bluuebunny/crossref_metadata_2025 huggingface dataset:
Severe pyrexia from nivolumab‐resistant advanced melanoma after successful combined therapy with encorafenib plus binimetinib
Authors: Amagai Ryo , Fujimura Taku , Kambayashi Yumi , Sato Yota , Tanita Kayo , Ohuchi Kentaro , Hashimoto Akira , Aiba Setsuya
Published: April 2020

Various serious adverse events (AE) have been reported to occur at a high rate in patients treated with BRAF plus mitogen‐activated protein kinase kinase (MEK) inhibitor combination therapy, but their subtypes differ among the BRAF/MEK inhibitors. Pyrexia or a spike of fever are well‐known AE of BRAF inhibitors, with or without MEK inhibitors, and have been reported to have a high incidence after dabrafenib/trametinib, but not after encorafenib/binimetinib. In this report, we describe three cases of severe pyrexia in nivolumab‐resistant advanced melanoma after successful combined therapy with encorafenib plus binimetinib. Interestingly, in all cases, the serum levels of soluble CD163 C‐X‐C motif chemokine (CXCL)9, CXCL10 and CXCL11, which are known biomarkers for adult‐onset Still’s disease (AOSD), increased in parallel with the development of pyrexia. Our present cases suggest that pyrexia caused by BRAF/MEK inhibitors may possess a similar pathophysiology as that of AOSD.
Metabolic mechanism of colistin resistance and its reverting in Vibrio alginolyticus
Authors: Li Lu , Su Yu‐bin , Peng Bo , Peng Xuan‐xian , Li Hui
Published: April 2020

Colistin is a last‐line antibiotic against Gram‐negative multidrug‐resistant bacteria, but the increased resistance poses a huge challenge to this drug. However, the mechanisms underlying such resistance are largely unexplored. The present study first identified the mutations of two genes encoding AceF subunit of pyruvate dehydrogenase (PDH) and TetR family transcriptional regulator in colistin‐resistant Vibrio alginolyticus (VA‐RCT) through genome sequencing. Then, gas chromatography‐mass spectroscopy‐based metabolomics was adopted to investigate metabolic responses since PDH plays a role in central carbon metabolism. Colistin resistance was associated with the reduction of the central carbon metabolism and energy metabolism, featuring the alteration of the pyruvate cycle, a recently characterized energy‐producing cycle. Metabolites in the pyruvate cycle reprogramed colistin‐resistant metabolome to colistin‐sensitive metabolome, resulting in increased gene expression, enzyme activity or protein abundance of the cycle and sodium‐translocating nicotinamide adenine dinucleotide‐ubiquinone oxidoreductase. This reprogramming promoted the production of the proton motive force that enhances the binding between colistin and lipid A in lipopolysaccharide. Moreover, this metabolic approach was effective against VA‐RCT in vitro and in vivo as well as other clinical isolates. These findings reveal a previously unknown mechanism of colistin resistance and develop a metabolome‐reprogramming approach to promote colistin efficiency to combat with colistin‐resistant bacteria.
The efficacy and safety of ramucirumab plus docetaxel in older patients with advanced non‐small cell lung cancer
Authors: Sakaguchi Tadashi , Furuya Naoki , Ito Kentaro , Hida Naoya , Morikawa Kei , Komase Yuko , Inoue Takeo , Hataji Osamu , Mineshita Masamichi
Published: April 2020

Background

Ramucirumab plus docetaxel (RAM+DOC) is expected to prolong survival in patients with advanced non‐small cell lung cancer (NSCLC); however, the efficacy and safety for older patients remains unknown. The objective of this study was to evaluate the efficacy and safety of RAM+DOC in patients 75 years and older.

Methods

We retrospectively reviewed consecutive patients with advanced NSCLC who had received RAM+DOC treatment at three institutions. We compared the efficacy and safety in patients 75 years and older to those under 75 years of age.

Results

A total of 114 patients were identified. The median progression‐free survival, time to treatment failure and overall survival was 3.6 (95% CI: 0.4–6.7), 3.1 (95% CI: 2.4–3.9) and 11.2 months (95% CI: 5.6–16.8) in the older group (N = 23), and 4.2 (95% CI: 3.3–5.0), 3.4 (95% CI: 3.3–5.0) and 12.2 months (95% CI: 9.1–15.4) in the younger group (N = 91), respectively. Survival curves were similar for each group, while the objective response rate was 30.4% (95% CI: 13.2–52.9%) in older patients and 35.2% (95% CI, 25.4–45.9%) for the younger group. A total of 22 older patients (95.7%) and 73 (80.2%) younger patients received primary prophylactic pegylated‐granulocyte‐colony stimulating factor (PEG‐G‐CSF). Four older patients (17.3%) and 14 younger patients (15.3%) discontinued RAM+DOC due to adverse events.

Conclusions

RAM+DOC is expected to be efficacious and tolerable in older patients when supported with prophylactic PEG‐G‐CSF therapy.

Key points

Significant findings of the study

・PFS, OS, and ORR in older patients were similar to those under 75 years of age.

・Safety of RAM+DOC was well tolerated in older patients with prophylactic PEG‐G‐CSF.

・Prophylactic PEG‐G‐CSF with RAM+DOC may contribute to better efficacy.

What this study adds

・This study suggests that RAM+DOC with prophylactic PEG‐G‐CSF is expected to be a useful option in older patients with advanced NSCLC.
First‐line immune checkpoint therapy in metastatic squamous cell lung cancer harboring both EGFR mutation and high expression of PD‐L1: A case report
Authors: Hamai Kosuke , Tanahashi Hiroki , Ueno Sayaka , Konishi Hanae , Matsumura Mirai , Nomura Akio , Nakamoto Kanako , Isoyama Shoko , Tanimoto Takuya , Shoda Hiroyasu , Ishikawa Nobuhisa
Published: April 2020

A 90‐year‐old female was admitted to our hospital with a history of a dry cough. Chest computed tomography (CT) scan showed a tumor shadow, and CT‐guided lung biopsy revealed squamous cell carcinoma harboring an EGFR mutation. In addition, programmed death‐ligand 1 (PD‐L1) was highly expressed with a tumor proportion score (TPS) of >75%. Pembrolizumab therapy in the first‐line setting was not effective, and the patient died at six months from the first visit. Squamous cell lung cancers (SCLCs) with both EGFR mutation and high expression of PD‐L1 are very rare.
MicroRNA‐125b as a tumor suppressor by targeting MMP11 in breast cancer
Authors: Wang Yanan , Wei Yaning , Fan Xiangyu , Zhang Pei , Wang Pan , Cheng Shujie , Zhang Jinku
Published: April 2020

Background

Breast cancer is a common type of tumor in women worldwide. MicroRNAs have been identified as regulators in many human cancers. The aim of this study was therefore to investigate the functional role of miR‐125b in regulating breast cancer progression.

Methods

We used the StarBase database to investigate the expression of miRNA‐125b in breast cancer and adjacent normal tissues. MMP11 3′‐UTR construct and luciferase reporter assays was performed for target genes. Cell proliferation was evaluated by CCK‐8 and colony formation assay. The migration and invasion were assessed by transwell assay.

Results

Luciferase reporter assays showed miRNA‐125b directly targeted MMP11. miRNA‐125b by transfection with its mimic in breast cancer cells significantly suppressed breast cancer cell proliferation and migration. Western blot revealed that overexpression of miRNA‐125b substantially reduced MMP11 protein expression. We used the UALCAN database to investigate the expression of MMP11 in human breast cancer and adjacent normal tissues. In addition, we found that miRNA‐125b spoiled MMP11 induced breast cancer cell proliferation and migration promotion effect.

Conclusions

miRNA‐125b mimic inhibited proliferation, migration, and invasion of breast cancer cells through targeting MMP11 protein.
miR‐181a regulates p62/SQSTM1, parkin, and protein DJ‐1 promoting mitochondrial dynamics in skeletal muscle aging
Authors: Goljanek‐Whysall Katarzyna , Soriano‐Arroquia Ana , McCormick Rachel , Chinda Caroline , McDonagh Brian
Published: April 2020

One of the key mechanisms underlying skeletal muscle functional deterioration during aging is disrupted mitochondrial dynamics. Regulation of mitochondrial dynamics is essential to maintain a healthy mitochondrial population and prevent the accumulation of damaged mitochondria; however, the regulatory mechanisms are poorly understood. We demonstrated loss of mitochondrial content and disrupted mitochondrial dynamics in muscle during aging concomitant with dysregulation of miR‐181a target interactions. Using functional approaches and mito‐QC assay, we have established that miR‐181a is an endogenous regulator of mitochondrial dynamics through concerted regulation of Park2, p62/SQSTM1, and DJ‐1 in vitro. Downregulation of miR‐181a with age was associated with an accumulation of autophagy‐related proteins and abnormal mitochondria. Restoring miR‐181a levels in old mice prevented accumulation of p62, DJ‐1, and PARK2, and improved mitochondrial quality and muscle function. These results provide physiological evidence for the potential of microRNA‐based interventions for age‐related muscle atrophy and of wider significance for diseases with disrupted mitochondrial dynamics.
Nuclear envelope dysfunction and its contribution to the aging process
Authors: Martins Filipa , Sousa Jéssica , Pereira Cátia D. , da Cruz e Silva Odete A. B. , Rebelo Sandra
Published: April 2020

The nuclear envelope (NE) is the central organizing unit of the eukaryotic cell serving as a genome protective barrier and mechanotransduction interface between the cytoplasm and the nucleus. The NE is mainly composed of a nuclear lamina and a double membrane connected at specific points where the nuclear pore complexes (NPCs) form. Physiological aging might be generically defined as a functional decline across lifespan observed from the cellular to organismal level. Therefore, during aging and premature aging, several cellular alterations occur, including nuclear‐specific changes, particularly, altered nuclear transport, increased genomic instability induced by DNA damage, and telomere attrition. Here, we highlight and discuss proteins associated with nuclear transport dysfunction induced by aging, particularly nucleoporins, nuclear transport factors, and lamins. Moreover, changes in the structure of chromatin and consequent heterochromatin rearrangement upon aging are discussed. These alterations correlate with NE dysfunction, particularly lamins’ alterations. Finally, telomere attrition is addressed and correlated with altered levels of nuclear lamins and nuclear lamina‐associated proteins. Overall, the identification of molecular mechanisms underlying NE dysfunction, including upstream and downstream events, which have yet to be unraveled, will be determinant not only to our understanding of several pathologies, but as here discussed, in the aging process.
Nicotine abolishes memory‐related synaptic strengthening and promotes synaptic depression in the neurogenic dentate gyrus of miR‐132/212 knockout mice
Authors: Stojanovic Tamara , Benes Hannah , Awad Amena , Bormann Daniel , Monje Francisco J.
Published: April 2020

Micro‐RNAs (miRNAs) are highly evolutionarily conserved short‐length/noncoding RNA molecules that modulate a wide range of cellular functions in many cell types by regulating the expression of a variety of targeted genes. miRNAs have also recently emerged as key regulators of neuronal genes mediating the effects of psychostimulant drugs and memory‐related neuroplasticity processes. Smoking is a predominant addictive behaviour associated with millions of deaths worldwide, and nicotine is a potent natural psychoactive agonist of cholinergic receptors, highly abundant in cigarettes. The influence of miRNAs modulation on cholinergic signalling in the nervous system remains however poorly explored. Using miRNA knockout mice and biochemical, electrophysiological and pharmacological approaches, we examined the effects of miR‐132/212 gene disruption on the levels of hippocampal nicotinic acetylcholine receptors, total ERK and phosphorylated ERK (pERK) and MeCP2 protein levels, and studied the impact of nicotine stimulation on hippocampal synaptic transmission and synaptic depression and strengthening. miR‐132/212 deletion significantly altered α7‐nAChR and pERK protein levels, but not total ERK or MeCP2, and resulted in both exacerbated synaptic depression and virtually abolished memory‐related synaptic strengthening upon nicotine stimulation. These observations reveal a functional miRNAs/nicotinergic signalling interplay critical for nicotinic‐receptor expression and neuroplasticity in brain structures relevant for drug addiction and learning and memory functions.
Accuracy of sonographic estimation of weight in fetuses with abdominal wall defects
Authors: Spaulding Portia , Edwards Andrew , Coombs Peter , Davies‐Tuck Miranda , Robinson Alice
Published: April 2020

Background

Accurate estimation of fetal weight is essential in guiding management of fetuses with abdominal wall defects (AWDs), as growth restriction is an important predictor of perinatal morbidity and mortality. Several sonographic formulae are available involving multiple biometric parameters, but abdominal circumference measurements may underestimate weight in fetuses with AWDs. No formula has yet shown superior accuracy.

Aims

The objectives of this study were to evaluate, in fetuses with gastroschisis and omphalocoele, the accuracy of a sonographic estimated fetal weight (EFW) formula proposed by Siemer and colleagues, specifically for use in fetuses with AWDs compared to the commonly used Hadlock IV formula in estimating fetal weight, and detecting small for gestational age (SGA) fetuses.

Materials and Methods

A retrospective cohort of 113 fetuses with AWDs was identified from an Australian teaching hospital over 13 years. Pregnancy data and sonographic fetal biometry parameters were obtained. The accuracy of each formula in predicting birthweight was compared using Bland–Altman limits of agreement, and the intraclass correlation coefficient between EFW and actual birthweight. Performance of each formula in detecting SGA fetuses was determined.

Results

The Siemer and Hadlock formulae have similar accuracies for predicting birthweight in fetuses with AWDs. The Hadlock formula has a higher detection rate for SGA < 10th centile and < 3rd centile compared to the Seimer formula (84% vs 68% and 83% vs 67% respectively), albeit with a higher false‐positive rate.

Conclusion

There is no clear clinical advantage in using the Siemer formula, which is specifically designed for fetuses with AWDs, over the Hadlock formula to estimate weight in fetuses with AWDs.
Open mesh removal combined with laparoscopic totally extraperitoneal inguinal hernia repair: A case report of a novel surgical technique for chronic postoperative inguinal pain
Authors: Kojima Shigehiro , Sakamoto Tsuguo , Yajima Kazuhito , Ogawa Fumihiro
Published: April 2020

A 74‐year‐old man presented for surgical treatment to alleviate chronic post‐herniorrhaphy inguinal pain. Physical and imaging examinations suggested that his pain was due to his ilioinguinal nerve being entrapped by a meshoma composed of bilayer mesh and plug mesh. The patient strongly desired mesh removal, although it appeared challenging because of adhesion of the meshes from the previous herniorrhaphies. Anticipating technical difficulty, we performed laparoscopic totally extraperitoneal repair followed by open mesh removal. Thus, the risk of damaging the peritoneum and visceral organs during open mesh removal was eliminated because the peritoneum had already been separated from the pathogenic mesh during the laparoscopic repair. The patient's chronic pain was drastically relieved. Combination surgery may therefore be a safe and useful technique in select patients with chronic postoperative inguinal pain. This approach could also prevent hernia recurrence.
Evaluation of influence of milk urea nitrogen on reproductive performance in smallholder dairy farms
Authors: Kananub S , Pechkerd P , VanLeeuwen J , Stryhn H , Arunvipas P
Published: April 2020

Objective

The aim of this study was to determine the relationship between milk urea nitrogen (MUN) and reproductive performance in dairy cows in western Thailand.

Design

All cows calving from November 2014 to April 2015 were included in the study, a total of 486 cows from 47 farms. Each cow had milk constituents and MUN tested monthly up to confirmed conception or until the 8th month after parturition. Each farm had a dietary assessment completed. Cox proportional hazard models with shared frailty were used to determine associations of conception rate.

Results

Cows became pregnant increasingly quickly over time, except during 100–150 days of lactation. A change in MUN from 12.5 to 13.5 mg/dL on the closet day to breeding was associated with a 5% decrease in conception. Milk protein was negatively associated with hazard of conception, whereas milk lactose and dietary protein:energy ratio had positive associations with conception rate. Breeding season was also significant; the highest conception rate was observed in cows inseminated during winter, whereas insemination during the humid rainy season resulted in the lowest conception rates. The farm random effect in the model was strongly significant.

Conclusion

Detrimental effects of higher MUN on rate of conception were identified. The rate of conception was positively associated with protein:energy ratio in the study. Therefore, good nutritional management leading to positive energy balance should benefit conception rates.
Efficient screening of predictive biomarkers for individual treatment selection
Authors: Sugasawa Shonosuke , Noma Hisashi
Published: April 2020

The development of molecular diagnostic tools to achieve individualized medicine requires identifying predictive biomarkers associated with subgroups of individuals who might receive beneficial or harmful effects from different available treatments. However, due to the large number of candidate biomarkers in the large‐scale genetic and molecular studies, and complex relationships among clinical outcome, biomarkers, and treatments, the ordinary statistical tests for the interactions between treatments and covariates have difficulties from their limited statistical powers. In this paper, we propose an efficient method for detecting predictive biomarkers. We employ weighted loss functions of Chenet al. to directly estimate individual treatment scores and propose synthetic posterior inference for effect sizes of biomarkers. We develop an empirical Bayes approach, namely, we estimate unknown hyperparameters in the prior distribution based on data. We then provide efficient screening methods for the candidate biomarkers via optimal discovery procedure with adequate control of false discovery rate. The proposed method is demonstrated in simulation studies and an application to a breast cancer clinical study in which the proposed method was shown to detect the much larger numbers of significant biomarkers than existing standard methods.
Factors associated with development and distribution of granular/fuzzy astrocytes in neurodegenerative diseases
Authors: Miki Tomoko , Yokota Osamu , Haraguchi Takashi , Ishizu Hideki , Hasegawa Masato , Ishihara Takeshi , Ueno Shu‐ichi , Takenoshita Shintaro , Terada Seishi , Yamada Norihito
Published: April 2020

Granular/fuzzy astrocytes (GFAs), a subtype of “aging‐related tau astrogliopathy,” are noted in cases bearing various neurodegenerative diseases. However, the pathogenic significance of GFAs remains unclear. We immunohistochemically examined the frontal cortex, caudate nucleus, putamen and amygdala in 105 cases composed of argyrophilic grain disease cases (AGD, N = 26), and progressive supranuclear palsy (PSP, N = 10), Alzheimer’s disease (AD, N = 20) and primary age‐related tauopathy cases (PART, N = 18) lacking AGD, as well as 31 cases bearing other various neurodegenerative diseases to clarify (i) the distribution patterns of GFAs in AGD, and PSP, AD and PART lacking AGD, (ii) the impacts of major pathological factors and age on GFA formation and (iii) immunohistochemical features useful to understand the formation process of GFAs. In AGD cases, GFAs consistently occurred in the amygdala (100%), followed by the putamen (69.2%) and caudate nucleus and frontal cortex (57.7%, respectively). In PSP cases without AGD, GFAs were almost consistently noted in all regions examined (90–100%). In AD cases without AGD, GFAs were less frequent, developing preferably in the putamen (35.0%) and caudate nucleus (30.0%). PART cases without AGD had GFAs most frequently in the amygdala (35.3%), being more similar to AGD than to AD cases. Ordered logistic regression analyses using all cases demonstrated that the strongest independent factor of GFA formation in the frontal cortex and striatum was the diagnosis of PSP, while that in the amygdala was AGD. The age was not significantly associated with GFA formation in any region. In GFAs in AGD cases, phosphorylation and conformational change of tau, Gallyas‐positive glial threads indistinguishable from those in tufted astrocytes, and the activation of autophagy occurred sequentially. Given these findings, AGD, PSP, AD and PART cases may show distinct distributions of GFAs, which may provide clues to predict the underlying processes of primary tauopathies.
Impacts of habitat on butterfly dispersal in tropical forests, parks and grassland patches embedded in an urban landscape
Authors: Jain Anuj , Chan Simon Kee Mun , Vlasanek Petr , Webb Edward L.
Published: April 2020

Dispersal distances of 17 species of butterflies in tropical Singapore were significantly greater in forest than in urban habitat. Butterflies in urban plots frequently moved within suitable habitat (park/grassland) patches but rarely crossed non‐habitat patches suggesting potential isolation and a need for urban corridors.
Synergistic effect of the inhibitors of RAF/MEK and AXL on KRAS‐mutated ovarian cancer cells with high AXL expression
Authors: Umemura Shiori , Sowa Yoshihiro , Iizumi Yosuke , Kitawaki Jo , Sakai Toshiyuki
Published: April 2020

KRAS mutation is frequently seen in a subtype of ovarian cancer categorized as type 1. The KRAS‐MAPK pathway, which is closely involved in type 1 cancer progression, is under the regulation of receptor tyrosine kinases (RTKs). AXL, one of the RTKs, has been reported to be overexpressed in ovarian cancer and contributes to the poor prognosis. However, there is no useful target‐based agent against such gene profiles. We examined the combined effect of the dual RAF/MEK inhibitor CH5126766 and AXL inhibitor R428 on the growth of ovarian cancer HEY‐T30 and OVCAR‐5 cell lines, both of which bear KRAS mutation and express AXL at a high level, using the WST‐8 assay and the colony formation assay. The synergistic effect of the combination was evaluated by the combination index. The apoptotic cells were analyzed by flow cytometry. The expression of apoptotic proteins and the phosphorylation of MAPK and AKT pathway proteins were investigated by western blotting. We found that CH5126766 and R428 suppressed the phosphorylation of ERK and AKT, respectively, and their combination synergistically inhibited the growth of both cell lines with enhancement of apoptosis accompanied by the Bim upregulation. Combined treatment with CH5126766 and R428 is expected as the novel therapeutic option for KRAS‐mutated ovarian cancer with high expression of AXL.
Mechanisms and impacts of an incentive‐based conservation program with evidence from a randomized control trial
Authors: Wiik Emma , Jones Julia P. G. , Pynegar Edwin , Bottazzi Patrick , Asquith Nigel , Gibbons James , Kontoleon Andreas
Published: April 2020

Conservation science needs more high‐quality impact evaluations, especially ones that explore mechanisms of success or failure. Randomized control trials (RCTs) provide particularly robust evidence of the effectiveness of interventions (although they have been criticized as reductionist and unable to provide insights into mechanisms), but there have been few such experiments investigating conservation at the landscape scale. We explored the impact of Watershared, an incentive‐based conservation program in the Bolivian Andes, with one of the few RCTs of landscape‐scale conservation in existence. There is strong interest in such incentive‐based conservation approaches as some argue they can avoid negative social impacts sometimes associated with protected areas. We focused on social and environmental outcomes based on responses from a household survey in 129 communities randomly allocated to control or treatment (conducted both at the baseline in 2010 and repeated in 2015–2016). We controlled for incomplete program uptake by combining standard RCT analysis with matching methods and investigated mechanisms by exploring intermediate and ultimate outcomes according to the underlying theory of change. Previous analyses, focused on single biophysical outcomes, showed that over its first 5 years Watershared did not slow deforestation or improve water quality at the landscape scale. We found that Watershared influenced some outcomes measured using the survey, but the effects were complex, and some were unexpected. We thus demonstrated how RCTs can provide insights into the pathways of impact, as well as whether an intervention has impact. This paper, one of the first registered reports in conservation science, demonstrates how preregistration can help make complex research designs more transparent, avoid cherry picking, and reduce publication bias.
Simultaneous pelvic exenteration and liver resection for primary rectal cancer with synchronous liver metastases: results from the PelvEx Collaborative
Authors:   PelvEx Collaborative
Published: April 2020

Aim

At presentation, 15–20% of patients with rectal cancer already have synchronous liver metastases. The aim of this study was to determine the surgical and survival outcomes in patients with advanced rectal cancer who underwent combined pelvic exenteration and liver (oligometastatic) resection.

Method

Data from 20 international institutions that performed simultaneous pelvic exenteration and liver resection between 2007 and 2017 were accumulated. Primarily, we examined perioperative outcomes, morbidity and mortality. We also assessed the impact that margin status had on survival.

Results

Of 128 patients, 72 (56.2%) were men with a median age of 60 years [interquartile range (IQR) 15 years]. The median size of the liver oligometastatic deposits was 2 cm (IQR 1.8 cm). The median duration of surgery was 406 min (IQR 240 min), with a median blood loss of 1090 ml (IQR 2010 ml). A negative resection margin (R0 resection) was achieved in 73.5% of pelvic exenterations and 66.4% of liver resections. The 30‐day mortality rate was 1.6%, and 32% of patients had a major postoperative complication. The 5‐year overall survival for patients in whom an R0 resection of both primary and metastatic disease was achieved was 54.6% compared with 20% for those with an R1/R2 resection (P = 0.006).

Conclusion

Simultaneous pelvic exenteration and liver resection is feasible, with acceptable morbidity and mortality. Simultaneous resection should only be performed where an R0 resection of both pelvic and hepatic disease is anticipated.
The past and future role of conservation science in saving biodiversity
Authors: Williams David R , Balmford Andrew , Wilcove David S
Published: April 2020

Global biodiversity losses continue despite tremendous growth in the volume of conservation science and many local successes. Research that can achieve conservation science's aims—arresting declines in biodiversity and preventing extinctions—is therefore of ever greater importance. Here, we ask whether conservation science, as currently performed, is progressing in such a way as to maximize its impact. We present a simple framework for how effective conservation research could progress, from identifying problems to diagnosing their proximate and ultimate causes, and from proposing, to designing, implementing, and testing responses. We then demonstrate that for three well‐known examples—South Asian vultures, whooping cranes, and bycatch of procellariform seabirds—published studies appear to follow this sequence, with considerable benefits. However, for a representative sample of the wider conservation literature, we find no evidence of such a progression. Instead, the vast majority of papers remain focused on describing the state of nature or on mechanisms directly causing changes, with very little research on designing or implementing conservation responses. This lack of research on the sorts of questions that might most help conservation science deliver its stated mission strongly suggests we will struggle to translate the huge increase in research activity into real‐world benefits.
Characteristics and survival impact of polymorphonuclear leucocyte‐predominant malignant pleural effusions secondary to lung cancer
Authors: Lee Jaehee , Lee Yong Hoon , Seo Hyewon , Do Young Woo , Lee Deok Heon , Lee Sang Yub , Lim Jae Kwang , Yoo Seung Soo , Lee Shin Yup , Cha Seung Ick , Park Jae Yong , Kim Chang Ho
Published: April 2020

Introduction

In comparison with mononuclear leucocyte (MNL)‐predominant malignant pleural effusions (MPEs), polymorphonuclear leucocyte (PMNL)‐predominant MPEs have rarely been investigated and may be associated with a poorer prognosis.

Objectives

To investigate the characteristics and survival impact of PMNL‐predominant MPEs secondary to lung cancer.

Methods

This retrospective study included patients with MPE secondary to lung cancer, which were classified into the PMNL‐ and MNL‐predominant groups according to cellular predominance in the pleural fluid. Clinical, hematological, radiological, and pleural fluid data were compared between the groups, and the survival impact of PMNL predominance in MPE was evaluated.

Results

Of the 193 MPEs included, 37 (19%) were characterised by PMNL predominance. Compared to the MNL‐predominant group, the PMNL‐predominant group showed significantly poorer patient performances (P = .001), higher white blood cell counts (P = .009), higher neutrophil counts, higher blood neutrophil‐to‐lymphocyte ratio (P = .046), higher serum C‐reactive protein (P = .003), lower serum albumin (P < .001), lower pleural fluid pH (P = .002) and higher pleural fluid lactate dehydrogenase (P = .029) levels. In contrast, most clinical and radiological findings, including the duration of symptoms, showed no significant intergroup differences. A shift towards MNL predominance was observed in only 38% of the PMNL‐predominant patients who underwent repeat thoracentesis. Overall survival of the PMNL‐predominant group was significantly shorter than the MNL‐predominant group (P = .003).

Conclusions

PMNL predominance in MPEs secondary to lung cancer may be observed in variable phases with respect to the duration of symptoms and the time of thoracentesis. Overall, PMNL‐predominant MPEs were associated with more advanced stages and poorer survival outcomes, compared to MNL‐predominant MPEs.
Lung allocation for transplant: The European perspective
Authors: Holm Are Martin , Immer Franz , Benden Christian
Published: April 2020

Since the first successful lung transplants in humans were done in the 1980s, lung transplantation has become an established treatment for end‐stage pulmonary disease. Because the access to transplantable organs is limited and unpredictable, rules that guide the allocation of lungs for transplants have emerged. Such rules are governed not only by medical and bioethical necessities, but also by local traditions, legislation, and practical circumstances. Therefore, there may be significant differences between the organ allocation practices in various parts of the world. In this brief communication, the European perspective on lung allocation is presented, also adding a very brief description of other parts of the world.
Availability, retail price and potency of legal and illegal cannabis in Canada after recreational cannabis legalisation
Authors: Mahamad Syed , Wadsworth Elle , Rynard Vicki , Goodman Samantha , Hammond David
Published: April 2020

Introduction and Aims

There is little objective market data on the price or potency of legal and illegal cannabis products following recreational cannabis legalisation.

Design and Methods

In the 2 months post‐legalisation in Canada (November–December 2018), legal and illegal cannabis retailers were identified from government lists and online directories. The store location, price and Δ9‐tetrahydrocannabinol (THC) and cannabidiol levels of dried herb and cannabis cookies were collected from retailer websites or Weedmaps.

Results

We identified 185 legal retailers (22 online stores, 163 storefronts; 65 government‐run stores, 120 private stores) and 944 illegal retailers (791 delivery‐only services, 157 storefronts). Relative to legal dried herb, illegal dried herb was lower in price (1 g: $10.23 vs. $11.08, ⅛ oz: $9.37/g vs. $10.88/g, ½ oz: $8.18/g vs. $8.85/g; P < 0.05 for all) and higher in potency (THC: 20.5% vs. 16.1%, cannabidiol: 2.4% vs. 1.7%; P < 0.05 for both). Legal private stores had higher prices for dried herb than government‐run stores (1 g: $13.08 vs. $10.89, ⅛ oz: $12.75/g vs. $10.45/g, ½ oz: $10.85/g vs. $8.71/g, 1 oz: $8.54/g vs. $7.22/g; P < 0.05 for all). On average, one cannabis cookie in the illegal market contained 96 mg of THC and cost $1.57 per 10 mg of THC.

Discussion and Conclusions

In the 2 months post‐legalisation, illegal cannabis was less expensive, with higher labelled THC content than legal cannabis, although the scope of these differences was more modest than estimates from other crowdsourced and self‐reported data. Direct monitoring of cannabis price and potency from legal and illegal retailers is needed to examine the impact of legalisation over time.
Gender difference in the impact of Ischaemic heart disease on heart failure
Authors: Kim Hyun‐Jin , Kim Myung‐A , Kim Hack‐Lyoung , Choi Dong‐Ju , Han Seongwoo , Jeon Eun‐Seok , Cho Myeong‐Chan , Kim Jae‐Joong , Yoo Byung‐Su , Shin Mi‐Seung , Kang Seok‐Min , Chae Shung Chull
Published: April 2020

Background

Although the impact of ischaemic heart disease (IHD) on heart failure (HF) is evolving, there is uncertainty about the role of IHD in determining the risk of clinical outcomes by gender. This study evaluated the gender difference in the impact of IHD on long‐term clinical outcomes in patients with heart failure reduced ejection fraction (HFrEF).

Methods

Study data were obtained from a nationwide registry, which is a prospective multicentre cohort that included 3200 patients who were hospitalized for HF. A total of 1638 patients with HFrEF were classified by gender. The primary outcome was all‐cause death during follow‐up.

Results

In total, 133 women (18.9%) died and 168 men (18.0%) died during the follow‐up (median, 489 days). Women with HFrEF with IHD had a significantly lower cumulative survival rate than women without IHD at the long‐term follow‐up (74.8% vs 84.9%, log‐rank P = .001). However, the survival rate was not different in men with HFrEF with IHD compared with men without IHD. A Cox regression analysis showed that IHD had a 1.43‐fold increased risk for all‐cause mortality independently in women after adjusting for confounding factors (odds ratio 1.43, 95% confidence interval 1.058‐1.929, P = .020).

Conclusion

Ischaemic heart disease was an independent risk factor for long‐term mortality in women with HFrEF. IHD should be actively evaluated in women with HF for predicting clinical outcomes and initiating appropriate treatment. Women with HF caused by IHD should be treated more meticulously to avoid a poor prognosis.
Macrophages in the pathophysiology of NAFLD: The role of sex differences
Authors: Ministrini Stefano , Montecucco Fabrizio , Sahebkar Amirhossein , Carbone Federico
Published: April 2020

Nonalcoholic fatty liver disease (NAFLD) is a multifactorial pathological condition, which recognizes a certain sexual dimorphism. Experimental and clinical studies provided evidence for a critical role of macrophages in NAFLD development and progression. Especially, liver‐resident macrophages (also known as Kupffer cells) are likely the common final pathway of several pro‐steatosic signals. A huge amount of danger‐associated molecular patterns recognized by Kupffer cells is provided within the liver by lipid and glucose toxicity. Other pro‐inflammatory signals come from surrounding tissues into the portal vein, directly to the liver: they come from dysfunctional adipocytes, adipose tissue macrophages and gut dysbiosis. These complex crosstalks are differently represented across sexes, as sexual hormones control many of these processes. Sexual dimorphism then modulates metabolic and inflammatory cascades driving the liver from a simple steatosis to NAFLD and beyond. Here, metabolic and inflammatory mechanisms underlying NALFD pathophysiology will be updated. A special attention will be paid to describe sex‐related differences that could provide insights for patient stratification and more tailored therapeutic approaches.
RATIONAL HEURISTICS? EXPECTATIONS AND BEHAVIORS IN EVOLVING ECONOMIES WITH HETEROGENEOUS INTERACTING AGENTS
Authors: Dosi Giovanni , Napoletano Mauro , Roventini Andrea , Stiglitz Joseph E. , Treibich Tania
Published: April 2020

We analyze the individual and macroeconomic impacts of heterogeneous expectations and action rules within an agent‐based model populated by heterogeneous, interacting firms. Agents have to cope with acomplex evolving economycharacterized by deep uncertainty resulting from technical change, imperfect information, coordination hurdles, and structural breaks. In these circumstances, we find that neither individual nor macroeconomic dynamics improve when agents replace myopic expectations with less naïve learning rules. Our results suggest that fast and frugal robust heuristics maynotbe a second‐best option but rather “rational” responses in complex and changing macroeconomic environments.(JELC63, D8, E32, E6, O4)
Phasic cholinergic signaling promotes emergence of local gamma rhythms in excitatory–inhibitory networks
Authors: Lu Yiqing , Sarter Martin , Zochowski Michal , Booth Victoria
Published: April 2020

Recent experimental results have shown that the detection of cues in behavioral attention tasks relies on transient increases of acetylcholine (ACh) release in frontal cortex and cholinergically driven oscillatory activity in the gamma frequency band (Howe et al. Journal of Neuroscience, 2017, 37, 3215). The cue‐induced gamma rhythmic activity requires stimulation of M1 muscarinic receptors. Using biophysical computational modeling, we show that a network of excitatory (E) and inhibitory (I) neurons that initially displays asynchronous firing can generate transient gamma oscillatory activity in response to simulated brief pulses of ACh. ACh effects are simulated as transient modulation of the conductance of an M‐type K+ current which is blocked by activation of muscarinic receptors and has significant effects on neuronal excitability. The ACh‐induced effects on the M current conductance, gKs, change network dynamics to promote the emergence of network gamma rhythmicity through a Pyramidal‐Interneuronal Network Gamma mechanism. Depending on connectivity strengths between and among E and I cells, gamma activity decays with the simulated gKs transient modulation or is sustained in the network after the gKs transient has completely dissipated. We investigated the sensitivity of the emergent gamma activity to synaptic strengths, external noise and simulated levels of gKs modulation. To address recent experimental findings that cholinergic signaling is likely spatially focused and dynamic, we show that localized gKs modulation can induce transient changes of cellular excitability in local subnetworks, subsequently causing population‐specific gamma oscillations. These results highlight dynamical mechanisms underlying localization of ACh‐driven responses and suggest that spatially localized, cholinergically induced gamma may contribute to selectivity in the processing of competing external stimuli, as occurs in attentional tasks.
Past, present and future contributions of evolutionary biology to wildlife forensics, management and conservation
Authors: Bourret Vincent , Albert Vicky , April Julien , Côté Guillaume , Morissette Olivier
Published: April 2020

Successfully implementing fundamental concepts into concrete applications is challenging in any given field. It requires communication, collaboration and shared will between researchers and practitioners. We argue that evolutionary biology, through research work linked to conservation, management and forensics, had a significant impact on wildlife agencies and department practices, where new frameworks and applications have been implemented over the last decades. The Quebec government's Wildlife Department (MFFP: Ministère des Forêts, de la Faune et des Parcs) has been proactive in reducing the “research–implementation” gap, thanks to prolific collaborations with many academic researchers. Among these associations, our department's outstanding partnership with Dr. Louis Bernatchez yielded significant contributions to harvest management, stocking programmes, definition of conservation units, recovery of threatened species, management of invasive species and forensic applications. We discuss key evolutionary biology concepts and resulting concrete examples of their successful implementation that derives directly or indirectly from this successful partnership. While old and new threats to wildlife are bringing new challenges, we expect recent developments in eDNA and genomics to provide innovative solutions as long as the research–implementation bridge remains open.
SARS‐CoV‐2, an evolutionary perspective of interaction with human ACE2 reveals undiscovered amino acids necessary for complex stability
Authors: Armijos‐Jaramillo Vinicio , Yeager Justin , Muslin Claire , Perez‐Castillo Yunierkis
Published: April 2020

The emergence of SARS‐CoV‐2 has resulted in nearly 1,280,000 infections and 73,000 deaths globally so far. This novel virus acquired the ability to infect human cells using the SARS‐CoV cell receptor hACE2. Because of this, it is essential to improve our understanding of the evolutionary dynamics surrounding the SARS‐CoV‐2 hACE2 interaction. One way theory predicts selection pressures should shape viral evolution is to enhance binding with host cells. We first assessed evolutionary dynamics in select betacoronavirus spike protein genes to predict whether these genomic regions are under directional or purifying selection between divergent viral lineages, at various scales of relatedness. With this analysis, we determine a region inside the receptor‐binding domain with putative sites under positive selection interspersed among highly conserved sites, which are implicated in structural stability of the viral spike protein and its union with human receptor ACE2. Next, to gain further insights into factors associated with recognition of the human host receptor, we performed modeling studies of five different betacoronaviruses and their potential binding to hACE2. Modeling results indicate that interfering with the salt bridges at hot spot 353 could be an effective strategy for inhibiting binding, and hence for the prevention of SARS‐CoV‐2 infections. We also propose that a glycine residue at the receptor‐binding domain of the spike glycoprotein can have a critical role in permitting bat SARS‐related coronaviruses to infect human cells.
Suspected primary mycotic rhinitis and paranasal sinusitis in seven horses (2013–2019)
Authors: Pujol R. , Tessier C. , Manneveau G. , De Fourmestraux C.
Published: April 2020

This manuscript reports seven horses suffering from mycotic rhinitis and paranasal sinusitis and describes the clinical signs, treatments and outcomes. Mycotic plaques were observed in the nasal portion of the ethmoidal labyrinth and ipsilateral nasal passage during rhinoscopy in one horse and in the paranasal sinuses during sinoscopy in six horses. Fungal culture was positive in five horses with predominance ofAspergillusspp. (n = 3). Surgical debridement was performed under rhinoscopic guidance and sinoscopic guidance through a trephine hole or directly via a bone flap. Medical treatment included topical application directly to the affected area with clotrimazole, enilconazole, nystatin or amphotericin B (mean of 10.1 ± 13.4 applications during hospitalisation) and additional inhalation of nystatin or amphotericin B (mean of 7.5 days of nebulisation during hospitalisation). The mean ± s.d. duration of hospitalisation was 12.9 ± 9.2 days. Six horses were available for long‐term follow‐up. The mean ± s.d. number of follow‐up examinations was 2.8 ± 2.6 consultations. Based on follow‐up endoscopic evaluations, it took up to 5 months to observe complete regression of the mycotic plaques. In conclusion, mycotic rhinitis and sinusitis can be effectively treated with repeated surgical debridement and topical antifungal therapeutics, associated with a good long‐term prognosis.
Successful surgical management of a medial humeral epicondyle fracture in a Thoroughbred foal
Authors: Mereu M. , Perez Olmos J. F. , Fischer C. , Mc Nally T. P.
Published: April 2020

A 2‐week‐old 75 kg Thoroughbred filly was presented for the investigation of an acute forelimb lameness. Radiographs revealed a fracture of the medial epicondylar physis of the left humerus (Salter–Harris type II fracture). The fragment was removed via arthrotomy under general anaesthesia. Two months post‐operatively, the foal was sound and at 2 years had resumed normal turn out. This case report describes a previously unreported surgical treatment for a fracture of the medial epicondylar physis in a foal.
Cooperation or Tension? Dyadic Coping in Cystic Fibrosis
Authors: Werner Shirli , Hochman Yael , Rosenne Hadas , Kurtz Shifra
Published: April 2020

Following a rise in the life expectancy of cystic fibrosis (CF) patients, many adults with CF form couple relationships. Yet, dyadic coping has not been previously examined in people with CF. This study examined how adults with CF and their partners cope as a couple with the illness, and what meanings each partner and the couple as a unit attribute to the experience. Seventeen adult CF patients and their partners participated in separate semi‐structured in‐depth interviews. Two main patterns of dyadic coping with CF were identified as follows: cooperation and tension. For couples in cooperation, the marital relationship served as a resource for adaptive coping. These couples were characterized by similarities in their perception of the place of CF in their lives and of their roles in the marital relationship. Couples in tension described the couple relationship as strained by difficulty of accepting the disease, proliferation of negative emotions, and a sense of burden and loneliness in the process of coping. Findings point to the importance of mutual empathy, clear and accepted division of roles between the partners, and open communication for facilitating coping as a couple.