bluuebunny/crossref_metadata_2025 huggingface dataset:
Mortality among twin individuals exposed to loss of a co-twin
Authors: Song Huan , Shang Yanan , Fang Fang , Almqvist Catarina , Pedersen Nancy L , Magnusson Patrik K E , Larsson Henrik , Valdimarsdóttir Unnur A
Published: July 2022

Background

Although the death of a child, sibling or spouse has been associated with elevated risk of mortality, less is known about the survival of twin siblings exposed to a co-twin loss.

Methods

In a Swedish population-based sibling-matched cohort, we compared the mortality of 5548 twin individuals who lost their co-twin between 1932 and 2011 with that of 27 740 age-matched and sex-matched twin individuals without such a loss and 6772 full siblings of these exposed twin individuals. Cox regression models were used to estimate the hazard ratios (HRs) of all-cause and cause-specific mortality.

Results

We found increased risk of all-cause mortality among twin individuals exposed to a co-twin loss compared with matched unexposed twin individuals (HR = 1.30, 95% CI: 1.18–1.43) and their full siblings (HR = 1.10, 95% CI: 0.96–1.27) after adjusting for multiple covariates. The all-cause mortality risk was greater for loss of a co-twin due to unnatural deaths (HR = 1.54, 95% CI: 1.17–2.03) than natural deaths (HR = 1.26, 95% CI: 1.14–1.40). For cause-specific mortality, co-twin loss was associated with a higher risk of unnatural deaths both among twin individuals who lost their co-twin due to unnatural deaths (HR = 1.98, 95% CI: 1.27–3.10) and those whose loss was due to natural deaths (HR = 1.48, 95% CI: 1.07–2.06). The risk elevations were generally stronger for loss of a monozygotic co-twin than loss of a dizygotic co-twin.

Conclusion

Loss of a co-twin, especially a monozygotic co-twin, was associated with increased mortality, particularly of unnatural causes, among the surviving twin individuals. The excess mortality is likely attributable to both shared disease susceptibility within the twin pair and the adverse health sequelae of bereavement.
Long-term exposure to low-level air pollution, genetic susceptibility and risk of dementia
Authors: Ma Hao , Li Xiang , Zhou Tao , Wang Mengying , Heianza Yoriko , Qi Lu
Published: July 2022

Background

We aimed to assess the association between low-level air pollution and the risk of dementia, and examine the modification effect by genetic susceptibility on the relationship.

Methods

A total of 164 447 participants who were free of dementia at baseline and aged ≥60 years were included. Annual average concentrations of particulate matter (PM) with diameters of ≤2.5 μm (PM2.5), between 2.5 and 10 μm (PMcoarse), PM2.5 absorbance and nitrogen dioxides (NO2) were evaluated using the Land Use Regression models. Cox proportional hazards regression was used to estimate the association between air pollutants and incident dementia.

Results

The adjusted hazard ratio (HR) of dementia for a 5-μg/m3 increase in NO2 was 1.09 (95% CI, 1.05–1.14); the adjusted HR of dementia for a 1-μg/m3 increase in PM2.5 was 1.10 (1.04–1.17). Such significant associations were present even within concentration ranges well below the present World Health Organization, US and European annual mean limit values. In addition, higher PM2.5 absorbance, a marker closely related to motorized traffic, was associated with higher risk of dementia. We found the risk of dementia associated with a combination of air pollutants (NO2 or PM2.5) and high genetic susceptibility (APOE-ε4 alleles or overall genetic susceptibility) was greater than the addition of the risk associated with each individual factor, indicating significant interactions on an additive scale (all P-interaction < 0.05).

Conclusion

Long-term exposure to PM2.5 or NO2, even at relatively low levels, is associated with a higher risk of dementia. Air pollution may additively interact with the genetic susceptibility on dementia risk.
The influence of adverse drug effects on health-related quality of life in chronic obstructive pulmonary disease patients
Authors: Altawalbeh Shoroq M , Almomani Basima A , Alefan Qais , Mohammad Momany Suleiman , Al-Share Qusai Y
Published: July 2022

Objectives

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Concerns have been raised about the influence of adverse drug effects on patient’s health-related quality of life (HRQoL) in COPD patients. This study aimed to evaluate the impact of COPD treatment-related adverse effects on HRQoL in COPD patients.

Methods

In a cross-sectional study, COPD patients aged 40 years or older were identified and interviewed during their hospital visits. The EuroQol 5 Dimension 5 Level (EQ-5D-5L) questionnaire was used for evaluating HRQoL. Potential treatment adverse effects were evaluated as experienced by participants during the last 2 weeks preceding the interview. The intensity of adverse effects was reported in the following categories: never, mild, moderate and severe. Multivariable linear regression model was performed to evaluate the influence of adverse drug effects on utility scores as an indicator of HRQoL.

Key findings

A total of 203 patients diagnosed with COPD were recruited in the current study. The mean utility score of the study sample was 0.68 (SD = 0.36). Moderate-severe constipation, moderate-severe confusion, mild urinary hesitation, moderate-severe urinary hesitation, moderate-severe dry eyes and moderate-severe drowsiness were significant predictors/determinants for the average utility scores (coefficients were −0.099, −0.191, −0.111, −0.157 and −0.144, respectively). In addition, having higher COPD Assessment Test scores and severe disease was negatively associated with average utility scores (coefficients were −0.287 and −0.124, respectively).

Conclusions

Higher intensity of COPD treatment-related adverse effects has a negative influence on HRQoL in COPD patients. Anticholinergic drug effects are of concern in COPD adults’ population.
Swedish community pharmacy employees’ knowledge and experience of substandard and falsified medical products: a cross-sectional descriptive survey
Authors: Persson A , Troein M , Lundin S , Midlöv P , Lenander C
Published: July 2022

Objectives

Substandard and falsified medical products are, according to the World Health Organization, a global threat to public health. To evaluate if community pharmacy employees can guide the public to safer medication purchases, their knowledge and experience about SF medical products was examined.

Methods

A digital questionnaire was distributed to the five dominating pharmacy companies in Sweden, representing 97% of the community pharmacies (1391/1433), giving the theoretical possibility of reaching 6200 employees. Three companies published a link to the questionnaire on their intranets, one distributed the link via e-mail to the responsible pharmacist for quality and knowledge, respectively. The fifth company did not pass on, due to technical problems. Employees aged 18 years or older with customer contact were invited to participate.

Key findings

The questionnaire was available for 74% of all community pharmacies (1067/1433), having approximately 4900 employees with customer contact. The response rate was 5% (228/4900). Of the respondents, 89% were pharmacists (203/228), 84% were women (191/228) and 43% were 35-49 years (98/228). The respondents worked in pharmacies of different size, located both in rural and urban areas. The definition of substandard and falsified medical products was known by 182 of the 228 respondents (80%) and the main source of knowledge was media (61%, 111/228). The common European logo for authorized online pharmacies was not recognized by 74% (169/228).

Conclusions

For pharmacy employees to guide the public to safer medication purchases, knowledge about substandard and falsified medical products needs to be enhanced specially about legal international e-commerce.
Cost-effectiveness analysis of implementing a secondary prevention programme in those patients who visited an emergency department for drug-related problems
Authors: Ruiz-Ramos Jesus , Juanes-Borrego Ana , Puig-Campany Mireia , Blazquez-Andión Marta , López-Vinardell Laia , Gilabert-Perramon Antonio , Guiu-Segura Josep María , Mangues-Bafalluy Maria Antonia
Published: July 2022

Objective

To evaluate the cost-effectiveness of a secondary prevention programme in patients admitted to the emergency department due to drug-related problems (DRPs).

Methods

A decision model compared costs and outcomes of patients with DRPs admitted to the emergency department. Model variables and costs, along with their distributions, were obtained from the trial results and literature. The study was performed from the perspective of the National Health System including only direct costs.

Key findings

The implementation of a secondary prevention programme for DRPs reduces costs associated with emergency department revisits, with an annual net benefit of €87 639. Considering a mortality rate attributable to readmission of 4.7%, the cost per life-years gained (LYG) with the implementation of this programme was €2205. In the short term, the reduction in the number of revisits following the programme implementation was the variable that most affected the model, with the benefit threshold value corresponding to a relative reduction of 12.4% of the number of revisits of patients with DRPs to obtain benefits.

Conclusions

Implementing a secondary prevention programme is cost-effective for patients with DRPs admitted to the emergency department. Implementation costs will be exceeded by reducing revisits to the emergency department.
Population pharmacokinetics of apramycin from first-in-human plasma and urine data to support prediction of efficacious dose
Authors: Zhao Chenyan , Chirkova Anna , Rosenborg Staffan , Palma Villar Rodrigo , Lindberg Johan , Hobbie Sven N , Friberg Lena E
Published: July 2022

Background

Apramycin is under development for human use as EBL-1003, a crystalline free base of apramycin, in face of increasing incidence of multidrug-resistant bacteria. Both toxicity and cross-resistance, commonly seen for other aminoglycosides, appear relatively low owing to its distinct chemical structure.

Objectives

To perform a population pharmacokinetic (PPK) analysis and predict an efficacious dose based on data from a first-in-human Phase I trial.

Methods

The drug was administered intravenously over 30 min in five ascending-dose groups ranging from 0.3 to 30 mg/kg. Plasma and urine samples were collected from 30 healthy volunteers. PPK model development was performed stepwise and the final model was used for PTA analysis.

Results

A mammillary four-compartment PPK model, with linear elimination and a renal fractional excretion of 90%, described the data. Apramycin clearance was proportional to the absolute estimated glomerular filtration rate (eGFR). All fixed effect parameters were allometrically scaled to total body weight (TBW). Clearance and steady-state volume of distribution were estimated to 5.5 L/h and 16 L, respectively, for a typical individual with absolute eGFR of 124 mL/min and TBW of 70 kg. PTA analyses demonstrated that the anticipated efficacious dose (30 mg/kg daily, 30 min intravenous infusion) reaches a probability of 96.4% for a free AUC/MIC target of 40, given an MIC of 8 mg/L, in a virtual Phase II patient population with an absolute eGFR extrapolated to 80 mL/min.

Conclusions

The results support further Phase II clinical trials with apramycin at an anticipated efficacious dose of 30 mg/kg once daily.
Tasks as needs: reframing the paradigm of clinical natural language processing research for real-world decision support
Authors: Lederman Asher , Lederman Reeva , Verspoor Karin
Published: July 2022

Electronic medical records are increasingly used to store patient information in hospitals and other clinical settings. There has been a corresponding proliferation of clinical natural language processing (cNLP) systems aimed at using text data in these records to improve clinical decision-making, in comparison to manual clinician search and clinical judgment alone. However, these systems have delivered marginal practical utility and are rarely deployed into healthcare settings, leading to proposals for technical and structural improvements. In this paper, we argue that this reflects a violation of Friedman’s “Fundamental Theorem of Biomedical Informatics,” and that a deeper epistemological change must occur in the cNLP field, as a parallel step alongside any technical or structural improvements. We propose that researchers shift away from designing cNLP systems independent of clinical needs, in which cNLP tasks are ends in themselves—“tasks as decisions”—and toward systems that are directly guided by the needs of clinicians in realistic decision-making contexts—“tasks as needs.” A case study example illustrates the potential benefits of developing cNLP systems that are designed to more directly support clinical needs.
Effects of Long-Term Low Oxygen Storage Treatment on Survival of Rice Weevil (Sitophilus oryzae) and Confused Flour Beetle (Tribolium confusum)
Authors: Liu Yong-Biao
Published: July 2022

There is a need for alternative treatments for postharvest pests on stored products. In this study, 45-d long-term controlled atmosphere (CA) treatments with 3, 5, 6.5, and 8% O2 were studied to determine effects on survival and development of rice weevil (Sitophilus oryzae) and confused flour beetle (Tribolium confusum) eggs and susceptibility of different life stages to a 14-d 5% O2 treatment. Low oxygen treatments were effective against S. oryzae and T. confusum. The 45-d CA treatments with 6.5, 5, and 3% O2 resulted in 0.26, 0.004, and 0% survival rates from egg to adult respectively for S. oryzae and 6.51, 0.14, and 0% survival rates from egg to later stages respectively for T. confusum. For both species, eggs were more susceptible to low oxygen treatment than larvae or pupae. A 14-d CA treatment with 5% O2 resulted in 4.9 and 3.3% survival of eggs of S. oryzae and T. confusum, respectively, as compared with over 50% survival of larvae and pupae for both species. S. oryzae adults, however, were very susceptible to low oxygen treatment and 14-d exposure to 5% O2 atmosphere resulted in zero survival. In contrast, the 14-d exposure to 5% O2 atmosphere resulted in over 94% survival for T. confusum adults. This study suggested there were considerable differences between stored product insects in susceptibility to low oxygen treatment and that long-term CA storage treatments with a low oxygen level of ≤6.5 and ≤5% have potential in controlling S. oryzae and T. confusum, respectively.
Shifting Wrongs to Rights: Lessons in Human Rights from the Situation of Mothers Impacted by Albinism in Africa
Authors: Ibhawoh Bonny , Reimer-Kirkham Sheryl , Ero Ikponwosa , Mgijima-Konopi Innocentia , Beaman Lori , Senkoro Perpetua , Astle Barbara , Strobell Emma , Imafidon Elvis
Published: July 2022

Debates about legitimizing human rights in Africa have centred on making universal human rights principles relevant to local social and cultural contexts. Localizing human rights norms requires seeing human rights in terms of relevance to specific situations rather than as the application of abstract principles. In this paper, scholars and advocates analyse the challenges in the practice of human rights, with a focus on mothers impacted by albinism, whether as mothers of children with albinism or as mothers with albinism themselves. Women and girls impacted by albinism are particularly vulnerable to human rights violations and reflect the unfulfilled promise of the United Nations principle to ‘Leave no one behind’. On account of intersecting factors—including denial of humanity; gendered stigma, discrimination and disenfranchisement; lack of access to the social determinants of health; and violence—mothers impacted by albinism are truly amongst those ‘furthest behind’. Drawing on the frameworks of vernacularization and culturalization, we conceptualize and contextualize human rights in relation to the unique experiences of mothers impacted by albinism in Tanzania, South Africa, and Ghana. Our analysis takes up four particularities that pose challenges to protecting the rights of mothers impacted by albinism: personhood as foundation for human rights; the communal nature of human rights; proportionality and human rights; and the intersectional nature of human rights. These particularities shed light on human rights practice for mothers impacted by albinism and carry implications for human rights practice more broadly.
Effect of radioiodine therapy under thyroid hormone withdrawal on health-related quality of life in patients with differentiated thyroid cancer
Authors: Ming Hui , Yu Hui , Liu Yangbao , Yang Lihua , Chen Yuanhao
Published: July 2022

Objective

To investigate the effect of radioactive iodine therapy under thyroid hormone withdrawal in differentiated thyroid cancer patients on health-related quality of life.

Methods

Patients who were diagnosed with differentiated thyroid cancer after thyroidectomy were involved in this study. All of them were managed with thyroid hormone withdrawal. Health-related quality of life was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and its thyroid cancer module at three different time points. Changes in health-related quality of life were evaluated by Wilcoxon and Kruskal–Wallis tests. Univariable logistic regression analysis was used to determine social-demographic and clinical factors associated with worse health-related quality of life.

Results

A total of 99 differentiated thyroid cancer patients were involved in this study. Changes in health-related quality of life at different time points showed that 1 month post-radioactive iodine treatment, an improvement in nausea and vomiting, insomnia and appetite loss was observed. Impairments of global health, role, cognitive and social function and problems of discomfort in the head and neck, voice concerns, dry mouth, fatigue, pain, dyspnea, thyroid fatigue, fear, tingling or numbness, joint pain and shoulder function increased after radioactive iodine treatment. Univariable logistic regression analysis demonstrated potential factors associated with worse health-related quality of life. Thyroid stimulating hormone and parathyroid hormone levels were more sensible to changes in functional domain. Patients aged ≥55-year-old, with annual income under ¥50 000, low parathyroid hormone and pT4 tumour stage experienced higher changes in symptom scales after radioactive iodine treatment.

Conclusion

After radioactive iodine treatment, differentiated thyroid cancer patients experienced negative health-related quality of life, and most of these impairments might not recover in the short term. Thyroid stimulating hormone and parathyroid hormone levels, annual income and pT tumours stage were independent risk factors for decreased health-related quality of life.
Complete mesocolic excision in comparison with conventional surgery for right colon cancer: a nationwide multicenter study of the Italian Society of Surgical Oncology colorectal cancer network (CoME-in trial). Study protocol for a randomized controlled trial
Authors: Degiuli Maurizio , Solej Mario , Resendiz Aguilar Hogla Aridai , Marchiori Giulia , Reddavid Rossella
Published: July 2022

Complete mesocolic excision with central vascular ligation, or simply CME, includes the sharp dissection along the mesocolic visceral and parietal layers, with the ligation of the main vessels at their origins. To date, there is low evidence on its safety and efficacy. This is a study-protocol of a multicenter, randomized, superiority trial in patients with right-sided colon cancer. It aims to investigate whether the complete mesocolic excision improves the oncological outcomes as compared with conventional right hemicolectomy, without worsening early outcomes. Data on efficacy and safety of complete mesocolic excision are available only from a large trial recruiting eastern patients and from a low-volume single-center western study. No results on survival are still available. For this reason, complete mesocolic excision continues to be a controversial topic in daily practice, particularly in western world. This new nationwide multicenter large-volume trial aims to provide further data on western patients, concerning both postoperative and survival outcomes.
Promoting Equity in Health Care through Human Flourishing, Justice, and Solidarity
Authors: Jotterand Fabrice , Spellecy Ryan , Homan Mary , Derse Arthur R
Published: July 2022

In this article, we develop a non-rights-based argument based on beneficence (i.e., the welfare of individuals and communities) and justice as the disposition to act justly to promote equity in health care resource allocation. To this end, we structured our analysis according to the following main sections. The first section examines the work of Amartya Sen and his equality of capabilities approach and outlines a framework of health care as a fundamental human need. In the subsequent section, we provide a definition of health equity based on the moral imperative to guarantee that every individual ought to have the freedom to pursue health goals and well-being. In the later part of the article, we outline a non-right approach to health care based on three pillars: (1) human flourishing, (2) justice as a disposition not a process, and (3) solidarity.
Clinical Presentation and Severity of Adenovirus Detection Alone vs Adenovirus Co-detection With Other Respiratory Viruses in US Children With Acute Respiratory Illness from 2016 to 2018
Authors: Probst Varvara , Spieker Andrew J , Stopczynski Tess , Stewart Laura S , Haddadin Zaid , Selvarangan Rangaraj , Harrison Christopher J , Schuster Jennifer E , Staat Mary A , McNeal Monica , Weinberg Geoffrey A , Szilagyi Peter G , Boom Julie A , Sahni Leila C , Piedra Pedro A , Englund Janet A , Klein Eileen J , Michaels Marian G , Williams John V , Campbell Angela P , Patel Manish , Gerber Susan I , Halasa Natasha B
Published: July 2022

Background

Human adenovirus (HAdV) is commonly associated with acute respiratory illnesses (ARI) in children and is also frequently co-detected with other viral pathogens. We compared clinical presentation and outcomes in young children with HAdV detected alone vs co-detected with other respiratory viruses.

Methods

We used data from a multicenter, prospective, viral surveillance study of children seen in the emergency department and inpatient pediatric settings at seven US sites. Children less than 18 years old with fever and/or respiratory symptoms were enrolled between 12/1/16 and 10/31/18 and tested by molecular methods for HAdV, human rhinovirus/enterovirus (HRV/EV), respiratory syncytial virus (RSV), parainfluenza (PIV, types 1–4), influenza (flu, types A-C), and human metapneumovirus (HMPV). Our primary measure of illness severity was hospitalization; among hospitalized children, secondary severity outcomes included oxygen support and length of stay (LOS).

Results

Of the 18,603 children enrolled, HAdV was detected in 1,136 (6.1%), among whom 646 (56.9%) had co-detection with at least one other respiratory virus. HRV/EV (n = 293, 45.3%) and RSV (n = 123, 19.0%) were the most frequent co-detections. Children with HRV/EV (aOR = 1.61; 95% CI = [1.11–2.34]), RSV (aOR = 4.48; 95% CI = [2.81–7.14]), HMPV (aOR = 3.39; 95% CI = [1.69–6.77]), or ≥ 2 co-detections (aOR = 1.95; 95% CI = [1.14–3.36]) had higher odds of hospitalization compared to children with HAdV alone. Among hospitalized children, HAdV co-detection with RSV or HMPV was each associated with higher odds of oxygen support, while co-detection with PIV or influenza viruses was each associated with higher mean LOS.

Conclusions

HAdV co-detection with other respiratory viruses was associated with greater disease severity among children with ARI compared to HAdV detection alone.
The African ‘Other’ as Displaced Enslaved and Refugee: Internal Borders across Time and Place
Authors: Olwig Karen Fog
Published: July 2022

Taking its point of departure in two historically separate legal cases involving the right to care for kin this article compares the perception and treatment of two groups subjected to forced migration—enslaved Africans and their descendants in the former Danish West Indian colonial society and African refugees in present-day Danish welfare society. Drawing on Balibar’s notion of ‘internal borders’ it demonstrates the key role of ‘the Other’ in the management of displaced people in contexts of structural inequality and their contradictory position of being legally embedded but socially detached in the society in which they are placed. This comparative historical lens illuminates how, across time and place, family and kin ties can figure as sites of contention between universal, ideal, morally accepted human rights and the actual rights bestowed by local authorities, whether in colonial plantation societies based on enslavement or in modern welfare states.
Formation of black widows through ultracompact X-ray binaries with He star companions
Authors: Guo Yunlang , Wang Bo , Han Zhanwen
Published: July 2022

Black widows (BWs) are a type of eclipsing millisecond pulsars (MSPs) with companion masses $M_2\lesssim 0.05\, \rm M_\odot$, which can be used to study the accretion history and the radiation of pulsars, as well as the origin of isolated MSPs. Recent observations indicate that there are two subtypes of BWs. One is the BWs with $M_2 \sim 0.01\!-\!0.05\, \rm M_\odot$, whereas another with $M_2 \lesssim 0.01\, \rm M_\odot$. However, the origin of the latter is still highly uncertain. In this paper, we investigated the formation of BWs with $M_2 \lesssim 0.01\, \rm M_\odot$ through ultracompact X-ray binaries (UCXBs) with He star companions, in which a neutron star (NS) accretes material from a He star through Roche lobe overflow. By considering different He star masses and evaporation efficiencies with the stellar evolution code Modules for Experiments in Stellar Astrophysics (mesa ), we evolved a series of NS+He star systems that can undergo UCXB stage. This channel can explain the formation of the BWs with $M_2 \lesssim 0.01\, \rm M_\odot$ within the Hubble time, especially three widely studied BWs, i.e. PSRs J1719−1438, J2322−2650, and J1311−3430. We found that X-ray irradiation feedback does not affect the evolutionary tracks of evaporation process. The simulations indicate that the UCXBs with He star companions are the potential progenitors of isolated MSPs, and that the origin of BWs with $M_2 \lesssim 0.01\, \rm M_\odot$ is different with another subtype of BWs. In addition, this work suggests that the BWs with $M_2 \lesssim 0.01\, \rm M_\odot$ may not be produced by redback systems.
Role of EXO1 nuclease activity in genome maintenance, the immune response and tumor suppression in Exo1D173A mice
Authors: Wang Shanzhi , Lee Kyeryoung , Gray Stephen , Zhang Yongwei , Tang Catherine , Morrish Rikke B , Tosti Elena , van Oers Johanna , Amin Mohammad Ruhul , Cohen Paula E , MacCarthy Thomas , Roa Sergio , Scharff Matthew D , Edelmann Winfried , Chahwan Richard
Published: July 2022

DNA damage response pathways rely extensively on nuclease activity to process DNA intermediates. Exonuclease 1 (EXO1) is a pleiotropic evolutionary conserved DNA exonuclease involved in various DNA repair pathways, replication, antibody diversification, and meiosis. But, whether EXO1 facilitates these DNA metabolic processes through its enzymatic or scaffolding functions remains unclear. Here, we dissect the contribution of EXO1 enzymatic versus scaffolding activity by comparing Exo1DA/DA mice expressing a proven nuclease-dead mutant form of EXO1 to entirely EXO1-deficient Exo1−/− and EXO1 wild type Exo1+/+ mice. We show that Exo1DA/DA and Exo1–/– mice are compromised in canonical DNA repair processing, suggesting that the EXO1 enzymatic role is important for error-free DNA mismatch and double-strand break repair pathways. However, in non-canonical repair pathways, EXO1 appears to have a more nuanced function. Next-generation sequencing of heavy chain V region in B cells showed the mutation spectra of Exo1DA/DA mice to be intermediate between Exo1+/+ and Exo1–/– mice, suggesting that both catalytic and scaffolding roles of EXO1 are important for somatic hypermutation. Similarly, while overall class switch recombination in Exo1DA/DA and Exo1–/– mice was comparably defective, switch junction analysis suggests that EXO1 might fulfill an additional scaffolding function downstream of class switching. In contrast to Exo1−/− mice that are infertile, meiosis progressed normally in Exo1DA/DA and Exo1+/+ cohorts, indicating that a structural but not the nuclease function of EXO1 is critical for meiosis. However, both Exo1DA/DA and Exo1–/– mice displayed similar mortality and cancer predisposition profiles. Taken together, these data demonstrate that EXO1 has both scaffolding and enzymatic functions in distinct DNA repair processes and suggest a more composite and intricate role for EXO1 in DNA metabolic processes and disease.
Ψ-Footprinting approach for the identification of protein synthesis inhibitor producers
Authors: Handel Franziska , Kulik Andreas , Wex Katharina W , Berscheid Anne , Saur Julian S , Winkler Anika , Wibberg Daniel , Kalinowski Jörn , Brötz-Oesterhelt Heike , Mast Yvonne
Published: July 2022

Today, one of the biggest challenges in antibiotic research is a targeted prioritization of natural compound producer strains and an efficient dereplication process to avoid undesired rediscovery of already known substances. Thereby, genome sequence-driven mining strategies are often superior to wet-lab experiments because they are generally faster and less resource-intensive. In the current study, we report on the development of a novel in silico screening approach to evaluate the genetic potential of bacterial strains to produce protein synthesis inhibitors (PSI), which was termed the protein synthesis inhibitor ('psi’) target gene footprinting approach = Ψ-footprinting. The strategy is based on the occurrence of protein synthesis associated self-resistance genes in genome sequences of natural compound producers. The screening approach was applied to 406 genome sequences of actinomycetes strains from the DSMZ strain collection, resulting in the prioritization of 15 potential PSI producer strains. For twelve of them, extract samples showed protein synthesis inhibitory properties in in vitro transcription/translation assays. For four strains, namely Saccharopolyspora flava DSM 44771, Micromonospora aurantiaca DSM 43813, Nocardioides albertanoniae DSM 25218, and Geodermatophilus nigrescens DSM 45408, the protein synthesis inhibitory substance amicoumacin was identified by HPLC-MS analysis, which proved the functionality of the in silico screening approach.
Estimating genotypic richness and proportion of identical multi-locus genotypes in aquatic microalgal populations
Authors: Sassenhagen Ingrid , Erdner Deana L , Lougheed Bryan C , Richlen Mindy L , SjÖqvist Conny
Published: July 2022

The majority of microalgal species reproduce asexually, yet population genetic studies rarely find identical multi-locus genotypes (MLG) in microalgal blooms. Instead, population genetic studies identify large genotypic diversity in most microalgal species. This paradox of frequent asexual reproduction but low number of identical genotypes hampers interpretations of microalgal genotypic diversity. We present a computer model for estimating, for the first time, the number of distinct MLGs by simulating microalgal population composition after defined exponential growth periods. The simulations highlighted the effects of initial genotypic diversity, sample size and intraspecific differences in growth rates on the probability of isolating identical genotypes. We estimated the genotypic richness for five natural microalgal species with available high-resolution population genetic data and monitoring-based growth rates, indicating 500 000 to 2 000 000 distinct genotypes for species with few observed clonal replicates (<5%). Furthermore, our simulations indicated high variability in genotypic richness over time and among microalgal species. Genotypic richness was also strongly impacted by intraspecific variability in growth rates. The probability of finding identical MLGs and sampling a representative fraction of genotypes decreased noticeably with smaller sample sizes, challenging the detection of differences in genotypic diversity with typical isolate numbers in the field.
Quis judicabit ipsos judices? A case study on the dynamics of competitive funding panel evaluations
Authors: Santos João M
Published: July 2022

Securing research funding is essential for all researchers. The standard evaluation method for competitive grants is through evaluation by a panel of experts. However, the literature notes that peer review has inherent flaws and is subject to biases, which can arise from differing interpretations of the criteria, the impossibility for a group of reviewers to be experts in all possible topics within their field, and the role of affect. As such, understanding the dynamics at play during panel evaluations is crucial to allow researchers a better chance at securing funding, and also for the reviewers themselves to be aware of the cognitive mechanisms underlying their decision-making. In this study, we conduct a case study based on application and evaluation data for two social sciences panels in a competitive state-funded call in Portugal. Using a mixed-methods approach, we find that qualitative evaluations largely resonate with the evaluation criteria, and the candidate’s scientific output is partially aligned with the qualitative evaluations, but scientometric indicators alone do not significantly influence the candidate’s evaluation. However, the polarity of the qualitative evaluation has a positive influence on the candidate’s evaluation. This paradox is discussed as possibly resulting from the occurrence of a halo effect in the panel’s judgment of the candidates. By providing a multi-methods approach, this study aims to provide insights that can be useful for all stakeholders involved in competitive funding evaluations.
Understanding why civil servants are reluctant to carry out transition tasks
Authors: Braams Rik B , Wesseling Joeri H , Meijer Albert J , Hekkert Marko P
Published: July 2022

The transition literature attributes various transition tasks to government to support socio-technical transitions toward overcoming societal challenges. It is, however, difficult for civil servants to execute these transition tasks, because they partly conflict with Public Administration (PA) traditions that provide legitimacy to their work. This dilemma is discussed in neither the transition literature nor the PA literature. In this paper, we ask civil servants about the normative arguments that reflect their role perception within the institutional structures of their ministry, when it comes to executing transition tasks. We see these situated and enacted normative arguments and underlying assumptions as implicit rules determining legitimacy. The arguments civil servants used confirm that transition tasks are currently difficult to execute within the civil service. We found seven institutionalized rules that explain this difficulty and highlight the inadequacy of civil servants to adhere to the PA traditions while trying to execute transition tasks.
Modest Dress at Work as Lived Religion: Women’s Dress in Religious Work Contexts in Saudi Arabia and the UK
Authors: Aune Kristin , Lewis Reina , Molokotos-Liederman Lina
Published: July 2022

This article explores how women in religious workplaces respond to organizational norms of and requirements for modest dress and behavior, both implicit and explicit. It compares two case studies: women working for faith-based organizations (FBOs) in the UK, and women working for secular organizations who travel for work to Saudi Arabia, where the state requirement to dress modesty meant wearing an abaya (slightly relaxed in 2019). Data come from semi-structured interviews with 43 women: 21 who travelled from the UK to Saudi Arabia and 22 who work in UK FBOs. It examines three themes: how women adapt to forms of modest dress, how they navigate dress regulation, and how they negotiate habitus and authenticity. The article proposes that women’s modest dress in workplaces governed by religious codes be understood as a form of lived religious practice and one that raises dilemmas of habitus and authenticity.
A toxicological profile of silica nanoparticles
Authors: Liu James Y , Sayes Christie M
Published: July 2022

Humans are regularly exposed to silica nanoparticles in environmental and occupational contexts, and these exposures have been implicated in the onset of adverse health effects. Existing reviews on silica nanoparticle toxicity are few and not comprehensive. There are natural and synthetic sources by which crystalline and amorphous silica nanoparticles are produced. These processes influence physiochemical properties, which are factors that can dictate toxicological effects. Toxicological assessment includes exposure scenario (e.g. environmental, occupational), route of exposure, toxicokinetics, and toxicodynamics. Broader considerations include pathology, risk assessment, regulation, and treatment after injury. This review aims to consolidate the most relevant and up-to-date research in these areas to provide an exhaustive toxicological profile of silica nanoparticles.
Reminiscence About Work Life in Retirement: What Is Remembered? Why Might it Matter?
Authors: Hommelhoff Sabine , Leickert Tina , Liao Hsiao-Wen
Published: July 2022

Retirement and reminiscence research prosper largely independent of another. The current research integrates both perspectives to explore what retirees remember when they look back upon their work life and whether reminiscing work life is related to their current well-being. Semi-structured interviews were conducted with six retirees to develop initial codebooks. To characterize work-related memories and explore links between memory characteristics and retirees’ well-being, 66 retirees participated in an online study. They reported memories in text and rated memory valence and indicators of subjective well-being. Qualitative content analyses of memory narratives show that retirees recalled both work tasks and workplace relationships that were particularly pleasant or conflict ridden. They reminisced about profound (e.g., job loss) and small events (e.g., appreciative gestures from the leadership). Most retirees described their work life in an accepting way, although some expressed bitterness. Correlational analyses indicate links between memory valence and retirees’ perceived stress in work life and subjective well-being. We discuss our findings within the resource perspective on retirement with consideration of reminiscence as internal resources with permanent access. We suggest that well-being in retirement depends not only on external resources, but also on what retirees reflect on and remember. Practically, we discuss how work could be designed to build up such internal resources. We conclude with future research ideas, emphasizing the importance of a rigorous mixed-methods approach to studying how the life chapter of work that is long gone may continue to shape the lives of retirees.
Management of epilepsy in brain tumor patients
Authors: van der Meer Pim B. , Taphoorn Martin J.B. , Koekkoek Johan A.F.
Published: July 2022

Purpose of review

A concise review of recent findings in brain tumor-related epilepsy (BTRE), with focus on the effect of antitumor treatment on seizure control and the management of antiepileptic drugs (AEDs).

Recent findings

Isocitrate dehydrogenase mutation and its active metabolite d-2-hydroxyglutarate seem important contributing factors to epileptogenesis in BTRE. A beneficial effect of antitumor treatment (i.e. surgery, radiotherapy, and chemotherapy) on seizure control has mainly been demonstrated in low-grade glioma. AED prophylaxis in seizure-naïve BTRE patients is not recommended, but AED treatment should be initiated after a first seizure has occurred. Comparative efficacy randomized controlled trials (RCTs) are currently lacking, but second-generation AED levetiracetam seems the preferred choice in BTRE. Levetiracetam lacks significant drug-drug interactions, has shown favorable efficacy compared to valproic acid in BTRE, generally causes no hematological or neurocognitive functioning adverse effects, but caution should be exercised with regard to psychiatric adverse effects. Potential add-on AEDs in case of uncontrolled seizures include lacosamide, perampanel, and valproic acid. Ultimately, in the end-of-life phase when oral intake of medication is hampered, benzodiazepines via nonoral administration routes are potential alternatives.

Management of seizures in BTRE is complex and with currently available evidence levetiracetam seems the preferred choice. Comparative efficacy RCTs in BTRE are warranted.
Clinical Significance of Transient Asymptomatic Elevations in Aminotransferase (TAEAT) in Oncology
Authors: Lewis James H. , Khaldoyanidi Sophia K. , Britten Carolyn D. , Wei Andrew H. , Subklewe Marion
Published: July 2022

Monitoring for liver injury remains an important aspect of drug safety assessment, including for oncotherapeutics. When present, drug-induced liver injury may limit the use or result in the discontinuation of these agents. Drug-induced liver injury can exhibit with a wide spectrum of clinical and biochemical manifestations, ranging from transient asymptomatic elevations in aminotransferases (TAEAT) to acute liver failure. Numerous oncotherapeutics have been associated with TAEAT, with published reports indicating a phenomenon in which patients may be asymptomatic without overt liver injury despite the presence of grade ≥3 aminotransferase elevations. In this review, we discuss the occurrence of TAEAT in the context of oncology clinical trials and clinical practice, as well as the clinical relevance of this phenomenon as an adverse event in response to oncotherapeutics and the related cellular and molecular mechanisms that may underlie its occurrence. We also identify several gaps in knowledge relevant to the diagnosis and the management of TAEAT in patients receiving oncotherapeutics, and identify areas warranting further study to enable the future development of consensus guidelines to support clinical decision-making.
Bactericidal Efficacy of High Irradiance Ultraviolet A Photoactivation of Riboflavin Versus Standard Corneal Cross-Linking Protocol In Vitro
Authors: Tarff Andreina , Drew-Bear Laura E. , Yee Rebecca , Cano Marisol , Zhang Ying , Behrens Ashley
Published: July 2022

Purpose:

The purpose of this study was to compare the efficacy of high ultraviolet A (UVA) irradiance photoactivation of riboflavin (vitamin B2) versus the standard corneal cross-linking protocol on bacterial viability.

Methods:

Methicillin-sensitive Staphylococcus aureus (MSSA) Newman strain and methicillin-resistant multidrug-resistant S. aureus (MDR-MRSA) USA300, CA409, CA127, GA656, and NY315 strains were exposed to a UVA energy dose of 5.4 to 6 J/cm2 by 2 high irradiance regimens: A) 30 mW/cm2 for 3 minutes and B) 10 mW/cm2 for 10 minutes with B2 0.1%. Control groups included B2/UVA alone, CA409 exposed to standard B2 0.1% + UVA (3 mW/cm2 for 30 minutes), and an untreated sample. Cell viability was assessed. Triplicate values were obtained. The Mann–Whitney test and Student t test were used for statistical analysis.

Results:

There was no difference comparing the median bacterial load (log CFU/mL) of the untreated samples versus regimen A: Newman P = 0.7, CA409 P = 0.3, USA300 P = 0.5, CA127 P = 0.6, GA656 P = 0.1, and NY315 P = 0.2 (P ≥ 0.1); and B: Newman P= 0.1, CA409 P = 0.3, USA300 P = 0.4, CA127 P = 0.6, GA656 P = 0.1, and NY315 P = 0.3 (P ≥ 0.1). Standard regimen killed 100% of CA409.

Conclusions:

Photoactivation of B2 by high UVA irradiance does not seem to be effective for bacterial eradication in this study.
Acute Hepatitis of Unknown Etiology Among Young Children: Research Agenda by the ESPGHAN Hepatology Committee
Authors: Indolfi Giuseppe , Czubkowski Piotr , Fitzpatrick Emer , Gonzales Emmanuel , Gupte Girish , Mancell Sara , Mozer-Glassberg Yael , Nicastro Emanuele , Norman Junge , Stephenne Xavier , Zellos Aglaia , Samyn Marianne
Published: July 2022

In April 2022, an increased incidence of acute hepatitis cases of unknown etiology among previously healthy children across the United Kingdom was described. Since, more than 270 cases from the United Kingdom and hundreds more from all across the world have been reported. The majority of affected children were younger than 6 years of age. The clinical presentation was nonspecific with diarrhea and vomiting usually preceding the appearance of jaundice, abdominal pain, nausea, and malaise. Approximately 5% have required liver transplantation. An infectious etiology has been considered likely given the epidemiological and clinical features of the reported cases. Between 50 and 60% of the children tested were diagnosed with adenovirus infection although a clear etiological connection has still to be demonstrated. No link with SARS-CoV-2 infection and COVID-19 vaccine was found. What is not clear to date is whether the high number of acute hepatitis cases reported is related to a true increase in incidence or heightened awareness following on from the initial reports from the United Kingdom. The Hepatology Committee of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) developed a paper on the current outbreak of acute hepatitis of unknown etiology recognizing its importance and the need of approaching the current situation with a scientifically rigorous approach. The aims of the article are to summarize the current knowledge and to identify the most pertinent issues regarding the diagnosis and management of this condition and the research questions raised.
Understanding the pathways leading to socioeconomic inequalities in HIV testing uptake in 18 sub-Saharan African countries
Authors: Ante-Testard Pearl Anne , Hamidouche Mohamed , Apouey Bénédicte , Baggaley Rachel , Larmarange Joseph , Benmarhnia Tarik , Temime Laura , Jean Kévin
Published: July 2022

Objective:

To better understand the different pathways linking socioeconomic position and HIV testing uptake in 18 sub-Saharan African countries.

Design:

We used cross-sectional population-based surveys between 2010 and 2018.

Methods:

Using a potential outcomes framework and the product method, we decomposed the total effect linking wealth and recent (<12 months) HIV testing into direct effects, and indirect effects, viainternal(related to individual's ability to perceive need for and to seek care) orexternal(ability to reach, pay for and engage in healthcare) mediators to calculate the proportion mediated (PM) by each mediator.

Results:

High levels of inequalities were observed in nine and 15 countries among women and men, respectively. The mediator indirect effect varied greatly across countries. The PM tended to be higher for internal than for external mediators. For instance, among women, HIV-related knowledge was estimated to mediate up to 12.1% of inequalities in Côte d’Ivoire; and up to 31.5% for positive attitudes towards people with HIV (PWH) in Senegal. For the four external mediators, the PM was systematically below 7%. Similar findings were found when repeating analyses on men for the internal mediators, with higher PM by attitudes towards PWH (up to 39.9% in Senegal).

Conclusions:

Our findings suggest that wealth-related inequalities in HIV testing may be mediated by internal more than external characteristics, with important variability across countries. Overall, the important heterogeneities in the pathways of wealth-related inequalities in HIV testing illustrate that addressing inequalities requires tailored efforts and upstream interventions.