bluuebunny/crossref_metadata_2025 huggingface dataset:
Ecological niche modeling for assessing potential distribution ofPterocarpus marsupiumRoxb. In Ranchi, eastern India
Authors: Kumar Amit , Kumar Anish , Adhikari Dibyendu , Gudasalamani Ravikanth , Saikia Purabi , Khan Mohammed Latif
Published: September 2020

The present study was conducted to predict the current and future potential distribution of a tree speciesPterocarpus marsupiumRoxb. in Ranchi, Eastern India using ecological niche modeling. Nine environmental variables comprising of isothermality, precipitation of wettest and warmest quarter, annual temperature range, soil type, human influence index, elevation, slope and land use cover were used to model the distribution of the species. Climatic variables governed the predicted distribution of the species as they contributed 56.7% as compared to the other nonclimatic variables (43.3%). Northern parts exhibited the most suitable niche of the species as compared to south‐east and central parts that showed low probability of occurrence due to high disturbances caused by rapid urbanization as well as over exploitation of the species for timber, edible and medicinal uses. The average test area under the receiver operating curve (AUC) (0.921) as well as the partial AUC indicated good model performance. The projected change scenarios of RCP2.6, RCP4.5 and RCP6.0 for the year 2050 reveal that the climatically suitable areas will be drastically reduced in Ranchi. The population of the species is declining due to its exploitation from natural habitats for timber and medicinal uses and is listed as near‐threatened by the current IUCN‐Red lists. The findings of this paper will help to identify the potential habitats for further conservation of this near‐threatened species in the changing climatic conditions and increasing anthropogenic pressure.
Low root functional dispersion enhances functionality of plant growth by influencing bacterial activities in European forest soils
Authors: Prada‐Salcedo Luis Daniel , Wambsganss Janna , Bauhus Jürgen , Buscot François , Goldmann Kezia
Published: September 2020

Current studies show that multispecies forests are beneficial regarding biodiversity and ecosystem functionality. However, there are only little efforts to understand the ecological mechanisms behind these advantages of multispecies forests. Bacteria are among the key plant growth‐promoting microorganisms that support tree growth and fitness. Thus, we investigated links between bacterial communities, their functionality and root trait dispersion within four major European forest types comprising multispecies and monospecific plots. Bacterial diversity revealed no major changes across the root functional dispersion gradient. In contrast, predicted gene profiles linked to plant growth activities suggest an increasing bacterial functionality from monospecific to multispecies forest. In multispecies forest plots, the bacterial functionality linked to plant growth activities declined with the increasing functional dispersion of the roots. Our findings indicate that enriched abundant bacterial operational taxonomic units are decoupled from bacterial functionality. We also found direct effects of tree species identity on bacterial community composition but no significant relations with root functional dispersion. Additionally, bacterial network analyses indicated that multispecies forests have a higher complexity in their bacterial communities, which points towards more stable forest systems with greater functionality. We identified a potential of root dispersion to facilitate bacterial interactions and consequently, plant growth activities.
Epidemiology and clinical features of emergency department patients with suspected and confirmedCOVID‐19: A multisite report from theCOVID‐19 Emergency DepartmentQuality Improvement Project for July 2020 (COVED‐3)
Authors: O'Reilly Gerard M , Mitchell Rob D , Mitra Biswadev , Akhlaghi Hamed , Tran Viet , Furyk Jeremy S , Buntine Paul , Bannon‐Murphy Holly , Amos Timothy , Udaya Kumar Maushmi , Perkins Emma , Prentice Alexandra , Szwarcberg Olivia , Loughman Ashley , Lowry Nicole , Colwell Steven , Noonan Michael P , Hiller Ryan , Paton Andrew , Smit De Villiers , Cameron Peter A ,   the COVED Project Team
Published: September 2020

Objective

The aim of the present study was to describe the epidemiology and clinical features of patients presenting to the ED with suspected and confirmed COVID‐19.

Methods

The COVID‐19 ED (COVED) Project is an ongoing prospective cohort study in Australian EDs. This analysis presents data from eight sites across Victoria and Tasmania for July 2020 (during Australia's ‘second wave’). All adult patients who met criteria for ‘suspected COVID‐19’ and underwent testing for SARS‐CoV‐2 in the ED were eligible for inclusion. Study outcomes included a positive SARS‐CoV‐2 test result and mechanical ventilation.

Results

In the period 1 July to 31 July 2020, there were 30 378 presentations to the participating EDs and 2917 (9.6%; 95% confidence interval 9.3–9.9) underwent testing for SARS‐CoV‐2. Of these, 50 (2%) patients returned a positive result. Among positive cases, two (4%) received mechanical ventilation during their hospital admission compared to 45 (2%) of the SARS‐CoV‐2 negative patients (odds ratio 1.7, 95% confidence interval 0.4–7.3;P= 0.47). Two (4%) SARS‐CoV‐2 positive patients died in hospital compared to 46 (2%) of the SARS‐CoV‐2 negative patients (odds ratio 1.7, 95% confidence interval 0.4–7.1;P= 0.49). Strong clinical predictors of a positive SARS‐CoV‐2 result included self‐reported fever, non‐smoking status, bilateral infiltrates on chest X‐ray and absence of a leucocytosis on first ED blood tests (P< 0.05).

Conclusion

In this prospective multi‐site study from July 2020, a substantial proportion of ED patients required SARS‐CoV‐2 testing, isolation and enhanced infection prevention and control precautions. Presence of SARS‐CoV‐2 on nasopharyngeal swab was not associated with death or mechanical ventilation.
Activity‐guided isolation of α‐amylase, α‐glucosidase, and pancreatic lipase inhibitory compounds from Rhus coriaria L
Authors: Gök Hasya Nazlı , Deliorman Orhan Didem , Gürbüz İlhan , Aslan Mustafa
Published: September 2020

The leaves and fruits of Rhus coriaria are traditionally used in Turkey for the treatment of diabetes. The aim of the present study is to determine α‐amylase, α‐glucosidase, and pancreatic lipase inhibitory activities of R. coriaria leaf and fruit ethanol extracts (80%), and to isolate active compounds against these enzymes. As a result of the activity‐guided isolation, the active compounds were determined as the amentoflavone, agathisflavone, and 1,2,3,4,6‐penta‐O‐galloyl‐β‐glucopyranose. Agathisflavone, amentoflavone, and penta‐O‐galloyl‐β‐glucopyranose inhibited α‐glucosidase with 11.4 ± 0.9, 11.3 ± 0.7, and 4.1 ± 0.1 µM IC50 values, respectively. Furthermore, penta‐O‐galloyl‐β‐glucopyranose inhibited α‐amylase with 6.32 ± 0.18 µM IC50. These three compounds also significantly inhibited (P < 0.05) pancreatic lipase. The results of high‐performance liquid chromatography analysis showed that penta‐O‐galloyl‐β‐D‐glycopyranose was one of the main compounds in both fruit and leaf extracts. Therefore, it may be considered that R. coriaria fruit and leaf extracts can be standardized on this substance and used in the development of both medicinal products and functional food for diabetes.

Practical Application

Rhus coriaria (Sumac) is one of the plants that is well known and used around the world as a spice. It is also used against diabetes traditionally. The determination of effective compounds can lead to the standardization and development of both medicinal products and functional foods for diabetes.

While the fruits of the plant are used as a spice all around the world, the leaves are generally throw away; therefore, the usage of the leaves to the food and medical industry can lead to beneficial effects on the economy.
Prognostic value of pretreatment smoking status for small cell lung cancer: A meta‐analysis
Authors: Huang Liling , Shi Yuankai
Published: September 2020

Background

Although tobacco exposure remains the most important risk factor of tumorigenesis of small cell lung cancer (SCLC), its prognostic value has failed to reach a consensus until now. Accordingly, we conducted a meta‐analysis to investigate the prognostic value of pretreatment smoking status (smokers vs. never‐smokers) in SCLC.

Methods

The four databases PubMed, Medline, Embase, and Cochrane library were searched to identify the relevant literature from the inception dates to 24 June 2020. The primary outcome was overall survival (OS), and the secondary endpoint was progression‐free survival (PFS). The hazard ratios (HRs) with 95% confidence intervals (CIs) were extracted to assess the relationship between pretreatment smoking status and patient survival. Sensitivity analysis was performed to assess the stability of the pooled results. Begg's funnel plot and Egger's test were applied to detect the publication bias. All statistical analyses were performed using RevMan V.5.3 and STATA version 15.0 software.

Results

A total of 27 studies involving 12 047 patients with SCLC (9137 smokers and 2910 never‐smokers) were included in this meta‐analysis. The results showed that smoking history was closely related to poorer survival outcome (OS: HR = 1.17, 95% CI: 1.12–1.23, P < 0.00001; I2 = 0%; PFS: HR = 1.20, 95% CI: 1.06–1.35, P = 0.004; I2 = 0%).

Conclusions

Smoking history should be considered as an independent poor prognostic factor for patients with SCLC. More large‐scale prospective studies are warranted to testify the prognostic value of pretreatment smoking status.
Audit Committee Members’ Reputation Incentives and Their Effectiveness in Monitoring the Financial Reporting Process
Authors: Khoo Eunice S. , Lim Youngdeok , Monroe Gary S.
Published: September 2020

We examine whether the reputation incentives of audit committee members are associated with their effectiveness in monitoring the financial reporting process. Prior research assumes that audit committee members allocate their effort proportionately across all memberships on which they serve. However, our findings suggest that audit committee members with multiple audit committee memberships tend to focus their attention on the memberships that provide them with the greatest reputation incentives. Specifically, firms with a larger proportion of audit committee members where the membership is the most prominent are associated with higher financial reporting quality and more effective monitoring of internal control. Additional tests reveal that audit committee members’ reputation incentives are driving our results rather than independent non‐audit committee members’ reputation incentives. We conclude that reputation is a strong incentive for audit committee members, such that it influences their monitoring effectiveness over the financial reporting process.
Financial Reporting by Charities: Why Do Some Choose to Report Under a More Extensive Reporting Framework?
Authors: Yang Yitang (Jenny) , Simnett Roger
Published: September 2020

While voluntary disclosure theory posits that profit‐oriented companies voluntarily disclose information to increase their market value, this does not explain why a charity would report in accordance with a more comprehensive financial reporting framework than required. Using a unique financial reporting framework choice available in Australia, our study examines factors associated with large charities’ choice of a General Purpose Financial Statements (GPFS) reporting framework, which encompasses expansive financial reporting requirements, versus a Special Purpose Financial Statements (SPFS) reporting framework, where management, within limits, effectively chooses that subset of accounting standards applicable to that charity. For those preparing GPFS, we then examine the factors that determine those charities that report in accordance with the complete set of Australian Accounting Standards (Tier 1) versus Reduced Disclosure Requirements (Tier 2). Using manually collected data from 11,471 large‐registered charities for 2014–2016, we find that the economic importance of the charity, its funding sources, and level of indebtedness are significant in explaining charities choosing a more comprehensive financial reporting framework. Further, we find a substantial increase in the proportion of large charities electing to disclose GPFS‐Tier 2 over this three‐year window. The choice of a large audit firm (Big 4 and mid‐tier audit firms) is significantly associated with charities both lodging more comprehensive GPFS, and also reporting GPFS in accordance with the less onerous GPFS‐Tier 2 framework. Our results provide insights into voluntary reporting choices made by charities and inform charities, accounting firms, and regulators of factors influencing charities’ choice of financial reporting frameworks.
Long‐term effects of forest fire on habitat use by siamangs in Southern Sumatra
Authors: Lappan S. , Sibarani M. , O’Brien T. G. , Nurcahyo A. , Andayani N. , Rustiati E. L. , Surya R. A. , Morino L.
Published: September 2020

Forest fires can cause direct mortality to wildlife, and the associated habitat damage can reduce carrying capacity and population densities. However, little is known about long‐term responses of animals to fire in the wet tropics. From 2000‐2015, we examined siamang ranging patterns in habitat damaged by fire to assess the effects on these arboreal frugivores. We mapped home ranges (HR) of seven siamang groups inhabiting contiguous HR 3‐5, 10‐12, and 17–18 years post‐fire. We predicted that if habitat connectivity or quality improved over time in burned areas, HR should become larger and centroid locations should shift toward recovering areas. Since territoriality constrains siamang ranging, we examined effects of social and habitat factors on ranging. By 18 years post‐fire, tree density in the burned area had returned to the 1997 baseline, but composite LandSat images indicated that tree species composition differed in burned and unburned forest. Our data and the associated models indicated that HR sizes in burned forest increased over time whereas those in unburned forest did not. Centroid locations moved little (15.5 ± 6.9 m y−1) and their movement appeared to be predominantly influenced by social factors, although HR centroids in burned habitat shifted further into the burned area while those in adjacent unburned forest did not. In a large burned area unused by siamangs before 2012, two new groups were observed 15‐17 years post‐fire, although one subsequently disappeared. This is the first study of the long‐term effects of fire on small ape habitat use. By 18 years post‐fire, siamangs had incorporated some burned areas into their HR, but did not use heavily damaged areas. Reduced frugivore densities in burned areas may inhibit forest regeneration by disrupting seed dispersal.
Effectiveness of drugs acting on adrenergic receptors in the treatment for tobacco or alcohol use disorders: systematic review and meta‐analysis
Authors: Vanderkam Paul , Solinas Marcello , Ingrand Isabelle , Doux Nicolas , Ebrahimighavam Soghra , Jaafari Nematollah , Lafay‐Chebassier Claire
Published: September 2020

Aim

To assess the efficacy of drugs directly acting on alpha‐ and beta‐adrenergic receptors in the treatment of patients suffering from tobacco or alcohol use disorder.

Methods

Using Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines, studies were identified through PUBMED, EMBASE, the Cochrane Central Register of Controlled Trials and clinicaltrial.gov. We selected only randomized controlled trials with adult patients with tobacco or alcohol use disorders according to DSM‐5 criteria. Interventions included any molecule having a direct pharmacological action on alpha‐ or beta‐adrenergic receptors (agonist or antagonist). Comparators were placebo or other validated pharmacotherapies. The duration of the intervention was a minimum of 1 month, with 3 months of follow‐up. Measurements included smoking cessation for tobacco; for alcohol, we selected abstinence, alcohol consumption (drinks per day or week) and heavy drinking days (HDD). Ten studies with tobacco and six with alcohol use disorder were included in the qualitative synthesis and fifteen studies in the quantitative analysis.

Results

We found that clonidine, an alpha‐2 agonist, significantly increased smoking abstinence [relative risk = 1.39 with a 95% confidence interval (CI) = 1.04, 1.84]. Beta‐blockers had no significant effect on smoking abstinence. The alpha‐1 antagonists prazosin and doxazosin decreased alcohol consumption [SMD = −0.32 (−0.56, −0.07)] but had no effect on abstinence or HDD.

Conclusions

The noradrenaline system may represent a promising mechanism to target in tobacco and alcohol use disorders.
Venous hepatic segmentation in dogs (Canis lupus familiaris—L. 1758)
Authors: de Morais‐Pinto Luciano , Pereira Vítor Pires , de Souza Vencato Marina , de Oliveira Alzido , Miglino Maria Angelica
Published: September 2020

The external shape of the liver is varied and determines specific vascular arrangements. This morphological relationship is important to establish hepatic segmentation in different species submitted to surgeries that aim to preserve a larger area of liver parenchyma. After observing 60 livers injected with Neoprene Latex and three plastic moulds obtained by corrosion, eight hepatic venous segments were identified, drained by six hepatic veins agrouped into segmental veins, which drained one sector (segments I, VI, VII and VIII) and intersegmental veins, which drained more than one sector (segments II/III and IV/V). They were described as follows: left intersegmental vein, formed by a segmental vein from the papillary process (segment I), two to three lateral left segmental veins that drained the segment II, and one to five left paramedian segmental veins that drained the segment III; sagittal intersegmental vein, formed by the confluence between segmental vein of the quadrate lobe (segment IV) and the medial right paramedian segmental vein, which derived from the segment V; lateral right paramedian vein drained the dorsocranial sector of the segment VI; the lateral right segmental vein, formed by one to four vessels that drained segment VII, and the segmental vein of the caudate process, which drained the segment VIII. Understanding the number and disposition of the hepatic veins in lobate livers is essential to reduce bleeding risks in surgeries. The nomenclature based on segmentation analogy of non‐lobate liver could be less confusing and, therefore, be more useful in the surgical approaches of lobate livers.
Big Banks versus Agricultural Banks: Has Too‐Big‐To‐Fail Regulation Affected Efficiency and Scale Economies Measures?
Authors: Regmi Madhav , Featherstone Allen M. , Cowley Cortney A. , Taylor Mykel R.
Published: September 2020

The Dodd‐Frank Wall Street Reform and Consumer Protection Act of 2010 aimed to improve the financial stability of the banking industry. This reform was intended to reduce the too‐big‐to‐fail practices for very large banks. However, it might also affect the performance of relatively small asset size banks with different lending portfolios. Using the Call Report data from 2006 to 2016, evidence suggests that the Dodd‐Frank Act has affected the estimates of cost efficiency and returns to scale measures of both big banks and small agricultural banks. Results indicate that Dodd‐Frank Act has increased cost efficiency, discouraged mergers, and encouraged product specialization for banks above the $50 billion asset size. However, none of these results hold for the banks just above the $10 billion asset size. This appears to suggest that Dodd‐Frank Act has mainly affected the economic measures of those very big banks that are subject to the more stringent regulations. Nevertheless, Dodd‐Frank has reduced agricultural banks' cost efficiency and increased incentives for mergers. In addition, the Dodd‐Frank Act has dampened the incentives for product diversification in agricultural banking. Likewise, evidence exists that this act has slowed productivity growth, efficiency, and technological change in agricultural banks. Taken together, Dodd‐Frank reduced consolidations in very big banks that are subject to greater oversight but adversely affected U.S. agricultural lending.
Circulating CD14+HLA‐DRlo/− monocytic cells as a biomarker for epithelial ovarian cancer progression
Authors: Stenzel Ashley E. , Abrams Scott I. , Joseph Janine M. , Goode Ellen L. , Tario Joseph D. , Wallace Paul K. , Kaur Divjot , Adamson Anna‐Kay , Buas Matthew F. , Lugade Amit A. , Laslavic Angela , Taylor Sarah E. , Orr Brian , Edwards Robert P. , Elishaev Esther , Odunsi Kunle , Mongiovi Jennifer M. , Etter John Lewis , Winham Stacey J. , Kaufmann Scott H. , Modugno Francesmary , Moysich Kirsten B.
Published: September 2020

Problem

Previous studies identified circulating CD14+HLA‐DRlo/− monocytic cells as an immune suppressive subset in solid malignancies, such as prostate, renal cell carcinoma, and pancreatic cancer. Such monocytic cells have been implicated not only in tumour progression but also as a potential barrier for immunotherapy. This study examined the relationship between the frequency of circulating monocytic cells and epithelial ovarian cancer (EOC) progression pre‐ and post‐frontline chemotherapy, defined by disease stage, which is a leading prognostic factor for this malignancy.

Method of study

Incident cases of 236 women with EOC were recruited and comprehensive flow cytometry was utilized to assess the frequency of peripheral blood CD33+CD11b+HLA‐DR−/lowCD14+CD15− monocytic cells, henceforth termed CD14+HLA‐DRlo/− monocytic cells, prior to and after completion of frontline chemotherapy. Multivariable odds ratios (OR) were used to estimate the association between CD14+HLA‐DRlo/− monocytic cell percentages and disease stage. Wilcoxon signed‐rank tests evaluated changes in these monocytic cell levels pre‐ and post‐chemotherapy in a patient subset (n = 70).

Results

Patients with elevated frequencies of circulating CD14+HLA‐DRlo/− monocytic cells at diagnosis were at 3.33‐fold greater odds of having advanced stage (III/IV) EOC (CI: 1.04‐10.64), with a significant trend in increasing CD14+HLA‐DRlo/−monocytic cell levels (P = .04). There was a 2.02% median decrease of these monocytic cells post‐chemotherapy among a subset of patients with advanced stage disease (P < .0001).

Conclusion

These findings support the potential clinical relevance of CD14+HLA‐DRlo/−monocytic cells in EOC for prognosis and may indicate a non‐invasive biomarker to measure disease progression.
Assessment of nest building and social interaction behavior in mice exposed to acute social defeat stress using a three‐dimensional depth camera
Authors: Otabi Hikari , Okayama Tsuyoshi , Toyoda Atsushi
Published: September 2020

Nest building is an instinctive behavior toward protection from predators, body temperature regulation, and courtship. Previously, we discovered that acute and chronic social defeat stress suppresses the onset of nest‐building behavior in male mice (C57BL/6J). Here, we analyzed nest building and other behavioral deficits induced by acute social defeat stress (ASDS). We utilized a customized cage and specifically developed observational programs for nest building, social avoidance, and other behaviors using an infrared depth camera to acquire three‐dimensional (3D) data of animal behavior (Negura system). We determined the volume of nesting materials from these 3D depth images. Mice exposed to ASDS showed increased spontaneous activities, decreased rearing, and delayed nest building; however, nest‐building activity was gradually recovered during the dark period of the 24 hr observation interval. At the endpoint following 24 hr, the ASDS and control groups showed no differences in nest volumes. Furthermore, we observed the time courses of both nest building and social avoidance behaviors and their relationship using the Negura system. Our data demonstrated a weak positive correlation between nest‐building delay and social avoidance in ASDS mice. The Negura system can observe various behaviors that reflect the effects of social defeat stress.
Effects of ear corn silage supplementation on milk production and milk fatty acid profiles in grazing dairy farms
Authors: Mitani Tomohiro , Asakuma Sadaki , Shinoda Yuka , Ueda Yasuko , Aoki Yasuhiro , Oshita Tomoko
Published: September 2020

This study investigated the effects of substituting ear corn silage (ECS) for commercial formula feed on milk production and milk fatty acid profiles in grazing dairy farms during the summer season. A field survey was conducted on five grazing dairy farms in every summer month of 2017, 2018, and 2019. Three of the five farms substituted fresh ECS for the commercial formula feed at a ratio of 2:1 from July of each year (ECS farms). Other farms maintained the same feeding management as before (non‐ECS farms). An interview survey was conducted on each farm to calculate feed intake and milk yield per cow. Feed and milk samples were collected in each survey. Milk compositions and milk fatty acid profiles were determined. The substitution of ECS for the commercial formula feed did not affect milk yield or milk composition, but ECS farms maintained low levels of milk urea compared with non‐ECS farms (p < .01). The ECS substitution also influenced some of the milk fatty acid proportions; C16:0 and C16:1 increased, and trans‐11 C18:1, cis‐9,trans‐11 C18:2, and the sum of polyunsaturated fatty acids decreased, while these fatty acid proportions were maintained in non‐ECS farms throughout the summer season (p < .05).
Introduction and elimination of Bovine Viral Diarrhoea Virus in a commercial beef herd: a case study
Authors: Allworth MB , Long R , Smith AK , Bergman EL , Hernandez‐Jover M
Published: September 2020

Routine Bovine Viral Diarrhoea Virus (BVDV) monitoring of a commercial beef herd in southern New South Wales over a 10‐year period provided an opportunity to assess the impact of the introduction of BVDV on that herd. BVDV antibody testing provided strong evidence that the herd was initially free of BVDV (2009–2011). Testing from 2012 suggested BVDV had been introduced into the herd and this was confirmed in 2015 with the identification of persistently infected (PI) animals. Having become established in the herd, the owners then set out to eliminate BVDV from the herd. Antigen testing aimed at identifying PI animals revealed BVDV was already absent from the herd. Subsequent antibody testing confirmed that the herd was now free from BVDV. Despite the incursion of BVDV in this herd, there was little measurable impact on reproductive performance (pregnancy rates), although suspected increased calf losses from birth to calf marking were reported. This is the first time such self‐clearance has been documented as part of a longitudinal study under Australian conditions.
Impact of the Goal‐directed Medication Review Electronic Decision Support System on Drug Burden Index: A cluster‐randomised clinical trial in primary care
Authors: Kouladjian O'Donnell Lisa , Gnjidic Danijela , Sawan Mouna , Reeve Emily , Kelly Patrick J. , Chen Timothy F. , Bell J. Simon , Hilmer Sarah N.
Published: September 2020

Aims

The Goal‐directed Medication Review Electronic Decision Support System (G‐MEDSS) assesses and reports a patient's goals, attitudes to deprescribing and Drug Burden Index (DBI) score, a measure of cumulative exposure to anticholinergic and sedative medications. This study evaluated the effect of implementing G‐MEDSS in home medicines reviews (HMRs) on DBI exposure and clinical outcomes.

Methods

A cluster‐randomised clinical trial was performed across Australia. Accredited clinical pharmacists were randomised into intervention (G‐MEDSS with usual care HMR) or comparison groups (usual care HMR alone). Patients were recruited by pharmacists from those routinely referred by general practitioners for HMR. The primary outcome was the proportion of patients with any reduction in DBI at 3‐months follow‐up. Secondary outcomes included change in DBI continuous score at 3‐months, HMR recommendations to change DBI and clinical outcomes.

Results

There were 201 patient participants at baseline (n = 88 intervention, n = 113 comparison), with 159 followed‐up at 3‐months (n = 63 intervention, n = 96 comparison). The proportion of patients with a reduction in DBI was not significantly different at 3‐months (intervention 17%, comparison 11%; adjusted odds ratio 1.44, 95% confidence interval 0.56–3.80). Regarding secondary outcomes, there was no difference in change in DBI score at 3‐months. However, the HMR report made recommendations to reduce DBI for a significantly greater proportion of patients in the intervention than in the comparison group (intervention 37%, comparison 14%; adjusted odds ratio 3.20, 95% confidence interval 1.50–6.90). No changes were observed in clinical outcomes.

Conclusion

Implementation of G‐MEDSS within HMR did not reduce patients' DBI at 3 months compared with usual care HMR.
Characterization of rapid cycling bipolar patients presenting with major depressive episode within the BRIDGE‐II‐MIX study
Authors: Antonietta Furio Maria , Popovic Dina , Vieta Eduard , Stukalin Yelena , Hagin Michal , Torrent Carla , Azorin Jean‐Michel , Angst Jules , Bowden Charles L. , Mosolov Sergey , Young Allan H. , Perugi Giulio ,   for the BRIDGE‐II‐Mix Study Group
Published: September 2020

Objectives

The “Bipolar Disorders: Improving Diagnosis, Guidance, and Education” (BRIDGE‐II‐Mix) study aimed to estimate the frequency of mixed states in patients with a major depressive episode (MDE) according to different definitions and to compare their clinical validity, looking into specific features such as rapid cycling (RC).

Methods

Psychiatric symptoms, socio‐demographic, and clinical variables were collected from a sample of 2811 MDE patients, of which 726 (25.8%) were diagnosed with bipolar disorder (BD). The characteristics of bipolar patients with RC (BD‐RC) and without (BD‐NRC) RC were compared.

Results

Of 726 BD patients, 159 (21.9%) met DSM‐5 criteria for RC. BD‐RC group presented a higher number of lifetime depressive episodes (p < 0.001) with shorter duration of depressive episodes, and more psychiatric comorbidities, as well as higher rates of atypical features (p = 0.016) and concomitant (hypo)manic symptoms (irritable mood (p = 0.001); risky behavior (p = 0.005); impulsivity (p = 0.006); and psychomotor agitation (p = 0.029)). Patients with RC had a worse functioning (p = 0.033), more obesity (p = 0.003), and were significantly more likely to be treated with three or more drugs (p = 0.007).

Conclusions

Important clinical differences between bipolar patients with and without a RC include more depressive morbidity, higher incidence of anxiety disorders, addiction, bulimia, and borderline personality disorder, as well as atypical features during depression and symptoms such as irritability, risky behavior, impulsivity, and agitation. RC patients had poorer functioning than patients without RC, more obesity, and had to be treated with more drugs.
Using the “Hidden” genome to improve classification of cancer types
Authors: Chakraborty Saptarshi , Begg Colin B. , Shen Ronglai
Published: September 2020

It is increasingly common clinically for cancer specimens to be examined using techniques that identify somatic mutations. In principle, these mutational profiles can be used to diagnose the tissue of origin, a critical task for the 3% to 5% of tumors that have an unknown primary site. Diagnosis of primary site is also critical for screening tests that employ circulating DNA. However, most mutations observed in any new tumor are very rarely occurring mutations, and indeed the preponderance of these may never have been observed in any previous recorded tumor. To create a viable diagnostic tool we need to harness the information content in this “hidden genome” of variants for which no direct information is available. To accomplish this we propose a multilevel meta‐feature regression to extract the critical information from rare variants in the training data in a way that permits us to also extract diagnostic information from any previously unobserved variants in the new tumor sample. A scalable implementation of the model is obtained by combining a high‐dimensional feature screening approach with a group‐lasso penalized maximum likelihood approach based on an equivalent mixed‐effect representation of the multilevel model. We apply the method to the Cancer Genome Atlas whole‐exome sequencing data set including 3702 tumor samples across seven common cancer sites. Results show that our multilevel approach can harness substantial diagnostic information from the hidden genome.
Optimism, pessimism, and health biomarkers in older couples
Authors: Arbel Reout , Segel‐Karpas Dikla , Chopik William
Published: September 2020

Objective

Studies have demonstrated the importance of optimism in predicting perceived general health. However, the handful of studies focusing on cardiovascular biomarkers show inconsistent effects. Additionally, no study examined whether spousal levels of optimism and pessimism affect an individual’s biological markers of cardiovascular health. Thus, our objectives were to examine whether partners’ optimism and pessimism affect individual biological markers, differentiating between between‐dyad associations and within‐dyad predictive processes.

Methods

Three waves of the Health and Retirement Study collected in 2006, 2010, and 2014 were used to test actor and partner effects of optimism and pessimism on C‐reactive protein (CRP) and high‐density lipoprotein. Multilevel longitudinal actor–partner models were used to examine the contribution of a partner’s optimism and pessimism to each biomarker, adjusting for respondent's age, sex, depression, body mass index, daily activity levels, and a summary score of respondent's doctor‐diagnosed chronic conditions.

Results

Partners’ pessimism and optimism levels were moderately associated. Results for within‐person effects were all non‐significant, both within and across waves. Associations at the between‐person level were also non‐significant, with the exception of a positive association between husbands’ pessimism and their own CRP, and husbands’ optimism and their wives’ CRP.

Conclusions

Results suggest that optimism and pessimism may not play a pertinent role in within variability of biomarkers of cardiovascular diseases and have a minor role in predicting to between‐person variability of biomarkers of cardiovascular diseases.
Distinct microglial and macrophage distribution patterns in the concentric and lamellar lesions in Baló's disease and neuromyelitis optica spectrum disorders
Authors: Hayashida Shotaro , Masaki Katsuhisa , Suzuki Satoshi O. , Yamasaki Ryo , Watanabe Mitsuru , Koyama Sachiko , Isobe Noriko , Matsushita Takuya , Takahashi Kazuya , Tabira Takeshi , Iwaki Toru , Kira Jun‐ichi
Published: September 2020

TMEM119 and purinergic receptor P2Y12 (P2RY12), which are not expressed by recruited peripheral blood macrophages, are proposed to discriminate microglia from macrophages. Therefore, we investigated the distribution patterns of microglia and macrophages in 10 concentric lesions from four autopsied Baló's disease cases and one neuromyelitis optica spectrum disorder (NMOSD) case, using quantitative immunohistochemistry for the markers TMEM119, P2RY12, CD68, CD163 and GLUT5. Three cases with Baló's disease had distal oligodendrogliopathy (DO) showing preferential loss of myelin‐associated glycoprotein and early active demyelination in the outermost demyelinating layer (termed DMY‐MO). In DMY‐MO with DO, TMEM119‐positive activated microglia expressing upregulated GLUT5 but markedly downregulated P2RY12 were significantly increased. These activated microglia expressed inducible nitric oxide synthase. Oligodendrocytes and their precursors showed apoptotic‐like nuclear condensation in DMY‐MO. TMEM119‐negative and CD68/CD163‐positive macrophages were distributed throughout the lesion center of DMY‐MO with DO and these cells demonstrated foamy morphology only in the inner portion but not in the outer portion. In concentric demyelinating lesions from another Baló's case and lamellar demyelinating lesions in an NMOSD case, which had late active demyelination without DO, the densities of TMEM119‐, GLUT5‐ and P2RY12‐positive microglia with ramified morphology were significantly increased in myelinated layers but not in demyelinating layers. In particular, in the NMOSD case, TMEM119‐positive microglia were confined to the outer portion of the myelinated layers. CD68‐positive macrophages with foamy morphology also expressing CD163 accumulated in myelinated as well as in demyelinated layers. These findings suggest that activated microglia expressing TMEM119 and GLUT5, but not P2RY12, are associated with apoptosis of oligodendrocytes in the leading edge of Baló's concentric lesions with DO, whereas TMEM119‐, GLUT5‐ and P2RY12‐positive microglia with ramified morphology are associated with myelin preservation in concentric lesions without DO in Baló's disease and NMOSD. These two types of microglia appear to play distinct roles in the formation of concentric lesions.
Discovery and characterization of ORM‐11372, a novel inhibitor of the sodium‐calcium exchanger with positive inotropic activity
Authors: Otsomaa Leena , Levijoki Jouko , Wohlfahrt Gerd , Chapman Hugh , Koivisto Ari‐Pekka , Syrjänen Kaisa , Koskelainen Tuula , Peltokorpi Saara‐Elisa , Finckenberg Piet , Heikkilä Aira , Abi‐Gerges Najah , Ghetti Andre , Miller Paul E. , Page Guy , Mervaala Eero , Nagy Norbert , Kohajda Zsófia , Jost Norbert , Virág László , Varró András , Papp Julius Gy.
Published: September 2020

Background and Purpose

The lack of selective sodium–calcium exchanger (NCX) inhibitors has hampered the exploration of physiological and pathophysiological roles of cardiac NCX 1.1. We aimed to discover more potent and selective drug like NCX 1.1 inhibitor.

Experimental Approach

A flavan series‐based pharmacophore model was constructed. Virtual screening helped us identify a novel scaffold for NCX inhibition. A distinctively different NCX 1.1 inhibitor, ORM‐11372, was discovered after lead optimization. Its potency against human and rat NCX 1.1 and selectivity against other ion channels was assessed. The cardiovascular effects of ORM‐11372 were studied in normal and infarcted rats and rabbits. Human cardiac safety was studied ex vivo using human ventricular trabeculae.

Key Results

ORM‐11372 inhibited human NCX 1.1 reverse and forward currents; IC50 values were 5 and 6 nM respectively. ORM‐11372 inhibited human cardiac sodium 1.5 (INa) and hERG KV11.1 currents (IhERG) in a concentration‐dependent manner; IC50 values were 23.2 and 10.0 μM. ORM‐11372 caused no changes in action potential duration; short‐term variability and triangulation were observed for concentrations of up to 10 μM. ORM‐11372 induced positive inotropic effects of 18 ± 6% and 35 ± 8% in anaesthetized rats with myocardial infarctions and in healthy rabbits respectively; no other haemodynamic effects were observed, except improved relaxation at the lowest dose.

Conclusion and Implications

ORM‐11372, a unique, novel, and potent inhibitor of human and rat NCX 1.1, is a positive inotropic compound. NCX inhibition can induce clinically relevant improvements in left ventricular contractions without affecting relaxation, heart rate, or BP, without pro‐arrhythmic risk.
Preclinical studies investigating the neural mechanisms involved in the co‐morbidity of migraine and temporomandibular disorders: the role of CGRP
Authors: Akerman Simon , Romero‐Reyes Marcela
Published: September 2020

Background and Purpose

Temporomandibular disorders (TMD) and migraine can be co‐morbid. This can be a significant factor in exacerbating and increasing the prevalence of migraine‐like symptoms. However, the underlying mechanisms involved are unknown. Our objective was to investigate these neural mechanisms and the role of CGRP as a key modulator in this co‐morbidity.

Experimental Approach

We combined experimental approaches using CGRP, which triggers a migraine‐like response in patients, with that of masseteric muscle injection of complete Freund's adjuvant (CFA), to model myofascial TMD‐like inflammation. Using validated electrophysiological methods to assess each of the above approaches independently or in combination, we examined their effects on the response properties of migraine‐like dural‐trigeminocervical neurons.

Key Results

Independently, in ~2/3 of animals (rats) each approach caused delayed migraine‐like activation and sensitisation of dural‐trigeminocervical neurons. The response to masseteric‐CFA was attenuated by a selective CGRP receptor antagonist. The combination approach caused a migraine‐like neuronal response in all animals tested, with somatosensory‐evoked cranial hypersensitivity significantly exacerbated.

Conclusion and Implications

The data demonstrate a neuronal phenotype that translates to the exacerbated clinical co‐morbid phenotype, supporting this combination approach as a relevant model to study the mechanisms involved. It provides a pathophysiological rationale for this exacerbated phenotype, strongly implicating the involvement of CGRP. The results provide support for targeting the CGRP pathway as a novel monotherapy approach for treating this co‐morbid condition. This has key implications into our understanding of this co‐morbid condition, as well as potentially addressing the major unmet need for novel and effective therapeutic approaches.
Nervous system regulated by POZ domain Krüppel‐like zinc finger (POK) family transcription repressor RP58
Authors: Okado Haruo
Published: September 2020

The POZ domain Krüppel‐like zinc finger transcription repressor (POK family) contains many important molecules, including RP58, Bcl6 and PLZF. They function as transcription repressors via chromatin remodelling and histone deacetylation and are known to be involved in the development and tumourigenesis of various organs. Furthermore, they are important in the formation and function of the nervous system. This review summarizes the role of the POK family transcription repressors in the nervous system. We particularly targeted Rp58 (also known as Znf238, Znp238 and Zbtb18), a sequence‐specific transcriptional repressor that is strongly expressed in developing glutamatergic projection neurons in the cerebral cortex. It regulates various physiological processes, including neuronal production, neuronal migration and neuronal maturation. Human studies suggest that reduced RP58 levels are involved in cognitive function impairment and brain tumour formation. This review particularly focuses on the mechanisms underlying RP58‐mediated neuronal development and function.

LINKED ARTICLES

This article is part of a themed issue on Neurochemistry in Japan. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.4/issuetoc
T‐LAK cell‐originated protein kinase (TOPK) is a Novel Prognostic and Therapeutic Target in Chordoma
Authors: Thanindratarn Pichaya , Dean Dylan C. , Nelson Scott D. , Hornicek Francis J. , Duan Zhenfeng
Published: September 2020

Objectives

To assess the expression, prognostic value, and functionality of T‐lymphokine‐activated killer (T‐LAK) cell‐originated protein kinase (TOPK) in chordoma pathogenesis.

Materials and Methods

TOPK expression in chordoma was assessed via immunohistochemical staining of a tissue microarray (TMA) and correlated with patient clinicopathology. TOPK expression in chordoma cell lines and fresh patient tissues was then evaluated by Western blot. TOPK small interfering RNA (siRNA) and the specific inhibitor OTS514 were applied to determine the roles of TOPK in chordoma pathogenicity. The effect of TOPK expression on chordoma cell clonogenicity was also investigated using clonogenic assays. A 3D cell culture model was utilized to mimic in vivo environment to validate the effect of TOPK inhibition on chordoma cells.

Results

TOPK was highly expressed in 78.2% of the chordoma specimens in the TMA and all chordoma cell lines. High TOPK expression significantly correlated with metastasis, recurrence, disease status and shorter overall survival. Knockdown of TOPK with specific siRNA resulted in significantly decrease chordoma cell viability. Inhibition of TOPK with OTS514 significantly inhibited chordoma cell growth and proliferation, colony‐forming capacity and ex vivo spheroid growth.

Conclusions

High expression of TOPK is an important predictor of poor prognosis in chordoma. Inhibition of TOPK resulted in significantly decrease chordoma cell proliferation and increase apoptosis. Our results indicate TOPK as a novel prognostic biomarker and therapeutic target for chordoma.
Precision Medicine, AI, and the Future of Personalized Health Care
Authors: Johnson Kevin B. , Wei Wei‐Qi , Weeraratne Dilhan , Frisse Mark E. , Misulis Karl , Rhee Kyu , Zhao Juan , Snowdon Jane L.
Published: September 2020

The convergence of artificial intelligence (AI) and precision medicine promises to revolutionize health care. Precision medicine methods identify phenotypes of patients with less‐common responses to treatment or unique healthcare needs. AI leverages sophisticated computation and inference to generate insights, enables the system to reason and learn, and empowers clinician decision making through augmented intelligence. Recent literature suggests that translational research exploring this convergence will help solve the most difficult challenges facing precision medicine, especially those in which nongenomic and genomic determinants, combined with information from patient symptoms, clinical history, and lifestyles, will facilitate personalized diagnosis and prognostication.
Approaches to triangulation of alcohol data in Scotland: Commentary on Rehm et al.
Authors: Robinson Mark , Kibuchi Eliud , Gray Linsay , McCartney Gerry
Published: September 2020

Rehm et al. highlight the ongoing difficulties in accurately estimating alcohol consumption using surveys. Population surveys, in particular, suffer from non‐response and sampling bias, which affects their representativeness, but they are one of the few ways of estimating differences in consumption across population subgroups. In this article, we highlight different approaches that have been taken in Scotland to try to overcome these problems, from the pragmatic to the sophisticated.