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The purpose of this study was to evaluate the long-term functional and neurodevelopmental outcomes in pediatric patients who underwent neurosurgical intervention following suspected abusive head trauma (AHT). We performed a single-center retrospective review (January 1, 2007, to December 31, 2019) of patients aged less than three years who had intracranial injury suspicious for AHT and received a neurosurgical procedure. Long-term functional outcome was measured using the Pediatric Cerebral Performance Category (PCPC), Pediatric Overall Performance Category (POPC), and the Mullen Scales of Early Learning (MSEL). Seventy-seven patients were identified; 53 survived to discharge and had at least one-year follow-up. To examine long-term functional outcome, PCPC at the last available visit was examined and found to be 1 or 2 (normal to mild disability) for 64% of patients and 3 or 4 (moderate to severe disability) for 36%. The last available MSEL composite score for neurodevelopmental assessment also demonstrated that 13% of patients scored in the "average" range, 17% in the "below average" range, and 70% in the "very low" range. There was no statistical difference in the last available PCPC or POPC score or the last available MSEL score for patients who received a craniotomy when compared with those who received an intracranial shunt. For patients with AHT who survived to discharge, functional improvements over time were noted in both patients who received craniotomy or who simply required shunt placement. These results suggest that, for patients who survive to discharge, operative management of AHT can lead to reasonable long-term functional outcomes. [ABSTRACT FROM AUTHOR]

Although preoperative function and range of motion (ROM) are determinants of postoperative outcome following reverse shoulder arthroplasty (RSA), there is limited data on the influence of preoperative rotator cuff status. The purpose of this study was to evaluate the relationship between preoperative rotator cuff physiologic cross-sectional area (PCSA) and strength on postoperative RSA outcome. A retrospective review was conducted on 53 primary RSAs from a multicenter database performed between 2015 and 2019 using a 135° humeral neck-shaft angle. Preoperative magnetic resonance imaging and computed tomographic scans were used to assess the PCSA of the subscapularis, supraspinatus, infraspinatus, and teres minor. American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES) scores, ROM, and strength were measured preoperatively and at a minimum of 2 years postoperatively. Correlation coefficients were used to determine the relationship between variables. There were no significant correlations between preoperative PCSA of any rotator cuff muscles and postoperative ASES scores. Preoperative subscapularis PCSA positively correlated with change in belly press (BP) strength following RSA (⍴ = 0.37, P =.006). Preoperative abduction strength was significantly correlated with postoperative abduction strength (⍴ = 0.297, P =.006). Preoperative external rotation (ER) strength was significantly correlated with postoperative ER (⍴ = 0.378, P =.005) and abduction (⍴ = 0.304; P =.032) strength. Preoperative BP strength negatively correlated with postoperative ASES (⍴ = –0.283, P =.042) but positively correlated with postoperative BP (⍴ = 0.411, P =.001) and abduction (⍴ = 0.367, P =.009) strength. With the use of a 135° humeral implant, there is limited correlation between preoperative PCSA and postoperative outcomes 2 years following RSA; the only significant correlation was between preoperative subscapularis PCSA and postoperative BP strength. Preoperative strength is positively correlated with postoperative strength but not ROM or ASES scores. [ABSTRACT FROM AUTHOR]

Diagnostic stewardship aims to improve diagnostic test utilization through evidence-based practices to improve care, quality, safety, and costs. Diagnostic stewardship is a collaborative effort that brings together multidisciplinary groups that have a common interest in promoting and ensuring best testing practices. For infectious disease testing, clinical microbiology laboratories are perhaps best positioned within their health care systems to lead these efforts, as they are not only diagnostic experts, but also directly oversee many of the tools and choices available to improve test performance and utilization. While some interventions may not fall under the direct purview of clinical microbiology laboratories, their expertise is nevertheless essential to inform these efforts, as well. Multiple stewardship strategies have been evaluated, providing laboratories with several opportunities to implement evidence-based practice changes to improve quality and outcomes. Further research is needed to continue advancing practice for well-established and emerging tests alike. [ABSTRACT FROM AUTHOR]

The neurophysiological effects of transcranial direct current stimulation (tDCS) are typically described with respect to changes in cortical excitability, defined by using transcranial magnetic stimulation pulses to determine changes in motor evoked potentials. However, how individual cortical neurons change firing patterns under the influence of tDCS is largely unknown. While the relatively weak currents produced in the brain by tDCS may not be adequate to directly depolarize neuronal membranes, ongoing neuronal activity, combined with subthreshold changes in membrane polarization might be sufficient to alter the threshold for neural firing. The purpose of this study was to determine the effects of tDCS on neurophysiological activity in motor cortex of freely moving, healthy rats. In nine healthy, ambulatory rats, each studied under six different stimulation conditions varying in current intensity (maximum current density = 39.8 A/m2 at 0.4 mA) and polarity (anodal or cathodal), neural activity was analyzed in response to 20 min of tDCS applied through bone screws insulated from the overlying scalp. After analysis of 480 multi-unit channels that satisfied a rigid set of neurophysiological criteria, we found no systematic effect of tDCS stimulation condition on firing rate or firing pattern. Restricting the analysis to the most responsive units, subtle, but statistically significant changes occurred only in the highest intensity anodal condition. These results confirm that at current densities typically used in human or animal tDCS studies, observed effects of tDCS are likely to occur via mechanisms other than direct neuronal depolarization. • In awake rats, tDCS had no effect on overall neuronal firing rate or pattern. • The highest intensity anodal condition had a greater proportion of responsive units. • tDCS does not result in widespread neuronal firing at typical current intensities. [ABSTRACT FROM AUTHOR]

Although both obesity and coronavirus disease 2019 (COVID-19) independently induce inflammation and thrombosis, the association between obesity class and risk of thrombosis in patients with COVID-19 remains unclear. This retrospective cohort study included consecutive patients hospitalized with COVID-19 at a single institution. Patients were categorized based on obesity class. The main outcomes were venous thromboembolism (VTE) and myocardial injury, a marker of microvascular thrombosis in COVID-19. Adjustments were made for sociodemographic variables, cardiovascular disease risk factors and comorbidities. 609 patients with COVID-19 were included. 351 (58%) patients were without obesity, 110 (18%) were patients with class I obesity, 76 (12%) were patients with class II obesity, and 72 (12%) were patients with class III obesity. Patients with class I and III obesity had significantly higher risk-adjusted odds of VTE compared to patients without obesity (OR = 2.54, 95% CI: 1.05–6.14 for class I obesity; and OR = 3.95, 95% CI: 1.40–11.14 for class III obesity). Patients with class III obesity had significantly higher risk-adjusted odds of myocardial injury compared to patients without obesity (OR = 2.15, 95% CI: 1.12–4.12). Both VTE and myocardial injury were significantly associated with greater risk-adjusted odds of mortality. This study demonstrates that both macrovascular and microvascular thromboses may contribute to the elevated morbidity and mortality in patients with obesity and COVID-19. [ABSTRACT FROM AUTHOR]

The nuclear receptor retinoic acid receptor-related orphan receptor gamma t (RORγt) is a transcription factor that drives Th17 cell differentiation and IL-17 production in both innate and adaptive immune cells. The IL-23/IL-17 pathway is implicated in major autoimmune and inflammatory diseases. RORγt lies at the core of this pathway and represents an attractive opportunity for intervention with a small molecule. Despite diverse chemical series having been reported, combining high potency and nuclear receptor selectivity with good physicochemical properties remains a challenging endeavor in the field of RORγt drug discovery. We describe the discovery and evaluation of a new class of potent and selective RORγt inverse agonists based on a thiazole core. Acid analog 1j demonstrated oral bioavailability in rats and was potent in a human whole blood assay, suggesting potential utility in treating autoimmune and inflammatory diseases such as psoriasis. X-ray crystallographic data helped to elucidate the molecular mechanism for RORγt inhibition with this series. [ABSTRACT FROM AUTHOR]

We identified 6-substituted quinolines as modulators of the retinoic acid receptor-related orphan receptor gamma t (RORγt). The synthesis of this class of RORγt modulators is reported, and optimization of the substituents at the quinoline 6-position that produced compounds with high affinity for the receptor is detailed. This effort identified molecules that act as potent, full inverse agonists in a RORγt-driven cell-based reporter assay. The X-ray crystal structures of two full inverse agonists from this chemical series bound to the RORγt ligand binding domain are disclosed, and we highlight the interaction of a hydrogen-bond acceptor on the 6-position substituent of the inverse agonist with Glu379:NH as a conserved binding contact. [ABSTRACT FROM AUTHOR]

Background Brachial-cephalic arteriovenous fistulas (BCFs) are associated with high-flow volumes, leading to potential risks such as arm swelling, steal syndrome, pseudoaneurysm (due to a pressurized access), and cephalic arch stenosis. We hypothesized that a proximal radial-cephalic fistula (prRCF) configuration mitigates these risks because a lower flow state is created. Furthermore, we also hypothesized that despite these lower flows, patencies (primary, primary assisted, secondary) are sustained. Methods Leveraging a prospectively collected database supplemented with detailed medical record data, analyses of patients undergoing BCF and prRCF were completed (November 2008 through March 2016). Preoperative clinical and imaging characteristics, operative variables, and postoperative complications were reviewed. The primary end point was a composite of arm swelling, steal, and pseudoaneurysm at 2 years. Fistulograms and interventions (surgical revision, thrombectomy, endovascular treatment of cephalic arch stenosis) censored at 2 years were compared between configurations. Patencies were plotted using Kaplan-Meier techniques and compared using Cox proportional hazards. Results During the study period, 345 arteriovenous fistulas and 72 prosthetic grafts were primarily placed; 56 patients underwent BCF and 50 patients underwent prRCF with a mean follow-up of 1.8 ± 1.7 (standard deviation) years. Except for prRCF patients being older, there was no difference between the groups with regard to preoperative characteristics. The artery diameter used for anastomosis was significantly larger in the BCF group (4.0 ± 1.1 mm vs 2.6 ± 0.8 mm; P < .001), with higher flow volumes at 6-week ultrasound examination (1060 ± 587 mL/min vs 735 ± 344 mL/min; P < .001). Complications (arm swelling, steal, pseudoaneurysm) were significantly more common in the BCF group ( P = .02). There was a trend, albeit statistically insignificant, for the BCF group to require more cephalic arch stenosis interventions. Of those patients needing dialysis within 1 year, both BCF and prRCF were successfully used in the majority of patients (n = 27 [66%] vs n = 25 [63%]; P = 1.0). Unadjusted and adjusted primary, primary assisted, and secondary patency rates were similar between the groups. Conclusions prRCFs have fewer complications yet similar midterm durability compared with BCFs. When it is anatomically feasible, prRCFs should be constructed over BCFs because of their superior physiology and clinical outcomes. [ABSTRACT FROM AUTHOR]

Invadopodia are a subset of invadosomes that are implicated in the integration of signals from the tumor microenvironment to support tumor cell invasion and dissemination. Recent progress has begun to define how tumor cells regulate the plasticity necessary for invadopodia to assemble and function efficiently in the different microenvironments encountered during dissemination in vivo . Exquisite mapping by many laboratories of the pathways involved in integrating diverse invadopodium initiation signals, from growth factors, to extracellular matrix (ECM) and cell–cell contact in the tumor microenvironment, has led to insight into the molecular basis of this plasticity. Here, we integrate this new information to discuss how the invadopodium is an important conductor that orchestrates tumor cell dissemination during metastasis. [ABSTRACT FROM AUTHOR]

A modification of the aqueous addition method for the synthesis of apatites is described. This one-step method does not require addition of reagents and no adjustment of solution pH and therefore requires less equipment and less time than the traditional aqueous addition method. It can be used with a variety of starting materials to produce both phosphate and vanadate apatites with good purity and yield. The method generally produces smaller crystallites with average size in the 30–50 nm range. The effects of synthesis variables such as the nature of the reactants, control of pH, and digestion temperature and time are discussed. [ABSTRACT FROM AUTHOR]

A high-throughput screen of the ligand binding domain of the nuclear receptor retinoic acid-related orphan receptor gamma t (RORγt) employing a thermal shift assay yielded a quinoline tertiary alcohol hit. Optimization of the 2-, 3- and 4-positions of the quinoline core using structure-activity relationships and structure-based drug design methods led to the discovery of a series of modulators with improved RORγt inhibitory potency and inverse agonism properties. [ABSTRACT FROM AUTHOR]

Pilonidal sinus disease (PSD) is a common acquired inflammatory condition of the skin and subcutaneous tissues that commonly affects the intergluteal cleft. In rare occurrences, PSD can occur outside the sacrococcygeal region. Here we detail a case of intermammary PSD in a 13-year-old female who presented with recurrent intermammary cysts and underwent successful wide local excision with primary closure. Intermammary PSD is a rare condition associated with young, obese females with large breasts kept in tight brassieres. A high index of suspicion is required as intermammary PSD is a clinical diagnosis. Wide local excision of the entire sinus tract with primary closure is the recommended treatment to decrease recurrence and optimize cosmetic outcome. Our case report adds to the limited pediatric literature for this diagnosis and highlights the rare presentation and management of intermammary PSD. • Intermammary pilonidal sinus disease is a rare presentation of a common disease. • Associated with young, obese females with large breasts who wear tight brassieres. • Wide local excision with primary closure is recommended. [ABSTRACT FROM AUTHOR]

Purpose: To identify barriers to follow-up eye care in children who failed a visual acuity screening conducted by their primary care provider. Methods: Children aged 3-14 years who failed a visual acuity screening were identified. A phone survey with the parent of every child was conducted 4 months after the screening. Family demographics, parental awareness of childhood eye diseases and eye care for children, and barriers to follow-up eye care were assessed. Results: Of 971 children sampled, 199 (20.5%) failed a visual acuity screening. The survey was completed by the parents of 58 children (29.1%), of whom 27 (46.6%) presented for follow-up examination. The most common reason for failure to follow-up was parental unawareness of screening results (29.3%). Follow-up rates were higher in children with previous eye examinations than in those without (81% versus 17%; P = 0.005) and in children who waited <2 months for a follow-up appointment than in those who had to wait longer (100% versus 63%; P = 0.024). Child's sex, ethnicity, and health insurance status, parent's marital, education and employment status, household income, and transportation access were not associated with statistically significant different follow-up rates. Conclusions: Parental unawareness of a failed visual acuity screening is an important barrier to obtaining follow-up. Strategies to improve follow-up rates after a failed visual acuity screening may include communicating the results clearly and consistently, providing education about the importance of timely follow-up, and offering logistic support for accessing eye appointments to families. [Copyright &y& Elsevier]

• Asphalt binder was modified with sub-epoxidized and poly (acrylated epoxidized) soybean oils. • The undesired properties of recycled asphalt were mitigated with soybean oil-derived modifiers. • The soybean oil-derived modifiers significantly improved the low temperature cracking resistance. • The bio-based polymer significantly improved the high temperature performance. • The bio-based modifiers can have a huge positive impact on the sustainability of pavements. Soybean oil-derived modifiers were used for the improvement of properties of asphalt materials prepared for a pavement demonstration project. The rheological properties of base, biomodified and extracted binders were measured/compared using rheometers. The binder modification resulted in a decrease of 1.2 °C and 2.3 °C in, respectively, the high-and low-temperature grades of base binder, and when the effect of RAP binder was considered, the continuous performance grade (PG) became almost identical with that of base/control binder. Due to the biomodification and the presence of RAP, the binder's elastic recovery (R) increased by 8.0% and its non-recoverable creep compliance (J nr) decreased by 0.13 kPa−1. The tests conducted to evaluate the mechanical performance of the mixtures proved the efficacy of the bio-modifiers used in reversing the undesired effects of reclaimed asphalt pavement (RAP) and improving the performance of asphalt pavements at different temperatures. For instance, the Hamburg wheel tracking (HWT) test results revealed that the presence of bio-modifiers resulted in the increase of stripping inflection point (SIP) by 3619 passes. The disk-shaped compact tension (DCT) test proved the effectiveness of the bio-modifiers used, as these modifiers increased the fracture energy by 113 J/m2. The master curves constructed for the asphalt binders and mixtures indicated an increased stiffness/elasticity at intermediate and high temperatures. [ABSTRACT FROM AUTHOR]

The application of label-independent biophysical assays (affinity assays) to carefully selected libraries of biochemicals, natural products and known bioactive molecules generates a powerful tool to identify ligands indicative of protein function. Detection of ligand binding does not require the measurement of enzyme activity, thus every cofactor, ion, reactant or product might be identified separately. One such assay, ThermoFluor®, monitors ligand perturbation of protein thermostability. In conjunction with a functional probe library (FPL), this assay has been used to decrypt the function of orphan proteins. [Copyright &y& Elsevier]

In light of increasing pressures to adopt a more sustainable approach to product design and manufacture, the requirement to develop sustainable products is one of the key challenges facing industry in the 21st century. Hence, the concept of developing sustainable products as well as services is evolving as a key element of Cleaner Production. Sustainable product development initiatives (mainly through eco-design) have been evolving for some time to support companies develop more sustainable products. Ireland has been running the highly successful Environmentally Superior Products (ESP) initiative that supports industrial companies to incorporate a more sustainable approach to the development of products and/or services. The lessons learned from the ESP and other global Sustainable Product and Service Developments in industry and research, are being used to develop a method for effective sustainable product and/or service development (SPSD) in industry. The method is designed to provide pragmatic guidance to business and industry for developing sustainable products and services as well as incorporating this approach within existing corporate strategy, cleaner production and product development systems. This method is being developed by the authors at the Environmental Policy and Management Group (EPMG), Department of Environmental Science and Technology, Imperial College London, UK in conjunction with industry and practitioners. The method provides a framework for implementing SPSD throughout the entire lifecycle of a product and/or service. It can be used to identify, assess and implement the options for optimum sustainability in the design and development of a product and/or service. This paper describes the key features of this method. [Copyright &y& Elsevier]

Cholinergic systems in the dorsal horn are involved in antinociception but little is known about the organisation of receptors that mediate this process. In this study we examined immunocytochemical properties of dorsal horn neuronal cell bodies that express the m2 muscarinic acetylcholine receptor. Tissue was examined with confocal laser scanning microscopy and quantitative analysis performed. Immunoreactive cells were found throughout the dorsal horn and in lamina X. Quantitative analysis revealed that 22% of neuronal somata in the dorsal horn possess the receptor. The greatest concentration of cells was found in deeper laminae (IV–VI) and around lamina X. A proportion of cholinergic cells (labelled with an antibody against choline acetyltransferase) were immunoreactive for the receptor (approximately, 40% of dorsal horn cells and 44% of lamina X cells). Populations of presumed inhibitory interneurons also displayed immunoreactivity for the receptor. Between 27–34% of cells immunoreactive for GABA, nitric oxide synthase and the somatostatin receptor2A expressed the receptor but only 8% of parvalbumin-immunoreactive cells displayed receptor immunoreactivity. Cells labelled with neurotensin, which belong to a subgroup of excitatory neurons, displayed no receptor immunoreactivity. A small number neurokinin-1 receptor-immunoreactive cells in lamina I possessed m2 immunoreactivity but 42% of laminae III/IV neurokinin-1 cells possessed it.This study shows that a significant proportion of cell bodies in the dorsal horn express the muscarinic m2 acetylcholine receptor. The receptor is present on some cholinergic neurons and therefore may function as an autoreceptor. It is associated with inhibitory local circuit neurons and may have a role in the modulation of specific inhibitory systems. It is also found on a proportion of projection cells that possess the neurokinin-1 receptor. This could be the basis of some of the antinociceptive actions of acetylcholine. [Copyright &y& Elsevier]

Intracellular recordings were made from neurones in laminae I and II of the dorsal horn of a longitudinal, parasagittal spinal cord slice from the neonatal rat. Their responses to peripheral nerve stimulation were first tested. Then the responses to bath application of [Sar9,Met(O2)11]-substance P and [D-Ala2,N-MePhe4,Gly-ol5]-enkephalin, neurokinin 1 (NK1) and μ-opioid receptor agonists respectively, were studied. Finally, the structure of each neurone was investigated by injecting neurobiotin intracellularly following recording, and immunocytochemical studies were performed on post-fixed tissues to reveal whether they expressed the NK1 receptor. Nine lamina I neurones where shown to express NK1 receptor and these were depolarised by [Sar9,Met(O2)11]-substance P. These neurones typically received a powerful C-fibre input that was strongly inhibited, presynaptically, by the μ-opioid receptor agonist.The structure, afferent input, opioid sensitivity and intrinsic properties of these neurones are all consistent with the view that they are a major relay for nociceptive information leading to intense pain. The characteristics of 10 other neurones studied in which the NK1 receptor was not found to be expressed at levels detectable by immunocytochemistry are briefly described for comparison.These results contribute to the emergent view that the large neurones in the most dorsal neuronal layer (lamina I) of the spinal cord, which express the principal receptor for substance P (NK1) over their entire soma and dendrites, are a major relay for information leading to intense pain. Inhibition of the relay of information by these neurones would be predicted to result in analgesia and hence, a detailed knowledge of their unique neurochemical characteristics is of paramount importance. [Copyright &y& Elsevier]

Life in urban areas presents special challenges for maternal child care practices. Data from a representative quantitative survey of households with children < 3 y of age in Accra, Ghana were used to test a number of hypothesized constraints to child care including various maternal (anthropometry, education, employment, marital status, age and ethnic group) and household-level factors (income, availability of food, quality of housing and asset ownership, availability of services, household size and crowding). Three care indices were created as follows: 1) a child feeding index; 2) a preventive health seeking index; and 3) a hygiene index. The first two indices were based on data from maternal recall; the hygiene index was based on spot-check observations of proxies of hygiene behaviors. Multivariate analyses (ordinary least-squares regression for the child feeding index and ordered probit for the two other indices) showed that maternal schooling was the most consistent constraint to all three categories of child care practices. None of the household-level characteristics were associated with child feeding practices, but household socioeconomic factors were associated with better preventive health seeking and hygiene behaviors. Thus, poor maternal schooling was a main constraint for child feeding, health seeking and hygiene practices in Accra, but the lack of household resources was a constraint only for health seeking and hygiene. The programmatic implications of these findings for interventions in nutrition education and behaviors in Accra are discussed. [ABSTRACT FROM AUTHOR]

Modifying the design and selectivity of commercial fishing gears can reduce unwanted catches. Most gear selectivity research focusses on trawl gears, and there are relatively few examples of modified static nets, such as gill and trammel nets, which are used all over the world. Fishers operating in the southeast England's common sole (Solea solea) static net fishery wanted to explore methods to try to reduce the unwanted catches of thornback ray (Raja clavata). In 2017, the fishery had common sole landings of 343 tonnes making it an important local fishery. The largest port, the beach launch port of Hastings, is the home port for 65 vessels. Here we describe the performance of a modified trammel net with reduced mesh size in the two outer walls, intended to reduce catches of thornback rays without reducing the landings of the target species of common sole. There no published studies on modifying the outer meshes of a trammel net. The fieldwork was undertaken onboard a vessel from Hastings, fishing over ten days. The catches from a standard gill net, a standard trammel net and a modified trammel net were compared. Six fleets of nets were fished, each made up of five different net sections. The three net designs were placed into the fleets in a random set design. All of the net designs had a minimum (inner) mesh size of 90 mm. There was no statistically significant difference in the number of thornback ray caught between the nets but the number of common sole was estimated at 87 % higher by value in the modified trammel net compared to the other nets. Therefore, when using the modified trammel net, considerably less fishing effort was required to catch the same quota of common sole, but with no increase in the rate of thornback ray catches. If this design were to be applied more widely in this fishery, it could reduce overall catches of thornback ray. The study shows the difference in selectivity towards common sole, plaice (Pleuronectes platessa), whiting (Merlangius merlangus) and thornback rays between a gill net and two trammel net designs. [ABSTRACT FROM AUTHOR]

Biomass (pellets, briquettes, logs) are a key contributor to many countries' strategies for decarbonising heat, particularly in domestic applications. The emissions from these small devices can be high and severely impact air quality, but their levels depend on the design, control, abatement and fuel options. This paper is concerned with the last case. A comparative study shows the emissions from a domestic wood stove for three biomass fuels and their torrefied counterparts. The fuels were burned in a multi-fuel stove along with two reload batches creating continuous combustion cycles: the initial cold start data is presented but not included in averaging and calculation of emission factors. Measurements were made using an FTIR instrument for carbon and nitrogen based gaseous emissions, particulates were measured using a smoke meter with micro-quartz filters as well as a size-selective impactor to obtain the particle size distribution. Particulate emissions were significantly reduced from the torrefied fuels and this is thought to be related to their pyrolysis fingerprint, which was investigated by pyrolysis-GC–MS. NOx was slightly reduced, despite increased fuel-N after torrefaction. In addition, the reduced moisture in the torrefied fuels decreases emissions of CO and CH 4 because of increased time of flaming combustion. • Compares emissions from combustion of raw and torrefied fuels in a domestic multi-fuel stove • Torrefied fuels emit significantly less particulate matter, and slightly less NOx/GJ energy. • CO and CH 4 emissions are reduced for the torrefied fuels. • Changes in pyrolysis products by PY-GC–MS can explain changes in particulate emission. [ABSTRACT FROM AUTHOR]

Isoquinoline-containing bidentate chelators with varying 1- and 3-connectivity prepared from tandem CuAAC methods are capable of forming stable 3:1 Ru(II) coordination compounds. Isoquinoline connectivity influences the spectroscopic properties of these complexes, while isoquinoline incorporation can significantly improve antibacterial properties relative to analogous complexes with pyridine-containing chelators. Bidentate chelators 1-(1-benzyl-1,2,3-triazol-4-yl)isoquinoline and 3-(1-benzyl-1,2,3-triazol-4-yl)isoquinoline were prepared from benzyl bromide and trimethylsilylethynylisoquinoline precursors using a tandem deprotection/substitution/CuAAC synthetic approach. Each chelator is capable of forming a stable 3:1 Ru(II) coordination compound, which forms as a geometric isomer mixture. These Ru(II) complexes possess unique MLCT absorbance signatures at 450/472 nm (1-isomer) and 367 nm (3-isomer) relative to their constituent chelating units. Minimum inhibitory concentration values as low as 0.4 μM are observed for Ru(II) complexes against representative Gram-positive bacteria Bacillus subtilis and Staphylococcus epidermidis. Comparing the MIC values of these isoquinoline compounds with analogous 2-(1-benzyl-1,2,3-triazol-4-yl)pyridine compounds shows a 2.5- to 40-fold improvement in potency. This study establishes that increased hydrophobicity introduced at the central chelating units of Ru(II) coordination compounds can be a useful means by which to optimize antimicrobial activity that is complimentary to the variation of peripheral substituent identity at the chelator's N1 triazole position. [ABSTRACT FROM AUTHOR]

We have previously reported the syntheses of a series of 3,6-disubstituted quinolines as modulators of the retinoic acid receptor-related orphan receptor gamma t (RORγt). These molecules, such as 1 , are potent binders but are high molecular weight and they exhibited poor solubility at pH 2 and pH 7. This manuscript details our efforts at improving physical chemical properties for this series of compounds by increasing the diversity at the 3-position (i.e. introducing heteroatoms and lowering the molecular weight). These efforts have led to molecules such as 27 and 30 which are potent binders with improved solubility. We have previously reported the syntheses of a series of 3,6-disubstituted quinolines as modulators of the retinoic acid receptor-related orphan receptor gamma t (RORγt). These molecules are potent binders but are high molecular weight and they exhibited poor solubility at pH 2 and pH 7. This manuscript details our efforts at improving physical chemical properties for this series of compounds by increasing the diversity at the 3-position (i.e. introducing heteroatoms and lowering the molecular weight). These efforts have led to molecules which are potent binders with improved solubility. [ABSTRACT FROM AUTHOR]

We designed and synthesized a new series of fatty acid synthase (FASN) inhibitors with potential utility for the treatment of cancer. Extensive SAR studies led to highly active FASN inhibitors with good cellular activity and oral bioavailability, exemplified by compound 34 . Compound 34 is a potent inhibitor of human FASN (IC 50  = 28 nM) that effectively inhibits proliferation of A2780 ovarian cells (IC 50  = 13 nM) in lipid-reduced serum (LRS). This cellular activity can be rescued by addition of palmitate, consistent with an on-target effect. Compound 34 is also active in many other cell types, including PC3M (IC 50  = 25 nM) and LnCaP-Vancouver prostate cells (IC 50  = 66 nM), and is highly bioavailable (F 61%) with good exposure after oral administration. In a pharmacodynamics study in H460 lung xenograft-bearing mice, oral treatment with compound 34 results in elevated tumor levels of malonyl-CoA and decreased tumor levels of palmitate, fully consistent with the desired target engagement. [ABSTRACT FROM AUTHOR]

To investigate the presence of sub-lethal contaminant effects in flounder (Platichthys flesus) populations in English estuaries, 16 sitesfrom 7 estuaries were sampled in September-December 1997. Determination of hepatic ethoxyresorufin O-deethylase (EROD) activity revealed that significant (p<0.05) induction of the mixed function oxygenase (MFO) system was apparent in flounder from several industrialised estuaries compared to the relatively unpolluted reference site - the Aldeestuary. The estuaries in increasing order of observed mean EROD activity were: Alde, Southampton Water, Humber, Tyne, Wear, Tees, Mersey. No significant gender differences in EROD induction or other measured variables were discovered for any site. Limited analytical data suggest a close link with EROD induction and hepatic polycyclic aromatic hydrocarbons (PAH)/polychlorinated biphenyls (PCB) concentrations but no strong correlations were discovered between EROD activity induction with any other measured variable across all estuaries. However, in the Tyne estuary strong negative correlations were discovered between mean female EROD and female gonado-somatic index (GSI) and femalecondition factor (CF) of r=-0.84 and -0.80, respectively. It is suggested that the `out of season' correlation of reproductive parameterswith EROD could be linked to contaminant interference, perhaps by xeno-oestrogens. It is clear that flounder populations in English industrialised estuaries are exhibiting widespread sub-lethal contaminant effects and more research is essential to understand the potential implications of this for reproduction and disease that could be affecting the future viability of these populations. [ABSTRACT FROM AUTHOR]

Abstract: Optimization through parallel synthesis of a novel series of hepatitis C virus (HCV) NS5B polymerase inhibitors led to the identification of (R)-11-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-10-(6-methylpyridine-2-carbonyl)-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one 11zc and (R)-11-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-10-(2,5-dimethyloxazol-4-carbonyl)-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one 11zk as potent (replicon EC50 =400nM and 270nM, respectively) and selective (CC50 >20μM) inhibitors of HCV replication. These data warrant further lead-optimization efforts. [Copyright &y& Elsevier]

The protein product of an essential gene of unknown function from Streptococcus pneumoniae was expressed and purified for screening in the ThermoFluor® affinity screening assay. This assay can detect ligand binding to proteins of unknown function. The recombinant protein was found to be in a dimeric, native-like folded state and to unfold cooperatively. ThermoFluor was used to screen the protein against a library of 3000 compounds that were specifically selected to provide information about possible biological functions. The results of this screen identified pyridoxal phosphate and pyridoxamine phosphate as equilibrium binding ligands (Kd ∼ 50 pM, Kd ∼2.5 μM, respectively), consistent with an enzymatic cofactor function. Several nucleotides and nucleotide sugars were also identified as ligands of this protein. Sequence comparison with two enzymes of known structure but relatively low overall sequence homology established that several key residues directly involved in pyridoxal phosphate binding were strictly conserved. Screening a collection of generic drugs and natural products identified the antifungal compound canescin A as an irreversible covalent modifier of the enzyme. Our investigation of this protein indicates that its probable biological role is that of a nucleoside diphospho-keto-sugar aminotransferase, although the preferred keto-sugar substrate remains unknown. These experiments demonstrate the utility of a generic affinity-based ligand binding technology in decrypting possible biological functions of a protein, an approach that is both independent of and complementary to existing genomic and proteomic technologies. [ABSTRACT FROM AUTHOR]

Abstract Understanding how species richness is distributed across landscapes and which variables may be used as predictors is important for spatially targeting management interventions. This study uses finely resolved data over a large geographical area to explore relationships between land-use intensity, habitat heterogeneity and species richness of multiple taxa. It aims to identify surrogate landscape metrics, valid for a range of taxa, which can be used to map and monitor High Nature Value farmland (HNV). Results show that variation in species richness is distributed along two axes: land-use intensity and habitat heterogeneity. At low intensity land-use, species rich groups include wetland plants, plant habitat indicators, upland birds and rare invertebrates, whilst richness of other species groups (farmland birds, butterflies, bees) was associated with higher land-use intensity. Habitat heterogeneity (broadleaved woodland connectivity, hedgerows, habitat diversity) was positively related to species richness of many taxa, both generalists (plants, butterflies, bees) and specialists (rare birds, woodland birds, plants, butterflies). The results were used to create maps of HNV farmland. The proportion of semi-natural vegetation is a useful metric for identifying HNV type 1. HNV type 2 (defined as a mosaic of low-intensity habitats and structural elements) is more difficult to predict from surrogate variables, due to complex relationships between biodiversity and habitat heterogeneity and inadequacies of current remotely sensed data. This approach, using fine-scaled field survey data collected at regular intervals, in conjunction with remotely sensed data offers potential for extrapolating modelled results nationally, and importantly, can be used to assess change over time. [ABSTRACT FROM AUTHOR]

Abstract Objectives Mycobacterium chimaera infection following cardiac surgery, due to contaminated cardiopulmonary bypass heater–cooler units, has been reported worldwide. However, the spectrum of clinical disease remains poorly understood. To address this, we report the clinical and laboratory features, treatment and outcome of the first 30 UK cases. Methods Case note review was performed for cases identified retrospectively through outbreak investigations and prospectively through ongoing surveillance. Case definition was Mycobacterium chimaera detected in any clinical specimen, history of cardiothoracic surgery with cardiopulmonary bypass, and compatible clinical presentation. Results Thirty patients were identified (28 with prosthetic material) exhibiting a spectrum of disease including prosthetic valve endocarditis (14/30), sternal wound infection (2/30), aortic graft infection (4/30) and disseminated (non-cardiac) disease (10/30). Patients presented a median of 14 months post surgery (maximum 5 years) most commonly complaining of fever and weight loss. Investigations frequently revealed lymphopenia, thrombocytopenia, liver cholestasis and non-necrotizing granulomatous inflammation. Diagnostic sensitivity for a single mycobacterial blood culture was 68% but increased if multiple samples were sent. In all, 27 patients started macrolide-based combination treatment and 14 had further surgery. To date, 18 patients have died (60%) a median of 30 months (interquartile range 20–39 months) after initial surgery. Survival analysis identified younger age, mitral valve surgery, mechanical valve replacement, higher serum sodium concentration and lower C-reactive protein as factors associated with better survival. Conclusions Mycobacterium chimaera infection following cardiac surgery is associated with a wide spectrum of disease. The diagnosis should be considered in all patients who develop an unexplained illness following cardiac surgery. [ABSTRACT FROM AUTHOR]

4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) is a nucleoside analog that, unlike approved anti-human immunodeficiency virus type 1 (HIV-1) nucleoside reverse transcriptase inhibitors, has a 3'-OH and exhibits remarkable potency against wild-type and drug-resistant HIVs. EFdA triphosphate (EFdATP) is unique among nucleoside reverse transcriptase inhibitors because it inhibits HIV-1 reverse transcriptase (RT) with multiple mechanisms. (a) EFdA-TP can block RT as a translocationdefective RT inhibitor that dramatically slows DNA synthesis, acting as a de facto immediate chain terminator. Although nontranslocated EFdA-MP-terminated primers can be unblocked, they can be efficiently converted back to the EFdA-MP-terminated form. (b) EFdA-TP can function as a delayed chain terminator, allowing incorporation of an additional dNTP before blocking DNA synthesis. In such cases, EFdA-MP-terminated primers are protected from excision. (c) EFdA-MP can be efficiently misincorporated by RT, leading to mismatched primers that are extremely hard to extend and are also protected from excision. The context of template sequence defines the relative contribution of each mechanism and affects the affinity of EFdA-MP for potential incorporation sites, explaining in part the lack of antagonism between EFdA and tenofovir. Changes in the type of nucleotide before EFdA-MP incorporation can alter its mechanism of inhibition from delayed chain terminator to immediate chain terminator. The versatility of EFdA in inhibiting HIV replication by multiple mechanisms may explain why resistance to EFdA is more difficult to emerge. [ABSTRACT FROM AUTHOR]

Abstract: We report heat capacity, thermogravimetry and thermal diffusivity data for carbonized mesophase pitch coated LiFePO4 (LFP) cathodes. The results are compared with the thermophysical properties of a conventional LFP-based electrode having a poly (vinylene) difluoride (PVDF) binder and conductive carbon diluents. The measured heat capacity of LFP as a function of temperature is in good agreement with model calculations based on first-principles methods. Thermal diffusivity data indicate that the mesophase pitch coated LFP compositions have a factor of two higher thermal diffusivity than the conventional electrode composition, suggesting that the coatings improve heat transfer. In the presence of an electrolyte mixture (1.2 M lithium hexa-fluorophosphate), differential scanning calorimetry (DSC) analysis of the LFP–pitch composite and LFP–PVDF–carbon composites showed similar onset temperature and heat evolution. [Copyright &y& Elsevier]

Background: The decision as to whether a patient can tolerate surgery is often subjective and can misjudge a patient's true physiologic state. The concept of frailty is an important assessment tool in the geriatric medical population, but has only recently gained attention in surgical patients. Frailty potentially represents a measureable phenotype, which, if quantified with a standardized protocol, could reliably estimate the risk of adverse surgical outcomes. Study Design: Frailty was prospectively evaluated in the clinic setting in patients consenting for major general, oncologic, and urologic procedures. Evaluation included an established assessment tool (Hopkins Frailty Score), self-administered questionnaires, clinical assessment of performance status, and biochemical measures. Primary outcome was 30-day postoperative complications. Results: There were189 patients evaluated: 117 from urology, 52 from surgical oncology, and 20 from general surgery clinics. Mean age was 62 years, 59.8% were male, and 71.4% were Caucasian. Patients who scored intermediately frail or frail on the Hopkins Frailty Score were more likely to experience postoperative complications (odds ratio [OR] 2.07, 95% CI 1.05 to 4.08, p = 0.036). Of all other preoperative assessment tools, only higher hemoglobin (p = 0.033) had a significant association and was protective for 30-day complications. Conclusions: The aggregate score of patients as “intermediately frail or frail” on the Hopkins Frailty Score was predictive of a patient experiencing a postoperative complication. This preoperative assessment tool may prove beneficial when weighing the risks and benefits of surgery, allowing objective data to guide surgical decision-making and patient counseling. [ABSTRACT FROM AUTHOR]

Background & Aims: TMC435 is a potent, once-daily, investigational hepatitis C virus (HCV) NS3/4A protease inhibitor in phase III clinical development. In the phase II trial TMC435-C202 (NCT00812331), TMC435 displayed potent activity in genotype 4, 5 and 6 patients and in 3/6 genotype 2 patients, whereas no activity was observed with genotype 3. Methods: Thirty-seven patients received TMC435 monotherapy (200mg once daily) for 7days. HCV RNA, NS3 protease sequences and the corresponding phenotypes were evaluated. Results: Genotype and isolate-specific baseline polymorphisms at NS3 positions known to affect HCV protease inhibitor activity were present in all genotypes. Consistent with the antiviral activity observed in genotypes 4 and 6, TMC435 was active in vitro against all genotype 4 isolates, and against most genotype 6 polymorphisms when tested as single or double mutants. In contrast, in genotype 3 where no HCV RNA decline was observed, isolates displayed >700-fold increases in EC50 attributed to the D168Q polymorphism. In genotypes 2 and 5, HCV RNA changes from baseline to Day 3 ranged between −0.3 to −3.6 and −1.5 to −4.0log10 IU/ml, respectively, and isolates or site-directed mutants displayed intermediate in vitro susceptibility to TMC435 with fold changes in EC50 between 15 and 78. Viral breakthrough in genotypes 4–6 was associated with emerging mutations including Q80R, R155K and/or D168E/V. Conclusions: Sequence and phenotypic analyses of baseline isolates identified polymorphisms which could explain the differences in antiviral activity between genotypes. Pathways of TMC435 resistance in genotypes 2–6 were similar to those identified in genotype 1. [ABSTRACT FROM AUTHOR]

Rilpivirine (RPV) is a second generation nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI) that efficiently inhibits HIV-1 resistant to first generation NNRTIs. Virological failure during therapy with RPV and emtricitabine is associated with the appearance of E138K and M184I mutations in RT. Here we investigate the biochemical mechanism of RT inhibition and resistance to RPV. We used two transient kinetics approaches (quench-flow and stopped-flow) to determine how subunit-specific mutations in RT p66 or p51 affect association and dissociation of RPV to RT as well as their impact on binding of dNTP and DNA and the catalytic incorporation of nucleotide. We comparedWTwith four subunit-specificRTmutants, p66M184I/p51WT, p66E138K/p51E138K, p66E138K/M184I/p51E138K, and p66M184I/p51E138K. Ile-184 in p66 (p66184I) decreased the catalytic efficiency of RT (kpol/Kd.dNTP), primarily through a decrease in dNTP binding (Kd.dNTP). Lys-138 either in both subunits or in p51 alone abrogated the negative effect of p66184I by restoring dNTP binding. Furthermore, p51138K reduced RPV susceptibility by altering the ratio of RPV dissociation to RPV association, resulting in a net reduction in RPV equilibrium binding affinity (Kd.RPV = koff.RPV/kon.RPV). Quantum mechanics/ molecular mechanics hybrid molecular modeling revealed that p51E138K affects access to the RPV binding site by disrupting the salt bridge between p51E138 and p66K101. p66184I caused repositioning of the Tyr-183 active site residue and decreased the efficiency of RT, whereas the addition of p51138K restored Tyr-183 to a WT-like conformation, thus abrogating the Ile- 184-induced functional defects. [ABSTRACT FROM AUTHOR]