bluuebunny/crossref_metadata_2025 huggingface dataset:
Region-specific, maladaptive, gray matter myelination is associated with differential susceptibility to stress-induced behavior in rats and humans
Authors: Long Kimberly L. P. , Chao Linda L. , Kazama Yurika , An Anjile , Hu Kelsey Y. , Peretz Lior , Muller Dyana C. Y. , Roan Vivian D. , Misra Rhea , Toth Claire E. , Breton Jocelyn M. , Casazza William , Mostafavi Sara , Huber Bertrand R. , Woodward Steven H. , Neylan Thomas C. , Kaufer Daniela
Published: February 2021

Individual reactions to traumatic stress vary dramatically, yet the biological basis of this variation remains poorly understood. Recent studies demonstrate the surprising plasticity of oligodendrocytes and myelin with stress and experience, providing a potential mechanism by which trauma induces aberrant structural and functional changes in the adult brain. In this study, we utilized a translational approach to test the hypothesis that gray matter myelin contributes to traumatic-stress-induced behavioral variation in both rats and humans. We exposed adult, male rats to a single, severe stressor and used a multimodal approach to characterize avoidance, startle, and fear-learning behavior, as well as oligodendrocyte and myelin content in multiple brain areas. We found that oligodendrocyte cell density and myelin content were correlated with behavioral outcomes in a region-specific manner. Specifically, stress-induced avoidance positively correlated with hippocampal dentate gyrus oligodendrocytes and myelin. Viral overexpression of the oligodendrogenic factor Olig1 in the dentate gyrus was sufficient to induce an anxiety-like behavioral phenotype. In contrast, contextual fear learning positively correlated with myelin in the amygdala and spatial processing regions of the hippocampus. In a group of trauma-exposed US veterans, T1-/T2-weighted magnetic resonance imaging estimates of hippocampal and amygdala myelin associated with symptom profiles in a region-specific manner that mirrored the findings in rats. These results demonstrate a species- independent relationship between region-specific, gray matter oligodendrocytes and myelin and differential behavioral phenotypes following traumatic stress exposure. This study suggests a novel mechanism for brain plasticity that underlies individual variance in sensitivity to traumatic stress.
Coordination between nucleotide excision repair and specialized polymerase DnaE2 action enables DNA damage survival in non-replicating bacteria
Authors: Joseph Asha Mary , Daw Saheli , Sadhir Ismath , Badrinarayanan Anjana
Published: February 2021

Translesion synthesis (TLS) is a highly conserved mutagenic DNA lesion tolerance pathway, which employs specialized, low-fidelity DNA polymerases to synthesize across lesions. Current models suggest that activity of these polymerases is predominantly associated with ongoing replication, functioning either at or behind the replication fork. Here we provide evidence for DNA damage-dependent function of a specialized polymerase, DnaE2, in replication-independent conditions. We develop an assay to follow lesion repair in non-replicatingCaulobacterand observe that components of the replication machinery localize on DNA in response to damage. These localizations persist in the absence of DnaE2 or if catalytic activity of the polymerase is mutated. Single-stranded DNA gaps for SSB binding and low-fidelity polymerase-mediated synthesis are generated by nucleotide excision repair, as replisome components fail to localize in its absence. This mechanism of gap-filling facilitates cell cycle restoration when cells are released into replication-permissive conditions. Thus, such cross-talk (between activity of NER and specialized polymerases in subsequent gap-filling) helps preserve genome integrity and enhances survival in a replication-independent manner.
Dynamic association of IκBα to chromatin is regulated by acetylation and cleavage of histone H4
Authors: Marruecos Laura , Bertran Joan , Álvarez-Villanueva Daniel , Floor Martin , Mulero María Carmen , Vert Anna , Guillén Yolanda , Arce Sara , Batlle Laura , Villà-Freixa Jordi , Ghosh Gourisankar , Bigas Anna , Espinosa Lluís
Published: February 2021

IκBs exert a principal function as cytoplasmic inhibitors of the NF-kB transcription factors. Additional functions for IκB homologues have been described including association to chromatin and transcriptional regulatioin. Phosphorylated and SUMOylated IκBα (pS-IκBα) binds histones H2A and H4 in the stem and progenitor compartment of skin and intestine, but the mechanisms controlling its recruitment to chromatin are largely unstudied.

We here show that serine 32-36 phosphorylation of IκBα favors its binding with nucleosomes and demonstrated that p-IκBα association to H4 is favored by acetylation at specific H4 lysine residues. N-terminal tail of H4 is lost during intestinal cell differentiation by proteolytic cleavage at residues 17-19 imposed ny trypsin or chymotrypsin, which interferes p-IκBα binding. Paradoxically, inhibition of trypsin and chymotrypsin activity in HT29 cells increased p-IκBα chromatin binding and impaired goblet cell differentiation, comparable to IκBα deletion. Together our results indicate that dynamic binding of IκBα to chromatin is a requirement for intestinal cell differentiation and provide a molecular base for the restricted nuclear distribution of p-IκBα at specific stem cell compartments.
In-depth single-cell analysis of translation-competent HIV-1 reservoirs identifies cellular sources of plasma viremia
Authors: Cole Basiel , Lambrechts Laurens , Gantner Pierre , Noppe Ytse , Bonine Noah , Witkowski Wojciech , Chen Lennie , Palmer Sarah , Mullins James I. , Chomont Nicolas , Pardons Marion , Vandekerckhove Linos
Published: February 2021

Clonal expansion of HIV-infected cells contributes to the long-term persistence of the HIV reservoir in ART-suppressed individuals. However, the contribution to plasma viremia from cell clones that harbor inducible proviruses is poorly understood. Here, we describe a single-cell approach to simultaneously sequence the TCR, integration sites and proviral genomes from translation-competent reservoir cells, called STIP-Seq. By applying this approach to blood samples from eight participants, we showed that the translation-competent reservoir mainly consists of proviruses with short deletions at the 5’-end of the genome, often involving the major splice donor site. TCR and integration site sequencing revealed that antigen-responsive cells can harbor inducible proviruses integrated into cancer-related genes. Furthermore, we found several matches between proviruses retrieved with STIP-Seq and plasma viruses obtained during ART and upon treatment interruption, showing that STIP-Seq can capture clones that are responsible for low-level viremia or viral rebound.
A quantitative study of the Golgi retention of glycosyltransferases
Authors: Sun Xiuping , Chen Bing , Song Zhiwei , Lu Lei
Published: February 2021

How Golgi glycosyltransferases and glycosidases (hereafter glycosyltransferases) localize to the Golgi is still unclear. Here, we first investigated the post-Golgi trafficking of glycosyltransferases. We found that glycosyltransferases can escape the Golgi to the plasma membrane, where they are subsequently endocytosed to the endolysosome. Post-Golgi glycosyltransferases are probably degraded by the ecto-domain shedding. We discovered that most glycosyltransferases are not retrieved from post-Golgi sites, indicating that retention but not retrieval should be the main mechanism for their Golgi localization. We proposed to use the Golgi residence time to study the Golgi retention of glycosyltransferases quantitatively and systematically. Various chimeras between ST6GAL1 and either transferrin receptor or tumor necrosis factor α quantitatively revealed the contributions of three regions of ST6GAL1, namely the N-terminal cytosolic tail, transmembrane domain and ecto-domain, to the Golgi retention. We found that each of the three regions is sufficient to produce a retention in an additive manner. The N-terminal cytosolic tail length negatively affects the Golgi retention of ST6GAL1, similar to what is known of the transmembrane domain. Therefore, long N-terminal cytosolic tail and transmembrane domain can be a Golgi export signal for transmembrane secretory cargos.
Quantitative susceptibility mapping of carotid arterial tissueex vivo: assessing sensitivity to vessel microstructural composition
Authors: Stone Alan J. , Tornifoglio Brooke , Johnston Robert D. , Shmueli Karin , Kerskens Christian , Lally Caitríona
Published: February 2021

Purpose

To characterise microstructural contributions to the magnetic susceptibility of carotid arteries.

Method

Arterial vessels were scanned using high resolution quantitative susceptibility mapping (QSM) at 7T. Models of vessel degradation were generated usingex vivoporcine carotid arteries that were subjected to several different enzymatic digestion treatments that selectively removed microstructural components (smooth muscle cells, collagen and elastin). Magnetic susceptibilities measured in these tissue models were compared to those in untreated (native) porcine arteries. Magnetic susceptibility measured in native porcine carotid arteries was further compared to the susceptibility of cadaveric human carotid arteries to investigate their similarity.

Results

The magnetic susceptibility of native porcine vessels was diamagnetic (𝒳native= −0.1820ppm), with higher susceptibilities in all models of vessel degradation (𝒳elastin degraded= −0.0163ppm; 𝒳collagen degraded= −0.1158ppm; 𝒳decellularised= −0.1379ppm; 𝒳fixed native= −0.2199ppm). Magnetic susceptibility was significantly higher incollagen degradedcompared tonativeporcine vessels (Tukey-Kramer, p<0.01) and betweenelastin degradedand all other models (includingnative, Tukey-Kramer, p<0.001). The susceptibility of fixed healthy human arterial tissue was diamagnetic and no significant difference was found between fixed human and fixed porcine arterial tissue susceptibilities (ANOVA, p>0.05).

Conclusions

Magnetic susceptibility measured using QSM is sensitive to the microstructural composition of arterial vessels – most notably to collagen. The similarity of human and porcine arterial tissue susceptibility values provides a solid basis for translational studies. As vessel microstructure becomes disrupted during the onset and progression of carotid atherosclerosis, QSM has the potential to provide a sensitive and specific marker of vessel disease.
Synaptotagmin-like protein 2a regulates lumen formation via Weibel-Palade body apical secretion of angiopoietin-2 during angiogenesis
Authors: Francis Caitlin R. , Claflin Shea , Kushner Erich J.
Published: February 2021

Objective

Vascular lumen formation requires the redistribution of intracellular proteins to instruct apico-basal polarity, thereby enforcing maturation of both luminal and basal domains. In the absence of proper apical signaling, lumen formation can be distorted leading to lumen collapse and cessation of blood flow. Synaptotagmin-like protein-2a (Slp2a) has been implicated in apical membrane signaling; however, the role of Slp2a in vascular lumen formation has never been assessed.

Approach and Results

Our results demonstrate that Slp2a is required for vascular lumen formation. Using a 3- dimensional sprouting assay, sub-cellular imaging, and zebrafish blood vessel development we establish that Slp2a resides at the apical membrane acting as a tether for Rab27a that decorates Weibel-Palade bodies (WPBs). Unique to endothelial tissue, we show that Slp2a regulates exocytic activity of WPBs, thus regulating release of WPB contents into the luminal space during angiogenesis. Angiopoietin-2 is a Tie-2 receptor ligand that is selectively released from WPB secretory granules. We identify a critical role for angiopoietin-2 in regulating endothelial lumenization and show that in the absence of Slp2a, WPB contents cannot fuse with the apical membrane. This disrupts the release of angiopoietin-2 and blocks Tie-2 signaling necessary for proper lumen formation.

Conclusions

Our results demonstrate a novel requirement of Slp2a for vascular lumen formation. Moreover, we show that Slp2a is required for the exocytic release of WPB secretory granule cargo during vascular lumen development, and thus is a core upstream component of the WPB secretory pathway. Furthermore, we provide evidence that WPB-housed angiopoietin-2 is required for vascular lumen formation.

HIGHLIGHTS

Synaptotagmin-like protein-2a (Slp2a) is required for vascular lumen formation via its interaction with Rab27a and Weibel Palade Body secretory granules.

Slp2a is recruited to the apical membrane where it regulates secretion of Weibel Palade Body components into the luminal space.

In the absence of Slp2a, Weibel Palade Body-housed angiopoietin-2 ligand cannot be exocytosed, this impedes activation of Tie-2 signaling required for lumen biogenesis.

Knockout of Slp2a or Tie-2 in zebrafish blunts the formation of vascular lumens during angiogenic development.
Predictive coding is a consequence of energy efficiency in recurrent neural networks
Authors: Ali Abdullahi , Ahmad Nasir , Groot Elgar de , van Gerven Marcel A. J. , Kietzmann Tim C.
Published: February 2021

Predictive coding represents a promising framework for understanding brain function. It postulates that the brain continuously inhibits predictable sensory input, ensuring a preferential processing of surprising elements. A central aspect of this view is its hierarchical connectivity, involving recurrent message passing between excitatory bottom-up signals and inhibitory top-down feedback. Here we use computational modelling to demonstrate that such architectural hard-wiring is not necessary. Rather, predictive coding is shown to emerge as a consequence of energy efficiency. When training recurrent neural networks to minimise their energy consumption while operating in predictive environments, the networks self-organise into prediction and error units with appropriate inhibitory and excitatory interconnections, and learn to inhibit predictable sensory input. Moving beyond the view of purely top-down driven predictions, we furthermore demonstrate, via virtual lesioning experiments, that networks perform predictions on two timescales: fast lateral predictions among sensory units, and slower prediction cycles that integrate evidence over time.
Cortical compensation for hearing loss, but not age, in neural tracking of the fundamental frequency of the voice
Authors: Canneyt Jana Van , Wouters Jan , Francart Tom
Published: February 2021

Auditory processing is affected by advancing age and hearing loss, but the underlying mechanisms are still unclear. We investigated the effects of age and hearing loss on temporal processing of naturalistic stimuli in the auditory system. We analysed neural phase-locking to the fundamental frequency of the voice (f0) in 54 normal-hearing and 14 hearing-impaired adults between 17 and 82 years old. We found that both subcortical and cortical neural sources contributed to the responses. Results indicated that advancing age was related to smaller responses with less cortical response contributions, consistent with an age-related decrease in neural phase-locking ability. Conversely, hearing impaired subjects displayed larger responses compared to age-matched normal hearing controls. This was due to additional cortical response contributions which were stronger for participants with more severe hearing loss. This is consistent with the recruitment of additional cortical sources for auditory processing in persons with hearing impairment.
The gut microbiome: a missing link in understanding the gastrointestinal manifestations of COVID-19?
Authors: Brooks Erin F. , Bhatt Ami S.
Published: February 2021

Coronavirus disease 2019 (COVID-19), which is caused by infection with SARS-CoV-2, presents with a broad constellation of both respiratory and nonrespiratory symptoms, although it is primarily considered a respiratory disease. Gastrointestinal symptoms—including nausea, abdominal pain, vomiting, and diarrhea—rank chief among these. When coupled with the presence of viral RNA in fecal samples, the presence of gastrointestinal symptoms raises relevant questions regarding whether SARS-CoV-2 can productively infect the upper or lower gastrointestinal tract. Despite the well-documented prevalence of gastrointestinal symptoms and the high rate of SARS-CoV-2 fecal RNA shedding, the biological, clinical, and epidemiological relevance of these findings is unclear. Furthermore, the isolation of replication-competent virus from fecal samples has not been reproducibly and rigorously demonstrated. Although SARS-CoV-2 shedding likely occurs in a high proportion of patients, gastrointestinal symptoms affect only a subset of individuals. Herein, we summarize what is known about gastrointestinal symptoms and fecal viral shedding in COVID-19, explore the role of the gut microbiome in other respiratory diseases, speculate on the role of the gut microbiota in COVID-19, and discuss potential future directions. Taking these concepts together, we propose that studying gut microbiota perturbations in COVID-19 will enhance our understanding of the symptomology and pathophysiology of this novel devastating disease.
Accelerating retail supply chain performance against pandemic disruption: adopting resilient strategies to mitigate the long-term effects
Authors: Sharma Manu , Luthra Sunil , Joshi Sudhanshu , Kumar Anil
Published: February 2021

Purpose

Coronavirus disease 2019 (COVID-19) has disrupted global supply chains, revealing dreadful gaps and exposing vulnerabilities. Retailers are challenged to tackle risks and organise themselves to fit into the “new normal” scenario. This global outbreak has established a volatile environment for supply chains; it has raised the question of survival in the market, forcing companies to rethink resilient strategies to be adopted for the post-pandemic situation to mitigate the long-term effects of this virus. This study explores the priorities for retail supply chains (RSCs) to align their business operations and strategies for the post-pandemic world.

Design/methodology/approach

This study has utilised integrated full consistency model (FUCOM) – best–worst method (BWM) for assessment of RSCs to enhance their business performance irrespective of pandemic disruptions. The FUCOM has been employed to identify the priorities of determinants enhancing business performance, whereas RSC strategies are evaluated using the BWM method.

Findings

The current study identifies “Collaboration Efficiency” as the main criterion for accelerating the performance of RSCs in a dynamic social environment. Also, the study concludes that “Order Fulfilment” and “Digital RSCs” are the most appropriate resilient business strategies to mitigate the long-term effects.

Research limitations/implications

Supply-demand balancing is a challenging task at the moment, but highly significant for the future. The pandemic disruptions have placed intense pressure on retailers to deliver products as per consumers' changing behaviours towards the purchase of essentials and other products. Hence, “Order Fulfilment” and “Digital RSCs” should be adopted for meeting customer requirements and to ensure sustainability in the post-pandemic business world.

Originality/value

This work sets out a comprehensive framework which will be helpful for accelerating RSCs performance against pandemic disruption by adopting resilient strategies to mitigate the long-term effects.
Oropharyngeal squamous cell carcinomas: Can imaging findings predict HPV status?
Authors: Fomin Igor , Hughes Ian , Bhuta Sandeep
Published: February 2021

Purpose

This is first Australian population‐based retrospective study in HPV‐induced OPSCCs utilising CT. Contrast enhanced computed tomography (CECT) was utilised to assess if imaging findings of metastatic cystic lymph nodes (LNs) can predict human papillomavirus (HPV) status, as defined by p16 immunostaining of oropharyngeal squamous cell carcinomas (OPSCCs).

Materials and Methods

The location and p16 status of primary tumours and LNs were recorded. Metastatic LNs were assessed for size, shape, margins and cystic changes. Hounsfield Units (HU) value of primary tumours and LNs were measured and tabulated. p16‐positive and p16‐negative groups were compared with respect to these variables. The two‐sample t test and two‐sample Mann–Whitney test was used.

Results

A total of 364 CECT scans were reviewed with 209 patients (187 p16 positive and 22 p16 negative). Primary sites of OPSCCs were tonsils (58.8%), base of tongue (37.4%) and other oropharyngeal sites (3.8%). The HU values of p16‐positive OPSCCs with mean of 78.6HU; 95% CI (76.5–80.8) were lower for p16‐negative tumours, mean 96.0 HU CI 95% (85.5–106.6) for all oropharyngeal sub‐sites. The mean HU values of p16‐positive and p16‐negative metastatic LNs were 38.8 HU 95% CI: (13–103 HU) versus 88.7 HU 95% CI: (54–131) (P < 0.0001).

Conclusions

The association between p16‐positive status and the tonsillar cancer site is very high. Imaging features of p16‐positive metastatic LNs include relatively large cystic neck nodes with low HU values. This is an imaging signature of p16‐positive OPSCCs and can potentially influence patient’s early diagnosis and prognosis.
National survey revealed variable practices in paediatric procedural sedation and patient monitoring
Authors: Tervonen Miikka , Kallio Merja , Peltoniemi Outi
Published: February 2021

Paediatric procedures requiring sedation are increasingly being performed off site, but there are no national guidelines for paediatric procedural sedation in Finland or studies on it. Therefore, the aim of this survey was to assess national practices for paediatric procedural sedation outside operation rooms and intensive care units in terms of indications, sedative medication, treatment facilities, patient safety and training of the personnel.

An online survey including single‐ and multiple‐choice questions and open‐ended questions was sent to Finnish paediatricians, paediatric surgeons and paediatric anaesthesiologists via the electronic mailing lists of national societies in December 2019.

A total of 71 responses were received. Lumbar puncture (41%), intra‐articular injections (38%) and MRI (17%) were the most common procedures that required routine sedation. Benzodiazepines were the most frequently used sedatives during both painful procedures (80%) and imaging (61%). Pulse oximetry monitoring was reported by 75% of the respondents, but other physiological parameters were rarely monitored (ECG 28%; blood pressure 39%; respiratory rate 34%). The level of sedation was not objectively assessed. Adrenaline (72%) and equipment for managing adverse respiratory outcomes (supplemental oxygen 98%; ventilation equipment 92%) were available in most facilities in which sedation was performed. Only one‐third of the respondents had undergone training for paediatric procedural sedation, and only 39% of the hospital units compiled statistical data on sedation‐related adverse events.

The paediatric procedural sedation practices vary across hospitals. National guidelines for patient monitoring and training of personnel could improve treatment quality and patient safety.
The value of human epididymis 4, D‐dimer, and fibrinogen compared with CA 125 alone in triaging women presenting with pelvic masses: a retrospective cohort study
Authors: McKendry Kate , Duff Stephen , Huang Yanmei , Redha Mostafa , Scanlon Áine , Abu Saadeh Feras , Gleeson Noreen , O’Leary John , Norris Lucy , O’Toole Sharon
Published: February 2021

Introduction

CA 125, the biomarker in common clinical use for ovarian cancer, is limited by low sensitivity for early disease and high false positives. The aim of this study was to evaluate several candidate biomarkers, alone or in combination, compared with CA 125 in the prediction of malignant/borderline vs benign tumor status in premenopausal and postmenopausal women with pelvic masses.

Material and methods

This was a retrospective observational cohort study set in St James’s Hospital, a tertiary referral center for gynecological malignancy in Dublin, Ireland. Women undergoing surgery for pelvic masses between 2012 and 2018 were included. Preoperative human epididymis protein 4 (HE4), the Risk of Ovarian Malignancy Algorithm, the Risk of Malignancy Index I and II, D‐dimer, and fibrinogen were assessed. Logistic regression models were fitted for each biomarker alone and in combination. Receiver operating characteristics‐area under the curve (ROC‐AUC) and partial AUCs in the 90%‐100% specificity range were determined.

Results

In all, 89 premenopausal and 185 postmenopausal women were included. In premenopausal women, no biomarker(s) outperformed CA 125 (AUC 0.73; 95% CI 0.63–0.84). In postmenopausal women, HE4 had a partial AUC (pAUC) of 0.71 (95% CI 0.64–0.79) compared with 0.57 (95% CI 0.51–0.69) for CA 125 (p = 0.009). HE4 + D‐dimer had an improved pAUC of 0.74 (95% CI 0.68–0.81, p < 0.001) and HE4 + D‐dimer + fibrinogen had a pAUC of 0.75 (95% CI 0.68–0.82).

Conclusions

A novel biomarker panel of HE4 ± D‐dimer ± fibrinogen outperformed CA 125 alone as a high‐specificity biomarker in postmenopausal women and could aid in the preoperative triaging of pelvic masses. No biomarker(s) outperformed CA 125 in premenopausal women.
Biased estimation with shared parameter models in the presence of competing dropout mechanisms
Authors: Vonesh Edward F. , Greene Tom
Published: February 2021

Recently, Thomadakis et al. quantified potential sources of bias that can occur when shared parameter (SP) models are used to jointly model longitudinal trends of a biomarker over time (e.g., a slope) and time‐to‐dropout in an effort to address concerns over possible informative censoring. Although SP models induce no bias under a missingness completely at random dropout mechanism, the authors demonstrate that bias can occur under a missingness at random (MAR) dropout mechanism wherein dropout depends on the observed biomarker data. To address this, the authors propose including the most recent observed marker value within the hazard function for the time‐to‐dropout portion of an SP model. They demonstrate via a limited simulation that the proposed model minimizes bias under a specific MAR dropout mechanism and a specific missingness not‐at‐random dropout mechanism. In the present article, we compare and contrast their work with that of previous authors by illustrating via simulation and an example the degree of bias or lack thereof that can occur when applying SP models, particularly, in the presence of competing dropout mechanisms. We propose the use of a competing risk SP model as a means to minimize bias whenever competing dropout mechanisms are suspected assuming the competing mechanisms result from distinct observable causes of dropout.
Are there gender differences in blood oxygen saturation in prepubertal children?
Authors: Frimer Zev , Goldberg Shmuel , Joseph Leon , Picard Elie
Published: February 2021

Introduction

Previous studies reported higher oxygen saturation (SpO2) in healthy young adult females as compared to males. The objective of the current study was to evaluate whether or not similar differences exist in prepubertal children.

Methods

SpO2 levels, respiratory rate, and pulse were measured in 4‐ to 10‐year‐old males and females. Anthropometric variables, including ethnic origin, age, height, weight, BMI (Body Mass Index), BSA (Body Surface Area), barometric pressure, and altitude above sea level were collected as well.

Results

Ninety five males and 93 females participated in the study. Groups were similar, in terms of respiratory rate, pulse, and anthropometric variables. Mean SpO2 in males was 96.95 ± 1.09%, similar to SpO2 in females measuring 96.85 ± 0.98%, P = .52.

Conclusion

In contrast to young adults, there is no gender‐related difference in mean oxygen saturation in prepubertal healthy children. It is likely that this difference is due to variations in age‐related sex hormones. Further studies are needed to explore the mechanism explaining why prepubertal children do not show gender‐specific differences in oxygen saturation in contrast to adults.
Liquidity Formation and Preopening Periods in Financial Markets
Authors: Hong Jieying , Pouget Sébastien
Published: February 2021

This paper studies the role of preopening periods in liquidity formation and welfare in financial markets. Because no transaction occurs during these preopening periods, their economic significance could be questioned. We model a market where costly participation and asymmetric information prevent latent liquidity from being expressed. At equilibrium, risk‐averse insiders use preopening periods to better coordinate supply and demand of liquidity by communicating liquidity needs, thus improving welfare. Partial or full communication of private signals by the insider with the asset at preopening periods does not always enhance liquidity formation, but improves welfare through reducing adverse selection risk faced by the outsider, and increasing the likelihood of her entry. Our findings have implications for portfolio management and the design of financial markets.
Critically evaluating sweet taste receptor expression and signaling through a molecular pharmacology lens
Authors: Smith Nicola J. , Grant Jennifer N. , Moon Justin I. , So Sean S. , Finch Angela M.
Published: February 2021

The class C G protein‐coupled sweet taste receptor (STR) is responsible for the perception of sweet‐tasting molecules. Considered an obligate heterodimer, it consists of taste 1 receptor 2 and taste 1 receptor 3 subunits. Interest in the STR has steadily grown, especially since its discovery in extraoral tissues hints at a metabolic role for the receptor. It is now known that many pharmacologically exploitable binding sites exist across the extracellular and transmembrane regions of both subunits of the STR, indicative of its potential amenability to pharmacotherapeutic modulation. In this review, we briefly describe the structural characteristics and functional relevance of the STR. Then, from a molecular pharmacology perspective, we dissect the research surrounding the regulation of STR surface expression and signal transduction, in both oral and extraoral tissues, and discuss the potential for the exploitation of biased agonists for the STR. We find that despite 20 years of research into the STR, the target remains frustratingly enigmatic. Not only are the mechanisms controlling and regulating the surface expression of the STR unclear, but also research into the full repertoire of signaling partners of the STR is at present inconclusive. Critically, the influence of receptor polymorphisms (including those associated with sugar consumption) on the molecular pharmacology of the receptor remains hitherto unexplored. Finally, we provide recommendations on the reporting of reference sequence identification numbers to avoid incorrect attribution of wild‐type to these biologically significant polymorphisms, which we argue may have led to some of the inconsistencies in the field.
Colitis‐associated colorectal adenocarcinomas frequently express claudin 18 isoform 2: implications for claudin 18.2 monoclonal antibody therapy
Authors: Iwaya Mai , Hayashi Hiroyuki , Nakajima Tomoyuki , Matsuda Kazuyuki , Kinugawa Yasuhiro , Tobe Yosuke , Tateishi Yoko , Iwaya Yugo , Uehara Takeshi , Ota Hiroyoshi
Published: February 2021

Aims

Claudin 18 (CLDN18) is a member of the claudin family of cell surface proteins, which are widely expressed in epithelial cells and play a role in cell–cell adhesion. CLDN18 isoform 2 (CLDN18.2) is specifically expressed in gastric epithelial cells, and is frequently expressed at high levels in gastric adenocarcinoma. On the basis of this, zolbetuximab, a targeted monoclonal antibody, has been developed for patients with CLDN18.2‐positive gastro‐oesophageal adenocarcinoma. Colitis‐associated colorectal adenocarcinomas (CACs) tend to lose intestinal markers and show aberrant gastric mucin expression. Furthermore, clinical trials of human epidermal growth factor receptor 2 (HER2) inhibitor therapy for colorectal carcinoma are ongoing. However, the expression profile of CLDN18.2 and HER2 has not been described in a series of human CACs.

Methods and results

We performed immunohistochemistry for CLDN18 and HER2 on 56 consecutive CACs from 55 inflammatory bowel disease patients, and compared the expression profile with that of a control group of 56 sporadic colorectal adenocarcinomas (CRCs). CLDN18.1 expression and CLDN18.2 expression were validated by reverse transcription polymerase chain reaction (PCR) in paraffin‐embedded CRC tissues. CLDN18 was positive in 27% (15/56) of CACs and in 5% (3/56) of sporadic CRCs (P = 0.004), and CLDN18‐positive CACs were more likely to have lymph node metastasis than CLDN18‐negative CACs (67% versus 36%; P = 0.017). CLDN18 expression was significantly associated with MUC5AC expression (P < 0.001) and loss of special AT‐rich sequence‐binding protein 2 expression (P = 0.005) in CACs. CLDN18.2 was expressed in CRCs that were immunoreactive for CLDN18. Only 4% of CACs were immunoreactive for HER2, and no differences were identified in sporadic CRCs.

Conclusions

These findings suggest that certain CAC cases may be candidates for targeted zolbetuximab therapy.
Septic shock: Clinical indicators and implications to critical patient care
Authors: Ramos Corrêa Pinto Luciana , Azzolin Karina de Oliveira , Lucena Amália de Fátima , Moretti Miriane M. S. , Haas Jaqueline S. , Moraes Rafael B. , Friedman Gilberto
Published: February 2021

Aims and Objective

To identify clinical indicators of septic shock in critical care patients.

Background

The identification of clinical indicators of septic shock is relevant to avoid clinical deterioration of patients with sepsis. However, the recognition of these factors, especially by the nursing team, is still deficient and reinforces the need for studies that investigate the subject in different realities such as that of Brazil.

Design

The study had a cross‐sectional design based on STROBE guidelines (see Appendix S1).

Methods

A sample of 392 patients with sepsis or septic shock was admitted to the Intensive Care Unit of a Brazilian university hospital. Data were collected from medical records of the Intrahospital Sepsis Combat Program referring to patients admitted between January 2018–January 2019. Sociodemographic and clinical data were collected, as well as information on the time from diagnosis of sepsis or septic shock to initiation of antibiotic therapy, length of stay, and discharge or death outcomes. Data were statically analysed.

Results

Out of the total sample, 190 (49%) patients were admitted with septic shock. Clinical indicators of septic shock were hypotension, mechanical ventilation, lactate levels between 2.0–3.9 or >4, hypothermia <36°C, radiotherapy‐associated chemotherapy, Sequential Organ Failure Assessment score >3 and admittance through the emergency unit. Among patients with septic shock, 85 (44.7%) were discharged and 105 (55.2%) died in the intensive care unit.

Conclusions

Patients with septic shock presented hyperlactataemia and greater organic dysfunction as clinical indicators when compared to patients with sepsis. Mechanical ventilation, chemotherapy and radiotherapy increased the risk of developing septic shock.

Relevance to clinical practice

Our results can support the nursing team by providing the main clinical indicators of septic shock and contributing to the interprofessional team in the prevention of septic shock.
Risk factors for leg ulceration in people who inject drugs: A cross‐sectional study
Authors: Coull Alison F. , Kyle Richard G. , Hanson Coral L. , Watterson Andrew E.
Published: February 2021

Aims and Objectives

The aim of this study was to assess, for the first time in a hard‐to‐reach population, the risk factors for leg ulceration among PWID, with the objective of making improvements to prevention and care.

Background

An estimated 4.8 million people globally inject drugs with potential for injecting‐related harm. Skin and vein damage associated with drug injecting is increasing. Leg ulceration is a chronic condition which in the UK has a prevalence of 15% among people who have injected drugs (PWID) compared with 1% in the general population. Glasgow has the highest rate of problematic drug use in Scotland with approximately 13,900 individuals, about 50% of whom are thought to inject. However, the reasons for high prevalence of leg ulceration among PWID are unknown. To support improvements in prevention and care, the dearth of evidence around risk factors for leg ulceration in PWID needs to be addressed.

Design

A cross‐sectional survey of 200 current and former injectors recruited from drug services in Glasgow, Scotland, to measure skin problems, leg ulceration and injecting habits is reported following STROBE guidelines. Logistic regression modelling examined whether demographics and injecting habits predicted leg ulceration.

Results

The likelihood of leg ulceration was increased for those who injected in the groin and the leg. Additionally, injecting in the groin and leg were associated with having a DVT.

Conclusion

The primary risk factors for leg ulceration in PWID are injecting in the groin and the legs and these are clinically linked to deep vein thrombosis. Injecting into the femoral vein is increasingly common practice for PWID and healthcare practitioners should advise injectors of the increased risk of leg ulceration and DVT and discourage injecting into these areas.
Problems people with spinal cord injury experience accessing help with bowel care when hospitalised outside a specialist spinal injury service
Authors: Pryor Julie , Haylen Denise , Fisher Murray
Published: February 2021

Aims and objectives

To examine the nature of problems experienced by people with spinal cord injury (SCI) when accessing help to maintain recommended bowel regimes while hospitalised outside a specialist spinal injury service.

Background

Bowel dysfunction is one particularly undesirable aspect of life with a SCI, with constipation and incontinence common.

Design

Descriptive qualitative.

Methods

Accounts of problems encountered in hospitals in New South Wales Australia collected during interviews with 11 people living with SCI and 12 responses provided by spinal clinicians via an online survey were subjected to thematic analysis. The COREQ guidelines were followed for reporting.

Results

There were similarities across data collected from both sources. Individuals with SCI described instances where their bowel care needs did not fit with the pace and processes in acute hospitals. The clinician data pointed to a failure of healthcare professionals to assist people with SCI to maintain bowel care regimes recommended by specialist spinal services. Both groups described times when bowel care received was unreliable and fragmented, along with reports of staff who were unwilling and/or unable to provide the assistance required. Many and varied physical and psychosocial repercussions for individuals were associated with these system failures. In some instances, rather than restoring health, being admitted to hospital represented a significant health risk.

Conclusion

A failure of hospital systems to meet the bowel care needs of people with SCI when hospitalised outside a specialist spinal unit was identified. System and individual factors contributed to these problems, hence addressing them requires both system and individual responses.

Relevance to clinical practice

If this problem is left unaddressed, the health and quality of life of people with SCI will continue to be compromised. Nursing scope of practice needs to be clarified and communicated to nurses outside specialist spinal injury units in relation to their role in maintaining bowel care regimes recommended for their patients by spinal specialists, and nurses need to ensure they possess the skills required. To allocate the time needed to provide this care, individual nurses need the support of the whole nursing team, including managers who are prepared to arrange additional staff when needed.
Adopting otitis media practice guidelines increases adherence within a large primary care network
Authors: Bradley Mikaela , Bacharouch Ali , Hart‐Johnson Tamera , Burrows Heather L , Blackwood R Alexander
Published: February 2021

Aim

Unnecessary antibiotic prescriptions to treat otitis media (OM) contribute to adverse drug reactions, increased cost and antibiotic resistance. Clinical care guidelines can help promote consistent treatment of conditions such as OM. This study evaluates adherence before and after implementation of an institutional guideline for the diagnosis and treatment of paediatric OM.

Methods

A retrospective chart review was performed to collect encounter information for paediatric patients seen within a primary care clinic network and diagnosed with OM before and after full implementation of a clinical care guideline. Patient cohorts from 2013 and 2016 were compared to determine which factors, including age, symptoms and diagnosis, were associated with treatment guideline adherence.

Results

Comparison of encounters from 2013 (n = 418) to 2016 (n = 635) revealed a significant difference in adherence to the 2013 Michigan Medicine Otitis Media Guideline. Overall adherence increased from 61.2% in 2013 to 70.6% in 2016 (χ2 = 9.85, P < 0.0017). Antibiotic use for acute OM decreased from 99.7% in 2013 to 96.7% in 2016 (χ2 = 10.04, P = 0.0015). Antibiotic prescriptions for OM with effusion decreased significantly from 42.9% in 2013 to 17.4% in 2016 (χ2 = 11.93, P < 0.0006).

Conclusion

Implementation of an institutional OM clinical practice guideline contributed to a significant increase in overall treatment adherence of OM for paediatric patients between the 2013 and 2016 cohorts. The number of antibiotic prescriptions for paediatric patients diagnosed with acute OM or OM with effusion significantly decreased from 2013 to 2016.
The legal conundrum over regulation of access and benefit sharing obligations in digital sequence information over genetic resources‐assessing indian position
Authors: Kharb Deepa
Published: February 2021

The agenda of Digital Sequence Information (DSI) on genetic resources was taken up for international debate at the 14th Conference of Parties to the Convention on Biological Diversity (CBD hereinafter) in 2018. The issue is of great significance to governments of the member countries as the new use of sequence information is replacing the existing practice of physical access to plants, animals, and so forth. It is everting the traditional approaches to access and benefit sharing (ABS hereinafter) under the CBD and encouraging bio‐piracy as the legal framework is not versed with the realities of technical advance. This legal conundrum and free‐for‐all access to sequence information is highly beneficial for user countries and the biotechnology industry which supports the open access model citing benefits related to climate change, public health, and food security. The current COVID‐19 pandemic related research has given strength to their argument that restriction of access would hamper research and development for the benefit of mankind as the sequence details of the virus has been made available under the public domain. On the other hand, source countries contend that allowing free access to sequence information of genetic resources without prior informed consent and mutually agreed terms as per the CBD and Nagoya Protocol (NP hereinafter) will be counterproductive to the interests of the indigenous people and local communities that foster and preserve biodiversity in their jurisdictions. The paper analyses the issues and arguments related to DSI and explore the possibility and prospects of the application of the ABS under CBD‐NP framework to DSI.
Blame, Damnation, and Evolved Dispositions: A Dilemma
Authors: Pedersen Daniel J.
Published: February 2021

Natural scientists have offered reasons to think that some vile human acts have evolutionary explanations. Christians would describe some of these acts as sins, and indeed as sins potentially worthy of damnation. However, I argue that, on the supposition that such sins have evolutionary causes, the agents who commit these sins are not justly damnable for the acts in question. This is because the justice of damnation minimally depends on two criteria: 1) that sinful acts are properly voluntary; and 2) that asymmetrical fault between sinners and God holds for said acts. Because, on the assumption that dispositions to sin have evolved, one or both of these criteria cannot be sustained, theologians face a choice. They must either affirm the evolutionary origins of some sinful acts and deny damnation in the relevant cases, or, if they wish to affirm damnation in all relevant cases, they must deny that there are evolved dispositions to sin. Whichever way it is resolved, the dilemma is serious and concrete. Because it is serious, it requires careful attention from all theologians, not only theology‐and‐science specialists. Because it is concrete, it cannot be dissolved with methodological strategies alone.
Regional anesthesia in pediatric patients with preexisting neurological disease
Authors: Cung Stephanie , Ritz Matthew L. , Masaracchia Melissa M.
Published: February 2021

Preexisting neurological disease in pediatric patients presents unique challenges to the anesthesiologist. In‐depth knowledge of the disease processes and awareness of sequalae that uniquely influence the risks and benefits of anesthetics are needed to make informed decisions. Because these vulnerable populations are often susceptible to perioperative airway or cardiopulmonary complications, the use of regional anesthesia can be advantageous. However, these clinical conditions already involve compromised neural tissue and, as such, create additional concern that regional anesthesia may result in new or worsened deficits. The following discussion is not intended to be a full review of each disease process, but rather provides a concise, yet thorough, discussion of the available literature on regional anesthesia in the more common, but still rare, pediatric neurological disorders. We aim to provide a framework for pediatric anesthesiologists to reengage in a healthy discussion about the risks and benefits of utilizing regional anesthesia in this vulnerable population.
Nitric oxide (NO) and salicylic acid (SA): A framework for their relationship in plant development under abiotic stress
Authors: Prakash V. , Singh V. P. , Tripathi D. K. , Sharma S. , Corpas F. J.
Published: February 2021

The free radical nitric oxide (NO) and the phenolic phytohormone salicylic acid (SA) are signal molecules which exert key functions at biochemical and physiological levels. Abiotic stresses, especially in early plant development, impose the biggest threats to agricultural systems and crop yield. These stresses impair plant growth and subsequently cause a reduction in root development, affecting nutrient uptake and crop productivity. The molecules NO and SA have been identified as robust tools for efficiently mitigating the negative effects of abiotic stress in plants. SA is engaged in an array of tasks under adverse environmental situations. The function of NO depends on its cellular concentration; at a low level, it acts as a signal molecule, while at a high level, it triggers nitro‐oxidative stress. The crosstalk between NO and SA involving different signalling molecules and regulatory factors modulate plant function during stressful situations. Crosstalk between these two signalling molecules induces plant tolerance to abiotic stress and needs further investigation. This review aims to highlight signalling aspects of NO and SA in higher plants and critically discusses the roles of these two molecules in alleviating abiotic stress.