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Summary Background Virtual Surgical Planning (VSP) is increasingly used in maxillomandibular osseous free flap reconstruction. Non-commercial (‘in-house') VSP may offer the same level of accuracy and other benefits, without the inflated costs and time delays inherent in using commercial providers. Comparisons between commercial and in-house methods are lacking. This study aims to determine the accuracy of VSP, comparing in-house and commercially planned cases, and to explore predictors of reconstruction error. Methods 76 patients who had a virtually planned maxillomandibular reconstruction between January 2012 and July 2020 were retrospectively identified. The pre-operative digital plan was compared to the post-operative CT scan in terms of: length of bone segments, angle between adjacent segments and intercondylar and intergonial angle distances (mandibular reconstructions only). Results 44 patients fulfilled the inclusion criteria. The mean intergonial and intercondylar distances error was 1.7 ± 1.01mm, mean segment length error was 1.3 ± 1.40mm, and mean angles error was 1.9 ± 2.32 degrees. The difference in error of in-house VSP compared to commercial VSP was not statistically significant for intercondylar and intergonial distance (p=0.76), segment length (p=0.15), or angle between segments (p=0.92). Increased error was associated with osteoradionecrosis as the indication for surgery, greater number of segments, and secondary reconstructions. Conclusion VSP is an accurate method of maxillary and mandibular reconstruction. In-house VSP may be similar in accuracy to commercial VSP options. Higher levels of inaccuracy are likely to occur in more complex reconstructions, particularly secondary reconstructions, and in the setting of osteoradionecrosis.

This review highlights recent advances in the understanding of eosinophils and eosinophilic diseases, particularly eosinophilic gastrointestinal diseases during the last year. The increasing incidence of diseases marked by eosinophilia has been documented and highlighted the need to understand eosinophil biology and eosinophilic contributions to disease. Significant insight into the nature of eosinophilic diseases has been achieved using next-generation sequencing technologies, proteomic analysis, and machine learning to analyze tissue biopsies. These technologies have elucidated mechanistic underpinnings of eosinophilic inflammation, delineated patient endotypes, and identified patient responses to therapeutic intervention. Importantly, recent clinical studies using monoclonal antibodies that interfere with type 2 cytokine signaling or deplete eosinophils point to multiple and complex roles of eosinophils in tissues. Several studies identified distinct activation features of eosinophils in different tissues and disease states. The confluence of these studies supports a new paradigm of tissue-resident eosinophils that have pro- and anti-inflammatory immunomodulatory roles in allergic disease. Improved understanding of unique eosinophil activation states is now poised to identify novel therapeutic targets for eosinophilic diseases.

Eosinophils accumulate adjacent to epithelial cells in the mucosa of patients with eosinophilic esophagitis (EoE), yet the bidirectional communication between these cells is not well understood. Herein, we investigated the crosstalk between human eosinophils and esophageal epithelial cells. We report that blood-derived eosinophils have prolonged survival when cocultured with epithelial cells; 96 ± 1% and 30 ± 6% viability was observed after 7 and 14 days of coculture, respectively, compared with 1 ± 0% and 0 ± 0% of monoculture. In the presence of IL-13 and epithelial cells, eosinophils had greater survival (68 ± 1%) at 14 days compared with cocultures lacking IL-13. Prolonged eosinophil viability did not require cellular contact and was observed when eosinophils were cultured in conditioned media from esophageal epithelial cells; neutralizing GM-CSF attenuated eosinophil survival. The majority of eosinophil transcripts (58%) were dysregulated in cocultured eosinophils compared with freshly isolated cells. Analysis of epithelial cell transcripts indicated that exposure to eosinophils induced differential expression of a subset of genes that were part of the EoE esophageal transcriptome. Collectively, these results uncover a network of crosstalk between eosinophils and esophageal epithelial cells involving epithelial mediated eosinophil survival and reciprocal changes in cellular transcripts, events likely to occur in EoE.

Digital transformation is rapidly changing the competitive landscape and the war on talent for today’s organizations. As part of this economy, organizations and their HR units must continuously reevaluate leadership structures and practices that exploit core competencies while allowing for innovation (i.e., leadership ambidexterity) and incorporate big data with predictive analytics. In this vein, understanding how HR executives can create better solutions around this problem remains sparse. Specifically, what frameworks can HR executives apply to identify potential alignment failures in leadership succession planning in light of newer emerging markets? What internal decision-making traps need to be recognized? Finally, what specific forms of data and evidence must test these plans for relevance and recharge and renew the talent-to-strategy pipeline? In this article, we examine these questions by reviewing the gaps in the literature and identifying through our four-step model how organizations can incorporate ambidexterity-building as a leadership succession planning practice.

The human-assisted movement of species beyond their native range facilitates novel interactions between invaders and native species that can determine whether an introduced species becomes invasive and the nature of any consequences for native communities. Avoiding costly interactions through recognition and avoidance can be compromised by the naïvety of native species to novel invaders and vice versa. We tested this hypothesis using the common wall lizard, Podarcis muralis, and the native lizard species with which it may now interact in Britain (common lizard, Zootoca vivipara, sand lizard, Lacerta agilis) and on Vancouver Island (northern alligator lizard, Elgaria coerulea) by exploring species' responses (tongue flicks, avoidance behaviour) to heterospecific scent cues in controlled experiments. The tongue flick response of P. muralis depended on the different species’ scent, with significantly more tongue flicks directed to E. coerulea scent than the other species and the control. This recognition did not result in any other behavioural response in P. muralis (i.e. attraction, aggression, avoidance). Lacerta agilis showed a strong recognition response to P. muralis scent, with more tongue flicks occurring close to the treatment stimuli than the control and aggressive behaviour directed towards the scent source. Conversely, Z. vivipara spent less time near P. muralis scent cues than the control but its tongue flick rate was higher towards this scent in this reduced time, consistent with an avoidance response. There was no evidence of E. coerulea recognition of P. muralis scent in terms of tongue flicks or time spent near the stimuli, although the native species did show a preference for P. muralis-scented refuges. Our results suggest a variable response of native species to the scent of P. muralis, from an avoidance response by Z. vivipara that mirrors patterns of exclusion observed in the field to direct aggression observed in L. agilis and an ambiguous reaction from E. coerulea which may reflect a diminished response to a cue with a low associated cost. These results have significant implications for the invasive success and potential impacts of introduced P. muralis populations on native lizards.

Summary Background Sciatica has a substantial impact on individuals and society. Stratified care has been shown to lead to better outcomes among patients with non-specific low back pain, but it has not been tested for sciatica. We aimed to investigate the clinical and cost-effectiveness of stratified care versus non-stratified usual care for patients presenting with sciatica in primary care. Methods We did a two-parallel arm, pragmatic, randomised controlled trial across three centres in the UK (North Staffordshire, North Shropshire/Wales, and Cheshire). Eligible patients were aged 18 years or older, had a clinical diagnosis of sciatica, access to a mobile phone or landline number, were not pregnant, were not currently receiving treatment for the same problem, and had no previous spinal surgery. Patients were recruited from general practices and randomly assigned (1:1) by a remote web-based service to stratified care or usual care, stratified by centre and stratification group allocation. In the stratified care arm, a combination of prognostic and clinical criteria associated with referral to spinal specialist services were used to allocate patients to one of three groups for matched care pathways. Group 1 was offered brief advice and support in up to two physiotherapy sessions; group 2 was offered up to six physiotherapy sessions; and group 3 was fast-tracked to MRI and spinal specialist assessment within 4 weeks of randomisation. The primary outcome was self-reported time to first resolution of sciatica symptoms, defined as “completely recovered” or “much better” on a 6-point ordinal scale, collected via text messages or telephone calls. Analyses were by intention to treat. Health-care costs and cost-effectiveness were also assessed. This trial is registered on the ISRCTN registry, ISRCTN75449581. Findings Between May 28, 2015, and July 18, 2017, 476 patients from 42 general practices around three UK centres were randomly assigned to stratified care or usual care (238 in each arm). For the primary outcome, the overall response rate was 89% (9467 of 10 601 text messages sent; 4688 [88%] of 5310 in the stratified care arm and 4779 [90%] of 5291 in the usual care arm). Median time to symptom resolution was 10 weeks (95% CI 6·4–13·6) in the stratified care arm and 12 weeks (9·4–14·6) in the usual care arm, with the survival analysis showing no significant difference between the arms (hazard ratio 1·14 [95% CI 0·89–1·46]). Stratified care was not cost-effective compared to usual care. Interpretation The stratified care model for patients with sciatica consulting in primary care was not better than usual care for either clinical or health economic outcomes. These results do not support a transition to this stratified care model for patients with sciatica. Funding National Institute for Health Research.

This study argues that several metrics are necessary to build up a picture of yield gain and nitrogen losses for ryegrass sheep pastures. Metrics of resource use efficiency, nitrous oxide emission factor, leached and emitted nitrogen per unit product are used to encompass yield gain and losses relating to nitrogen. These metrics are calculated from field system simulations using the DAYCENT model, validated from field sensor measurements and observations relating to crop yield, fertilizer applied, ammonium in soil and nitrate in soil and water, nitrous oxide and soil moisture. Three ryegrass pastures with traditional management for sheep grazing and silage are studied. As expected, the metrics between long-term ryegrass swards in this study are not very dissimilar. Slight differences between simulations of different field systems likely result from varying soil bulk density, as revealed by a sensitivity analysis applied to DAYCENT. The field with the highest resource use efficiency was also the field with the lowest leached inorganic nitrogen per unit product, and vice versa. Field system simulation using climate projections indicates an increase in nitrogen loss to water and air, with a corresponding increase in biomass. If we simulate both nitrogen loss by leaching and by gaseous emission, we obtain a fuller picture. Under climate projections, the field with the lowest determined nitrous oxide emissions factor, had a relatively high leached nitrogen per product amongst the three fields. When management differences were investigated, the amount of nitrous oxide per unit biomass was found to be significantly higher for an annual management of grazing only, than a silage harvest plus grazing, likely relating to the increased period of livestock on pasture. This work emphasizes how several metrics validated by auto-sampled data provide a measure of nitrogen loss, efficiency and best management practise.

Elements of the new-age sharing economy rely heavily on the internet, and this includes ride and accommodation services. The sharing systems are both online and offline, generating substantial offline outcomes such as access to scarce urban resources like housing and transport. We provide evidence on how sharing economy platforms like Uber and Airbnb in Australia can unevenly allocate scarce urban resources across racial and ethnic groups. The sharing economy transcends the online and offline worlds, encompassing cyber interactions as well as physical exchanges and presence. Access to real worlds scarce urban resources are determined. A geographical research agenda is advocated, including: audit testing for prevalence; case studies for successful anti-racist regulation; and smaller scale analyses of impacts and pro-social action. We review anti-racist regulation within and from outside the platforms, and press the case for new forms of peer and state regulation in an era of roll-out and roll-back neo-liberalism.

Invasive and non-native species can pose risks to vulnerable ecosystems by co-introducing bacterial pathogens. Alternatively, co-introduced bacterial pathogens may regulate invasive population size and invasive traits. We describe a novel candidate genus and species of bacteria (‘Candidatus Aquirickettsiella gammari’) found to infect Gammarus fossarum, from its native range in Poland. The bacterium develops intracellularly within the haemocytes and cells of the musculature, hepatopancreas, connective tissues, nervous system and gonad of the host. The developmental cycle of ‘Candidatus Aquirickettsiella gammari’ includes an elementary body (496.73 nm ± 37.56 nm in length, and 176.89 nm ± 36.29 nm in width), an elliptical, condensed spherical stage (737.61 nm ± 44.51 nm in length and 300.07 nm ± 44.02 nm in width), a divisional stage, and a spherical initial body (1397.59 nm ± 21.26 nm in diameter). We provide a partial genome for ‘Candidatus Aquirickettsiella gammari’, which clades phylogenetically alongside environmental 16S rRNA sequences from aquatic habitats, and bacterial symbionts from aquatic isopods (Asellus aquaticus), grouping separately from the Rickettsiella, a genus that includes bacterial pathogens of terrestrial insects and isopods. Increased understanding of the diversity of symbionts carried by G. fossarum identifies those that might regulate host population size, or those that could pose a risk to native species in the invasive range. Identification of ‘Candidatus Aquirickettsiella gammari’ and its potential for adaptation as a biological control agent is explored.

Background Context\ud Evidence is lacking on the prognosis and prognostic factors of back-related leg pain and sciatica in patients seeing their primary care physicians. This evidence could guide timely appropriate treatment and referral decisions.\ud \ud Purpose\ud The present study aims to describe the prognosis and prognostic factors in primary care patients with low back-related leg pain and sciatica.\ud \ud Study Design\ud This is a prospective cohort study.\ud \ud Patient Sample\ud The present study included adults visiting their family doctor with back-related leg pain in the United Kingdom.\ud \ud Outcome Measures\ud Information about pain, function, psychological, and clinical variables, was collected. Good outcome was defined as 30% or more reduction in disability (Roland-Morris Disability Questionnaire).\ud \ud Methods\ud Participants completed the questionnaires, underwent clinical assessments, received a magnetic resonance imaging scan, and were followed-up 12 months later. Mixed-effects logistic regression evaluated the prognostic value of six a priori defined variable sets (leg pain duration, pain intensity, neuropathic pain, psychological factors, clinical examination, and imaging variables). A combined model, including variables from all models, examined independent effects. The National Institute for Health Research funded the study. There are no conflicts of interest.\ud \ud Results\ud A total of 609 patients were included. At 12 months, 55% of patients improved in both the total sample and the sciatica group. For the whole cohort, longer leg pain duration (odds ratio [OR] 0.41; confidence interval [CI] 0.19–0.90), higher identity score (OR 0.70; CI 0.53–0.93), and patient's belief that the problem will last a long time (OR 0.27; CI 0.13–0.57) were the strongest independent prognostic factors negatively associated with improvement. These last two factors were similarly negatively associated with improvement in the sciatica subgroup.\ud \ud Conclusions\ud The present study provides new evidence on the prognosis and prognostic factors of back-related leg pain and sciatica in primary care. Just over half of patients improved at 12 months. Patient's belief of recovery timescale and number of other symptoms attributed to the pain are independent prognostic factors. These factors can be used to inform and direct decisions about timing and intensity of available therapeutic options.

Polymeric structures fabricated using Fused Filament Fabrication (FFF) suffer from poor inter-laminar fracture toughness. As a result, these materials exhibit only a fraction of the mechanical performance of those manufactured through more traditional means. Here we show that thermal annealing of confined structures manufactured using the FFF technique dramatically increases their inter-laminar toughness. Single Edge Notch Bend (SENB) fracture specimens made from acrylonitrile-butadiene-styrene (ABS) feedstock were isothermally heated in a supporting fixture, post-manufacture, across a range of times and temperatures. Fracture testing was then used to quantify the changes in inter-laminar toughness offered by annealing through measurements of the Mode I critical elastic-plastic strain energy release rate, JIc. Under the most aggressive annealing conditions, the inter-laminar toughness increased by more than 2700% over the non-annealed baseline material. Void migration and aggregation during the annealing process was analyzed using X-ray tomography and provides insight into the toughening mechanisms. Time-scales of reptation and polymer mobility at the interface during annealing are also modeled and agree with fracture experiments.

Summary: The serine/threonine protein phosphatase 5 (PP5) regulates multiple cellular signaling networks. A number of cellular factors, including heat shock protein 90 (Hsp90), promote the activation of PP5. However, it is unclear whether post-translational modifications also influence PP5 phosphatase activity. Here, we show an “on/off switch” mechanism for PP5 regulation. The casein kinase 1δ (CK1δ) phosphorylates T362 in the catalytic domain of PP5, which activates and enhances phosphatase activity independent of Hsp90. Overexpression of the phosphomimetic T362E-PP5 mutant hyper-dephosphorylates substrates such as the co-chaperone Cdc37 and glucocorticoid receptor in cells. Our proteomic approach revealed that the tumor suppressor von Hippel-Lindau protein (VHL) interacts with and ubiquitinates K185/K199-PP5 for proteasomal degradation in a hypoxia- and prolyl-hydroxylation-independent manner. Finally, VHL-deficient clear cell renal cell carcinoma (ccRCC) cell lines and patient tumors exhibit elevated PP5 levels. Downregulation of PP5 causes ccRCC cells to undergo apoptosis, suggesting a prosurvival role for PP5 in kidney cancer. : Dushukyan et al. show that casein kinase 1δ phosphorylates and activates protein phosphatase 5 (PP5), whereas von Hippel-Lindau protein (VHL) ubiquitinates and degrades PP5 in the proteasome. Kidney cancer cells with mutations and inactivation of VHL have elevated levels of PP5. Downregulation of PP5 causes apoptosis, demonstrating a prosurvival function for PP5 in kidney cancer. Keywords: serine/threonine phosphatase 5, molecular chaperone, co-chaperone, heat shock protein 90, clear cell renal cell carcinoma, kidney cancer, PP5, casein kinase-1 δ, von Hippel-Lindau protein, VHL

Despite the increased identification of specific antibody deficiency (SAD) in chronic rhinosinusitis (CRS), little is known about the relationship between SAD severity and the severity and comorbidities of CRS. The prevalence of an impaired antibody response in the general population is also unknown.The objective of this study was to determine if the SAD severity stratification applies to real-life data of patients with CRS.An electronic health record database was used to identify patients with CRS evaluated for humoral immunodeficiency with quantitative immunoglobulins and Streptococcus pneumoniae antibody titers before and after pneumococcal vaccine. SAD severity was defined, according to the guidelines, based on the numbers of titers ≥1.3 μg/dL after vaccination: severe (≤2 serotypes), moderate (3-6 serotypes), and mild (7-10 serotypes). Comorbidities and therapeutic response were assessed. The prevalence of an impaired antibody response in a normal population was assessed.Twenty-four percent of the patients with CRS evaluated for immunodeficiency had SAD, whereas 11% of a normal population had an impaired immune response to polysaccharide vaccination (P.05). When evaluated by the practice parameter definition, 239 of 595 (40%) met the definition of SAD. Twenty-four (10%) had severe SAD, 120 (50%) had moderate SAD, and 95 (40%) had mild SAD. Patients with moderate-to-severe SAD had worse asthma, a greater likelihood of pneumonia, and more antibiotic courses in the 2 years after vaccination than patients with mild SAD.This study provides real world data supporting stratification of SAD by severity, demonstrating a significant increase in the comorbid severity of asthma and infections in CRS patients with moderate-to-severe SAD compared with those with mild SAD and those without SAD.

Summary Tumor endothelial marker 1 (TEM1) is an emerging cancer target with a unique dual expression profile. First, TEM1 is expressed in the stroma and neo-vasculature of many human carcinomas but is largely absent from healthy adult tissues. Second, TEM1 is expressed by tumor cells of mesenchymal origin, notably sarcoma. Here, we present two fully human anti-TEM1 single-chain variable fragment (scFv) reagents, namely, 1C1m and 7G22, that recognize distinct regions of the extracellular domain and possess substantially different affinities. In contrast to other, well-described anti-TEM1 binders, these fragments confer cytolytic activity when expressed as 2nd generation chimeric antigen receptors (CARs). Moreover, both molecules selectively redirect human T cell effector functions toward TEM1+ tumor cells when incorporated into experimental soluble bispecific trivalent engagers that we term TriloBiTEs (tBs). Furthermore, systemic delivery of 1C1m-tB prevents the establishment of Ewing sarcoma tumors in a xenograft model. Our observations confirm TEM1 as a promising target for cancer immunotherapy and illustrate the prospective translational potential of certain scFv-based reagents., Graphical abstract, Highlights Discovery and characterization of two fully human scFv binders targeting human TEM1 Specific killing of TEM1+ cancer cell lines Demonstration of a versatile soluble heterodimeric trivalent T cell engager format, Fierle et al. describe the targeting of the human TEM1 (CD248/endosialin) tumor marker by redirecting the lytic activity of T cells. This study indicates that both cell-based CAR and soluble engager paradigms may have utility in this regard and suggests a potential immunotherapeutic approach for the treatment of soft-tissue sarcomas.

Although often perceived as being “easy” or “natural,” breastfeeding can be a complex and emotional experience for new mothers and their families. Breastfeeding mothers often receive varied and conflicting advice from multiple providers. This paper presents an integrated infant mental health model of breastfeeding support called the Trifecta for the breastfed infant. Developed in 2011 in the Breastfeeding Management Clinic at the Children's Hospital Colorado, this unique program evolved to best meet the needs of the breastfeeding mother–infant dyad. The Trifecta team integrates a pediatrician with breastfeeding medicine experience, a nurse/lactation consultant, and a psychologist with expertise in infant mental health to provide multidisciplinary breastfeeding support. Integrating infant mental health and breastfeeding support provides a unique opportunity to promote health and mental health in the youngest babies. A program description, case examples, five years of demographic data, limitations, and challenges are provided and discussed.

Synthesis of new 1-aryl-3-substituted propanol derivatives followed by structure-activity relationship, in silico drug-likeness, cytotoxicity, genotoxicity, in silico metabolism, in silico pharmacophore modeling, and in vivo studies led to the identification of compounds 22 and 23 with significant in vitro antiplasmodial activity against drug sensitive (D6 IC50 ≤ 0.19 μM) and multidrug resistant (FCR-3 IC50 ≤ 0.40 μM and C235 IC50 ≤ 0.28 μM) strains of Plasmodium falciparum. Adequate selectivity index and absence of genotoxicity was also observed. Notably, compound 22 displays excellent parasitemia reduction (98 ± 1%), and complete cure with all treated mice surviving through the entire period with no signs of toxicity. One important factor is the agreement between in vitro potency and in vivo studies. Target exploration was performed; this chemotype series exhibits an alternative antimalarial mechanism., Graphical abstract Image 1, Highlights • New aryl-substituted propanol derivatives (APD) show promising antimalarial activity. • γ-amino alcohol moiety is significant antimalarial chemotype. • Compound 22 displays excellent in vivo parasitemia reduction (98%) and complete cure. • APD are active against drug sensitive and multidrug resistant strains.

Multidrug resistance to current Food and Drug Administration-approved HIV-1 protease (PR) inhibitors drives the need to understand the fundamental mechanisms of how drug pressure-selected mutations, which are oftentimes natural polymorphisms, elicit their effect on enzyme function and resistance. Here, the impacts of the hinge-region natural polymorphism at residue 35, glutamate to aspartate (E35D), alone and in conjunction with residue 57, arginine to lysine (R57K), are characterized with the goal of understanding how altered salt bridge interactions between the hinge and flap regions are associated with changes in structure, motional dynamics, conformational sampling, kinetic parameters, and inhibitor affinity. The combined results reveal that the single E35D substitution leads to diminished salt bridge interactions between residues 35 and 57 and gives rise to the stabilization of open-like conformational states with overall increased backbone dynamics. In HIV-1 PR constructs where sites 35 and 57 are both mutated (e.g. E35D and R57K), x-ray structures reveal an altered network of interactions that replace the salt bridge thus stabilizing the structural integrity between the flap and hinge regions. Despite the altered conformational sampling and dynamics when the salt bridge is disrupted, enzyme kinetic parameters and inhibition constants are similar to those obtained for subtype B PR. Results demonstrate that these hinge-region natural polymorphisms, which may arise as drug pressure secondary mutations, alter protein dynamics and the conformational landscape, which are important thermodynamic parameters to consider for development of inhibitors that target for non-subtype B PR.

Background About one-third of patients with unexplained acute-onset heart failure (HF) recover left ventricular (LV) function; however, characterization of these patients in the setting of contemporary HF therapies is limited. We aim to describe baseline characteristics and predictors of recovery in patients with acute-onset cardiomyopathy. Methods We previously described 851 patients with unexplained HF undergoing endomyocardial biopsy. In this study, 235 patients with acute-onset HF were further retrospectively examined. Results Follow-up LV ejection fraction (LVEF) was available for 138 patients. At 1 year, 48 of 138 (33%) had LVEF recovery (follow-up LVEF ≥50%), and 90 of 138 (65%) had incomplete or lack of recovery. Higher cardiac index ( P =.019), smaller LV diastolic diameter ( P =.002), and lack of an intraventricular conduction delay (IVCD) ( P =.002) were associated with LVEF recovery. IVCD ( P =.001) and myocarditis ( P =.016) were independent predictors of the composite end point of death, LV assist device placement, and/or transplant at 1 year. Those with an IVCD had a significantly lower 1-year survival than those without ( P =.007). Conclusions Patients with a smaller LV end-diastolic diameter, higher cardiac index, and lack of IVCD at presentation for acute-onset HF were more likely to have LVEF recovery. IVCD was a poor prognostic marker in all patients presenting with acute cardiomyopathy.

Patients with severe asthma and concomitant chronic rhinosinusitis often have severe, refractory upper and lower airway inflammation. This inflammation has been proposed to be similar throughout the upper and lower airways leading to the unified airways concept. This article reviews chronic rhinosinusitis with and without nasal polyps, and the subgroup with aspirin-exacerbated respiratory disease, while focusing on the relationship with asthma. Additionally, diagnosis and treatment with current and newer therapies are discussed.

There has been a growing interest among clinicians and researchers about a condition where people restrict their diet based not on quantity of food they consume, but based on its quality. Bratman (1997) coined the term "orthorexia nervosa" to describe people whose extreme diets - intended for health reasons - are in fact leading to malnutrition and/or impairment of daily functioning. There has also recently been intense media interest in people whose highly restrictive "healthy" diet leads to disordered eating. Despite this condition being first described in the U.S., and receiving recent media interest here, orthorexia has largely gone unnoticed in the North American literature. This review article details the literature of orthorexia nervosa, describing its emergence as a condition first described by a physician in a yoga magazine, to its being discussed in the scientific literature. It also reviews prevalence studies and discusses marked shortcomings in the literature. Finally, diagnostic criteria are proposed, as are future directions for research.

Marine Invasive Alien Species (IAS) can have devastating impacts on the environment, infrastructure and human well-being. Prevention measures, such as biosecurity, are essential to reducing the introduction and spread of IAS and are central to international and national IAS policy. Understanding the motivations of stakeholders can help determine the effectiveness of existing policy instruments on behaviour. 14 semi-structured interviews were conducted between two case study stakeholder groups in England and Wales (marine shellfish aquaculture industry and the recreational boating sector) in early 2018. Biosecurity practices were deeply embedded in the heavily regulated practices to control shellfish disease within the shellfish industry. Motivations to undertake biosecurity were driven by economic incentives, and penalties for non-compliance with legislation controlling disease. In contrast, there are little regulatory policy instruments to drive IAS biosecurity within the recreational boating sector, which instead relies heavily on voluntary instruments to motivate stakeholders and encourage behavioural changes. Behavioural changes, however, were restricted by lack of infrastructure and enforcement. Our findings suggest it is important to use a combination of approaches to achieve behavioural changes but recognising where regulations and penalties cannot be enforced, voluntary instruments are likely to be most effective. Existing social norms and investment into infrastructure should ‘nudge’ individuals into socially desirable behaviours, especially in the recreational boating sector. For policy makers and regulators, this research reveals the importance of tailoring biosecurity strategies to different stakeholder groups as motivations and collective experience differ.

Polymeric components manufactured via freeform fabrication (FFF) typically have poor inter-laminar toughness resulting from incomplete bonding across layers during production. Here we study the effect of printing and post-processing on the inter-laminar toughness of additively manufactured semi-crystalline (poly-lactide (PLA)) structures. Specimens were subject to post-print thermal annealing to promote inter-laminar bonding, while post-annealing quenching rates were chosen to vary the induced degree of crystallinity in the final structure, as characterized via dynamic scanning calorimetry (DSC). Critical elastic-plastic strain energy release rates (JIc) of annealed samples were evaluated using the single edge notched bend (SENB) geometry and post-testing fractography. The results show that as-printed PLA adopts an amorphous character with good inter-laminar toughness and ductility. Post-print annealing can double the toughness via increased interfacial wetting, but only if the material is quenched rapidly to preserve the amorphous character. In contrast, post-print annealing followed by slow cooling results in a semi-crystalline state (≈25% crystallinity) with low fracture toughness and brittle fracture behavior.

The marine environment is particularly at risk from the intentional and unintentional introduction and spread of invasive alien species (IAS); preventing their introduction and spread from occurring is therefore, a key component in the on-going management of marine IAS. Ensuring legislation is coherent and consistent is essential to the success of managing the existing and future impacts of marine IAS. We explore the coherence (determined as consistency and interaction) of marine biosecurity legislation for IAS at different geopolitical scales. There was consistency between both the Bern Convention and Convention on Biological Diversity and European and national legislation that had been created in response. There was a lack of interaction evidenced by the Ballast Water Management Convention, which had not yet been transposed into regional (mainly European) or national legislation. Implementation measures such as legislation should be coherent as any failure in the chain could potentially weaken the overall effort to establish and maintain biosecurity and achieve behaviour change.

Lower extremity chronic wounds affect 4.5 million Americans annually. Due to inadequate access to wound experts in underserved areas, many patients receive non-uniform, non-standard wound care, resulting in increased costs and lower quality of life. We explored machine learning classifiers to generate actionable wound care decisions about four chronic wound types (diabetic foot, pressure, venous, and arterial ulcers). These decisions (target classes) were: (1) Continue current treatment, (2) Request non-urgent change in treatment from a wound specialist, (3) Refer patient to a wound specialist. We compare classification methods (single classifiers, bagged & boosted ensembles, and a deep learning network) to investigate (1) whether visual wound features are sufficient for generating a decision and (2) whether adding unstructured text from wound experts increases classifier accuracy. Using 205 wound images, the Gradient Boosted Machine (XGBoost) outperformed other methods when using both visual and textual wound features, achieving 81% accuracy. Using only visual features decreased the accuracy to 76%, achieved by a Support Vector Machine classifier. We conclude that machine learning classifiers can generate accurate wound care decisions on lower extremity chronic wounds, an important step toward objective, standardized wound care. Higher decision-making accuracy was achieved by leveraging clinical comments from wound experts.

SUMMARY The molecular chaperone Hsp90 protects deregulated signaling proteins that are vital for tumor growth and survival. Tumors generally display sensitivity and selectivity toward Hsp90 inhibitors; however, the molecular mechanism underlying this phenotype remains undefined. We report that the mitotic checkpoint kinase Mps1 phosphorylates a conserved threonine residue in the amino-domain of Hsp90. This, in turn, regulates chaperone function by reducing Hsp90 ATPase activity while fostering Hsp90 association with kinase clients, including Mps1. Phosphorylation of Hsp90 is also essential for the mitotic checkpoint because it confers Mps1 stability and activity. We identified Cdc14 as the phosphatase that dephosphorylates Hsp90 and disrupts its interaction with Mps1. This causes Mps1 degradation, thus providing a mechanism for its inactivation. Finally, Hsp90 phosphorylation sensitizes cells to its inhibitors, and elevated Mps1 levels confer renal cell carcinoma selectivity to Hsp90 drugs. Mps1 expression level can potentially serve as a predictive indicator of tumor response to Hsp90 inhibitors., Graphical abstract

Hearing loss is one of the most common human sensory disabilities, adversely affecting communication, socialization, mood, physical functioning, and quality of life. In addition to age and noise-induced damage, ototoxicity is a common cause of sensorineural hearing loss with chemotherapeutic agents, for example, cisplatin, being a major contributor. Zebrafish (Danio rerio) are an excellent model to study hearing loss as they have neurosensory hair cells on their body surface that are structurally similar to those within the human inner ear. Anatomic assays of toxin-mediated hair cell damage in zebrafish have been established; however, using fish swimming behavior--rheotaxis--as a biomarker for this anatomic damage was only recently described. We hypothesized that, in parallel, multilane measurements of rheotaxis could be used to create a high-throughput platform for drug development assessing both ototoxic and potentially otoprotective compounds in real time. Such a device was created, and results demonstrated a clear dose response between cisplatin exposure, progressive hair cell damage, and reduced rheotaxis in zebrafish. Furthermore, pre-exposure to the otoprotective medication dexamethasone, before cisplatin exposure, partially rescued rheotaxis swimming behavior and hair cell integrity. These results provide the first evidence that rescued swimming behavior can serve as a biomarker for rescued hair cell function. Developing a drug against hearing loss represents an unmet clinical need with global implications. Because hearing loss from diverse etiologies may result from common end-effects at the hair cell level, lessons learned from the present study may be broadly used.

The purpose of this study was to investigate the relationship between doctors' bad news delivery style and their experience of physiological stress during simulated bad news consultations.31 doctors participated in two simulated breaking bad news (BBN) consultations. Delivery style was categorized as either blunt, forecasting or stalling (i.e. avoidant), based on the time to deliver the bad news and qualitative analysis of the interaction content and doctor's language style. Doctors' heart rate (HR) and skin conductance (SC) were recorded in consecutive 30s epochs.Doctors experienced a significant decrease in HR (F(1,36)=44.9, p.0001) and SC (F(1,48)=5.6, p.001) between the pre- and post-news delivery phases of the consultation. Between-group comparisons for the three delivery styles did not identify any significant differences in HR (F(2,36)=2.2, p.05) or SC (F(2,48)=.66, p.05).Doctors experience heightened stress in the pre-news delivery phase of breaking bad news interactions. Delaying the delivery of bad news exposes doctors to a longer period of increased stress.This suggests that medical students and doctors should be taught to deliver bad news without delay, to help mitigate their response to this stressful encounter.