bluuebunny/crossref_metadata_2025 huggingface dataset:
Time courses of COVID-19 infection and local variation in socioeconomic and health disparities in England
Authors: Liu Shelley H. , Liu Bian , Li Yan , Norbury Agnes
Published: May 2020

Objective

To identify factors associated with local variation in the time course of COVID-19 case burden in England.

Methods

We analyzed laboratory-confirmed COVID-19 case data for 150 upper tier local authorities, from the period from January 30 to May 6, 2020, as reported by Public Health England. Using methods suitable for time-series data, we identified clusters of local authorities with distinct trajectories of daily cases, after adjusting for population size. We then tested for differences in sociodemographic, economic, and health disparity factors between these clusters.

Results

Two clusters of local authorities were identified: a higher case trajectory that rose faster over time to reach higher peak infection levels, and a lower case trajectory cluster that emerged more slowly, and had a lower peak. The higher case trajectory cluster (79 local authorities) had higher population density (p<0.001), higher proportion of Black and Asian residents (p=0.03; p=0.02), higher multiple deprivation scores (p<0.001), a lower proportions of older adults (p=0.005), and higher preventable mortality rates (p=0.03). Local authorities with higher proportions of Black residents were more likely to belong to the high case trajectory cluster, even after adjusting for population density, deprivation, proportion of older adults and preventable mortality (p=0.04).

Conclusion

Areas belonging to the trajectory with significantly higher COVID-19 case burden were more deprived, and had higher proportions of ethnic minority residents. A higher proportion of Black residents in regions belonging to the high trajectory cluster was not fully explained by differences in population density, deprivation, and other overall health disparities between the clusters.

What is already known on this subject?

Emerging evidence suggests that the burden of COVID-19 infection is falling unequally across England, with provisional data suggesting higher overall infection and mortality rates for Black, Asian, and mixed race/ethnicity individuals.

What does this study add?

We found that regions with greater socioeconomic deprivation and poorer population health measures showed a faster rise in COVID-19 cases, and reached higher peak case levels. Areas with a higher proportion of Black residents were more likely to show this kind of time course, even after adjusting for multiple co-occurring factors, including population density. This finding merits further investigation in terms of the intersecting vulnerability factors Black and other minority ethnic individuals face in England (e.g. proportion of people working in service and caring roles, and the role of structural discrimination), and has implications for the ongoing allocation of public health resources, in order to better mitigate such inequalities.
Use of the Spatial Access Ratio to Measure Geospatial Access to Emergency Surgical Services in California
Authors: Wan Neng , Lizotte Steven , Han Jiuying , Varghese Thomas , Nirula Raminder , McCrum Marta
Published: May 2020

Background

Emergency general surgery (EGS) diseases carry a substantial public health burden, accounting for over 3 million admissions annually. Due to their time-sensitive nature, ensuring adequate access to EGS services is critical for reducing patient morbidity and mortality. Travel-time alone, without consideration of resource supply and demand, may be insufficient to determine a regional health care system’s ability to provide timely access to EGS care. Spatial Access Ratio (SPAR) incorporates travel-time, as well as hospital-specific resources and capacity, to determine healthcare accessibility which may be more appropriate for surgical specialties. We therefore compared SPAR to travel-time in their ability to differentiate spatial access to EGS care for vulnerable populations.

Methods

We constructed a Geographic Information Science (GIS) platform using existing road networks, and mapped population location, race and socioeconomic characteristics, as well as all EGS-capable hospitals in California. We then compared the shortest travel time method to the gravity-based SPAR in their ability to identify disparities in spatial access for the population as a whole, and subsequently to describe socio-demographic disparities. Reduced spatial access was defined at > 60 minutes travel time, or lowest three classes of SPAR.

Results

283 EGS-capable hospitals were mapped, 142 (50%) of which had advanced resources. Using shortest travel time, 36.98M people (94.8%) were within 20-minutes driving time to any EGS capable hospital, and 33.49M (85.9%) to an advanced-resourced center. Only 166, 950 (0.4%) experienced prolonged (>60 minutes) travel time to any EGS-capable hospital, which increased to 1.05M (2.7%) for advanced-resources. Using SPAR, 11.5M (29.5%) of people had reduced spatial access to any EGS hospital, which increased to 13.9M (35.7%) when evaluating advanced-resource hospitals. The greatest disparities in spatial access to care were found for rural residents and Native Americans for both overall and advanced EGS services.

Conclusions

While travel time and SPAR showed similar overall patterns of spatial access to EGS-capable hospitals, SPAR showed greater differentiation of spatial access across the state. Nearly one-third of California residents have limited or poor access to EGS hospitals, with the greatest disparities noted for Native American and rural residents. These findings argue for the use of gravity-based models such as SPAR that incorporate measures of population demand and hospital capacity when assessing spatial access to surgical services, and have implications for the allocation of healthcare resources to address disparities.
Regression Analysis of COVID-19 Spread in India and its Different States
Authors: Chauhan Poonam , Kumar Ashok , Jamdagni Pooja
Published: May 2020

Linear and polynomial regression model has been used to investigate the COVID-19 outbreak in India and its different states using time series epidemiological data up to 26th May 2020. The data driven analysis shows that the case fatality rate (CFR) for India (3.14% with 95% confidence interval of 3.12% to 3.16%) is half of the global fatality rate, while higher than the CFR of the immediate neighbors i.e. Bangladesh, Pakistan and Sri Lanka. Among Indian states, CFR of West Bengal (8.70%, CI: 8.21–9.18%) and Gujrat (6.05%, CI: 4.90–7.19%) is estimated to be higher than national rate, whereas CFR of Bihar, Odisha and Tamil Nadu is less than 1%. The polynomial regression model for India and its different states is trained with data from 21st March 2020 to 19th May 2020 (60 days). The performance of the model is estimated using test data of 7 days from 20th May 2020 to 26th May 2020 by calculating RMSE and % error. The model is then used to predict number of patients in India and its different states up to 16th June 2020 (21 days). Based on the polynomial regression analysis, Maharashtra, Gujrat, Delhi and Tamil Nadu are continue to remain most affected states in India.
Fine-tuned spatiotemporal dynamics of sporophylls in movement-assisted dichogamy: a study onClerodendrum infortunatum
Authors: Mukhopadhyay Amritendu , Quader Suhel
Published: May 2020

Over 70% of flowering plants are hermaphroditic, with male and female parts in the same flower. Hermaphroditism is cost-effective because a common investment in reward and attractive structures yields benefits through both male and female reproductive success. However, the advantage is accompanied by an increased risk of self-pollen deposition, which is disadvantageous for both self-compatible and self-incompatible species. Hermaphroditic plants reduce self-pollen deposition by separating sporophylls (male and female reproductive parts) either spatially (herkogamy) or temporally (dichogamy). In movement-assisted dichogamy, both sporophylls are involved in a coordinated motion, where they move in opposite directions. However, the effectiveness of this adaptation in reducing self-pollen deposition may be compromised at the point when the sporophylls cross each other and are close enough to interfere, resulting in a transition phase problem. The solution to this problem lies in the details of the spatiotemporal dynamics of the sporophylls in relation to their reproductive maturity. We studied these details across the floral lifetime of a protandrous shrubClerodendrum infortunatum(Lamiaceae), in rainforest fragments of the Western Ghats, India. We took photos of flowers at regular time intervals and measured sporophyll angles from the images. We also carried out a field experiment to determine stigma receptivity. The findings suggest that the effectiveness of dichogamy is maximised through two properties of the transition phase: physical resistance to self-pollen deposition by narrow stigma lobe opening, and chemical non-receptivity of the stigma during this phase. This study emphasises the importance of accessory adaptations in movement-assisted dichogamy to tackle the transition phase problem, which is inherent in this particular form of dichogamy.
Social media efficacy and workplace relationships
Authors: Snyder Jason , Cistulli Mark D.
Published: May 2020

Purpose

With the increase of social media usage in the workplace as a background, this paper specifically addresses social media efficacy's and social media privacy's impact on supervisor and subordinate trust, affective organizational commitment (AOC) and organizational citizenship behavior (OCB) through the theoretical lens of communication privacy management (CPM) theory.

Design/methodology/approach

An online survey of 337 full- and part-time workers was conducted.

Findings

Path models showed that social media efficacy positively influenced social media privacy which in turn impacted both supervisor trust and subordinate trust. Supervisor trust was positively related to AOC, while subordinate trust positively influenced OCB. t-tests revealed differences between workers who have social media relationships with supervisors and/or subordinates and those workers without such relationships.

Practical implications

If workers believe they are adept at using social media, they will also be less concerned about the company's ability to infringe upon privacy through unwanted access to social media content. If social media efficacy drives perceptions of social media privacy and indirectly influences trust and organizational outcomes then it may be worthwhile for organizations to help enhance workers' feelings of social media efficacy through professional development programs.

Originality/value

This study is the first to extend research on workplace communication privacy into the realm of social media. Social media relationships also influence the work environment. These findings can be used as information in future research as well as policy development and professional development programs.
Affective events theory as a theoretical lens for improving the working environment of academics in developing economies
Authors: Ghasemy Majid , Erfanian Mahdiyeh , Gaskin James Eric
Published: May 2020

Purpose

The rapid pace of progress in academic institutions in developing economies has created stressful and relatively toxic workplaces, resulting in different negative organizational outcomes indicating the need to transform universities into healthier academic workplaces. However, a review of the higher education literature in both developed and developing countries shows that the antecedents and consequences of academics' affective states has been a relatively unexplored area. Hence, our study aims at testing basic tenets of Affective Events Theory (AET) in a higher education context to address this issue.

Design/methodology/approach

This is a quantitative study which applies CB-SEM methodology in analyzing the collected data from 2,324 academics in Malaysian higher education sector. We analyzed the data using EQS software package.

Findings

Our results provided substantial support for the applicability and relevancy of AET in higher education domain. Specifically, welfare and supervisory support were identified as the two work environment features which significantly and equally contribute to academics' job satisfaction. In addition, the results showed that positive affect, in comparison with negative affect, was three times stronger in influencing academics' job satisfaction.

Practical implications

Given the considerable role of positive affect in our study, higher education policy makers are urged to make relevant policies to transform universities into more emotionally safe workplaces. In addition, policies should be formulated in a way that encourages supervisory support and decreases workloads to ensure that the conflicts in general are reduced among academics.

Originality/value

This work is the first large-scale study testing the main tenets of AET in the higher education context. In addition, it addresses the problem of multivariate normality and solves this problem based on the robust methodology which corrects standard errors and fit indices, thereby providing more precise and unbiased results.
Size‐ and stage‐dependence in cause‐specific mortality of migratory brown trout
Authors: Nater Chloé R. , Vindenes Yngvild , Aass Per , Cole Diana , Langangen Øystein , Moe S. Jannicke , Rustadbakken Atle , Turek Daniel , Vøllestad Leif Asbjørn , Ergon Torbjørn
Published: May 2020

Evidence‐based management of natural populations under strong human influence frequently requires not only estimates of survival but also knowledge about how much mortality is due to anthropogenic vs. natural causes. This is the case particularly when individuals vary in their vulnerability to different causes of mortality due to traits, life history stages, or locations.

Here, we estimated harvest and background (other cause) mortality of landlocked migratory salmonids over half a century. In doing so, we quantified among‐individual variation in vulnerability to cause‐specific mortality resulting from differences in body size and spawning location relative to a hydropower dam.

We constructed a multistate mark–recapture model to estimate harvest and background mortality hazard rates as functions of a discrete state (spawning location) and an individual time‐varying covariate (body size). We further accounted for among‐year variation in mortality and migratory behaviour and fit the model to a unique 50‐year time series of mark–recapture–recovery data on brown trout (Salmo trutta) in Norway.

Harvest mortality was highest for intermediate‐sized trout, and outweighed background mortality for most of the observed size range. Background mortality decreased with body size for trout spawning above the dam and increased for those spawning below. All vital rates varied substantially over time, but a trend was evident only in estimates of fishers' reporting rate, which decreased from over 50% to less than 10% throughout the study period.

We highlight the importance of body size for cause‐specific mortality and demonstrate how this can be estimated using a novel hazard rate parameterization for mark–recapture models. Our approach allows estimating effects of individual traits and environment on cause‐specific mortality without confounding, and provides an intuitive way to estimate temporal patterns within and correlation among different mortality sources.
Genetic background and thermal environment differentially influence the ontogeny of immune components during early life in an ectothermic vertebrate
Authors: Palacios Maria G. , Gangloff Eric J. , Reding Dawn M. , Bronikowski Anne M.
Published: May 2020

An understudied aspect of vertebrate ecoimmunology has been the relative contributions of environmental factors (E), genetic background (G) and their interaction (G × E) in shaping immune development and function. Environmental temperature is known to affect many aspects of immune function and alterations in temperature regimes have been implicated in emergent disease outbreaks, making it a critical environmental factor to study in the context of immune phenotype determinants of wild animals.

We assessed the relative influences of environmental temperature, genetic background and their interaction on first‐year development of innate and adaptive immune defences of captive‐born garter snakes Thamnophis elegans using a reciprocal transplant laboratory experiment. We used a full‐factorial design with snakes from two divergent life‐history ecotypes, which are known to differ in immune function in their native habitats, raised under conditions mimicking the natural thermal regime—that is, warmer and cooler—of each habitat.

Genetic background (ecotype) and thermal regime influenced innate and adaptive immune parameters of snakes, but in an immune‐component specific manner. We found some evidence of G × E interactions but no indication of adaptive plasticity with respect to thermal environment. At the individual level, the effects of thermal environment on resource allocation decisions varied between the fast‐ and the slow‐paced life‐history ecotypes. Under warmer conditions, which increased food consumption of individuals in both ecotypes, the former invested mostly in growth, whereas the latter invested more evenly between growth and immune development.

Overall, immune parameters were highly flexible, but results suggest that other environmental factors are likely more important than temperature per se in driving the ecotype differences in immunity previously documented in the snakes under field conditions. Our results also add to the understanding of investment in immune development and growth during early postnatal life under different thermal environments. Our finding of immune‐component specific patterns strongly cautions against oversimplification of the highly complex immune system in ecoimmunological studies. In conjunction, these results deepen our understanding of the degree of immunological flexibility wild animals present, information that is ever more vital in the context of rapid global environmental change.
Attack and aggregation of a major squash pest: Parsing the role of plant chemistry and beetle pheromones across spatial scales
Authors: Brzozowski Lauren J. , Gardner Jeffrey , Hoffmann Michael P. , Kessler André , Agrawal Anurag A. , Mazourek Michael
Published: May 2020

Successful management of insect crop pests requires an understanding of the cues and spatial scales at which they function to affect rates of attack of preferred and non‐preferred host plants. A long‐standing conceptual framework in insect–plant ecology posits that there is hierarchical structure spanning host location, acceptance and attack that could be exploited for integrated pest management.

We investigated how plant‐ and insect‐derived chemical cues affect successive decisions of host choice in aggregating insects, and tested predictions in the Cucurbita pepo–Acalymma vittatum system. Acalymma vittatum is an aggregating specialist beetle pest that strongly prefers zucchini (C. p. pepo) to summer squash (C. p. ovifera), two independent domesticates of C. pepo. We hypothesized that subspecies‐specific plant traits, especially volatile cues, interact with the male‐produced aggregation pheromone to amplify beetle preference for C. p. pepo.

Differential beetle attack of C. pepo subspecies in the field is not determined by plant traits that affect host finding or differential aggregation due to pheromones: across two years, beetles had strong density‐dependent attraction to both subspecies when male beetles were feeding, and no interactions between plant volatiles and the male‐produced pheromone were detected. In the absence of male pheromone emission, beetles were equally unattracted to plants with or without beetle feeding.

In contrast, plant traits that mediate insect acceptance appear to underlie differences in preference. At a local scale, beetles did not accept and emigrated from C. p. ovifera compared to C. p. pepo. Distinct volatile emissions were observed between subspecies, but further work is needed to identify if these volatiles promote emigration.

Synthesis and applications. By dissecting pest preference during successive host choice decisions, we isolated a trait with implications for pest management. Beetles on cucurbits can be managed by employing cultivars with differential susceptibility (e.g. trap cropping), and the mechanistic knowledge presented here informs best practices and limitations for on‐farm applications. More broadly, pest management in diversified cropping systems can be enhanced through understanding how plant preference gradients affect herbivore movement and behaviour, and plant breeders can target traits to reduce herbivory in such systems.
Salidroside protects against diabetes mellitus‐induced kidney injury and renal fibrosis by attenuating TGF‐β1 and Wnt1/3a/β‐catenin signalling
Authors: Shati Ali A. , Alfaifi Mohammad Y.
Published: May 2020

This study evaluated if the nephroprotective effect of Salidroside in type 1 diabetes mellitus (T1DM) involves modulation of Wnt/β‐catenin signalling pathways. Control or Streptozotocin (STZ, 50 mg/kg, iv)‐induced T1DM adult male Wister rats were treated with the vehicle and Salidroside (100 mg/kg, orally) for 8 weeks daily. As compared to T1DM‐induced rats, Salidroside improved kidney structure, reduced urinary protein and albumin level, increased creatinine clearance, and suppressed renal fibrosis. It also decreased mRNA and protein levels of Wnt1, Wnt3, and TGF‐β1, phosphorylation of Smad‐3, total and nuclear levels of β‐catenin, and levels and activities of cleaved caspase‐3. Concomitantly, Salidroside significantly increased the levels of p‐β‐catenin (Ser33/37/Thr41) and suppressed protein levels of Axin‐2, fibronectin, and, mRNA and protein levels of collagen IIIa, the main targets of β‐catenin. In both control and T1DM rats, Salidroside significantly lowered fasting glucose levels and reduced renal levels of reactive oxygen species (ROS) p‐and GS3Kβ (Ser9) but significantly increased levels of SOD and GSH. In conclusion, Salidroside protected the kidney of rats against T1DM‐induced injury and fibrosis by activating GS3Kβ‐induced inhibition of Wnt1/Wnt3a β‐catenin. This was associated with hypoglycaemic and antioxidant effects.
Children's active outdoor play: ‘good’ mothering and the organisation of children's free time
Authors: Clark Emily , Dumas Alex
Published: May 2020

This qualitative study draws on the Foucault‐inspired notion of biopedagogies to examine and problematise the salient factors of contemporary motherhood impacting children's active outdoor play (AOP). The study positions mothering as a practice, through which children's health and bodies are constructed and disciplined. A discourse analysis of 21 interviews with Canadian mothers identified three discursive constructions of the ‘good mother’: mothers as time managers, risk managers and screen‐time managers. Each was characterised by discursive conflicts that compromised the provision of AOP by mothers. This study provides data necessary for successfully including AOP as a leisure practice within family‐centred health promotion.
A comparative analysis of current blood pressure management guidelines in people with and without diabetes
Authors: Xu Yu , Wu Shujing , Niu Jingya , Li Mian , Lu Jieli , Wang Weiqing , He Jiang , Solomon Henry A. , Bi Yufang , Ning Guang
Published: May 2020

Hypertension is the leading global risk factor for cardiovascular disease and premature death. Recommendations from current guidelines of blood pressure (BP) management differ in many ways; therefore, we did an overview and comparative analysis of major clinical guidelines of BP management in people with and without diabetes, including the definition and classification of hypertension, initiation of antihypertensive drug therapy, BP control targets, and antihypertensive treatment strategies. BP management in patients with diabetes was discussed in great detail using both hypertension and diabetes guidelines. We conclude that high‐level evidence from high‐quality clinical studies is urgently needed to settle uncertainties on BP management recommendations.
Global burden of noncommunicable diseases attributable to high fasting plasma glucose
Authors: Ye Lingxia , Xu Jingya , Zhang Tianyue , Lin Xiling , Pan Xiaowen , Zeng Wenheng , Ren Yuezhong , Shan Pengfei
Published: May 2020

Background

Hyperglycemia is a major public health concern. An understanding of the latest trends of the global burden of noncommunicable diseases (NCDs) by high fasting plasma glucose (HFPG) is critical for determining research priorities and planning health policy.

Methods

This is a comparative burden‐of‐disease study. We obtained global, regional, and national data on deaths and disability‐adjusted life years (DALYs) of NCDs attributable to HFPG from the Global Burden of Disease Study 2017, performed a secondary analysis of deaths and DALYs by time, age, gender, location, and specific causes, and analyzed their associations.

Results

In 2017, 6.39 million deaths and 166.36 million DALYs from NCDs were attributable to HFPG, accounting for 15.6% and 10.7% of all deaths and DALYs, respectively. The burden's rate decreased with time, increased with age and was significantly higher in males. A negative association was found between the sociodemographic index (SDI) and disease burden, and a positive association was found between SDI and male superiority by gender difference and gender ratio.

Conclusions

The burden of NCDs attributable to HFPG has increased significantly since 1990 and varied widely across regions. Greater efforts are needed to prevent and control hyperglycemia, especially in less developed countries and among males.
A practical approach to measuring the biodiversity impacts of land conversion
Authors: Durán América P. , Green Jonathan M. H. , West Christopher D. , Visconti Piero , Burgess Neil D. , Virah‐Sawmy Malika , Balmford Andrew
Published: May 2020

Further progress in reducing biodiversity loss relies on the improved quantification of the connections between drivers of habitat loss and subsequent biodiversity impacts. To this end, biodiversity impact metrics should be able to report linked trends in specific human activities and changes in biodiversity state, accounting for both the ecology of different species and the cumulative effects of historical habitat losses. These characteristics are not currently captured within a single metric.

Here, we develop a globally applicable methodological framework that uses freely and publicly available datasets to quantify the relative impacts of anthropogenic activities on biodiversity. We use species‐specific habitat suitability models to link specific land uses to ensuing changes in the likelihood that local populations of those species will persist. To illustrate our approach, we assess the impacts of soy expansion and other land uses within the Brazilian Cerrado on over 2,000 species of amphibians, birds, mammals and plants for three periods between 2000 and 2014.

Our results showed that mammals and plants suffered the greatest overall reduction of suitable habitat. However, among endemic and near‐endemic species—which face greatest risk of global extinction from habitat conversion in the Cerrado—birds and mammals were the most affected groups. While conversion of natural vegetation to grassland and planted pastures were together responsible for most of the biodiversity impact of recent changes, soy expansion (via direct conversion of natural vegetation) had the greatest impact per unit area. The total biodiversity impact of recent land‐use change was concentrated in the southern states of the Cerrado—Minas Geráis, Goiás and Mato Grosso—but the impact on biodiversity of production of soy was greatest within the agricultural frontiers of Bahía and Piauí.

The flexibility of our approach to examine linkages between biodiversity loss and specific human activities has clear potential to better characterize the pathways by which habitat loss drivers operate. Its capacity to incorporate species‐specific ecological needs, through a globally applicable methodology, can improve the tangibility of biodiversity loss assessments.
Garbage as Racialization
Authors: Millar Kathleen M.
Published: May 2020

This essay examines parallels between the representation of garbage and the racialized production of the category of the human. In recent years, waste has become a ubiquitous metaphor for understanding the lives of the jobless poor, perceived as discarded by global capitalism and thereby rendered “disposable life.” The essay questions the conflation of waste with abjection through an ethnographic analysis of a film and art project produced on a garbage dump in Rio de Janeiro.
Primed Goals and Primed Actions: A Commentary from an Action Theory Point of View
Authors: Frese Michael
Published: May 2020

The meta‐analysis by Chen et al. (2020) opened up an area for new research—priming of goals works to enhance performance similar to goal setting theory. This commentary uses an action theory point of view to add some research questions to be answered in the future.
The Hedging Strategy of Small Arab Gulf States
Authors: Hamdi Sofie , Salman Mohammad
Published: May 2020

In light of growing tensions in the Persian Gulf between Iran and Saudi Arabia, the search for a formula of security in the five small Gulf States—Bahrain, Kuwait, Oman, Qatar, and the United Arab Emirates (UAE)—has become a complex issue. The question that arises is how these small Gulf States can maintain security and stability in the prevailing scenario. As the weaknesses of the small Gulf States tends to polarize the region even more, it is argued that a hedging strategy can best capture the security dilemma that the small Gulf States are facing. This article examines how the five small Gulf States are facing the current security dilemma by following (or not) a hedging strategy. The results of a qualitative content analysis of news articles, official government's documents, and academic literature show that the Gulf States vary in warmth toward Iran or Saudi Arabia. Oman, and to a lesser extent Kuwait, seem to have good relations with both sides. Qatar currently enjoys relatively warm relations with Iran, while the UAE and Bahrain lean more toward the Saudi side.
Tablets or oral suspension for posaconazole in lung transplant recipients? Consequences for trough concentrations of tacrolimus and everolimus
Authors: Chanoine Sébastien , Gautier‐Veyret Elodie , Pluchart Hélène , Tonini Julia , Fonrose Xavier , Claustre Johanna , Bedouch Pierrick , Stanke‐Labesque Françoise
Published: May 2020

Aims

A new formulation of posaconazole (PCZ), delayed‐release tablets (PCZ‐tab), increases PCZ bioavailability and plasma trough concentrations (Cmin) over those achieved with an oral suspension (PCZ‐susp). PCZ is an inhibitor of cytochrome P450 3A4 and P‐glycoprotein. We therefore investigated the impact of PCZ‐tab treatment on blood Cmin and doses of tacrolimus (TAC) and everolimus (EVR).

Methods

Eighteen lung transplant patients receiving TAC (n = 13) or TAC + EVR (n = 5) between June 2015 and March 2016 were retrospectively included. Ten of these patients received both PCZ‐tab and PCZ‐susp (i.e. switched patients); the other 8 received only PCZ‐tab. Plasma Cmin of PCZ (n = 64), blood Cmin of TAC (n = 299) and EVR (n = 80) were determined during routine therapeutic drug monitoring by liquid chromatography–tandem mass spectrometry.

Results

PCZ Cmin on PCZ‐tab treatment (n = 48) was 2.5 times higher than that on PCZ‐susp therapy (n = 16), for both PCZ patients (P < .0001) and for switched patients (P = .003). PCZ initiation, regardless of galenic form, increased TAC and EVR Cmin adjusted for dose (D), 3‐fold and 3.5‐fold, respectively (P < .0001 for both). PCZ‐tab treatment was associated with a higher TAC Cmin/D (PCZ‐tab vs PCZ‐susp: 0.004 ± 0.004 L−1 vs 0.009 ± 0.006 L−1, P < .0001) and lower TAC daily dose than PCZ‐susp (PCZ‐tab vs PCZ‐susp: 1.08 ± 0.92 vs 2.32 ± 1.62 mg d–1, P < .0001). EVR Cmin/D was higher and EVR dose tended to be lower on PCZ‐tab than on PCZ‐susp.

Conclusion

The greater PCZ exposure achieved during PCZ‐tab treatment increased drug–drug interactions with TAC and EVR, resulting in greater exposure, potentially exposing patients to higher risks of adverse effects.
Primary care providers' use of and attitudes towards placebos: An exploratory focus group study with US physicians
Authors: Bernstein Michael H. , Locher Cosima , Stewart‐Ferrer Sif , Buergler Sarah , DesRoches Catherine M. , Dossett Michelle L. , Miller Franklin G. , Grose Deborah , Blease Charlotte R.
Published: May 2020

Objective

To examine how primary care physicians define placebo concepts, use placebos in clinical practice, and view open‐label placebos (OLPs).

Design

Semi‐structured focus groups that were audio‐recorded and content‐coded.

Methods

Two focus groups with a total of 15 primary care physicians occurred at medical centres in the New England region of the United States. Prior experience using placebo treatments and attitudes towards open‐label placebos were explored. Themes were analysed using an inductive data‐driven approach.

Results

Physicians displayed a nuanced understanding of placebos and placebo effects in clinical contexts which sometimes focused on relational factors. Some respondents reported that they prescribed treatments with no known pharmacological effect for certain conditions and symptoms (‘impure placebos’) and that such prescriptions were more common for pain disorders, functional disorders, and medically unexplained symptoms. Opinions about OLP were mixed: Some viewed OLPs favourably or considered them ‘harmless’; however, others strongly rejected OLPs as disrespectful to patients. Other issues in relation to OLPs included the following: lack of guidelines, legal and reputational concerns, and the notion that such treatments would run counter to customary medical practice.

Conclusions

A number of physicians reported prescribing impure placebos in clinical care. Although some primary care physicians were resistant to the possibility of recommending OLPs, others regarded OLPs more favourably, viewing them as potential treatments, albeit with restricted potential.

Statement of contribution

What is already known?

Many physicians report prescribing drugs for the purposes of eliciting a placebo effect.

Initial evidence for the efficacy of open‐label placebos is promising.

What does this study add?

A more nuanced description of the circumstances under which primary care physicians report placebo prescribing.

A qualitative account of physician attitudes about using open‐label placebos in clinical practice.
Caregiving burden among informal caregivers of people with disability
Authors: Sit Hao Fong , Huang Lei , Chang Kay , Chau Wai I , Hall Brian J.
Published: May 2020

Objective

Chinese informal caregivers experience burden due to their caregiving responsibilities that violate their belief of reciprocal parent–child relationship, but little is known about this burden and coping processes among Chinese. It is believed that internal coping (i.e., self‐reliance) and external coping (i.e., seeking help from others) better captured cultural characteristics of coping styles observed among Chinese. Thus, the aim of this study was to estimate the prevalence of mental ill health, identify correlates, investigate the impact of caregiving burden on mental health, and explore the potentially moderating role of two coping strategies.

Design

A purposive sample of 234 informal caregivers of family with intellectual or mental disability in Macao (SAR), China, from August to September 2018 was investigated.

Methods

DASS‐21, Caregiving Burden Inventory (CBI), Perceived Difficulty Scale (PD), and a modified Chinese Coping Scale were used. Multiple regression analyses were conducted.

Results

CBI and PD were associated with depression, anxiety, and stress. Whereas internal coping buffered the effect of PD on depression and anxiety, external coping exacerbated the effect of PD on anxiety and the effect of CBI on depression and anxiety.

Conclusion

Poor mental health among caregivers is associated with greater caregiving challenges and burdens. Internal coping helped to buffer but external coping worsened the effect of burdens on mental health outcomes. Interventions that improve internal coping and mental health might be helpful for ageing informal caregivers.
Metformin mitigates gastrointestinal radiotoxicity and radiosensitises P53 mutation colorectal tumours via optimising autophagy
Authors: Chen Long , Liao Fengying , Jiang Zhongyong , Zhang Chi , Wang Ziwen , Luo Peng , Jiang Qingzhi , Wu Jie , Wang Qing , Luo Min , Li Xueru , Leng Yu , Ma Le , Shen Gufang , Chen Zelin , Wang Yu , Tan Xu , Gan Yibo , Liu Dengqun , Liu Yunsheng , Shi Chunmeng
Published: May 2020

Background and Purpose

There is an urgent but unmet need for mitigating radiation‐induced intestinal toxicity while radio sensitising tumours for abdominal radiotherapy. We aimed to investigate the effects of metformin on radiation‐induced intestinal toxicity and radiosensitivity of colorectal tumours.

Experimental Approach

Acute and chronic histological injuries of the intestine from mice were used to assess radioprotection and IEC‐6 cell line was used to investigate the mechanisms in vitro. The fractionated abdominal radiation model of HCT116 and HT29 tumour grafts was used to determine the effects on colorectal cancer.

Key Results

Metformin alleviated radiation‐induced acute and chronic intestinal toxicity by optimising mitophagy which was AMPK‐dependent. In addition, our data indicated that metformin increased the radiosensitivity of colorectal tumours with P53 mutation both in vitro and in vivo.

Conclusion and Implications

Metformin may be a radiotherapy adjuvant agent for colorectal cancers especially those carrying P53 mutation. Our findings provide a new strategy for further precise clinical trials for metformin on radiotherapy.
Clonal lineage from normal endometrium to ovarian clear cell carcinoma through ovarian endometriosis
Authors: Suda Kazuaki , Cruz Diaz Luis Antonio , Yoshihara Kosuke , Nakaoka Hirofumi , Yachida Nozomi , Motoyama Teiichi , Inoue Ituro , Enomoto Takayuki
Published: May 2020

Clear cell carcinoma of the ovary is thought to arise from endometriosis. In addition, retrograde menstruation of shed endometrium is considered the origin of endometriosis. However, little evidence supports cellular continuity from uterine endometrium to clear cell carcinoma through endometriosis at the genomic level. Here, we performed multiregional whole‐exome sequencing to clarify clonal relationships among uterine endometrium, ovarian endometriosis and ovarian clear cell carcinoma in a 56‐year‐old patient. Many somatic mutations including cancer‐associated gene mutations in ARID1A, ATM, CDH4, NRAS and PIK3CA were shared among epithelium samples from uterine endometrium, endometriotic lesions distant from and adjacent to the carcinoma, and the carcinoma. The mutant allele frequencies of shared mutations increased from uterine endometrium to distant endometriosis, adjacent endometriosis, and carcinoma. Although a splice site mutation of ARID1A was shared among the four epithelium samples, a frameshift insertion in ARID1A was shared by adjacent endometriosis and carcinoma samples, suggesting that the biallelic mutations triggered malignant transformation. Somatic copy number alterations, including loss of heterozygosity events at PIK3CA and ATM, were identified only in adjacent endometriosis and carcinoma, suggesting that mutant allele‐specific imbalance is another key factor driving malignant transformation. By reconstructing a clonal evolution tree based on the somatic mutations, we showed that the epithelium samples were derived from a single ancestral clone. Although the study was limited to a single patient, the results from this illustrative case could suggest the possibility that epithelial cells of ovarian endometriosis and clear cell carcinoma were descendants of uterine endometrial epithelium.
Highly expressed tumoral emmprin and stromal CD73 predict a poor prognosis for external auditory canal carcinoma
Authors: Miyazaki Masaru , Aoki Mikiko , Okado Yasuko , Koga Kaori , Hamasaki Makoto , Nakagawa Takashi , Sakata Toshifumi , Nabeshima Kazuki
Published: May 2020

Squamous cell carcinoma of the external auditory canal (SCC‐EAC) is rare and has a poor prognosis. The SCC‐EAC cases with high‐grade tumor budding (TB) or poorly differentiated clusters (PDCs) are associated with shorter survival than those with low‐grade TB or PDCs. Extracellular matrix metalloproteinase inducer (emmprin) is a protein expressed in tumor cells that stimulates the production of MMP‐2 by stromal fibroblasts to facilitate tumor invasion. Recently, we reported that emmprin forms a complex with CD73 to regulate MMP‐2 production from fibroblasts in vitro. Here, we examined the association of emmprin and CD73 expression with TB or PDCs as well as with survival in 34 biopsy specimens of SCC‐EAC patients. High tumoral emmprin expression was associated with high­grade TB, whereas high stromal CD73 expression was associated with high‐grade PDCs. Furthermore, concurrent elevated expression of tumoral emmprin and stromal CD73 was determined to be an independent poor prognostic factor. In immunoprecipitation analyses, complex formation between emmprin and CD73 was demonstrated in vitro. Production of MMP‐2 from fibroblasts was more abundant when cocultured with tumor cells than from fibroblasts cultured alone. Furthermore, MMP‐2 production was reduced by the transfection of CD73 siRNA in fibroblasts cocultured with tumor cells. The colocalization of emmprin and CD73 was enhanced in not only the peripheral cells of the tumor cell clusters that interact with fibroblasts but also in the cells of intratumor clusters. Overall, this study provides novel insights into the roles of emmprin, CD73, and MMP‐2 in tumor invasiveness.
Whole blood transcriptional variations between responders and non‐responders in asthma patients receiving omalizumab
Authors: Upchurch Katherine , Wiest Matthew , Cardenas Jacob , Skinner Jason , Nattami Durgha , Lanier Bobby , Millard Mark , Joo HyeMee , Turner Jacob , Oh SangKon
Published: May 2020

Background

Anti‐IgE (omalizumab) has been used for the treatment of moderate‐to‐severe asthma that is not controlled by inhaled steroids. Despite its success, it does not always provide patients with significant clinical benefits.

Objective

To investigate the transcriptional variations between omalizumab responders and non‐responders and to study the mechanisms of action of omalizumab.

Methods

The whole blood transcriptomes of moderate‐to‐severe adult asthma patients (N = 45:34 responders and 11 non‐responders) were analysed over the course of omalizumab treatment. Non‐asthmatic healthy controls (N = 17) were used as controls.

Results

Transcriptome variations between responders and non‐responders were identified using the genes significant (FDR < 0.05) in at least one comparison of each patient response status and time point compared with control subjects. Using gene ontology and network analysis, eight clusters of genes were identified. Longitudinal analyses of individual clusters revealed that responders could maintain changes induced with omalizumab treatment and become more similar to the control subjects, while non‐responders tend to remain more similar to their pre‐treatment baseline. Further analysis of an inflammatory gene cluster revealed that genes associated with neutrophil/eosinophil activities were up‐regulated in non‐responders and, more importantly, omalizumab did not significantly alter their expression levels. The application of modular analysis supported our findings and further revealed variations between responders and non‐responders.

Conclusion and Clinical Relevance

This study provides not only transcriptional variations between omalizumab responders and non‐responders, but also molecular insights for controlling asthma by omalizumab.
Identifying research needs to inform white‐nose syndrome management decisions
Authors: Bernard Riley F. , Reichard Jonathan D. , Coleman Jeremy T. H. , Blackwood Julie C. , Verant Michelle L. , Segers Jordi L. , Lorch Jeffery M. , Paul White John , Moore Marianne S. , Russell Amy L. , Katz Rachel A. , Lindner Daniel L. , Toomey Rickard S. , Turner Gregory G. , Frick Winifred F. , Vonhof Maarten J. , Willis Craig K. R. , Grant Evan H. C.
Published: May 2020

Ecological understanding of host–pathogen dynamics is the basis for managing wildlife diseases. Since 2008, federal, state, and provincial agencies and tribal and private organizations have collaborated on bat and white‐nose syndrome (WNS) surveillance and monitoring, research, and management programs. Accordingly, scientists and managers have learned a lot about the hosts, pathogen, and dynamics of WNS. However, effective mitigation measures to combat WNS remain elusive. Host–pathogen systems are complex, and identifying ecological research priorities to improve management, choosing among various actions, and deciding when to implement those actions can be challenging. Through a cross‐disciplinary approach, a group of diverse subject matter experts created an influence diagram used to identify uncertainties and prioritize research needs for WNS management. Critical knowledge gaps were identified, particularly with respect to how WNS dynamics and impacts may differ among bat species. We highlight critical uncertainties and identify targets for WNS research. This tool can be used to maximize the likelihood of achieving bat conservation goals within the context and limitations of specific real‐world scenarios.
Annual Bleeding Rates: Pitfalls of Clinical Trial Outcomes in Hemophilia Patients
Authors: Keipert Christine , Müller‐Olling Mirco , Gauly Franca , Arras‐Reiter Cornelia , Hilger Anneliese
Published: May 2020

Emerging treatment options for hemophilia, including gene therapy, modified factor products, antibody‐based products, and other nonreplacement therapies, are in development or on their way to marketing authorization. For proof of efficacy, annual bleeding rates (ABRs) have become an increasingly important endpoint in hemophilia trials. We hypothesized that ABR analyses differ substantially between and within medicinal product classes and that the ABR observation period constitutes a major bias. For ABR characterization, an internal factor VIII (FVIII) treatment database has been built based on confidential clinical trial data submitted to the Paul‐Ehrlich‐Institut (PEI). Furthermore, anonymized data from 46 trial protocols submitted for review to the PEI were analyzed (FVIII replacement, n = 27; antibody‐based, n = 12; and gene therapy, n = 7) for methodology. Definitions of bleeding episodes and ABR observational periods differed substantially in clinical trials. In the initial observation phase, individual ABRs of patients, treated prophylactically for 1 year, vary by about 40% (P < 0.001), which finally led to a significant reduction of the ABR group mean by 20% (P < 0.05). Furthermore, the high variance in ABRs constitutes a major challenge in statistical analyses. In conclusion, considerable heterogeneity and bias in the ABR estimation in clinical trials was identified, which makes it substantially more difficult to compare the efficacy of different treatment regimens and products. Thus, awareness of the important pitfalls when using ABR as a clinical outcome is needed in the evaluation of hemophilia therapies for patients, physicians, regulators, and health technology assessment agencies.