Population Pharmacokinetic Modeling and Probability of Pharmacodynamic Target Attainment for Ceftazidime-Avibactam in Pediatric Patients Aged 3 Months and Older.

Increasing prevalence of infections caused by antimicrobial-resistant gram-negative bacteria represents a global health crisis, and while several novel therapies that target various aspects of antimicrobial resistance have been introduced in recent years, few are currently approved for children. Ceftazidime-avibactam is a novel ß-lactam ß-lactamase inhibitor combination approved for adults and children 3 months and older with complicated intra-abdominal infection, and complicated urinary tract infection or hospital-acquired ventilator-associated pneumonia (adults only in the United States) caused by susceptible gram-negative bacteria. Extensive population pharmacokinetic (PK) data sets for ceftazidime and avibactam obtained during the adult clinical development program were used to iteratively select, modify, and validate the approved adult dosage regimen (2,000-500 mg by 2-hour intravenous (IV) infusion every 8 hours (q8h), with adjustments for renal function). Following the completion of one phase I (NCT01893346) and two phase II ceftazidime-avibactam studies (NCT02475733 and NCT02497781) in children, adult PK data sets were updated with pediatric PK data. This paper describes the development of updated combined adult and pediatric population PK models and their application in characterizing the population PK of ceftazidime and avibactam in children, and in dose selection for further pediatric evaluation. The updated models supported the approval of ceftazidime-avibactam pediatric dosage regimens (all by 2-hour IV infusion) of 50-12.5 mg/kg (maximum 2,000-500 mg) q8h for those ≥6 months to 18 years old, and 40-10 mg/kg q8h for those ≥3 to 6 months old with creatinine clearance > 50 mL/min/1.73 m2 .

A report on the impact of rapid prenatal exome sequencing on the clinical management of 52 ongoing pregnancies: a retrospective review.

OBJECTIVE: Studies have shown that prenatal exome sequencing (PES) improves diagnostic yield in cases of fetal structural malformation. We have retrospectively analysed PES cases from two of the largest fetal medicine centres in the UK to determine the impact of results on management of a pregnancy. DESIGN: A retrospective review of clinical case notes. SETTING: Two tertiary fetal medicine centres. POPULATION: Pregnancies with fetal structural abnormalities referred to clinical genetics via a multidisciplinary team. METHODS: We retrospectively reviewed the notes of all patients who had undergone PES. DNA samples were obtained via chorionic villus sampling or amniocentesis. Variants were filtered using patient-specific panels and interpreted using American College of Medical Genetics guidelines. RESULTS: A molecular diagnosis was made in 42% (18/43) ongoing pregnancies; of this group, there was a significant management implication in 44% (8/18). A positive result contributed to the decision to terminate a pregnancy in 16% (7/43) of cases. A negative result had a significant impact on management in two cases by affirming the decision to continue pregnancy. CONCLUSIONS: We demonstrate that the results of PES can inform pregnancy management. Challenges include variant interpretation with limited phenotype information. These results emphasise the importance of the MDT and collecting phenotype and variant data. As this testing is soon to be widely available, we should look to move beyond diagnostic yield as a measure of the value of PES. TWEETABLE ABSTRACT: Prenatal exome sequencing can aid decision-making in pregnancy management; review ahead of routine implementation in NHS.

Metagenomics Reveals a Core Macrolide Resistome Related to Microbiota in Chronic Respiratory Disease.

Rationale: Long-term antibiotic use for managing chronic respiratory disease is increasing; however, the role of the airway resistome and its relationship to host microbiomes remains unknown.Objectives: To evaluate airway resistomes and relate them to host and environmental microbiomes using ultradeep metagenomic shotgun sequencing.Methods: Airway specimens from 85 individuals with and without chronic respiratory disease (severe asthma, chronic obstructive pulmonary disease, and bronchiectasis) were subjected to metagenomic sequencing to an average depth exceeding 20 million reads. Respiratory and device-associated microbiomes were evaluated on the basis of taxonomical classification and functional annotation including the Comprehensive Antibiotic Resistance Database to determine airway resistomes. Co-occurrence networks of gene-microbe association were constructed to determine potential microbial sources of the airway resistome. Paired patient-inhaler metagenomes were compared (n = 31) to assess for the presence of airway-environment overlap in microbiomes and/or resistomes.Measurements and Main Results: Airway metagenomes exhibit taxonomic and metabolic diversity and distinct antimicrobial resistance patterns. A "core" airway resistome dominated by macrolide but with high prevalence of ß-lactam, fluoroquinolone, and tetracycline resistance genes exists and is independent of disease status or antibiotic exposure. Streptococcus and Actinomyces are key potential microbial reservoirs of macrolide resistance including the ermX, ermF, and msrD genes. Significant patient-inhaler overlap in airway microbiomes and their resistomes is identified where the latter may be a proxy for airway microbiome assessment in chronic respiratory disease.Conclusions: Metagenomic analysis of the airway reveals a core macrolide resistome harbored by the host microbiome.

Environmental fungal sensitisation associates with poorer clinical outcomes in COPD.

INTRODUCTION: Allergic sensitisation to fungi such as Aspergillus are associated to poor clinical outcomes in asthma, bronchiectasis and cystic fibrosis; however, clinical relevance in COPD remains unclear. METHODS: Patients with stable COPD (n=446) and nondiseased controls (n=51) were prospectively recruited across three countries (Singapore, Malaysia and Hong Kong) and screened against a comprehensive allergen panel including house dust mites, pollens, cockroach and fungi. For the first time, using a metagenomics approach, we assessed outdoor and indoor environmental allergen exposure in COPD. We identified key fungi in outdoor air and developed specific-IgE assays against the top culturable fungi, linking sensitisation responses to COPD outcomes. Indoor air and surface allergens were prospectively evaluated by metagenomics in the homes of 11 COPD patients and linked to clinical outcome. RESULTS: High frequencies of sensitisation to a broad range of allergens occur in COPD. Fungal sensitisation associates with frequent exacerbations, and unsupervised clustering reveals a "highly sensitised fungal predominant" subgroup demonstrating significant symptomatology, frequent exacerbations and poor lung function. Outdoor and indoor environments serve as important reservoirs of fungal allergen exposure in COPD and promote a sensitisation response to outdoor air fungi. Indoor (home) environments with high fungal allergens associate with greater COPD symptoms and poorer lung function, illustrating the importance of environmental exposures on clinical outcomes in COPD. CONCLUSION: Fungal sensitisation is prevalent in COPD and associates with frequent exacerbations representing a potential treatable trait. Outdoor and indoor (home) environments represent a key source of fungal allergen exposure, amenable to intervention, in "sensitised" COPD.

Polyvinyl alcohol/chitosan hydrogels with enhanced antioxidant and antibacterial properties induced by lignin nanoparticles.

Polyvinyl alcohol/chitosan (PVA/Ch) hydrogels containing 1 and 3wt% of lignin nanoparticles (LNPs) were prepared through a freezing-thaw procedure. Results from microstructural, thermal and mechanical characterization of LNPs based PVA/Ch demonstrated that the lowest amount of LNPs (1wt%) was beneficial, whereas the presence of agglomerates at higher LNP content limited the effect. Moreover, a different swelling behaviour was observed for hydrogels containing LNPs with respect of PVA/Ch, due to the formation of a porous honeycomb-like structure. A synergic effect of Ch and LNPs was revealed in terms of antioxidative response by DPPH (1,1-Diphenyl-2-picryl-hydrazyl) activity of migrated substances, whereas results from antimicrobial tests confirmed LNPs as effective against Gram negative bacteria (E. coli) when compared to Gram positive (S.aureus and S. epidermidis) strains. The obtained results suggested the possible use of produced PVA/Ch hydrogels incorporating LNPs in many different sectors, such as drug delivery, food packaging, wound dressing.

Effect of cellulose and lignin on disintegration, antimicrobial and antioxidant properties of PLA active films.

This study reports the effects on antimicrobial, antioxidant, migration and disintegrability activities of ternary nanocomposite films based on poly(lactic acid) incorporating two biobased nanofillers, (cellulose nanocrystals (CNC) and lignin nanoparticles (LNP)), in two different amounts (1 and 3% wt.). Results from antimicrobial tests revealed a capacity to inhibit the Gram negative bacterial growth of Xanthomonas axonopodis pv. vesicatoria and Xanthomonas arboricola pv. pruni along the time, offering innovative opportunities against dangerous bacterial plant pathogens. LNP proved to be highly efficient in antioxidation activity, based on the disappearance of the absorption band at 517nm of the free radical, 2,2-diphenyl-1-picrylhydrazyl (DPPH) upon reduction by an antiradical compound; moreover the combination of LNP and CNC generates a synergistic positive effect in the antioxidation response of PLA ternary films. Furthermore, all the studied formulations showed a disintegrability value up to 90% after 15days of incubation in composting conditions. Migration results showed that the films can be considered suitable for application in food packaging field.

Reusing surgical instruments during Mohs micrographic surgery: safe from infection, but not free from risk.

We report several scenarios of compromise in patient safety owing to the re-use of mis-assigned patient's surgical instruments in Mohs micrographic surgery.We discuss the breaks in universal protocols that others may experience in their practices and describe corrective measures that our institutions employed to avoid such future events.There is a lack of publication in the literature on the topic of mis-assigned instrument use in Mohs surgery. We believe that the  practice of re-using instruments is cost-effective and therefore common. Based on our humbling experience, this publication may initiate important discussion among dermatologist regarding safety protocols at their respective institutions.

Spline modelling electron insert factors using routine measurements.

There are many methods available to predict electron output factors; however, many centres still measure the factors for each irregular electron field. Creating an electron output factor prediction model that approaches measurement accuracy--but uses already available data and is simple to implement--would be advantageous in the clinical setting. This work presents an empirical spline model for output factor prediction that requires only the measured factors for arbitrary insert shapes. Equivalent ellipses of the insert shapes are determined and then parameterised by width and ratio of perimeter to area. This takes into account changes in lateral scatter, bremsstrahlung produced in the insert material, and scatter from the edge of the insert. Agreement between prediction and measurement for the 12 MeV validation data had an uncertainty of 0.4% (1SD). The maximum recorded deviation between measurement and prediction over the range of energies was 1.0%. The validation methodology showed that one may expect an approximate uncertainty of 0.5% (1SD) when as little as eight data points are used. The level of accuracy combined with the ease with which this model can be generated demonstrates its suitability for clinical use. Implementation of this method is freely available for download at https://github.com/SimonBiggs/electronfactors.

Examination of the properties of IMRT and VMAT beams and evaluation against pre-treatment quality assurance results.

This study aimed to provide a detailed evaluation and comparison of a range of modulated beam evaluation metrics, in terms of their correlation with QA testing results and their variation between treatment sites, for a large number of treatments. Ten metrics including the modulation index (MI), fluence map complexity, modulation complexity score (MCS), mean aperture displacement (MAD) and small aperture score (SAS) were evaluated for 546 beams from 122 intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) treatment plans targeting the anus, rectum, endometrium, brain, head and neck and prostate. The calculated sets of metrics were evaluated in terms of their relationships to each other and their correlation with the results of electronic portal imaging based quality assurance (QA) evaluations of the treatment beams. Evaluation of the MI, MAD and SAS suggested that beams used in treatments of the anus, rectum, head and neck were more complex than the prostate and brain treatment beams. Seven of the ten beam complexity metrics were found to be strongly correlated with the results from QA testing of the IMRT beams (p < 0.00008). For example, values of SAS (with multileaf collimator apertures narrower than 10 mm defined as 'small') less than 0.2 also identified QA passing IMRT beams with 100% specificity. However, few of the metrics are correlated with the results from QA testing of the VMAT beams, whether they were evaluated as whole 360° arcs or as 60° sub-arcs. Select evaluation of beam complexity metrics (at least MI, MCS and SAS) is therefore recommended, as an intermediate step in the IMRT QA chain. Such evaluation may also be useful as a means of periodically reviewing VMAT planning or optimiser performance.

Keratins extracted from Merino wool and Brown Alpaca fibres: thermal, mechanical and biological properties of PLLA based biocomposites.

Keratins extracted from Merino wool (KM) and Brown Alpaca fibres (KA) by sulphitolysis and commercial hydrolyzed keratins (KH) were used as fillers in poly(l-lactic) acid based biocomposites processed by solvent casting in chloroform. Different contents (1 wt.% and 5 wt.%) of keratins were considered and the morphological, thermal, mechanical, chemical and biological behaviours of the developed PLLA biocomposites were investigated. The results confirmed that surface morphologies of biocomposites revealed specific round-like surface topography function of different microsized keratin particles in different weight contents, such as the analysis of bulk morphologies which confirmed a phase adhesion strictly dependent by the keratin source. Transparency and thermal responses were deeply affected by the presence of the different keratins and their interaction with the PLLA matrix. Tensile test results underlined the possibility to modulate the mechanical behaviour of PLLA selecting the keratin type and content in order to influence positively the elastic and/or plastic response. It was demonstrated that surface characteristics of PLLA/KA systems also influenced the bovine serum albumin adsorption, moreover PLLA and PLLA biocomposites based on different kinds of keratins supported the culture of human bone-marrow mesenchymal stem cells, indicating that these biocomposites could be useful materials for medical applications.

Treatment plan complexity metrics for predicting IMRT pre-treatment quality assurance results.

The planning of IMRT treatments requires a compromise between dose conformity (complexity) and deliverability. This study investigates established and novel treatment complexity metrics for 122 IMRT beams from prostate treatment plans. The Treatment and Dose Assessor software was used to extract the necessary data from exported treatment plan files and calculate the metrics. For most of the metrics, there was strong overlap between the calculated values for plans that passed and failed their quality assurance (QA) tests. However, statistically significant variation between plans that passed and failed QA measurements was found for the established modulation index and for a novel metric describing the proportion of small apertures in each beam. The 'small aperture score' provided threshold values which successfully distinguished deliverable treatment plans from plans that did not pass QA, with a low false negative rate.

A practical and theoretical definition of very small field size for radiotherapy output factor measurements.

PURPOSE: This work introduces the concept of very small field size. Output factor (OPF) measurements at these field sizes require extremely careful experimental methodology including the measurement of dosimetric field size at the same time as each OPF measurement. Two quantifiable scientific definitions of the threshold of very small field size are presented. METHODS: A practical definition was established by quantifying the effect that a 1 mm error in field size or detector position had on OPFs and setting acceptable uncertainties on OPF at 1%. Alternatively, for a theoretical definition of very small field size, the OPFs were separated into additional factors to investigate the specific effects of lateral electronic disequilibrium, photon scatter in the phantom, and source occlusion. The dominant effect was established and formed the basis of a theoretical definition of very small fields. Each factor was obtained using Monte Carlo simulations of a Varian iX linear accelerator for various square field sizes of side length from 4 to 100 mm, using a nominal photon energy of 6 MV. RESULTS: According to the practical definition established in this project, field sizes ≤ 15 mm were considered to be very small for 6 MV beams for maximal field size uncertainties of 1 mm. If the acceptable uncertainty in the OPF was increased from 1.0% to 2.0%, or field size uncertainties are 0.5 mm, field sizes ≤ 12 mm were considered to be very small. Lateral electronic disequilibrium in the phantom was the dominant cause of change in OPF at very small field sizes. Thus the theoretical definition of very small field size coincided to the field size at which lateral electronic disequilibrium clearly caused a greater change in OPF than any other effects. This was found to occur at field sizes ≤ 12 mm. Source occlusion also caused a large change in OPF for field sizes ≤ 8 mm. Based on the results of this study, field sizes ≤ 12 mm were considered to be theoretically very small for 6 MV beams. CONCLUSIONS: Extremely careful experimental methodology including the measurement of dosimetric field size at the same time as output factor measurement for each field size setting and also very precise detector alignment is required at field sizes at least ≤ 12 mm and more conservatively ≤ 15 mm for 6 MV beams. These recommendations should be applied in addition to all the usual considerations for small field dosimetry, including careful detector selection.

PVA bio-nanocomposites: a new take-off using cellulose nanocrystals and PLGA nanoparticles.

The formation of a new generation of hybrid bio-nanocomposites is reported: these are intended at modulating the mechanical, thermal and biocompatibility properties of the poly(vinyl alcohol) (PVA) by the combination of cellulose nanocrystals (CNC) and poly (D,L-lactide-co-glycolide) (PLGA) nanoparticles (NPs) loaded with bovine serum albumin fluorescein isothiocynate conjugate (FITC-BSA). CNC were synthesized from microcrystalline cellulose by hydrolysis, while PLGA nanoparticles were produced by a double emulsion with subsequent solvent evaporation. Firstly, binary bio-nanocomposites with different CNC amounts were developed in order to select the right content of CNC. Next, ternary PVA/CNC/NPs bio-nanocomposites were developed. The addition of CNC increased the elongation properties without compromising the other mechanical responses. Thermal analysis underlined the nucleation effect of the synergic presence of cellulose and nanoparticles. Remarkably, bio-nanocomposite films are suitable to vehiculate biopolymeric nanoparticles to adult bone marrow mesenchymal stem cells successfully, thus representing a new tool for drug delivery strategies.

A physiologically based pharmacokinetic modeling approach to predict disease-drug interactions: suppression of CYP3A by IL-6.

Elevated cytokine levels are known to downregulate expression and suppress activity of cytochrome P450 enzymes (CYPs). Cytokine-modulating therapeutic proteins (TPs) used in the treatment of inflammation or infection could reverse suppression, manifesting as TP-drug-drug interactions (TP-DDIs). A physiologically based pharmacokinetic model was used to quantitatively predict the impact of interleukin-6 (IL-6) on sensitive CYP3A4 substrates. Elevated simvastatin area under the plasma concentration-time curve (AUC) in virtual rheumatoid arthritis (RA) patients, following 100 pg/ml of IL-6, was comparable to observed clinical data (59 vs. 58%). In virtual bone marrow transplant (BMT) patients, 500 pg/ml of IL-6 resulted in an increase in cyclosporine AUC, also in good agreement with the observed data (45 vs. 39%). In a different group of BMT patients treated with cyclosporine, the magnitude of interaction with IL-6 was underpredicted by threefold. The complexity of TP-DDIs highlights underlying pathophysiological factors to be considered, but these simulations provide valuable first steps toward predicting TP-DDI risk.

Interplay effects during Enhanced Dynamic Wedge deliveries.

In this study the interplay effects for Enhanced Dynamic Wedge (EDW) treatments are experimentally investigated. Single and multiple field EDW plans for different wedge angles were delivered to a phantom and detector on a moving platform, with various periods, amplitudes for parallel and perpendicular motions. A four field 4D CT planned lung EDW treatment was delivered to a dummy tumor over four fractions. For the single field parallel case the amplitude and the period of motion both affect the interplay resulting in the appearance of a step function and penumbral cut off with the discrepancy worst where collimator-tumor speed is similar. For perpendicular motion the amplitude of tumor motion is the only dominant factor. For large wedge angle the dose discrepancy is more pronounced compared to the small wedge angle for the same field size and amplitude-period values. For a small field size i.e. 5 × 5 cm(2) the loss of wedged distribution was observed for both 60° and 15° wedge angles for parallel and perpendicular motions. Film results from 4D CT planned delivery displayed a mix of over and under dosages over 4 fractions, with the gamma pass rate of 40% for the averaged film image at 3%/1 mm DTA (Distance to Agreement). Amplitude and period of the tumor motion both affect the interplay for single and multi-field EDW treatments and for a limited (4 or 5) fraction delivery there is a possibility of non-averaging of the EDW interplay.

Monte Carlo verification of gel dosimetry measurements for stereotactic radiotherapy.

The quality assurance of stereotactic radiotherapy and radiosurgery treatments requires the use of small-field dose measurements that can be experimentally challenging. This study used Monte Carlo simulations to establish that PAGAT dosimetry gel can be used to provide accurate, high-resolution, three-dimensional dose measurements of stereotactic radiotherapy fields. A small cylindrical container (4 cm height, 4.2 cm diameter) was filled with PAGAT gel, placed in the parietal region inside a CIRS head phantom and irradiated with a 12-field stereotactic radiotherapy plan. The resulting three-dimensional dose measurement was read out using an optical CT scanner and compared with the treatment planning prediction of the dose delivered to the gel during the treatment. A BEAMnrc/DOSXYZnrc simulation of this treatment was completed, to provide a standard against which the accuracy of the gel measurement could be gauged. The three-dimensional dose distributions obtained from Monte Carlo and from the gel measurement were found to be in better agreement with each other than with the dose distribution provided by the treatment planning system's pencil beam calculation. Both sets of data showed close agreement with the treatment planning system's dose distribution through the centre of the irradiated volume and substantial disagreement with the treatment planning system at the penumbrae. The Monte Carlo calculations and gel measurements both indicated that the treated volume was up to 3 mm narrower, with steeper penumbrae and more variable out-of-field dose, than predicted by the treatment planning system. The Monte Carlo simulations allowed the accuracy of the PAGAT gel dosimeter to be verified in this case, allowing PAGAT gel to be utilized in the measurement of dose from stereotactic and other radiotherapy treatments, with greater confidence in the future.

Effectiveness and safety of posterior titanium instrumentation in children with adolescent idiopathic scoliosis: a prospective study.

OBJECTIVES: This study aims to determine the effectiveness and the relative safety of posterior spinal fusion with titanium instrumentation in children with adolescent idiopathic scoliosis (AIS). PATIENTS AND METHODS: A prospective cohort (case-only) study was conducted to determine this effectiveness and safety. There were 24 patients (21 girls, 3 boys; mean age 14.1±1.8 years; range 11 to 17 years) who underwent surgery between January 2002 and December 2003 in our clinic, with a minimum of two years follow-up. Upper thoracic, thoracic, and thoracolumbar coronal curves as well as kyphosis from T5-T12 were measured as main outcome variables and repeated measure ANOVA was used to assess the data. RESULTS: The main thoracic curve (coronal plane) correction achieved at the first erect period (the first 4 weeks postoperative) (mean 12.21±9.78 degrees), this correction was maintained at 24 months follow-up (mean 15.71±7.15 degrees) and both were significantly lower than the preoperative values (mean 57.0±12.75 degrees), (p<0.001). Sagittal plane (kyphosis angle between T5-T12) curve was not worsened by posterior titanium instrumentation and it was 19.50±10.53 degrees preoperatively, 16.45±6.68 degrees at the first erect period and 17.73±8.40 degrees at the 24 months follow-up (p=0.74). There were no evidence of pseudoarthrosis, no loss of correction and no infections. CONCLUSION: Posterior titanium instrumentation in the treatment of AIS is effective due to its ability to achieve and maintain curve correction. Further, this instrumentation does not worsen hypokyphosis and is safe since there were no adverse events.

Improved image quality for X-ray CT imaging of gel dosimeters.

PURPOSE: This study provides a simple method for improving precision of X-ray computed tomography (CT) scans of irradiated polymer gel dosimetry. The noise affecting CT scans of irradiated gels has been an impediment to the use of clinical CT scanners for gel dosimetry studies. METHODS: In this study, it is shown that multiple scans of a single PAGAT gel dosimeter can be used to extrapolate a "zero-scan" image which displays a similar level of precision to an image obtained by averaging multiple CT images, without the compromised dose measurement resulting from the exposure of the gel to radiation from the CT scanner. RESULTS: When extrapolating the zero-scan image, it is shown that exponential and simple linear fits to the relationship between Hounsfield unit and scan number, for each pixel in the image, provide an accurate indication of gel density. CONCLUSIONS: It is expected that this work will be utilized in the analysis of three-dimensional gel volumes irradiated using complex radiotherapy treatments.