Cardiovascular disease in Alpha 1 antitrypsin deficiency: an observational study assessing the role of neutrophil proteinase activity and the suitability of validated screening tools.

BACKGROUND: Alpha 1 Antitrypsin Deficiency (AATD) is a rare, inherited lung disease which shares features with Chronic Obstructive Pulmonary Disease (COPD) but has a greater burden of proteinase related tissue damage. These proteinases are associated with cardiovascular disease (CVD) in the general population. It is unclear whether patients with AATD have a greater risk of CVD compared to usual COPD, how best to screen for this, and whether neutrophil proteinases are implicated in AATD-associated CVD. This study had three aims. To compare CVD risk in never-augmented AATD patients to non-AATD COPD and healthy controls (HC). To assess relationships between CVD risk and lung physiology. To determine if neutrophil proteinase activity was associated with CVD risk in AATD. Cardiovascular risk was assessed by QRISK2® score and aortic stiffness measurements using carotid-femoral (aortic) pulse wave velocity (aPWV). Medical history, computed tomography scans and post-bronchodilator lung function parameters were reviewed. Systemic proteinase 3 activity was measured. Patients were followed for 4 years, to assess CVD development. RESULTS: 228 patients with AATD, 50 with non-AATD COPD and 51 healthy controls were recruited. In all COPD and HC participants, QRISK2® and aPWV gave concordant results (with both measures either high or in the normal range). This was not the case in AATD. Once aPWV was adjusted for age and smoking history, aPWV was highest and QRISK2® lowest in AATD patients compared to the COPD or HC participants. Higher aPWV was associated with impairments in lung physiology, the presence of emphysema on CT scan and proteinase 3 activity following adjustment for age, smoking status and traditional CVD risk factors (using QRISK2® scores) in AATD. There were no such relationships with QRISK2® in AATD. AATD patients with confirmed CVD at four-year follow up had a higher aPWV but not QRISK2® at baseline assessment. CONCLUSION: aPWV measured CVD risk is elevated in AATD. This risk is not captured by QRISK2®. There is a relationship between aPWV, lung disease and proteinase-3 activity. Proteinase-driven breakdown of elastin fibres in large arteries and lungs is a putative mechanism and forms a potential therapeutic target for CVD in AATD.

Onboarding of siponimod in secondary progressive multiple sclerosis patients in Australia: Novel, real-world evidence from the MSGo digital support programme.

Background: Siponimod is approved for use in people with secondary progressive multiple sclerosis (pwSPMS). An integrated digital platform, MSGo, was developed for pwSPMS and clinicians to help navigate the multiple steps of the pre-siponimod work-up. Objective: To explore real-world onboarding experiences of siponimod amongst pwSPMS in Australia. Methods: Retrospective, non-interventional, longitudinal, secondary analysis of data extracted from MSGo (20 April 2022). The primary endpoint was the average time for siponimod onboarding; secondary endpoints were adherence and sub-group analyses of variables influencing onboarding. Results: Mixed-cure modelling estimated that 58% of participants (N = 368, females 71%, median age of 59 years) registered in MSGo would ever initiate siponimod. The median time to initiation was 56 days (95% CI [47-59] days). Half of the participants cited 'waiting for vaccination' as the reason for initiation delay. Cox regression analyses found participants with a nominated care partner had faster onboarding (HR 2.1, 95% CI [1.5-3.0]) and were more likely to continue self-reporting daily siponimod dosing than were those without a care partner (HR 2.2, 95% CI [1.3-3.7]). Conclusions: Despite the limitations of self-reported data and the challenges of the COVID-19 pandemic, this study provides insights into siponimod onboarding in Australia and demonstrates the positive impact of care partner support.

In-hospital extracorporeal cardiopulmonary resuscitation for patients with an out-of-hospital cardiac arrest in a semi-rural setting: An observational study on the implementation of a helicopter emergency medical services pathway.

Aim: In this study, we aimed to investigate the efficacy of a helicopter emergency medical service (HEMS) facilitated pathway for in-hospital extracorporeal cardiopulmonary resuscitation (ECPR) for patients with an out of hospital cardiac arrest (OHCA) in a semi-rural setting. Methods: We retrospectively reviewed all patients with an OHCA attended by a UK HEMS service between 1 January 2018 and 20 September 2021, when a dedicated ECPR pathway was in effect to facilitate transport of eligible patients to the nearest ECLS centre. The primary endpoint was the number of patients meeting ECPR eligibility criteria at three pre-defined time points: at HEMS dispatch, during on-scene evaluation and upon arrival in hospital. Results: During the study period, 162 patients attended met ECPR pathway dispatch criteria. After on-scene evaluation, 74 patients (45%) had a return of spontaneously circulation before arrival of HEMS, 60 (37%) did not meet eligibility criteria regarding initial rhythm or etiology of the OHCA, and 15 (9%) had deteriorated (mainly into asystole) and were no longer suitable candidates upon arrival of HEMS. Eleven patients were eligible for ECPR and transported to hospital in arrest, and a further two patients were transported for post-ROSC ECLS. Nine patients deteriorated during transport and were no longer suitable ECPR candidates upon arrival. ECLS was successfully initiated in two patients (one intra-arrest, and one post-ROSC). Conclusion: In-hospital ECPR is of limited value for patients with refractory OHCA in a semi-rural setting, even when a dedicated pathway is in place. Potentially eligible patients often cannot be transported within an appropriate timeframe and/or deteriorate before arrival in hospital.

Microstructural characterization data of as received IG-110, 2114 and ETU-10 nuclear graphite grades and oxidation characterization data of IG-110.

This manuscript provides optical microscopy, scanning electron microscopy, and transmission electron microscopy micrographs that show the microstructure of three superfine nuclear graphite grades IG-110, 2114 and ETU-10. This collection of microstructural data showcases the microstructure of these materials and helps to differentiate the most important features or phases of these graphite grades. In particular, the microstructural data illustrate the filler and binder morphology of these grades. Moreover, samples of as-received and oxidized IG-110 were characterized via optical microscopy and x-ray computed tomography. The microstructural data of oxidized IG-110 shows the porosity generated by oxidation experiments. These micrographs and data provide a unique insight into the microstructural features and oxidation effects in nuclear graphite and can be used to perform quantitative porosity analysis. This collection of microstructural data complements the modeling and characterization described in the associated manuscript, "Using porous random fields to predict the elastic modulus of unoxidized and oxidized superfine graphite (Arregui-Mena et al., 2022)."

A type VI acromioclavicular joint injury: subcoracoid dislocation in a patient with polytrauma.

The Rockwood type VI acromioclavicular joint injury describes subcoracoid dislocation of the distal end of the clavicle. This injury pattern is exceedingly rare, with only 12 cases described in the literature. Diagnosis can be challenging; it is often the result of a high-energy mechanism and patients frequently have other severe distracting injuries. We report the case of a 23-year-old man who presented to our department after falling from a fifth-floor balcony. Alongside multiple intra-abdominal and musculoskeletal injuries, the patient sustained a type VI acromioclavicular joint dislocation. This injury was not picked up on the initial clinical assessment or described in the initial radiology report, with the diagnosis only made upon subsequent repeat review of the imaging by the admitting team. Fortunately, this delay did not increase the time to the patient receiving appropriate treatment. Despite its rarity, awareness of this injury pattern and its association with polytrauma is essential to reduce the risk of the diagnosis being overlooked in the acute setting.

Validating the portal population of the United Kingdom Multiple Sclerosis Register.

The UK Multiple Sclerosis Register (UKMSR) is a large cohort study designed to capture 'real world' information about living with multiple sclerosis (MS) in the UK from diverse sources. The primary source of data is directly from people with Multiple Sclerosis (pwMS) captured by longitudinal questionnaires via an internet portal. This population's diagnosis of MS is self-reported and therefore unverified. The second data source is clinical data which is captured from MS Specialist Treatment centres across the UK. This includes a clinically confirmed diagnosis of MS (by Macdonald criteria) for consented patients. A proportion of the internet population have also been consented at their hospital making comparisons possible. This dataset is called the 'linked dataset'. The purpose of this paper is to examine the characteristics of the three datasets: the self-reported portal data, clinical data and linked data, in order to assess the validity of the self-reported portal data. The internet (n = 11,021) and clinical (n = 3,003) populations were studied for key shared characteristics. We found them to be closely matched for mean age at diagnosis (clinical = 37.39, portal = 39.28) and gender ratio (female %, portal = 73.1, clinical = 75.2). The Two Sample Kolmogorov-Smirnov test was for the continuous variables to examine is they were drawn from the same distribution. The null hypothesis was rejected only for age at diagnosis (D = 0.078, p < 0.01). The populations therefore, were drawn from different distributions, as there are more patients with relapsing disease in the clinical cohort. In all other analyses performed, the populations were shown to be drawn from the same distribution. Our analysis has shown that the UKMSR portal population is highly analogous to the entirely clinical (validated) population. This supports the validity of the self-reported diagnosis and therefore that the portal population can be utilised as a viable and valid cohort of people with Multiple Sclerosis for study.

Are older drivers' driving patterns during an on-road driving task representative of their real-world driving patterns?

OBJECTIVE: The current study investigated whether older drivers' driving patterns during a customized on-road driving task were representative of their real-world driving patterns. METHODS: Two hundred and eight participants (male: 68.80%; mean age = 81.52 years, SD = 3.37 years, range = 76.00-96.00 years) completed a customized on-road driving task that commenced from their home and was conducted in their own vehicle. Participants' real-world driving patterns for the preceding 4-month period were also collected via an in-car recording device (ICRD) that was installed in each participant's vehicle. RESULTS: During the 4-month period prior to completing the on-road driving task, participants' median real-world driving trip distance was 2.66 km (interquartile range [IQR] = 1.14-5.79 km) and their median on-road driving task trip distance was 4.41 km (IQR = 2.83-6.35 km). Most participants' on-road driving task trip distances were classified as representative of their real-world driving trip distances (95.2%, n = 198). CONCLUSIONS: These findings suggest that most older drivers were able to devise a driving route that was representative of their real-world driving trip distance. Future research will examine whether additional aspects of the on-road driving task (e.g., average speed, proportion of trips in different speed zones) are representative of participants' real-world driving patterns.

Anatomical subgroup analysis of the MERIDIAN cohort: failed commissuration.

OBJECTIVE: To assess the contribution of fetal magnetic resonance imaging (MRI) in fetuses of the MERIDIAN cohort diagnosed with either agenesis or hypogenesis of the corpus callosum (referred to collectively as failed commissuration) on antenatal ultrasound. METHODS: This was a subgroup analysis of the MERIDIAN study of fetuses with failed commissuration (with or without ventriculomegaly) diagnosed on ultrasound in women who had MRI assessment within 2 weeks of ultrasound and for whom outcome reference data were available. The diagnostic accuracy of ultrasound and MRI was studied, as well as indicators of diagnostic confidence and effects on prognosis/clinical management. Appropriate diagnostic confidence was assessed by the score-based weighted average method, which combines diagnostic accuracy with diagnostic confidence data. RESULTS: In the MERIDIAN cohort, 79 fetuses were diagnosed with failed commissuration on ultrasound (55 with agenesis and 24 with hypogenesis of the corpus callosum). The diagnostic accuracy for detecting failed commissuration was 34.2% for ultrasound and 94.9% for MRI (difference, 60.7% (95% CI, 47.6-73.9%), P < 0.0001). The diagnostic accuracy for detecting hypogenesis of the corpus callosum as a discrete entity was 8.3% for ultrasound and 87.5% for MRI, and for detecting agenesis of the corpus callosum as a distinct entity was 40.0% for ultrasound and 92.7% for MRI. There was a statistically significant improvement in 'appropriate' diagnostic confidence when using MRI as assessed by the score-based weighted average method (P < 0.0001). Prognostic information given to the women changed in 36/79 (45.6%) cases after MRI and its overall effect on clinical management was 'significant', 'major' or 'decisive' in 35/79 cases (44.3%). CONCLUSIONS: Our data suggest that any woman whose fetus has failed commissuration as the only intracranial finding detected on ultrasound should have MRI examination for further evaluation. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Anatomical subgroup analysis of the MERIDIAN cohort: ventriculomegaly.

OBJECTIVE: To assess the contribution of fetal magnetic resonance imaging (MRI) in fetuses of the MERIDIAN cohort diagnosed with ventriculomegaly (VM) as the only abnormal intracranial finding on antenatal ultrasound. METHODS: This was a subgroup analysis of the MERIDIAN study of fetuses with only VM diagnosed on ultrasound in women who had a subsequent MRI examination within 2 weeks and for whom outcome reference data were available. The diagnostic accuracy of ultrasound and MRI was reported in relation to the severity of VM. The difference in measurements of trigone size on the two imaging methods and the clinical impact of adding MRI to the diagnostic pathway were also studied. RESULTS: In 306 fetuses with VM, ultrasound failed to detect 31 additional brain abnormalities, having an overall diagnostic accuracy of 89.9% for ultrasound, whilst MRI correctly detected 27 of the additional brain abnormalities, having a diagnostic accuracy of 98.7% (P < 0.0001). There were other brain abnormalities in 14/244 fetuses with mild VM on ultrasound (diagnostic accuracy, 94.3%) and MRI correctly diagnosed 12 of these (diagnostic accuracy, 99.2%; P = 0.0005). There was a close agreement between the size of trigones measured on ultrasound and on MRI, with categorical differences in only 16% of cases, showing that MRI did not systematically overestimate or underestimate trigone size. Complete prognostic data were available in 295/306 fetuses and the prognosis category changed after MRI in 69/295 (23.4%) cases. The overall effect of MRI on clinical management was considered to be 'significant', 'major' or 'decisive' in 76/295 (25.8%) cases. CONCLUSION: Our data suggest that a woman carrying a fetus with VM as the only intracranial finding on ultrasound should be offered an adjuvant investigation by MRI for further evaluation. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Arteriosclerosis in the ventral aorta and epicarditis in the bulbus arteriosus of Atlantic salmon (Salmo salar L).

Spontaneous mortality of seemingly healthy, farmed Atlantic salmon (Salmo salar L) is an increasing problem in Norwegian aquaculture. In this study, we present a morphological study of the previously undescribed syndrome of arteriosclerosis of the ventral aorta and epicarditis of the adjacent bulbus arteriosus found in farmed Atlantic salmon, with wild-captured fish as a control group. Both the ventral aorta and epicardium are vital for correct arterial compliance and vascular resistance in the respiratory capillaries of the gills. We discuss the possible implications of ventral aorta arteriosclerosis and epicarditis for blood vascular health and in particular for the increasing frequency of spontaneous gill bleeding in farmed salmon. As both these conditions primarily occur in farmed salmon, we suggest that they should be considered pathological.

Trials based on specific fracture configuration and surgical procedures likely to be more relevant for decision making in the management of fractures of the proximal humerus: Findings of a meta-analysis.

OBJECTIVES: The objective of this study was to perform a meta-analysis of all randomised controlled trials (RCTs) comparing surgical and non-surgical management of fractures of the proximal humerus, and to determine whether further analyses based on complexity of fracture, or the type of surgical intervention, produced disparate findings on patient outcomes. METHODS: A systematic review of the literature was performed identifying all RCTs that compared surgical and non-surgical management of fractures of the proximal humerus. Meta-analysis of clinical outcomes was performed where possible. Subgroup analysis based on the type of fracture, and a sensitivity analysis based on the type of surgical intervention, were also performed. RESULTS: Seven studies including 528 patients were included. The overall meta-analysis found that there was no difference in clinical outcomes. However, subgroup and sensitivity analyses found improved patient outcomes for more complex fractures managed surgically. Four-part fractures that underwent surgery had improved long-term health utility scores (mean difference, MD 95% CI 0.04 to 0.28; p = 0.007). They were also less likely to result in osteoarthritis, osteonecrosis and non/malunion (OR 7.38, 95% CI 1.97 to 27.60; p = 0.003). Another significant subgroup finding was that secondary surgery was more common for patients that underwent internal fixation compared with conservative management within the studies with predominantly three-part fractures (OR 0.15, 95% CI 0.04 to 0.63; p = 0.009). CONCLUSION: This meta-analysis has demonstrated that differences in the type of fracture and surgical treatment result in outcomes that are distinct from those generated from analysis of all types of fracture and surgical treatments grouped together. This has important implications for clinical decision making and should highlight the need for future trials to adopt more specific inclusion criteria.Cite this article: S. Sabharwal, N. K. Patel, D. Griffiths, T. Athanasiou, C. M. Gupte, P. Reilly. Trials based on specific fracture configuration and surgical procedures likely to be more relevant for decision making in the management of fractures of the proximal humerus: Findings of a meta-analysisBone Joint Res 2016;5:470-480. DOI: 10.1302/2046-3758.510.2000638.

Medium- and long-term results of high tibial osteotomy using Garches external fixator and gait analysis for dynamic correction in varus osteoarthritis of the knee.

In arthritis of the varus knee, a high tibial osteotomy (HTO) redistributes load from the diseased medial compartment to the unaffected lateral compartment. We report the outcome of 36 patients (33 men and three women) with 42 varus, arthritic knees who underwent HTO and dynamic correction using a Garches external fixator until they felt that normal alignment had been restored. The mean age of the patients was 54.11 years (34 to 68). Normal alignment was achieved at a mean 5.5 weeks (3 to 10) post-operatively. Radiographs, gait analysis and visual analogue scores for pain were measured pre- and post-operatively, at one year and at medium-term follow-up (mean six years; 2 to 10). Failure was defined as conversion to knee arthroplasty. Pre-operative gait analysis divided the 42 knees into two equal groups with high (17 patients) or low (19 patients) adductor moments. After correction, a statistically significant (p < 0.001, t-test,) change in adductor moment was achieved and maintained in both groups, with a rate of failure of three knees (7.1%), and 89% (95% confidence interval (CI) 84.9 to 94.7) survivorship at medium-term follow-up. At final follow-up, after a mean of 15.9 years (12 to 20), there was a survivorship of 59% (95% CI 59.6 to 68.9) irrespective of adductor moment group, with a mean time to conversion to knee arthroplasty of 9.5 years (3 to 18; 95% confidence interval ± 2.5). HTO remains a useful option in the medium-term for the treatment of medial compartment osteoarthritis of the knee but does not last in the long-term. Cite this article: Bone Joint J 2016;98-B:601-7.

A Grassroots Remote Sensing Toolkit Using Live Coding, Smartphones, Kites and Lightweight Drones.

This manuscript describes the development of an android-based smartphone application for capturing aerial photographs and spatial metadata automatically, for use in grassroots mapping applications. The aim of the project was to exploit the plethora of on-board sensors within modern smartphones (accelerometer, GPS, compass, camera) to generate ready-to-use spatial data from lightweight aerial platforms such as drones or kites. A visual coding 'scheme blocks' framework was used to build the application ('app'), so that users could customise their own data capture tools in the field. The paper reports on the coding framework, then shows the results of test flights from kites and lightweight drones and finally shows how open-source geospatial toolkits were used to generate geographical information system (GIS)-ready GeoTIFF images from the metadata stored by the app. Two Android smartphones were used in testing-a high specification OnePlus One handset and a lower cost Acer Liquid Z3 handset, to test the operational limits of the app on phones with different sensor sets. We demonstrate that best results were obtained when the phone was attached to a stable single line kite or to a gliding drone. Results show that engine or motor vibrations from powered aircraft required dampening to ensure capture of high quality images. We demonstrate how the products generated from the open-source processing workflow are easily used in GIS. The app can be downloaded freely from the Google store by searching for 'UAV toolkit' (UAV toolkit 2016), and used wherever an Android smartphone and aerial platform are available to deliver rapid spatial data (e.g. in supporting decision-making in humanitarian disaster-relief zones, in teaching or for grassroots remote sensing and democratic mapping).

Colectomy in pediatric ulcerative colitis: A single center experience of indications, outcomes, and complications.

BACKGROUND/PURPOSE: There is a paucity of data on outcomes and complications of colectomy for pediatric ulcerative colitis (UC). This study reports the experience of a regional center for 18years. METHODS: Patients were identified from a prospective database and data obtained by note review. Median height/weight-SDS were calculated preoperatively and postoperatively. Data are expressed as median values (range). RESULTS: 220 patients with UC (diagnosed <17years) were identified, and 19 (9%) had undergone colectomy. Age at diagnosis was 11.6years (1.3-16.5), and 42% of patients were male. Time from diagnosis to surgery was 2.2years (0.1-13.1). All patients had failed maximal medical therapy. Fifteen patients had urgent scheduled operation, and 4 had emergency procedures, with 2 for (11%) acute-severe colitis (1 Clostridium difficile colitis) and 2 for acute-severe colitis with toxic dilatation. All initial procedures were subtotal-colectomy with ileostomy. Nine patients (47%) had early complications (during initial admission), 7 (37%) requiring reoperation. Six (32%) had late complications, with 5 requiring laparotomy. No patients had both early and late complications. Height-SDS was -0.27 before surgery and -0.23 (maximal follow-up). Weight-SDS was 0.32 and 0.05 (maximal follow-up). CONCLUSION: Approximately 1/11 children with UC required colectomy during childhood. Half of patients had acute complications, and 1/3 of patients required another operation during their first admission. 1/3 of patients developed late complications.

Transdisciplinary care in the emergency department: A qualitative analysis.

In response to increasing demands some emergency departments have introduced transdisciplinary care coordination teams. Such teams comprise staff from multiple disciplines who are trained to perform roles outside their usual scope of practice. This study aimed to critically evaluate the patient, carer and ED staff perceptions of the transdisciplinary model of care in an emergency department in a Melbourne metropolitan hospital. The evaluation of the transdisciplinary team involved interviews with patients and carers who have received the transdisciplinary team services, and focus groups with emergency nursing and transdisciplinary team staff. Analysis of the data revealed that the transdisciplinary model provided an essential service, where staff members were capable of delivering care across all disciplines. The ability to perform comprehensive patient assessments ensured safe discharge, with follow-up services in place. The existence of this team was seen to free up time for the emergency nursing staff, enabling them to see other patients, and improving department efficiency while providing quality care and increasing staff satisfaction. This study identified several important factors which contributed to the success of the transdisciplinary team, which was well integrated into the larger emergency department team.

Emergence and spread of predominantly community-onset Clostridium difficile PCR ribotype 244 infection in Australia, 2010 to 2012.

We describe an Australia-wide Clostridium difficile outbreak in 2011 and 2012 involving the previously uncommon ribotype 244. In Western Australia, 14 of 25 cases were community-associated, 11 were detected in patients younger than 65 years, 14 presented to emergency/outpatient departments, and 14 to non-tertiary/community hospitals. Using whole genome sequencing, we confirm ribotype 244 is from the same C. difficile clade as the epidemic ribotype 027. Like ribotype 027, it produces toxins A, B, and binary toxin, however it is fluoroquinolone-susceptible and thousands of single nucleotide variants distinct from ribotype 027. Fifteen outbreak isolates from across Australia were sequenced. Despite their geographic separation, all were genetically highly related without evidence of geographic clustering, consistent with a point source, for example affecting the national food chain. Comparison with reference laboratory strains revealed the outbreak clone shared a common ancestor with isolates from the United States and United Kingdom (UK). A strain obtained in the UK was phylogenetically related to our outbreak. Follow-up of that case revealed the patient had recently returned from Australia. Our data demonstrate new C. difficile strains are an on-going threat, with potential for rapid spread. Active surveillance is needed to identify and control emerging lineages.

Renal tumours in a Tsc2(+/-) mouse model do not show feedback inhibition of Akt and are effectively prevented by rapamycin.

Tuberous sclerosis (TSC) is an inherited syndrome in which tumours in multiple organs are characterised by activation of mammalian target of rapamycin complex 1 (mTORC1). Previous work suggests that mTORC1 activation is associated with feedback inhibition of Akt, a substrate of mTORC2. This could limit TSC-associated tumour growth but lead to paradoxical promotion of tumour cell survival upon treatment with mTOR inhibitors. However, Akt/mTOR signalling has not been fully investigated in TSC-associated tumours and it has been uncertain whether mTOR inhibition can prevent TSC-associated renal tumourigenesis. In this study, we investigated Akt/mTOR signalling in renal tumours using a Tsc2(+/-) mouse model and tested whether mTOR inhibition could prevent renal tumourigenesis. We found that all renal lesions including cysts, adenomas and carcinomas exhibited activation of both Akt and mTORC1 as evidenced by increased protein expression and phosphorylation of Akt and mTOR and their downstream targets. Protein kinase Cα was also highly expressed and phosphorylated in these lesions, consistent with activation of mTORC2. Surprisingly, IRS proteins were highly expressed, in contrast to a striking decrease seen in cultured Tsc2(-/-) mouse embryonic fibroblasts, suggesting one mechanism through which loss of feedback inhibition of Akt may occur in mTORC1 hyperactivated Tsc-associated tumours. Long-term treatment with rapamycin reduced both Akt and mTORC1 activity in normal kidney tissues and blocked the development of all types of renal lesions. In conclusion, in contrast to previous studies, we found that Akt signalling is not inhibited in Tsc-associated renal lesions and that by partially inhibiting the Akt/mTOR pathway, rapamycin is highly effective in preventing Tsc-associated tumours.

Variation in reporting of cancer extent and benign histology in prostate biopsies among European pathologists.

It is not known how uropathologists currently report histopathological features of prostate biopsies such as core length, tumor extent, perineural invasion, and non-tumor-associated features such as inflammation and hyperplasia in needle biopsies. A web-based survey was distributed among 661 members of the European Network of Uropathology. Complete replies were received from 266 pathologists in 22 European countries. Total core lengths were reported by 64 %. The numbers of cores positive for cancer was given by 79 %. Linear cancer extent was reported by 81 %, most often given in millimeters for each core (53 %) followed by the estimation of percentage of cancer in each core (40 %). A gap of benign tissue between separate cancer foci in a single core would always be subtracted by 48 % and by 63 % if cancer foci were minute and widely separated. Perineural invasion was reported by 97 %. Fat invasion by tumor was interpreted as extraprostatic extension by 81 %. Chronic and active/acute inflammation was always reported by 32 and 56 % but only if pronounced by 54 and 39 %, respectively. While most (79 %) would never diagnose benign prostatic hyperplasia on needle biopsy, 21 % would attempt to make this diagnosis. Reporting practices for prostate biopsies are variable among European pathologists. The great variation in some methodologies used suggests a need for further international consensus, in order for retrospective data to be comparable between different institutions.

Surgery for children with Crohn's disease: indications, complications and outcome.

BACKGROUND: Outcome data for surgery in paediatric Crohn's disease are limited. We report 10 years' experience at a regional paediatric gastroenterology centre. METHODS: Children undergoing surgery for Crohn's disease (January 2002-December 2012) were identified from an onsite patient register. Patients were followed until transition to adult services. Data were obtained from medical records and are expressed as median (range). RESULTS: Sixty-nine children, aged 13.8 years (6.3-17.0) at diagnosis, were included. 42 were male (61%). Follow-up was 1.8 years (27 days-6 years). Surgery followed diagnosis by 9 months (0 days-7 years). 52 children (75%) received thiopurines and 5 (7%) anti-TNF (tumour necrosis factor) therapy preoperatively. 58 (84%) underwent intra-abdominal surgery (40 right hemicolectomy, 8 stoma formation, 2 subtotal colectomy, 2 small bowel resection, 6 other) and 10 (14%) underwent surgery for perianal disease. The commonest indications for intra-abdominal surgery were stricturing disease 35 (60%) and unresponsive luminal disease 13 (22%). There were 13 (22%) early, and 5 (8.6%) late, complications following intra-abdominal surgery. Nine children had disease relapse, five required further surgery. Height SD scores (SDS) did not increase between diagnosis; -0.5 (-3.4-2.1) and most recent follow up; -0.4 (-3.0-1.1). Body Mass Index (BMI) SDS increased from -1.0 (-6.3-1.5) to -0.3 (-3.3-2.0) (p<0.05). CONCLUSIONS: Surgery was associated with a 22% early complication rate and a 15% risk of relapse. 21% of patients required a second unplanned intra-abdominal procedure. Surgical intervention was associated with an increase in BMI SDS, but not in height SDS.