bluuebunny/crossref_metadata_2025 huggingface dataset:
Holistic similarity-based prediction of phosphorylation sites for understudied kinases
Authors: Ma Renfei , Li Shangfu , Parisi Luca , Li Wenshuo , Huang Hsien-Da , Lee Tzong-Yi
Published: February 2023

Phosphorylation is an essential mechanism for regulating protein activities. Determining kinase-specific phosphorylation sites by experiments involves time-consuming and expensive analyzes. Although several studies proposed computational methods to model kinase-specific phosphorylation sites, they typically required abundant experimentally verified phosphorylation sites to yield reliable predictions. Nevertheless, the number of experimentally verified phosphorylation sites for most kinases is relatively small, and the targeting phosphorylation sites are still unidentified for some kinases. In fact, there is little research related to these understudied kinases in the literature. Thus, this study aims to create predictive models for these understudied kinases. A kinase–kinase similarity network was generated by merging the sequence-, functional-, protein-domain- and ‘STRING’-related similarities. Thus, besides sequence data, protein–protein interactions and functional pathways were also considered to aid predictive modelling. This similarity network was then integrated with a classification of kinase groups to yield highly similar kinases to a specific understudied type of kinase. Their experimentally verified phosphorylation sites were leveraged as positive sites to train predictive models. The experimentally verified phosphorylation sites of the understudied kinase were used for validation. Results demonstrate that 82 out of 116 understudied kinases were predicted with adequate performance via the proposed modelling strategy, achieving a balanced accuracy of 0.81, 0.78, 0.84, 0.84, 0.85, 0.82, 0.90, 0.82 and 0.85, for the ‘TK’, ‘Other’, ‘STE’, ‘CAMK’, ‘TKL’, ‘CMGC’, ‘AGC’, ‘CK1’ and ‘Atypical’ groups, respectively. Therefore, this study demonstrates that web-like predictive networks can reliably capture the underlying patterns in such understudied kinases by harnessing relevant sources of similarities to predict their specific phosphorylation sites.
Association of homelessness and skin conditions: a Danish population-based cohort study
Authors: Nilsson Sandra F , Ali Zarqa , Laursen Thomas M , Thyssen Jacob P , Egeberg Alexander  , Nordentoft Merete , Hjorthøj Carsten , Thomsen Simon F
Published: February 2023

Background

Research has linked homelessness with an increased risk of skin conditions. However, representative studies of diagnosis-specific information on skin conditions in people experiencing homelessness are lacking.

Objectives

To examine the association between homelessness and diagnosed skin conditions, prescribed medication and type of ­consultation.

Methods

This cohort study included data from the Danish nationwide health, social and administrative registers from 1 January 1999 to 31 December 2018. All people of Danish origin living in Denmark and aged at least 15 years at some point during the study period were included. Homelessness, measured by homeless shelter contacts, was the exposure. The outcome was any diagnosis of a skin disorder and specific skin disorders recorded in the Danish National Patient Register. Information on diagnostic consultation type (i.e. dermatological, nondermatological and emergency room) and dermatological prescriptions was studied. We estimated adjusted incidence rate ratio (aIRR) (adjusted for sex, age and calendar year) and cumulative incidence.

Results

In total, 5 054 238 individuals (50.6% female) were included in the study population, accounting for 73 477 258 person-years at risk, with a start mean (SD) age of 39.4 (21.1) years. Of the total number of individuals, 759 991 (15.0%) received a skin diagnosis and 38 071 (0.7%) experienced homelessness. A 2.31-times [95% confidence interval (CI) 2.25–2.36] higher IRR of any diagnosed skin condition was associated with homelessness, higher for nondermatological and emergency room consultations. Homelessness was associated with a reduced IRR of a skin neoplasm diagnosis (aIRR 0.76, 95% CI 0.71–8.82) compared with no homelessness. By the end of follow-up, 2.8% (95% CI 2.5–3.0) of individuals experiencing homelessness had a skin neoplasm diagnosis vs. 5.1% (95% CI 4.9–5.3) of individuals not experiencing homelessness. Five or more shelter contacts during the first year from first contact was associated with the highest aIRR of any diagnosed skin condition (7.33, 95% CI 5.57–9.65) compared with no contacts.

Conclusions

Individuals experiencing homelessness have high rates of most diagnosed skin conditions, but a lower occurrence of skin cancer diagnosis. Diagnostic and medical patterns for skin disorders differed clearly between people experiencing homelessness and individuals without these experiences. The time after first homeless shelter contact is an important window of opportunity for mitigating and preventing skin disorders.
Aglycosylated extracellular loop of inwardly rectifying potassium channel 4.1 (KCNJ10) provides a target for autoimmune neuroinflammation
Authors: Nicot Arnaud B , Harb Jean , Garcia Alexandra , Guillot Flora , Mai Hoa-Le , Mathé Camille V , Morille Jérémy , Vallino Amélie , Dugast Emilie , Shah Sita P , Lefrère Fabienne , Moyon Mélinda , Wiertlewski Sandrine , Le Berre Ludmilla , Renaudin Karine , Soulillou Jean-Paul , van Pesch Vincent , Brouard Sophie , Berthelot Laureline , Laplaud David-Axel
Published: February 2023

Multiple sclerosis is an autoimmune disease of the central nervous system. Yet, the autoimmune targets are still undefined. The extracellular e1 sequence of KCNJ10, the inwardly rectifying potassium channel 4.1, has been subject to fierce debate for its role as a candidate autoantigen in multiple sclerosis. Inwardly rectifying potassium channel 4.1 is expressed in the central nervous system but also in peripheral tissues, raising concerns about the central nervous system-specificity of such autoreactivity. Immunization of C57Bl6/J female mice with the e1 peptide (amino acids 83–120 of Kir4.1) induced anti-e1 immunoglobulin G- and T-cell responses and promoted demyelinating encephalomyelitis with B cell central nervous system enrichment in leptomeninges and T cells/macrophages in central nervous system parenchyma from forebrain to spinal cord, mostly in the white matter. Within our cohort of multiple sclerosis patients (n = 252), 6% exhibited high anti-e1 immunoglobulin G levels in serum as compared to 0.7% in the control cohort (n = 127; P = 0.015). Immunolabelling of inwardly rectifying potassium channel 4.1-expressing white matter glia with the anti-e1 serum from immunized mice increased during murine autoimmune neuroinflammation and in multiple sclerosis white matter as compared with controls. Strikingly, the mouse and human anti-e1 sera labelled astrocytoma cells when N-glycosylation was blocked with tunicamycin. Western blot confirmed that neuroinflammation induces Kir4.1 expression, including its shorter aglycosylated form in murine experimental autoencephalomyelitis and multiple sclerosis. In addition, recognition of inwardly rectifying potassium channel 4.1 using mouse anti-e1 serum in Western blot experiments under unreduced conditions or in cells transfected with the N-glycosylation defective N104Q mutant as compared to the wild type further suggests that autoantibodies target an e1 conformational epitope in its aglycosylated form. These data highlight the e1 sequence of inwardly rectifying potassium channel 4.1 as a valid central nervous system autoantigen with a disease/tissue-specific post-translational antigen modification as potential contributor to autoimmunity in some multiple sclerosis patients.
The Coronavirus Disease 2019 Rebound Study: A Prospective Cohort Study to Evaluate Viral and Symptom Rebound Differences in Participants Treated With Nirmatrelvir Plus Ritonavir Versus Untreated Controls
Authors: Pandit Jay A , Radin Jennifer M , Chiang Danielle C , Spencer Emily G , Pawelek Jeff B , Diwan Mira , Roumani Leila , Mina Michael J
Published: February 2023

Background

The uptake of nirmatrelvir plus ritonavir (NPR) in patients with coronavirus disease 2019 (COVID-19) has been limited by concerns around the rebound phenomenon despite the scarcity of evidence around its epidemiology. The purpose of this study was to prospectively compare the epidemiology of rebound in NPR-treated and untreated participants with acute COVID-19 infection.

Methods

We designed a prospective, observational study in which participants who tested positive for COVID-19 and were clinically eligible for NPR were recruited to be evaluated for either viral or symptom clearance and rebound. Participants were assigned to the treatment or control group based on their decision to take NPR. Following initial diagnosis, both groups were provided 12 rapid antigen tests and asked to test on a regular schedule for 16 days and answer symptom surveys. Viral rebound based on test results and COVID-19 symptom rebound based on patient-reported symptoms were evaluated.

Results

Viral rebound incidence was 14.2% in the NPR treatment group (n = 127) and 9.3% in the control group (n = 43). Symptom rebound incidence was higher in the treatment group (18.9%) compared to controls (7.0%). There were no notable differences in viral rebound by age, gender, preexisting conditions, or major symptom groups during the acute phase or at the 1-month interval.

Conclusions

This preliminary report suggests that rebound after clearance of test positivity or symptom resolution is higher than previously reported. However, notably we observed a similar rate of rebound in both the NPR treatment and control groups. Large studies with diverse participants and extended follow-up are needed to better understand the rebound phenomena.
Phosphodiesterase 8 governs cAMP/PKA-dependent reduction of L-type calcium current in human atrial fibrillation: a novel arrhythmogenic mechanism
Authors: Grammatika Pavlidou Nefeli , Dobrev Shokoufeh , Beneke Kira , Reinhardt Franziska , Pecha Simon , Jacquet Eric , Abu-Taha Issam H , Schmidt Constanze , Voigt Niels , Kamler Markus , Schnabel Renate B , Baczkó Istvan , Garnier Anne , Reichenspurner Hermann , Nikolaev Viacheslav O , Dobrev Dobromir , Molina Cristina E
Published: February 2023

Aims

Atrial fibrillation (AF) is associated with altered cAMP/PKA signaling and an AF-promoting reduction of L-type Ca2+-current (ICa,L), the mechanisms of which are poorly understood. Cyclic-nucleotide phosphodiesterases (PDEs) degrade cAMP and regulate PKA-dependent phosphorylation of key calcium-handling proteins, including the ICa,L-carrying Cav1.2α1C subunit. The aim was to assess whether altered function of PDE type-8 (PDE8) isoforms contributes to the reduction of ICa,L in persistent (chronic) AF (cAF) patients.

Methods and results

mRNA, protein levels, and localization of PDE8A and PDE8B isoforms were measured by RT-qPCR, western blot, co-immunoprecipitation and immunofluorescence. PDE8 function was assessed by FRET, patch-clamp and sharp-electrode recordings. PDE8A gene and protein levels were higher in paroxysmal AF (pAF) vs. sinus rhythm (SR) patients, whereas PDE8B was upregulated in cAF only. Cytosolic abundance of PDE8A was higher in atrial pAF myocytes, whereas PDE8B tended to be more abundant at the plasmalemma in cAF myocytes. In co-immunoprecipitation, only PDE8B2 showed binding to Cav1.2α1C subunit which was strongly increased in cAF. Accordingly, Cav1.2α1C showed a lower phosphorylation at Ser1928 in association with decreased ICa,L in cAF. Selective PDE8 inhibition increased Ser1928 phosphorylation of Cav1.2α1C, enhanced cAMP at the subsarcolemma and rescued the lower ICa,L in cAF, which was accompanied by a prolongation of action potential duration at 50% of repolarization.

Conclusion

Both PDE8A and PDE8B are expressed in human heart. Upregulation of PDE8B isoforms in cAF reduces ICa,L via direct interaction of PDE8B2 with the Cav1.2α1C subunit. Thus, upregulated PDE8B2 might serve as a novel molecular mechanism of the proarrhythmic reduction of ICa,L in cAF.
A scoping review of evidence-based guidance and guidelines published by general practice professional organizations
Authors: O’Brien Emer , Duffy Seamus , Harkins Velma , Smith Susan M , O’Herlihy Noirin , Walsh Aisling , Clyne Barbara , Wallace Emma
Published: February 2023

Background

General practitioners (GPs) need robust, up-to-date evidence to deliver high-quality patient care. There is limited literature regarding the role of international GP professional organizations in developing and publishing clinical guidelines to support GPs clinical decision making.

Objective

To identify evidence-based guidance and clinical guidelines produced by GP professional organizations and summarize their content, structure, and methods of development and dissemination.

Methods

Scoping review of GP professional organizations following Joanna Briggs Institute guidance. Four databases were searched and a grey literature search was conducted. Studies were included if they were: (i) evidence-based guidance documents or clinical guidelines produced de novo by a national GP professional organization, (ii) developed to support GPs clinical care, and (iii) published in the last 10 years. GP professional organizations were contacted to provide supplementary information. A narrative synthesis was performed.

Results

Six GP professional organizations and 60 guidelines were included. The most common de novo guideline topics were mental health, cardiovascular disease, neurology, pregnancy and women’s health and preventive care. All guidelines were developed using a standard evidence-synthesis method. All included documents were disseminated through downloadable pdfs and peer review publications. GP professional organizations indicated that they generally collaborate with or endorse guidelines developed by national or international guideline producing bodies.

Conclusion

The findings of this scoping review provide an overview of de novo guideline development by GP professional organizations and can support collaboration between GP organizations worldwide thus reducing duplication of effort, facilitating reproducibility, and identifying areas of standardization.

Protocol registration

Open Science Framework: https://doi.org/10.17605/OSF.IO/JXQ26.
Methylation of CENP-A/Cse4 on arginine 143 and lysine 131 regulates kinetochore stability in yeast
Authors: Tran Nguyen Tra My , Munhoven Arno , Samel-Pommerencke Anke , Kshirsagar Rucha , Cuomo Alessandro , Bonaldi Tiziana , Ehrenhofer-Murray Ann E
Published: February 2023

Post-translational modifications on histones are well known to regulate chromatin structure and function, but much less information is available on modifications of the centromeric histone H3 variant and their effect at the kinetochore. Here, we report two modifications on the centromeric histone H3 variant CENP-A/Cse4 in the yeast Saccharomyces cerevisiae, methylation at arginine 143 (R143me) and lysine 131 (K131me), that affect centromere stability and kinetochore function. Both R143me and K131me lie in the core region of the centromeric nucleosome, near the entry/exit sites of the DNA from the nucleosome. Unexpectedly, mutation of Cse4-R143 (cse4-R143A) exacerbated the kinetochore defect of mutations in components of the NDC80 complex of the outer kinetochore (spc25-1) and the MIND complex (dsn1-7). The analysis of suppressor mutations of the spc25-1 cse4-R143A growth defect highlighted residues in Spc24, Ndc80, and Spc25 that localize to the tetramerization domain of the NDC80 complex and the Spc24-Spc25 stalk, suggesting that the mutations enhance interactions among NDC80 complex components and thus stabilize the complex. Furthermore, the Set2 histone methyltransferase inhibited kinetochore function in spc25-1 cse4-R143A cells, possibly by methylating Cse4-K131. Taken together, our data suggest that Cse4-R143 methylation and Cse4-K131 methylation affect the stability of the centromeric nucleosome, which is detrimental in the context of defective NDC80 tetramerization and can be compensated for by strengthening interactions among NDC80 complex components.
Direct and Indirect Effects of Socioeconomic Status and Discrimination on Subjective Cognitive Decline: A Longitudinal Study of African American Women
Authors: Simons Ronald L , Ong Mei Ling , Beach Steven R H , Lei Man-Kit , Philibert Robert , Mielke Michelle M
Published: February 2023

Objectives

The present study builds on recent findings suggesting that the stress of institutional and interpersonal racism may contribute to African Americans’ elevated risk for dementia. We investigated the extent to which 2 consequences of racism—low socioeconomic status (SES) and discrimination—predict self-reported cognitive decline (SCD) 19 years later. Further, we examined potential mediating pathways that might link SES and discrimination to cognitive decline. Potential mediators included depression, accelerated biological aging, and onset of chronic illnesses.

Methods

Hypotheses were tested using a sample of 293 African American women. SCD was assessed using the Everyday Cognition Scale. Structural equation modeling was used to assess the effects of SES and racial discrimination, both measured in 2002, on SCD reported in 2021. Turning to the mediators, midlife depression was assessed in 2002, accelerated aging in 2019, and chronic illness in 2019. Age and prodrome depression were included as covariates.

Results

There were direct effects of SES and discrimination on SCD. In addition, these 2 stressors showed a significant indirect effect on SCD through depression. Finally, there was evidence for a more complex pathway where SES and discrimination accelerate biological aging, with accelerated aging, in turn leading to chronic illness, which then predicted SCD.

Discussion

Results of the present study add to a growing literature indicating that living in a racialized society is a central factor in explaining the high risk for dementia among Black Americans. Future research should continue to emphasize the various ways that exposure to racism over the life course effects cognition.
Difference-managing and difference-reducing community storytelling in urban neighborhoods: a communication infrastructure theory perspective
Authors: Kim Yong-Chan , Shin Euikyung , Kim Yeran , Chae Young-Gil
Published: February 2023

This study is to understand how urban residents experience and address difference through communicative actions in urban neighborhoods. The first purpose of this study was to test the scales of difference-managing community storytelling (DMCS) and difference-reducing community storytelling (DRCS) as two communicative actions for addressing differences in urban neighborhoods. The second was to identify socioeconomic and community engagement variables correlated with the two scales. We used both qualitative and quantitative data collected in Seoul by adopting a mixed-method research design, and the study was theoretically guided by communication infrastructure theory. Based on exploratory and confirmatory factor analyses, we confirmed the two-dimensional model of community storytelling, with DMCS being positively related to integrated connectedness to a community storytelling network (ICSN) and all of the community engagement variables included in the current study. In comparison, DRCS was negatively related to ICSN and neighborhood participation and was positively related to informal social control.
Colorblind on the color line: critical ethnography of racial inequity in a human service organization serving a community of single-mother families at the margins
Authors: Williams Savaughn E , Gist-Mackey Angela N , Jewell Anna
Published: February 2023

This study takes an in-depth critical ethnographic look at a local nonprofit human service organization, Lavender Refuge, that supports marginalized families. This study explored the communication of staff/volunteers and residential clients that facilitate or inhibit the nonprofit’s aims to create an inclusive community culture. Critical race theory and social identity theory were utilized as theoretical frameworks to better understand the culture of Lavender Refuge’s community. Findings revealed three dominant themes related to issues of racial (in)equity at Lavender Refuge. The desire for positive identities, controlled performances within the community hindering race conscious (Crenshaw, K. (1995). Race, reform, retrenchment: Transformation and legitimation in anti-discrimination law. In K. Crenshaw, N. Gotanda, G. Peller, & K. Thomas (Eds.), Critical race theory: The key writings that formed the movement (pp. 103–126). New Press: Distributed by W.W. Norton & Co.) communication. Further, conversations about race were seen as fostering intergroup competition along racial lines, explaining resistance to race communication. Our research team concludes with practical recommendations, resources, and training in hopes they could change the community culture so racial diversity is embraced and equity fostered.
Systematic assessment of the contribution of structural variants to inherited retinal diseases
Authors: Wen Shu , Wang Meng , Qian Xinye , Li Yumei , Wang Keqing , Choi Jongsu , Pennesi Mark E , Yang Paul , Marra Molly , Koenekoop Robert K , Lopez Irma , Matynia Anna , Gorin Michael , Sui Ruifang , Yao Fengxia , Goetz Kerry , Porto Fernanda Belga Ottoni , Chen Rui
Published: February 2023

Despite increasing success in determining genetic diagnosis for patients with inherited retinal diseases (IRDs), mutations in about 30% of the IRD cases remain unclear or unsettled after targeted gene panel or whole exome sequencing. In this study, we aimed to investigate the contributions of structural variants (SVs) to settling the molecular diagnosis of IRD with whole-genome sequencing (WGS). A cohort of 755 IRD patients whose pathogenic mutations remain undefined were subjected to WGS. Four SV calling algorithms including include MANTA, DELLY, LUMPY and CNVnator were used to detect SVs throughout the genome. All SVs identified by any one of these four algorithms were included for further analysis. AnnotSV was used to annotate these SVs. SVs that overlap with known IRD-associated genes were examined with sequencing coverage, junction reads and discordant read pairs. Polymerase Chain Reaction (PCR) followed by Sanger sequencing was used to further confirm the SVs and identify the breakpoints. Segregation of the candidate pathogenic alleles with the disease was performed when possible. A total of 16 candidate pathogenic SVs were identified in 16 families, including deletions and inversions, representing 2.1% of patients with previously unsolved IRDs. Autosomal dominant, autosomal recessive and X-linked inheritance of disease-causing SVs were observed in 12 different genes. Among these, SVs in CLN3, EYS and PRPF31 were found in multiple families. Our study suggests that the contribution of SVs detected by short-read WGS is about 0.25% of our IRD patient cohort and is significantly lower than that of single nucleotide changes and small insertions and deletions.
Assessing the net benefit of machine learning models in the presence of resource constraints
Authors: Singh Karandeep , Shah Nigam H , Vickers Andrew J
Published: February 2023

Objective

The objective of this study is to provide a method to calculate model performance measures in the presence of resource constraints, with a focus on net benefit (NB).

Materials and Methods

To quantify a model’s clinical utility, the Equator Network’s TRIPOD guidelines recommend the calculation of the NB, which reflects whether the benefits conferred by intervening on true positives outweigh the harms conferred by intervening on false positives. We refer to the NB achievable in the presence of resource constraints as the realized net benefit (RNB), and provide formulae for calculating the RNB.

Results

Using 4 case studies, we demonstrate the degree to which an absolute constraint (eg, only 3 available intensive care unit [ICU] beds) diminishes the RNB of a hypothetical ICU admission model. We show how the introduction of a relative constraint (eg, surgical beds that can be converted to ICU beds for very high-risk patients) allows us to recoup some of the RNB but with a higher penalty for false positives.

Discussion

RNB can be calculated in silico before the model’s output is used to guide care. Accounting for the constraint changes the optimal strategy for ICU bed allocation.

Conclusions

This study provides a method to account for resource constraints when planning model-based interventions, either to avoid implementations where constraints are expected to play a larger role or to design more creative solutions (eg, converted ICU beds) to overcome absolute constraints when possible.
Characteristics of patient navigation programs in the Cancer Moonshot ACCSIS colorectal cancer screening initiative
Authors: Coronado Gloria D , Ferrari Renée M , Barnes Autumn , Castañeda Sheila F , Cromo Mark , Davis Melinda M , Doescher Mark P , English Kevin , Hatcher Jenna , Kim Karen E , Kobrin Sarah , Liebovitz David , Mishra Shiraz I , Nodora Jesse N , Norton Wynne E , Oliveri Jill M , Reuland Daniel S , Subramanian Sujha , Thompson Jamie H , Paskett Electra D
Published: February 2023

Background

Although patient navigation has shown promise for increasing participation in colorectal cancer screening and follow-up, little evidence is available to guide implementation of patient navigation in clinical practice. We characterize 8 patient navigation programs being implemented as part of multi-component interventions of the National Cancer Institute's Cancer Moonshot Accelerating Colorectal Cancer Screening and Follow-Up Through Implementation Science (ACCSIS) initiative.

Methods

We developed a data collection template organized by ACCSIS framework domains. The template was populated by a representative from each of the 8 ACCSIS research projects. We report standardized descriptions of 1) the socio-ecological context in which the navigation program was being conducted, 2) navigation program characteristics, 3) activities undertaken to facilitate program implementation (eg, training), and 4) outcomes used in program evaluation.

Results

ACCSIS patient navigation programs varied broadly in their socio-ecological context and settings, the populations they served, and how they were implemented in practice. Six research projects adapted and implemented evidence-based patient navigation programs; the remaining projects developed new programs. Five projects began navigation when patients were due for initial colorectal cancer screening; 3 projects began navigation later in the screening process, when patients were due for follow-up colonoscopy after an abnormal stool-test result. Seven projects relied on existing clinical staff to deliver the navigation; 1 hired a centralized research navigator. All project researchers plan to evaluate the effectiveness and implementation of their programs.

Conclusions

Our detailed program descriptions may facilitate cross-project comparisons and guide future implementation and evaluation of patient navigation programs in clinical practice.
Surgical therapy of aorto-iliac aneurysm in a patient with congenital solitary pelvic kidney (CSPK): case report and literature review
Authors: Capone Amedeo , Fargion Aaron Thomas , Esposito Davide , Calugi Gianmarco , Innocenti Alessandro Alessi , Dorigo Walter , Pratesi Carlo , Pulli Raffaele
Published: February 2023

We report a case of a man with an Aorto-Iliac aneurysm and a congenital solitary pelvic kidney (CSPK). The maximum diameter of the aneurysm was 58 mm and the pelvic kidney was perfused by a single renal artery originating from the aortic bifurcation. A computed tomography scan was used for pre-operative planning and the patient underwent aorto-iliac aneurysm replacement with a Dacron graft. The renal artery was reimplanted on the Dacron right limb with a ‘Carrel patch’. Several strategies were adopted to prevent renal ischemia such as sequential aortic cross clamping, selective cold perfusion of renal artery and a temporary Pruitt–Inahara shunt. The post-operative course was characterized by a transient increase in serum creatinine that did not require treatments and the patient was discharged after seven days. Congenital anomalies such as CSPK represent a challenge for the surgeon; however, the adoption of different intraoperative available strategies allowed to reduce possible complications.
Factors associated with delay in seeking healthcare for imported malaria: a retrospective study in a French hospital
Authors: Flateau Clara , Picque Marie , Cornaglia Carole , Pitsch Aurélia , Youbong Tracie , Leroy Pierre , de Pontfarcy Astrid , Jault Thierry , Thach Caroline , Camus Maryse , Dolveck François , Diamantis Sylvain
Published: February 2023

Background

Delayed treatment is associated with a higher risk of severe malaria. In malaria-endemic areas, the main factors associated with delay in seeking healthcare are low educational level and traditional beliefs. In imported malaria, determinants of delay in seeking healthcare are currently unknown.

Methods

We studied all patients presenting with malaria, from 1 January 2017 to 14 February 2022, in the hospital of Melun, France. Demographic and medical data were recorded for all patients, and socio-professional data were recorded for a subgroup of hospitalized adults. Relative-risks and 95% confidence intervals were determined using univariate analysis by cross-tabulation.

Results

There were 234 patients included, all travelling from Africa. Among them, 218 (93%) were infected with P. falciparum, 77 (33%) had severe malaria, 26 (11%) were <18 years old and 81 were included during the SARS-CoV-2 pandemic. There were 135 hospitalized adults (58% of all patients). The median time to hospital admission (THA) , defined by the period from onset of symptoms to arrival at hospital, was 3 days (IQR = 2–5). A THA ≥3 days tended to be more frequent in travellers visiting friends and relatives (VFR; RR = 1.44, 95% CI = [1.0–2.05], P = 0.06), while it was less frequent in children and teenagers (RR = 0.58, 95% CI = [0.39–0.84], P = 0.01). Gender, African background, unemployment, living alone and absence of referring physician were not associated with delay in seeking healthcare. Consulting during the SARS-CoV-2 pandemic was neither associated with a longer THA nor with a higher rate of severe malaria.

Conclusion

In contrast to an endemic area, socio-economic factors did not impact on delay in seeking healthcare in imported malaria. Prevention should focus on VFR subjects, who tend to consult later than other travellers.
3D Printing as an Effective Quality Assurance Implementation in Massive-Scale SARS-CoV-2 Testing at a SwabSeq Next-Generation Sequencing Laboratory
Authors: Sathe Laila M , Khan Nishrat N , Williams Jazmine M , Saul Rosita , Jajieh Kane , Sartippour Maryam R , Young Rachel , Xie Joanna , Marquette Dawn M , Duncan Tiffany , Eskin Eleazar , Arboleda Valerie A
Published: February 2023

Massive-scale SARS-CoV-2 testing using the SwabSeq diagnostic platform came with quality assurance challenges due to the novelty and scale of sequencing-based testing. The SwabSeq platform relies on accurate mapping between specimen identifiers and molecular barcodes to match a result back to a patient specimen. To identify and mitigate mapping errors, we instituted quality control using placement of negative controls within a rack of patient samples. We designed 2-dimensional paper templates to fit over a 96-position rack of specimens with holes to show the control tube placements. We designed and 3-dimensionally printed plastic templates that fit onto 4 racks of patient specimens and provide accurate indications of the correct control tube placements. The final plastic templates dramatically reduced plate mapping errors from 22.55% in January 2021 to less than 1% after implementation and training in January 2021. We show how 3D printing can be a cost-effective quality assurance tool to mitigate human error in the clinical laboratory.
Time series analysis of bright TESS RRc stars: additional modes, phase variations, and more
Authors: Benkő J M , Plachy E , Netzel H , Bódi A , Molnár L , Pál A
Published: February 2023

Using two years of data from the TESS space telescope, we have investigated the time series of 633 overtone pulsating field RR Lyrae (RRc) stars. The majority of stars (82.8 per cent) contain additional frequencies beyond the main pulsation. In addition to the frequencies previously explained by the ℓ = 8 and 9 non-radial modes, we have identified a group of stars where the additional frequencies may belong to the ℓ = 10 non-radial modes. We found that stars with no additional frequencies are more common among stars with shorter periods, while stars with longer periods almost always show additional frequencies. The incidence rate and this period distribution both agree well with the predictions of recent theoretical models. The amplitude and phase of additional frequencies are varying in time. The frequencies of different non-radial modes appearing in a given star seem to vary on different time-scales. We have determined a 10.4 per cent incidence rate for the Blazhko effect. For several stars we have detected continuous annual-scale phase change without significant amplitude variation. This type of variation offers a plausible explanation for the ‘phase jump’ phenomenon reported in many RRc stars. The main pulsation frequency could show quasi-periodic phase and amplitude fluctuations. This fluctuation is clearly related to additional frequencies present in the star: stars with two non-radial modes show the strongest fluctuations, while stars with no such modes show no fluctuations at all. The summation of the phase fluctuation over time may explain the O−C variations that have long been known for many non-Blazhko RRc stars.
Chromosome Fissions and Fusions Act as Barriers to Gene Flow betweenBrenthisFritillary Butterflies
Authors: Mackintosh Alexander , Vila Roger , Laetsch Dominik R , Hayward Alex , Martin Simon H , Lohse Konrad
Published: February 2023

Chromosome rearrangements are thought to promote reproductive isolation between incipient species. However, it is unclear how often, and under what conditions, fission and fusion rearrangements act as barriers to gene flow. Here we investigate speciation between two largely sympatric fritillary butterflies, Brenthis daphne and Brenthis ino. We use a composite likelihood approach to infer the demographic history of these species from whole-genome sequence data. We then compare chromosome-level genome assemblies of individuals from each species and identify a total of nine chromosome fissions and fusions. Finally, we fit a demographic model where effective population sizes and effective migration rate vary across the genome, allowing us to quantify the effects of chromosome rearrangements on reproductive isolation. We show that chromosomes involved in rearrangements experienced less effective migration since the onset of species divergence and that genomic regions near rearrangement points have a further reduction in effective migration rate. Our results suggest that the evolution of multiple rearrangements in the B. daphne and B. ino populations, including alternative fusions of the same chromosomes, have resulted in a reduction in gene flow. Although fission and fusion of chromosomes are unlikely to be the only processes that have led to speciation between these butterflies, this study shows that these rearrangements can directly promote reproductive isolation and may be involved in speciation when karyotypes evolve quickly.
Multi-ancestry genome-wide association study of 4069 children with glioma identifies 9p21.3 risk locus
Authors: Foss-Skiftesvik Jon , Li Shaobo , Rosenbaum Adam , Hagen Christian Munch , Stoltze Ulrik Kristoffer , Ljungqvist Sally , Hjalmars Ulf , Schmiegelow Kjeld , Morimoto Libby , de Smith Adam J , Mathiasen René , Metayer Catherine , Hougaard David , Melin Beatrice , Walsh Kyle M , Bybjerg-Grauholm Jonas , Dahlin Anna M , Wiemels Joseph L
Published: February 2023

Background

Although recent sequencing studies have revealed that 10% of childhood gliomas are caused by rare germline mutations, the role of common variants is undetermined and no genome-wide significant risk loci for pediatric central nervous system tumors have been identified to date.

Methods

Meta-analysis of 3 population-based genome-wide association studies comprising 4069 children with glioma and 8778 controls of multiple genetic ancestries. Replication was performed in a separate case–control cohort. Quantitative trait loci analyses and a transcriptome-wide association study were conducted to assess possible links with brain tissue expression across 18 628 genes.

Results

Common variants in CDKN2B-AS1 at 9p21.3 were significantly associated with astrocytoma, the most common subtype of glioma in children (rs573687, P-value of 6.974e-10, OR 1.273, 95% CI 1.179–1.374). The association was driven by low-grade astrocytoma (P-value of 3.815e-9) and exhibited unidirectional effects across all 6 genetic ancestries. For glioma overall, the association approached genome-wide significance (rs3731239, P-value of 5.411e-8), while no significant association was observed for high-grade tumors. Predicted decreased brain tissue expression of CDKN2B was significantly associated with astrocytoma (P-value of 8.090e-8).

Conclusions

In this population-based genome-wide association study meta-analysis, we identify and replicate 9p21.3 (CDKN2B-AS1) as a risk locus for childhood astrocytoma, thereby establishing the first genome-wide significant evidence of common variant predisposition in pediatric neuro-oncology. We furthermore provide a functional basis for the association by showing a possible link to decreased brain tissue CDKN2B expression and substantiate that genetic susceptibility differs between low- and high-grade astrocytoma.
The association between circulating 25-hydroxyvitamin D levels and preeclampsia: a systematic review and dose-response meta-analysis of epidemiologic studies with GRADE assessment
Authors: Rouhani Parisa , Mokhtari Elahe , Lotfi Keyhan , Saneei Parvane
Published: February 2023

Context

Although some studies have examined the connection between circulating 25-hydroxyvitamin D (25(OH)D) concentrations and preeclampsia (PE) risk, the results were inconsistent.

Objective

A dose-response meta-analysis on epidemiologic investigations was conducted to evaluate the relation of 25(OH)D concentration and PE.

Data Source

Electronic databases, including Scopus, MEDLINE (PubMed), the Institute for Scientific Information, Embase, and Google Scholar, were comprehensively search until July 2021.

Data Extraction

A total of 65 observational studies evaluating the link between circulating 25(OH)D concentrations and PE were included. The body of evidence was assessed by the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach.

Data Analysis

Combining 32 effect sizes from 32 prospective studies with 76 394 participants revealed that highest vs lowest circulating 25(OH)D concentrations was significantly related to a 33% reduced risk of PE (relative risk [RR], 0.67; 95%CI, 0.54–0.83). Subgroup analysis by study design revealed that PE risk has significantly decreased in cohort and case-cohort studies (RR, 0.72; 95%CI, 0.61–0.85), and a slight decline was found in nested case-control studies (RR, 0.62; 95%CI, 0.38–1.02). Dose–response analysis in 27 prospective studies with 73 626 participants illustrated that each 10 ng/mL increment in circulating 25(OH)D concentration led to a 14% reduced incidence of PE (RR, 0.86; 95%CI, 0.83–0.90). A U-shaped significant association in nonlinear dose–response analysis was found between 25(OH)D and PE. A significant inverse association was also found between highest vs lowest circulating 25(OH)D concentration and PE in 32 nonprospective studies with 37 477 participants (odd ratio, 0.37; 95%CI, 0.27–0.52). This inverse association was significant in almost all subgroups, based on different covariates.

Conclusion

This meta-analysis of observational investigations showed blood 25(OH)D levels were negatively related to PE risk, in a dose-response manner.

Systematic Review Registration

PROSPERO registration no. CRD42021267486.
A Phase Ib/II Study of WNT974 + Encorafenib + Cetuximab in Patients With BRAFV600E-MutantKRASWild-Type Metastatic Colorectal Cancer
Authors: Tabernero Josep , Van Cutsem Eric , Garralda Elena , Tai David , De Braud Filippo , Geva Ravit , van Bussel Mark T J , Fiorella Dotti Katia , Elez Elena , de Miguel María J , Litwiler Kevin , Murphy Danielle , Edwards Michelle , Morris Van Karlyle
Published: February 2023

Background

WNT974 is a small molecule inhibitor of Wnt signaling that specifically inhibits porcupine O-acyltransferase. This phase Ib dose-­escalation study evaluated the maximum tolerated dose of WNT974 in combination with encorafenib and cetuximab in patients with BRAF V600E-mutant metastatic colorectal cancer with RNF43 mutations or RSPO fusions.

Patients and Methods

Patients received once-daily encorafenib and weekly cetuximab, in addition to once-daily WNT974, in sequential dosing cohorts. In the first cohort, patients received 10-mg WNT974 (COMBO10), which was reduced in subsequent cohorts to 7.5-mg (COMBO7.5) or 5-mg (COMBO5) after dose–limiting toxicities (DLTs) were observed. Primary endpoints were incidence of DLTs and exposure to WNT974 and encorafenib. Secondary endpoints were anti-tumor activity and safety.

Results

Twenty patients were enrolled (COMBO10, n = 4; COMBO7.5, n = 6; COMBO5, n = 10). DLTs were observed in 4 patients, including grade 3 hypercalcemia (COMBO10, n = 1; COMBO7.5, n = 1), grade 2 dysgeusia (COMBO10, n = 1), and lipase increased (COMBO10, n = 1). A high incidence of bone toxicities (n = 9) was reported, including rib fracture, spinal compression fracture, pathological fracture, foot fracture, hip fracture, and lumbar vertebral fracture. Serious adverse events were reported in 15 patients, most frequently bone fracture, hypercalcemia, and pleural effusion. The overall response rate was 10% and disease control rate 85%; most patients achieved stable disease as their best response.

Conclusion

Concerns surrounding the safety and lack of preliminary evidence of improved anti-tumor activity of WNT974 + encorafenib + cetuximab, compared with previous encorafenib + cetuximab data, ultimately led to study discontinuation. Phase II was not initiated.

Trial registration

ClinicalTrials.gov, NCT02278133
Ignorance
Authors: Peels Rik
Published: February 2023

This book rigorously develops a full-blown epistemology of ignorance. It answers questions that are rarely addressed in philosophy; for example, what is ignorance of facts or truths? Is it simply the absence of knowledge, or are things more complex? Can there also be ignorance of entities and ignorance of how to do something? How does ignorance of facts relate to ignorance on some topic, say, quantum mechanics? If one holds a false belief but one also believes one should not hold that belief because it is irrational, does one still count as ignorant? What varieties of ignorance are there? For instance, should we distinguish between disbelief and suspension of judgment and not even being able to grasp a proposition? What is it for groups to be ignorant? And how should we construe degrees of ignorance? This book then shows what difference this epistemology of ignorance makes by applying it to six contemporary debates on sometimes controversial topics in and beyond philosophy: white ignorance, practices of making people ignorant as studied in agnotology, the conditions under which ignorance counts as an excuse, responsibility and particularly culpability for ignorance, educational practices that aim at ignorance, and asserting that one is ignorant. In each case, it turns out that the epistemology of ignorance developed in the first part of the book provides the resources to take the debate important steps further and, in some cases, even to resolve philosophical problems.
Allelic variation of MdMYB123 controls malic acid content by regulating MdMa1 and MdMa11 expression in apple
Authors: Zheng Litong , Liao Liao , Duan Chenbo , Ma Wenfang , Peng Yunjing , Yuan Yangyang , Han Yuepeng , Ma Fengwang , Li Mingjun , Ma Baiquan
Published: February 2023

Acidity is a key determinant of fruit organoleptic quality. Here, a candidate gene for fruit acidity, designated MdMYB123, was identified from a comparative transcriptome study of two Ma1Ma1 apple (Malus domestica) varieties, “Qinguan (QG)” and “Honeycrisp (HC)” with different malic acid content. Sequence analysis identified an A→T SNP, which was located in the last exon, resulting in a truncating mutation, designated mdmyb123. This SNP was significantly associated with fruit malic acid content, accounting for 9.5% of the observed phenotypic variation in apple germplasm. Differential MdMYB123- and mdmyb123-mediated regulation of malic acid accumulation was observed in transgenic apple calli, fruits, and plantlets. Two genes, MdMa1 and MdMa11, were up- and down-regulated in transgenic apple plantlets overexpressing MdMYB123 and mdmyb123, respectively. MdMYB123 could directly bind to the promoter of MdMa1 and MdMa11, and induce their expression. In contrast, mdmyb123 could directly bind to the promoters of MdMa1 and MdMa11, but with no transcriptional activation of both genes. In addition, gene expression analysis in 20 different apple genotypes based on SNP locus from “QG” × “HC” hybrid population confirmed a correlation between A/T SNP with expression levels of MdMa1 and MdMa11. Our finding provides valuable functional validation of MdMYB123 and its role in the transcriptional regulation of both MdMa1 and MdMa11, and apple fruit malic acid accumulation.
A strong culture of clinical research is essential for the training of medical postgraduates in China
Authors: Du Yi , Luo Wenjing
Published: February 2023

Postgraduate medical students are the mainstay of future medical research, and clinical research is one of the most important components of medical research. In recent years, the Chinese government has increased the number of postgraduate students in China. Therefore, the quality of postgraduate training has received widespread attention. This article discusses the advantages and challenges faced by Chinese graduate students when they conduct their clinical research. To address the current misconception that Chinese graduate students only focus on developing their competence in basic biomedical research, the authors call for increased support for clinical research from the Chinese government as well as from schools and teaching hospitals.