bluuebunny/crossref_metadata_2025 huggingface dataset:
Decision‐making for mitigating wildlife diseases: From theory to practice for an emerging fungal pathogen of amphibians
Authors: Canessa Stefano , Bozzuto Claudio , Campbell Grant Evan H. , Cruickshank Sam S. , Fisher Matthew C. , Koella Jacob C. , Lötters Stefan , Martel An , Pasmans Frank , Scheele Ben C. , Spitzen‐van der Sluijs Annemarieke , Steinfartz Sebastian , Schmidt Benedikt R.
Published: January 2018

Conservation science can be most effective in its decision‐support role when seeking answers to clearly formulated questions of direct management relevance. Emerging wildlife diseases, a driver of global biodiversity loss, illustrate the challenges of performing this role: in spite of considerable research, successful disease mitigation is uncommon. Decision analysis is increasingly advocated to guide mitigation planning, but its application remains rare.

Using an integral projection model, we explored potential mitigation actions for avoiding population declines and the ongoing spatial spread of the fungus Batrachochytrium salamandrivorans (Bsal). This fungus has recently caused severe amphibian declines in north‐western Europe and currently threatens Palearctic salamander diversity.

Available evidence suggests that a Bsal outbreak in a fire salamander (Salamandra salamandra) population will lead to its rapid extirpation. Treatments such as antifungals or probiotics would need to effectively interrupt transmission (reduce probability of infection by nearly 90%) in order to reduce the risk of host extirpation and successfully eradicate the pathogen.

Improving the survival of infected hosts is most likely to be detrimental as it increases the potential for pathogen transmission and spread. Active removal of a large proportion of the host population has some potential to locally eradicate Bsal and interrupt its spread, depending on the presence of Bsal reservoirs and on the host's spatial dynamics, which should therefore represent research priorities.

Synthesis and applications. Mitigation of Batrachochytrium salamandrivorans epidemics in susceptible host species is highly challenging, requiring effective interruption of transmission and radical removal of host individuals. More generally, our study illustrates the advantages of framing conservation science directly in the management decision context, rather than adapting to it a posteriori.
Linking landscape composition to predator‐specific nest predation requires examining multiple landscape scales
Authors: Chiavacci Scott J. , Benson Thomas J. , Ward Michael P.
Published: January 2018

Landscape composition around bird nests can strongly influence nest predation, a major cause of reproductive failure for many species. Understanding this relationship may improve the effectiveness of management actions aimed at reducing predation. Despite attempts to link landscape composition to nest predation, consistent patterns have proven elusive, likely because studies often examine only one landscape scale, thereby overlooking scale‐specific interactions between predators and landscape features.

To demonstrate the value of incorporating scale‐dependence when connecting nest predation to landscape composition, we identified predators and analysed predator‐specific patterns among land cover types at four scales (200 m, 500 m, 1 km, 2.5 km). We video monitored 468 nests of 22 shrub‐nesting bird species, documented 212 predation events, and modelled relationships between landscape composition and predation by seven common predators.

The direction and strength of predator‐specific relationships varied among land cover types and scales. No single scale best predicted predation by all predators, though effects appeared to be stronger at larger scales. Two ecologically similar predators (fox snakes [Pantherophis vulpinus] and black ratsnakes [P. obsoletus]) showed contrasting relationships with different land cover types and one commonly cited predator (raccoon [Procyon lotor]) showed positive and negative links to developed cover across scales.

Synthesis and applications. Our results illustrate that elucidating the complex relationships between different nest predator species and the landscape composition surrounding nests requires the incorporation of scale‐dependence. Although such an undertaking may involve intensive nest monitoring to identify predators, it can provide managers with a more complete understanding of the linkages between predation and the landscape surrounding nests. With this knowledge, managers could employ structured decision making in an adaptive management framework to identify optimal strategies that address nest predation and allow them to confront potentially unexpected changes in predation patterns following management actions. Ultimately, by acknowledging that predator species differ in their relationships with landscape composition among different landscape scales, and incorporating this fact into future research, we can improve our ability to focus management on the habitats and scales most likely to impact predators of interest.
Modeling Semicontinuous Longitudinal Expenditures: A Practical Guide
Authors: Smith Valerie A. , Maciejewski Matthew L. , Olsen Maren K.
Published: January 2018

Objective

To compare different strategies for analyzing longitudinal expenditure data that have a point mass at $0. We provide guidance on parameter interpretation, research questions, and model selection.

Data Sources, Study Design, and Data Collection

One‐part models, uncorrelated two‐part models, correlated conditional two‐part (CTP) models, and correlated marginalized two‐part (MTP) models have been proposed for longitudinal expenditures that often exhibit a large proportion of zeros and a distribution of continuous, highly right‐skewed positive values. Guidance on implementing and interpreting each of these model is illustrated with an example of longitudinal (2000–2003) specialty care expenditures of veterans with hypertension, drawn from Veterans Administration data.

Principal Findings

The four strategies answer different research questions, are appropriate for different structures of data, and provide different results. If there is a point mass at $0, then theMTPmodel may be most useful if the primary interest is in mean expenditures of the entire population. ACTPmodel may be most useful if the primary interest is in the level of expenditures conditional on them being incurred.

Conclusions

Researchers should consider which modeling strategy for longitudinal expenditure outcomes is both consistent with research aims and appropriate for the data at hand.
Homicide–Suicide in Cuyahoga County, Ohio, 1991–2016
Authors: Regoeczi Wendy C. , Gilson Thomas
Published: January 2018

Research on homicides followed by suicides has relied heavily on small samples and relatively short time spans of data. This study helps to fill this gap by examining 26 years of homicide–suicide data from Cuyahoga County, Ohio, between 1991 and 2016. The main data source for the study is medical examiner files. Analyses of the data indicate the rate of homicide–suicide in Cuyahoga County is consistent with other studies but fluctuates considerably across years studied. The majority of victims are female while perpetrators are overwhelmingly male. Black people are overrepresented as victims and offenders. Use of drugs and/or alcohol leading up to the incident is common among perpetrators. Both the homicides and suicides were overwhelming committed with firearms. When comparing our results to the typology of murder–suicides developed by Marzuk, Tardiff, and Hirsch (JAMA 1992;267:3179), we find amorous jealousy is a significant motivating factor in a many cases, including those involving nonintimate partners. Our findings underscore the importance of widespread use of lethality assessment instruments.
Effects of sun compass error on spatial search by Clark's nutcrackers
Authors: KELLY Debbie M. , CHENG Ken , BALDA Russell , KAMIL Alan C.
Published: January 2018

Animals employ compasses during navigation, but little attention has been paid to how accuracy is maintained in the face of compass error, which is inevitable in biological systems. The use of multiple landmarks may minimize the effect of compass error. We allowed Clark's nutcrackers to cache seeds in an outdoor aviary with either one or four landmarks present, and subsequently subjected them to small clock‐shifts mimicking the effects of compass error. As predicted, the results showed a significant decrease in search accuracy following the clock‐shift when one landmark was present but not when four landmarks were present. These results support that nutcrackers encode information from the sun as well as terrestrial landmarks, and these spatial cues are used in a flexible manner. Overall, our results are important as they support the hypothesis that multiple landmarks may be used during situations where the sun compass has even a small amount of error.
Potential impacts of shipping noise on Indo‐Pacific humpback dolphins and implications for regulation and mitigation: a review
Authors: LI Songhai , LIU Mingming , DONG Lijun , DONG Jianchen , WANG Ding
Published: January 2018

Shipping noise is a widespread and relatively loud sound source among human‐induced underwater sounds. The impacts of shipping noise are of special concern for Indo‐Pacific humpback dolphins (Sousa chinensis), as they inhabit shallow and nearshore habitats and are highly dependent on sound for survival. This study synthesizes our current understanding of the potential impacts of shipping noise on Indo‐Pacific humpback dolphins combined with knowledge on sound production and hearing of these animals and the impacts of noise on other whales and dolphins. For further protection and management of Indo‐Pacific humpback dolphins and their habitats, shipping noise should be regulated and mitigated to modify sound from ships, to reduce overall noise levels, and to set more marine protected areas (MPAs) covering most Indo‐Pacific humpback dolphin habitats with seasonal and geographical restrictions to avoid ensonification of shipping noise. The emphasis for future research should be on obtaining more baseline information about the population distribution, sound production, hearing capabilities at the population level, behavior, and stress hormones of the humpback dolphins under different noise conditions or under different noise‐producing activities, and/or in high‐noise areas compared with relatively quiet areas, and the noise characteristics of ships of different types, sizes and speeds.
Regional anesthesia decreases complications and resource utilization in shoulder arthroplasty patients
Authors: Herrick M. D. , Liu H. , Davis M. , Bell J.‐E. , Sites B. D.
Published: January 2018

Background

Regional anesthesia can be used as part of the anesthetic to optimize anesthesia and analgesia during shoulder arthroplasty, but little is known about the overall effect that regional anesthesia has on perioperative outcomes and resource utilization. We hypothesized that regional anesthesia may decrease complication rates and resource utilization in shoulder arthroplasty patients.

Methods

We examined administrative data from 588 US hospitals from 2010 to 2015. Logistic regression was used to examine the relationship between type of anesthesia and perioperative complications.

Results

Among patients who underwent shoulder arthroplasty, 79.1% (53,243) had general anesthesia alone, 17.8% (12,011) had general anesthesia and a nerve block, and 3.1% (2062) had a nerve block alone. Overall, the complication rate was 13.3% and 30‐day mortality was 1.2 per 1000 (95% CI 0.9, 1.4). In adjusted analyses, patients who had general anesthesia alone (compared to general anesthesia and nerve block) had a 16% increase in all cause infectious complications (OR 1.16, 95% CI: 1.03, 1.31) and were 2.6 times more likely to develop pulmonary complications (OR 2.6, 95% CI: 1.14, 5.78). General anesthesia alone (relative to either block only or general anesthesia and block) was associated with substantial increases in the likelihood of blood transfusions, intensive care unit transfers, and prolonged length of stay.

Conclusion

Patients receiving regional anesthesia for shoulder arthroplasty may have a reduction in perioperative complications, the need for intensive care unit transfers, blood transfusions, and prolonged hospital stays.
Effectiveness of Interventions to Decrease Image Ordering for Low Back Pain Presentations in the Emergency Department: A Systematic Review
Authors: Liu Chaocheng , Desai Shashwat , Krebs Lynette D. , Kirkland Scott W. , Keto‐Lambert Diana , Rowe Brian H. ,   the PRIHS‐2 Choosing Wisely Team
Published: January 2018

Background

Low back pain (LBP) is an extremely frequent reason for patients to present to an emergency department (ED). Despite evidence against the utility of imaging, simple and advanced imaging (i.e., computed tomography [CT], magnetic resonance imaging) for patients with LBP has become increasingly frequent in the ED. The objective of this review was to identify and examine the effectiveness of interventions aimed at reducing image ordering in the ED for LBP patients.

Methods

A protocol was developed a priori, following the PRISMA guidelines, and registered with PROSPERO. Six bibliographic databases (including MEDLINE, EMBASE, EBM Reviews, SCOPUS, CINAHL, and Dissertation Abstracts) and the gray literature were searched. Comparative studies assessing interventions that targeted image ordering in the ED for adult patients with LBP were eligible for inclusion. Two reviewers independently screened study eligibility and completed data extraction. Study quality was completed independently by two reviewers using the before–after quality assessment checklist, with a third‐party mediator resolving any differences. Due to a limited number of studies and significant heterogeneity, only a descriptive analysis was performed.

Results

The search yielded 603 unique citations of which a total of five before–after studies were included. Quality assessment identified potential biases relating to comparability between the pre‐ and postintervention groups, reliable assessment of outcomes, and an overall lack of information on the intervention (i.e., time point, description, intervention data collection). The type of interventions utilized included clinical decision support tools, clinical practice guidelines, a knowledge translation initiative, and multidisciplinary protocols. Overall, four studies reported a decrease in the relative percentage change in imaging in a specific image modality (22.7%–47.4%) following implementation of the interventions; however, one study reported a 35% increase in patient referrals to radiography, while another study reported a subsequent 15.4% increase in referrals to CT and myelography after implementing an intervention which reduced referrals for simple radiography.

Discussion

While imaging of LBP has been identified as a key area of imaging overuse (e.g., Choosing Wisely recommendation), evidence on interventions to reduce image ordering for ED patients with LBP is sparse. There is some evidence to suggest that interventions can reduce the use of simple imaging in LBP in the ED; however, a shift in imaging modality has also been demonstrated. Additional studies employing higher‐quality methods and measuring intervention fidelity are strongly recommended to further explore the potential of ED‐based interventions to reduce image ordering for this patient population.
House dust mite impairs antiviral response in asthma exacerbation models through its effects on TLR3
Authors: Akbarshahi H. , Menzel M. , Ramu S. , Mahmutovic Persson I. , Bjermer L. , Uller L.
Published: January 2018

Background

Impaired antiviral interferon expression may be involved in asthma exacerbations commonly caused by rhinovirus infections. Allergy is a known risk factor for viral‐induced asthma exacerbation, but little is known whether allergens may affect interferon responses.

Objective

Our hypothesis is that house dust mite (HDM) impairs viral stimulus‐induced antiviral signalling.

Methods

Experimental asthma exacerbations were produced in vitro in human bronchial epithelial cells (HBECs) and in mice using sequential challenges with HDM and a viral infection mimic, Poly(I:C). We examined rhinovirus pattern recognition receptors (PRRs) signalling pathways and potential mechanisms of impaired interferon response.

Results

HBECs and mice exposed to HDM prior to Poly(I:C) exhibited a reduced antiviral response compared to Poly(I:C) alone, including reduced IFN‐β, IFN‐λ, TLR3, RIG‐I, MDA5, IRF‐3 and IRF‐7. Heat inactivation of HDM partially restored the TLR3‐induced interferon response in vitro and in vivo. Our HBEC‐data further showed that HDM directly affects TLR3 signalling by targeting the receptor glycosylation level.

Conclusions

Direct effects of allergens such as HDM on PRRs can present as potential mechanism for defective antiviral airway responses. Accordingly, therapeutic measures targeting inhibitory effects of allergens on antiviral PRRs may find use as a strategy to boost antiviral response and ameliorate exacerbations in asthmatic patients.
In chronic spontaneous urticaria, IgE against staphylococcal enterotoxins is common and functional
Authors: Altrichter S. , Hawro T. , Liedtke M. , Holtappels G. , Bachert C. , Skov P. S. , Maurer M.
Published: January 2018

Background

Chronic spontaneous urticaria (CSU) is a frequent disorder with recurrent itchy wheals and/or angioedema. Despite the known effectiveness of omalizumab therapy, the relevant IgE antigens are largely unknown. Recently, increased rates of elevated levels of IgE towards Staphylococcus aureus enterotoxins (SEs) were described in CSU.

Aim

To assess the prevalence and functional relevance of IgE to SEs in CSU.

Method

We investigated serum levels of IgE against SEs in 49 CSU patients and in 15 CSU patients additional specific IgE to SE components and basophil histamine release (BHR). Sera of 15 healthy controls (HCs) served as control group.

Results

Twenty‐five (51%) of the CSU patients had detectable levels of SE‐IgE as compared to 5 (33%) of HCs. Specific IgE to one of the SEs, Staphylococcus enterotoxin B (SEB), was present in 5 (33%) of 15 randomly selected CSU patients vs 3 (20%) of HC. Total IgE serum levels in CSU patients were significantly correlated with SE‐IgE (r = .52, P < .001) and SEB‐IgE (r = .54, P = .04) serum concentrations. Interestingly, SEB‐IgE levels were strongly correlated with disease activity (UASday) in CSU patients (r = .657, P = .01). Furthermore, BHR in response to SEB was significantly higher in basophils loaded with the serum of CSU patients compared to HC (P < .05) and was clinically correlated with duration of disease (r > .51, P < .05).

Discussion

IgE against SEs may contribute to the pathogenesis of CSU in a subpopulation of patients. Its role and relevance in the pathophysiology of CSU need to be further analysed.
Subcutaneous immunotherapy with purified Der p1 and 2 suppresses type 2 immunity in a murine asthma model
Authors: Hesse L. , van Ieperen N. , Habraken C. , Petersen A. H. , Korn S. , Smilda T. , Goedewaagen B. , Ruiters M. H. , van der Graaf A. C. , Nawijn M. C.
Published: January 2018

Background

Allergen‐specific immunotherapy can induce long‐term suppression of allergic symptoms, reduce medication use, and prevent exacerbations of allergic rhinitis and asthma. Current treatment is based on crude allergen extracts, which contain immunostimulatory components such as β‐glucans, chitins, and endotoxin. Use of purified or recombinant allergens might therefore increase efficacy of treatment.

Aims

Here, we test application of purified natural group 1 and 2 allergens from Dermatophagoides pteronyssinus (Der p) for subcutaneous immunotherapy (SCIT) treatment in a house dust mite (HDM)‐driven mouse model of allergic asthma.

Materials and methods

HDM‐sensitized mice received SCIT with crude HDM extract, a mixture of purified Der p1 and 2 (DerP1/2), or placebo. Upon challenges, we measured specific immunoglobulin responses, allergen‐induced ear swelling response (ESR), airway hyperresponsiveness (AHR), and inflammation in bronchoalveolar lavage fluid (BAL) and lung tissue.

Results

ESR measurement shows suppression of early allergic response in HDM‐SCIT– and DerP1/2‐SCIT–treated mice. Both HDM‐SCIT and DerP1/2‐SCIT are able to suppress AHR and eosinophilic inflammation. In contrast, only DerP1/2‐SCIT is able to significantly suppress type 2 cytokines in lung tissue and BAL fluid. Moreover, DerP1/2‐SCIT treatment is uniquely able suppress CCL20 and showed a trend toward suppression of IL‐33, CCL17 and eotaxin levels in lung tissue.

Discussion

Taken together, these data show that purified DerP1/2‐SCIT is able to not only suppress AHR and inflammation, but also has superior activity toward suppression of Th2 cells and HDM‐induced activation of lung structural cells including airway epithelium.

Conclusions

We postulate that treatment with purified natural major allergens derived from HDM will likely increase clinical efficacy of SCIT.
Fish oil in infancy protects against food allergy in Iceland—Results from a birth cohort study
Authors: Clausen M. , Jonasson K. , Keil T. , Beyer K. , Sigurdardottir S. T.
Published: January 2018

Background

Consumption of oily fish or fish oil during pregnancy, lactation and infancy has been linked to a reduction in the development of allergic diseases in childhood.

Methods

In an observational study, Icelandic children (n = 1304) were prospectively followed from birth to 2.5 years with detailed questionnaires administered at birth and at 1 and 2 years of age, including questions about fish oil supplementation. Children with suspected food allergy were invited for physical examinations, allergic sensitization tests, and a double‐blind, placebo‐controlled food challenge if the allergy testing or clinical history indicated food allergy. The study investigated the development of sensitization to food and confirmed food allergy according to age and frequency of postnatal fish oil supplementation using proportional hazards modelling.

Results

The incidence of diagnosed food sensitization was significantly lower in children who received regular fish oil supplementation (relative risk: 0.51, 95% confidence interval: 0.32‐0.82). The incidence of challenge‐confirmed food allergy was also reduced, although not statistically significant (0.57, 0.30‐1.12). Children who began to receive fish oil in their first half year of life were significantly more protected than those who began later (P = .045 for sensitization, P = .018 for allergy). Indicators of allergy severity decreased with increased fish oil consumption (P = .013). Adjusting for parent education and allergic family history did not change the results.

Conclusion

Postnatal fish oil consumption is associated with decreased food sensitization and food allergies in infants and may provide an intervention strategy for allergy prevention.
Similar localization of conformational IgE epitopes on the house dust mite allergens Der p 5 and Der p 21 despite limited IgE cross‐reactivity
Authors: Curin M. , Garmatiuk T. , Resch‐Marat Y. , Chen K. W. , Hofer G. , Fauland K. , Keller W. , Hemmer W. , Vrtala S. , Focke‐Tejkl M. , Valenta R.
Published: January 2018

Background

Due to high IgE recognition frequency and high allergenic activity, Der p 5 and Der p 21 are clinically important house dust mite (HDM) allergens. The objective of this study was to characterize the immunodominant IgE epitopes of Der p 5 and Der p 21 responsible for their high allergenic activity.

Methods

A panel of 12 overlapping peptides spanning the Der p 5 and Der p 21 sequence were synthesized to search for sequential IgE epitopes by direct testing for allergic patients' IgE reactivity. Peptide‐specific antibodies raised in rabbits were used in inhibition studies for localizing conformational IgE epitopes which were visualized on the surfaces of the allergen structures by molecular modelling. IgE cross‐reactivity between the allergens was investigated by IgE inhibition studies.

Results

Immunodominant IgE epitopes defined by allergic patients' IgE on Der p 5 and Der p 21 were primarily of the conformational, discontinuous type including N‐ and C‐terminal portions of the protein. They could be located on each allergen on one area with similar localization, but despite similar structure of the allergens, no relevant IgE cross‐reactivity could be detected.

Conclusion

Our study shows that Der p 5 and Der p 21 contain a major conformational IgE epitope‐containing area located on similar portions of their structure, but they lack relevant IgE cross‐reactivity. These data are important for the development of modern allergy vaccines based on defined molecules for allergen‐specific immunotherapy of HDM allergy.
A systematic review of outcomes in postoperative pain studies in paediatric and adolescent patients: towards development of a core outcome set
Authors: Ross A. , Young J. , Hedin R. , Aran G. , Demand A. , Stafford A. , Worley J. , Moore M. , Vassar M.
Published: January 2018

Systematic reviews of postoperative pain in children have called into question the consistency of outcomes measured by clinical triallists as well as the measurement instruments used for assessment. Core outcome set methodology may be a solution to improve standardisation. This study provides an evidence‐based foundation for the development of a core outcome set for paediatric postoperative pain studies. We searched ClinicalTrials.gov to identify relevant postoperative pain studies in children. The search yielded 300 registered trials. The following data were then extracted from each of the trials: phase of trial; study type; study design; sample size; all outcomes; whether the outcome was listed as primary, secondary, or tertiary; the measurement instrument for each reported outcome; the specific metric for each outcome; and the type of clinical procedure. Following screening, 134 studies were included in our study. Pain measurement was the most commonly reported outcome (n = 123), followed by total postoperative analgesic dosage (n = 83) and side‐effects (n = 25). Temporal trends indicated that pain assessment and unexpected events increased in use between 2000 and 2016, whereas postoperative analgesia measurement decreased. We found a lack of standardisation among outcomes and measurement instruments in paediatric postoperative pain studies. Development of a core outcome set may improve the quality of future trials and allow for more accurate study‐to‐study comparisons.
Acute lumbar paraspinal compartment syndrome: a systematic review
Authors: Alexander William , Low Nelson , Pratt George
Published: January 2018

While still a rare entity, acute lumbar paraspinal compartment syndrome has an increasing incidence. Similar to other compartment syndromes, acute lumbar paraspinal compartment syndrome is defined by raised pressure within a closed fibro‐osseous space, limiting tissue perfusion within that space. The resultant tissue ischaemia presents as acute pain, and if left untreated, it may result in permanent tissue damage. A literature search of ‘paraspinal compartment syndrome’ revealed 21 articles. The details from a case encountered by the authors are also included. A common data set was extracted, focusing on demographics, aetiology, clinical features, management and outcomes. There are 23 reported cases of acute compartment syndrome. These are typically caused by weight‐lifting exercises, but may also result from other exercises, direct trauma or non‐spinal surgery. Pain, tenderness and paraspinal paraesthesia are key clinical findings. Serum creatine kinase, magnetic resonance imaging and intracompartment pressure measurement confirm the diagnosis. Half of the reported cases have been managed with surgical fasciotomy, and these patients have all had good outcomes relative to those managed with conservative measures with or without hyperbaric oxygen therapy. These good outcomes were despite significant delays to operative intervention. The diagnostic uncertainty and subsequent delay to fasciotomy result from the rarity of this disease entity, and a high level of suspicion is recommended in the appropriate setting. This is particularly true in light of the current popularity of extreme weight lifting in non‐professional athletes. Operative intervention is strongly recommended in all cases based on the available evidence.
Immune checkpoint molecules in acute myeloid leukaemia: managing the double‐edged sword
Authors: Hobo Willemijn , Hutten Tim J. A. , Schaap Nicolaas P. M. , Dolstra Harry
Published: January 2018

New immunotherapeutic interventions have revolutionized cancer treatment. The immune responsiveness of acute myeloid leukaemia (AML) was first demonstrated by allogeneic stem cell transplantation. In addition, milder immunotherapeutic approaches are exploited. However, the long‐term efficacy of these therapies is hampered by various immune resistance and editing mechanisms. In this regard, co‐inhibitory signalling pathways have been shown to play a crucial role. Via up‐regulation of inhibitory checkpoints, tumour‐reactive T cell and Natural Killer cell responses can be strongly impeded. Accordingly, the introduction of checkpoint inhibitors targeting CTLA‐4 (CTLA4) and PD‐1 (PDCD1, CD279)/PD‐L1 (CD274, PDCD1LG1) accomplished a breakthrough in cancer treatment, with impressive clinical responses. Numerous new co‐inhibitory players and novel combination therapies are currently investigated for their potential to boost anti‐tumour immunity and improve survival of cancer patients. Although the challenge here remains to avoid severe systemic toxicity. This review addresses the involvement of co‐inhibitory signalling in AML immune evasion and discusses the opportunities for checkpoint blockers in AML treatment.
Moving on: Transitions out of care for young people with learning disabilities in England and Sweden
Authors: Roberts Helen , Ingold Anne , Liabo Kristin , Manzotti Grazia , Reeves David , Bradby Hannah
Published: January 2018

Accessible summary

When young people with learning disabilities leave the care system, they can experience many problems.

Here we describe some of these problems and what they do (or would like us to do) to improve things.

Young people do not always want the same things that professionals or family carers want.

We do not spend enough time listening to what young people can tell us.

Background

Young people with learning disabilities are frequently underrepresented in research accounts. This study describes the experiences of young people moving from the care system.

Methods

We scoped the English and Swedish literature for first‐hand accounts and interviewed four young people with learning disabilities leaving the English care system. We combined findings from both sources.

Findings

“Grey” and campaigning literature are more likely than academic studies to include the voices of service users, but even then, the voices tend to be those of professional or family carers. Both the literature and interviews demonstrate young peoples’ awareness and understanding of the social as well as financial benefits of work. Good foster care could be precarious, and young people in unhappy placements lacked direction. Exploitation around a young person's housing and finances could be problems. There was evidence of “threshold” difficulties in accessing services.

Conclusions

Despite an NHS commitment to listening to users in the UK, and similar aspirations in Sweden, our search of the literature identified few studies reporting care leavers' with learning disabilities own words. Our data add to the voices of a group frequently silent or silenced. We found evidence of resilience and hope as well as difficulties and frustrations. The accounts in the literature and our interviews provide data on what it can be like to try to operate “the system.” The people we spoke with and those whose accounts we found in the literature were thoughtful and engaging. They provide an important source of knowledge for policy and practice.
The natural compound, formononetin, extracted from Astragalus membranaceus increases adipocyte thermogenesis by modulating PPARγ activity
Authors: Nie Tao , Zhao Shiting , Mao Liufeng , Yang Yiting , Sun Wei , Lin Xiaoliang , Liu Shuo , Li Kuai , Sun Yirong , Li Peng , Zhou Zhiguang , Lin Shaoqiang , Hui Xiaoyan , Xu Aimin , Ma Chung Wah , Xu Yong , Wang Cunchuan , Dunbar P Rod , Wu Donghai
Published: January 2018

Background and Purpose

Increasing energy expenditure through adipocyte thermogenesis is generally accepted as a promising strategy to mitigate obesity and its related diseases. However, few clinically effective and safe agents are known to promote adipocyte thermogenesis. In this study, 20 traditional Chinese herbal medicines were screened to examine whether they induced adipocyte thermogenesis.

Experimental Approach

The effects of Chinese herbal medicines or components isolated from extracts of A. membranaceus, on adipocyte thermogenesis were analysed by assessing expression of uncoupling protein 1 (UCP1) by qPCR. Eight‐week‐old C57BL6/J male mice were fed a high‐fat diet for 8 weeks and then randomized to two groups treated with vehicle or formononetin for another 8 weeks. Glucose tolerance tests and staining of adipose tissue with haematoxylin and eosin were carried out. Whole‐body oxygen consumption was measured with an open‐circuit indirect calorimetry system.

Key Results

Extracts of A. membranaceus increased expression of Ucp1 in primary cultures of mouse adipocytes. Formononetin was the only known component of A. membranaceus extracts to increase adipocyte Ucp1 expression. Diet‐induced obese mice treated with formononetin gained less weight and showed higher energy expenditure than untreated mice. In addition, formononetin binds directly with PPARγ.

Conclusions and Implication

Taken together, our study demonstrates that the Chinese herbal medicine from A. membranaceus and its constituent formononetin have the potential to reduce obesity and associated metabolic disorders. Our results suggest that formononetin regulates adipocyte thermogenesis as a non‐classical PPARγ agonist.
Partial rescue of F508del‐cystic fibrosis transmembrane conductance regulator channel gating with modest improvement of protein processing, but not stability, by a dual‐acting small molecule
Authors: Liu Jia , Bihler Hermann , Farinha Carlos M , Awatade Nikhil T , Romão Ana M , Mercadante Dayna , Cheng Yi , Musisi Isaac , Jantarajit Walailak , Wang Yiting , Cai Zhiwei , Amaral Margarida D , Mense Martin , Sheppard David N
Published: January 2018

Background and Purpose

Rescue of F508del‐cystic fibrosis (CF) transmembrane conductance regulator (CFTR), the most common CF mutation, requires small molecules that overcome protein processing, stability and channel gating defects. Here, we investigate F508del‐CFTR rescue by CFFT‐004, a small molecule designed to independently correct protein processing and channel gating defects.

Experimental Approach

Using CFTR‐expressing recombinant cells and CF patient‐derived bronchial epithelial cells, we studied CFTR expression by Western blotting and channel gating and stability with the patch‐clamp and Ussing chamber techniques.

Key Results

Chronic treatment with CFFT‐004 improved modestly F508del‐CFTR processing, but not its plasma membrane stability. By contrast, CFFT‐004 rescued F508del‐CFTR channel gating better than C18, an analogue of the clinically used CFTR corrector lumacaftor. Subsequent acute addition of CFFT‐004, but not C18, potentiated F508del‐CFTR channel gating. However, CFFT‐004 was without effect on A561E‐CFTR, a CF mutation with a comparable mechanism of CFTR dysfunction as F508del‐CFTR. To investigate the mechanism of action of CFFT‐004, we used F508del‐CFTR revertant mutations. Potentiation by CFFT‐004 was unaffected by revertant mutations, but correction was abolished by the revertant mutation G550E. These data suggest that correction, but not potentiation, by CFFT‐004 might involve nucleotide‐binding domain 1 of CFTR.

Conclusions and Implications

CFFT‐004 is a dual‐acting small molecule with independent corrector and potentiator activities that partially rescues F508del‐CFTR in recombinant cells and native airway epithelia. The limited efficacy and potency of CFFT‐004 suggests that combinations of small molecules targeting different defects in F508del‐CFTR might be a more effective therapeutic strategy than a single agent.
Driving chronicity in rheumatoid arthritis: perpetuating role of myeloid cells
Authors: Alivernini S , Tolusso B , Ferraccioli G , Gremese E , Kurowska-Stolarska M , McInnes I B
Published: January 2018

Acute inflammation is a complex and tightly regulated homeostatic process that includes leucocyte migration from the vasculature into tissues to eliminate the pathogen/injury, followed by a pro-resolving response promoting tissue repair. However, if inflammation is uncontrolled as in chronic diseases such as rheumatoid arthritis (RA), it leads to tissue damage and disability. Synovial tissue inflammation in RA patients is maintained by sustained activation of multiple inflammatory positive-feedback regulatory pathways in a variety of cells, including myeloid cells. In this review, we will highlight recent evidence uncovering biological mechanisms contributing to the aberrant activation of myeloid cells that contributes to perpetuation of inflammation in RA, and discuss emerging data on anti-inflammatory mediators contributing to sustained remission that may inform a novel category of therapeutic targets.
Substance use among older youth transitioning from foster care: Examining the protective effects of religious and spiritual capital
Authors: Scott Lionel D. , Hodge David R. , White Tony , Munson Michelle R.
Published: January 2018

Among older youth transitioning from the foster care system, this longitudinal study examined the association of religious and spiritual capital to substance use in the past year at age 19. Participants consisted of African American (N = 179) and White non‐Hispanic (N = 133) older youth in foster care. Drawing from social capital theory, it was posited that religious service attendance (a proxy for religious capital) and belief in a spiritual force (a proxy for spiritual capital) would be inversely associated with substance use. Multiple logistic regression results indicated support for the first and second hypothesis for White foster youth only. Among White foster youth, more frequent religious service attendance and greater belief in a spiritual force were associated with a lower likelihood of illegal substance and polysubstance use. No association between religious or spiritual capital and substance use was found among African American foster youth. The findings underscore the importance of conducting spiritual assessments to help ensure older foster youth who have strong religious or spiritual orientations are in environments where they are accommodated and supported.
Temporally Consistent Motion Segmentation From RGB‐D Video
Authors: Bertholet P. , Ichim A.E. , Zwicker M.
Published: January 2018

Temporally consistent motion segmentation from RGB‐D videos is challenging because of the limitations of current RGB‐D sensors. We formulate segmentation as a motion assignment problem, where a motion is a sequence of rigid transformations through all frames of the input. We capture the quality of each potential assignment by defining an appropriate energy function that accounts for occlusions and a sensor‐specific noise model. To make energy minimization tractable, we work with a discrete set instead of the continuous, high dimensional space of motions, where the discrete motion set provides an upper bound for the original energy. We repeatedly minimize our energy, and in each step extend and refine the motion set to further lower the bound. A quantitative comparison to the current state of the art demonstrates the benefits of our approach in difficult scenarios.
4,6,4′‐trimethylangelicin shows high anti‐proliferative activity on DU145 cells under both UVA and blue light
Authors: Miolo G. , Sturaro G. , Cigolini G. , Menilli L. , Tasso A. , Zago I. , Conconi M. T.
Published: January 2018

Objectives

Furocoumarins (psoralens and angelicins) have been already used under ultraviolet A light (UVA) for the treatment of skin diseases and cutaneous T‐cell lymphoma. Besides their high anti‐proliferative activity, some severe long‐term side effects have been observed, for example genotoxicity and mutagenicity, likely strictly related to the formation of crosslinks. It has been demonstrated that blue light (BL) activation of 8‐methoxypsoralen, an FDA‐approved drug, leads to less mutagenic monoadducts in the DNA. So far, in this work the less toxic and more penetrating BL is proposed to activate 4,6,4′‐trimethylangelicin (TMA), an already known UVA photoactivatable compound.

Materials and methods

Photocleavage, crosslink formation and oxidative damage were detected in pBR322 plasmid DNA treated with 300.0 μmol/L TMA activated with various exposures of BL. Anti‐proliferative activity, reactive oxygen species (ROS) formation and activation status of some signalling pathways involved in cell growth and apoptosis were verified on DU145 cells treated with 5.0 μmol/L TMA plus 2.0 J/cm2 of BL.

Results

Under BL‐TMA, no mutagenic crosslinks, no photocleavage and neither photooxidative lesions were detected on isolated plasmid DNA. TMA showed high anti‐proliferative activity on DU145 cells through induction of apoptosis. Besides ROS generation, the proapoptotic effect seemed to be related to activation of p38 and inhibition of p44/42 phosphorylation. Interestingly, the decrease in nuclear β‐catenin was coupled with a significant dropping of CD44‐positive cells.

Conclusion

Overall, our results indicate that TMA can be activated by BL and may be considered for targeted phototherapy of prostate cancer lesions.
Association of hypoglycaemia severity with clinical, patient‐reported and economic outcomes in US patients with type 2 diabetes using basal insulin
Authors: Meneghini Luigi F. , Lee Lulu K. , Gupta Shaloo , Preblick Ron
Published: January 2018

Aims

To evaluate the clinical and patient‐reported outcomes and healthcare utilization and costs associated with patient‐reported hypoglycaemia in US adults with type 2 diabetes (T2D) treated with basal insulin.

Materials and methods

This was an observational, cross‐sectional, survey‐based study of adults with T2D on basal insulin ± oral antidiabetes drugs (OADs) or rapid‐acting/premixed insulin, who had in the past ever experienced hypoglycaemia, using US data from the National Health and Wellness Survey. Eligible patients were categorized as having no hypoglycaemia (38.7%), non‐severe hypoglycaemia (55.1%), or severe hypoglycaemia (6.2%) in the preceding 3 months. Outcomes included health‐related quality of life (HRQoL), work productivity and activity impairment, healthcare resource utilization, and estimated direct and indirect costs. Multivariable regression models were performed to control for patient characteristics.

Results

Patients who experienced severe hypoglycaemia had significantly (P < .05) lower HRQoL scores, greater overall impairment of work productivity and activity, greater healthcare resource utilization, and higher costs compared with those who experienced non‐severe or no hypoglycaemia. Patients with non‐severe hypoglycaemia also reported an impact on the number of provider visits, indirect costs, and HRQoL.

Conclusions

Patients with T2D using basal insulin ± OADs or rapid‐acting/premixed insulin in the United States who experienced severe hypoglycaemia had greater impairment of activity and work productivity, utilized more healthcare resources, and incurred higher associated costs than those with non‐severe or no hypoglycaemia. The study also demonstrated the impact that non‐severe hypoglycaemic events have on economic and HRQoL outcomes. Reducing the incidence and severity of hypoglycaemia could lead to clinically meaningful improvements in HRQoL and may result in lower healthcare utilization and associated costs.
Dapagliflozin for prednisone‐induced hyperglycaemia in acute exacerbation of chronic obstructive pulmonary disease
Authors: Gerards Maaike C. , Venema Gerdien E. , Patberg Kornelis W. , Kross Martijn , Potter van Loon Bert Jan , Hageman Ilse M. G. , Snijders Dominic , Brandjes Dees P.M. , Hoekstra Joost B. L. , Vriesendorp Titia M. , Gerdes Victor E. A.
Published: January 2018

The aim of the present study was to compare the effectiveness and safety of add‐on treatment with dapagliflozin to placebo in patients with prednisone‐induced hyperglycaemia during treatment for acute exacerbation of chronic obstructive pulmonary disease (AECOPD). We enrolled 46 patients hospitalized for an AECOPD in a multicentre double‐blind randomized controlled study in which add‐on treatment with dapagliflozin 10 mg was compared with placebo. Glycaemic control and incidence of hypoglycaemia were measured through a blinded subcutaneous continuous glucose monitoring device. Participants in the dapagliflozin group spent 54 ± 27.7% of the time in target range (3.9–10 mmol/L) and participants in the placebo group spent 53.6 ± 23.4% of the time in target range (P = .96). The mean glucose concentration was 10.1 mmol/L in the dapagliflozin group and 10.4 mmol/L in the placebo group (P = .66). One participant using dapagliflozin and 2 participants using placebo experienced symptomatic hypoglycaemia. Treatment with dapagliflozin was safe and there was no difference in risk of hypoglycaemia compared with placebo. Dapagliflozin did not result in better glycaemic control compared with placebo in participants with prednisone‐induced hyperglycaemia during AECOPD.
Long‐term safety and efficacy of tofogliflozin as add‐on to insulin in patients with type 2 diabetes: Results from a 52‐week, multicentre, randomized, double‐blind, open‐label extension, Phase 4 study in Japan (J‐STEP/INS)
Authors: Terauchi Yasuo , Tamura Masahiro , Senda Masayuki , Gunji Ryoji , Kaku Kohei
Published: January 2018

Aims

To evaluate the long‐term safety and efficacy of tofogliflozin as an add‐on treatment to insulin over 52 weeks.

Materials and methods

This 52‐week, multicentre, Phase 4 study consisted of a 16‐week, randomized, double‐blind, placebo‐controlled phase and a 36‐week open label extension phase (NCT02201004). Japanese patients with type 2 diabetes mellitus, aged 20 to 75 years, with suboptimal glycaemic control (7.5%‐10.5%) receiving insulin monotherapy (basal‐bolus, bolus, premix [low and high] and basal) or receiving combination therapy with basal insulin and dipeptidyl peptidase‐4 inhibitor were eligible for participation. Patients who received tofogliflozin throughout the study (52 weeks) were referred to as the ‘tofo‐tofo group’ and patients who received placebo and tofogliflozin (36 weeks) were referred to as the ‘pla‐tofo group’.

Results

A total of 210 patients received treatment per randomization. Hypoglycaemia was the most common treatment‐emergent adverse event (AE) (42.9% in the tofo‐tofo group and 29.4% in the pla‐tofo group). Patients reported genital infection, urinary tract infection, excessive urination and AEs related to volume depletion (2.1%, 2.1%, 7.1% and 10.0% of patients in the tofo‐tofo group, and 0%, 1.5%, 2.9% and 7.4% of patients in the pla‐tofo group, respectively). Mean HbA1c and body weight at baseline (mean changes ± standard error from baseline to Week 52) in the tofo‐tofo and pla‐tofo groups were 8.53% (−0.76% ± 0.077) and 8.40% (−0.73% ± 0.102); 68.84 kg (−1.52 kg ± 0.207) and 72.24 kg (−2.13 kg ± 0.313), respectively.

Conclusions

This study demonstrates the safety and efficacy of tofogliflozin as add‐on to insulin therapy in type 2 diabetes mellitus patients, offering a new therapeutic solution to diabetes management.
QUESTIONS AND ANSWERS: THE FUTURE OF SOCIAL SECURITY
Authors: Diamond Peter A.
Published: January 2018

Comments, questions, and answers about the future of Social Security. (JEL H55)