bluuebunny/crossref_metadata_2025 huggingface dataset:
Precocious sexual maturation: Unravelling the mechanisms of pubertal onset through clinical observations
Authors: Soriano‐Guillén Leandro , Tena‐Sempere Manuel , Seraphim Carlos E. , Latronico Ana C. , Argente Jesús
Published: April 2021

Puberty is a crucial biological process normally occurring at a specific time during the lifespan, during which sexual and somatic maturation are completed, and reproductive capacity is reached. Pubertal timing is not only determined by genetics, but also by endogenous and environmental cues, including nutritional and metabolic signals. During the last decade, we have learned much regarding the essential roles of kisspeptins and the neuropeptide pathways that converge on these neurones to modulate kisspeptin signalling, as well as neurokinin B and dynorphin, the co‐transmitters of Kiss1 neurones in the arcuate nucleus, and the effects of melanocortins on puberty. Indeed, melanocortins are involved in transmitting the regulatory actions of metabolic cues on pubertal maturation. Intracellular metabolic sensors, such as the AMP‐activated protein kinase and the fuel‐sensing deacetylase SIRT1, have been shown to contribute to puberty. Further understanding of these signals and regulatory circuits will help uncover the intimacies of the central control of puberty, as well as how alterations in metabolic status, ranging from undernutrition to obesity, affect the pubertal process. Precocious puberty is rare and has a clear female predominance. Central precocious puberty (CPP) is diagnosed when premature activation of the hypothalamic‐pituitary axis occurs. Its causes are heterogeneous, with alterations of the central nervous system being of special interest, and with environmental factors also playing a role in some cases. During the last decade, several mutations in different genes (including KISS1, KISS1R, MKRN3 and DLK1) that cause CPP have been discovered. Loss‐of‐function mutations in MKRN3 are the most common monogenic cause of CPP known to date. Here, we review and update what is known regarding the genotype‐phenotype relationship in patients with CPP.
Reinvestment Risk and the Equity Term Structure
Authors: GONÇALVES ANDREI S.
Published: April 2021

The equity term structure is downward sloping at long maturities. I estimate an Intertemporal Capital Asset Pricing Model (ICAPM) to show that the trade‐off between market and reinvestment risk explains this pattern. Intuitively, while long‐term dividend claims are highly exposed to market risk, they are good hedges for reinvestment risk because dividend prices rise as expected returns decline, and longer‐term claims are more sensitive to discount rates. In the estimated ICAPM, reinvestment risk dominates at long maturities, inducing relatively low risk premia on long‐term dividend claims. The model is also consistent with the equity term structure cyclicality and the upward‐sloping bond term structure.
The Impact of Surgical Guide Fixation and Implant Location on Accuracy of Static Computer‐Assisted Implant Surgery
Authors: Pessoa Roberto , Siqueira Rafael , Li Junying , Saleh Islam , Meneghetti Priscila , Bezerra Fábio , Wang Hom‐Lay , Mendonça Gustavo
Published: April 2021

Purpose

To evaluate the accuracy of static computer‐assisted implant surgery (sCAIS) for tooth‐supported free‐end dental implantation with the aid/and without the aid of fixation pins to secure the surgical template through comparison between planned, 3D printed guide position and placement implant position.

Materials and Methods

Thirty‐two duplicated maxillary resin models were used in the present in vitro study. Digital planning was performed and fabrication of a surgical template that allowed implant placement on the distal extension edentulous site of the model (maxillary left side). A first optical scan was performed after fitting the surgical template on the model to assess the deviation at the surgical guide level. After placing implants in the model using the surgical guide, scan bodies were attached to the implants, and a second scan was performed to record the position of placed implants. The digital representations were later superimposed to the pre‐operative scan and measurements of implant deviations were performed. Global (coronal and apical), horizontal (coronal and apical), depth and angular deviations were recorded between planned implant position, guide position, and placement implant position. Three‐way ANOVA was used to compare implant location (#13, 14, and 15), fixation pin (with or without pin), and guide comparison (planned, guided, and placement).

Results

Final implant placement based on the digital plan and based on the 3D printed guide were very similar except for depth deviation. Use of fixation pin had a statistically significant effect on the depth and angular deviation. Overall, without fixation pins and based on guide versus placement, mean global coronal (0.88 ± 0.36 mm), horizontal coronal (0.55 ± 0.32 mm), and apical (1.44 ± 0.75 mm), and angular deviations (4.28 ± 2.01°) were similar to deviations with fixation pins: mean global coronal (0.88 ± 0.36 mm); horizontal coronal (0.67 ± 0.22 mm) and apical (1.60 ± 0.69 mm); and angular deviations (4.53 ± 2.04°). Horizontal apical without pins (1.63 ± 0.69 mm) and with fixation pins (1.72 ± 0.70 mm) was statistically significant (p = 0.044). Depth deviation without pins (–0.5 ± 0.5 mm) and with fixation pins (–0.16 ± 0.62 mm) was also statistically significant (p = 0.005). Further analysis demonstrated that the final sleeve position on the 3D printed guide was on average 0.5 mm more coronal than the digital plan.

Conclusions

The use of surgical guides with or without fixation pins can provide clinically acceptable outcomes in terms of accuracy in implant position. There was a statistically significant difference in the accuracy of implant position when utilizing fixation pins only for horizontal apical and depth deviation. Additionally, a statistically significant difference between the planned and the 3D printed surgical guide when considering the sleeve position was detected.
Critical review of sensory texture descriptors: From pureed to transitional foods for dysphagia patients
Authors: Guénard‐Lampron Valérie , Masson Marine , Blumenthal David
Published: April 2021

Dysphagic people need to change their diet to avoid pain or risk of choking. For example, they can eat texture modified foods (including pureed and transitional foods, that is, food that start with one texture and change into another because of moisture or heating). Simple testing methods proposed by the IDDSI initiative can be performed to characterize texture modified food but these methods are not always relevant for understanding oral texture and mouthfeel properties. Sensory characterization is essential to develop or optimize a food product and to meet consumer's expectations and needs especially for dysphagic persons. However, sensory methods and texture descriptors are complex to target and evaluate for different severity of dysphagia. Sensory texture descriptors can be determined by different methods and assessed in different ways. This review is useful for listing the sensory methods used to generate sensory descriptors to characterize the oral texture of cereal and pureed foods. We found that 55% of the reviewed publications used specific oral texture descriptors and that 17 descriptors could be identified as the most used and relevant for all the products studied (sticky), for pureed (e.g., cohesiveness, floury, and soft) and for cereal‐based foods (e.g., hard, fatty, and crispy). These results should be considered to facilitate the choice of sensory texture descriptors in future studies on pureed and transitional foods such as cereal‐based foods according to the IDDSI level. This review also demonstrates that it is difficult to find a consensus between studies using different evaluation methods for the same descriptor.
The curious case of case study research
Authors: Cleland Jennifer , MacLeod Anna , Ellaway Rachel Helen
Published: April 2021

The conceptualisation of ‘good’ medical education research as hypothesis testing to identify universal truths that are generalisable across contexts has been challenged. Joining this conversation, the field of health professions education research is complex and contextual and there are ways of examining and reporting locally based activities and innovations, which can be of general value. This position leads to a focus on case study research (CSR), inquiry bound in time and place that generates thick descriptions and close interpretations to reach explanations. CSR has grown in sophistication in recent years and can inform practice and advance the science of medical and health professions education. The authors evaluated the current state of the science of CSR in the medical education literature by identifying and reviewing 160 papers. Most articles presented as ‘case studies’ were not in fact CSR. Moreover, most articles failed to go beyond a ‘we did this’ account. The authors explore definitions of CSR, and they examine dominant CSR methodologists, Yin, Stake and Merriam, and their respective approaches to CSR. They then set out some of the basic tenets of CSR (case definition, methods of data collection and analysis) and consider the logics of CSR (its structures, purposes, assumptions and symbols). CSR challenges are considered next (such as emic and etic perspectives; ethical complexities; generalisability; quality; and reporting and reflexivity). The authors conclude that context is a mechanism, which needs to be understood, and rigorous CSR provides the structures and criticality to do so, opening up new areas of understanding and inquiry.
Effectiveness and safety of AV node ablation after His bundle pacing in patients with uncontrolled atrial arrhythmias
Authors: Moriña‐Vázquez Pablo , Moraleda‐Salas María Teresa , Arce‐León Álvaro , Venegas‐Gamero José , Fernández‐Gómez Juan Manuel , Díaz‐Fernández José Francisco
Published: April 2021

Introduction

In patients with uncontrolled atrial fibrillation, atrioventricular (AV) node ablation after permanent His bundle pacing (p‐HBP) could be a therapeutic option for heart rate (HR) control. We aimed to demonstrate the advantages of AV node ablation with p‐HBP, and to describe its effectiveness and safety.

Methods

This descriptive observational study included patients with uncontrolled permanent atrial arrhythmias who were candidates for HR control (January 2019 to July 2020) and underwent p‐HBP and AV node ablation.

Results

A total of 39 patients were included. The median left ventricular ejection fraction (LVEF) was 55% (45–60); 46.1% in NYHA class II and 43.6% in NYHA class III. p‐HBP was achieved in 92.3% (n = 36), and AV node ablation was successfully performed in all patients. The LVEF improved in patients with reduced LVEF (baseline, 35% [23.8–45.3%]; follow‐up, 40% [35–56.5%], p < 0.05); the NYHA class also showed improvement (baseline, 71.4% patients in class III and 7.1% in class II, and at follow‐up, 78.6% patients in class II and 14.3% in class I). In patients with previously normal LVEF, LVEF remained stable; nevertheless, a significant NYHA class improvement was observed (baseline, 63.6% class II and 31.8% class III patients; follow‐up, 54.5% class I and 45.5% class II patients). The His thresholds and lead parameter values did not significantly change during the follow‐up and remained stable.

Conclusions

In patients with uncontrolled atrial arrhythmias who underwent AV node ablation after p‐HBP, the NYHA class improved and the LVEF increased in those with reduced baseline LVEF. The values of pacing parameters were acceptable and remained stable during the follow‐up.
Stress management in aquaculture: a review of dietary interventions
Authors: Ciji Alexander , Akhtar Mohammad S.
Published: April 2021

Over the last few decades, the demand‐driven growth in aquaculture has been tremendous due to development and adoption of cutting‐edge technologies and production systems such as intensification and high input aquaculture. This growth, however, has witnessed an insurgence of various environmental and husbandry‐related stressors posing major challenges to the aquaculture sector limiting its further expansion worldwide. These stressful conditions impair the health of cultured animals and predispose them to diseases resulting in economic losses. Hence, optimizing the stress resilience of the cultured species is paramount to ensure sustainable development of aquaculture sector. Addressing the concerns of stress mitigation in aquaculture, a plethora of research investigations have been intensively carried out all over the world targeting the management of cultured environment as well as cultured species. Among various mitigation strategies, dietary interventions appear to be pliable and a sustainable approach to develop immunocompetence and stress resistance in fish as requirement of several nutrients may increase under stressful conditions. The suboptimal and/or excessive levels of several essential and non‐essential nutrients modulate the immune response and stress/disease resistance. Hence, the present review is an inclusive and informative compilation of dietary interventions for management of stress in aquaculture. This review highlights the stress‐mitigating roles of different nutritive and non‐nutritive compounds/additives such as amino acids, essential fatty acids, phospholipids, vitamins, minerals, carotenoids, different synthetic chemicals and biological derivatives from bacteria, yeast, fungi, algae, plants and animals as a promising stress management strategy to enhance the overall performance of the cultured species.
Does self‐esteem inflation mitigate mortality salience effects on suicide attitudes?
Authors: Kheibari Athena , Cerel Julie
Published: April 2021

Introduction

Suicide stigma is a major barrier to prevention and intervention efforts. Using terror management theory as the guiding framework, the present study examined whether enhancing self‐esteem would buffer against suicide stigma and lead to prosocial attitudes and behavior.

Methods

Experimental methods were utilized in the present study. After being primed with death‐related thoughts, participants were randomly assigned to one of two conditions: (1) positive feedback (experimental group) and (2) no feedback (control group). The dependent variables included (1) evaluations of a suicide decedent, (2) intentions to intervene against suicide, and (3) charitable donation behavior toward a suicide prevention organization.

Results

The most consistent findings for the self‐esteem boost hypothesis were for the interaction effects of death anxiety and self‐esteem boost for the donation allocation task and intentions to intervene against suicide. For participants who were reminded of death, the self‐esteem boost intervention mitigated the negative impact of death anxiety on donation behavior (i.e., an average difference of $16.37). Positive feedback for participants with reported low self‐esteem also led to increased willingness to intervene against suicide.

Conclusion

These findings provide some promising potential for the self‐esteem enhancement intervention to attenuate defensive reactions to suicide.
Staphylococcus epidermidisundergoes global changes in gene expression during biofilm maturation in platelet concentrates
Authors: Loza‐Correa Maria , Yousuf Basit , Ramirez‐Arcos Sandra
Published: April 2021

Background

Staphylococcus epidermidisforms surface‐attached aggregates (biofilms) when grown in platelet concentrates (PCs). Comparative transcriptome analyses were undertaken to investigate differential gene expression ofS. epidermidisbiofilms grown in PCs.

Study design and methods

TwoS. epidermidisstrains isolated from human skin (AZ22 and AZ39) and one strain isolated from contaminated PCs (ST02) were grown in glucose‐supplemented Trypticase Soy Broth (TSBg) and PCs. RNA was extracted and sequenced using Illumina HiSeq. Differential expression analysis was done using DESeq, and significantly differentially expressed genes (DEGs) were selected. DEGs were subjected to Kyoto encyclopedia of genes and genomes and Gene Ontology analyses. Differential gene expression was validated with quantitative reverse transcription‐PCR.

Results

A total of 436, 442, and 384 genes were expressed in AZ22, AZ39, and ST02, respectively. DEG analysis showed that 170, 172, and 117 genes were upregulated in PCs in comparison to TSBg, whereas 120, 135, and 89 genes were downregulated (p < .05) in mature biofilms of AZ22, AZ39, and ST02, respectively. Twenty‐seven DEGs were shared by all three strains. While 76 DEGs were shared by AZ22 and AZ39, only 34 and 21 DEGs were common between ST02, and AZ22 and AZ39, respectively. Significant transcriptional expression changes were observed in genes involved in platelet‐bacteria interaction, biofilm formation, production of virulence factors, and resistance to antimicrobial peptides and antibiotics.

Conclusion

Differential gene expression inS. epidermidisis triggered by the stressful PC storage environment. Upregulation of virulence and antimicrobial resistance genes could have clinical implications for transfusion patients.
Implementation of measures to improve blood collection center employee safety and reduce callouts during the 2019 novel coronavirus pandemic
Authors: Coberly Emily , Korich Erin , Henesy Michelle , Doerksen Kate , Young Pampee
Published: April 2021

Background

Blood collection center (BCC) employees are essential workers during the COVID‐19 pandemic. The employee callout rate, defined as the percentage of scheduled employees unable to report to work for any cause including COVID‐19 illness or asymptomatic quarantine, was tracked to determine the impact of safety measures including social distancing, masks, enhanced disinfection protocols, and temperature screening.

Study design and methods

A contact tracing and quarantine program was implemented for all employees, followed by additional safety measures including social distancing, masks, enhanced disinfection protocols, and temperature screening. The weekly callout rate was tracked nationally for 19,517 BCC employees over 9 months, from March to December 2020.

Results

Weekly employee callout rates increased after implementation of the contact tracing program due to asymptomatic employees placed into COVID‐19‐related quarantine. Mobile collections callouts increased by nearly fivefold the pre‐pandemic baseline within the first 4 weeks, peaking at 9.7% in early April. Peaks for fixed site collections (5.0%) and manufacturing (6.7%) occurred nearly simultaneously. Shortly after implementation of all safety measures, the weekly callout rate declined for all three employee groups and has remained relatively stable with a mean callout rate of 4.3% for mobile collections, 2.4% for fixed site collections, and 3.7% for manufacturing despite further increase in new COVID‐19 cases in the United States.

Conclusion

Callouts for BCC employees during the COVID‐19 pandemic initially increased, but subsequently declined and stabilized after implementation of safety measures. Since multiple interventions were implemented simultaneously, it is not possible to determine the individual impact of each measure on callout rate.
Facebook como herramienta de comunicación en procesos educativos
Authors: Ortiz Vizuete Fernando , Molina Loyola Cecilia , Ávila Solano Bolívar , Maldonado Vélez Ángela María
Published: April 2021

Este artículo se enmarca en el proyecto de investigación “Usos y aplicaciones de la Red Social Facebook en la Universidad de Cuenca”. Nos interesó conocer si facebook ha generado escenarios de aprendizaje complementarios a los procesos formales y escolarizados, o, si constituye una herramienta de comunicación en las dinámicas educativas. La metodología se basó en una encuesta aplicada a 375  estudiantes y 287 docentes de la Universidad de Cuenca, en grupos focales y en entrevistas a profundidad realizadas a profesores de diferentes facultades. El artículo analiza a  facebook  como una herramienta de mediación entre profesores y estudiantes. Se plantea la necesidad de establecer procesos más abiertos para comprender las formas cómo los estudiantes se comunican, aprenden y conviven en esta red social, que es un escenario de interactividad docente-estudiante, estudiante-estudiante, y, que se vislumbra como un espacio para establecer diálogos orientados a la generación de conocimientos compartidos.
Design and Analysis of a Novel Reconfigurable Parallel Manipulator With Kirigami-Inspired Bennett Plano-Spherical Linkages and Angular Pouch Motors
Authors: Zhang Ketao , Liu Chen
Published: April 2021

Drawing inspiration from kirigami, this article first presents the crease pattern of a kirigami model which is kinematically equivalent to a Bennett plano-spherical linkage. In terms of the screw theory, distinct closed-loop motion branches of the linkage are revealed. This article then introduces a new reconfigurable parallel manipulator with three hybrid kinematic limbs. Each limb consists of closed-loop subchain, the Bennett plano-spherical linkage, and a R(RR) serial chain. Constraints provided by the hybrid limb are explored by analyzing constraint screws of serial limbs kinematically equivalent to the hybrid limb in different motion branches. The analysis reveals motion characteristics of the moving platform when the parallel manipulator is in different motion branches. The kinematic model provides a unified mapping between joint inputs and outputs of the reconfigurable manipulator in all three motion branches. This article further presents a new inflatable angular pouch motor and fabricated a prototype using a rectangular tile origami base and adhesive fabric. The pouch motors are then integrated with 3D printed prototypes of the Bennett plano-spherical linkage and the parallel manipulator for the purpose of reconfiguring motion branches.
Socioeconomic status determines COVID-19 incidence and related mortality in Santiago, Chile
Authors: Mena Gonzalo E. , Martinez Pamela P. , Mahmud Ayesha S. , Marquet Pablo A. , Buckee Caroline O. , Santillana Mauricio
Published: April 2021

Urban socioeconomics and mortality

Santiago, Chile, is a highly segregated city with distinct zones of affluence and deprivation. This setting offers a window on how social factors propel the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic in an economically vulnerable society with high levels of income inequality. Mena
et al.
analyzed incidence and mortality attributed to SARS-CoV-2 to understand spatial variations in disease burden. Infection fatality rates were higher in lower-income municipalities because of comorbidities and lack of access to health care. Disparities between municipalities in the quality of their health care delivery system became apparent in testing delays and capacity. These indicators explain a large part of the variation in COVID-19 underreporting and deaths and show that these inequalities disproportionately affected younger people.

Science
, abg5298, this issue p.
eabg5298
Select hyperactivating NLRP3 ligands enhance the T
H
1- and T
H
17-inducing potential of human type 2 conventional dendritic cells
Authors: Hatscher Lukas , Lehmann Christian H. K. , Purbojo Ariawan , Onderka Constantin , Liang Chunguang , Hartmann Arndt , Cesnjevar Robert , Bruns Heiko , Gross Olaf , Nimmerjahn Falk , Ivanović-Burmazović Ivana , Kunz Meik , Heger Lukas , Dudziak Diana
Published: April 2021

Type 2 conventional dendritic cells mediate superior immune responses to specific inflammasome ligands.
Incompatibility Group I1 (IncI1) Plasmids: Their Genetics, Biology, and Public Health Relevance
Authors: Foley Steven L. , Kaldhone Pravin R. , Ricke Steven C. , Han Jing
Published: April 2021

Bacterial plasmids are extrachromosomal genetic elements that often carry antimicrobial resistance (AMR) genes and genes encoding increased virulence and can be transmissible among bacteria by conjugation. One key group of plasmids is the incompatibility group I1 (IncI1) plasmids that have been isolated from multiple
Enterobacteriaceae
of food animal origin and clinically ill human patients.
A Facile High-Throughput Model of Surface-Independent Staphylococcus aureus Biofilms by Spontaneous Aggregation
Authors: Cheng Terrence , Torres Nelson S. , Chen Ping , Srinivasan Anand , Cardona Sandra , Lee Grace C. , Leung Kai P. , Lopez-Ribot Jose L. , Ramasubramanian Anand K.
Published: April 2021

The canonical model of biofilm formation begins with the attachment and growth of microbial cells on a surface. While these
in vitro
models reasonably mimic biofilms formed on foreign bodies such as catheters and implants, this is not the case for biofilms formed in cystic fibrosis and chronic wound infections, which appear to present as aggregates not attached to a surface.
Household economic burden of childhood severe pneumonia in Bangladesh: a cost-of-illness study
Authors: Sultana Marufa , Alam Nur H , Ali Nausad , Faruque A S G , Fuchs George J , Gyr Niklaus , Chisti Md Jobayer , Ahmed Tahmeed , Gold Lisa
Published: April 2021

Objective

To estimate household cost of illness (COI) for children with severe pneumonia in Bangladesh.

Design

An incidence-based COI study was performed for one episode of childhood severe pneumonia from a household perspective. Face-to-face interviews collected data on socioeconomic, resource use and cost from caregivers. A micro-costing bottom-up approach was applied to calculate medical, non-medical and time costs. Multiple regression analysis was applied to explore the factors associated with COI. Sensitivity analysis explored the robustness of cost parameters.

Setting

Four urban and rural study sites from two districts in Bangladesh.

Patients

Children aged 2–59 months with severe pneumonia.

Results

1472 children with severe pneumonia were enrolled between November 2015 and March 2019. The mean age of children was 12 months (SD ±10.2) and 64% were male. The mean household cost per episode was US$147 (95% CI 141.1 to 152.7). Indirect costs were the main cost drivers (65%, US$96). Household costs for the poorest income quintile were lower in absolute terms, but formed a higher proportion of monthly income. COI was significantly higher if treatment was received from urban health facilities compared with rural health facilities (difference US$84.9, 95% CI 73.3 to 96.3). Child age, household income, healthcare facility and hospital length of stay (LoS) were significant predictors of household COI. Costs were most sensitive to hospital LoS and productivity loss.

Conclusions

Severe pneumonia in young children is associated with high household economic burden and cost varies significantly across socioeconomic parameters. Management strategies with improved accessibility are needed particularly for the poor to make treatment affordable in order to reduce household economic burden.
Successful peripheral nerve block under dexmedetomidine sedation for femoral neck fracture fixation in a 97-year-old patient
Authors: Ishida Yoshiaki , Ogura Fumiko , Kondo Satoko , Toba Yoshie
Published: April 2021

Hip fracture is a common injury in elderly patients. In Japan, the number of super-old patients—age >90 years—with hip fractures has increased drastically over time. Available strategies for anaesthetic management for hip fracture surgery include general anaesthesia, neuraxial anaesthesia and peripheral nerve block. However, general and neuraxial anaesthesia are often avoided for various reasons, particularly in elderly patients. In recent years, peripheral nerve block has proven effective in various surgical procedures. Additionally, dexmedetomidine exhibits neuroprotective effects and has been used safely in super-old patients. Herein, we demonstrate successful anaesthetic management with peripheral nerve block under dexmedetomidine sedation for open reduction and internal fixation of a femoral neck fracture in a 97-year-old patient.
Life-threatening complications of Ludwig’s angina: a series of cases in a developed country
Authors: Silva Catarina Mendes , Paixão Joana , Tavares Pedro Neves , Baptista João Pedro
Published: April 2021

Ludwig’s angina is a deep neck space infection defined as a rapidly progressive bilateral cellulitis of the submandibular space. In spite of being an uncommon entity in developed countries and the reduction of mortality and morbidity due to modern era of antibiotics, improved imaging and airway management, it is still an important and potentially life-threatening condition. The authors present 3 cases of Ludwig’s angina that occurred in a developed country, and that required admission in intensive care unit and extensive surgical and medical treatment.
What is CAR T-cell therapy?
Authors: Kew Kayleigh
Published: April 2021

The emergence of targeted and precision therapies has increased treatment options for people living with cancer. Of particular note is the development and approval of chimeric antigen receptor (CAR) T-cell therapies that involve the use of a patient’s own immune system to treat cancers that have proven resistant to other approaches. Keeping abreast of treatment changes and practice guidelines is a challenge for all healthcare professionals, and the pressure of doing so becomes most acute with innovations in cancer therapeutics that have the potential to extend or save lives. Though uncommon, step changes like CAR T-cell therapy pose a challenge, often requiring completely new ways of thinking about efficacy evidence, basic science, ethics and service delivery. At a time when patients are able and empowered to readily access information about novel and exploratory treatments, healthcare professionals need to feel informed enough to help patients with life-changing or life-limiting cancers who approach them for advice. This article gives an overview of the basic principles of CAR T-cell therapy including how it is delivered, who is eligible to receive it in the UK, and a brief outline of current evidence of its efficacy and safety. The information is intended to provide healthcare professionals with an introduction to CAR T-cell therapy to help them advise potentially eligible patients or those already undergoing treatment about what to expect.
Life course socioeconomic position and DNA methylation age acceleration in mid-life
Authors: George Anitha , Hardy Rebecca , Castillo Fernandez Juan , Kelly Yvonne , Maddock Jane
Published: April 2021

Background

Ageing biomarkers can help us better understand how well-established socioeconomic position (SEP) disparities in ageing occur. A promising new set of DNAm methylation (DNAm)-based ageing biomarkers indicate through their age acceleration (AA) measures if biological ageing is slower or faster than chronological ageing. Few studies have investigated the association between SEP and DNAm AA.

Methods

We used linear regression to examine the sex-adjusted relationships between childhood social class, adult social class, intergenerational social class change, education and adult household earnings with first (Horvath AA and Hannum AA) and second generation (PhenoAge AA and GrimAge AA) DNAm AA markers using data from the MRC National Survey of Health and Development.

Results

In the first-generation biomarkers, there was little evidence of any associations with Horvath AA but associations of childhood social class and income with Hannum AA were observed. Strong associations were seen between greater disadvantage in childhood and adult SEP and greater AA in the second generation biomarkers. For example, those with fathers in an unskilled occupational social class in childhood had 3.6 years greater PhenoAge AA (95% CI 1.8 to 5.4) than those with fathers from a professional social class. Individuals without qualifications had higher AA compared with those with higher education (4.1 years greater GrimAge AA (95% CI 3.1 to 5.0)).

Conclusion

Our findings highlight the importance of exposure to social disadvantage in childhood to the biological ageing process. The second generation clocks appear to be more sensitive to the accumulation of social disadvantage across the life course.
Social deprivation as a risk factor for COVID-19 mortality among women and men in the UK Biobank: nature of risk and context suggests that social interventions are essential to mitigate the effects of future pandemics
Authors: Woodward Mark , Peters Sanne A E , Harris Katie
Published: April 2021

Objectives

To investigate sex differences in the effects of social deprivation on COVID-19 mortality and to place these effects in context with other diseases.

Design

Prospective population-based study.

Setting

UK Biobank.

Participants

501 865 participants (54% women).

Main outcome measure

COVID-19 as the underlying cause of death.

Results

Of 472 946 participants alive when COVID-19 was first apparent in the UK (taken as 1 February 2020), 217 (34% women) died from COVID-19 over the next 10 months, resulting in an incidence, per 100 000 person years, of 100.65 (95% CI 79.47 to 121.84) for women and 228.59 (95% CI 194.88 to 262.30) for men. Greater social deprivation, quantified using the Townsend Deprivation Score, was associated with greater risk of fatal COVD-19. Adjusted for age and ethnicity, HRs for women and men, comparing those in the most with the least deprived national fifths, were 3.66 (2.82 to 4.75) for women and 3.00 (2.46 to 3.66) for men. Adjustments for key baseline lifestyle factors attenuated these HRs to 2.20 (1.63 to 2.96) and 2.62 (2.12 to 3.24), respectively. There was evidence of a log-linear trend in the deprivation–fatal COVID-19 association, of similar magnitude to the equivalent trends for the associations between deprivation and fatal influenza or pneumonia and fatal cardiovascular disease. For all three causes of death, there was no evidence of a sex difference in the associations.

Conclusions

Higher social deprivation is a risk factor for death from COVID-19 on a continuous scale, with two to three times the risk in the most disadvantaged 20% compared with the least. Similarities between the social gradients in COVID-19, influenza/pneumonia and cardiovascular disease mortality, the lack of sex differences in these effects, and the partial mediation of lifestyle factors suggest that better social policies are crucial to alleviate the general medical burden, including from the current, and potential future, viral pandemics.
Defining functional brain networks underlying obsessive–compulsive disorder (OCD) using treatment-induced neuroimaging changes: a systematic review of the literature
Authors: Bijanki Kelly R. , Pathak Yagna J. , Najera Ricardo A. , Storch Eric A. , Goodman Wayne K , Simpson H. Blair , Sheth Sameer A.
Published: April 2021

Approximately 2%–3% of the population suffers from obsessive–compulsive disorder (OCD). Several brain regions have been implicated in the pathophysiology of OCD, but their various contributions remain unclear. We examined changes in structural and functional neuroimaging before and after a variety of therapeutic interventions as an index into identifying the underlying networks involved. We identified 64 studies from 1990 to 2020 comparing pretreatment and post-treatment imaging of patients with OCD, including metabolic and perfusion, neurochemical, structural, functional and connectivity-based modalities. Treatment class included pharmacotherapy, cognitive–behavioural therapy/exposure and response prevention, stereotactic lesions, deep brain stimulation and transcranial magnetic stimulation. Changes in several brain regions are consistent and correspond with treatment response despite the heterogeneity in treatments and neuroimaging modalities. Most notable are decreases in metabolism and perfusion of the caudate, anterior cingulate cortex, thalamus and regions of prefrontal cortex (PFC) including the orbitofrontal cortex (OFC), dorsolateral PFC (DLPFC), ventromedial PFC (VMPFC) and ventrolateral PFC (VLPFC). Modulating activity within regions of the cortico-striato-thalamo-cortical system may be a common therapeutic mechanism across treatments. We identify future needs and current knowledge gaps that can be mitigated by implementing integrative methods. Future studies should incorporate a systematic, analytical approach to testing objective correlates of treatment response to better understand neurophysiological mechanisms of dysfunction.
Early life involvement in C9orf72 repeat expansion carriers
Authors: Gossink Flora , Dols Annemiek , Stek Max L , Scheltens Philip , Nijmeijer Bas , Cohn Hokke Petra , Dijkstra Anke , Van Ruissen Fred , Aalfs Cora , Pijnenburg Yolande A L
Published: April 2021

Objectives

The chromosome 9 open reading frame 72 gene (C9orf72) hexanucleotide repeat expansion (C9orf72RE) is the most common genetic cause of behavioural variant frontotemporal dementia (bvFTD). Since the onset of the C9orf72RE-associated disease is sometimes hard to define, we hypothesise that C9orf72REmay cause a lifelong neuropsychiatric vulnerability. The first aim of our study was to explore lifelong behavioural and personality characteristics in C9orf72RE. Second, we aimed to describe distinctive characteristics of C9orf72REduring disease course.

Methods

Out of 183 patients from the Amsterdam Dementia Cohort that underwent genetic testing between 2011 and 2018, 20 C9orf72REbvFTD patients and 23 C9orf72REnegative bvFTD patients were included. Patients and their relatives were interviewed extensively to chart their biography. Data analysis was performed through a mixed-methods approach including qualitative and quantitative analyses.

Results

Education, type of professional career and number of intimate partners were not different between carriers and non-carriers. Carriers were more often described by their relatives as having ‘fixed behavioural patterns in daily life’ and with limited empathy already years before onset of bvFTD symptoms. In carriers, disease course was more often characterised by excessive buying and obsessive physical exercise than in non-carriers.

Conclusion

This is the first study thoroughly exploring biographies of bvFTD patients with C9orf72RE, revealing that subtle personality traits may be present early in life. Our study suggests that C9orf72REexerts a lifelong neuropsychiatric vulnerability. This may strengthen hypotheses of links between neurodevelopmental and neurodegenerative diseases. Moreover, the presence of a distinct C9orf72RE-associated syndrome within the FTD spectrum opens doors for investigation of vulnerable neuronal networks.
Shift work is associated with positive COVID-19 status in hospitalised patients
Authors: Maidstone Robert , Anderson Simon G , Ray David W , Rutter Martin K , Durrington Hannah J , Blaikley John F
Published: April 2021

Introduction

Shift work is associated with lung disease and infections. We therefore investigated the impact of shift work on significant COVID-19 illness.

Methods

501 000 UK Biobank participants were linked to secondary care SARS-CoV-2 PCR results from Public Health England. Healthcare worker occupational testing and those without an occupational history were excluded from analysis.

Results

Multivariate logistic regression (age, sex, ethnicity and deprivation index) revealed that irregular shift work (OR 2.42, 95% CI 1.92 to 3.05), permanent shift work (OR 2.5, 95% CI 1.95 to 3.19), day shift work (OR 2.01, 95% CI 1.55 to 2.6), irregular night shift work (OR 3.04, 95% CI 2.37 to 3.9) and permanent night shift work (OR 2.49, 95% CI 1.67 to 3.7) were all associated with positive COVID-19 tests compared with participants that did not perform shift work. This relationship persisted after adding sleep duration, chronotype, premorbid disease, body mass index, alcohol and smoking to the model. The effects of workplace were controlled for in three ways: (1) by adding in work factors (proximity to a colleague combined with estimated disease exposure) to the multivariate model or (2) comparing participants within each job sector (non-essential, essential and healthcare) and (3) comparing shift work and non-shift working colleagues. In all cases, shift work was significantly associated with COVID-19. In 2017, 120 307 UK Biobank participants had their occupational history reprofiled. Using this updated occupational data shift work remained associated with COVID-19 (OR 4.48 (95% CI 1.8 to 11.18).

Conclusions

Shift work is associated with a higher likelihood of in-hospital COVID-19 positivity. This risk could potentially be mitigated via additional workplace precautions or vaccination.
Secondhand smoke exposure and oral cancer risk: a systematic review and meta-analysis
Authors: Mariano Lorena C. , Warnakulasuriya Saman , Straif Kurt , Monteiro Luís
Published: April 2021

Objectives

Inhalation of secondhand smoke (SHS) causes several diseases, including lung cancer. Tobacco smoking is a known cause of oral cancer; however, it has not been established whether SHS also causes oral cancer . The aim of this study was to evaluate the potential association between SHS exposure and the risk of oral cancer.

Methods

A systematic review and meta-analysis study (following the PRISMA guidelines) was developed to examine the studies reporting on the associations of SHS and the risk of oral cancer, employing a search strategy on electronic databases (PubMed, Web of Science, Scopus, Cochrane Library, Open Grey, and ProQuest databases for dissertations) until 10 May 2020. Meta-analyses and sensitivity analyses were performed using random-effect models. The protocol was registered in PROSPERO (CRD42020189970).

Results

Following the application of eligibility criteria, five studies were included, comprising a total of 1179 cases and 5798 controls, with 3452 individuals exposed and 3525 individuals not exposed to SHS. An overall OR of 1.51 (95% CI 1.2o to 1.91, p=0.0004) for oral cancer was observed, without significant heterogeneity (I2=0%, p=0.41). The duration of exposure of more than 10 or 15 years increased the risk of oral cancer (OR 2.07, 95% CI 1.54 to 2.79, p<0.00001), compared with non-exposed individuals, without significant heterogeneity (I2=0%, p=0.76).

Conclusions

This systematic review and meta-analysis supports a causal association between SHS exposure and oral cancer. Our results could provide guidance to public health professionals, researchers, and policymakers to further support effective SHS exposure prevention programs worldwide.
Seabed disturbance and sediment mobility due to tidal current and waves on the continental shelves of Canada
Authors: Li Michael Z. , Wu Yongsheng , Hannah Charles G. , Perrie Will A.
Published: April 2021

Waves and tidal currents can interact to produce strong seabed shear stress and mobilization of sediments on continental shelves. Modelled wave and tidal current data for a 3-year period were used in a combined-flow sediment transport model to simulate the seabed shear stresses and the mobilization of uniform medium sand on the continental shelves of Canada. The modelling results are presented to establish the first national framework of seabed disturbance and sediment mobility on the continental shelves of Canada. Strong waves and tidal currents on the Canadian continental shelves produce mean bed shear velocity >5 cm·s−1. Medium sand can be mobilized >50% of the time over many areas on the shelves. The mobilization by tidal currents occurs over 36% and by waves over 50% of the shelf area, demonstrating that mobilization of sediments is dominated by waves on the Canadian continental shelves. Combined shear stresses due to wave and tidal current interaction further increase sediment mobilization to over 68% of the shelf area. The spatial variation of the relative importance of wave and tidal disturbances allows classification of the continental shelves into six disturbance types. Innovative Seabed Disturbance (SDI) and Sediment Mobility (SMI) indices are proposed to quantify the seabed exposure to oceanographic processes and sediment mobilization, incorporating both the magnitude and frequency of these processes. The proposed SDI and SMI, together with the disturbance type classification, can be used as standard parameters to best quantify seabed disturbance and sediment mobility on other shelves of the world.
Early-stage dark treatment promotes hypocotyl elongation associated with varying effects on yield and quality in sunflower and arugula microgreens
Authors: Kong Yun , Zheng Youbin
Published: April 2021

Microgreens growing under electric (artificial) lighting in controlled environments often have short hypocotyls, which can be difficult for machine harvest. To investigate whether early-stage dark treatment can promote hypocotyl elongation without compromising microgreen yield and quality, two different seed-size species, sunflower (Helianthus annuus ‘Black oil’) and arugula (Eruca sativa ‘Rocket’), were tested. Seeds of sunflower and arugula were sown in pots, and the pots were placed inside support trays. During the first 5 days after seeding, half of the pots per species within each tray were covered with an upside-down black tray as dark treatment, and another half were kept under light. The light treatment was provided by continuous (24-h) lighting with a combination of red (85%) and blue (15%) light-emitting diodes at a photosynthetic photo flux density of around 100 μmol·m−2·s−1. After 5 days of dark treatment, the black covers were removed and the plants were grown under the above lighting treatment till harvesting. The microgreens were harvested at 7 d and 12 d after seeding for sunflower and arugula, respectively. Early-stage dark treatment promoted hypocotyl elongation by 26% and 28% for sunflower and arugula, respectively. Microgreen yield was increased by 13% for sunflower and reduced by 24% for arugula under dark treatment. Dark treatment increased cotyledon succulence by 14% for sunflower, but reduced cotyledon size by about 25% for arugula despite increases in red color and succulence of arugula hypocotyls. For both species, cotyledon color and soluble solids content were not affected by dark treatment.
Integral foliated simplicial volume and circle foliations
Authors: Campagnolo Caterina , Corro Diego
Published: April 2021

We show that the integral foliated simplicial volume of a compact oriented smooth manifold with a regular foliation by circles vanishes.
Comparison of Common Ground Models for Human--Computer Dialogue
Authors: Rothwell Clayton D. , Shalin Valerie L. , Romigh Griffin D.
Published: April 2021

Common ground processes [26] can improve performance in communication tasks [72, 42, 43, 24], and understanding these processes will likely benefit human--computer dialogue interfaces. However, there are multiple proposed theories with different implications for interface design. Fusaroli and Tylén [40] achieved a direct comparison by designing two models: one based on alignment theory and the other based on complementarity theory that encapsulated interpersonal synergy and audience design. The current research used these models, extending them to differentiate between interpersonal synergy and audience design. Few studies have tested multiple common ground models against tasks representative of envisioned human--computer interaction (HCI) applications. We report on four such tests, which allowed examination of generalizability of findings. Results supported the complementarity models over the alignment model, and were suggestive of the audience design variant of complementarity, providing guidance for HCI design that differs from contemporary approaches.