bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression of fatty acid synthase genes and their role in development and arboviral infection of Aedes aegypti
Authors: Chotiwan Nunya , Brito-Sierra Carlos A. , Ramirez Gabriella , Lian Elena , Hill Catherine A. , Perera Rushika
Published: February 2022

Background

Fatty acids are the building blocks of complex lipids essential for living organisms. In mosquitoes, fatty acids are involved in cell membrane production, energy conservation and expenditure, innate immunity, development, and reproduction. Fatty acids are synthesized by a multifunctional enzyme complex called fatty acid synthase (FAS). Several paralogues of FAS were found in the Aedes aegypti (Ae. aegypti) mosquito. However, the molecular characteristics and the expression of some of these paralogues have not been investigated.

Methods

Genome assemblies of Ae. aegypti were analyzed and orthologues of human FAS were identified. Phylogenetic analysis and in silico molecular characterization were performed to identify the functional domains of the Ae. aegypti FAS (AaFAS). Quantitative analysis and loss-of-function experiments were performed to determine the significance of different AaFAS transcripts in various stages of development, expression following different diets and the impact of AaFAS on dengue virus, serotype 2 (DENV2) infection and transmission.

Results

We identified seven putative FAS genes in the Ae. aegypti genome assembly, based on nucleotide similarity to the FAS proteins (tBLASTn) of humans, other mosquitoes and invertebrates. Bioinformatics and molecular analyses suggested that only five of the FAS genes produce mRNA and therefore represent complete gene models. Expression levels of AaFAS varied among developmental stages and between male and female Ae. aegypti. Quantitative analyses revealed that expression of AaFAS1, the putative orthologue of the human FAS, was highest in adult females. Transient knockdown (KD) of AaFAS1 did not induce a complete compensation by other AaFAS genes but limited DENV2 infection of Aag2 cells in culture and the midgut of the mosquito.

Conclusion

AaFAS1 is the predominant AaFAS in the adult mosquitoes. It has the highest amino acid similarity to human FAS and contains all enzymatic domains typical of human FAS. AaFAS1 also facilitated DENV2 replication in both cell culture and in mosquito midguts. Our data suggest that AaFAS1 may play a role in transmission of dengue viruses, and could represent a target for intervention strategies.
Efficacy and Safety of Tregopil, a Novel, Ultra-Rapid Acting Oral Prandial Insulin Analog, as Part of a Basal-Bolus Regimen in Type 2 Diabetes: A Randomized, Active Controlled Phase 3 Study
Authors: Lebovitz Harold E , Fleming Alexander , Cherrington Alan D , Joshi Shashank , Athalye Sandeep N. , Loganathan Subramanian , Vishweswaramurthy Ashwini , Panda Jayanti , Marwah Ashwani
Published: February 2022

OBJECTIVE

Efficacy and safety of ultra-rapid acting oral prandial insulin Tregopil (Tregopil) was compared with insulin aspart (IAsp) in patients with type-2 diabetes on stable doses of insulin glargine and metformin.

RESEARCH DESIGN AND METHODS

In this open-label, active-controlled trial, patients with type-2 diabetes, with HbA1c ≥7% and ≤9% and 2-h postprandial glucose (PPG) ≥180 mg/dL were randomized (1:1:1) to Tregopil (30 mg [n=30], 45 mg [n=31]) and IAsp (n=30; dose titrated based on self-monitored blood glucose [SMBG]). Postprandial plasma glucose excursion (PPGE) and PPG were assessed from the standardized test meal (STM) and 9- point SMBG. The primary outcome measure was change from baseline (CFB) in HbA1c at week 24.

RESULTS

The Tregopil (30 mg) arm showed significantly lesser 1-h PPGE (CFB) excursion after the STM versus IAsp (Estimated Treatment Difference [ETD], 95% CI, -45.33 mg/dL [-71.91, -8.75], P=0.001) and 1-h PPG trended towards a better control. The combined Tregopil group (30+45 mg) showed lower PPGE at 15 mins as compared to IAsp. Meal-wise analysis showed lower 1-h PPGE and PPG in the Tregopil groups post-breakfast. Clinically significant hypoglycemia was lower with Tregopil groups versus IAsp (rate ratio: 0.69).

CONCLUSIONS

Tregopil demonstrated an ultra-fast onset and short-duration prandial insulin profile with good safety. Tregopil improved the 1-h PPG and overall PPG control compared to IAsp. A further reduction in HbA1c compared to baseline was not observed, likely as a result of variability in the control of fasting glucose level over the duration of the study.
Transcriptional and functional consequences of alterations to MEF2C and its topological organization in neuronal models
Authors: Mohajeri Kiana , Yadav Rachita , D’haene Eva , Boone Philip M. , Erdin Serkan , Gao Dadi , Moyses-Oliveira Mariana , Bhavsar Riya , Currall Benjamin , O’Keefe Kathryn , Lowther Chelsea , Lucente Diane , Burt Nicholas D. , Salani Monica , Larson Matthew , Menten Björn , Tai Derek J.C. , Gusella James F. , Vergult Sarah , Talkowski Michael E.
Published: February 2022

Point mutations and structural variants directly disrupting the coding sequence of MEF2C have been associated with a spectrum of neurodevelopmental disorders (NDDs), while recent studies have also implicated altered noncoding regulation of MEF2C expression in NDDs. However, the impact of haploinsufficiency of MEF2C on neurodevelopmental pathways and synaptic processes is not well understood, nor are the complex mechanisms that govern regulation of MEF2C. To explore the transcriptional and functional changes associated with coding and noncoding structural variants, we generated an allelic series of 204 isogenic iPSC-derived neuronal cell lines harboring CRISPR-engineered mutations that directly delete predominant isoforms of MEF2C, as well as deletions to the boundaries of topologically associating domains (TADs) and chromatin loops encompassing MEF2C. We then performed systematic profiling of mutation-specific alterations to transcriptional signatures, regulatory interactions, chromatin contacts, and electrophysiological effects. Our analyses reveal that direct deletion of MEF2C causes differential expression of genes enriched for neurodevelopmental and synaptic-associated pathways, accompanied by a significant reduction in synaptic firing and synchrony in neurons. By contrast, we observe robust buffering against MEF2C regulatory disruption upon deletion of a distal 5q14.3 TAD and loop boundary; however, homozygous loss of proximal loop boundary resulted in significant down-regulation of MEF2C expression and significantly reduced electrophysiological activity that was comparable to direct MEF2C disruption. Collectively, our findings demonstrate the functional impact of MEF2C haploinsufficiency in human-derived neural models and highlight the complex interactions of gene regulation and chromatin topology that challenge a priori regulatory predictions of structural variant disruption to three-dimensional genome organization.
Revisiting the origin of interleukin 1 (IL-1) based on biological activities of IL-1 in anamniotes and their sub-functionalization in amniotes
Authors: Hasel de Carvalho Eva , Bartok Eva , Stölting Helen , Bajoghli Baubak , Leptin Maria
Published: February 2022

The cytokine Interleukin 1 (IL-1) is an evolutionary innovation of vertebrates. Fish and amphibia have oneIL1gene, while mammals have two copies ofIL1,IL1AandIL1B, with distinct expression patterns and differences in their proteolytic activation. Our current understanding of the evolutionary history of IL-1 is mainly based on phylogenetic analyses, but this approach provides no information on potentially different functions of IL-1 homologs, and it remains unclear which biological activities identified for IL-1α and IL-1β in mammals are present in lower vertebrates. Here, we usein vitroandin vivoexperimental models to examine the expression patterns and cleavage of IL-1 proteins from various species. We found that IL-1 in the teleost medaka shares the transcriptional patterns of mammalian IL-1α, and its processing also resembles that of mammalian IL-1α, which is sensitive to cysteine protease inhibitors specific for the calpain and cathepsin families. By contrast, IL-1 proteins in reptiles also include biological properties of IL-1β. Therefore, we propose that duplication of the ancestral IL1 gene led to segregation of expression patterns and protein processing that characterizes the two extant forms of IL-1 in mammals.
The connectional anatomy of visual mental imagery: evidence from a patient with left occipito-temporal damage
Authors: Hajhajate Dounia , Kaufmann Brigitte , Liu Jianghao , Siuda-Krzywicka Katarzyna , Bartolomeo Paolo
Published: February 2022

Most of us can use our “mind’s eye” to mentally visualize things that are not in our direct line of sight, an ability known as visual mental imagery. Extensive left temporal damage can impair patients’ visual mental imagery experience, but the critical locus of lesion is unknown. Our recent meta-analysis of 27 fMRI studies of visual mental imagery highlighted a well-delimited region in the left lateral midfusiform gyrus, which was consistently activated during visual mental imagery, and which we called the Fusiform Imagery Node (FIN). Here we describe the connectional anatomy of FIN in neurotypical participants and in RDS, a right-handed patient with an extensive occipitotemporal stroke in the left hemisphere. The stroke provoked right homonymous hemianopia, alexia without agraphia, and color anomia. Despite these deficits, RDS had normal subjective experience of visual mental imagery and reasonably preserved behavioral performance on tests of visual mental imagery of object shape, object color, letters, faces, and spatial relationships. We found that the FIN was spared by the lesion. We then assessed the connectional anatomy of the FIN in the MNI space and in the patient’s native space, by visualizing the fibers of the inferior longitudinal fasciculus (ILF) and of the arcuate fasciculus (AF) passing through the FIN. In both spaces, the ILF connected the FIN with the anterior temporal lobe, and the AF linked it with frontal regions. Our evidence is consistent with the hypothesis that the FIN is a node of a brain network dedicated to voluntary visual mental imagery. The FIN could act as a bridge between visual information and semantic knowledge processed in the anterior temporal lobe and in the language circuits.
Engineering Agrobacterium tumefaciens adhesion to target cells
Authors: Pierrat Xavier , Pham Alix , Wong Jeremy P. H. , Al-Mayyah Zainebe , Persat Alexandre
Published: February 2022

Agrobacterium tumefaciens is a plant pathogen commonly repurposed for genetic modification of crops. Despite its versatility, it remains inefficient at transferring DNA to many hosts, including to animal cells. Like many pathogens, physical contact between A. tumefaciens and host cells promotes infection efficacy. Thus, improving the strength and specificity of A. tumefaciens to target cells has the potential for enhancing DNA transfer for biotechnological and therapeutic purposes. Here we demonstrate a methodology for engineering genetically-encoded exogeneous adhesins at the surface of A. tumefaciens. We identified an autotransporter gene we named Aat, that is predicted to show canonical β-barrel and passenger domains. We engineered the β-barrel scaffold and linker (Aatβ) to display synthetic adhesins susceptible to rewire A. tumefaciens to alternative host targets. As a proof of concept, we leveraged the versatility of a VHH domain to rewire A. tumefaciens adhesion to yeast and mammalian hosts displaying a GFP target receptor. Finally, to demonstrate how synthetic A. tumefaciens adhesion can improve transfer to host cells, we showed improved protein translocation into HeLa cells using a sensitive split luciferase reporter system. Engineering A. tumefaciens adhesion has therefore a strong potential in generating complex heterogeneous cellular assemblies and in improving DNA transfer efficiency against non-natural hosts.
Destabilization of F-actin by Mechanical Stress Deprivation or Tpm3.1 Inhibition Promotes a Pathological Phenotype in Tendon Cells
Authors: Inguito Kameron L. , Schofield Mandy M. , Faghri Arya D. , Bloom Ellen T. , Heino Marissa , Elliott Dawn M. , Parreno Justin
Published: February 2022

The actin cytoskeleton is a central mediator between mechanical force and cellular phenotype. In tendon, it is speculated that mechanical stress deprivation regulates gene expression by filamentous (F−) actin destabilization. However, the molecular mechanisms that stabilize tenocyte F-actin networks remain unclear. Tropomyosins (Tpms) are master regulators of F-actin networks. There are over 40 mammalian Tpm isoforms, with each isoform having the unique capability to stabilize F-actin sub-populations. Thus, the specific Tpm(s) expressed by a cell defines overall F-actin organization. Here, we investigated F-actin destabilization by stress deprivation of tendon and tested the hypothesis that stress fiber-associated Tpm(s) stabilize tenocyte F-actin to regulate cellular phenotype. Stress deprivation of mouse tail tendon fascicles downregulated tenocyte genes (collagen-I, tenascin-C, scleraxis, α-smooth muscle actin) and upregulated matrix metalloproteinase-3. Concomitant with mRNA modulation were increases in DNAse-I/Phallodin (G/F-actin) staining, confirming F-actin destabilization by tendon stress deprivation. To investigate the molecular regulation of F-actin stabilization, we first identified the Tpms expressed by mouse tendons. Tendon cells from different origins (tail, Achilles, plantaris) express three isoforms in common: Tpm1.6, 3.1, and 4.2. We examined the function of Tpm3.1 since we previously determined that it stabilizes F-actin stress fibers in lens epithelial cells. Tpm3.1 associated with F-actin stress fibers in native and primary tendon cells. Inhibition of Tpm3.1 depolymerized F-actin, leading to decreases in tenogenic expression, increases in chondrogenic expression, and enhancement of protease expression. These expression changes by Tpm3.1 inhibition are consistent with tendinosis progression. A further understanding of F-actin stability in musculoskeletal cells could lead to new therapeutic interventions to prevent alterations in cellular phenotype during disease progression.
Transcriptomic mapping of the metzincin landscape in human trophoblasts
Authors: Wächter Jasmin , Shannon Matthew J , Castellana Barbara , Baltayeva Jennet , Beristain Alexander G.
Published: February 2022

The metzincin family of metalloproteases coordinates cell and tissue developmental processes through regulation of growth factor availability, receptor signaling, and cell-cell/cell-matrix adhesion. During placental development, while distinct roles for metzincin proteases in controlling specific trophoblast functions have been described, a comprehensive assessment of metzincins during discrete stages of trophoblast differentiation has yet to be performed. Here we provide a comprehensive single cell transcriptomic resource of metzincin protease expression in diverse states of human trophoblasts from first trimester placental and decidual tissues. In the 8 distinct trophoblasts states categorized [four progenitor cytotrophoblast (CTB), one syncytiotrophoblast precursor (SCTp), two column CTB (cCTB), and one extravillous trophoblast (EVT) state], we identified 24 metzincin genes. These included 12 adamalysins, 2 pappalysins, 3 astacins and 7 matrixins. Cell trajectory modeling shows that expression of most (19/24) metzincins increases across CTB to EVT differentiation, though select proteases also increase as CTB fuse into syncytiotrophoblast. Within the CTB niche, single-cell velocity ordering identified 11 metzincins (ADAM10, -17, MMP14, -15, -19, -23B, ADAMTS1, -6, -19, TLL-1, -2) expressed in progenitors proximal to the predicted origin. Analysis of metzincin-substrate interactions within the CTB niche revealed ∼150 substrates and binding partners, includingFBN2as anADAMTS6-specific substrate preferentially expressed in trophoblast progenitors. Together, this work characterizes the metzincin transcriptomic landscape in human first trimester trophoblasts and establishes insight into the roles specific proteases perform within distinct trophoblast niches and across differentiation. This resource serves as a guide for future investigations into the roles of metzincin proteases in human placental development.

Summary Statement

Single cell RNA sequencing characterizes the expression of multiple metzincin proteases within first trimester placental trophoblasts. Examination of protease-substrate interactions within cytotrophoblasts identifies potential interactions between ADAMTS6 and FBN2.

Highlights

Single cell RNA sequencing identifies 24 distinct metzincin proteases expressed in human first trimester trophoblasts

Lineage trajectory modelling shows that metzincin genes are dynamic and likely control processes in progenitor, mid-point, and end-point states of trophoblast differentiation.

ADAMTS6, and its putative substrate FBN2, localize specifically to progenitor trophoblasts
A mixing-flow reactor for time-resolved reaction measurements distributed in space
Authors: Beauvais Michelle L. , Sanchez Monserrate Bryan A. , Feng Tianshi , Chen Renkun , Liu Ping , Chupas Peter J. , Chapman Karena W.
Published: February 2022

Probing short-lived reaction species is challenging owing to the need for both high signal-to-noise ratio, which can require long measurement time, and fast time resolution. Here, a novel in situ sample environment is presented that decouples time resolution from measurement time by distributing reaction time over space for the reaction under flow. In the mixing-flow reactor, precursor solutions are mixed at a specific position along the flow path, where the reaction is initiated. As the reaction mixture flows within a reaction capillary, the reaction time increases with distance from the mixing point. A measurement can be taken at a specific distance from the mixing point for as long as is needed to accumulate good statistics without compromising the time resolution of the measurement. Applications of the mixing-flow reactor for pair distribution function measurements of the initial nuclei formed during the hydrolysis of Al3+ at high pH are shown.
Unreal influence: leveraging AI in influencer marketing
Authors: Sands Sean , Campbell Colin L. , Plangger Kirk , Ferraro Carla
Published: February 2022

Purpose

This paper aims to examine how consumers respond to social media influencers that are created through artificial intelligence (AI) and compares effects to traditional (human) influencers.

Design/methodology/approach

Across two empirical studies, the authors examine the efficacy of AI social media influencers. With Study 1, the authors establish baseline effects for AI influencers and investigate how social-psychological distance impacts consumer perceptions. The authors also investigate the role of an influencer’s agency – being autonomous or externally managed – to test the boundaries of the results and determine the interactive effects between influencer type and influencer agency. Study 2 acts as an extension and validation of Study 1, whereby the authors provide generalisability and overlay the role of need for uniqueness as a moderated mediator.

Findings

The authors show that there are similarities and differences in the ways in which consumers view AI and human influencers. Importantly, the authors find no difference in terms of intention to follow or personalisation. This suggests that consumers are equally open to follow an AI or human influencer, and they perceive the level of personalisation provided by either influencer type as similar. Furthermore, while an AI influencer is generally perceived as having lower source trust, they are more likely to evoke word-of-mouth intentions. In understanding these effects, the authors show that social distance mediates the relationship between influencer type and the outcomes the authors investigate. Results also show that AI influencers can have a greater effect on consumers who have a high need for uniqueness. Finally, the authors find that a lack of influencer agency has a detrimental effect.

Research limitations/implications

The studies investigate consumers’ general response to AI influencers within the context of Instagram, however, future research might examine consumers’ response to posts promoting specific products across a variety of category contexts and within different social media platforms.

Practical implications

The authors find that in some ways, an AI influencer can be as effective as a human influencer. Indeed, the authors suggest that there may be a spill-over effect from consumer experiences with other AI recommendation systems, meaning that consumers are open to AI influencer recommendations. However, the authors find consistent evidence that AI influencers are trusted less than traditional influencers, hence the authors caution brands from rushing to replace human influencers with their AI counterparts.

Originality/value

This paper offers novel insight into the increasingly prominent phenomenon of the AI influencer. Specifically, it takes initial steps towards developing understanding as to how consumers respond to AI influencers and contrast these effects with human influencers.
Stressed out public servants? Testing the stress appraisal of psychological and emotional stressors on stress reactions through psychological capital
Authors: Borst Rick T. , Blom Rutger
Published: February 2022

Purpose

PA scholars argue that two gaps are present in the stress literature: (1) “stress” is too simply treated as deleterious and (2) insufficient efforts are made to capture public servants' stress appraisal, i.e. the degree to which stressors are appraised as hindering or challenging. Overcoming Gap 1, this study aims to study stress as a continuum; from distress to eustress. Overcoming Gap 2, stress appraisal is studied through testing the interaction of PsyCap with the two most common clusters of public servants' job stressors: emotional and psychological stressors.

Design/methodology/approach

Hypotheses are tested through structural equation modeling. A sample is used in this study of 1,853 Dutch public servants.

Findings

The results show that emotional and psychological stressors are high, but public servants often appraise them as challenging or as “part of the job”, with consequently no increased distress or decreased eustress. Moreover, psychological capital helps public servants to appraise some of the negative effects of emotional, but not psychological, stressors as less deleterious.

Originality/value

By approaching stress as a continuum, the authors bring in a more complete picture of public servants' stress in PA literature. Moreover, this research shows that the ambiguous results in the existing stress literature about the consequences of emotional and psychological stressors on distress/eustress can partially be explained by sector differences as well as personality differences (i.e. PsyCap). Finally, this study criticizes the one-sided attention to PsyCap as purely positive. PsyCap is not only unhelpful in coping with psychological stressors, it also drains the challenging properties of psychological stressors for dedication.
The impact of digitalization on supply chain resilience: an empirical study of the Chinese manufacturing industry
Authors: Shi Yangyan , Zheng Xiaofei , Venkatesh V.G. , Humdan Eias AI , Paul Sanjoy Kumar
Published: February 2022

Purpose

Facing turbulent environments, firms have strived to achieve greater supply chain resilience (SCR) to leverage the resources and knowledge of supply chain members. Both SCR and supply chain integration (SCI) require digitization in the supply chain, but their interrelationships have rarely been researched empirically. This paper aims to uncover the impact of digital technology (DT) on SCR and SCI and the role of SCI in mediating between DT and SCR.

Design/methodology/approach

China manufacturing enterprises were surveyed through a Web-based questionnaire, and 96 responses were received. Structural equation modeling was used to test the conceptual model.

Findings

The level of enterprise digitization is not directly related to supply chain resilience, but the level of enterprise digitization has a positive impact on the improvement of SCI and SCI also has a positive effect on SCR. Therefore, SCI has a complete intermediary effect between the level of DT and SCR.

Originality/value

This is a pioneer study to examine the relationships among DT, SCI and SCR. The findings of this study present that firms need to improve DT, SCI and SCR consequently.
Class size, student behaviors and educational outcomes
Authors: Wang Liz , Calvano Lisa
Published: February 2022

Purpose

While many business schools use large classes for the sake of efficiency, faculty and students tend to perceive large classes as an impediment to learning. Although class size is a contested issue, research on its impact is inconclusive, mainly focusing on academic performance outcomes such as test scores and does not address classroom dynamics. This study aims to expand the focus of class size research to include classroom dynamics and subjective educational outcomes (e.g. student learning outcomes and satisfaction).

Design/methodology/approach

Using Finn et al.’s (2003) theoretical framework and research conducted in introductory business classes, this study investigates how student academic and social engagement influence educational outcomes in different class sizes.

Findings

Results highlight the critical role that student involvement and teacher interaction play on student success and student satisfaction regardless of class sizes. In addition, the results indicate that students perceive lower levels of teacher interaction and satisfaction in larger classes.

Originality/value

This study applies Finn’s framework of student engagement in the classroom to understand the dynamics of class size in business education. The results reveal the influential roles of academic and social engagements on educational outcomes. Practical strategies are offered to improve learning outcomes and student satisfaction in large classes.
Did the Siebel Systems Case Limit the SEC's Ability to Enforce Regulation Fair Disclosure?
Authors: ALLEE KRISTIAN D. , BUSHEE BRIAN J. , KLEPPE TYLER J. , PIERCE ANDREW T.
Published: February 2022

We examine whether a shock to the enforceability of Regulation Fair Disclosure (Reg FD) limited its ability to restrict the flow of private information between managers and investors. Although prior work provides evidence that Reg FD reduced managers’ selective disclosure of material information immediately following its promulgation, we posit that private information flows returned as a result of the Securities and Exchange Commission's (SEC's) public enforcement failure inSEC v. Siebel Systems, Inc. Using multiple settings, we find consistent evidence suggesting thatSiebelchanged the cost–benefit tradeoff for Reg FD compliance and effectively reversed the initial effects of the regulation. We also find thatSiebeldisrupted the equilibrium of selective disclosure activity, resulting in anunlevelingeffect among investors with respect to private information advantages. Finally, we find thatSiebelalso had real effects by altering managers’ capital structure decisions. Our findings run counter to the prevailing “mosaic theory” and gradual learning explanations for private information advantages in the extended post–Reg FD period and highlight the importance of enforcement in achieving intended regulatory outcomes.
LC‐MS/MS method for the simultaneous quantification of pyriproxyfen and bifenthrin and their dissipation kinetics under field conditions in chili and brinjal
Authors: Chaudhary Reema , Singh Rakhi , Singh Monica , Mogha Navin Kumar , Kumari Premlata , Paliwal Gaurao , Singh Prabal Pratap , Das Mukul
Published: February 2022

Bifenthrin, a synthetic pyrethroid, and pyriproxyfen, a plant growth regulator, are used extensively in agriculture for controlling the different insect pests. The present study was undertaken to examine the dissipation behavior of a formulation with a combination of pyriproxyfen and bifenthrin on chili and brinjal under field conditions at four different locations. Dissipation study of combination of pyriproxyfen and bifenthrin revealed swift degradation in both crops with a half‐life of 2.5–2.6 and 2.0–2.1 days in brinjal and chili, respectively. Also, a simple method for simultaneous quantification of pyriproxyfen and bifenthrin was developed and validated using modified QuEChERS (quick, easy, cheap, effective, rugged, and safe) technique on liquid chromatography with tandem mass spectrometry (LC‐MS/MS). Recovery of the method was found to be under an acceptable range of 90.0%–93.5% and 88.7%–94.3% in chili and 92.4%–96.6% and 97.4%–100.9% in brinjal for pyriproxyfen and bifenthrin, respectively. At harvest time, the terminal residues of bifenthrin and pyriproxyfen were below the maximum residue limits set by European Union in chili and brinjal, respectively, suggesting that the use of this pesticide formulation is safe and does not impose harmful effects on human health.

Practical Application

In this paper, dissipation behavior of a pesticide formulation with a combination of pyriproxyfen and bifenthrin was undertaken under field conditions at four different locations on chili and brinjal in India. The simultaneous quantification of pyriproxyfen and bifenthrin using LC‐MS/MS technique has been validated incorporating modified QuEChERS extraction method with limit of detection at 0.005 µg/g and limit of quantification at 0.01 µg/g, which is well below the EU‐MRLs (European Union legislation Maximum Residue Level) of pyriproxyfen and bifenthrin in both chili and brinjal. Furthermore, dissipation kinetics of a formulation undertaken under field conditions at four different locations on chili and brinjal suggested that the terminal residues of both bifenthrin and pyriproxyfen were below the maximum residue limits set by European Union in chili and brinjal, respectively, at the time of harvest and that the use of this pesticide formulation is safe.
Adjuvant chemotherapy, extent of resection, and immunoistochemical neuroendocrine markers as prognostic factors of early‐stage large‐cell neuroendocrine carcinoma
Authors: Andreetti Claudio , Ibrahim Mohsen , Gagliardi Antonio , Poggi Camilla , Maurizi Giulio , Armillotta Domenico , Peritone Valentina , Teodonio Leonardo , Rendina Erino Angelo , Venuta Federico , Anile Marco , Natale Giovanni , Santini Mario , Fiorelli Alfonso
Published: February 2022

Background

We investigated whether adjuvant chemotherapy, extent of resection, and immunoistochemical neuroendocrine markers affected survival of patients with the early stage of large‐cell neuroendocrine cancer.

Methods

This was a retrospective multicenter study including consecutive patients undergoing resection of node negative large‐cell neuroendocrine carcinoma. Five‐year survival and disease‐free survival rate were evaluated by the Kaplan–Meier method and the log‐rank test in relation to adjuvant chemotherapy, extent of resection, and immunoistochemical neuroendocrine markers (synaptophysin, chromogranin A, and neuron‐specific enolase).

Results

Our study population included 117 patients; 47 (40%) of these received adjuvant chemotherapy. Patients treated with adjuvant chemotherapy had better survival (74% vs. 45%, p = 0.002) and disease‐free survival (79% vs. 40%, p = 0.001) in all cases except patients with tumor <20 mm (79.5% vs. 57.4%, p = 0.43). Lobectomy compared to sublobar resection was associated with better survival (67% vs. 0.1%, p < 0.0001) and disease‐free survival (65% vs. 0.1%, p < 0.0001) also in patients with tumor <20 mm (79% vs. 28%, p = 0.001). Patients with triple‐positive neuroendocrine markers had better survival (79% vs. 35%, p = 0.0001) and disease‐free survival (69% vs. 42%, p = 0.0008). Regression analysis showed that tumor size <20 mm, lobectomy, adjuvant chemotherapy, and triple‐positive immunistochemical neuroendocrine markers were significant favorable prognostic factors for survival outcomes.

Conclusions

Lobectomy seems to be the management of choice in patients with large‐cell neuroendocrine cancer <20 mm while adjuvant chemotherapy should be administered only in patients with tumor >20 mm.
Continuous monitoring of vital sign abnormalities; association to clinical complications in 500 postoperative patients
Authors: Haahr‐Raunkjaer Camilla , Mølgaard Jesper , Elvekjaer Mikkel , Rasmussen Søren M. , Achiam Michael P. , Jorgensen Lars N. , Søgaard Mette I.V. , Grønbæk Katja K. , Oxbøll Anne‐Britt , Sørensen Helge B. D. , Meyhoff Christian S. , Aasvang Eske K.
Published: February 2022

Background

Patients undergoing major surgery are at risk of complications, so‐called serious adverse events (SAE). Continuous monitoring may detect deteriorating patients by recording abnormal vital signs. We aimed to assess the association between abnormal vital signs inspired by Early Warning Score thresholds and subsequent SAEs in patients undergoing major abdominal surgery.

Methods

Prospective observational cohort study continuously monitoring heart rate, respiratory rate, peripheral oxygen saturation, and blood pressure for up to 96 h in 500 postoperative patients admitted to the general ward. Exposure variables were vital sign abnormalities, primary outcome was any serious adverse event occurring within 30 postoperative days. The primary analysis investigated the association between exposure variables per 24 h and subsequent serious adverse events.

Results

Serious adverse events occurred in 37% of patients, with 38% occurring during monitoring. Among patients with SAE during monitoring, the median duration of vital sign abnormalities was 272 min (IQR 110–447), compared to 259 min (IQR 153–394) in patients with SAE after monitoring and 261 min (IQR 132–468) in the patients without any SAE (p = .62 for all three group comparisons). Episodes of heart rate ≥110 bpm occurred in 16%, 7.1%, and 3.9% of patients in the time before SAE during monitoring, after monitoring, and without SAE, respectively (p < .002). Patients with SAE after monitoring experienced more episodes of hypotension ≤90 mm Hg/24 h (p = .001).

Conclusion

Overall duration of vital sign abnormalities at current thresholds were not significantly associated with subsequent serious adverse events, but more patients with tachycardia and hypotension had subsequent serious adverse events.

Trial registration

Clinicaltrials.gov, identifier NCT03491137.
Ambulance crew‐initiated non‐conveyance in the Helsinki EMS system—A retrospective cohort study
Authors: Heinonen Kari , Puolakka Tuukka , Salmi Heli , Boyd James , Laiho Mia , Porthan Kari , Harve‐Rytsälä Heini , Kuisma Markku
Published: February 2022

Background

Ambulance patients are usually transported to the hospital in the emergency medical service (EMS) system. The aim of this study was to describe the non‐conveyance practice in the Helsinki EMS system and to report mortality following non‐conveyance decisions.

Methods

All prehospital patients ≥16 years attended by the EMS but not transported to a hospital during 2013–2017 were included in the study. EMS mission‐ and patient‐related factors were collected and examined in relation to patient death within 30 days of the EMS non‐conveyance decision.

Results

The EMS performed 324,207 missions with a patient during the study period. The patient was not transported in 95,909 (29.6%) missions; 72,233 missions met the study criteria. The patient mean age (standard deviation) was 59.5 (22.5) years; 55.5% of patients were female. The most common dispatch codes were malaise (15.0%), suspected decline in vital signs (14.0%), and falling over (12.9%). A total of 960 (1.3%) patients died within 30 days after the non‐conveyance decision. Multivariate logistic regression analysis revealed that mortality was associated with the patient's inability to walk (odds ratio 3.19, 95% confidence interval 2.67–3.80), ambulance dispatch due to shortness of breath (2.73, 2.27–3.27), decreased level of consciousness (2.72, 1.75–4.10), decreased blood oxygen saturation (2.64, 2.27–3.06), and abnormal systolic blood pressure (2.48, 1.79–3.37).

Conclusion

One‐third of EMS missions did not result in patient transport to the hospital. Thirty‐day mortality was 1.3%. Abnormalities in multiple respiratory‐related vital signs were associated with an increased likelihood of death within 30 days.
Rural emergency care facilities may be adapting to their context: A population‐level study of resources and workforce
Authors: Baker Tim , Moore Katie , Lim Jolene , Papanastasiou Cerissa , McCarthy Sally , Schreve Franco , Lawson Mary , Versace Vincent
Published: February 2022

Objective

To provide a structured understanding of rural hospital‐based emergency care facility workforce and resources.

Design

The resources of regional training hubs were used to survey eligible emergency care facilities in their surrounding region.

Setting

Rural emergency care facilities manage more than one third of Australia's emergency presentations. These emergency care facilities include emergency departments and less‐resourced facilities in smaller towns.

Participants

Hospital facilities located outside metropolitan areas that report emergency presentations to the Australian Institute of Health and Welfare.

Interventions

A survey tool was sent by email.

Main outcome measures

Presence of human, diagnostic and other resources as reported on a questionnaire.

Results

A completed questionnaire was received from 195 emergency care facilities. Over 60% of Small hospitals had on‐call doctors only. General practitioners/generalists and nurses with extended emergency skills were found in all hospital types. Emergency physicians were present across all remoteness areas, but more commonly seen in larger facilities. All Major/Large facilities and most Medium facilities reported having onsite pathology and radiology. Point of care testing and clinician radiography were more commonly reported in smaller facilities. Among Small hospitals, Very Remote hospitals were more likely than Inner Regional hospitals to have an onsite doctor in the emergency care facility and/or a high dependency unit.

Conclusion

Smaller and more remote facilities appear to adapt by using different workforce structures and bedside investigations.
Exploring risk factors for admission to children's Learning Disability hospitals using interpretative phenomenological analysis
Authors: Ross Helen , Dodds Nicola
Published: February 2022

Background

There are few identified risk factors that may contribute to the increased risk of hospital admission for children and young people with intellectual disabilities. This qualitative study aimed to identify the key risk factors that precipitate admissions to Tier 4 child and adolescent mental health services (CAMHS) inpatient services for young people with an intellectual disability living in the North East of England in accordance with the Transforming Care programme.

Methods

This qualitative study captures the narrative of five young people admitted to hospital following a crisis period. Semi‐structured interviews were carried out with two adolescents with an intellectual disability and five caregivers of a young person with an intellectual disability to identify challenges from those with lived experience.

Findings

The findings were analysed using interpretative phenomenological analysis and indicated pathological, interpersonal, social, education and intervention challenges. Nine re‐emerging central themes highlighted that young people experienced particular difficulties before admission such as behaviours which challenge, comorbid diagnoses, isolation, insufficient crisis planning, care coordination problems, familial stressors, availability of community service provision, school placements and late intervention.

Conclusions

These results have contributed to developing the children's Tier 4 CAMHS Learning Disability pathways within a large NHS Foundation Trust as practitioners and professionals are mindful of these areas exacerbating risks and challenges that a young person with an intellectual disability and their family may experience. Findings could be considered when nationally reviewing services following the Transforming Care programme, aiming to provide care as close to home as possible. This may contribute to future research developing “At Risk” screening tools and formal “At Risk” registers for those with an intellectual disability.
Mechanistic modelling of enzyme‐restoration effects of new recombinant liver‐targeted proteins in acute intermittent porphyria
Authors: Vera‐Yunca Diego , Córdoba Karol M. , Parra‐Guillen Zinnia P. , Jericó Daniel , Fontanellas Antonio , Trocóniz Iñaki F.
Published: February 2022

Background and Purpose

Acute intermittent porphyria (AIP) is a rare disease caused by a genetic mutation in the hepatic activity of the porphobilinogen‐deaminase. We aimed to develop a mechanistic model of the enzymatic restoration effects of a novel therapy based on the administration of different formulations of recombinant human‐PBGD (rhPBGD) linked to the ApoAI lipoprotein. This fusion protein circulates in blood, incorporating into HDL and penetrating hepatocytes.

Experimental Approach

Single i.v. dose of different formulations of rhPBGD linked to ApoAI were administered to AIP mice in which a porphyric attack was triggered by i.p. phenobarbital. Data consist on 24 h urine excreted amounts of heme precursors, 5‐aminolevulinic acid (ALA), PBG and total porphyrins that were analysed using non‐linear mixed‐effects analysis.

Key Results

The mechanistic model successfully characterized over time the amounts excreted in urine of the three heme precursors for different formulations of rhPBGD and unravelled several mechanisms in the heme pathway, such as the regulation in ALA synthesis by heme. Treatment with rhPBGD formulations restored PBGD activity, increasing up to 51 times the value of the rate of tPOR formation estimated from baseline. Model‐based simulations showed that several formulation prototypes provided efficient protective effects when administered up to 1 week prior to the occurrence of the AIP attack.

Conclusion and Implications

The model developed had excellent performance over a range of doses and formulation type. This mechanistic model warrants use beyond ApoAI‐conjugates and represents a useful tool towards more efficient drug treatments of other enzymopenias as well as for acute intermittent porphyria.
Physiological adaptations affecting drug pharmacokinetics in space: what do we really know? A critical review of the literature
Authors: Dello Russo Cinzia , Bandiera Tiziano , Monici Monica , Surdo Leonardo , Yip Vincent Lai Ming , Wotring Virginia , Morbidelli Lucia
Published: February 2022

As human spaceflight progresses with extended mission durations, the demand for effective and safe drugs will necessarily increase. To date, the accepted medications used during missions (for space motion sickness, sleep disturbances, allergies, pain, and sinus congestion) are administered under the assumption that they act as safely and efficaciously as on Earth. However, physiological changes have been documented in human subjects in spaceflight involving fluid shifts, muscle and bone loss, immune system dysregulation, and adjustments in the gastrointestinal tract and metabolism. These alterations may change the pharmacokinetics (PK) and pharmacodynamics of commonly used medications. Frustratingly, the information gained from bed rest studies and from in‐flight observations is incomplete and also demonstrates a high variability in drug PK. Therefore, the objectives of this review are to report (i) the impact of the space environmental stressors on human physiology in relation to PK; (ii) the state‐of‐the‐art on experimental data in space and/or in ground‐based models; (iii) the validation of ground‐based models for PK studies; and (iv) the identification of research gaps.
Learning outcomes measured in zoo and aquarium conservation education
Authors: Schilbert Jana , Scheersoi Annette
Published: February 2022

Communicating the topic of conservation to the public and encouraging proenvironmental behaviors can mitigate loss of biodiversity. Thus, the evaluation of educational efforts is important to ascertain the educational effects and provide high‐quality conservation education. The learning outcomes of conservation education are diverse (e.g., attitudes, knowledge, and behavior). Considering the specific characteristics of these different outcomes and the factors that influence them is crucial to delivering successful conservation education. We reviewed 29 peer‐reviewed articles published in English from January 2011 to April 2020 on empirical studies of learning outcomes of on‐site conservation education in zoos and aquaria, institutions that seek to educate the public about conservation. We examined the range of learning outcomes, their definitions, and factors that influenced them. Cognitive outcomes were most frequently investigated (37%) in comparison with other outcomes (e.g., affective outcomes, 31%). The articles did not use explicit definitions for learning outcomes, and implicit or explorative definitions provided were inconsistent. Outcomes were influenced by various factors (e.g., prior experiences, staff interaction, animal behavior). Our results suggest the agenda of conservation education research should be broadened by examining all learning outcomes relevant to behavior change. Educational and behavior change theories should be used as a background for conservation education research to ensure clear and consistent definitions, derive appropriate instruments to measure learning outcomes, and relate learning outcomes to influencing factors. We recommend conservation education researchers and practitioners to treat conservation education holistically and acknowledge its learning outcomes’ full complexity.
Evaluating the success of functional restoration after reintroduction of a lost avian pollinator
Authors: Andrews Caitlin E. , Anderson Sandra H. , van der Walt Karin , Thorogood Rose , Ewen John G.
Published: February 2022

Conservation translocation is a common method for species recovery, for which one increasingly frequent objective is restoring lost ecological functions to promote ecosystem recovery. However, few conservation translocation programs explicitly state or monitor function as an objective, limiting the ability to test assumptions, learn from past efforts, and improve management. We evaluated whether translocations of hihi (Notiomystis cincta), a threatened New Zealand passerine, achieved their implicit objective of restoring lost pollination function. Through a pollinator‐exclusion experiment, we quantified, with log response ratios (lnR), the effects of birds on fruit set and seed quality in hangehange (Geniostoma ligustrifolium), a native flowering shrub. We isolated the contributions of hihi by making comparisons across sites with and without hihi. Birds improved fruit set more at sites without hihi (lnR = 1.27) than sites with hihi (lnR = 0.50), suggesting other avian pollinators compensated for and even exceeded hihi contributions to fruit set. Although birds improved seed germination only at hihi sites (lnR = 0.22–0.41), plants at sites without hihi had germination rates similar to hihi sites because they produced 26% more filled seeds, regardless of pollination condition. Therefore, although our results showed hihi improved seed quality, they also highlighted the complexity of ecological functions. When an important species is lost, ecosystems may be able to achieve similar function through different means. Our results underscore the importance of stating and monitoring the ecological benefits of conservation translocations when functional restoration is a motivation to ensure these programs are achieving their objectives.