Novel irreversible peptidic inhibitors of transglutaminase 2.

Transglutaminase 2 (TG2), also referred to as tissue transglutaminase, plays crucial roles in both protein crosslinking and cell signalling. It is capable of both catalysing transamidation and acting as a G-protein, these activities being conformation-dependent, mutually exclusive, and tightly regulated. The dysregulation of both activities has been implicated in numerous pathologies. TG2 is expressed ubiquitously in humans and is localized both intracellularly and extracellularly. Targeted TG2 therapies have been developed but have faced numerous hurdles including decreased efficacy in vivo. Our latest efforts in inhibitor optimization involve the modification of a previous lead compound's scaffold by insertion of various amino acid residues into the peptidomimetic backbone, and derivatization of the N-terminus with substituted phenylacetic acids, resulting in 28 novel irreversible inhibitors. These inhibitors were evaluated for their ability to inhibit TG2 in vitro and their pharmacokinetic properties, and the most promising candidate 35 (k inact/K I = 760 × 103 M-1 min-1) was tested in a cancer stem cell model. Although these inhibitors display exceptional potency versus TG2, with k inact/K I ratios nearly ten-fold higher than their parent compound, their pharmacokinetic properties and cellular activity limit their therapeutic potential. However, they do serve as a scaffold for the development of potent research tools.

Lung volume reduction surgery versus endobronchial valves: a randomised controlled trial.

BACKGROUND: Lung volume reduction surgery (LVRS) and bronchoscopic lung volume reduction (BLVR) with endobronchial valves can improve outcomes in appropriately selected patients with emphysema. However, no direct comparison data exist to inform clinical decision making in people who appear suitable for both procedures. Our aim was to investigate whether LVRS produces superior health outcomes when compared with BLVR at 12 months. METHODS: This multicentre, single-blind, parallel-group trial randomised patients from five UK hospitals, who were suitable for a targeted lung volume reduction procedure, to either LVRS or BLVR and compared outcomes at 1 year using the i-BODE score. This composite disease severity measure includes body mass index, airflow obstruction, dyspnoea and exercise capacity (incremental shuttle walk test). The researchers responsible for collecting outcomes were masked to treatment allocation. All outcomes were assessed in the intention-to-treat population. RESULTS: 88 participants (48% female, mean±sd age 64.6±7.7 years, forced expiratory volume in 1 s percent predicted 31.0±7.9%) were recruited at five specialist centres across the UK and randomised to either LVRS (n=41) or BLVR (n=47). At 12 months follow-up, the complete i-BODE was available in 49 participants (21 LVRS/28 BLVR). Neither improvement in the i-BODE score (LVRS -1.10±1.44 versus BLVR -0.82±1.61; p=0.54) nor in its individual components differed between groups. Both treatments produced similar improvements in gas trapping (residual volume percent predicted: LVRS -36.1% (95% CI -54.6- -10%) versus BLVR -30.1% (95% CI -53.7- -9%); p=0.81). There was one death in each treatment arm. CONCLUSION: Our findings do not support the hypothesis that LVRS is a substantially superior treatment to BLVR in individuals who are suitable for both treatments.

Pheromone Deployment Strategies for Mating Disruption of a Vineyard Mealybug.

The mealybug, Planococcus ficus (Signoret), is a primary vineyard pest in California and other grape-growing regions throughout the World. Mating disruption programs are commercially available to manage Pl. ficus, but widespread adoption has been limited, in part, by high costs compared with insecticide programs. To improve mating disruption economic effectiveness, different deployment technologies (passive, aerosol, and microencapsulated formulations) were individually examined. Adult male Pl. ficus captures in pheromone traps and categorical ratings of vine infestation or crop damage suggest that all deployment strategies lowered mealybug densities or damage. Using passive dispensers, deployment rates of 310 and 465 per ha lowered Pl. ficus crop damage similar to 615 per ha, a rate commonly used in commercial operations; reduced rates would lower product and deployment costs. Meso dispensers, containing more a.i., deployed at 35 per ha did not have a treatment impact, but a microencapsulated formulation and aerosol canisters lowered male flight captures and/or crop damage. Male mealybug flight activity was greatest from 0500-1100 hr, which coincided with temperatures >16° and <32°C. These restricted times and temperatures suggest programable dispensers might allow pheromone deployment to coincide only with flight patterns. A large field trial using passive dispensers found greater treatment separation after 3 yr of pheromone deployment. Discrepancies in results among vineyards may be related to Pl. ficus density, but combined results from all trials suggest that different deployment technologies can be used to impact Pl. ficus densities and damage, even at reduced rates, especially with continued use over multiple seasons.

Draft Genome Sequence of the Yeast Ogataea degrootiae Strain UCD465, Isolated from Soil in Ireland.

Ogataea degrootiae is an ascomycete yeast that was first isolated in the Netherlands in 2017. It is a member of the Pichiaceae clade. Here, we present the genome sequence of O. degrootiae UCD465, which was isolated from soil in Ireland. This genome is 14.6 Mb and haploid.

Community diabetes nurse specialists: service evaluation to describe their professional role.

This paper presents a service evaluation on the role of Community Diabetes Nurse Specialists (CDNS), which was undertaken as a response to various changes. Quantitative and qualitative data were captured over 6 months. It was found that GPs refer patients to CDNSs four times more frequently than other health professionals. The clinical care of CDNSs mainly relates to diabetes education, insulin, assessment and self-management. Telehealth is used twice as frequently as face-to-face communications. The CDNSs do not refer patients onto other health professionals, but have multiple communications with other health professionals and agencies. They manage very complex clinical and social situations, using high-level clinical decision making and balancing person-centred care and patient safety. Structured patient education is being delivered. CDNSs mentor other staff and students, although their own formal professional development is very limited. To conclude, CDNSs are the end point for patient care in the community, managing complex patient situations, while adopting a person-centred approach.

Community recommendations on biobank governance: Results from a deliberative community engagement in California.

United States-based biorepositories are on the cusp of substantial change in regulatory oversight at the same time that they are increasingly including samples and data from large populations, e.g. all patients in healthcare system. It is appropriate to engage stakeholders from these populations in new governance arrangements. We sought to describe community recommendations for biorepository governance and oversight using deliberative community engagement (DCE), a qualitative research method designed to elicit lay perspectives on complex technical issues. We asked for stakeholders to provide input on governance of large biorepositories at the University of California (UC), a public university. We defined state residents as stakeholders and recruited residents from two large metropolitan areas, Los Angeles (LA) and San Francisco (SF). In LA, we recruited English and Spanish speakers; in SF the DCE was conducted in English only. We recruited individuals who had completed the 2009 California Health Interview Survey and were willing to be re-contacted for future studies. Using stratified random sampling (by age, education, race/ethnicity), we contacted 162 potential deliberants of whom 53 agreed to participate and 51 completed the 4-day DCE in June (LA) and September-October (SF), 2013. Each DCE included discussion among deliberants facilitated by a trained staff and simultaneously-translated in LA. Deliberants also received a briefing book describing biorepository operations and regulation. During the final day of the DCE, deliberants voted on governance and oversight recommendations using an audience response system. This paper describes 23 recommendations (of 57 total) that address issues including: educating the public, sharing samples broadly, monitoring researcher behavior, using informative consent procedures, and involving community members in a transparent process of biobank governance. This project demonstrates the feasibility of obtaining meaningful input on biorepository governance from diverse lay stakeholders. Such input should be considered as research institutions respond to changes in biorepository regulation.

EngageUC: Developing an Efficient and Ethical Approach to Biobanking Research at the University of California.

Biorepositories, or biobanks, provide researchers with access to biological samples and associated data in support of translational research. Efficient operation and ethical stewardship of biobanks involves coordinated efforts among multiple stakeholders including researchers who manage and use the repository, institutional officials charged with its oversight, and patients and volunteers who contribute samples and data. As advancements in translational research increasingly involve more data derived from larger numbers of diverse samples, the size and governance challenges facing biorepositories have grown. We describe an approach to developing efficient and ethical biobank governance that includes all major stakeholders. This model provides a pathway for addressing the technical and ethical challenges that must be resolved to ensure biorepositories continue to support translational research.

Gratitude buffers the adverse effect of viewing the thin ideal on body dissatisfaction.

Gratitude has robust associations with multiple aspects of well-being. However, little research has explored whether the psychological benefits of gratitude extend to body image. We used a repeated measures experimental design to test whether a brief period of grateful reflection would buffer the adverse effect of exposure to thin-ideal media. Female undergraduates (N=67) completed three sessions one week apart. The conditions were specifically designed to isolate (a) the effects of viewing thin models on body dissatisfaction and (b) the moderating effect of grateful contemplation. Results showed that body dissatisfaction scores were lower for women who engaged in a brief period of grateful contemplation before viewing photographs of thin models than for women who reflected upon life hassles before viewing the same photographs. The magnitude of this decrease depended on BMI. Gratitude offers an innovative direction for future research directed toward helping women to accept their bodies.

Guideline funding and conflicts of interest: article 4 in Integrating and coordinating efforts in COPD guideline development. An official ATS/ERS workshop report.

INTRODUCTION: Professional societies, like many other organizations around the world, have recognized the need to use more rigorous processes to ensure that healthcare recommendations are informed by the best available research evidence. This is the fourth of a series of 14 articles prepared to advise guideline developers in respiratory and other disease. It focuses on commercial funding of guidelines and managing conflict of interest effectively in the context of guidelines. METHODS: In this review, we addressed the following topics and questions. (1) How are clinical practice guidelines funded? (2) What are the risks associated with commercial sponsorship of guidelines? (3) What relationships should guideline committee members be required to disclose? (4) What is the most efficient way to obtain complete and accurate disclosures? (5) How should disclosures be publicly shared? (6) When do relationships require management? (7) How should individual conflicts of interest be managed? (8) How could conflict of interest policies be enforced? The literature review included a search of PubMed and other databases for existing systematic reviews and relevant methodological research. Our conclusions are based on available evidence, consideration of what guideline developers are doing, and workshop discussions. RESULTS AND DISCUSSION: Professional societies often depend on industry funding to support clinical practice guideline development. In addition, members of guideline committees frequently have financial relationships with commercial entities, are invested in their intellectual work, or have conflicts related to clinical revenue streams. No systematic reviews or other rigorous evidence regarding best practices for funding models, disclosure mechanisms, management strategies, or enforcement presently exist, but the panel drew several conclusions that could improve transparency and process.

Evaluation of monitoring traps with novel bait for navel orangeworm (Lepidoptera: Pyralidae) in California almond and pistachio orchards.

Experiments conducted in three almond, Prunus dulcis (Rosales: Rosaceae), orchards and three pistachio, Pistacia vera (Sapindales: Anicardiaceae), orchards in 2009 and 2010, and determined that sticky bottom wing traps baited with ground pistachio mummies, or a combination of ground pistachio plus ground almond mummies, trapped more adult female navel orangeworm, Amyelois transitella (Walker) (Lepidoptera: Pyralidae), than did traps baited with ground almond mummies alone. During both years of this study, 2.9 and 1.8 more moths were caught in traps baited with pistachio mummies compared with traps baited with almond mummies in almond orchards and pistachio orchards, respectively. Also, traps located in pistachio orchards caught 5.9 and 8.3 times more navel orangeworm than were trapped from almond orchards in 2009 and 2010, respectively. Implications for use of this novel baited trap in almond and pistachio orchard integrated pest management programs are discussed.

Swimsuit issues: promoting positive body image in young women's magazines.

ISSUE ADDRESSED: This preliminary study reviews the promotion of healthy body image to young Australian women, following the 2009 introduction of the voluntary Industry Code of Conduct on Body Image. The Code includes using diverse sized models in magazines. METHOD: A qualitative content analysis of the 2010 annual 'swimsuit issues' was conducted on 10 Australian young women's magazines. Pictorial and/or textual editorial evidence of promoting diverse body shapes and sizes was regarded as indicative of the magazines' upholding aspects of the voluntary Code of Conduct for Body Image. RESULTS: Diverse sized models were incorporated in four of the seven magazines with swimsuit features sampled. Body size differentials were presented as part of the swimsuit features in three of the magazines sampled. Tips for diverse body type enhancement were included in four of the magazines. All magazines met at least one criterion. One magazine displayed evidence of all three criteria. CONCLUSION: Preliminary examination suggests that more than half of young women's magazines are upholding elements of the voluntary Code of Conduct for Body Image, through representation of diverse-sized women in their swimsuit issues.

"It's not just what the doctor tells me:" factors that influence surrogate decision-makers' perceptions of prognosis.

OBJECTIVE: Physicians and surrogate decision-makers for seriously ill patients often have different views of patients' prognoses. We sought to understand what sources of knowledge surrogates rely on when estimating a patient's prognosis. DESIGN: Prospective, mixed-methods study using face-to-face, semistructured interviews with surrogate decision-makers. SETTING: Four intensive care units at the University of California, San Francisco Medical Center in 2006 to 2007. PARTICIPANTS: Participants were 179 surrogate decision-makers for 142 incapacitated, critically ill patients at high risk for death. MAIN RESULTS: Less than 2% (3 of 179) of surrogates reported that their beliefs about the patients' prognoses hinged exclusively on prognostic information provided to them by physicians. The majority cited other factors in addition to physicians' predictions that also contributed to their beliefs about the patients' prognoses, including perceptions of the patient's individual strength of character and will to live; the patient's unique history of illness and survival; the surrogate's own observations of the patient's physical appearance; the surrogate's belief that their presence at the bedside may improve the prognosis; and the surrogate's optimism, intuition, and faith. For some surrogates, these other sources of knowledge superseded the importance of the physician's prognostication. However, most surrogates endeavored to balance their own knowledge of the patient with physicians' biomedical knowledge. CONCLUSIONS: Surrogates use diverse types of knowledge when estimating their loved ones' prognoses, including individualized attributes of the patient, such as their strength of character and life history, of which physicians may be unaware. Attention to these considerations may help clinicians identify and overcome disagreements about prognosis.

Feasibility and effectiveness of the NEST13+ as a screening tool for advanced illness care needs.

BACKGROUND: A comprehensive whole-person approach might improve processes and outcomes of care for patients with cancer. OBJECTIVE: To assess the ability of NEST13+ (Needs of a social nature; Existential concerns; Symptoms; and Therapeutic interaction), a screening and assessment tool, to identify social, emotional, physical, and care-system needs and to improve clinical outcomes for cancer patients in tertiary care. DESIGN, SETTING, PATIENTS: A controlled trial involving 451 patients hospitalized for cancer care at a comprehensive cancer center. INTERVENTION: Patients responded to 13 screening questions regarding possible care needs. When an individual response exceeded threshold levels, additional in-depth questions for the relevant need were asked. For patients in the intervention arm, clinical recommendations for each dimension of need were generated based on a previously developed NEST-response-driven menu, and were reported to the clinical team. MEASUREMENTS: Documented needs, clinician response, patient perception of goals alignment, and overall quality of palliative care. RESULTS: Using the NEST13+ tool in the clinical setting facilitated greater documentation of illness-related needs than routine clinical assessment. Improvement in secondary outcomes was attenuated: changes in the clinician response were modest; changes in outcomes were not significant. CONCLUSION: The NEST13+ tool facilitated identification of a wider range of important needs than traditional evaluation, while care outcomes were not improved. Traditional evaluation may need improvement. Future trials of the NEST13+ should focus on more intensive clinician-directed interventions.

Frequency tunable near-infrared metamaterials based on VO2 phase transition.

Engineering metamaterials with tunable resonances from mid-infrared to near-infrared wavelengths could have far-reaching consequences for chip based optical devices, active filters, modulators, and sensors. Utilizing the metal-insulator phase transition in vanadium oxide (VO(2)), we demonstrate frequency-tunable metamaterials in the near-IR range, from 1.5 - 5 microns. Arrays of Ag split ring resonators (SRRs) are patterned with e-beam lithography onto planar VO(2) and etched via reactive ion etching to yield Ag/VO(2) hybrid SRRs. FTIR reflection data and FDTD simulation results show the resonant peak position red shifts upon heating above the phase transition temperature. We also show that, by including coupling elements in the design of these hybrid Ag/VO(2) bi-layer structures, we can achieve resonant peak position tuning of up to 110 nm.

Surrogate decision-makers' perspectives on discussing prognosis in the face of uncertainty.

RATIONALE: Many physicians are reluctant to discuss a patient's prognosis when there is significant prognostic uncertainty. OBJECTIVES: We sought to understand surrogate decision makers' views regarding whether physicians should discuss prognosis in the face of uncertainty. METHODS: We conducted semi-structured interviews with 179 surrogates for 142 incapacitated patients at high risk of death in four intensive care units at an academic medical center. The interviews explored surrogates' attitudes about whether physicians should discuss prognosis when they cannot be certain their prognostic estimates are correct. We used constant comparative methods to analyze the transcripts. Validation methods included triangulation by multidisciplinary analysis and member checking. MEASUREMENTS AND MAIN RESULTS: Eighty-seven percent (155/179) of surrogates wanted physicians to discuss an uncertain prognosis. We identified five main reasons for this, including surrogates' belief that prognostic uncertainty is unavoidable, that physicians are their only source for prognostic information, and that discussing prognostic uncertainty leaves room for realistic hope, increases surrogates' trust in the physician, and signals a need to prepare for possible bereavement. Twelve percent (22/179) of surrogates felt that discussions about an uncertain prognosis should be avoided. The main explanation was that it is not worth the potential emotional distress if the prognostications are incorrect. Surrogates suggested that physicians should explicitly discuss uncertainty when prognosticating. CONCLUSIONS: The majority of surrogates of patients that are critically ill want physicians to disclose their prognostic estimates even if they cannot be certain they are correct. This stems from surrogates' belief that prognostic uncertainty is simultaneously unavoidable and acceptable.

Mentoring urban Black Middle-School Male Students: Implications for Academic Achievement.

Researchers have called for innovative and culturally responsive intervention programs to enhance male, African American middle school students' academic achievement. Mentoring has received considerable attention as a novel remedy. Although anecdotal evidence supports the positive role of mentoring on academic achievement, these results are not consistent. The Benjamin E. Mays Institute (BEMI) builds on the ideals of mentoring to counter the effects academic underachievement among adolescent Black males by building a model that is Afro-centric, uses pro-social modeling, and emphasizes cultural strengths and pride, and single-sex instruction in a dual-sex educational environment. Sixty-one middle-school Black males were enrolled (BEMI: n=29; Comparison: n=32) in this study. Results revealed that students in the BEMI program had significantly greater academic attachment scores and academic success than their non-mentored peers. Additionally, racial identity attitudes of immersion/emersion and internalization and identification with academics were also significantly associated with standardized achievement tests and GPA. Policy and practice implications are discussed.

Hope, truth, and preparing for death: perspectives of surrogate decision makers.

BACKGROUND: Although many physicians worry that openly discussing a poor prognosis will cause patients and families to lose hope, surrogate decision makers' perspectives on this topic are largely unknown. OBJECTIVE: To determine surrogate decision makers' attitudes toward balancing hope and telling the truth when discussing prognosis. DESIGN: Prospective, mixed-methods cohort study. SETTING: 4 intensive care units at the University of California, San Francisco, Medical Center, San Francisco, California. PARTICIPANTS: 179 surrogate decision makers for incapacitated patients at high risk for death. MEASUREMENTS: One-on-one, semistructured interviews with surrogates were conducted on the patients' 5th day of receiving mechanical ventilation. Constant comparative methods were used to inductively develop a framework to describe participants' responses. Validation methods included multidisciplinary analysis and member checking. RESULTS: Overall, 93% (166 of 179) of surrogates felt that avoiding discussions about prognosis is an unacceptable way to maintain hope. The main explanatory theme was that timely discussion of prognosis is essential to allow family members to prepare emotionally and logistically for the possibility of a patient's death. Other themes that emerged included surrogates' belief that an accurate understanding of a patient's prognosis allows them to better support the patient and each other, a moral aversion to the idea of false hope, the perception that physicians have an obligation to discuss prognosis, and the notion that some surrogates look to physicians primarily for truth and seek hope elsewhere. A few surrogates (6 of 179) felt that physicians should withhold prognostic information because of a belief that discussing death could be emotionally damaging to the family or could negatively affect the patient's health. LIMITATION: The authors did not longitudinally assess whether early disclosure about prognosis predicts fewer adverse bereavement outcomes. CONCLUSION: Most surrogates of critically ill patients do not view withholding prognostic information as an acceptable way to maintain hope, largely because timely discussions about prognosis help families begin to prepare emotionally, existentially, and practically for the possibility that a patient will die.

Reporting science and conflicts of interest in the lay press.

BACKGROUND: Forthright reporting of financial ties and conflicts of interest of researchers is associated with public trust in and esteem for the scientific enterprise. METHODS/PRINCIPAL FINDINGS: We searched Lexis/Nexis Academic News for the top news stories in science published in 2004 and 2005. We conducted a content analysis of 1152 newspaper stories. Funders of the research were identified in 38% of stories, financial ties of the researchers were reported in 11% of stories, and 5% reported financial ties of sources quoted. Of 73 stories not reporting on financial ties, 27% had financial ties publicly disclosed in scholarly journals. CONCLUSIONS/SIGNIFICANCE: Because science journalists often did not report conflict of interest information, adherence to gold-standard recommendations for science journalism was low. Journalists work under many different constraints, but nonetheless news reports of scientific research were incomplete, potentially eroding public trust in science.

Defining financial conflicts and managing research relationships: an analysis of university conflict of interest committee decisions.

Despite a decade of federal regulation and debate over the appropriateness of financial ties in research and their management, little is known about the actual decision-making processes of university conflict of interest (COI) committees. This paper analyzes in detail the discussions and decisions of three COI committees at three public universities in California. University committee members struggle to understand complex financial relationships and reconcile institutional, state, and federal policies and at the same time work to protect the integrity of the scientific process, the autonomy and intellectual freedom of their faculty colleagues and students, and the financial interests of the university.