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Protein misfolding and aggregation are cardinal features of neurodegenerative disease (NDD) and they contribute to pathophysiology by both loss-of-function (LOF) and gain-of-function (GOF) mechanisms. This is well exemplified by TDP-43 which aggregates and mislocalizes in several NDDs. The depletion of nuclear TDP-43 leads to reduction in its normal function in RNA metabolism and the cytoplasmic accumulation of TDP-43 leads to aberrant protein homeostasis. A modifier screen found that loss of rad23 suppressed TDP-43 pathology in invertebrate and tissue culture models. Here we show in the TAR4 mouse model of TDP-43 pathology that genetic or antisense oligonucleotide (ASO)-mediated reduction of rad23a confers benefits on survival and behavior, histological hallmarks of disease and reduction of mislocalized and aggregated TDP-43. This results in improved function of the ubiquitin-proteasome system (UPS) and correction of transcriptomic alterations evoked by pathologic TDP-43. RAD23A-dependent remodeling of the insoluble proteome appears to be a key event driving pathology in this model. As TDP-43 pathology is prevalent in both familial and sporadic NDD, targeting RAD23A may have therapeutic potential.

Introducción: existe preocupación mundial sobre la necesidad de mejorar el desempeño en los procedimientos endoscópicos, y una situación similar de inquietud surge en Latinoamérica. Un estudio de calidad comprende una endoscopia bien indicada, diagnóstico y terapia adecuados, con menores riesgos. El consenso PEnQuIN, realizado por expertos de Norteamérica y Europa, estableció indicadores de calidad estándar endoscópica pediátrica en tres momentos: preprocedimiento, intraprocedimiento y posprocedimiento. El objetivo es elaborar un consenso de expertos sobre los indicadores de calidad de endoscopia digestiva pediátrica en Latinoamérica. Metodología: considerando la evidencia científica disponible, unos enunciados se definieron y sometieron a consenso con el método Delphi en tiempo real. Se finalizaron rondas hasta lograr un acuerdo del 80% de los integrantes y más de 0,8 en alfa de Cronbach. Los 24 gastroenterólogos pediatras se eligieron utilizando el cuestionario modificado similar al usado en las cortes de California. Resultados: de 44 enunciados iniciales, se alcanzó un consenso en 36, los cuales se establecieron como indicadores de calidad en endoscopia digestiva pediátrica. Un acuerdo unánime se logró en ocho indicadores. El alfa de Cronbach alcanzado en este cuestionario Delphi fue de 0,85. Se clasificaron en 13 indicaciones preprocedimiento, 20 indicaciones intraprocedimiento y 3 indicaciones posprocedimiento. Conclusiones: los indicadores de calidad redactados como Consenso Delphi pueden ser utilizados en cualquier unidad de endoscopia pediátrica, son de fácil aplicación y adecuados a las definiciones de calidad en salud y de endoscopia. Estos indicadores pueden medirse y, al emplearlos, se minimizan las diferencias de recursos humanos y materiales de los países.

Abstract Two major mature oilfields with multiple rigs (> 150) delivering hundreds of thousands of drilled metres annually, suffered from severe induced losses during their ongoing development and also redevelopment phases. These events of course significantly impacted the overall drilling performance, leading to substantial production issues and poor economics. Although the fundamental underlying nature of the losses varied; proven success in both cases was to significantly reduce the mud weight. Additionally, in both cases, the key to achieving this needed to be a solution using low-cost, minimal rig modification approaches while at the same time retaining the well productivity at equivalent levels. The applied solutions Team both identified and screened a number of approaches for achieving an effective MW reduction, and this process resulted in the proposal for the use of Hollow Glass Spheres (HGS) as the preferred methodology. A thorough study of the available literature and previous industry experience had demonstrated that HGS potentially met all of the requirements. In order to confirm the compatibility of the HGS, a series of laboratory tests were planned and performed; followed by a set of structured field trials, confirming the suitability of this technology. These results were then collated into a Basis of Design (BoD) for a drilling fluid system utilising HGS for drilling through target zones with abnormally low pore pressures, capturing lessons learned from all stages of their application. This paper will describe the details of the screening for the available solutions; as well as performing the feasibility study through laboratory tests and field trials. It will report on the phased approach taken for piloting the technology, describing the challenges and risks that were assessed, faced, and mitigated during both the testing and trialling stages. A review of the post-deployment lessons learned, techniques used, and approaches corrected during subsequent trial period(s) will be presented. A summary of the economic assumptions made, and their evolution will be covered; and then discussed with regards to technology upscaling and the further proposed developments and enhancements. The results of the HGS technical solution have greatly exceeded the original expectations and continuous improvement of the technology indicates much more to come. Discussions of the possible modifications and improvement to the HGS fluid system are ongoing and involve formulation, HGS type, logistics, strategy of HGS mud utilisation … etc. The use of HGS on these two oilfields has been novel and has resulted in a generally greater interest and appetite within the industry for this area of application.

Abstract Karim and Haradh reservoirs within the Karim Small Fields (KSF) cluster in the South of the Sultanate of Oman are characterized by low to medium permeability and significant heterogeneity and contain medium to heavy crude oil. Reservoir depths are in the range of 1500 to 2000 m and productive areas are relatively small (around 2 km2 per field). Over the past 10 years, fields development did not result in sustained oil production despite the close well spacing. Geological and reservoir studies indicated that this is mainly due to the heterogeneity, lack of reservoir continuity and presence of significant wellbore damage in most wells. Accordingly, the KSF operator initiated an appraisal campaign focusing on hydraulic fracturing to stimulate the producing wells and improve the extension of their drainage areas. This campaign resulted in significant improvement in well productivity and the analysis of results indicates good potential for improving the ultimate oil recovery from these reservoirs. Although the results from hydraulic fracturing campaign are encouraging, they also indicate that appropriate selection of well candidates, key parameters in the fracturing procedure, effects of well completion and impact of well age are very important for successful oil gain. As a result, a comprehensive procedure for selecting and ranking candidate wells for hydraulic fracturing in Karim and Haradh formations has been developed. The procedure includes assessing the impacts of key properties such as fracture height, depth of oil-water contact, thickness of oil column, and distance to faults. In addition, the lessons learned from the previous appraisal campaign will contribute to achieving optimum fracture geometry in future campaigns. The candidate selection workflow involves understanding the geology, geomechanics, and petrophysics of the wells in which a fracturing operation was performed previously in different formations in KSF. More than 20 existing wells were screened through the candidate selection process using a clear workflow to incorporate all the relevant aspects of the selection criteria. The outcome of the candidate selection phase led to selection of the best wells for fracturing operations in the Karim and Haradh formations. The improvements on the fracturing design have been followed to obtain the optimum fracturing design for the selected wells.

RNA interference (RNAi) offers a promising therapeutic approach for dominant genetic disorders that involve gain-of-function mechanisms. One candidate disease for RNAi therapy application is myotonic dystrophy type 1 (DM1), which results from toxicity of a mutant mRNA. DM1 is caused by expansion of a CTG repeat in the 3' UTR of the DMPK gene. The expression of DMPK mRNA containing an expanded CUG repeat (CUG(exp)) leads to defects in RNA biogenesis and turnover. We designed miRNA-based RNAi hairpins to target the CUG(exp) mRNA in the human α-skeletal muscle actin long-repeat (HSA(LR)) mouse model of DM1. RNAi expression cassettes were delivered to HSA(LR) mice using recombinant adeno-associated viral (rAAV) vectors injected intravenously as a route to systemic gene therapy. Vector delivery significantly reduced disease pathology in muscles of the HSA(LR) mice, including a reduction in the CUG(exp) mRNA, a reduction in myotonic discharges, a shift toward adult pre-mRNA splicing patterns, reduced myofiber hypertrophy and a decrease in myonuclear foci containing the CUG(exp) mRNA. Significant reversal of hallmarks of DM1 in the rAAV RNAi-treated HSA(LR) mice indicate that defects characteristic of DM1 can be mitigated with a systemic RNAi approach targeting the nuclei of terminally differentiated myofibers. Efficient rAAV-mediated delivery of RNAi has the potential to provide a long-term therapy for DM1 and other dominant muscular dystrophies.

Abstract Good perforating practices are equally important for water injectors as for producers to achieve effective and efficient reservoir pressure support, which, in turn, results in better field productivity. An aspect of good perforating practice is to achieve clean perforations so that the injection skin is minimized. Dirty perforations, whether due to perforation debris or crushed zones around the perforation tunnel can affect a well's injectivity. This problem is further compounded when well injection starts as particles in injection water quickly accumulate at the perforations, causing rapid injectivity drop. Therefore, clean perforations are important to deliver good well injectivity. This is a case study of a wellbore implosion technique on perforations of injector wells in a field in Oman. Compared to perforating in a high-pressure reservoir, achieving clean perforations in a low-pressure reservoir is more difficult as perforating has less potential to breakdown the crushed zone and to purge the crushed material together with the debris from the perforation tunnels. This problem may be overcome by the wellbore implosion technique, using a dynamic underbalance system. Various perforating systems were tried for injector wells in this field. Reactive liner shaped charge, propellant system, and post-perforating dynamic underbalance techniques were used in the same well. A dynamic underbalance gun that creates wellbore implosion was designed, and recorded pressure gauge data were matched to the simulated data. Reservoir properties of each well from the logs and from the well injectivities after applying the above-mentioned perforating systems were compared. As the principle in this case study is perforation cleanup, it is also relevant to producers. It is also relevant to other wells whether on land or offshore, both producers and injectors of any pressure regime that could be suffering from poor cleanup of perforations.

Real-time Ultrasound (US) image fusion with a pre-acquired second imaging dataset - Computed Tomography (CT), Magnetic Resonance Imaging (MRI) and/or CT/PET - has become widely used in recent years for both diagnosis and image-guided interventional procedures. Liver and kidneys are the main focused anatomical districts, related to abdominal application. There are still nowadays some drawbacks, regarding the adoption of the fusion imaging technique in everyday practice especially regarding its ease of use and the time needed in order to obtain a precise real-time fusion between US and the second imaging modality. The present work is a preliminary study on the feasibility and practical use of an Automatic registration algorithm for CT-US real-time fusion imaging. Data obtained by tests performed on a Doppler phantom, for the assessment of the precision of the registration procedure and in-vivo Automatic registration tests, are presented.

To determine the targeting error of a novel stereotactic prostate biopsy system that integrates preinterventional MRI with peri-interventional ultrasonography (US) for perineal navigated prostate biopsies. We performed stereotactic biopsies on five prostate phantoms (one CIRS 053-MM and four CIRS 066). Phantom 053-MM incorporates three MRI- and transrectal ultrasonography (TRUS)-visible lesions, while lesions within phantom 066 are only detectable on MRI. In both phantoms, the 0.5 cc volume lesions are placed randomly. The phantoms were examined by 3T-MRI preinterventionally. Then three stereotactic biopsies from one lesion in phantom 053-MM and from all US-invisible lesions in the 066 phantoms were taken under live-fusion imaging guidance. During intervention, a mix of blue ink and gadobutrol was injected into each biopsy channel. Afterward, another 3T-MRI was obtained. These MRI images were then fused again with the intraoperative TRUS data. Thus, the targeting error (TE) between the planned and performed biopsy cores could be measured. In addition, the procedural targeting error (PTE) between the virtually planned biopsy trajectory and the manually registered three-dimensional needle position of every single biopsy core taken was calculated. The overall TE of the 39 biopsy cores taken was 0.83 mm (standard deviation [SD]: 0.48 mm) with the highest TE in the sagittal plane (1.09 ± 0.54 mm), followed by the coronal (0.72 ± 0.43 mm) and axial (0.69 ± 0.34 mm) planes. The procedural TE, which is provided intraoperatively, was 0.26 mm on average (SD: 0.46 mm). Comparing PTE and TE, there was no statistically significant difference (P=0.39). The TE of stereotactic biopsies using our novel perineal prostate biopsy system is below 1 mm and can be estimated in vivo by the automatically calculated procedural TE. Thus, stereotactic prostate biopsies guided by the combination of MRI and US allow effective and precise examination of MRI lesions.