bluuebunny/crossref_metadata_2025 huggingface dataset:
Primary HPV cervical screening: Clinical audit of outcomes of women seen at a tertiary referral centre for colposcopy in Australia
Authors: Chin Felicia H. X. , Wrede C. David H. , Richards Anthony , Steele Angela , Vicario Estefania , McNally Orla M. , Tan Jeffrey H. J.
Published: May 2021

Background

Primary human papillomavirus (HPV) screening was introduced in Australia in December 2017.

Aims

Outcomes for women after positive HPV in their cervical screening test (CST).

Materials and Methods

A retrospective observational study of 4458 women seen at the Royal Women’s Hospital Colposcopy Clinic from 1 January 2018 to 31 July 2020.

Results

HPV16/18 was positive (considered higher‐risk CST) in 42.2% of women in the study, 16.6% with reflex possible with high‐grade squamous intraepithelial lesions (pHSIL) or worse and 54.9% with normal cytology. There were 24.8% of women with positive HPV16/18 who had histological confirmed cervical intraepithelial neoplasia grade 2 or worse (CIN2+), 10.3% CIN2+ (including six cancers) among women with reflex negative cytology and 87.7% CIN2+ among women with reflex HSIL cytology. In women with positive HPV (not 16/18), CIN2+ was found in 60.2% with reflex pHSIL or worse cytology (higher risk) and 10.2% with reflex low‐grade SIL (LSIL) or normal cytology (intermediate risk). Median waiting time to colposcopy with the intermediate‐risk group went up to 181 days. Our colposcopists were able to achieve a positive predictive value (PPV) for CIN2+ of 69.9%, higher than 57.8% PPV in the National Cervical Screening Program (NCSP) 2020 monitoring report. Women with type 3 transformation zone on colposcopy could be followed up with CST if no HSIL was suspected on screening or at colposcopy as their risk of CIN2+ was only 2.5%.

Conclusions

Our findings support direct referral to colposcopy for women with higher‐risk CST, with all cancers confined to this group. The NCSP recommendation to refer for colposcopy only after three intermediate‐risk CST will need monitoring with the LSIL triage group.
Predicting QT interval prolongation in patients diagnosed with the 2019 novel coronavirus infection
Authors: Zhao Wei , Gandhi Nikhil , Affas Saif , Szpunar Susan , Mesiha Nancy , Saravolatz Louis
Published: May 2021

Introduction

2019 novel coronavirus (COVID‐19) patients frequently develop QT interval prolongation that predisposes them to Torsades de Pointes and sudden cardiac death. Continuous cardiac monitoring has been recommended for any COVID‐19 patient with a Tisdale Score of seven or more. This recommendation, however, has not been validated.

Methods

We included 178 COVID‐19 patients admitted to a non‐intensive care unit setting of a tertiary academic medical center. A receiver operating characteristics curve was plotted to determine the accuracy of the Tisdale Score to predict QT interval prolongation. Multivariable analysis was performed to identify additional predictors.

Results

The area under the curve of the Tisdale Score was 0.60 (CI 95%, 0.46–0.75). Using the cutoff of seven to stratify COVID‐19, patients had a sensitivity of 85.7% and a specificity of 7.6%. Risk factors independently associated with QT interval prolongation included a history of end‐stage renal disease (ESRD) (OR, 6.42; CI 95%, 1.28–32.13), QTc ≥450 ms on admission (OR, 5.90; CI 95%, 1.62–21.50), and serum potassium ≤3.5 mmol/L during hospitalization (OR, 4.97; CI 95%, 1.51–16.36).

Conclusion

The Tisdale Score is not a useful tool to stratify hospitalized non‐critical COVID‐19 patients based on their risks of developing QT interval prolongation. Clinicians should initiate continuous cardiac monitoring for patients who present with a history of ESRD, QTc ≥450 ms on admission or serum potassium ≤3.5 mmol/L.
Information criteria for inhomogeneous spatial point processes
Authors: Choiruddin Achmad , Coeurjolly Jean‐François , Waagepetersen Rasmus
Published: May 2021

The theoretical foundation for a number of model selection criteria is established in the context of inhomogeneous point processes and under various asymptotic settings: infill, increasing domain and combinations of these. For inhomogeneous Poisson processes we consider Akaike's information criterion and the Bayesian information criterion, and in particular we identify the point process analogue of ‘sample size’ needed for the Bayesian information criterion. Considering general inhomogeneous point processes we derive new composite likelihood and composite Bayesian information criteria for selecting a regression model for the intensity function. The proposed model selection criteria are evaluated using simulations of Poisson processes and cluster point processes.
Mental health literacy: A systematic review of knowledge and beliefs about mental disorders in Malaysia
Authors: Munawar Khadeeja , Mukhtar Firdaus , Choudhry Fahad Riaz , Ng Alvin Lai Oon
Published: May 2021

Background

Mental health problems in Malaysia are on a rise. This study aimed at performing a systematic review of mental health literacy (MHL) in Malaysia.

Methods

Medline, Embase, ERIC/Proquest, ScienceDirect, Pubmed, PsycINFO, CINAHL, Scopus, EBM Reviews ‐ Cochrane Central Register of Controlled Trials, Ovid Emcare and reference lists of included studies were searched in February 2020. Studies that evaluated at least one of the main components of MHL, including (1) knowledge related to mental health issues, and (2) stigma, were included irrespective of study design. As secondary findings, the review also synthesized results related to facilitators and barriers to seeking mental health services. Depending on the research design, the quality of each study was assessed through checklists.

Results

Forty six studies published between 1995 to 2019 were included. Most studies used cross‐sectional designs to investigate MHL. Findings indicate that most Malaysians have stigmatizing attitudes towards mental health problems. Participants in the included studies endorsed multifactorial explanations of mental health issues with a dominance of supernatural and religious aetiologies. Likewise, the commonest barrier was considering sources other than professional sources of mental‐health services. Presence of adequate knowledge and considering providers as competent facilitated help‐seeking. Additionally, there was considerable heterogeneity in studies and a lack of standardized measures assessing MHL.

Conclusions

There is an increase in studies on MHL in Malaysia. A few of these studies, based on experimental design, have shown positive effects. Researchers, practitioners, and policymakers should develop standardized measures and interventional studies based on all the components of MHL.
Rapid‐acting antidepressants and the regulation of TrkB neurotrophic signalling—Insights from ketamine, nitrous oxide, seizures and anaesthesia
Authors: Kohtala Samuel , Rantamäki Tomi
Published: May 2021

Increased glutamatergic neurotransmission and synaptic plasticity in the prefrontal cortex have been associated with the rapid antidepressant effects of ketamine. Activation of BDNF (brain‐derived neurotrophic factor) receptor TrkB is considered a key molecular event for antidepressant‐induced functional and structural synaptic plasticity. Several mechanisms have been proposed to underlie ketamine's effects on TrkB, but much remains unclear. Notably, preliminary studies suggest that besides ketamine, nitrous oxide (N2O) can rapidly alleviate depressive symptoms. We have shown nitrous oxide to evoke TrkB signalling preferentially after the acute pharmacological effects have dissipated (ie after receptor disengagement), when slow delta frequency electroencephalogram (EEG) activity is up‐regulated. Our findings also demonstrate that various anaesthetics and sedatives activate TrkB signalling, further highlighting the complex mechanisms underlying TrkB activation. We hypothesize that rapid‐acting antidepressants share the ability to regulate TrkB signalling during homeostatically evoked slow‐wave activity and that this mechanism is important for sustained antidepressant effects. Our observations urge the examination of rapid and sustained antidepressant effects beyond conventional receptor pharmacology by focusing on brain physiology and temporally distributed signalling patterns spanning both wake and sleep. Potential implications of this approach for the improvement of current therapies and discovery of novel antidepressants are discussed.
Emotion network density is a potential clinical marker for anxiety and depression: Comparison of ecological momentary assessment and daily diary
Authors: Shin Ki Eun , Newman Michelle G. , Jacobson Nicholas C.
Published: May 2021

Objectives

Using two intensive longitudinal data sets with different timescales (90 minutes, daily), we examined emotion network density, a metric of emotional inflexibility, as a predictor of clinical‐level anxiety and depression.

Design

Mobile‐based intensive longitudinal assessments.

Methods

119 participants (61 anxious and depressed, 58 healthy controls) completed ecological momentary assessment (EMA) to rate a variety of negative (NE) and positive emotions (PE) 9 times per day for 8 days using a mobile phone application. 169 participants (97 anxious and depressed and 72 healthy controls) completed an online daily diary on their NE and PE for 50 days. Multilevel vector autoregressive models were run to compute NE and PE network densities in each data set.

Results

In the EMA data set, both NE and PE network densities significantly predicted participants’ diagnostic status above and beyond demographics and the mean and standard deviation of NE and PE. Greater NE network density and lower PE network density were associated with anxiety and depression diagnoses. In the daily diary data set, NE and PE network densities did not significantly predict the diagnostic status.

Conclusions

Greater inflexibility of NE and lower inflexibility of PE, indexed by emotion network density, are potential clinical markers of anxiety and depressive disorders when assessed at intra‐daily levels as opposed to daily levels. Considering emotion network density, as well as the mean level and variability of emotions in daily life, may contribute to diagnostic prediction of anxiety and depressive disorders.

Practitioner points

Emotion network density, or the degree to which prior emotions predict and influence current emotions, indicates an inflexible or change‐resistant emotion system.

Emotional inflexibility or change resistance over a few hours, but not daily, may characterize anxiety and depressive disorders.

Inflexible negative emotion systems are associated with anxiety and depressive disorders, whereas inflexible positive emotion systems may indicate psychological health.

Considering emotional inflexibility within days may provide additional information beyond demographics and mean level and variability of emotions in daily life for detecting anxiety and depressive disorders.
The influence of policy and context on teachers’ social media use
Authors: Greenhalgh Spencer P. , Rosenberg Joshua M. , Russell Annelise
Published: May 2021

Research on teachers’ use of social media has typically assumed that it is a) driven by a need for professional learning and b) best understood in terms of individual motivations. In this study, we use a dataset of nearly 600,000 tweets posted to one or more of 48 Regional Educational Twitter Hashtags associated with 44 U.S. states. To explore the influence of local contextual factors on hashtag‐ and account‐level activity in these hashtags, we use an analytic approach heretofore uncommon in social media‐focussed education research: generalised linear and multilevel modelling. At the hashtag level, higher numbers of teachers within a state, proportions of students receiving subsidised meals, student‐to‐teacher ratios, and amounts of state spending per child are associated with more activity within a regional hashtag; by contrast, more left‐leaning state governments and citizenries are associated with less activity. At the account level, more experienced accounts and accounts in more right‐leaning states contribute more tweets to these hashtags. These findings reinforce established understandings of Twitter as a site for teacher learning; however, they also underline the importance of acknowledging other important purposes of teachers’ Twitter use, including receiving emotional support and engaging in activism.

Practitioner notes

What is already known about this topic

Many teachers use Twitter (and other social media platforms) for professional purposes.

Teachers have identified professional learning—among other purposes—as motivating their use of Twitter.

Regional Educational Twitter Hashtags are diverse learning spaces for teachers and other education stakeholders.

What this paper adds

Local context and policy factors help influence teachers’ use of Twitter.

Teachers may turn to Twitter because of a lack of emotional or political support—not just a lack of material support or professional development opportunities.

Individual and idiosyncratic factors remain important in explaining teachers’ engagement with social media.

Implications for practice and/or policy

Informal spaces like social media may supplement formal support mechanisms for teachers.

Teachers’ use of social media may help administrators and policymakers identify existing gaps to be repaired in those formal support mechanisms.

Support for teachers should be conceived holistically and include emotional and political support.
Adapting educational practices in emergency remote education: Continuity and change from a student perspective
Authors: Manca Stefania , Delfino Manuela
Published: May 2021

In this study, we adopt an ecological perspective to reflect on how a specific Italian school cluster adapted to the challenges of the COVID‐19 pandemic by focusing on how students experienced the interplay between continuity and change in school teaching and learning practices caused by the pandemic. Specifically, the study investigates how the school's physical/virtual learning system was (re)configured to provide new opportunities for learning to a thousand‐plus population of primary and secondary students, and how they reacted to the transition to distance learning in terms of participation, autonomy, motivation and engagement. The research adopts a mixed method approach, based on school management system data and a survey tool, and analyses the students’ response to the emergency from the perspectives of the students themselves, their teachers and their parents. While these converged in positive evaluation of the experience, a number of lessons were learnt, such as the importance of building on favourable pre‐existing conditions and leveraging a solid shared school culture to promote a prompt reaction to the emergency. Significantly, students with an immigrant background displayed varying degrees of participation in online activities. Overall, for each of the three stakeholder groups surveyed, solid pre‐existing digital competence levels and close collaboration within the school community were the most important factors for non‐traumatic transition to distance learning.

Practitioner notes

What is already known about this topic?

Research on the relationship between the COVID‐19 pandemic and the effects on teaching and learning processes is constantly increasing.

Most recently published studies focus on higher education, while very few investigate the impact of the COVID‐19 pandemic on K‐12 education.

Very few papers have studied the interplay between change and continuity within an educational ecosystem in times of crisis.

What this paper adds?

This is one of the first studies to analyse the process of systematic transition from onsite learning to online learning within the Italian school system in response to the pandemic.

This study employs a multiple perspective research approach to analyse Emergency Remote Education in a sizeable school cluster, with a specific focus on student response.

Teachers, students and their families all saw solid pre‐existing digital competence and close school community collaboration as key factors facilitating rapid adjustment to the emergency.

Implications for practice and policy

Having a solid common school culture to rely on facilitates prompt emergency reaction.

Encouraging the creation of professional communities of practice that comprise both expert and novice teachers can help prepare educators to deal with an educational emergency through adoption and appropriate use of technological solutions.

Collaboration between school and families proves to be a key factor for dealing with emergencies.
Risk stratification in men with a negative prostate biopsy: an interim analysis of a prospective cohort study
Authors: Sandahl Mads , Pedersen Bodil Ginnerup , Ulhøi Benedicte Parm , Borre Michael , Sørensen Karina Dalsgaard
Published: May 2021

Objective

To investigate whether a risk score for prostate cancer (PCa) lifetime risk can be used to optimise triaging of patients with a negative prostate biopsy, but under sustained suspicion of PCa.

Patients and Methods

In this prospective clinical study, we included, and risk scored patients who had a PCa‐negative transrectal ultrasonography (TRUS)‐guided prostate biopsy, but elevated prostate‐specific antigen (PSA), a suspicious prostate digital rectal examination and/or a positive family history (FH) of PCa. The risk score estimated individual lifetime risk of PCa, based on a polygenic risk score (33 single nucleotide polymorphisms), age, and FH of PCa. Patients were followed, under urological supervision, for up to 4 years with annual controls, always including PSA measurements. Multiparametric magnetic resonance imaging (mpMRI) and/or prostate biopsy was performed at selected annual controls depending on risk score and at the urologist’s/patient’s discretion, which means that the follow‐up differed based on the risk score.

Results

We included 429 patients. After risk scoring, 376/429 (88%) patients were allocated to a normal‐risk group (<30% PCa lifetime risk) and 53/429 (12%) to a high‐risk group (≥30% PCa lifetime risk). The high‐risk group had significantly different follow‐up, with more biopsy and mpMRI sessions compared to the normal‐risk group. PCa was detected in 89/429 (21%) patients, with 67/376 (18%) patients diagnosed in the normal‐risk group and 22/53 (42%) in the high‐risk group. There was no statistically significant difference in the cumulative incidence of PCa between the normal‐risk group and the high‐risk group after 4 years of follow‐up. Currently, 67/429 (16%) patients are still being followed in this ongoing study.

Conclusion

In a 4‐year perspective, our PCa lifetime risk score did not demonstrate significant prognostic value for triaging patients, with a negative TRUS‐guided biopsy and sustained suspicion of PCa.
Assessment of prostate‐specific antigen screening: an evidence‐based report by the German Institute for Quality and Efficiency in Health Care
Authors: Paschen Ulrike , Sturtz Sibylle , Fleer Daniel , Lampert Ulrike , Skoetz Nicole , Dahm Philipp
Published: May 2021

Context

Prostate‐specific antigen (PSA) testing increases prostate cancer diagnoses and reduces long‐term disease‐specific mortality, but also results in overdiagnoses and treatment‐related harms.

Objective

To systematically assess the benefits and harms of population‐based PSA screening and the potential net benefit to inform health policy decision‐makers in Germany.

Evidence Acquisition

We performed a protocol‐guided comprehensive literature search according to the Preferred Reporting Items for Systematic Reviews and Meta‐analyses (PRISMA) statement. All steps were performed by one or two investigators; any discrepancies were resolved by consensus. To allow subgroup analyses for identifying the optimal screening parameters, the eight national trials conducted under the umbrella of the European Randomised study of Screening for Prostate Cancer (ERSPC) were included as individual trials.

Evidence Synthesis

We included a total 11 randomised controlled trials (RCTs) with a total of 416 000 study participants. For all‐cause mortality, we found neither benefit nor harm. PSA screening was associated with a reduced risk of both prostate cancer mortality and the development of metastases. For the outcomes of health‐related quality of life, adverse effects and the consequences of false‐negative screening results there was no difference; however, this was due to the lack of eligible RCT data. Finally, PSA screening was associated with large numbers of overdiagnoses with adverse downstream consequences of unnecessary treatment (e.g. incontinence, erectile dysfunction) and large numbers of false‐positive PSA tests leading to biopsies associated with a small but not negligible risk of complications. Limitations of this assessment include the clinical heterogeneity and methodological limitations of the underlying studies.

Conclusions

The benefits of PSA‐based prostate cancer screening do not outweigh its harms. We failed to identify eligible screening studies of newer biomarkers, PSA derivatives or modern imaging modalities, which may alter the balance of benefit to harm.

Patient Summary

In the present study, we reviewed the evidence on the PSA blood test to screen men without symptoms for prostate cancer. We found that the small benefits experienced by some men do not outweigh the harms to many more men.
Attitude is everything: keep probe pitch neutral during side‐fire prostate biopsy. A simulator study
Authors: Zhang Zhou , Lampotang Samsun , Yu Yichao , Acar Yahya A. , Wakim Jonathan , Mei Vincent , Ahmad Ardalan E. , Shenot Patrick , Lee Jason , Perlis Nathan , Moy Louis , Johnson William T. , DeStephens Anthony , Bigos Andre K. , Lizdas David E. , Stringer Thomas
Published: May 2021

Objectives

To develop and validate on a simulator a learnable technique to decrease deviation of biopsied cores from the template schema during freehand, side‐fire systematic prostate biopsy (sPBx) with the goal of reducing prostate biopsy (PBx) false‐negatives, thereby facilitating earlier sampling, diagnosis and treatment of clinically significant prostate cancer.

Participants and Methods

Using a PBx simulator with real‐time three‐dimensional visualization, we devised a freehand, pitch‐neutral (0°, horizontal plane), side‐fire, transrectal ultrasonography (TRUS)‐guided sPBx technique in the left lateral decubitus position. Thirty‐four trainees on four Canadian and US urology programmes learned the technique on the same simulator, which recorded deviation from the intended template location in a double‐sextant template as well as the TRUS probe pitch at the time of sampling. We defined deviation as the shortest distance in millimeters between a core centre and its intended template location, template deviation as the mean of all deviations in a template, and mastery as achieving a template deviation ≤5.0 mm.

Results

All results are reported as mean ± sd. The mean absolute pitch and template deviation before learning the technique (baseline) were 8.2 ± 4.1° and 8.0 ± 2.7 mm, respectively, and after mastering the technique decreased to 4.5 ± 2.7° (P = 0.001) and 4.5 ± 0.6 mm (P < 0.001). Template deviation was related to mean absolute pitch (P < 0.001) and increased by 0.5 mm on average with each 1° increase in mean absolute pitch. Participants achieved mastery after practising 3.9 ± 2.9 double‐sextant sets. There was no difference in time to perform a double‐sextant set at baseline (277 ± 102 s) and mastery (283 ± 101 s; P = 0.39).

Conclusion

A pitch‐neutral side‐fire technique reduced template deviation during simulated freehand TRUS‐guided sPBx, suggesting it may also reduce PBx false‐negatives in patients in a future clinical trial. This pitch‐neutral technique can be taught and learned; the University of Florida has been teaching it to all Urology residents for the last 2 years.
Editorial: Moving forward
Authors: Nind Melanie
Published: May 2021

Accessible Summary

Some of the papers in this issue focus on supporting people with learning disabilities and challenging behaviour.

One paper is about support during Covid‐19 times and some papers are about therapy support following difficult times in people’s lives, including (alleged) abuse.

There are also papers about using mobile phones, learning to do research, and parents adjusting to advocate for their child with learning disabilities.

In journal updates, the editors will be discussing accessibility of journal papers with the authors of the In Response papers.
The representative agent bias in cost of living indices
Authors: Bandyopadhyay Sutirtha , Ramaswami Bharat
Published: May 2021

The aggregate cost of the living index requires averaging across household indices. But what if the aggregate index was constructed for the “representative” household as is usually done? The paper examines the resulting bias in the Tornqvist index, widely used for constructing superlative indices as well as for the Cobb–Douglas index, which has a similar functional form. We show that the difference between the two consists of a “plutocratic” bias and a “curvature” bias. The former is well known, but the latter has not been recognized earlier. In empirical applications, the curvature bias is small and orders of magnitude smaller than the plutocratic bias. This suggests much of the overall bias would be removed by constructing the representative agent by democratic averages of budget shares.
Angiotensin II augments renal vascular smooth muscle soluble GC expression via an AT1 receptor–forkhead box subclass O transcription factor signalling axis
Authors: Galley Joseph C. , Hahn Scott A. , Miller Megan P. , Durgin Brittany G. , Jackson Edwin K. , Stocker Sean D. , Straub Adam C.
Published: May 2021

Background and Purpose

Reduced renal blood flow triggers activation of the renin‐angiotensin‐aldosterone system (RAAS) leading to renovascular hypertension. Renal vascular smooth muscle expression of the NO receptor, soluble GC (sGC), modulates the vasodilator response needed to control renal vascular tone and blood flow. Here, we tested if angiotensin II (Ang II) affects sGC expression via an AT1 receptor‐forkhead box subclass O (FoxO) transcription factor dependent mechanism.

Experimental Approach

Using a murine two‐kidney‐one‐clip (2K1C) renovascular hypertension model, we measured renal artery vasodilatory function and sGC expression. Additionally, we conducted cell culture studies using rat renal pre‐glomerular smooth muscle cells (RPGSMCs) to test the in vitro mechanistic effects of Ang II treatment on sGC expression and downstream function.

Key Results

Contralateral, unclipped renal arteries in 2K1C mice showed increased NO‐dependent vasorelaxation compared to sham control mice. Immunofluorescence studies revealed increased sGC protein expression in 2K1C contralateral renal arteries over sham controls. RPGSMCs treated with Ang II caused a significant up‐regulation of sGC mRNA and protein expression as well as downstream sGC‐dependent signalling. Ang II signalling effects on sGC expression occurred through an AT1 receptor and FoxO transcription factor‐dependent mechanism at both the mRNA and protein expression levels.

Conclusion and Implications

Renal artery smooth muscle, in vivo and in vitro, up‐regulates expression of sGC following RAAS activity. In both cases, up‐regulation of sGC leads to increased downstream cGMP signalling, suggesting a previously unrecognized protective mechanism to improve renal blood flow in the uninjured contralateral renal artery.

LINKED ARTICLES

This article is part of a themed issue on cGMP Signalling in Cell Growth and Survival. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.11/issuetoc
Seed ‘primeomics’: plants memorize their germination under stress
Authors: Srivastava Ashish Kumar , Suresh Kumar Jisha , Suprasanna Penna
Published: May 2021

Seed priming is a pre‐germination treatment administered through various chemical, physical and biological agents, which induce mild stress during the early phases of germination. Priming facilitates synchronized seed germination, better seedling establishment, improved plant growth and enhanced yield, especially in stressful environments. In parallel, the phenomenon of ‘stress memory’ in which exposure to a sub‐lethal stress leads to better responses to future or recurring lethal stresses has gained widespread attention in recent years. The versatility and realistic yield gains associated with seed priming and its connection with stress memory make a critical examination useful for the design of robust approaches for maximizing future yield gains. Herein, a literature review identified selenium, salicylic acid, poly‐ethylene glycol, CaCl2 and thiourea as the seed priming agents (SPRs) for which the most studies have been carried out. The average priming duration for SPRs generally ranged from 2 to 48 h, i.e. during phase I/II of germination. The major signalling events for regulating early seed germination, including the DOG1 (delay of germination 1)–abscisic acid (ABA)–heme regulatory module, ABA–gibberellic acid antagonism and nucleus–organelle communication are detailed. We propose that both seed priming and stress memory invoke a ‘bet‐hedging’ strategy in plants, wherein their growth under optimal conditions is compromised in exchange for better growth under stressful conditions. The molecular basis of stress memory is explained at the level of chromatin reorganization, alternative transcript splicing, metabolite accumulation and autophagy. This provides a useful framework to study similar mechanisms operating during seed priming. In addition, we highlight the potential for merging findings on seed priming with those of stress memory, with the dual benefit of advancing fundamental research and boosting crop productivity. Finally, a roadmap for future work, entailing identification of SPR‐responsive varieties and the development of dual/multiple‐benefit SPRs, is proposed for enhancing SPR‐mediated agricultural productivity worldwide.
Tracking hidden innovations in tourism
Authors: Nordli Anne Jørgensen , Rønningen Martin
Published: May 2021

Hidden innovations are innovations that have been overlooked, forgotten or ignored. In this context, this study explores hidden innovations in tourism—innovations not captured by frequently used quantitative instruments such as the Eurostat's community innovation survey (CIS). The study also explains why several innovations have remained hidden in the tourism industry. It identifies and analyses processes producing hidden innovations and determines the characteristics and types of these innovations. The study analyses 13 interviews in four tourism businesses—one Alpine centre and three hotels. Empirical testing indicates the inadequacy of CIS measurement in capturing these innovations. The findings reveal several hidden innovations. In the tourism context, we find two types of hidden innovations—hidden stage‐wise and stage‐merged innovations. These hidden innovations have two triggers. The first trigger refers to the evaluation of work processes carried out at the decentralized levels of companies. The second trigger is the work climate combining staff willingness (W) and opportunities (O) (WO‐oriented work climate)—where the employees are willing to engage with innovation and are provided with an innovation opportunity. This study has important implications for extending the understanding of hidden innovations, especially in tourism, and guiding managers to facilitate, motivate and support work environments that allow employees' freedom and help them take responsibility to generate ideas and innovations.
Upregulation of Nogo‐B by hypoxia inducible factor‐1 and activator protein‐1 in hepatocellular carcinoma
Authors: Han Dingding , Yang Penggao , Qin Bo , Ji Guoqing , Wu Yanhua , Yu Long , Zhang Hong
Published: May 2021

Nogo‐B is an important regulator of tumor angiogenesis. Expression of Nogo‐B is remarkably upregulated in multiple tumor types, especially hepatocellular carcinoma (HCC). Here, we show the transcriptional regulation mechanisms of Nogo‐B in liver cancer. In response to hypoxia, expression of Nogo‐B significantly increased in HCC tissues and cells. The distal hypoxia‐responsive element in the promoter was essential for transcriptional activation of Nogo‐B under hypoxic conditions, which is the specific site for hypoxia inducible factor‐1α (HIF‐1α) binding. In addition, Nogo‐B expression was associated with c‐Fos expression in HCC tissues. Nogo‐B expression was induced by c‐Fos, yet inhibited by a dominant negative mutant A‐Fos. Deletion and mutation analysis of the predicted activator protein‐1 binding sites revealed that functional element mediated the induction of Nogo‐B promoter activity, which was confirmed by ChIP. These results indicate that HIF‐1α and c‐Fos induce the expression of Nogo‐B depending on tumor microenvironments, such as hypoxia and low levels of nutrients, and play a role in upregulation of Nogo‐B in tumor angiogenesis.
Delineating binding potential, stability of Sulforaphane‐N‐acetyl‐cysteine in the active site of histone deacetylase 2 and testing its cytotoxicity against distinct cancer lines through stringent molecular dynamics, DFT and cell‐based assays
Authors: Ganai Shabir Ahmad , Srinivasan Pappu , Rajamanikandan Sundaraj , Shah Basit Amin , Mohan Suma , Gani Mudasir , Padder Bilal Ahmad , Qadri Raies A. , Bhat M. A. , Baba Zahoor Ahmad , Yatoo Manzoor Ahmad
Published: May 2021

Histone deacetylase 2 (HDAC2), an isozyme of Class I HDACs has potent imputations in actuating neurodegenerative signaling. Currently, there are sizeable therapeutic disquiets with the use of synthetic histone deacetylase inhibitors in disease management. This strongly suggests the unfulfilled medical necessity of plant substitutes for therapeutic intervention. Sulforaphane‐N‐acetyl‐cysteine (SFN‐N‐acetylcysteine or SFN‐NAC), a sulforaphane metabolite has shown significantly worthier activity against HDACs under in vitro conditions. However, the atomistic studies of SFN‐NAC against HDAC2 are currently lacking. Thus, the present study employed a hybrid strategy including extra‐precision (XP) grid‐based flexible molecular docking, molecular mechanics generalized born surface area (MM‐GBSA), e‐Pharmacophores method, and molecular dynamics simulation for exploring the binding strengh, mode of interaction, e‐Pharmacophoric features, and stability of SFN‐NAC towards HDAC2. Further, the globally acknowledged density functional theory (DFT) study was performed on SFN‐NAC and entinostat individually in complex state with HDAC2. Apart from this, these inhibitors were tested against three distinct cancer cell models and one transformed cell line for cytotoxic activity. Moreover, double mutant of HDAC2 was generated and the binding orientation and interaction of SFN‐NAC was scrutinized in this state. On the whole, this study unbosomed and explained the comparatively higher binding affinity of entinostat for HDAC2 and its wide spectrum cytotoxicity than SFN‐NAC.
3‐O‐trans‐caffeoyloleanolic acid improves acute lung injury via anti‐inflammation and antioxidative stress‐involved PI3K/AKT pathway
Authors: Huang Jianhua , Nong Xueping , Chen Yanling , Zhang Aimei , Chen Lerong
Published: May 2021

3‐O‐trans‐caffeoyloleanolic acid (COA) is a pentacyclic triterpenoid compound, with significant anti‐inflammatory effects. In this study, we report the protective effects of COA on lipopolysaccharide (LPS)‐induced acute lung injury (ALI) and explored its mechanism of action. LPS was used to construct in vivo mouse ALI models to observe the effects of COA pretreatment on lung pathology, inflammation, and oxidative stress. In vitro, mouse alveolar macrophages MH‐S cells were cultured and stimulated with LPS to investigate the effects of COA pretreatment on inflammation and oxidative stress. Western blotting was used to investigate the expression of iNOS, TLR4, p‐p65, p‐AKT, and p‐PI3K from in vivo and in vitro samples. The results showed that COA significantly improved lung injury, inhibited neutrophil infiltration, prevented macrophage infiltration, inhibited the release of inflammatory factors, reduced oxidative stress, and down‐regulated the expression of iNOS, TLR4, p‐p65, p‐AKT, and p‐PI3K in ALI mice caused by LPS. In vitro, COA inhibited the release of inflammatory factors, reduced oxidative stress, and down‐regulated the expression of iNOS, TLR4, p‐p65, p‐AKT, and p‐PI3K in MH‐S cells stimulated with LPS. Of interest, the protective effects of COA were significantly attenuated in MH‐S cells pretreated with the PI3K phosphopeptide activator 740Y‐P with no effect on TLR4 expression observed. Taken together, these findings confirm the protective effects of COA on ALI. We further demonstrate that the anti‐inflammation and antioxidant effects of COA are mediated through its effects on PI3K/AKT and potentially TLR4.
Caspase‐3: A primary target for natural and synthetic compounds for cancer therapy
Authors: Yadav Poonam , Yadav Ramakant , Jain Shweta , Vaidya Ankur
Published: May 2021

Caspases, a group of protease enzymes (cysteine proteases), exist as inactive zymogens in the cells and execute apoptosis (programmed cell death). Caspase‐3, an executioner caspase, plays an imperative role in apoptosis and becomes a primary target for cancer treatment. A number of analogues of quinazoline, quinazolinone, indoloquinazolines, quinone, naphthoquinones, pyrroloiminoquinones, styrylquinolines, tetheredtetrahydroquinoline, fluoroquinolone, thiosemicarbazones, benzotriazole, pyrimidines, chalcone, and carbazoles have been reported till date, representing caspase‐3 mediated apoptosis for cancer therapy. Simultaneously, plant isolates, including lysicamine, podophyllotoxin, and majoranolide, have also been claimed for caspase‐3‐mediated apoptosis‐induced cytotoxicity. Procaspase‐activating compound‐1 (PAC‐1) is the first FDA approved orphan drug, and its synthetic derivative WF‐208 also showed fascinating caspase‐3 mediated anticancer activity. Till date, a large number of compounds have been reported and patented for their caspase‐3‐mediated cytotoxicity and now scientist is also focusing to introduce new compounds in market to encompass anticancer activity.
Synthesis and evolution of neuroprotective effects of oxymatrine derivatives as anti‐Alzheimer’s disease agents
Authors: Dong Pei‐Liang , Li ZhengQing , Teng Cui‐li , Yin Xin , Cao Xian‐Kai , Han Hua
Published: May 2021

While screening for natural product scaffolds as potential anti‐Alzheimer's disease (AD), oxymatrine (OMT) was found to relieve symptoms of AD through diminishing death of neuronal cells caused by microglia‐induced inflammation. In this study, 13 derivatives of OMT were synthesized and their neuroprotective effects were evaluated on Aβ1‐42‐induced PC12 cells using MTT method. In addition, the best neuroprotective potencies were obtained with compounds 4, 6e, and 6f, which were selected for evaluation of decrease in IL‐1β and TNF‐α in Aβ1‐42‐treated PC12 cells. Collectively, these data reveal that derivatives 6e and 6f possess the best ability of diminish IL‐1β production and reverse cell damage in all compounds, which are possible to develop as therapeutic agents for AD.
Temporomandibular‐disorder‐related pain as a predictor of severe headaches
Authors: Ashraf Javed , Närhi Matti , Suominen Anna Liisa , Zaproudina Nina , Saxlin Tuomas
Published: May 2021

Objective

The current study aimed to investigate the association of temporomandibular disorders (TMD)‐related pain with the presence of migraine or tension‐type headaches (TTH) over a follow‐up period of 11 years.

Methods

Data sets from Finnish national health surveys, the Health 2000 Survey (baseline), and the Health 2011 Survey (follow‐up) were utilized. Study participants are undergoing clinical TMD examination at baseline and answering questions related to the presence of migraine and TTH at follow‐up were included in the study (n = 530). For analyses, the study sample was divided into two data sets: One with those excluded suffering from migraine at baseline (Data set I, n = 345), and the other excluding those having TTH at baseline (Data set II, n = 464).

Results

Based on logistic regression modelling, no consistent association between TMD‐related pain and the presence of migraine was observed, although jTMD associated with elevated estimates for migraine. However, participants with muscle‐related TMD pain (mTMD) at baseline had markedly higher odds for having TTH at follow‐up than participants without mTMD at baseline (OR 2.1, 95% CI 1.2‐3.8). Joint‐related TMD pain (jTMD) at baseline was inversely associated with the presence of TTH at follow‐up (OR 0.4, 95% CI 0.1‐1.3).

Conclusion

Contrasting patterns of the associations of TMD‐related pain with different severe headaches point towards a more thorough and systematic research approach are needed to understand the mechanisms behind these associations.
The use of biologics in food allergy
Authors: Fiocchi Alessandro , Vickery Brian P. , Wood Robert A.
Published: May 2021

Background

Food allergy continues to pose problems due to its increased frequency and its increasingly high severity. In this context, alongside the traditional avoidance strategies of allergenic foods and desensitization through the cautious progression of exposure to foods in the context of oral immunotherapy (OIT), alternative strategies have made their way in the last decades. We review the possibilities of intervention in food allergy with the use of biological drugs capable of interfering with the synthesis of IgE, with their mechanisms of action, or with complex biological mechanisms that lead to the establishment of a food allergy.

Methods

Repeated Entrez PubMed searches using the template algorithm “Food allergy” and “biologics” or “Omalizumab” or “Dupilumab” or “milk desensitization” or “oral tolerance induction” or “oral immunotherapy” or “Etokimab” or “Tezepelumab” or “Quilizumab” or “Ligelizumab” or “Tralokinumab” or “Nemolizumab” or “Mepolizumab” or “Reslizumab” or “Benralizumab”. The authors’ clinical experience in paediatric allergy units of University hospitals was also drawn upon.

Results

The landscape in this context has changed dramatically over the past 10 years. We have acquired knowledge mainly on the effect of different types of anti‐IgE treatments in poliallergic patients with food allergy, and in patients treated with OIT. However, other mediators are being targeted by specific biologic treatments. Among them, the alarmins Il‐33 and TSLP, IL‐4 and IL‐13, eosinophil‐related molecules as IL‐6, IL‐8, IL‐10, IL‐12, and mostly IL‐5, and integrins involved in the pathogenesis of eosinophilic gastrointestinal diseases (EGIDs), as SIGLEC‐8.

Conclusions

The ever‐better knowledge of the mechanisms of food allergy allowing these developments will improve not only the perspective of patients with the most serious immediate food allergies such as anaphylaxis, but also those of patients with related diseases such as atopic dermatitis, eosinophilic esophagitis, and EGIDs. Biologics are also intended to complement OIT strategies that have developed over the years.
Establishment of a novel double-monoclonal antibody sandwich enzyme-linked immunosorbent assay (ELISA): tool for human B7-H4 detection in autoimmune diseases
Authors: Ding Sisi , Zhou Hengxin , Gu Yanzheng , Shen Yu , Zhang Li , Zhao Huayang , Wu Jian , Zhang Xueguang , Chang Xin , Liu Cuiping
Published: May 2021

B7-H4, one of the immunoregulatory proteins, plays an inhibitory role by inhibiting T cell proliferation and cytokine production. Nevertheless, the significance of soluble B7-H4 (sB7-H4) in autoimmune diseases is unclear. In our study, we developed two novel mouse anti-human B7-H4 monoclonal antibodies (mAbs) (clones 8D4 and 7E1) with utilities for flow cytometry, immunoblotting and immunofluorescence. We characterized 7E1 as a functional antibody with antagonistic activity, which could promote T cell proliferation and regulate cytokine production. Furthermore, based on the different epitope specificities, we established a novel enzyme-linked immunosorbent assay (ELISA) which could detect sB7-H4 sensitively and specifically. Using this ELISA kit, sB7-H4 was observed in a high proportion of autoimmune diseases patients. We found that the levels of sB7-H4 were significantly higher in patients with systemic lupus erythematosus (SLE), type I diabetes (T1D) and Graves’ disease (GD). Together, sB7-H4 in human serum is regarded not only as a regulator of T cell activation but may also be a diagnostic marker of autoimmune diseases.
Spinocerebellar ataxia type 2 from an evolutionary perspective: Systematic review and meta‐analysis
Authors: Sena Lucas Schenatto , dos Santos Pinheiro Jordânia , Hasan Ali , Saraiva‐Pereira Maria Luiza , Jardim Laura Bannach
Published: May 2021

Dominant diseases due to expanded CAG repeat tracts, such as spinocerebellar ataxia type 2 (SCA2), are prone to anticipation and worsening of clinical picture in subsequent generations. There is insufficient data about selective forces acting on the maintenance of these diseases in populations. We made a systematic review and meta‐analysis on the effect of the CAG length over age at onset, instability of transmissions, anticipation,de novoor sporadic cases, fitness, segregation of alleles, and ancestral haplotypes. The correlation between CAG expanded and age at onset was r2 = 0.577, and transmission of the mutant allele was associated with an increase of 2.42 CAG repeats in the next generation and an anticipation of 14.62 years per generation, on average. Onede novoand 18 sporadic cases were detected. Affected SCA2 individuals seem to have more children than controls. The expanded allele was less segregated than the 22‐repeat allele in children of SCA2 subjects. Several ancestral SCA2 haplotypes were published. Data suggest that SCA2 lineages may tend to disappear eventually, due to strong anticipation phenomena. Whether or not the novel cases come from common haplotypes associated with a predisposition to further expansions is a question that needs to be addressed by future studies.
PPP3CA truncating variants clustered in the regulatory domain cause early‐onset refractory epilepsy
Authors: Panneerselvam Sugi , Wang Julia , Zhu Wenmiao , Dai Hongzheng , Pappas John G. , Rabin Rachel , Low Karen J. , Rosenfeld Jill A. , Emrick Lisa , Xiao Rui , Xia Fan , Yang Yaping , Eng Christine M. , Anderson Anne , Chau Vann , Soler‐Alfonso Claudia , Streff Haley , Lalani Seema R. , Mercimek‐Andrews Saadet ,   Undiagnosed Diseases Network,   the DDD Study, Bi Weimin
Published: May 2021

PPP3CA encodes the catalytic subunit of calcineurin, a calcium‐calmodulin‐regulated serine–threonine phosphatase. Loss‐of‐function (LoF) variants in the catalytic domain have been associated with epilepsy, while gain‐of‐function (GoF) variants in the auto‐inhibitory domain cause multiple congenital abnormalities. We herein report five new patients with de novo PPP3CA variants. Interestingly, the two frameshift variants in this study and the six truncating variants reported previously are all located within a 26‐amino acid region in the regulatory domain (RD). Patients with a truncating variant had more severe earlier onset seizures compared to patients with a LoF missense variant, while autism spectrum disorder was a more frequent feature in the latter. Expression studies of a truncating variant showed apparent RNA expression from the mutant allele, but no detectable mutant protein. Our data suggest that PPP3CA truncating variants clustered in the RD, causing more severe early‐onset refractory epilepsy and representing a type of variants distinct from LoF or GoF missense variants.