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Background Procalcitonin (PCT)-guided antibiotic stewardship (ABS) has been shown to reduce antibiotics (ABxs), with lower side-effects and an improvement in clinical outcomes. The aim of this experts workshop was to derive a PCT algorithm ABS for easier implementation into clinical routine across different clinical settings. Methods Clinical evidence and practical experience with PCT-guided ABS was analyzed and discussed, with a focus on optimal PCT use in the clinical context and increased adherence to PCT protocols. Using a Delphi process, the experts group reached consensus on different PCT algorithms based on clinical severity of the patient and probability of bacterial infection. Results The group agreed that there is strong evidence that PCT-guided ABS supports individual decisions on initiation and duration of ABx treatment in patients with acute respiratory infections and sepsis from any source, thereby reducing overall ABx exposure and associated side effects, and improving clinical outcomes. To simplify practical application, the expert group refined the established PCT algorithms by incorporating severity of illness and probability of bacterial infection and reducing the fixed cut-offs to only one for mild to moderate and one for severe disease (0.25 μg/L and 0.5 μg/L, respectively). Further, guidance on interpretation of PCT results to initiate, withhold or discontinue ABx treatment was included. Conclusions A combination of clinical patient assessment with PCT levels in well-defined ABS algorithms, in context with continuous education and regular feedback to all ABS stakeholders, has the potential to improve the diagnostic and therapeutic management of patients suspected of bacterial infection, thereby improving ABS effectiveness.

Robust data on the outcome of MET-aberrant NSCLC with nontargeted therapies are limited, especially in consideration of the heterogeneity of MET-amplified tumors (METamp).A total of 337 tumor specimens of patients with MET-altered Union for International Cancer Control stage IIIB/IV NSCLC were analyzed using next-generation sequencing, fluorescence in situ hybridization, and immunohistochemistry. The evaluation focused on the type of MET aberration, co-occurring mutations, programmed death-ligand 1 expression, and overall survival (OS).METamp tumors (n = 278) had a high frequency of co-occurring mutations (80% for all amplification levels), whereas 57.6% of the 59 patients with MET gene and exon 14 (METex14) tumors had no additional mutations. In the METamp tumors, with increasing gene copy number (GCN), the frequency of inactivating TP53 mutations increased (GCN4: 58.2%; GCN ≥ 10: 76.5%), whereas the frequency of KRAS mutations decreased (GCN4: 43.2%; GCN ≥ 10: 11.8%). A total of 10.1% of all the METamp tumors with a GCN ≥ 10 had a significant worse OS (4.0 mo; 95% CI: 1.9-6.0) compared with the tumors with GCN10 (12.0 mo; 95% confidence interval [CI]: 9.4-14.6). In the METamp NSCLC, OS with immune checkpoint inhibitor (ICI) therapy was significantly better compared with chemotherapy with 19.0 months (95% CI: 15.8-22.2) versus 8.0 months (95% CI: 5.8-10.2, p0.0001). No significant difference in median OS was found between ICI therapy and chemotherapy in the patients with METex14 (p = 0.147).METex14, METamp GCN ≥ 10, and METamp GCN10 represent the subgroups of MET-dysregulated NSCLC with distinct molecular and clinical features. The patients with METex14 do not seem to benefit from immunotherapy in contrast to the patients with METamp, which is of particular relevance for the prognostically poor METamp GCN ≥ 10 subgroup.

The following paper presents a new high temperature Coiled Tubing Drilling (CTD) Bottom Hole Assembly (BHA) with its technical improvements and adjustments needed, to operate beyond previous temperature limitations and in more challenging formations. It summarizes the field-test results and first achievements of the BHA in the increasing High Temperature (HT) re-entry drilling environment. The introduced HT CTD BHA incorporates a new generation of electronics and adjusted technical solution to operate in this challenging environment. The developed designs address the increased temperature impact to the downhole electronics, the various integrated sensors and mechanical components like the oil hydraulic system of the BHA. Details on these technical improvements are provided in combination with an overview on the changing CTD market segment to higher temperature application. The results and performance of the new CTD BHA within the first deployments in the Middle East are presented, and details of the associated application are provided.

In areas of the United Kingdom Continental Shelf (UKCS) operators are progressively seeking to drill increasingly complex well profiles to access un-swept reserves. Wells of such complexity require the introduction of new drilling technology to meet the challenge. In a recent UKCS operation, operator objectives for a wellbore required continuously high rates of curvature and tight dogleg severity control in a soft formation with unconfined compressive strengths (UCS) of 5 to 10 kpsi.A new, integrated high build-up rate rotary steerable system (RSS), capable of delivering up to 12°/100ft in an 8½-in. hole, was implemented as a solution to achieve and optimize the wellbore placement, thus accessing untapped reserves beneath the offshore platform. In this mature field, collision avoidance with existing wells presented an additional challenge. Focusing on a total system approach, new polycrystalline diamond compact (PDC) drill bit technology was designed to integrate with the high build-up rate (BUR) drilling system. The PDC bit includes features for a smooth torque response, enhanced rate of penetration (ROP), improved durability, and precise steering control. Proprietary software provided confidence in the planning phase that the bit responses, in combination with the deployed steering system and the overall BHA set-up, would deliver the demanding well profile.This paper presents the details of the integrated drilling technology, as well as the background of pre-drill planning and setup processes necessary for the successful application where no offset experience was available. In addition, this paper details the process management and implementation steps during the service introduction of the new drilling technology. The final performance of the integrated system that drilled the ‘corkscrew’ profile in one drilling run, providing the required well placement and hole quality will be shown. The overall new approach enables the industry to utilize previously inaccessible reserves and drive field economics further.

Sensors 13(1), 898-917 (2013). doi:10.18154/RWTH-CONV-071697, Published by MDPI, Basel

Different digital terrestrial television (DTT) systems are in use around the world today. A rapidly growing number of TV sets used for terrestrial broadcast reception is also equipped with broadband connectivity. However, the distribution of TV content relies either solely on terrestrial broadcast or on broadband delivery. Redundancy on Demand (RoD) on the other hand utilizes the broadband connectivity to enhance terrestrial broadcast reception. RoD is a fully backward compatible extension to terrestrial broadcast systems. It provides supporting data, i.e. additional redundancy, on demand to broadcast receivers via a broadband connection. Receivers even in unfavorable reception conditions are then able to successfully decode the broadcast signal. The supporting data is provided by an RoD server extending the broadcast network. An RoD DTT receiver is able to estimate the signal quality, request and receive the redundancy data if required and decode the broadcast signal with the help of the broadband data. As the second generation terrestrial Digital Video Broadcasting (DVB-T2) will be introduced in Germany starting in 2016, a DVB-T2 trial network was set up in Berlin. This network gave the opportunity to evaluate the performance of RoD with DVB-T2 in a real world environment. This paper presents results of the field trial.

More than 20 years ago, the first e-line coiled tubing drilling (CTD) systems were introduced. Since then, the technology has evolved and proven to be an efficient, economic means of enabling additional production from aging oil and gas fields. These systems are now established as a standard, viable solution for re-entry drilling in a variety of maturing fields and applications. Corresponding technologies and procedures were developed, and continuously improved. Utilizing project data from more than 20 years of operational experience, this paper describes the progression from the first e-line CTD bottom hole assembly (BHA) applications in Europe through to today's continuous operations in several areas worldwide. It presents the technology changes and procedural adjustments that were necessary to address new challenges related to extending the economic life and improving the production of mature fields by economically accessing stranded reserves, and includes: Wellbore design changes from single re-entry to multilateral wells, along with the envelope extension from pure geometric wellbore placement according to plan, to real-time reservoir navigation utilizing geo and bio-steering services.Introduction of special applications such as precise kick-off from vertical, dual casing exits and extended reach drilling (ERD) with CT technology.Progression from overbalanced drilling operations to full underbalanced (UB) applications, with nitrogen injection through the CT string and the requirement to manage production while drilling.Equipment development to enable safe pressure deployment of the drilling BHA, enabling a move from conventional tower set-ups to dedicated highly mobile coiled tubing rigs. Continual improvements of technology and steady implementation of new developments in many aspects of CTD technology were the result of innovative re-entry projects executed worldwide. To achieve the necessary efficiency and economic goals, improvements and new technology developments occurred in the downhole BHA technology, casing exit equipment, surface equipment, rig and other associated systems. Simultaneously, processes and procedures were also optimized with new ones introduced to adapt for changing environments and observed challenges. Based on worldwide CTD experience, the trend of technology developments and continuous improvement will continue. The goal is to further drive project efficiencies and economics, enabling the life of maturing fields to be extended, deferring abandonment and improving ultimate recovery.

Objectives Ceftaroline (active form of the prodrug ceftaroline fosamil) is a novel cephalosporin with activity against pathogens commonly associated with community-acquired pneumonia (CAP), including Streptococcus pneumoniae and Gram-negative pathogens. This randomized, double-blind, Phase III study evaluated the efficacy and safety of ceftaroline fosamil in treating patients with CAP. The primary objective was to determine non-inferiority [lower limit of 95% confidence interval (CI) ≥ -10%] of clinical cure rates achieved with ceftaroline fosamil compared with those achieved with ceftriaxone in the clinically evaluable (CE) and modified intent-to-treat efficacy (MITTE) populations. Methods Patients hospitalized in a non-intensive care unit setting with CAP of Pneumonia Outcomes Research Team (PORT) risk class III or IV requiring intravenous (iv) therapy were randomized (1:1) to receive 600 mg of ceftaroline fosamil iv every 12 h or 1 g of ceftriaxone iv every 24 h. Clinical cure, microbiological response, adverse events (AEs) and laboratory tests were assessed. FOCUS 2 registration number NCT00509106 (http://clinicaltrials.gov/ct2/show/NCT00509106). Results The study enrolled 627 patients, 315 of whom received ceftaroline fosamil and 307 of whom received ceftriaxone. Patients in both treatment groups had comparable baseline characteristics. Clinical cure rates were as follows: CE population, 82.1% (193/235) for ceftaroline fosamil and 77.2% (166/215) for ceftriaxone [difference (95% CI), 4.9% (-2.5, 12.5)]; and MITTE population, 81.3% (235/289) for ceftaroline fosamil and 75.5% (206/273) for ceftriaxone [difference (95% CI), 5.9% (-1.0, 12.7)]. Clinical cure rates for CAP caused by S. pneumoniae in the microbiological MITTE (mMITTE) population were 83.3% (35/42) and 70.0% (28/40) for ceftaroline fosamil and ceftriaxone, respectively. Ceftaroline fosamil and ceftriaxone were well tolerated, with similar rates of AEs, serious AEs, deaths and discontinuations due to an AE. The most common AEs for ceftaroline fosamil-treated patients were diarrhoea, headache, hypokalaemia, insomnia and phlebitis, and the most common AEs for ceftriaxone-treated patients were diarrhoea, insomnia, phlebitis and hypertension. Conclusions Ceftaroline fosamil achieved high clinical cure and microbiological response rates in patients hospitalized with CAP of PORT risk class III or IV. Ceftaroline fosamil was well tolerated, with a safety profile that is similar to that of ceftriaxone and other cephalosporins. Ceftaroline fosamil is a promising agent for the treatment of CAP.

N-Acetyltransferase (NAT) 2 is an important enzyme involved in the metabolism of different xenobiotics, including potential carcinogens. Allelic variants of the NAT2 gene are determined by a pattern of single nucleotide polymorphisms (SNPs) resulting in slow (SA), intermediate (IA) or rapid acetylator (RA) phenotypes and causing the individual differences in the NAT2 metabolic capacity. To clarify the potential modifying role of the NAT2 acetylator status in microsatellite stable (MSS) colorectal cancer (CRC), we studied 140 patients with sporadic CRC (group 1) and 69 patients with CRC who met at least one criterion of the revised Bethesda guidelines (group 2). We did not observe any significant difference in the NAT2 acetylator status frequency between patients in both groups and 100 healthy controls (P=0.486). Regardless of a younger median age of tumour onset (AO) of 41 years in group 2 patients compared to 64 years in group 1 patients, no significant difference in AO was found between RA and SA status patients in both groups. The median AO in group 1 was 65 years in patients with RA and 63 years with SA status (P=0.065). The median AO in group 2 was 40 years in patients with RA and 42 years with SA status (P=0.814). Multivariate Cox regression analysis revealed that neither the NAT2 acetylator status (P=0.064 and 0.810, respectively) nor the gender (P=0.165 and 0.918, respectively) was a risk factor for the AO in both groups. These data do not support the hypothesis that the NAT2 acetylatorship acts as a modifying factor on the AO in sporadic and familial, microsatellite stable CRC.

During the last 15 years, coiled tubing drilling (CTD) projects in the Middle East (ME) have proven an efficient and economic means of increasing and sustaining production for the oil and gas industry. CTD was implemented in 1998 and since then established as a standard, viable solution for the existing re-entry challenges in various maturing fields and applications. During this time frame corresponding technologies and procedures have been developed and continuously improved to address existing and new challenges in this growing market segment. This paper describes the use of CTD from the first activity in Oman through operations in the Kingdom of Saudi Arabia, utilizing project data collected during 15 years of operational experience. The paper includes the technology and procedural changes that addressed new and special challenges observed within the aforementioned projects and drove production from these maturing fields such as: The coverage of low- and high-pressure reservoirs in various fields with high temperature and high H2S challenges.The movement from single re-entry wells to multilateral wellbore designs, alongside the envelope extension from pure directional wellbore placement according to plan, to real-time reservoir navigation by geo- and bio-steering processes.The introduction of special applications such as ERD and precise kick off from vertical wells with coiled tubing (CT) technology.The extension of drilling operations from overbalanced to fully underbalanced (UB) operation, with maximum N2 injection through the CT string and the requirement to deal with production while drilling.Development of other equipment to enable the pressure deployment of the BHA, allowing a move away from conventional tower set-ups to a dedicated highly mobile coil tubing rig. The projects resulted in constant technology improvement and implementation of new developments in all aspects of CTD technology. To achieve the necessary efficiency and economic goals for the re-entry projects, new technology must include downhole bottom hole assembly (BHA) technology, casing exit equipment, surface equipment of the overall rig and other associated equipment such as the underbalanced drilling (UBD) package. Similar to the utilized technology, the corresponding procedures were also optimized and new ones introduced to adapt to changing environments and challenges. Based on the previous and current achievements of CTD in the Middle East, this trend of adjusted developments and continuous improvements will continue to further drive project efficiencies and economics.

Background: Epidermal cyst of the breast is a rare benign intramammary lesion; however, a common finding in other parts of the body and most often located in the scalp, back, and neck. Only a few cases of epidermal cysts of the breast have been reported in literature. Case report: The patient presented with a small movable left breast lump. Mammography and ultrasonography did not show features of a benign lesion. Ultrasound-guided core biopsy was undertaken. Histology showed an epidermal cyst. The patient returned with an inflammation at the puncture site and a small abscess seen on ultrasound. The abscess was removed surgically. Conclusion: Mammographic and sonographic features of an epidermal cyst may mimick a malignant lesion. Biopsy can result in complications, such as inflammation. In addition, an association between epidermal cyst and squamous carcinoma has been reported. Therefore, it is recommended that these lesions are resected.

We characterized genome alterations in 1255 clinically annotated lung tumors of all histological subgroups to identify genetically defined and clinically relevant subtypes. More than 55% of all cases had at least one oncogenic genome alteration potentially amenable to specific therapeutic intervention, including several personalized treatment approaches that are already in clinical evaluation. Marked differences in the pattern of genomic alterations existed between and within histological subtypes, thus challenging the original histomorphological diagnosis. Immunohistochemical studies confirmed many of these reassigned subtypes. The reassignment eliminated almost all cases of large cell carcinomas, some of which had therapeutically relevant alterations. Prospective testing of our genomics-based diagnostic algorithm in 5145 lung cancer patients enabled a genome-based diagnosis in 3863 (75%) patients, confirmed the feasibility of rational reassignments of large cell lung cancer, and led to improvement in overall survival in patients with EGFR-mutant or ALK-rearranged cancers. Thus, our findings provide support for broad implementation of genome-based diagnosis of lung cancer.

Biomedical engineering online 12, 7 (2013). doi:10.1186/1475-925X-12-7, Published by BioMed Central, London

For wing design purposes the value of maximum lift angle is an important quantity. At the high Reynolds Numbers in naval architecture flows the onset and development of turbulent separation is the deciding value for the maximum lift angle. For the calculation of separated turbulent flows usually fully viscous flow solvers, like e.g. Reynolds averaged Navier Stokes (RANS) Solvers, are used. Instead of this kind of solvers, which are expensive by means of computational time, also interacting boundary layer (IBL) methods can be used. Due to the viscous-inviscid coupling, these methods are able to compute flows with limited separation up to the maximum lift angle and represent a cheap and robust alternative to higher value viscous solvers. In this paper a turbulent boundary layer method solving the integral momentum equation together with the integral energy equation of the boundary layer in an inverse formulation is described. The method is combined with an existing inviscid flow solver for 2D wing section flows and a laminar boundary layer method code including transition forecast.Copyright © 2012 by ASME

Heterotaxy syndrome is a rare clinical entity in adults, characterized by situs ambiguus, congenital heart defects, and splenic malformations. We report the case of an adult with heterotaxy syndrome (including situs ambiguus, bilateral superior vena cava, hypoplastic right-sided spleen and portosystemic shunts) presenting with dyspnea due to severe pulmonary hypertension. Vasodilatory therapy was initiated, leading to marked reduction of clinical symptoms. This case exhibits 2 particular and partially novel features: primary diagnosis of heterotaxy syndrome may be delayed until adulthood, and heterotaxy syndrome may be associated with pulmonary hypertension, possibly on the basis of longstanding portosystemic shunts.

The effects of missense changes and small in-frame deletions and insertions on protein function are not easy to predict, and the identification of such variants in individuals at risk of a genetic disease can complicate genetic counselling. One option is to perform functional tests to assess whether the variants affect protein function. We have used this strategy to characterize variants identified in the TSC1 and TSC2 genes in individuals with, or suspected of having, Tuberous Sclerosis Complex (TSC). Here we present an overview of our functional studies on 45 TSC1 and 107 TSC2 variants. Using a standardized protocol we classified 16 TSC1 variants and 70 TSC2 variants as pathogenic. In addition we identified eight putative splice site mutations (five TSC1 and three TSC2). The remaining 24 TSC1 and 34 TSC2 variants were classified as probably neutral. Hum Mutat 32: 424-435, 2011. (C) 2011 Wiley-Liss, Inc.

Basal cell carcinoma (BCC), the most common cutaneous malignant tumor, may display neuroendocrine differentiation in very rare instances. We here describe a case of a BCC with neuroendocrine differentiation that arose in a scar resulting from a trauma 75 years earlier. Neuroendocrine differentiation was proven by immunohistochemistry and electron microscopy. The simultaneous occurrence of BCC development in a scar and neuroendocrine differentiation is quite rare.

As a noninvasive method, exhaled breath condensate (EBC) has gained importance to improve monitoring of lung diseases and to detect biomarkers. The aim of the study was to investigate, whether erythropoietin (EPO) is detectable in EBC. EBC was collected from 22 consecutive patients as well as from healthy individuals. Using a multiplex fluorescent bead immunoassay, we detected EPO in EBC, as well as tumour necrosis factor-α(TNF-α) in 13 out of 22 patients simultaneously (EPO 0.21±0.03 in U/mL and TNF-α34.6±4.2 in pg/mL, mean±SEM). No significant differences for EPO levels or correlation between EPO and TNF-αwere found but TNF-αwas significantly higher in patients with chronic obstructive pulmonary disease (COPD) than in non-COPD (obstructive sleep apnoea, OSA, and lung healthy patients). This is the first report of detection of EPO in EBC. Due to the small study size more data is needed to clarify the role of EPO in EBC.

Primary synovial chondromatosis (PSC) is a rare, usually monoarticular disorder of synovial joints. PSC is characterised by the formation of osteocartilaginous nodules in the synovial connective tissue. We report the case of a 32-year-old male with PSC of the left hip. At clinical examination abduction of the left hip was limited and rotation was painful. Ultrasound examination of the hip revealed joint effusion and multiple hyperechogenic foci due to distal acoustic shadowing. Plain radiographs showed a slight soft tissue swelling around the femoral neck and multiple round or ovoid calcifications of a uniform size. MRI revealed a large joint effusion with multiple small filling defects. Open total synovectomy was performed after dislocation of the femoral head. The diagnosis of PSC was confirmed by histological examination of the excised material. The majority of cells failed to exhibit any staining for cerb B-2 and ki-67. None of the sections showed more than 5% labelling for DNA-fragmentation proven by terminal deoxytransferase-mediated dUTD nick-end labeling (TUNEL), and all were completely non-reactive for p53 as well. In conclusion, immunohistochemical analysis suggests that in this case PSC originated from metaplasia and not from a proliferative process. After two years, the patient was free of symptoms and radiological control did not show evidence of recurrence or femoral head necrosis. Physical findings, diagnosis, histological features and management of PSC are discussed.