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Background and Purpose: Development of core concepts in disciplines such as biochemistry, microbiology and physiology have transformed teaching. They provide the foundation for the development of teaching resources for global educators, as well as valid and reliable approaches to assessment. An international research consensus recently identified 25 core concepts of pharmacology. The current study aimed to define and unpack these concepts. Experimental Approach: A two‐phase, iterative approach, involving 60 international pharmacology education experts, was used. The first phase involved drafting definitions for core concepts and identifying key sub‐concepts via a series of online meetings and asynchronous work. These were refined in the second phase, through a 2‐day hybrid workshop followed by a further series of online meetings and asynchronous work. Key Results: The project produced consensus definitions for a final list of 24 core concepts and 103 sub‐concepts of pharmacology. The iterative, discursive methodology resulted in modification of concepts from the original study, including change of 'drug–receptor interaction' to 'drug–target interaction' and the change of the core concept 'agonists and antagonists' to sub‐concepts of drug–target interaction. Conclusions and Implications: Definitions and sub‐concepts of 24 core concepts provide an evidence‐based foundation for pharmacology curricula development and evaluation. The next steps for this project include the development of a concept inventory to assess acquisition of concepts, as well as the development of case studies and educational resources to support teaching by the global pharmacology community, and student learning of the most critical and fundamental concepts of the discipline. [ABSTRACT FROM AUTHOR]

Background: Understanding the natural history of developmental speech and language impairments can support the selection of children whose difficulties are persistent rather than transitory. It can also provide information against which the effectiveness of intervention can be evaluated. However, natural history data are difficult to collect ethically. Furthermore, as soon as an impairment is identified, the behaviour of those around changes, thus creating some level of intervention. Longitudinal cohort studies, where intervention is minimal, or the control arm of randomized trials have provided the best evidence. However, occasional opportunities arise where service waiting lists can provide data about the progress of children who have not received intervention. This natural history study arose within an ethnically diverse, community paediatric speech and language therapy service in the UK where levels of social disadvantage are high. Aims: To identify (1) the characteristics of the children who attended initial assessment and were selected for treatment; (2) the differences between children who did and did not attend reassessment; and (3) the factors associated with outcomes. Methods & Procedures: A cohort of 545 children were referred and assessed as in need of therapy. Due to resource constraints, intervention was not available for an average of 12 months. Children were invited to attend for a reassessment of need. Initial and follow‐up assessments were conducted by experienced clinicians using service guidelines and the Therapy Outcomes Measures Impairment Scale (TOM‐I). Descriptive and multivariate regression analyses examined child outcomes for changes in communication impairment, demographic factors and length of wait. Outcomes & Results: At initial assessment, 55% of children presented with severe and profound communication impairments. Children offered appointments at clinics in areas of high social disadvantage were less likely to attend reassessment. By reassessment, 54% of children showed spontaneous improvement (mean TOM‐I rating change = 0.58). However, 83% were still judged to require therapy. Approximately 20% of children changed their diagnostic category. Age and impairment severity at initial assessment were the best predictors of continuing requirement for input. Conclusions & Implications: Although children do make spontaneous progress post‐assessment and without intervention, it is likely that the majority will continue to be assigned case status by a Speech and Language Therapist. However, when evaluating the effectiveness of interventions, clinicians need to factor in the progress that a proportion of the caseload will make spontaneously. Services should be mindful that a lengthy wait may disproportionately impact children who already face health and educational inequalities. What This Paper Adds: What is already known on the subject: Data from longitudinal cohorts (where intervention has been minimal) and the no treatment control arms of randomized controlled trials have provided the best evidence of the natural progression of speech and language impairments in children. These studies provide a varied rate of resolution and progress depending on the case definitions and measurements used. What this study adds to existing knowledge: Uniquely, this study has evaluated the natural history of a large cohort of children who had been waiting for treatment for up to 18 months. Data showed that, over a period of waiting for intervention, the majority of those identified as a case by a Speech and Language Therapist remained a case. Using the TOM, on average children in the cohort made just over half a rating point progress during their waiting period. What are the potential or actual clinical implications of this work?: The maintenance of treatment waiting lists is probably an unhelpful service strategy for two reasons: first, the case status of the majority of the children is unlikely to change whilst they await intervention and thus children and their families are subjected to further limbo waiting time; second, the dropout from the waiting list may disproportionately affect children who are offered appointments in clinics where there are higher levels of social disadvantage, thus exacerbating inequalities in the system. Currently, a suggested reasonable outcome of intervention is a 0.5 rating change in one domain of TOMs. Study findings suggest this is insufficiently stringent for a paediatric community clinic caseload. There is a need to evaluate spontaneous improvement which may occur in other TOM domains (i.e., Activity, Participation and Wellbeing) and to agree an appropriate change metric for a community paediatric caseload. [ABSTRACT FROM AUTHOR]

This study sought to examine differences in measures of intense periods of physical performance during competitive match-play, between one-match (1 match weeks) and two-match microcycles (2 match week). 1, 3 and 5 min "peak" and mean averages for total distance (TD), high-speed running (HSR) and metabolic power (MP) were analysed for each 15 min period of match-play. Linear mixed models were employed to examine the differences in dependent variables for each method of measurement between the 1 and 2 game microcycles. No differences were reported for "peak" values for all epoch lengths, however, results revealed significantly reduced "average" values, during periods of fixture congestion, for 1, 3 and 5 min epochs for average TD, and 3 min epochs for average HSR towards the end of the match (75–90 min split). There was, however, a trend for the opposite response to occur in the 60–75-min period. The current data suggests that players potentially display altered pacing strategies during periods of fixture congestion, with these observed responses being dependent on sampling method and epoch length. [ABSTRACT FROM AUTHOR]

Background: Women considering immediate breast reconstruction require high-quality information about the likely need for secondary reconstruction and the long-term risk of revisional surgery to make fully informed decisions about different reconstructive options. Such data are currently lacking. This study aimed to explore the impact of reconstruction type on the number of revisions and secondary reconstructions performed 3, 5, and 8 years after immediate breast reconstruction in a large population-based cohort. Methods: Women undergoing unilateral mastectomy and immediate breast reconstruction for breast cancer or ductal carcinoma in situ in England between 1 April 2009 and 31 March 2015 were identified from National Health Service Hospital Episode Statistics. Numbers of revisions and secondary reconstructions in women undergoing primary definitive immediate breast reconstruction were compared by procedure type at 3, 5, and 8 years after index surgery. Results: Some 16 897 women underwent immediate breast reconstruction with at least 3 years' follow-up. Of these, 14 069 had a definitive reconstruction with an implant only (5193), latissimus dorsi flap with (3110) or without (2373) an implant, or abdominal free flap (3393). Women undergoing implant-only reconstruction were more likely to require revision, with 69.5 per cent (747 of 1075) undergoing at least one revision by 8 years compared with 49.3 per cent (1568 of 3180) in other reconstruction groups. They were also more likely to undergo secondary reconstruction, with the proportion of women having further reconstructive procedures increasing over time: 12.8 per cent (663 of 5193) at 3 years, 14.3 per cent (535 of 3752) at 5 years, and 17.6 per cent (189 of 1075) at 8 years. Conclusion: Long-term rates of revisions and secondary reconstructions were considerably higher after primary implant-based reconstruction than autologous procedures. These results should be shared with patients to support informed decision-making. [ABSTRACT FROM AUTHOR]

Background and Purpose: In recent decades, a focus on the most critical and fundamental concepts has proven highly advantageous to students and educators in many science disciplines. Pharmacology, unlike microbiology, biochemistry, or physiology, lacks a consensus list of such core concepts. Experimental Approach: We sought to develop a research‐based, globally relevant list of core concepts that all students completing a foundational pharmacology course should master. This two‐part project consisted of exploratory and refinement phases. The exploratory phase involved empirical data mining of the introductory sections of five key textbooks, in parallel with an online survey of over 200 pharmacology educators from 17 countries across six continents. The refinement phase involved three Delphi rounds involving 24 experts from 15 countries across six continents. Key Results: The exploratory phase resulted in a consolidated list of 74 candidate core concepts. In the refinement phase, the expert group produced a consensus list of 25 core concepts of pharmacology. Conclusion and Implications: This list will allow pharmacology educators everywhere to focus their efforts on the conceptual knowledge perceived to matter most by experts within the discipline. Next steps for this project include defining and unpacking each core concept and developing resources to help pharmacology educators globally teach and assess these concepts within their educational contexts. [ABSTRACT FROM AUTHOR]

Passive acoustic inversion techniques for measuring gas flux into the water column have the potential to be a powerful tool for the long-term monitoring and quantification of natural marine seeps and anthropogenic emissions. Prior inversion techniques have had limited precision due to lack of constraints on the initial amplitude of a bubble's excitation following its release into the water column ( R ε 0 i ). R ε 0 i is determined by observing the acoustic signal of bubbles released from sediment in a controlled experiment and its use is demonstrated by quantifying the flux from a volcanic CO2 seep offshore Panarea (Italy), improving the precision by 78%. [ABSTRACT FROM AUTHOR]

The Correspondence of Charles Darwin will be completed in 2022. This essay looks briefly at the history of editing Darwin and compares the modern edition with the Victorian practice of narrating an exemplary life through letters, with commemorative volumes produced by a family member or friend and private material carefully selected to document personal character. How is a scientific life composed? What kind of character is expressed in scientific work? [ABSTRACT FROM AUTHOR]

The maneuvering characteristics of a surface ship play a critical role in the safety of navigation both in port and in an open seaway, and are vital to the overall operational ability of the ship. The vast majority of maneuvering analyses for ships have been performed under the assumption of calm water, yet ships mostly operate in waves. Understanding of maneuvering in waves is limited by the complexity of the problem and the challenges of performing physical experiments and numerical simulations. In this work, a new fast-running method that allows for the study of maneuvering in waves is formulated. The newly formulated approach is categorized as a "hybrid method," taking its name from the multiple numerical methods and force models used to predict the total hydrodynamic force acting on the vessel maneuvering in waves. The framework presented here uses a combination of Computational Fluid Dynamics, a linear time-domain boundary element method, and a propeller-force model for efficient computation of the total hydrodynamic force. [ABSTRACT FROM AUTHOR]

Traumatic brain injury is a leading cause of death and disability worldwide. Interventions that mitigate secondary brain injury have the potential to improve outcomes for patients and reduce the impact on communities and society. Increased circulating catecholamines are associated with worse outcomes and there are supportive animal data and indications in human studies of benefit from beta-blockade after severe traumatic brain injury. Here, we present the protocol for a dose-finding study using esmolol in adults commenced within 24 h of severe traumatic brain injury. Esmolol has practical advantages and theoretical benefits as a neuroprotective agent in this setting, but these must be balanced against the known risk of secondary injury from hypotension. The aim of this study is to determine a dose schedule for esmolol, using the continual reassessment method, that combines a clinically significant reduction in heart rate as a surrogate for catecholamine drive with maintenance of cerebral perfusion pressure. The maximum tolerated dosing schedule for esmolol can then be tested for patient benefit in subsequent randomized controlled trials. Trial registration ISRCTN, ISRCTN11038397, registered retrospectively 07/01/2021 https://www.isrctn.com/ISRCTN11038397 [ABSTRACT FROM AUTHOR]

It has long been understood that the North Atlantic Oscillation (NAO) is a key driver of regional climate in Great Britain and across Europe. However, studies have also noted that there is spatio-temporal variability in NAO-rainfall signatures which arguably limits its practical inclusion in water management. In this study we quantify, at high spatio-temporal resolution, the influence of a broader set of atmospheric circulations on monthly precipitation. Using Standardised Precipitation Indices for the Integrated Hydrological Unit (IHU) Groups of Great Britain we apply univariate and multivariate regression models to understand the potential of five atmospheric circulation indices to explain precipitation variability. As far as we are aware this represents the first high spatial and temporal resolution analysis quantifying the influence of a broad set of atmospheric circulations, both individually and in combination. We highlight the influence of each circulation and establish that the NAO only partially explains precipitation variability, especially in the southern regions and during the summer months, where circulations, such as the East Atlantic Pattern, also have an important influence. In summary, we suggest that there is significant explanatory value in looking beyond the NAO when seeking to understand hydroclimatological variability in Great Britain, and there is potential for future work to explore how this understanding can translate into the practical application of atmospheric circulation indices in water management. [ABSTRACT FROM AUTHOR]

This article reports on a U.K. research study encompassing two surveys which used evidence-based scales of awareness, confidence to intervene, and intervention opportunities and action regarding sexual and domestic abuse on campus. They were sent to all first-year incoming undergraduates (> n = 7,000) at one post-1992 U.K. university and received n = 1,604 responses. The study finds that survey respondents demonstrated low awareness of sexual and domestic abuse as a problem on campus. In the analysis of Survey 2, respondents were divided into three groups, those receiving active intervention, passive intervention, and no intervention from a university social norms marketing campaign challenging abuse on campus. The study drives the field forward by considering how confidence to act mediates the relationship between awareness and positive action. It finds associations between active intervention and raised awareness that is not noted in passive or no intervention. Active intervention potentially brings together the mediating variable of confidence where awareness + confidence = positive action. This article makes recommendations for first-year incoming undergraduates to receive awareness raising information about sexual and domestic abuse, prior to coming to university. Universities may also consider working with schools to counter a lack of awareness, which may emanate from normalization discourses learnt prior to coming to university and perpetuated once there. Managing low awareness of sexual and domestic abuse should be a priority of bystander programs and some form of active intervention is potentially beneficial as early as possible in university student journeys. [ABSTRACT FROM AUTHOR]

Use of herbal medications and supplements has experienced immense growth over the last two decades, with retail sales in the USA exceeding $13 billion in 2021. Since the Dietary Supplement Health and Education Act (DSHEA) of 1994 reduced FDA oversight, these products have become less regulated. Data from 2012 shows 18% of U.S. adults used non-vitamin, non-mineral natural products. Prevalence varies regionally, with higher use in Western states. Among preoperative patients, the most commonly used herbal medications included garlic, ginseng, ginkgo, St. John's wort, and echinacea. However, 50–70% of surgical patients fail to disclose their use of herbal medications to their physicians, and most fail to discontinue them preoperatively. Since herbal medications can interact with anesthetic medications administered during surgery, the American Society of Anesthesiologists (ASA) and the American Association of Nurse Anesthetists (AANA) recommend stopping herbal medications 1–2 weeks before elective surgical procedures. Potential adverse drug effects related to preoperative use of herbal medications involve the coagulation system (e.g., increasing the risk of perioperative bleeding), the cardiovascular system (e.g., arrhythmias, hypotension, hypertension), the central nervous system (e.g., sedation, confusion, seizures), pulmonary (e.g., coughing, bronchospasm), renal (e.g., diuresis) and endocrine-metabolic (e.g., hepatic dysfunction, altered metabolism of anesthetic drugs). During the preoperative evaluation, anesthesiologists should inquire about the use of herbal medications to anticipate potential adverse drug interactions during the perioperative period. • This review article summarizes the pharmacologic effects and side effects of the most commonly used herbal medications. • Adverse side effects and potential drug interactions between herbal medications used by patients in the preoperative period. • This review provides anesthesia providers with a concise summary of the available pharmacologic data on herbal medications. • Limited scientific evidence in medical literature on herbal medication effects and dosages concerns anesthesia practitioners. • A lack of standardization in the manufacturing/marketing of herbal products also remains a concern for anesthesia providers. [ABSTRACT FROM AUTHOR]

Pharmacology education currently lacks an agreed knowledge curriculum. Evidence from physics and biology education indicates that core concepts are useful and effective structures around which such a curriculum can be designed to facilitate student learning. Building on previous work, we developed a novel, criterion‐based method to identify the core concepts of pharmacology education. Five novel criteria were developed, based on a literature search, to separate core concepts in pharmacology from topics and facts. Core concepts were agreed to be big ideas, enduring, difficult, applicable across contexts, and useful to solve problems. An exploratory survey of 33 pharmacology educators from Australia and New Zealand produced 109 terms, which were reduced to a working list of 26 concepts during an online workshop. Next, an expert group of 12 educators refined the working list to 19 concepts, by applying the five criteria and consolidating synonyms, and added three additional concepts that emerged during discussions. A confirmatory survey of a larger group resulted in 17 core concepts of pharmacology education. This list may be useful for educators to evaluate existing curricula, design new curricula, and to inform the development of a concept inventory to test attainment of the core concepts in pharmacology.Over 50 pharmacology educators from Australia and New Zealand worked together to identify the core concepts of pharmacology education. The figure shows the 19 concepts identified and the process taken to produce this list [ABSTRACT FROM AUTHOR]

Dynamics in complexes of porphyrin cage compounds and viologen‐derived guest molecules are investigated by selective exchange NMR spectroscopy (1D EXSY). Exchange rates were found to be independent of excess guest concentration, revealing a dissociative exchange mechanism, which is accompanied by negative activation entropies, indicating significant reorganization of the host–guest complex during dissociation. Nonsymmetric viologen guests with bulky head groups had more unidirectional binding and slower exchange rates than guests with less‐bulky head groups. Thermodynamic and kinetic studies revealed that the exchange process is primarily driven by the thermodynamics of binding and that guest binding can be influenced by introducing steric and electronic groups on the host. Exchange studies with guests bearing a polymer chain revealed that both slippage and full dissociation takes place and the rate constants for both processes were determined. The slippage rate constant revealed that for smaller guests exchange takes place nearly exclusively under thermodynamic control. [ABSTRACT FROM AUTHOR]

Dynamics in complexes of porphyrin cage compounds and viologen‐derived guest molecules are investigated by selective exchange NMR spectroscopy (1D EXSY). Exchange rates were found to be independent of excess guest concentration, revealing a dissociative exchange mechanism, which is accompanied by negative activation entropies, indicating significant reorganization of the host–guest complex during dissociation. Nonsymmetric viologen guests with bulky head groups had more unidirectional binding and slower exchange rates than guests with less‐bulky head groups. Thermodynamic and kinetic studies revealed that the exchange process is primarily driven by the thermodynamics of binding and that guest binding can be influenced by introducing steric and electronic groups on the host. Exchange studies with guests bearing a polymer chain revealed that both slippage and full dissociation takes place and the rate constants for both processes were determined. The slippage rate constant revealed that for smaller guests exchange takes place nearly exclusively under thermodynamic control. [ABSTRACT FROM AUTHOR]

Background: One of the most common congenital conditions in the world, cleft lip and/or palate (CL/P) has been shown to potentially impact long‐term physical and developmental outcomes in affected children. However, little is known about the factors that contribute to such outcomes, and there is a lack of consensus about which screening tools may be most effective. The aims of the current study were (a) to assess parent‐reported socioemotional and cognitive development in children born with CL/P at 18 months of age; (b) to identify factors associated with the incidence of developmental concerns; and (c) to assess the utility of the widely recommended Ages and Stages Questionnaires (ASQs) in identifying developmental concerns from an early age in the CL/P population. Methods: Parent‐reported questionnaire data were extracted from The Cleft Collective Cohort Study for 322 mothers of children with CL/P aged 18 months. Results: Mean scores across both ASQ measures indicated typical development in the study sample overall. However, 31.1% of children met a referral criterion on at least one domain. Child‐related risk factors included problems with physical development and feeding method. Parent‐related risk factors included the mother's levels of anxiety and depression and mother's marital status. Additional developmental concerns extracted from mothers' qualitative data included feeding difficulties, speech development, sleep patterns, aggressive behaviours, vision, oral health, hearing, breathing and motor skills. Conclusions: The majority of children in this study were developing as expected at 18 months of age. However, parent‐reported developmental concerns were identified in a minority of children, suggesting a need to screen for potential risk factors in routine practice. Further, the ASQ appears to offer a viable option in the early identification of developmental concerns in children with CL/P. A combined medical and systemic approach to healthcare is recommended to support the prevention of long‐term developmental concerns in the child and poor psychological adjustment in parents. [ABSTRACT FROM AUTHOR]

Understanding how collective behaviour of animals is influenced by anthropogenic activity is important for their conservation in an increasingly urbanised world. River infrastructure, e.g. for transport and electricity generation, and associated construction and operation, produces sound that can disrupt ecological processes.Adopting a reductionist manipulative experimental approach using Eurasian minnow (Phoxinus phoxinus) as a model shoaling species, we compared the response of individuals and groups of five fish to a broadband acoustic stimulus in a tank containing still water.Four metrics were calculated 10 min immediately before (control–sound stimulus absent) and during the acoustic treatment: (1) swimming speed, (2) persistence of swim paths, (3) cohesion of the group, and (4) orientation of group members.On presentation of the stimulus, groups exhibited a consistent escape response compared to individuals for which behaviour was more variable. Thereafter, individuals swam faster and their swim paths were less persistent than during the control; no difference was observed for groups. Conversely, group integrity became more cohesive and members were more likely to orient in a common direction during the treatment compared to the control.This study provides insight into the importance of collective behaviour of fish in relation to antipredator‐like response to anthropogenic noise. Short‐term shifts in behaviour are context specific and depend on whether fish are members of a shoal or solitary. The results indicate the potential for negative impacts of unnatural sound on the ecology of shoaling species that inhabit engineered freshwater environments. [ABSTRACT FROM AUTHOR]

The need for automated methods to detect and extract marine mammal vocalizations from acoustic data has increased in the last few decades due to the increased availability of long-term recording systems. Automated dolphin whistle extraction represents a challenging problem due to the time-varying number of overlapping whistles present in, potentially, noisy recordings. Typical methods utilize image processing techniques or single target tracking, but often result in fragmentation of whistle contours and/or partial whistle detection. This study casts the problem into a more general statistical multi-target tracking framework and uses the probability hypothesis density filter as a practical approximation to the optimal Bayesian multi-target filter. In particular, a particle version, referred to as a sequential Monte Carlo probability hypothesis density (SMC-PHD) filter, is adapted for frequency tracking and specific models are developed for this application. Based on these models, two versions of the SMC-PHD filter are proposed and the performance of these versions is investigated on an extensive real-world dataset of dolphin acoustic recordings. The proposed filters are shown to be efficient tools for automated extraction of whistles, suitable for realtime implementation. [ABSTRACT FROM AUTHOR]

On 1 January 1582 the poet and scholar Jean Passerat (1534–1602) sent a gift to his patron Henri de Mesmes: a poem in Latin hexameters about nothing ("De nihilo"). It became a literary sensation, prompting, over the next decades, a long and varied sequence of poetic and prose responses in Latin and vernacular languages by various authors competing to out-do Passerat, and one another, in ingenuity. Why did this poem catch the imagination of so many as the sixteenth century turned into the seventeenth? This article offers the first complete account of the 'Nothing' phenomenon, as it passed between multiple languages, literary genres and cultural contexts. It traces its dissemination via networks linked to institutions of learning, to academies and salons, to patrons and to coteries of poets. Focusing on the French context in particular, it then goes on to argue that the literary and political significance of these texts is greater than has hitherto been recognized. [ABSTRACT FROM AUTHOR]

The discovery of novel corrosion inhibitors for solution and coating applications is still an empirical process because of the large number of parameters that impact efficacy and the varied environmental conditions in which inhibitors are deployed. Moreover, conventional methods such as electrochemical and analytical techniques, and coating standard specifications can be extremely end-use focused, time and material intensive, and costly, making it prohibitive to screen new materials quickly at early stages of the discovery process. In an effort to address these challenges, we have continued to develop and deploy models and assays that can assist in accelerating the materials discovery process around novel corrosion inhibitors for different metals. In this paper we present how computational modelling, coupled with high-throughput optical and high-throughput electrochemical solution and coating assays, can be powerful tools that allow the rapid identification of prime candidates for further study. These experimental techniques are consistent with conventional % inhibition efficiency and neutral salt spray measurements, and provide additional and insightful information that cannot be easily or quickly obtained by traditional methods. Information extracted from the study of these chromium-based and small organic heterocyclic compounds reveals interesting structure–activity and structure–property relationships that will be applied in the design and discovery of new corrosion inhibitors. [ABSTRACT FROM AUTHOR]

Unlike clinicians, no established competency framework or career pathway exists for the non-clinical workforce from which to establish formal training. This study tests the feasibility of implementing what the authors believe is the first competency framework of its kind for the non-clinical workforce, at level two of a four-tiered career pathway. Level two includes care navigation and signposting roles, capable of reducing clinical workload and improving patient care. Five Community Education Provider Networks (CEPNs) in South London collaborated to deliver training using the competency framework developed by OHSEL. They recruited employees from community health and social care providers, with predominant interest from primary care. Training included Apprenticeships and CEPN-developed modular training. Results for this largely part-time workforce identified enthusiasm for learning; increased confidence and commitment; a desire for career progression and preference for flexible training with skills directly usable at work. Workplace findings included the need for manager training in coaching and mentoring to support employees implementing new skills, and willingness from clinicians and managers to embrace new roles. Feedback was overwhelmingly positive with outcomes used to develop on-line accredited training. Larger studies are needed to confirm the impact on clinical time and patient care. [ABSTRACT FROM AUTHOR]

The use of polymeric nanoparticles (NPs) as therapeutics has been steadily increasing over past decades. In vivo imaging of NPs is necessary to advance the therapeutic performance. 19F Magnetic Resonance Imaging (19F MRI) offers multiple advantages for in vivo imaging. However, design of a probe for both biodistribution and degradation has not been realized yet. We developed polymeric NPs loaded with two fluorocarbons as promising imaging tools to monitor NP biodistribution and degradation by 19F MRI. These 200 nm NPs consist of poly(lactic- co -glycolic acid) (PLGA) loaded with perfluoro-15-crown-5 ether (PFCE) and PERFECTA. PERFECTA/PFCE-PLGA NPs have a fractal sphere structure, in which both fluorocarbons are distributed in the polymeric matrix of the fractal building blocks, which differs from PFCE-PLGA NPs and is unique for fluorocarbon-loaded colloids. This structure leads to changes of magnetic resonance properties of both fluorocarbons after hydrolysis of NPs. PERFECTA/PFCE-PLGA NPs are colloidally stable in serum and biocompatible. Both fluorocarbons show a single resonance in 19F MRI that can be imaged separately using different excitation pulses. In the future, these findings may be used for biodistribution and degradation studies of NPs by 19F MRI in vivo using "two color" labeling leading to improvement of drug delivery agents. [ABSTRACT FROM AUTHOR]

We report synthesis and enzymatic assays on human histone lysine methyltransferase catalysed methylation of histones that possess lysine and its geometrically constrained analogues containing rigid (E)-alkene (KE), (Z)-alkene (KZ) and alkyne (Kyne) moieties. Methyltransferases G9a and GLP do have a capacity to catalyse methylation in the order K ≫; KE > KZ ∼ Kyne, whereas monomethyltransferase SETD8 catalyses only methylation of K and KE. [ABSTRACT FROM AUTHOR]

Behavioral guidance systems are commonly used in freshwater fish conservation. The biological relevance of sound to fish and recorded responses to human-generated noise supports the viability of the use of acoustics as an effective stimulus in such technologies. Relatively little information exists on the long-term responses and recovery of fish to repeated acoustic exposures. In a controlled laboratory study, the response and tolerance of Eurasian minnow (Phoxinus phoxinus) shoals to tonal signals (150 Hz of 1 s pulse duration) differing only in temporal characteristics ("continuous," "slow," "intermediate," or "fast" pulse repetition rate) were investigated. In comparison to independent control groups, fish increased their mean group swimming speed, decreased inter-individual distance, and became more aligned in response to the onset of all four acoustic treatments. The magnitude of response, and time taken to develop a tolerance to a treatment differed according to pulse repetition rate. Groups were found to have the greatest and longest lasting response to tone sequences tested in this study when they were pulsed at an intermediate rate of 0.2 s−1. This study illustrates the importance of understanding the response of fish to acoustic signals, and will assist toward the development of longer-term effective acoustic guidance systems. [ABSTRACT FROM AUTHOR]

European eel, Anguilla anguilla (L.), is vulnerable to entrainment at a variety of man‐made intakes, including those that lead to hydropower turbines or other abstraction points. Two experiments were conducted to investigate the potential for acoustic stimuli to improve the efficiency of a vertical bar screen to guide downstream moving eel. Three underwater speakers were installed along the channel wall of an external flume, upstream of the screen. In the first experiment (a), screen guidance efficiency recorded in the presence (treatment) and absence (control) of a continuous broadband stimulus was individually compared between fish from two respective groups. Adopting a "before‐after" design, the second experiment (b) assessed individually the guidance of control eels from the group previously used in experiment 1 when exposed to a 100 Hz pulse. The majority of eels reached the bypass in both experiments with only three passing through the screen during the controls against one during each acoustic treatment. Rejection of the area adjacent to the speakers was more common during the acoustic treatment, with eels moving past the speakers more rapidly in the presence of sound. The results suggest that employing acoustic stimuli enhances the guidance efficiency of physical screens. [ABSTRACT FROM AUTHOR]

Underwater noise from commercial shipping throughout the oceans has been increasing over the past decades and the environmental impact of this noise remains an area of great uncertainty. This has led to the measurement of noise from commercial vessels in order to understand the impacts that these vessels may engender. Hydrofoils are used by ferries in various locations around the world and locally may be a significant contributing factor of the soundscape. However, the investigation on underwater radiated noise from the activity of hydrofoils in the field has not been widely conducted. This article is an attempt to characterize the noise from hydrofoils in the field. Detailed measurements in the coastal water close to the Panarea port, Italy are reported. The investigation describes the broadband frequency spectrum with the main energy approximately centered on 30–130 Hz but covering frequencies up to tens of kHz. A key result was that the spectrum of the noise varied between the three stages (displacement, transition, and foiling) of the hydrofoils heading into or out of the port. [ABSTRACT FROM AUTHOR]

While the governance of the Internet is often assumed to be merely a technical matter, it is actually a fiercely contested political arena, in which institutional arrangements are still being shaped. This paper aims to demonstrate how, and why, the politics surrounding Internet governance are of significance for international peace and stability. The Internet has great potential as a facilitator of the peacebuilding process, but it can also be used as a tool of oppression, a channel for disinformation and propaganda, and even as a means of waging war. The institutions that are built around Internet governance will determine in whose hands ultimate control of the network will lie, and will ultimately decide whether the Internet is to be a vehicle of human liberation and peacebuilding, or a tool of oppression and conflict. To accomplish the latter, there is a need to move away from traditional state‐based assumptions around global governance and security. [ABSTRACT FROM AUTHOR]

In 2004, Leighton hypothesized that the acoustic calls emitted by humpback whales when feeding using bubble nets, may enhance the effectiveness of the net in confining prey (such as herring) by forming a "wall of sound" with a quiet zone within. Modelling of the acoustics of this phenomenon was previously restricted to 2D; this paper conducts a 3D model of the propagation of signals resembling those emitted by humpback whales when bubble netting, projected into an upward spiral bubble net which data to date suggest is the accurate form for the bubble net in 3D space. In this study, the feeding calls were analyzed in the time-frequency domain to extract acoustic information sufficient to allow modeling of the resulting spatial distribution of acoustic pressure and particle velocity, and how they vary over the duration of the call. Sound propagation in the bubble net was described by using a linear steady-state formulation for an effective medium of bubbly water. Using the predicted attenuation, phase velocity and density in bubbly water, a 3D finite element model was constructed to numerically simulate the upward-spiral bubble net which consists of a mixture of bubbles that exhibit a range of radii. The acoustic pressure field and particle motion field were both calculated within the bubble net. The simulation results show that the energy of the whale feeding call could be effectively focused in the bubble net, generating intensive sound pressure and particle motion fields in the bubbly arm of the net, but with some "quiet" regions closer to the center of the net, as Leighton hypothesized. Furthermore, when the hearing ability of herring is taken into consideration, the results suggest that this acoustic focusing effect could be a plausible factor in trapping them in the bubble net. It also allows speculation on the possible enhancements that the time-varying nature of the call during feeding could give to the whale in this mechanism for the bubble net feeding by humpback whales. [ABSTRACT FROM AUTHOR]

• Direct Black 38 was mutagenic in bone marrow, stomach, small intestine and colon. • Sudan I was mutagenic in bone marrow and bladder. • Para Red was mutagenic in colon, suggesting important role of azo-reduction. • Direct Black 38 and Para Red, but not Sudan I, mutagenic in primary hepatocytes. The mutagenicity of Direct Black 38, Sudan I, and Para Red were evaluated in the in vivo MutaMouse assay and the in vitro MutaMouse primary hepatocyte (PH) assay. Direct Black 38 is an International Agency for Research on Cancer (IARC) Group 1 carcinogen and a prototypical benzidine-based azo compound that requires azo-reduction to yield a DNA-reactive metabolite. Sudan I and Para Red are structurally related azo compounds that have been detected as illegal contaminants in foods. Sudan I is an in vivo mutagen, and both it and Para Red are known to be mutagenic in vitro. Sudan I is oxidized by hepatic and/or bladder enzymes to yield a mutagenic metabolite, but little is known about Para Red. In the present study, Direct Black 38 elicited a significant mutagenic response in the bone marrow, glandular stomach, small intestine and colon in vivo , and in PHs in vitro. Sudan I elicited a weak positive response in the bone marrow and a marginally significant treatment effect in the bladder (p = 0.059); it did not elicit a significant response in PHs in vitro. Para Red elicited a positive response in the colon, as well as in PHs in vitro , albeit at a cytotoxic concentration. The findings are well aligned with the known mechanisms of action of Direct Black 38 and Sudan I; they suggest that intestinal azo-reduction plays an important role in the activation of Para Red. The MutaMouse pH results illustrate the ability of this assay to detect chemicals requiring azo-reduction; however, they also demonstrate a gap in applicability domain, as MutaMouse PHs elicit a negative response following exposure to Sudan I. Elucidation of the mechanisms underlying this gap will require further study. [ABSTRACT FROM AUTHOR]

Accurate determination of seabed gas flux is important for understanding natural processes as well as giving confidence that the size of any leaks from marine infrastructure can be properly assessed. Acoustic methods for flux determination require a relatively quiet underwater environment, and can fail when there is too much noise from other natural or anthropogenic sources. This study applies an acoustic monitoring example of seabed gas leakage in terms of sound level intensity, to statistically assess and minimize the impact from oceanic noise on seabed acoustic experiments which require a relative quiet environment. It addresses the question: how far from a source of radiated ambient noise does a recording hydrophone and location of seabed gas need to be so that acoustic methods for remotely determining gas flux are successful. We develop a model to assess impacts of ambient noise under various conditions, incorporating sound/noise sources (seabed gas leaks, sea surface agitation and shipping) and underwater acoustic propagation. The reliability of the model is tested by comparing measured seabed ambient noise in the central North Sea, and the robustness of it is verified by presenting statistical outliers and a receiver operating characteristic (ROC) curve. A range of scenarios are presented for several gas flow rates, which show the threshold of detection when the recording hydrophone is at different distances from the location of seabed gas escape, and competing noise sources (including shipping and surface waves). [ABSTRACT FROM AUTHOR]

Bare board AudioMoth recorders offer a low-cost, open-source solution to passive acoustic monitoring (PAM) but need protecting in an enclosure. We were concerned that the choice of enclosure may alter the spectral characteristics of recordings. We focus on polythene bags as the simplest enclosure and assess how their use affects acoustic metrics. Using an anechoic chamber, a series of pure sinusoidal tones from 100 Hz to 20 kHz were recorded on 10 AudioMoth devices and a calibrated Class 1 sound level meter. The recordings were made on bare board AudioMoth devices, as well as after covering them with different bags. Linear phase finite impulse response filters were designed to replicate the frequency response functions between the incident pressure wave and the recorded signals. We applied these filters to ~1000 sound recordings to assess the effects of the AudioMoth and the bags on 19 acoustic metrics. While bare board AudioMoth showed very consistent spectral responses with accentuation in the higher frequencies, bag enclosures led to significant and erratic attenuation inconsistent between frequencies. Few acoustic metrics were insensitive to this uncertainty, rendering index comparisons unreliable. Biases due to enclosures on PAM devices may need to be considered when choosing appropriate acoustic indices for ecological studies. Archived recordings without adequate metadata may potentially produce biased acoustic index values and should be treated cautiously. [ABSTRACT FROM AUTHOR]

This paper details the development and psychometric validation of the Everyday Colourism Scale (ECS), a measure designed to capture perceived skin shade prejudice from the ingroup (ethnic peers) and the outgroup (White people). The ECS was adapted from the Everyday Discrimination Scale using existing research, expert reviews, and acceptability interviews. Exploratory and confirmatory factor analysis, and reliability and validity analyses were conducted based on responses from 540 people of colour living in the UK. Predictive validity was tested based on data from an additional 201 participants. Results supported a 2-factor model, with good internal and test–retest reliability, and construct validity. Colourism from White people was associated with more frequent experiences of racism, higher internalized colourism, and greater anxiety. Colourism from participants' ethnic peers was associated with lower self-esteem and perceived social support. Findings suggest the ECS is a promising new tool for assessing perceived colourism among a multi-ethnic UK sample. [ABSTRACT FROM AUTHOR]

Background: The overall survival of IDH‐wildtype glioblastoma patients is poor despite best available treatments. There is an urgent need for new biomarkers to inform more precise disease stratification. Previous studies have identified insulin‐like growth factor binding protein‐2 (IGFBP‐2) as a potential biomarker for glioblastoma diagnosis and therapeutic targeting. Other studies have indicated links between the insulin‐like growth factor (IGF) axis and tumorigenic functions of a molecular chaperone glucose related protein of 78 kDa (GRP78). We aimed to interrogate the oncogenic effects of IGFBP‐2 and GRP78 in our glioma stem cell (GSC) lines and clinical cohort. Methods: Immunoblotting, reverse transcription quantitative real‐time PCR were used to quantify protein and mRNA levels derived from GSCs and non‐malignant neural stem cells (NSCs). Microarray analysis was used to compare the differences in IGFBP‐2 (IGFBP‐2) and GRP78 (HSPA5) transcript expression between NSCs, GSCs and adult human cortex samples. Immunohistochemistry was used to quantify IGFBP‐2 and GRP78 expression in IDH‐wildtype glioblastoma tissue sections (n = 92) and clinical implications assessed using survival analysis. Finally, the relationship between IGFBP‐2 and GRP78 was further explored molecularly using coimmunoprecipitation. Results: Here, we demonstrate that IGFBP‐2 and HSPA5 mRNA is overexpressed in GSCs and NSCs in comparison to non‐malignant brain tissue. We also determined a relationship in which G144 and G26 GSCs expressed higher IGFBP‐2 protein and mRNA than GRP78, and this was reversed in mRNA isolated from adult human cortex samples. Clinical cohort analysis revealed that Glioblastomas with high IGFBP‐2 protein expression paired with low GRP78 protein expression were significantly associated with a much shorter survival time (Median = 4 months, p = 0.019) compared with 12‐14 months for any other combination of high/low protein expression. Conclusions: Inverse levels of IGFBP‐2 and GRP78 may be adverse clinical prognostic markers in IDH‐wildtype glioblastoma. Further interrogation of the mechanistic link between IGFBP‐2 and GRP78 may be important for rationalisation of their potential as biomarkers and therapeutic targets. [ABSTRACT FROM AUTHOR]

Objective: To establish the point prevalence of cognitive impairment among a representative group of homeless people in Cairns. The sample included a large number of Aboriginal and/or Torres Strait Islander people. Method: This research was conducted among an opportunistic sample of participants residing in a homeless shelter. An interview administered cross‐sectional survey was conducted with 60 participants over 12 weeks. The Kimberly Indigenous Cognitive Assessment (KICA‐Cog) and a clinical diagnosis by a psychiatrist (using DSM‐V criteria) were used to establish cognitive impairment. The 36‐item version of the World Health Organisation Disability Assessment Survey 2.0 (WHODAS 2.0) was employed to ascertain limitations in daily living activities. Results: Seventy‐five percent of participants were Aboriginal and/or Torres Strait Islander people. Thirty‐five percent of the sample had a cognitive impairment based on the KICA‐cog while over 70% of the sample had a cognitive impairment based on clinical criteria. Being screened for dementia or global cognitive impairment according to the KICA‐Cog was significantly correlated with having greater difficulty across the following WHODAS domains: understanding or communicating, self‐care, and life activities. Conclusions: Many people who are homeless have a cognitive impairment and this impairment impacts their ability to participate in society. A shift in practice is necessary to support homeless populations with a high proportion of Aboriginal and/or Torres Strait Islander people. It is important that culturally appropriate methods—focusing on cognitive health—are employed to support Aboriginal and/or Torres Strait Islander people who are homeless. [ABSTRACT FROM AUTHOR]

The adenosine A 2B receptor (A 2B AR) is one of four adenosine receptor subtypes belonging to the Class A family of G protein-coupled receptors (GPCRs). Until recently, the A 2B AR remained poorly characterised, in part due to its relatively low affinity for the endogenous agonist adenosine and therefore presumed minor physiological significance. However, the substantial increase in extracellular adenosine concentration, the sensitisation of the receptor and the upregulation of A 2B AR expression under conditions of hypoxia and inflammation, suggest the A 2B AR as an exciting therapeutic target in a variety of pathological disease states. Here we discuss the pharmacology of the A 2B AR and outline its role in pathophysiology including ischaemia-reperfusion injury, fibrosis, inflammation and cancer. [ABSTRACT FROM AUTHOR]

Sugarcane grows on over 170,000 ha in the state of Louisiana as part of a sugar industry that generates over $2 billion in annual economic impact. The multipurpose crop produces sugar, molasses, bagasse, boiler fly ash, filter press mud, water, and electricity. As a component of a theoretical bioenergy economy, bagasse and sugarcane itself may find a value-added niche as a renewable feedstock source. The objectives were to characterize yields of 'Ho 02-113' at two locations over 2 years and compare two harvest strategies, green-cane harvest (stalks-only), or complete biomass harvest (intact plants). The first- and second-ratoon crop and the plant-cane and first-ratoon crop were harvested monthly at the Ardoyne Farm or Spanish Trail, respectively. Total biomass yields of 120 Mg ha−1 and up to 35 Mg dry matter (DM) ha−1 at the Ardoyne Farm and total biomass > 140 Mg ha−1 and 50 Mg DM ha−1 at Spanish Trail were observed. Sucrose levels ranging from 2000 to 8000 kg ha−1 were recorded between August and September of each year. However, freezing conditions rapidly reduced sucrose levels from as high as 12,000 kg ha−1 to below detection limits within 60 days. Dry matter energy content of intact plants, stalks, and dry leaves was 17.0, 17.4, and 16.5 kJ g−1, respectively. The overall energy yields were 530 and 620 GJ ha−1 for the Ardoyne Farm and Spanish Trail, respectively. Results demonstrate that Ho 02-113 is a versatile feedstock and can meet sucrose and/or lignocellulosic feedstock needs in areas with temperate to subtropical temperatures. [ABSTRACT FROM AUTHOR]

Highlights • An infrasound (12 Hz) source modified adult eel behaviour during seaward migration. • Eel exhibited longer and more erratic swim paths during operation. • Avoidance was insufficient to reduce overall passage rate at a water intake. • Infrasound may be beneficial in multimodal systems for eel behavioural guidance. Abstract Behavioural guidance technologies that employ stimuli to attract or repel fish offer potential to enhance, or even replace, costly physical and mechanical screens traditionally used to protect fish at river infrastructure such as hydropower and water intakes. At these structures, eel can suffer high rates of damage and mortality if entrained in pumps or turbines, or impinged on screens intended to protect them. This study used acoustic telemetry to quantify the behavioural response of adult European eel (Anguilla anguilla) to infrasound (12 Hz) under field settings. Eel (n = 50) were tracked after release immediately upstream of the forebay of a redundant hydropower facility. An infrasound deterrent located at the water intake either emitted continuously (ON) or was switched OFF. Treatment (ON/OFF) was alternated nightly over 10 consecutive nights with five eel released during a single trial conducted each night. Seventy eight percent of the 41 eel that moved downstream into the forebay passed the intake. Although the infrasound deterrent had no effect on passage rate, fine-scale differences in movement patterns were determined. When the infrasound was ON, eel trajectories were on average over twice as long with frequent erratic turns and milling behaviour (i.e. repeated lateral movements perpendicular to the principal flow direction), and they were less active within the intake channel close to the device. It is important to consider the influence of site characteristics, especially water velocities that dictate the potential for eel to respond to an acoustic field created. Infrasound deterrents that induce avoidance could be used to protect eel, either through enhancing the efficiency of physical screens or as part of multimodel behavioural guidance systems. [ABSTRACT FROM AUTHOR]

We report the face-selective threading of a chiral porphyrin cage compound onto viologen guests that are provided on both ends with substituents of different sizes. Depending on the types of terminal groups on the guest the cage compound orients itself in one of two possible directions. [ABSTRACT FROM AUTHOR]

Fibromyalgia is a chronic musculoskeletal condition characterized by widespread pain in the body and is associated with tender points at the shoulder, back and hip regions. A wide variety of pharmacologic drugs and dietary supplements have been used with limited success in treating the musculoskeletal pain. Early clinical studies with low level laser therapy (LLLT) alone or in combination with drugs commonly used to treat fibromyalgia suggested that LLLT may be effective in reducing musculoskeletal pain and stiffness, as well as the number of tender locations. However, a sham-controlled study reported that LLLT was not significantly better than the sham treatment and kinesiotape. Preliminary studies with high-intensity laser therapy (HILT) suggest that it may be more effective than LLLT for treating chronic pain syndromes. Therefore, we evaluated low (1 W), intermediate (42 W) and high level (75 W) HILT in a woman with long-standing fibromyalgia syndrome which was resistant to both standard pharmacotherapy and treatment in an interdisciplinary pain management program. The patient received a series of treatments with a HILT device (Phoenix Thera-lase) at a wavelength of 1275 nm administered at both the paraspinous region and tender points in the shoulder and hip regions. Although the 1 W treatment produced minimal symptom relief, both the 42 and the 75 W treatments produced a dramatic reduction in her overall pain, improved quality of sleep, and increased her level of physical activity for 4–10 days after these treatment sessions. This case illustrates the potential beneficial effects of using higher power levels of HILT for patients with fibromyalgia syndrome who have failed to respond to conventional interdisciplinary treatment regimens. [ABSTRACT FROM AUTHOR]

A nationwide model of groundwater recharge for New Zealand (NGRM), as described in this paper, demonstrated the benefits of satellite data and global models to improve the spatial definition of recharge and the estimation of recharge uncertainty. NGRM was inspired by the global-scale WaterGAP model but with the key development of rainfall recharge calculation on scales relevant to national- and catchment-scale studies (i.e., a 1 km × 1 km cell size and a monthly timestep in the period 2000-2014) provided by satellite data (i.e., MODIS-derived evapotranspiration, AET and vegetation) in combination with national datasets of rainfall, elevation, soil and geology. The resulting nationwide model calculates groundwater recharge estimates, including their uncertainty, consistent across the country, which makes the model unique compared to all other New Zealand estimates targeted towards groundwater recharge. At the national scale, NGRM estimated an average recharge of 2500 m3/s, or 298 mm/year, with a model uncertainty of 17%. Those results were similar to the WaterGAP model, but the improved input data resulted in better spatial characteristics of recharge estimates. Multiple uncertainty analyses led to these main conclusions: the NGRM model could give valuable initial estimates in data-sparse areas, since it compared well to most ground-observed lysimeter data and local recharge models; and the nationwide input data of rainfall and geology caused the largest uncertainty in the model equation, which revealed that the satellite data could improve spatial characteristics without significantly increasing the uncertainty. Clearly the increasing volume and availability of large-scale satellite data is creating more opportunities for the application of national-scale models at the catchment, and smaller, scales. This should result in improved utility of these models including provision of initial estimates in data-sparse areas. Topics for future collaborative research associated with the NGRM model include: improvement of rainfall-runoff models, establishment of snowmelt and river recharge modules, further improvement of estimates of rainfall and AET, and satellite-derived AET in irrigated areas. Importantly, the quantification of uncertainty, which should be associated with all future models, should give further impetus to field measurements of rainfall recharge for the purpose of model calibration. [ABSTRACT FROM AUTHOR]

Unlike their descendants, mitochondria and plastids, bacteria do not have dedicated protein import systems. However, paradoxically, import of protein bacteriocins, the mechanisms of which are poorly understood, underpins competition among pathogenic and commensal bacteria alike. Here, using X-ray crystallography, isothermal titration calorimetry, confocal fluorescence microscopy, and in vivo photoactivatable cross-linking of stalled translocation intermediates, we demonstrate how the iron transporter FpvAI in the opportunistic pathogen Pseudomonas aeruginosa is hijacked to translocate the bacteriocin pyocin S2 (pyoS2) across the outer membrane (OM). FpvAI is a TonB-dependent transporter (TBDT) that actively imports the small siderophore ferripyoverdine (Fe-Pvd) by coupling to the proton motive force (PMF) via the inner membrane (IM) protein TonB1. The crystal structure of the N-terminal domain of pyoS2 (pyoS2NTD) bound to FpvAI (Kd = 240 pM) reveals that the pyocin mimics Fe-Pvd, inducing the same conformational changes in the receptor. Mimicry leads to fluorescently labeled pyoS2NTD being imported into FpvAI-expressing P. aeruginosa cells by a process analogous to that used by bona fide TBDT ligands. PyoS2NTD induces unfolding by TonB1 of a force-labile portion of the plug domain that normally occludes the central channel of FpvAI. The pyocin is then dragged through this narrow channel following delivery of its own TonB1-binding epitope to the periplasm. Hence, energized nutrient transporters in bacteria also serve as rudimentary protein import systems, which, in the case of FpvAI, results in a protein antibiotic 60-fold bigger than the transporter's natural substrate being translocated across the OM. [ABSTRACT FROM AUTHOR]

A complementary application of three analytical techniques, viz. multidimensional nuclear magnetic resonance spectroscopy (NMR), mass spectrometry (MS), and single-crystal X-ray diffractometry was required to identify and refine two natural products isolated from Millettia versicolor and solvent of crystallization. The two compounds, namely 3-(2 H-1,3-benzodioxol-5-yl)-6-methoxy-8,8-dimethyl-4 H,8 H-pyrano[2,3- h]chromen-4-one, or durmillone, (I), and (2 E)-1-(4-{[(2 E)-3,7-dimethylocta-2,6-dien-1-yl]oxy}-2-hydroxyphenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one, (II), could not be separated by routine column chromatography and cocrystallized in a 2:1 ratio with 0.13 molecules of ethanol solvent. Compound (II) and ethanol could not be initially identified by single-crystal X-ray analysis due to complex disorder in the aliphatic chain region of (II). Mass spectrometry ensured that (II) represented only one species disordered over several positions in the solid state, rather than several species cohabitating on the same crystallographic site. The atomic identification and connectivity in (II) were established by several 2D (two-dimensional) NMR techniques, which in turn relied on a knowledge of its exact mass. The derived connectivity was then used in the single-crystal analysis to model the disorder of the aliphatic chain in (II) over three positions and allowed identification of a partially occupied ethanol solvent molecule that was disordered over an inversion center. The disordered moieties were refined with restraints and constraints. [ABSTRACT FROM AUTHOR]

The ambulatory setting offers potential advantages for elderly patients undergoing elective surgery due to the advancement in both surgical and anesthetic techniques resulting in quicker recovery times, fewer complications, higher patient satisfaction, and reduced costs of care. This review article aims to provide a practical guide to anesthetic management of elderly outpatients. Important considerations in the preoperative evaluation of elderly outpatients with co-existing diseases, as well as the advantages and disadvantages of different anesthetic techniques on a procedural-specific basis, and recommendations regarding the management of common postoperative complications (e.g., pain, postoperative nausea and vomiting [PONV], delirium and cognitive dysfunction, and gastrointestinal dysfunction) are discussed. The role of anesthesiologists as perioperative physicians is important for optimizing surgical outcomes for elderly patients undergoing ambulatory surgery. The implementation of high-quality, evidence-based perioperative care programs for the elderly on an ambulatory basis has assumed increased importance. Optimal management of perioperative pain using opioid-sparing multimodal analgesic techniques and preventing PONV using prophylactic antiemetics are key elements for achieving enhanced recovery after surgery. [ABSTRACT FROM AUTHOR]

Background: A multi-institutional, randomized phase II trial of continuous dosing of dabrafenib with or without trametinib is ongoing in metastatic thyroid cancer. Preclinical evidence and emerging clinical experience in other cancers support evaluating intermittent dosing of these two agents to achieve more durable response, while being better tolerated and more cost effective. Patients: Two consecutive patients with symptomatic, metastatic radioactive iodine-resistant BRAFV600E mutated papillary thyroid cancer and poor performance status were treated initially with dabrafenib 150 mg twice daily plus trametinib 2mg once daily, first in continuous daily dosing, then in a five-week-on and three-week-off schedule. Results: Both patients showed rapid clinical improvement upon starting the regimen. They also noted improved tolerance of treatment upon transitioning to the intermittent dosing schedule. They continue to show evidence of antitumor activity 27 and 18 months respectively from the start of treatment and 15 and 13 months respectively from the start of the first break using intermittent dosing. Conclusions: Achieving durable palliation in these consecutive patients supports evaluating the intermittent dosing schedule of dabrafenib and trametinib in BRAFV600E mutated papillary thyroid cancer. Results of the ongoing phase 3 trial of continuous daily dosing and a subsequent trial of intermittent dosing, as is being tested in other cancers, will be needed to confirm that an intermittent dosing strategy in thyroid cancer can forestall resistant disease, improve tolerability, and decrease the cost of care. [ABSTRACT FROM AUTHOR]