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Aisling A Jennings, Naoihse Guerin, Tony Foley Department of General Practice, University College Cork, Cork, Ireland Background: Despite their adverse effects, antipsychotics are frequently used to manage behavioral and psychological symptoms of dementia. Regular monitoring of antipsychotic prescribing has been shown to improve the appropriateness of prescribing. However, there is currently no consensus on what the components of such a monitoring tool would be. Aim: The aim of this study was to use an expert consensus process to identify the key components of an antipsychotic repeat prescribing tool for use with people with dementia in a general practice setting. Methods: A modified eDelphi technique was employed. We invited multidisciplinary experts in antipsychotic prescribing to people with dementia to participate. These experts included general practitioners (GPs), geriatricians and old age psychiatrists. The list of statements for round 1 was developed through a review of existing monitoring tools and international best practice guidelines. In the second round of the Delphi, any statement that had not reached consensus in the first round was presented for re-rating, with personalized feedback on the group and the individual’s response to the specific statement. The final round consisted of a face-to-face expert meeting to resolve any uncertainties from round 2. Results: A total of 23 items were rated over two eDelphi rounds and one face-to-face consensus meeting to yield a total of 18 endorsed items and five rejected items. The endorsed statements informed the development of a structured, repeat prescribing tool for monitoring antipsychotics in people with dementia in primary care. Conclusion: The development of repeat prescribing tool provides GPs with practical advice that is lacking in current guidelines and will help to support GPs by providing a structured format to use when reviewing antipsychotic prescriptions for people with dementia, ultimately improving patient care. The feasibility and acceptability of the tool now need to be evaluated in clinical practice. Keywords: dementia, antipsychotics, prescribing, eDelphi, consensus, general practice

Heart rate (fH) measurement offers the possibility to monitor energy expenditure (EE) in wild animals if the EE/fH relationship for the species, physiological stages and activities of interest is known. This relationship has been extensively studied using oxygen consumption rate (VO2 measurement in captive, repeatedly handled king penguins (Aptenodytes patagonicus). Unfortunately, the potential effects of stress on the observed relationships resulting from handling and confinement were not considered. This study is the first involving undisturbed animals, and determines the EE/fH relationship in naturally fasting and freely incubating or captivity-acclimatized male and female king penguins. EE determination was based on (1) the measurement of body mass loss during periods of phase II fasting, and (2) the calculation of its energy equivalent from changes in body composition, i.e. 23.9kJg-1. fH levels in freely incubating and captivity-acclimatized birds were found to be 50-70% lower than those previously reported for resting king penguins during VO2 measurements. Significant EE/fH relationships were found in freely incubating and captive males and females (R2=0.59 to 0.84), with no difference observed between genders. The best overall relationship was obtained by including fasting duration (t, days) in the model: EE=818+43.7XfH+36.3t-1.4tXfH (R2=0.91). This equation yielded EE estimates approximately 26% higher than the previously reported `best' predictive equation in king penguins, and even more so when fH was low. This result suggests that stress induces a disproportionate increase of fH vs O2 consumption, and that the use of EE/fH relationships obtained in stressed birds could lead to underestimated EE values. [ABSTRACT FROM AUTHOR]

Presents information on a study which investigated the performances of methods used for the computation of the free space Green's function for doubly periodic arrays. Expression of the Green's function; Methodology.

Objective: Mental health lived experience organizations (LEOs) and their lived experience workforce are increasingly recognized as invaluable. However, a deeper understanding of the elements that enhance or inhibit LEOs' efficacy is required to learn how to sustain LEOs and support their workforce. Rapid international expansion has resulted in significant LEO growth and change, challenging many LEOs to adapt. With this rapid expansion, the field is evolving faster than many LEOs can keep pace with. This review, codesigned and coproduced in partnership with a LEO to draw on both lived experience and academic perspectives, aims for a deeper understanding of which elements within a LEO enhance or inhibit its efficacy, growth, and support for its lived experience workforce., Methods: A systematic search of peer-reviewed and non-peer-reviewed literature, following the PRISMA-ScR guidelines and JBI methodology, identified 60 records published in English between 2000 and 2022., Results: The results indicate general agreement regarding which LEO elements are important (e.g., culture, leadership, board composition, organizational structure, financial arrangements, and professionalization). However, considerable disagreements exist regarding the relative influence of several of these elements, especially funding arrangements, in which funder and LEO values often diverge; training for increased lived experience professionalization; and partnerships with medical model-focused mental health services., Conclusions: Organizational disagreements relate to managing future LEO growth and advancing the lived experience workforce while preserving LEOs' unique characteristics that make them valued mental health services. Further research should examine community differences among LEOs, including hybrid LEOs within services and non-LEO mental health organizations.

D-peptides, the mirror image of canonical L-peptides, offer numerous biological advantages that make them effective therapeutics. This article details how to use DexDesign, the newest OSPREY-based algorithm, for designing these D-peptides de novo . OSPREY physics-based models precisely mimic energy-equivariant reflection operations, enabling the generation of D-peptide scaffolds from L-peptide templates. Due to the scarcity of D-peptide:L-protein structural data, DexDesign calls a geometric hashing algorithm, Method of Accelerated Search for Tertiary Ensemble Representatives, as a subroutine to produce a synthetic structural dataset. DexDesign enables mixed-chirality designs with a new user interface and also reduces the conformation and sequence search space using three new design techniques: Minimum Flexible Set, Inverse Alanine Scanning, and K*-based Mutational Scanning.

With over 270 unique occurrences in the human genome, peptide-recognizing PDZ domains play a central role in modulating polarization, signaling, and trafficking pathways. Mutations in PDZ domains lead to diseases such as cancer and cystic fibrosis, making PDZ domains attractive targets for therapeutic intervention. D-peptide inhibitors offer unique advantages as therapeutics, including increased metabolic stability and low immunogenicity. Here, we introduce DexDesign, a novel OSPREY-based algorithm for computationally designing de novo D-peptide inhibitors. DexDesign leverages three novel techniques that are broadly applicable to computational protein design: the Minimum Flexible Set, K*-based Mutational Scan, and Inverse Alanine Scan, which enable exponential reductions in the size of the peptide sequence search space. We apply these techniques and DexDesign to generate novel D-peptide inhibitors of two biomedically important PDZ domain targets: CAL and MAST2. We introduce a new framework for analyzing de novo peptides-evaluation along a replication/restitution axis-and apply it to the DexDesign-generated D-peptides. Notably, the peptides we generated are predicted to bind their targets tighter than their targets' endogenous ligands, validating the peptides' potential as lead therapeutic candidates. We provide an implementation of DexDesign in the free and open source computational protein design software OSPREY.

With over 270 unique occurrences in the human genome, peptide-recognizing PDZ domains play a central role in modulating polarization, signaling, and trafficking pathways. Mutations in PDZ domains lead to diseases such as cancer and cystic fibrosis, making PDZ domains attractive targets for therapeutic intervention. D-peptide inhibitors offer unique advantages as therapeutics, including increased metabolic stability and low immunogenicity. Here, we introduce DexDesign, a novel OSPREY-based algorithm for computationally designing de novo D-peptide inhibitors. DexDesign leverages three novel techniques that are broadly applicable to computational protein design: the Minimum Flexible Set, K*-based Mutational Scan, and Inverse Alanine Scan. We apply these techniques and DexDesign to generate novel D-peptide inhibitors of two biomedically important PDZ domain targets: CAL and MAST2. We introduce a framework for analyzing de novo peptides-evaluation along a replication/restitution axis-and apply it to the DexDesign-generated D-peptides. Notably, the peptides we generated are predicted to bind their targets tighter than their targets' endogenous ligands, validating the peptides' potential as lead inhibitors. We also provide an implementation of DexDesign in the free and open source computational protein design software OSPREY., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Explaining why someone repeats high-cost cooperation towards non-reciprocating strangers is difficult. Warm glow offers an explanation. We argue that warm glow, as a mechanism to sustain long-term cooperation, cools off over time but can be warmed up with a simple intervention message. We tested our predictions in the context of repeat voluntary blood donation (high-cost helping of a non-reciprocating stranger) across 6 studies: a field-based experiment (n = 5,821) comparing warm-glow and impure-altruism messages; an implementation study comparing a 3-yr pre-implementation period among all first-time donors in Australia (N = 270,353) with a 2-yr post-implementation period (N = 170, 317); and 4 studies (n = 716, 1,124, 932, 1,592) exploring mechanisms. We show that there are relatively warm and cool cooperators, not cooling cooperators. Cooperation among cool cooperators is enhanced by a warm-glow-plus-identity message. Furthermore, the behavioural facilitation of future cooperation, by booking an appointment, is associated with being a warm cooperator. Societal implications are discussed., (© 2023. The Author(s).)

We report an Osprey-based computational protocol to prospectively identify oncogenic mutations that act via disruption of molecular interactions. It is applicable to analyse both protein-protein and protein-DNA interfaces and it is validated on a dataset of clinically relevant mutations. In addition, it is used to predict previously uncharacterised patient mutations in CDK6 and p16 genes, which are experimentally confirmed to impair complex formation., (© 2023. The Author(s).)

l-Asparaginase is a cornerstone of acute lymphoblastic leukemia (ALL) therapy since lymphoblasts lack asparagine synthetase (ASNS) and rely on extracellular asparagine availability for survival. Resistance mechanisms are associated with increased ASNS expression in ALL. However, the association between ASNS and l-Asparaginase efficacy in solid tumors remains unclear, thus limiting clinical development. Interestingly, l-Asparaginase also has a glutaminase co-activity that is crucial in pancreatic cancer where KRAS mutations activate glutamine metabolism. By developing l-Asparaginase-resistant pancreatic cancer cells and using OMICS approaches, we identified glutamine synthetase (GS) as a marker of resistance to l-Asparaginase. GS is the only enzyme able to synthesize glutamine, and its expression also correlates with l-Asparaginase efficacy in 27 human cell lines from 11 cancer indications. Finally, we further demonstrated that GS inhibition prevents cancer cell adaptation to l-Asparaginase-induced glutamine starvation. These findings could pave the way to the development of promising drug combinations to overcome l-Asparaginase resistance., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Rossignol Rodrigue reports financial support was provided by Erytech Pharma SA. Rama Nicolas reports financial support was provided by Erytech Pharma SA., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Prospective predictions of drug-resistant protein mutants could improve the design of therapeutics less prone to resistance. Here, we describe RESISTOR, an algorithm that uses structure- and sequence-based criteria to predict resistance mutations. We demonstrate the process of using RESISTOR to predict ERK2 mutants likely to arise in melanoma ablating the efficacy of the ERK1/2 inhibitor SCH779284. RESISTOR is included in the free and open-source computational protein design software OSPREY. For complete details on the use and execution of this protocol, please refer to Guerin et al.. 1 ., Competing Interests: Declaration of interests B.R.D. is a founder of Ten63 Therapeutics, Inc., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Youth gambling is associated with a range of harms. This study aimed to examine, among Australian adolescents, the prevalence of gambling (ever, in the last month, at-risk and problem), the most frequent gambling types and modalities, and to explore the student characteristics associated with gambling in the last month and with at-risk or problem gambling. Students aged 12-17 years from Victoria and Queensland answered gambling questions as part of the Australian Secondary School Alcohol and Drug (ASSAD) Survey in 2017. The ASSAD also included a series of questions about smoking, alcohol and other drug use, and mental health. A total of 6377 students from 93 schools were included in analysis. The prevalence of ever gambling and gambling in the last month was 31% and 6% respectively. Of students who had gambled in the last month, 34% were classified as at-risk and 15% were classified as problem gamblers. The most frequent types of gambling in the last month were horse or dog race and sports betting. Students who gambled in the last month did so most frequently via a parent or guardian purchasing or playing for them, at home or at a friends' house, and online or using an app. Regression analysis indicated that male gender, having money available to spend on self, alcohol consumption in the last seven days, the number of types of advertisements seen in the last month, and the number of peer or family members who gambled in the last month, were significantly associated with the likelihood of students gambling in the last month. Male gender, some age categories, and exposure to more types of gambling advertising were also significant predictors of being classified as an at-risk or problem gambler. This large study of youth gambling provides data on gambling behaviours and related variables from a large sample of Australian secondary school students. Student characteristics, including male gender and exposure to more types of gambling advertising, were associated with an increased likelihood of gambling in the last month and of being classified as an at-risk or problem gambler. Further implications of the study findings are discussed., (© 2022. The Author(s).)

Background: Early in the COVID-19 pandemic, Australian donors aged 70 and over were advised to temporarily stop donating. The aim of this research was to understand the factors associated with some of these donors continuing to donate despite the advice, and whether adherence to the advice had negative implications for donor retention., Study Design and Methods: Survey data from 2078 donors were analyzed to understand the factors associated with donating blood during the first 6 months of the pandemic, and the impact of following stay-at-home advice during the first 6 months of the pandemic on donor return 6-12 months into the pandemic. Panel data were used to gain an overview of donation behavior before, during, and after the initial phase of the pandemic., Results: Donations by donors aged 70 and over decreased disproportionately to other age groups during the early stages of the pandemic. Sex, total donation count, awareness of stay-at-home advice from the Blood Collection Agency, the mode of receiving stay-at-home advice, donor risk perceptions and attitudes toward stay-at-home advice were associated with donation behavior in the first 6 months of the pandemic. Donors who did not donate in the first 6 months of the pandemic had lower odds of returning 6-12 months into the pandemic., Conclusion: Stay-at-home advice was partially successful in preventing older donors from donating; however, more tailored communication approaches may have prevented more donors from donating. Implementation of stay-at-home advice should be accompanied by strategies to prevent ongoing donor lapse in the medium- to long-term., (© 2022 The Authors. Transfusion published by Wiley Periodicals LLC on behalf of AABB.)

Computational, in silico prediction of resistance-conferring escape mutations could accelerate the design of therapeutics less prone to resistance. This article describes how to use the Resistor algorithm to predict escape mutations. Resistor employs Pareto optimization on four resistance-conferring criteria-positive and negative design, mutational probability, and hotspot cardinality-to assign a Pareto rank to each prospective mutant. It also predicts the mechanism of resistance, that is, whether a mutant ablates binding to a drug, strengthens binding to the endogenous ligand, or a combination of these two factors, and provides structural models of the mutants. Resistor is part of the free and open-source computational protein design software OSPREY.

Resistance to pharmacological treatments is a major public health challenge. Here, we introduce Resistor-a structure- and sequence-based algorithm that prospectively predicts resistance mutations for drug design. Resistor computes the Pareto frontier of four resistance-causing criteria: the change in binding affinity (ΔK a ) of the (1) drug and (2) endogenous ligand upon a protein's mutation; (3) the probability a mutation will occur based on empirically derived mutational signatures; and (4) the cardinality of mutations comprising a hotspot. For validation, we applied Resistor to EGFR and BRAF kinase inhibitors treating lung adenocarcinoma and melanoma. Resistor correctly identified eight clinically significant EGFR resistance mutations, including the erlotinib and gefitinib "gatekeeper" T790M mutation and five known osimertinib resistance mutations. Furthermore, Resistor predictions are consistent with BRAF inhibitor sensitivity data from both retrospective and prospective experiments using KinCon biosensors. Resistor is available in the open-source protein design software OSPREY., Competing Interests: Declaration of interests B.R.D. is a founder of Ten63 Therapeutics, Inc. E.S. is a founder of KinCon Biolabs. KinCon reporters are subjects of pending patent applications., (Published by Elsevier Inc.)

Introduction and Aims: Smoking is a major cause of preventable illness for Indigenous peoples. As most regular smoking is established during adolescence when other substances are often first used, effective tobacco prevention requires an understanding of the patterns of related substance use for Indigenous youth., Design and Methods: We reviewed smoking among Indigenous students through cross-sectional analyses of the 2017 Australian Secondary Students' Alcohol and Drug survey and compared findings to non-Indigenous participants. We used logistic regression to evaluate differences in prevalence of tobacco, alcohol and cannabis use, and how smoking and other substance use were related., Results: Past month smoking was strongly associated with alcohol and cannabis use for both Indigenous and non-Indigenous students. The association between tobacco and cannabis use did not differ by Indigenous status, but the tobacco and alcohol use association was weaker for Indigenous students (P = 0.004). However, the prevalence of tobacco [odds ratio (OR) 1.91 (95% confidence interval; CI 1.55, 2.36)], alcohol [OR 1.44 (1.25, 1.66)] and cannabis [OR 1.97 (1.56, 2.48)] use in the past month was significantly higher in Indigenous than non-Indigenous students. Even within the most socially advantaged sub-group, Indigenous students were more likely to smoke than non-Indigenous students [OR 3.37 (2.23, 5.09)]., Discussion and Conclusions: Cannabis and alcohol use are important predictors of smoking for all students. Tobacco policies and community programs must address common determinants of tobacco and other substance use, including resilience and social influence skills as well as broader family and community factors that may be different for Indigenous students., (© 2020 Australasian Professional Society on Alcohol and other Drugs.)

Objective: Smoking is a major cause of preventable illness for Aboriginal and Torres Strait Islander people, with most commencing in adolescence. Understanding trends in youth tobacco use can inform prevention policies and programs., Methods: Logistic regression models examined smoking trends among Aboriginal and Torres Strait Islander and all students aged 12-17 years, in five nationally representative triennial surveys, 2005-2017. Outcomes measured lifetime, past month, past week tobacco use and number of cigarettes smoked daily (smoking intensity)., Results: Aboriginal and Torres Strait Islander students' never smoking increased (2005: 49%, 2017: 70%) with corresponding declines in past month and week smoking. Smoking intensity reduced among current smokers (low intensity increased 2005: 67%, 2017: 77%). Trends over time were similar for Aboriginal and Torres Strait Islander students as for all students (8-10% annual increase in never smoking)., Conclusions: Most Aboriginal and Torres Strait Islander students are now never smokers. Comparable declines indicate similar policy impact for Aboriginal and Torres Strait Islander and all students. Implications for Public Health: Comprehensive population-based tobacco control policies can impact all students. Continued investment, including in communities, is needed to maintain and accelerate reductions among Aboriginal and Torres Strait Islander students to achieve equivalent prevalence rates and reduce health inequities., (© 2020 The Authors.)

Objective: To examine the effect of a mass media campaign designed to increase bowel cancer screening participation., Methods: We assessed weekly participation, from January 2015 to December 2017, in the Australian National Bowel Cancer Screening Program in Victoria, where a seven-week campaign aired in mid-2017, and in the adjacent comparison state of South Australia. Participation, defined as the number of immunochemical faecal occult blood tests returned out of those invited by the Screening Program in the past 16 weeks, was analysed using negative binomial regression., Results: Compared with non-campaign weeks, there was an increase in the return rate in the campaign state during campaign weeks (adjusted return rates non-campaign weeks = 34.4% vs. campaign weeks = 45.3%, p < 0.01), not observed in the comparison state (38.3% vs. 40.3%, p > 0.05). The increase in the return rate was significantly greater in the campaign state (Rate Ratio of Campaign/Non-Campaign weeks = 1.31, p < 0.01) than the comparison state (1.05, p > 0.05, interaction p < 0.001), and did not differ significantly by age, sex or socio-economic area. The relative increase was greater among never-participants (Rate Ratio of Campaign/Non-Campaign weeks = 1.24) than previous-participants (1.16), interaction p < 0.001)., Conclusions: This mass media campaign increased bowel cancer screening participation, including from never and low participation subgroups. To maximize participation and ensure equitable population benefit, repeated campaigns that reach eligible people about bowel cancer risks and potential life-saving benefits of screening should be standard.

Problems associated with eyewitness identification decisions have long been highlighted by memory researchers (e.g., Loftus, 1979), with overwhelming evidence that witnesses can err, sometimes with disastrous consequences. Guided by the rationale that witnesses have access to potentially probative memorial information not captured by the traditional categorical lineup responses, an alternative procedure was examined in 6 experiments with adult (N = 1,669) and child (N = 273) witnesses. Instead of witnesses being asked to identify the offender from the lineup, they rated their confidence in the match between the offender and each lineup member and then variations in the maximum (max) confidence values assigned (i.e., the highest rated lineup members) were examined. Specifically, we evaluated how well max confidence values predicted suspect guilt or innocence. When suspects (guilty or innocent) in a lineup received the max confidence rating, the probability of guilt increased with the max. When the suspect received a rating lower than the max, they were generally more likely to be innocent. Max confidence patterns also predicted guilt where a traditional positive identification would have been unlikely: for example, when the max was low, when the witness gave the max to multiple lineup members, or when a filler received the max but the suspect also received a high rating. The data indicate that witnesses have access to probative memorial information often not captured by the traditional lineup responses when identifying someone or rejecting the lineup. Guidelines for the use and interpretation of this theoretically informed futuristic alternative to existing lineup procedures are provided. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

The practice of using green manure for ecological restoration has grown so significantly that there is a shortage of seeds for purchase on the market. Nonetheless, there is very little literature available demonstrating the effects and benefits commonly cited for green manure for addressing important environmental filters, such as herbivory and invasive grasses. Our objective is to determine which spatial sowing arrangement including green manure promotes the lowest rates of herbivory on native species and decreases cover by invasive grasses in ecological restoration. We experimentally tested three sowing configurations of green manure intercropping with native species: T1 the lowest herbivoy rate for both native and green manure, mixture of native and green manure species in the same row, T2, alternating rows of green manure and native species, and T3, rows of native species intercropped with a 2 m wide strip of green manure. We found that (1) green manure species experience greater damage from herbivory than do native species, with average values ranging from 1.8 times higher values in green manure than natives in T1, 2.9 times in T2, and 2.7 times in T3 (when sown in rows and in broader strips, green manure and native species attract more herbivorous insects than if they were sown together [muvuca]); and (2) when green manure and native species are planted mixed in the same row they produce greater soil cover, and thus limit invasion by undesired species. The use of green manure has been identified as an alternative method for overcoming the environmental filters of herbivory and invasive grasses in restoration areas. Considering the demand for information that supports the use of green manure for purposes of ecological restoration, the novel results of the present study fill a void and should prove to be of great interest to researchers and practitioners. In addition, the presented results provide information on efficient and low-cost restoration techniques that are necessary for the activity to gain scale, enabling countries to meet the large restoration targets., (© 2019 by the Ecological Society of America.)

Objective: To assess the long-term impact of plain packaging (PP) of cigarettes with larger graphic health warnings (HW) introduced in December 2012 on adolescents' relevant tobacco-related perceptions., Methods: Cross-sectional school-based surveys of 12 to 17 year olds in 2011 (n=4413), 2013 (n=4423), 2014 (n=4576) and 2017 (n=4266). Students rated the character of four popular cigarette brands, indicated their agreement regarding brand differences in smoking ease, quitting, addictiveness, harmfulness and pack attractiveness and positive/negative perceptions of pack image. The frequency of students reading, attending to, thinking and talking about HW was assessed. Responses of students seeing cigarette packs in the previous 6 months (2011: 63%; 2013: 67%, 2014: 56%, 2017: 56%) were examined., Results: Smoking prevalence declined from 2011 to 2017. Among students who had recently seen packs, cigarette packs were rated less positively and more negatively in 2017 than in 2011 (p<0.001) with ratings similar between 2013 and 2017. Positive character ratings for each brand reduced between 2011 and 2013 (ps<0.05) with further reductions between 2013 and 2017 (ps<0.05). Fewer students agreed, and more were uncertain, that brands differed in their smoking ease, addictiveness, harmfulness and pack attractiveness in 2017 than 2011. The frequency of students reading, attending, talking or thinking about HW did not change between 2011 and 2017., Conclusions: PP's initial impact in reducing adolescent's positive perceptions of cigarette packs and brand differences continued in the following years with tobacco packaging less appealing to young people in 2017 than 2011 and students more uncertain about brand differences., Competing Interests: Competing interests: No, there are no competing interests., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Renal cell carcinoma represents 3-5% of adult malignant tumors. Metastases are found in 30-40% of patients and brain metastases occurred in more than 10% of them. Despite significant progress in medical treatment, patients with brain metastases still have a limited survival. Cabozantinib, a tyrosine kinase inhibitor directed against vascular endothelial growth factor receptors, was recently registered for the treatment of metastatic renal cell carcinoma. Almost no data are, however, available on patients with brain metastases., Case Presentation: Case 1 is a 51-year-old man of North African origin; Case 2 is a 55-year-old European man. Case 1 and Case 2 had metastases of renal carcinoma at initial diagnosis and were treated with vascular endothelial growth factor receptors tyrosine kinase inhibitors. Case 1 had clear cell renal carcinoma and underwent nephrectomy; he then received several lines of tyrosine kinase inhibitor directed against vascular endothelial growth factor receptors and the mTor complex. During the second treatment a brain metastasis was diagnosed and treated with radiosurgery with rapid efficacy. Two years later he received nivolumab, an antibody directed against the programmed death-1 and programmed death-ligand 1 complex, but disease progression was observed with the reappearance of the brain metastasis together with neurologic symptoms. Cabozantinib was administered and induced a rapid clinical improvement as well as tumor regression in all sites including his brain. Sequencing of his tumor evidenced a mutation of the MET gene. Case 2 had a papillary renal carcinoma with brain metastases at time of diagnosis. After radiation of the brain tumors, a vascular endothelial growth factor receptor tyrosine kinase inhibitor was administered for 3 years. The disease was under control in all sites except in his brain; several new brain metastases requiring new radiation treatments developed. The disease finally progressed at all metastatic sites including his brain and he had several neurological symptoms. Cabozantinib was administered and rapidly induced a clinical improvement; a further computed tomography scan and brain magnetic resonance imaging showed significant tumor regressions. No MET gene mutation or amplification was observed in the tumor analysis., Conclusions: These case reports indicate that cabozantinib was able, first, to reach brain tumors and second, to induce significant regressions in renal carcinoma brain metastases that were resistant to radiation as well as to previous systemic vascular endothelial growth factor receptor tyrosine kinase inhibitors.

This article seeks to reopen a major question raised by the Lacanian nosology of the psychoses, by looking closely at Lacan's formulations of what he never ceased referring to as "paranoia". While almost all classification systems of modern psychiatry, such as the ICD-10 and the DSM-5, have abandoned the specific category of paranoia, Lacan always viewed paranoia as a major category of "functional psychosis". He held that paranoia was a qualitatively different disorder than schizophrenia, and considered it to be the principal or exemplary form of psychosis. Furthermore, in the middle period of his work, Lacan thought of paranoia in much broader terms than those of the definition proposed by Kraepelin, which he revisited, point by point, developing his theory of Freud's concept of " Verwerfung " or foreclosure; the latter became the focal diagnostic criterion in his nosographic construction. Lacan's privileging of and evolving theoretical views on paranoia provide a structural approach to what he called the "resistant nucleus" of psychosis; his work serves as a counterpoint to the more descriptive neo-Kraepelinian approach of contemporary psychiatric nosology.

Control of hepatitis B through routine infant immunization in more than 95% of countries has reduced the prevalence of chronic hepatitis carriers to less than 1%-2% in immunized cohorts of children even in high endemicity countries. In that context the authors of this editorial found the results of a paper by Gras et al in this issue concerning. They performed a Delphi survey of 37 French immunization experts and the results concluded that delayed hepatitis B immunization would cause "potential damage" only after 11 years. Large cohorts of French children and adolescents remain susceptible to hepatitis B infection. Given the high rates of immigration to France from areas of higher endemicity, the higher birth rate and degree of integration of these groups into the health system, plus the lower age of sexual debut and the use of injectable drugs in the general population, we cannot agree that a delay of 11 years is acceptable. Rates of adolescent immunization are quite low so relying on protection at this age will yield little in terms of population protection. Loss of confidence in Hepatitis B vaccine following disproved allegations that the vaccine caused Multiple Sclerosis persists in France, and we believe the results of this paper sends a damaging message to health workers and parents in France and beyond.

Pompe disease is a glycogen storage disease caused by acid α-glucosidase enzyme deficiency. Currently, the unique treatment is lifelong enzyme replacement therapy ERT with frequent intravenous administration of the recombinant analog alglucosidase-α (AGA), which ultimately generates a sustained humoral response resulting in treatment discontinuation. Our aim is to use the tolerogenic properties of antigen-encapsulated red blood cells (RBCs) to abolish the humoral response against AGA and to restore tolerance to replacement therapy. To demonstrate that our approach could prevent the AGA-induced immune response, mice were intravenously injected three times with AGA encapsulated into RBCs before being sensitized to AGA with several adjuvant molecules. Control animals received injections of free AGA instead of the encapsulated molecule. One-week after treatment with AGA-loaded RBCs, a strong decrease in specific humoral response was observed despite three stimulations with AGA and adjuvant molecules. Furthermore, this specific immunomodulation was maintained for at least two months without affecting the overall immune response. AGA-loaded RBCs represent a promising strategy to induce or restore tolerance in Pompe disease patients who develop hypersensitivity reactions following repeated AGA administrations., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The solvent-cast direct-write fabrication of microstructures is shown using a thermoplastic polymer solution ink. The method employs the robotically controlled microextrusion of a filament combined with a rapid solvent evaporation. Upon drying, the increased rigidity of the extruded filament enables the creation of complex freeform 3D shapes., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Over the past two decades, the headwaters of the Xingu Basin in the Amazon have been subjected to one of the highest deforestation rates in Brazil, with negative effects on both terrestrial and aquatic systems. The environmental consequences of forest land conversion have concerned the indigenous people living downstream, and this was the first motivation for the Y Ikatu Xingu campaign--'save the good water of the Xingu'. Among the objectives of the initiative was to restore riparian forests on private land across the basin. For a region where the rivers, rainstorms, forest remnants, distances and farms are huge, the challenges were equally large: crossing the biotic and abiotic thresholds of degradation, as well as addressing the lack of technology, know-how, seeds, forest nurseries, trained personnel and roads, and the lack of motivation for restoration. After 6 years, despite the remarkable advances in terms of technical innovation coupled with a broad and effective social involvement, the restored areas represent only a small portion of those aimed for. The still high costs of restoration, the uncertainties of legislation and also the global economy have been strong forces constraining the expansion of restored forests. Additional efforts and strategies are necessary to overcome these barriers.

The goal of most current vaccines in tumor immunology is to induce an efficient immune response against the tumor cells. The use of red blood cells (RBCs) for the delivery of tumor-associated antigen to antigen-presenting cells is an innovative approach for cancer immunotherapy. The induction of antigen-specific immune responses after administration of antigen-loaded RBCs has been demonstrated previously in mice. In this paper, we show the utility of this delivery system for cancer immunotherapy in 2 tumor mouse models, using the E.G7-OVA and the B16F10 tumor cells. The non-self-antigen, ovalbumin, loaded in RBCs and the self-tumor antigen, tyrosinase-related protein 2, loaded in RBCs were tested in the E.G7-OVA and the B16F10 tumor models, respectively. We showed that not only protein but also peptide could be efficiently entrapped in RBCs by a controlled lysis/resealing process. In both antigen models, the administration of a small quantity of antigen loaded in RBCs combined with polyinosinic-polycytidylic acid induced an antigen-specific T-cell response and the control of tumor growth in mice, whereas the injection of the same quantity of free antigen did not. The intensity of the T-cell response was dependent on the concentrations of antigen entrapped and the treatment performed on the RBC membrane (antibody coating and heat treatment) to improve antigen delivery. In summary, these results support the use of RBCs as an antigen delivery system for a powerful cancer immunotherapy approach.

Purpose: Medical practices in oncology are expected to be multidisciplinary, yet few articles studied how this may be concretely applied. In the present study, we evaluated the organization of two multidisciplinary committees, one for breast cancer and one for sarcoma, in a French Comprehensive Cancer Centre., Methods: Both tumours were specifically chosen so as to emphasise substantial differences in relation with incidence, histological subtypes, management strategy, and scientific evidence. Between 2003 and 2004, 404 decision processes were observed, 210 for sarcoma (26 meetings) and 194 for breast cancer (10 meetings). The number of physicians who took part in the discussions and their medical specialties were systematically noted as well as the number of contradictory discussions, medical specialties represented in these contradictory discussions and the topics of contradiction. The last measured data was whether the final committee's decision was in conformity with the referent preferences or not. All these measures were related to the referent's medical speciality and working place, to the stage of the disease and to the disease management stage., Results: Committees' specificities concerned their organization, referent's medical specialties, the number of participants in discussions and their medical specialties. Discussions in the sarcoma committee tended to be more multidisciplinary, involving more specialties. Initial strategy proposal for one patient was modified during the discussions for 86 patients out of 210 (41%) and for 62 out of 194 (32%) respectively for sarcoma and breast cancer. However, there was no significant difference in the rate of contradictory discussions between breast cancer and sarcoma committees (32% versus 41% respectively; P = 0.08). The rates of contradictory discussions were similar for localized cancers, local relapse and metastasis disease (37%, 41% and 34% respectively; P = 0.86)., Conclusions: The present study reports more than 30% of changes concerning strategy for patient with cancer due to multidisciplinary discussions. This indicates that, providing tumour committees are adapted to the pathologies' characteristics, they can promote a collective and multidisciplinary approach to oncology.