SP mountain data analysis

An analysis of synthetic aperture radar data of SP Mountain was undertaken to demonstrate the use of digital image processing techniques to aid in geologic interpretation of SAR data. These data were collected with the ERIM X- and L-band airborne SAR using like- and cross-polarizations. The resulting signal films were used to produce computer compatible tapes, from which four-channel imagery was generated. Slant range-to-ground range and range-azimuth-scale corrections were made in order to facilitate image registration; intensity corrections were also made. Manual interpretation of the imagery showed that L-band represented the geology of the area better than X-band. Several differences between the various images were also noted. Further digital analysis of the corrected data was done for enhancement purposes. This analysis included application of an MSS differencing routine and development of a routine for removal of relief displacement. It was found that accurate registration of the SAR channels is critical to the effectiveness of the differencing routine. Use of the relief displacement algorithm on the SP Mountain data demonstrated the feasibility of the technique

The Differences in Antibiotic Decision-making Between Acute Surgical and Acute Medical Teams: An Ethnographic Study of Culture and Team Dynamics

Background Cultural and social determinants influence antibiotic decision-making in hospitals. We investigated and compared cultural determinants of antibiotic decision-making in acute medical and surgical specialties. Methods An ethnographic observational study of antibiotic decision-making in acute medical and surgical teams at a London teaching hospital was conducted (August 2015–May 2017). Data collection included 500 hours of direct observations, and face-to-face interviews with 23 key informants. A grounded theory approach, aided by Nvivo 11 software, analyzed the emerging themes. An iterative and recursive process of analysis ensured saturation of the themes. The multiple modes of enquiry enabled cross-validation and triangulation of the findings. Results In medicine, accepted norms of the decision-making process are characterized as collectivist (input from pharmacists, infectious disease, and medical microbiology teams), rationalized, and policy-informed, with emphasis on de-escalation of therapy. The gaps in antibiotic decision-making in acute medicine occur chiefly in the transition between the emergency department and inpatient teams, where ownership of the antibiotic prescription is lost. In surgery, team priorities are split between 3 settings: operating room, outpatient clinic, and ward. Senior surgeons are often absent from the ward, leaving junior staff to make complex medical decisions. This results in defensive antibiotic decision-making, leading to prolonged and inappropriate antibiotic use. Conclusions In medicine, the legacy of infection diagnosis made in the emergency department determines antibiotic decision-making. In surgery, antibiotic decision-making is perceived as a nonsurgical intervention that can be delegated to junior staff or other specialties. Different, bespoke approaches to optimize antibiotic prescribing are therefore needed to address these specific challenges

TGFβ1 single-nucleotide polymorphism C-509T alters mucosal cell function in pediatric eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is a chronic Th2 antigen-driven disorder associated with tissue remodeling. Inflammation and remodeling lead to esophageal rigidity, strictures, and dysphagia. TGFβ1 drives esophageal remodeling including epithelial barrier dysfunction and subepithelial fibrosis. A functional SNP in the TGFβ1 gene that increases its transcription (C-509T) is associated with elevated numbers of esophageal TGFβ1-expressing cells. We utilized esophageal biopsies and fibroblasts from TT-genotype EoE children to understand if TGFβ1 influenced fibroblast and epithelial cell function in vivo. Genotype TT EoE esophageal fibroblasts had higher baseline TGFβ1, collagen1α1, periostin, and MMP2 (p < 0.05) gene expression and distinct contractile properties compared with CC genotype (n = 6 subjects per genotype). In vitro TGFβ1 exposure caused greater induction of target gene expression in genotype CC fibroblasts (p < 0.05). Esophageal biopsies from TT-genotype subjects had significantly less epithelial membrane-bound E-cadherin (p < 0.01) and wider cluster distribution at nanometer resolution. TGFβ1 treatment of stratified primary human esophageal epithelial cells and spheroids disrupted transepithelial resistance (p < 0.001) and E-cadherin localization (p < 0.0001). A TGFβ1-receptor-I inhibitor improved TGFβ1-mediated E-cadherin mislocalization. These data suggest that EoE severity can depend on genotypic differences that increase in vivo exposure to TGFβ1. TGFβ1 inhibition may be a useful therapy in subsets of EoE patients

Closed-loop control of continuous piperacillin delivery: an in silico study

Background and objective: Sub-therapeutic dosing of piperacillin-tazobactam in critically-ill patients is associated with poor clinical outcomes and may promote the emergence of drug-resistant infections. In this paper, an in silico investigation of whether closed-loop control can improve pharmacokinetic-pharmacodynamic (PK-PD) target attainment is described. Method: An in silico platform was developed using PK data from 20 critically-ill patients receiving piperacillin-tazobactam where serum and tissue interstitial fluid (ISF) PK were defined. Intra-day variability on renal clearance, ISF sensor error, and infusion constraints were taken into account. Proportional-integral-derivative (PID) control was selected for drug delivery modulation. Dose adjustment was made based on ISF sensor data with a 30-minute sampling period, targeting a serum piperacillin concentration between 32-64 mg/L. A single tuning parameter set was employed across the virtual population. The PID controller was compared to standard therapy, including bolus and continuous infusion of piperacillin-tazobactam. Results: Despite significant inter-subject and simulated intra-day PK variability and sensor error, PID demonstrated a significant improvement in target attainment compared to traditional bolus and continuous infusion approaches. Conclusion: A PID controller driven by ISF drug concentration measurements has the potential to precisely deliver piperacillin-tazobactam in critically-ill patients undergoing treatment for sepsis

Machine learning and synthetic outcome estimation for individualised antimicrobial cessation

The decision on when it is appropriate to stop antimicrobial treatment in an individual patient is complex and under-researched. Ceasing too early can drive treatment failure, while excessive treatment risks adverse events. Under- and over-treatment can promote the development of antimicrobial resistance (AMR). We extracted routinely collected electronic health record data from the MIMIC-IV database for 18,988 patients (22,845 unique stays) who received intravenous antibiotic treatment during an intensive care unit (ICU) admission. A model was developed that utilises a recurrent neural network autoencoder and a synthetic control-based approach to estimate patients’ ICU length of stay (LOS) and mortality outcomes for any given day, under the alternative scenarios of if they were to stop vs. continue antibiotic treatment. Control days where our model should reproduce labels demonstrated minimal difference for both stopping and continuing scenarios indicating estimations are reliable (LOS results of 0.24 and 0.42 days mean delta, 1.93 and 3.76 root mean squared error, respectively). Meanwhile, impact days where we assess the potential effect of the unobserved scenario showed that stopping antibiotic therapy earlier had a statistically significant shorter LOS (mean reduction 2.71 days, p-value <0.01). No impact on mortality was observed. In summary, we have developed a model to reliably estimate patient outcomes under the contrasting scenarios of stopping or continuing antibiotic treatment. Retrospective results are in line with previous clinical studies that demonstrate shorter antibiotic treatment durations are often non-inferior. With additional development into a clinical decision support system, this could be used to support individualised antimicrobial cessation decision-making, reduce the excessive use of antibiotics, and address the problem of AMR

Rapid diagnostic test value and implementation in antimicrobial stewardship across low-to-middle and high-income countries: a mixed-methods review

Despite technological advancements in infectious disease rapid diagnostic tests (RDTs) and use to direct therapy at the per-patient level, RDT utilisation in antimicrobial stewardship programmes (ASPs) is variable across low-to-middle income and high-income countries. Key insights from a panel of seven infectious disease experts from Colombia, Japan, Nigeria, Thailand, the UK, and the USA, combined with evidence from a literature review, were used to assess the value of RDTs in ASPs. From this, a value framework is proposed which aims to define the benefits of RDT use in ASPs, separate from per-patient benefits. Expert insights highlight that, to realise the value of RDTs within ASPs, effective implementation is key; actionable advice for choosing an RDT is proposed. Experts advocate the inclusion of RDTs in the World Health Organization Model List of essential in vitro diagnostics and in iterative development of national action plans

Using a SMALP platform to determine a sub-nm single particle cryo-EM membrane protein structure

The field of membrane protein structural biology has been revolutionized over the last few years with a number of high profile structures being solved using cryo-EM including Piezo, Ryanodine receptor, TRPV1 and the Glutamate receptor. Further developments in the EM field hold the promise of even greater progress in terms of greater resolution, which for membrane proteins is still typically within the 4-7 angstrom range. One advantage of a cryo-EM approach is the ability to study membrane proteins in more "native" like environments for example proteoliposomes, amphipols and nanodiscs. Recently, styrene maleic acid co-polymers (SMA) have been used to extract membrane proteins surrounded by native lipids (SMALPs) maintaining a more natural environment. We report here the structure of the Escherichia coli multidrug efflux transporter AcrB in a SMALP scaffold to sub-nm resolution, with the resulting map being consistent with high resolution crystal structures and other EM derived maps. However, both the C-terminal helix (TM12) and TM7 are poorly defined in the map. These helices are at the exterior of the helical bundle and form the greater interaction with the native lipids and SMA polymer and may represent a more dynamic region of the protein. This work shows the promise of using an SMA approach for single particle cryo-EM studies to provide sub-nm structures.Peer reviewe

Exploring the pharmacokinetics of phenoxymethylpenicillin (Penicillin-V) in adults: a healthy volunteer study

This healthy volunteer study aimed to explore Phenoxymethylpenicillin (Penicillin-V) pharmacokinetics (PK) to support the planning of large, dosing studies in adults. Volunteers were dosed with penicillin-V at steady state. Total and unbound penicillin-V serum concentration was determined and a base population PK model were fitted to the data

Metabolic Basis of Creatine in Health and Disease: A Bioinformatics-Assisted Review

Creatine (Cr) is a ubiquitous molecule that is synthesized mainly in the liver, kidneys, and pancreas. Most of the Cr pool is found in tissues with high-energy demands. Cr enters target cells through a specific symporter called Na+/Cl--dependent Cr transporter (CRT). Once within cells, creatine kinase (CK) catalyzes the reversible transphosphorylation reaction between [Mg2+:ATP4-]2- and Cr to produce phosphocreatine (PCr) and [Mg2+:ADP3-]-. We aimed to perform a comprehensive and bioinformatics-assisted review of the most recent research findings regarding Cr metabolism. Specifically, several public databases, repositories, and bioinformatics tools were utilized for this endeavor. Topics of biological complexity ranging from structural biology to cellular dynamics were addressed herein. In this sense, we sought to address certain pre-specified questions including: (i) What happens when creatine is transported into cells? (ii) How is the CK/PCr system involved in cellular bioenergetics? (iii) How is the CK/PCr system compartmentalized throughout the cell? (iv) What is the role of creatine amongst different tissues? and (v) What is the basis of creatine transport? Under the cellular allostasis paradigm, the CK/PCr system is physiologically essential for life (cell survival, growth, proliferation, differentiation, and migration/motility) by providing an evolutionary advantage for rapid, local, and temporal support of energy- and mechanical-dependent processes. Thus, we suggest the CK/PCr system acts as a dynamic biosensor based on chemo-mechanical energy transduction, which might explain why dysregulation in Cr metabolism contributes to a wide range of diseases besides the mitigating effect that Cr supplementation may have in some of these disease states