedure was more often required in older children than infants (4 children, 2 infants, p = 0.016). Adhesiolysis was required on four occasions and redo Ladd procedure in two; these were evenly distributed between both groups. One child was found to have distal bowel obstruction at reoperation. There were three deaths (2.3%), all in the infant group. One was directly associated with malrotation with extensive bowel necrosis. The other two died of unrelated sepsis several months later. Conclusions Malrotation surgery in older children is associated with a significantly higher emergency reoperation rate. The primary duodenal bypass procedure should always be considered with longstanding chronic intermittent obstruction associated with malrotation if the simple Ladd procedure is deemed inadequate.

Multiple guidelines exist in adult practice regarding the timing of cholecystectomy for gallstone pancreatitis. Current evidence to support their application to pediatric practice is minimal. This study sought to determine the effect of timing of cholecystectomy for gallstone pancreatitis in children on the risk of readmission.All patients younger than 19years of age presenting to an acute NHS trust in England with a diagnosis of gallstone pancreatitis between 1 January 1999 and 31st December 2009 were included. Patient level data were extracted from the English Hospital Episode Statistic Database. ICD10, OPCS4.6 and hospital administrative data were used to determine: diagnosis, age, associated comorbidities and subsequent procedures performed.670 cases of gallstone related pancreatitis were recorded in younger than 19 years old between 1999 and 2009 resulting in 3 deaths during this period. The majority (534/670) underwent a cholecystectomy which was performed less than two weeks from primary admission in 33% (174/534) of cases. Cholecystectomy within two weeks provides an actual risk reduction (ARR) of readmission of 57.5% (95% CI 50.1 to 64.4%, p0.0001, NNT 2). No significant difference was identified in operative complications or mortality following early cholecystectomy in this group (p0.05).Readmissions can be significantly reduced in this population by performing a cholecystectomy within two weeks with no apparent rise in surgical complications.

The history of the development of anaesthesia can be traced back for many centuries and is closely linked with the development of surgery. Most current descriptions of this history tend to focus on the affluent Western World from the mid-nineteenth century onwards. Although rich in stories about many aspects of anaesthesia development, this provides a very narrow viewpoint and ignores the contributions made by early civilisations that are difficult to quantify due to inadequate translations of original documents and persistent repetition of inaccurate myths. The history of anaesthesia varies from country to country and should always be considered in relation to who has written the document. It is a process that is still continuing and there is much still to be learnt and recorded from the past and present. Key Concepts Anaesthesia history varies according to the culture from which it is written. Anaesthesia history varies from country to country as historians tend to emphasise their own cultural contributions to the exclusion of others. Much in anaesthesia history can be traced back for centuries as an understanding of human physiology slowly evolved. It is likely that there are many written documents, particularly in Arabic and Indian languages, that could augment current understanding of anaesthesia history significantly. Many anaesthesia historians continue to repeat previously published stories without any attempt to verify their accuracy. The development of modern anaesthesia has allowed the anaesthetist increasing control over a patient's physiology that has in turn permitted surgery to expand and develop. The history of anaesthesia in the less affluent world may well be limited to a few decades and bear no relationship to that seen in the affluent world. Keywords: anaesthesia; history; ether; chloroform; equipment; monitoring

Congenital diaphragmatic hernia (CDH) is associated with high mortality due to lung hypoplasia, pulmonary hypertension and co-existent anomalies. This paper highlights recent progress in the perinatal management of CDH and addresses long term outcome issues for survivors indicating the need for multidisciplinary follow up.

Cartilage destruction is a key characteristic of arthritic disease, a process now widely established to be mediated by metzincins such as MMPs. Despite showing promise in preclinical trials during the 1990s, MMP inhibitors for the blockade of extracellular matrix turnover in the treatment of cancer and arthritis failed clinically, primarily due to poor selectivity for target MMPs. In recent years, roles for serine proteinases in the proteolytic cascades leading to cartilage destruction have become increasingly apparent, renewing interest in the potential for new therapeutic strategies that utilize pharmacological inhibitors against this class of proteinases. Herein, we describe key serine proteinases with likely importance in arthritic disease and highlight recent advances in this field. LINKED ARTICLES: This article is part of a themed section on Translating the Matrix. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.1/issuetoc.

Increasing evidence implicates serine proteinases in the proteolytic cascades leading to the pathological destruction of extracellular matrices such as cartilage in osteoarthritis (OA). We have previously demonstrated that the type II transmembrane serine proteinase (TTSP) matriptase acts as a novel initiator of cartilage destruction via the induction and activation of matrix metalloproteinases (MMPs). Hepsin is another TTSP expressed in OA cartilage such that we hypothesized this proteinase may also contribute to matrix turnover. Herein, we demonstrate that addition of hepsin to OA cartilage in explant culture induced significant collagen and aggrecan release and activated proMMP-1 and proMMP-3. Furthermore, hepsin directly cleaved the aggrecan core protein at a novel cleavage site within the interglobular domain. Hepsin expression correlated with synovitis as well as tumour necrosis factor α expression, and was induced in cartilage by a pro-inflammatory stimulus. However, a major difference compared to matriptase was that hepsin demonstrated markedly reduced capacity to activate proteinase-activated receptor-2. Overall, our data suggest that hepsin, like matriptase, induces potent destruction of the extracellular matrix whilst displaying distinct efficiencies for the cleavage of specific substrates.

The importance of aldehyde oxidase (AOX) is becoming increasingly recognized in the prediction of human pharmacokinetic parameters from animal data. The objectives of these studies were to ascertain whether an in vitro-in vivo correlation existed in the clearance and metabolic pathways of AOX substrates and to establish whether the minipig represented an appropriate non-rodent model for man in the pre-clinical development of drugs metabolized by AOX. Using the AOX substrates carbazeran, 6-deoxypenciclovir and zaleplon, clearance was estimated from in vitro depletion experiments with minipig and human liver cytosol and microsomes and scaled before comparison with data generated in parallel in vivo studies in minipigs. In vitro and in vivo metabolic pathways were characterized by LC-MS/MS. Scaling of in vitro metabolism data to predict in vivo clearance underestimated in vivo values, although the rank order of clearance for the three compounds was preserved. Prediction of human in vivo clearance from scaled minipig in vivo data produced results which correlated well with published clinical values. Overall, this study is the first to compare minipig in vitro metabolism data with in vivo pharmacokinetic data for compounds metabolized by AOX and provides a scientific rationale for the selection of this species as a model for humans in the development of drugs which are substrates of AOX.

Objective To assess the role of glycogen synthase kinase 3 (GSK-3) as a regulator of cartilage destruction in human tissue and a murine model of osteoarthritis (OA). Methods Surgical destabilization of the medial meniscus (DMM) was performed to induce experimental murine OA, and joint damage was assessed histologically. Bovine nasal and human OA cartilage samples were incubated with interleukin-1 (IL-1) plus oncostatin M (OSM) and GSK-3 inhibitor. Collagen and proteoglycan release was assessed by hydroxyproline measurement and dye binding assay, collagenase activity was assessed by bioassay, and gene expression was analyzed by real-time polymerase chain reaction. Human articular chondrocytes were isolated by enzymatic digestion and cultured prior to gene silencing and immunoblotting of cell lysates and nuclear fractions. Results Mice treated with GSK-3 inhibitor exhibited significantly greater cartilage damage compared with sham-operated control mice. GSK-3 inhibition in bovine cartilage dramatically accelerated IL-1 plus OSM–stimulated degradation, concomitant with a profound increase in collagenase activity. GSK-3 inhibitor induced collagen release from human OA cartilage in the presence of IL-1 plus OSM and increased proteoglycan loss. Gene expression profiling of resorbing OA cartilage revealed a marked procatabolic switch in gene expression upon GSK-3 inhibition. This was mirrored in human articular chondrocytes following GSK3 silencing, particularly with the GSK-3β isoform. GSK-3 inhibition or silencing led to enhanced IL-1 plus OSM–stimulated abundance and activity of Jun, and silencing of c-jun ameliorated GSK-3 inhibitor–mediated procatabolic gene expression. Conclusion GSK-3 is an important regulator of matrix metalloproteinase (MMP)–mediated joint destruction, the inhibition of which by proinflammatory stimuli de-represses catabolic gene expression. Therapeutic strategies that maintain cartilage GSK-3 activity may therefore help curtail aberrant MMP activity during pathologic joint destruction.

Objectives To determine whether the process of ubiquitination and/or activity of the 26S proteasome are involved in the induction of osteoarthritis (OA). Methods Bovine cartilage resorption assays, chondrocyte cell-line SW1353 and primary human articular chondrocytes were used with the general proteasome inhibitor MG132 or vehicle to identify a role of the ubiquitin–proteasome system (UPS) in cartilage destruction and matrix metalloproteinase-13 (MMP13) expression. In vivo, MG132 or vehicle, were delivered subcutaneously to mice following destabilisation of the medial meniscus (DMM)-induced OA. Subsequently, DMM was induced in Lys-to-Arg (K48R and K63R) mutant ubiquitin (Ub) transgenic mice. Cytokine signalling in SW1353s was monitored by immunoblotting and novel ubiquitinated substrates identified using Tandem Ubiquitin Binding Entities purification followed by mass spectrometry. The ubiquitination of TRAFD1 was assessed via immunoprecipitation and immunoblotting and its role in cytokine signal-transduction determined using RNA interference and real-time RT-PCR for MMP13 and interleukin-6 (IL6). Results Supplementation with the proteasome inhibitor MG132 protected cartilage from cytokine-mediated resorption and degradation in vivo in mice following DMM-induced OA. Using transgenic animals only K48R-mutated Ub partially protected against OA compared to wild-type or wild-type Ub transgenic mice, and this was only evident on the medial femoral condyle. After confirming ubiquitination was vital for NF-κB signalling and MMP13 expression, a screen for novel ubiquitinated substrates involved in cytokine-signalling identified TRAFD1; the depletion of which reduced inflammatory mediator-induced MMP13 and IL6 expression. Conclusions Our data for the first time identifies a role for ubiquitination and the proteasome in the induction of OA via regulation of inflammatory mediator-induced MMP13 expression. These data open avenues of research to determine whether the proteasome, or K48-linked ubiquitination, are potential therapeutic targets in OA.

Background: Initial validation and feasibility for the Post-operative Quality of Recovery Scale (PQRS) was published in 2010. Ongoing validation includes studies to determine whether this scale can discriminate differences in recovery between cohorts. Methods: A prospective cohort study included 61 patients, 18-40 years, and 61 patients, aged ≥65 years, undergoing knee arthroscopy under general anaesthesia; and 13 patients, aged ≥65 years, undergoing total knee replacement under general anaesthesia. Patients were assessed using the PQRS. Assessments were performed pre-surgery, at 15 and 40min, 1 and 3 days, and 3 months after surgery. Results: The effect of age was assessed by comparing young versus older arthroscopy patients. There were minimal differences in recovery profiles, other than for the nociceptive domain, where pain recovery was significantly better in the older arthroscopy patients (P

Summary Introduction Circumcision has long been the mainstay of management for genitourinary lichen sclerosus et atrophicus (LS); however, there has been growing interest in surgical techniques that preserve the foreskin. Objective The aim of this study was to assess population-based surgical management of LS in England and determine surgical outcomes. Study design Cases of LS treated in English NHS trusts (2002–2011) were extracted from the Hospital Episode Statistics (HES) Database. Cases were identified by both an ICD-10 code for LS and either an OPCS4.6 code for circumcision or preputioplasty (with/without injection of steroid). Subsequent admissions were analysed for related complications/procedures. Data are presented as median (interquartile range) unless otherwise stated. Results 7893 patients had surgery for LS, of whom 7567 (95.8%) underwent circumcision ( Table ). Primary preputioplasty was performed in 326 (4.1%) in 44/130 centres; of these 151/326 had concomitant injection of steroid. Age at surgical intervention was 9 (6–11) years. There were no postoperative bleeds following preputioplasty. Of those treated with preputioplasty, 74 (22%) had subsequent circumcision at a median of 677 (277–1203) days post operation. Concomitant steroid injection reduced the risk of subsequent circumcision (21/151 (14%) vs. 53/175 (30%), p Conclusion Although circumcision is the predominant treatment for LS, these data suggest that preputioplasty is a valid option in management, albeit with a higher re-intervention rate. Selection bias may play a role and a randomized controlled trial is needed. Preputioplasty combined with steroid injection appears to reduce the chance of completion circumcision. Table . Comparison between circumcisions and preputioplasties. Age at primary operation Day-case procedures Infection Postoperative bleeding Further meatal intervention Further urethral intervention Circumcisions (N = 7567) 9 (6–11) 6960 (92%) 48 (0.6%) 61 (0.8%) 421 (5.6%) 129 (1.7%) Preputioplasties (N = 326) 9 (7–11) 303 (92.9%) 1 (0.3%) 0 10 (3.1%) 8 (2.5%) p-value 0.292 0.528a 0.723b 0.182b 0.051a 0.205a Continuous variable displayed using median (IQR) and compared using Mann–Whitney U Test. Categorical variables portrayed as n (%) and compared using chi-squarea and Fisher's Exact test.b Note subgroup analysis presented in the main text.

Background Cognitive problems early after surgery are often considered transient in nature. Neuropsychological performance and its relation to other recovery parameters have rarely been systematically assessed during this period. Methods A subanalysis of the Post-operative Quality of Recovery Scale (PQRS) feasibility study included patients who completed the PQRS on day 3, and were categorised as recovered or not recovered in the cognitive domain using the revised scoring method. Results Of the 449 patients included in this paper, 388 (86.4%) recovered in the cognitive domain and 61 (13.6%) had not recovered at 3 days. Cognitive recovery in the early post-operative time points up to day 1 was significantly lower in patients who had not recovered at day 3 (P

Context Previous research has shown that most patients are satisfied with their anaesthetic care. For those who are not the causes may be multifactorial including dissatisfaction with surgical outcomes. Objectives We aimed to identify whether quality of recovery after anaesthesia and surgery measured in multiple domains affects patient satisfaction. Design Sub-group analysis of previously published observational cohort study of quality of recovery after surgery (using the Postoperative Quality of Recovery Scale) was used to identify predictors of incomplete satisfaction 3 days after surgery. Setting Multicentre perioperative surgery. Patients Patients � 6 years old, undergoing a variety of operation types and all receiving general anaesthesia. Observations Of 701 patients, 573 completed the satisfaction question on day 3. Satisfaction was rated by a single fivepoint rating question. Patients were divided into two groups: 477 (83%) were completely satisfied and 96 (17%) were not completely satisfied. Multivariable logistic regression analysis was performed on preoperative and patient characteristics and recovery in five domains as follows: physiological, nociceptive (pain and nausea), emotive (anxiety and depression), activities of daily living and cognition. Recovery was defined as return to baseline values or better for all questions within each domain. Results Incomplete satisfaction was predicted by persistent pain or nausea at day 3 [OR 8.2 (95% CI 2.5 to 27), P

Irreversible breakdown of cartilage extracellular matrix (ECM) by the collagenase matrix metalloproteinase 13 (MMP13) represents a key event in osteoarthritis (OA) progression. Although inflammation is most commonly associated with inflammatory joint diseases, it also occurs in OA and is thus relevant to the prevalent tissue destruction. Here, inflammation generates a cFOS AP-1 early response that indirectly affects MMP13 gene expression. To ascertain a more direct effect on prolonged MMP13 production we examined the potential molecular events occurring between the rapid, transient expression of cFOS and the subsequent MMP13 induction. Importantly, we show MMP13 mRNA expression is mirrored by nascent hnRNA transcription. Employing ChIP assays, cFOS recruitment to the MMP13 promoter occurs at an early stage prior to gene transcription and that recruitment of transcriptional initiation markers also correlated with MMP13 expression. Moreover, protein synthesis inhibition following early FOS expression resulted in a significant decrease in MMP13 expression thus indicating a role for different regulatory factors modulating expression of the gene. Subsequent mRNA transcriptome analyses highlighted several genes induced soon after FOS that could contribute to MMP13 expression. Specific small interfering RNA-mediated silencing highlighted that ATF3 was as highly selective for MMP13 as cFOS. Moreover, ATF3 expression was AP-1(cFOS/cJUN)-dependent and expression levels were maintained after the early transient cFOS response. Furthermore, ATF3 bound the proximal MMP13 AP-1 motif in stimulated chondrocytes at time points that no longer supported binding of FOS. Consequently, these findings support roles for both cFOS (indirect) and ATF3 (direct) in effecting MMP13 transcription in human chondrocytes.

The CXCR2 antagonist AZD5069 has been synthesized in tritium and carbon-14-labelled forms. [(3) H]AZD5069 was prepared via reductive dehalogenation of an iodinated precursor with tritium gas to provide material with a specific activity of 25.1 Ci/mmol. [(14) C]AZD5069 was labelled in the pyrimidine ring from [(14) C]thiourea in an overall radiochemical yield of 18%. In addition, a synthetic route to the major metabolite of AZD5069 was developed. The synthesis of this metabolite was achieved from AZD5069 using a chemoselective Lindgren-Pinnick reaction in order to minimize oxidation of the sulphide group.

Background We previously reported our short-term experience of foreskin preputioplasty as an alternative to circumcision for the treatment of foreskin balanitis xerotica obliterans (BXO). In this study, we aimed to compare this technique with circumcision over a longer period. Methods Between 2002 and 2007, boys requiring surgery for BXO were offered either foreskin preputioplasty or primary circumcision. The preputioplasty technique involved triradiate preputial incisions and injection of triamcinolone intralesionally. Retrospective case-note analysis was performed to identify patient demographics, symptoms, and outcomes. Results One hundred thirty-six boys underwent primary surgery for histologically confirmed BXO. One hundred four boys opted for foreskin preputioplasty, and 32, for circumcision. At a median follow-up of 14 months (interquartile range, 2.5-17.8), 84 (81%) of 104 in the preputioplasty group had a fully retractile and no macroscopic evidence of BXO. Of 104, 14 (13%) developed recurrent symptoms/BXO requiring circumcision or repeat foreskin preputioplasty. In the circumcision group, 23 (72%) of 32 had no macroscopic evidence of BXO. The incidence of meatal stenosis was significantly less in the foreskin preputioplasty group, 6 (6%) of 104 vs 6 (19%) of 32 ( P = .034). Conclusion Our results show a good outcome for most boys undergoing foreskin preputioplasty and intralesional triamcinolone for BXO. There is a small risk of recurrent BXO, but rates of meatal stenosis may be reduced.

Background Good postoperative recovery is increasingly recognized as an important outcome after surgery. The authors created a new Post-operative Quality Recovery Scale (PQRS) that tracks multiple domains of recovery from immediate to long-term time periods in patients of varying ages, languages, and cultures. Methods The parameters of importance to both clinicians and patients were identified. After an initial pilot study of 133 patients, the PQRS was refined. It consists of six domains (physiologic, nociceptive, emotive, activities of daily living, cognitive, and overall patient perspective). An observational study of 701 patients was performed with the refined PQRS to assess its capacity to evaluate and track recovery and to discriminate between patients. It was conducted in eight countries and in five languages, involving patients more than or equal to 6 yr undergoing elective surgery with general anesthesia. Recovery was assessed before surgery and at multiple time periods postoperatively. Recovery was defined as return to baseline values or better. Results Seven hundred one patients completed the PQRS. Mean completion time was 4.8 (SD 2.8) min. Recovery scores improved with time. Physiologic recovery was complete in 34% of subjects by 40 min. By the third postoperative day, complete recovery was obtained in 11% of cases (all domains): 48.7% nociceptive, 81.8% emotive, 68.8% activities of daily living, and only 33.5% cognitive. Overall, 95.8% of the patients reported that they were "satisfied or totally satisfied" with their anesthetic care. Conclusion The scores on the PQRS demonstrated an improvement over time, consistent with an expected recovery after surgery and anesthesia, and an ability to discriminate between individuals. Many patients had incomplete recovery by the third postoperative day.