bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of kidney registries in expediting large-scale collection of patient-reported outcome measures for people with chronic kidney disease
Authors: van der Veer Sabine N , Couchoud Cecile , Morton Rachael L
Published: March 2021

In this issue of Clinical Kidney Journal, Van der Willik et al. report findings from a pilot study where they introduced collection of patient-reported outcome measures (PROMs) into routine kidney care in Dutch dialysis centres. It is comparable to a registry-led PROMs initiative in Sweden, published in Clinical Kidney Journal in 2020. Both studies reported low average PROMs response rates with substantial between-centre variation, and both identified suboptimal patient and staff engagement as a key barrier to implementing PROMs in routine care for people with chronic kidney disease (CKD). This suggests that national kidney registries could be well placed to facilitate large-scale collection of PROMs data, but that they may require additional guidance on how to do this successfully. In this editorial, we discuss the current state-of-play of PROMs collection by kidney registries and provide an overview of what is (un)known about the feasibility and effectiveness of PROMs in CKD and other conditions. We anticipate that the fast-growing evidence base on whether, and how, PROMs can be of value in CKD settings will expedite registry-based PROMs collection, which will ultimately lead to more valuable and person-centred services and to enhanced health and well-being of people with CKD.
SARS-CoV-2 Vaccination in IBD: Past Lessons, Current Evidence, and Future Challenges
Authors: Wellens Judith , Colombel Jean-Frédéric , Satsangi Jack J , Wong Serre-Yu
Published: March 2021

Since the beginning of the pandemic, patients with inflammatory bowel diseases [IBD] have been considered at high risk for infection and complications of COVID-19. IBD patients and patients taking immunosuppressive therapy were excluded from clinical phase III vaccine trials, complicating the assessment of effectiveness of these new vaccines. From past experience we know that adapted vaccination strategies may be appropriate in some IBD patients to optimise immunogenicity. We review current evidence on SARS-CoV-2 vaccination relevant to IBD patients, including immune responses from humoral to cellular, emerging data on new variants, and off-label vaccination schemes. We also identify clinical and scientific knowledge gaps that can be translated into both large-scale population-based studies and targeted vaccine studies to describe the precise immune responses induced by SARS-CoV-2 vaccines in IBD patients. We strongly endorse the recommendation of vaccinating IBD patients to ensure maximal protection from COVID-19 both for the individual and the community.
Ethnic Differences in the Smoking-related Risk of Inflammatory Bowel Disease: A Systematic Review and Meta-analysis
Authors: Piovani Daniele , Pansieri Claudia , Kotha Soumya R R , Piazza Amanda C , Comberg Celia-Louise , Peyrin-Biroulet Laurent , Danese Silvio , Bonovas Stefanos
Published: March 2021

Background and Aims

The association between smoking and inflammatory bowel disease [IBD] relies on old meta-analyses including exclusively non-Jewish White populations. Uncertainty persists regarding the role of smoking in other ethnicities.

Methods

We systematically searched Medline/PubMed, Embase, and Scopus for studies examining tobacco smoking and the risk of developing IBD, ie, Crohn’s disease [CD] or ulcerative colitis [UC]. Two authors independently extracted study data and assessed each study’s risk of bias. We examined heterogeneity and small-study effect, and calculated summary estimates using random-effects models. Stratified analyses and meta-regression were employed to study the association between study-level characteristics and effect estimates. The strength of epidemiological evidence was assessed through prespecified criteria.

Results

We synthesised 57 studies examining the smoking-related risk of developing CD and UC. Non-Jewish White smokers were at increased risk of CD (29 studies; relative risk [RR]: 1.95, 95% confidence interval [CI]: 1.69‒2.24; moderate evidence). No association was observed in Asian, Jewish. and Latin-American populations [11 studies; RR: 0.97; 95% CI: 0.83–1.13], with no evidence of heterogeneity across these ethnicities. Smokers were at reduced risk of UC [51 studies; RR: 0.55, 95% CI: 0.48–0.64; weak evidence] irrespectively of ethnicity; however, cohort studies, large studies, and those recently published showed attenuated associations.

Conclusions

This meta-analysis did not identify any increased risk of CD in smokers in ethnicities other than non-Jewish Whites, and confirmed the protective effect of smoking on UC occurrence. Future research should characterise the genetic background of CD patients across different ethnicities to improve our understanding of the role of smoking in CD pathogenesis.
Progression of cardiac disease in patients with lamin A/C mutations
Authors: Skjølsvik Eystein T , Haugen Lie Øyvind , Chivulescu Monica , Ribe Margareth , Castrini Anna Isotta , Broch Kaspar , Pripp Are Hugo , Edvardsen Thor , Haugaa Kristina H
Published: March 2021

Aims

We aimed to study the progression of cardiac dysfunction in patients with lamin A/C mutations and explore markers of adverse cardiac outcome.

Methods and results

We followed consecutive lamin A/C genotype-positive patients divided into tertiles according to age. Patients underwent repeated clinical examinations, electrocardiograms (ECGs), and echocardiograms. We followed left ventricular (LV) and right ventricular (RV) size and function, and the severity atrioventricular-valve regurgitations. Outcome was death, LVAD implant, or cardiac transplantation. We included 101 patients [age 44 (29–54) years, 39% probands, 50% female]. We analysed 576 echocardiograms and 258 ECGs during a follow-up of 4.9 (interquartile range 2.5–8.2) years. The PR-interval increased at young age from 204 ± 73 to 212 ± 69 ms (P < 0.001), LV ejection fraction (LVEF) declined from middle age from 50 ± 12% to 47 ± 13% (P < 0.001), while LV volumes remained unchanged. RV function and tricuspid regurgitation worsened from middle age with accelerating rates. Progression of RV dysfunction [odds ratio (OR) 1.3, 95% confidence interval (CI) (1.03–1.65), P = 0.03] and tricuspid regurgitation [OR 4.9, 95% CI (1.64–14.9), P = 0.004] were associated with outcome when adjusted for age, sex, comorbidities, LVEF, and New York Heart Association functional class.

Conclusion

In patients with lamin A/C genotype, electrical disease started at young age. From middle age, LV function deteriorated progressively, while LV size remained unchanged. Worsening of RV function and tricuspid regurgitation accelerated in older age and were associated with outcome. Our systematic map on cardiac deterioration may help optimal monitoring and prognostication in lamin A/C disease.
Cardiac sarcoidosis masquerading as arrhythmogenic right ventricular cardiomyopathy: a case report
Authors: Pendela Venkata Satish , Kudaravalli Pujitha , Feitell Scott , Parikh Vishal
Published: March 2021

Background

Cardiac sarcoidosis (CS) and arrhythmogenic right ventricular cardiomyopathy (ARVC) are rare causes of ventricular arrhythmias and are associated with sudden cardiac death. Differentiation between both is important for proper management.

Case summary

We present a 56-year-old man with sudden cardiac arrest and was diagnosed to have ARVC based on cardiac magnetic resonance imaging (MRI). He developed gradually worsening shortness of breath over the next 1 year. CS was unmasked after a cardiac positron emission tomography (PET). Patient was treated with methotrexate. A repeat cardiac PET scan showed improvement.

Discussion

The distinction between ARVC and CS is challenging. Both these entities have a patchy involvement and can have similar presentations. ARVC has a predominant right heart involvement. It is diagnosed with the help of an MRI, which shows regional right ventricular wall motion abnormality. These findings can have an overlap with CS. It is important to note that, even though sarcoidosis is a pathologic diagnosis, cardiac biopsy is rarely done owing to its patchy involvement. Cardiac PET scan has a high sensitivity and specificity to diagnose this entity. Once diagnosis is made, patients should be treated with immunosuppressants and should be closely followed. Repeat imaging should be considered at intervals to monitor disease progression. This case highlights the importance of multimodality imaging and tissue diagnosis to unmask the diagnosis of CS, a treatable infiltrative disorder which shares features with a potentially untreatable ARVC.
Uncertainty, Wages and the Business Cycle
Authors: Cacciatore Matteo , Ravenna Federico
Published: March 2021

We show that limited wage flexibility in economic downturns generates strong and state-dependent amplification of uncertainty shocks. It also explains the cyclical behaviour of empirical measures of uncertainty. In the presence of matching frictions, an occasionally binding constraint on downward wage adjustment enhances the concavity of firms’ hiring rule, resulting in an endogenous profit risk-premium. In turn, higher uncertainty increases the profit risk-premium when the economy operates close to the wage constraint, deepening a recession. Non-linear local projections and vector autoregression estimates support the model predictions. In addition, we show that measured uncertainty rises in a recession even without uncertainty shocks.
Phylogeographic distribution of rhizobia nodulating common bean (Phaseolus vulgaris L.) in Ethiopia
Authors: Hailu Gunnabo Ashenafi , Geurts Rene , Wolde-meskel Endalkachew , Degefu Tulu , E. Giller Ken , van Heerwaarden Joost
Published: March 2021

Rhizobia are soilborne bacteria that form symbiotic relations with legumes and fix atmospheric nitrogen. The nitrogen fixation potential depends on several factors such as the type of host and symbionts and on environmental factors that affect the distribution of rhizobia. We isolated bacteria nodulating common bean in Southern Ethiopia to evaluate their genetic diversity and phylogeography at nucleotide, locus (gene/haplotype) and species levels of genetic hierarchy. Phylogenetically, eight rhizobial genospecies (including previous collections) were determined that had less genetic diversity than found among reference strains. The limited genetic diversity of the Ethiopian collections was due to absence of many of the Rhizobium lineages known to nodulate beans. Rhizobium etli and Rhizobiumphaseoli were predominant strains of bean-nodulating rhizobia in Ethiopia. We found no evidence for a phylogeographic pattern in strain distribution. However, joint analysis of the current and previous collections revealed differences between the two collections at nucleotide level of genetic hierarchy. The differences were due to genospecies Rhizobium aethiopicum that was only isolated in the earlier collection.
A genetic screen for temperature-sensitive morphogenesis-defective Caenorhabditis elegans mutants
Authors: Jud Molly C , Lowry Josh , Padilla Thalia , Clifford Erin , Yang Yuqi , Fennell Francesca , Miller Alexander K , Hamill Danielle , Harvey Austin M , Avila-Zavala Martha , Shao Hong , Nguyen Tran Nhan , Bao Zhirong , Bowerman Bruce
Published: March 2021

Morphogenesis involves coordinated cell migrations and cell shape changes that generate tissues and organs, and organize the body plan. Cell adhesion and the cytoskeleton are important for executing morphogenesis, but their regulation remains poorly understood. As genes required for embryonic morphogenesis may have earlier roles in development, temperature-sensitive embryonic-lethal mutations are useful tools for investigating this process. From a collection of ∼200 such Caenorhabditis elegans mutants, we have identified 17 that have highly penetrant embryonic morphogenesis defects after upshifts from the permissive to the restrictive temperature, just prior to the cell shape changes that mediate elongation of the ovoid embryo into a vermiform larva. Using whole genome sequencing, we identified the causal mutations in seven affected genes. These include three genes that have roles in producing the extracellular matrix, which is known to affect the morphogenesis of epithelial tissues in multicellular organisms: the rib-1 and rib-2 genes encode glycosyltransferases, and the emb-9 gene encodes a collagen subunit. We also used live imaging to characterize epidermal cell shape dynamics in one mutant, or1219ts, and observed cell elongation defects during dorsal intercalation and ventral enclosure that may be responsible for the body elongation defects. These results indicate that our screen has identified factors that influence morphogenesis and provides a platform for advancing our understanding of this fundamental biological process.
AC. elegansgenome-wide RNAi screen for altered levamisole sensitivity identifies genes required for muscle function
Authors: Chaya Timothy , Patel Shrey , Smith Erin M , Lam Andy , Miller Elaine N , Clupper Michael , Kervin Kirsten , Tanis Jessica E
Published: March 2021

At the neuromuscular junction (NMJ), postsynaptic ionotropic acetylcholine receptors (AChRs) transduce a chemical signal released from a cholinergic motor neuron into an electrical signal to induce muscle contraction. To identify regulators of postsynaptic function, we conducted a genome-wide RNAi screen for genes required for proper response to levamisole, a pharmacological agonist of ionotropic L-AChRs at the Caenorhabditis elegans NMJ. A total of 117 gene knockdowns were found to cause levamisole hypersensitivity, while 18 resulted in levamisole resistance. Our screen identified conserved genes important for muscle function including some that are mutated in congenital myasthenic syndrome, congenital muscular dystrophy, congenital myopathy, myotonic dystrophy, and mitochondrial myopathy. Of the genes found in the screen, we further investigated those predicted to play a role in endocytosis of cell surface receptors. Loss of the Epsin homolog epn-1 caused levamisole hypersensitivity and had opposing effects on the levels of postsynaptic L-AChRs and GABAA receptors, resulting in increased and decreased abundance, respectively. We also examined other genes that resulted in a levamisole-hypersensitive phenotype when knocked down including gas-1, which functions in Complex I of the mitochondrial electron transport chain. Consistent with altered ATP synthesis impacting levamisole response, treatment of wild-type animals with levamisole resulted in L-AChR–dependent depletion of ATP levels. These results suggest that the paralytic effects of levamisole ultimately lead to metabolic exhaustion.
Methods and tools for spatial mapping of single-cell RNAseq clusters inDrosophila
Authors: Mohr Stephanie E , Tattikota Sudhir Gopal , Xu Jun , Zirin Jonathan , Hu Yanhui , Perrimon Norbert
Published: March 2021

Single-cell RNA sequencing (scRNAseq) experiments provide a powerful means to identify clusters of cells that share common gene expression signatures. A major challenge in scRNAseq studies is to map the clusters to specific anatomical regions along the body and within tissues. Existing data, such as information obtained from large-scale in situ RNA hybridization studies, cell type specific transcriptomics, gene expression reporters, antibody stainings, and fluorescent tagged proteins, can help to map clusters to anatomy. However, in many cases, additional validation is needed to precisely map the spatial location of cells in clusters. Several approaches are available for spatial resolution in Drosophila, including mining of existing datasets, and use of existing or new tools for direct or indirect detection of RNA, or direct detection of proteins. Here, we review available resources and emerging technologies that will facilitate spatial mapping of scRNAseq clusters at high resolution in Drosophila. Importantly, we discuss the need, available approaches, and reagents for multiplexing gene expression detection in situ, as in most cases scRNAseq clusters are defined by the unique coexpression of sets of genes.
A novel allele of SIR2 reveals a heritable intermediate state of gene silencing
Authors: Farris Delaney , Saxton Daniel S , Rine Jasper
Published: March 2021

Genetic information acquires additional meaning through epigenetic regulation, the process by which genetically identical cells can exhibit heritable differences in gene expression and phenotype. Inheritance of epigenetic information is a critical step in maintaining cellular identity and organismal health. In Saccharomyces cerevisiae, one form of epigenetic regulation is the transcriptional silencing of two mating-type loci, HML and HMR, by the SIR-protein complex. To focus on the epigenetic dimension of this gene regulation, we conducted a forward mutagenesis screen to identify mutants exhibiting an epigenetic or metastable silencing defect. We utilized fluorescent reporters at HML and HMR, and screened yeast colonies for epigenetic silencing defects. We uncovered numerous independent sir1 alleles, a gene known to be required for stable epigenetic inheritance. More interestingly, we recovered a missense mutation within SIR2, which encodes a highly conserved histone deacetylase. In contrast to sir1Δ, which exhibits states that are either fully silenced or fully expressed, this sir2 allele exhibited heritable states that were either fully silenced or expressed at an intermediate level. The heritable nature of this unique silencing defect was influenced by, but not completely dependent on, changes in rDNA copy number. Therefore, this study revealed a heritable state of intermediate silencing and linked this state to a central silencing factor, Sir2.
The case for using mapped exonic non-duplicate reads when reporting RNA-sequencing depth: examples from pediatric cancer datasets
Authors: Beale Holly C , Roger Jacquelyn M , Cattle Matthew A , McKay Liam T , Thompson Drew K A , Learned Katrina , Lyle A Geoffrey , Kephart Ellen T , Currie Rob , Lam Du Linh , Sanders Lauren , Pfeil Jacob , Vivian John , Bjork Isabel , Salama Sofie R , Haussler David , Vaske Olena M
Published: March 2021

Background

The reproducibility of gene expression measured by RNA sequencing (RNA-Seq) is dependent on the sequencing depth. While unmapped or non-exonic reads do not contribute to gene expression quantification, duplicate reads contribute to the quantification but are not informative for reproducibility. We show that mapped, exonic, non-duplicate (MEND) reads are a useful measure of reproducibility of RNA-Seq datasets used for gene expression analysis.

Findings

In bulk RNA-Seq datasets from 2,179 tumors in 48 cohorts, the fraction of reads that contribute to the reproducibility of gene expression analysis varies greatly. Unmapped reads constitute 1–77% of all reads (median [IQR], 3% [3–6%]); duplicate reads constitute 3–100% of mapped reads (median [IQR], 27% [13–43%]); and non-exonic reads constitute 4–97% of mapped, non-duplicate reads (median [IQR], 25% [16–37%]). MEND reads constitute 0–79% of total reads (median [IQR], 50% [30–61%]).

Conclusions

Because not all reads in an RNA-Seq dataset are informative for reproducibility of gene expression measurements and the fraction of reads that are informative varies, we propose reporting a dataset's sequencing depth in MEND reads, which definitively inform the reproducibility of gene expression, rather than total, mapped, or exonic reads. We provide a Docker image containing (i) the existing required tools (RSeQC, sambamba, and samblaster) and (ii) a custom script to calculate MEND reads from RNA-Seq data files. We recommend that all RNA-Seq gene expression experiments, sensitivity studies, and depth recommendations use MEND units for sequencing depth.
Perception-Action Integration Is Modulated by the Catecholaminergic System Depending on Learning Experience
Authors: Eggert Elena , Bluschke Annet , Takacs Adam , Kleimaker Maximilian , Münchau Alexander , Roessner Veit , Mückschel Moritz , Beste Christian
Published: March 2021

Background

The process underlying the integration of perception and action is a focal topic in neuroscientific research and cognitive frameworks such as the theory of event coding have been developed to explain the mechanisms of perception-action integration. The neurobiological underpinnings are poorly understood. While it has been suggested that the catecholaminergic system may play a role, there are opposing predictions regarding the effects of catecholamines on perception-action integration.

Methods

Methylphenidate (MPH) is a compound commonly used to modulate the catecholaminergic system. In a double-blind, randomized crossover study design, we examined the effect of MPH (0.25 mg/kg) on perception-action integration using an established “event file coding” paradigm in a group of n = 45 healthy young adults.

Results

The data reveal that, compared with the placebo, MPH attenuates binding effects based on the established associations between stimuli and responses, provided participants are already familiar with the task. However, without prior task experience, MPH did not modulate performance compared with the placebo.

Conclusions

Catecholamines and learning experience interactively modulate perception-action integration, especially when perception-action associations have to be reconfigured. The data suggest there is a gain control–based mechanism underlying the interactive effects of learning/task experience and catecholaminergic activity during perception-action integration.
Out With the Old and in With the New? Factors Involved in Migration of Older and Newer Generation Stereotactic Breast Biopsy Markers
Authors: Stahl Brian , Li Yufeng , Hermecz Brittany , Woodard Stefanie
Published: March 2021

Objective

The purpose of this study was to investigate four commonly used stereotactic biopsy markers, two older and two newer generation, assessing percentage migration and factors influencing migration distance.

Methods

This was an IRB–approved retrospective review of upright stereotactic breast biopsies from May 2018 to May 2020 involving either older (Cork, Hourglass) or newer (Vision, X-shaped) generation markers. Markers were assessed for migration rate by two-sample Z-test and migration distance by analysis of variance. Univariate analysis was used to assess relationships between marker type and generation, patient characteristics, breast composition and thickness, procedure techniques, trainee involvement, and complications, correlating with migration distance. Multivariable analysis was performed for variables with P-value < 0.1 on univariate analysis. Tukey’s test was used to compare groups (P < 0.05).

Results

In total, 732 stereotactic biopsies were performed with 508 using a Cork, Hourglass, Vision, or X-shaped marker. Overall migration rate was 181/508 (35.6%) with no difference between markers. Breast thickness and density were negatively associated with migration distance in univariate analysis. Older marker migration distance was greater than newer (2.6 cm vs 1.9 cm, respectively), which was significant after adjusting for breast thickness and density (P = 0.037). Density was a significant factor in migration distance, comparing fatty to nonfatty breasts (P < 0.05) in univariate analysis.

Conclusion

No difference in migration rate was seen between the four markers. Vision and X-shaped markers demonstrate lower migration distance than Cork and Hourglass in multivariate analysis. There is an inverse relationship between breast density and marker migration distance.
Using Payroll Tax Variation to Unpack the Black Box of Firm-Level Production
Authors: Benzarti Youssef , Harju Jarkko
Published: March 2021

This paper uses quasi-experimental variation in payroll tax rates in Finland to investigate how firms use their input factors. We find that higher payroll tax rates lead to large employment responses and have no effects on employee-level earnings. As payroll taxes increase, firms substitute away from low-skilled, routine, and manual workers. Higher firm-level payroll tax rates also slightly decrease the total output of firms. Our results imply that firm-level production and input factor choices are clearly affected by payroll taxes.
Design of a New Distributed NoSQL Database with Distributed Hash Tables
Authors: San Román Guzmán Agustín , Valdeolmillos Diego , Rivas Alberto , González Arrieta Angélica , Chamoso Pablo
Published: March 2021

Databases play a fundamental role in today’s world, being used by most companies, especially those that offer services through the Internet. Today there is a wide variety of database models, each adapted for use according to the specific requirements of each application. Traditionally, the relational models with centralized architectures have been used mostly due to their simplicity and general-purpose query language, which made relational systems suitable for almost any application. However, with the growth of the Internet in recent decades, both in the number of users and in the amount of information, those centralized models began to suffer availability and scalability issues. To address those issues, the use of decentralized architectures and alternative database models began to arise, eventually replacing relational databases and centralized architectures when the requirements on availability and scalability are high. Those database models alternative to the traditional relational model are grouped under the name of NoSQL (Not only Structured Query Language). In this article, we present a NoSQL database developed as an end of degree work, with a flexible data model based on documents and a fully decentralized architecture based on the Gossip protocol for node discovery and a distributed hash table, in particular the rendezvous hashing algorithm, used to distribute and replicate the data across all the nodes. The main goals of the system are to achieve high availability (the data should be almost always accessible) and high scalability (the system should be able to scale by increasing the number of nodes to increase its capacity both on data and number of users). High availability is achieved thanks to the replication of the data, while high scalability is achieved by its decentralized architecture, which allows multiple entry points from the requests, and the data distribution, effectively increasing the database capacity by increasing the number of nodes.
Climatic factors and population demography in big-eared woodrat,Neotoma macrotis
Authors: Rolland Virginie , Tietje William D , Polyakov Anne Y , Chaudhary Vratika , Oli Madan K
Published: March 2021

Changes in temperature and rainfall patterns can have marked impacts on small mammal populations that inhabit environments with highly fluctuating water availability. With projected increases in droughts and fewer but more intense rainfall events in the Southwestern United States, the persistence of many wildlife populations may be threatened. Our goal was to assess how temperature and rainfall during distinct dry and wet seasons influenced the dynamics of a population of big-eared woodrats (Neotoma macrotis) in a mixed oak woodland of coastal central California. We applied Pradel’s temporal symmetry models to our 21-year biannual capture–mark–recapture data set (1993–2014) to determine the effects of climatic factors on the woodrats’ apparent survival (Φ) and recruitment rate (f). Monthly Φ averaged 0.945 ± 0.001 and varied with season. Monthly f was 0.064 ± 0.001 in the wet season (f was fixed to 0 in the dry season). Monthly population growth rate (λ) varied from 0.996 ± 0.001 during the dry season to 1.001 ± 0.001 during the wet season, which indicated a stable population (0.999 ± 0.001). Total rainfall from the previous season and mean temperature during the same season positively influenced Φ and f. By contrast, Φ and f were negatively influenced by mean temperature from the previous season and total rainfall in the same season. The resulting λ fluctuated with total rainfall, particularly in the wet season. Our results suggest that the big-eared woodrat population may not be substantially affected by warm temperatures per se, potentially because of the microclimate provided by its stick houses. We also discuss its adaptability to local food resources and relatively slow life history relative to other cricetids, and propose that the big-eared woodrat population may be equipped to cope with future climate change.
Progression of Frailty in Survivors of Childhood Cancer: A St. Jude Lifetime Cohort Report
Authors: Delaney Angela , Howell Carrie R , Krull Kevin R , Brinkman Tara M , Armstrong Gregory T , Chemaitilly Wassim , Wilson Carmen L , Mulrooney Daniel A , Wang Zhaoming , Lanctot Jennifer Q , Johnson Ruth E , Krull Matthew R , Partin Robyn E , Shelton Kyla C , Srivastava Deo Kumar , Robison Leslie L , Hudson Melissa M , Ness Kirsten K
Published: March 2021

Background

Some adult survivors of childhood cancers develop frailty at higher rates than expected based on their chronological age. This study examined the incidence of frailty among survivors at 10 or more years after diagnosis, frailty prevalence 5 years later, and risk factors for becoming frail.

Methods

Frailty was measured at study entry and 5 years later. Logistic regression tested the associations of several factors with having frailty at 5 years for all participants and separately by sex and by study entry frailty status. Cox models evaluated the hazard of death associated with entry frailty considering covariates.

Results

Cancer survivors (range = 0-22 years at diagnosis, median = 7 years) were ages 18-45 years (median = 30 years) at study entry. Frailty prevalence increased from 6.2% (95% confidence interval [CI] = 5.0% to 7.5%) to 13.6% (95% CI = 11.9% to 15.4%) at 5 years. Risk factors for frailty at follow-up among all survivors included chest radiation 20 Gy or higher (odds ratio [OR] = 1.98, 95% CI = 1.29 to 3.05), cardiac (OR = 1.58, 95% CI = 1.02 to 2.46), and neurological (OR = 2.58, 95% CI = 1.69 to 3.92) conditions; lack of strength training (OR = 1.74, 95% CI = 1.14 to 2.66); sedentary lifestyle (OR = 1.75, 95% CI = 1.18 to 2.59); and frailty at study entry (OR = 11.12, 95% CI = 6.64 to 18.61). The strongest risk factor for death during follow-up was prior frailty (OR = 3.52, 95% CI = 1.95 to 6.32).

Conclusions

Prevalent frailty more than doubled at 5 years after study entry among adult childhood cancer survivors. Frailty at entry was the strongest risk factor for death. Because treatment exposures cannot be changed, mitigation of other risk factors for frailty, including lack of strength training and sedentary lifestyle, may decrease risk of adverse health events and improve longevity in survivors.
Novel Glutamine Antagonist JHU395 Suppresses MYC-Driven Medulloblastoma Growth and Induces Apoptosis
Authors: Pham Khoa , Maxwell Micah J , Sweeney Heather , Alt Jesse , Rais Rana , Eberhart Charles G , Slusher Barbara S , Raabe Eric H
Published: March 2021

Medulloblastoma is the most common malignant pediatric brain tumor. Amplification of c-MYC is a hallmark of a subset of poor-prognosis medulloblastoma. MYC upregulates glutamine metabolism across many types of cancer. We modified the naturally occurring glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) by adding 2 promoeities to increase its lipophilicity and brain penetration creating the prodrug isopropyl 6-diazo-5-oxo-2-(((phenyl (pivaloyloxy) methoxy) - carbonyl) amino) hexanoate, termed JHU395. This prodrug was shown to have a 10-fold improved CSF-to-plasma ratio and brain-to-plasma ratio relative to DON. We hypothesized that JHU395 would have superior cell penetration compared with DON and would effectively and more potently kill MYC-expressing medulloblastoma. JHU395 treatment caused decreased growth and increased apoptosis in multiple human high-MYC medulloblastoma cell lines at lower concentrations than DON. Parenteral administration of JHU395 in Nu/Nu mice led to the accumulation of micromolar concentrations of DON in brain. Treatment of mice bearing orthotopic xenografts of human MYC-amplified medulloblastoma with JHU395 increased median survival from 26 to 45 days compared with vehicle control mice (p < 0.001 by log-rank test). These data provide preclinical justification for the ongoing development and testing of brain-targeted DON prodrugs for use in medulloblastoma.
Predicting photosynthetic capacity in tobacco using shortwave infrared spectral reflectance
Authors: Sexton Thomas , Sankaran Sindhuja , Cousins Asaph B
Published: March 2021

Plateauing yield and stressful environmental conditions necessitate selecting crops for superior physiological traits with untapped potential to enhance crop performance. Plant productivity is often limited by carbon fixation rates that could be improved by increasing maximum photosynthetic carboxylation capacity (Vcmax). However, Vcmax measurements using gas exchange and biochemical assays are slow and laborious, prohibiting selection in breeding programs. Rapid hyperspectral reflectance measurements show potential for predicting Vcmax using regression models. While several hyperspectral models have been developed, contributions from different spectral regions to predictions of Vcmax have not been clearly identified or linked to biochemical variation contributing to Vcmax. In this study, hyperspectral reflectance data from 350–2500 nm were used to build partial least squares regression models predicting in vivo and in vitro Vcmax. Wild-type and transgenic tobacco plants with antisense reductions in Rubisco content were used to alter Vcmax independent from chlorophyll, carbon, and nitrogen content. Different spectral regions were used to independently build partial least squares regression models and identify key regions linked to Vcmax and other leaf traits. The greatest Vcmax prediction accuracy used a portion of the shortwave infrared region from 2070 nm to 2470 nm, where the inclusion of fewer spectral regions resulted in more accurate models.
A Commissioner’s Day: Quantitative approaches to the study of evidence in royal commissions of inquiry
Authors: Parkinson Naomi , Doherty Stephen , Ford Lisa
Published: March 2021

This article uses statistical data gathered from digitized and indexed journals to quantify the identity, status, purpose, and impact of visitors to a series of Royal Commissions of Inquiry dispatched to the Cape and Mauritius from 1823. The 1819–38 Commissions of Inquiry were unprecedented in their scope and unparalleled in their impacts. They generated an archive spanning over 150,000 handwritten pages and recommended the complete overhaul of legal systems; colonial governance and systems of slavery on the basis of their findings. Yet, making sense of this enormous archive and understanding whose testimony shaped empire-wide reform remains a daunting task. Here, we focus on one small, but significant, portion of that archive: commissioners’ journals of proceedings. By collating, analysing, and visualizing data on names, status, gender, and topics of inquiry, we test the value of these documents as a frame to navigate the wider archive and to explore patterns in who was attending commissions, how often, and how their testimony was received. In contextualizing this data, we identify different rhythms of inquiry within and between colonies and conclude that a quantitative approach enabled us to test hypotheses based on archival research and uncover previously hidden patterns leading to new lines of future inquiry.
Molecular mechanism of RNase R substrate sensitivity for RNA ribose methylation
Authors: Abula Abudureyimu , Li Xiaona , Quan Xing , Yang Tingting , Liu Yue , Guo Hangtian , Li Tinghan , Ji Xiaoyun
Published: March 2021

RNA 2′-O-methylation is widely distributed and plays important roles in various cellular processes. Mycoplasma genitalium RNase R (MgR), a prokaryotic member of the RNase II/RNB family, is a 3′-5′ exoribonuclease and is particularly sensitive to RNA 2′-O-methylation. However, how RNase R interacts with various RNA species and exhibits remarkable sensitivity to substrate 2′-O-methyl modifications remains elusive. Here we report high-resolution crystal structures of MgR in apo form and in complex with various RNA substrates. The structural data together with extensive biochemical analysis quantitively illustrate MgR’s ribonuclease activity and significant sensitivity to RNA 2′-O-methylation. Comparison to its related homologs reveals an exquisite mechanism for the recognition and degradation of RNA substrates. Through structural and mutagenesis studies, we identified proline 277 to be responsible for the significant sensitivity of MgR to RNA 2′-O-methylation within the RNase II/RNB family. We also generated several MgR variants with modulated activities. Our work provides a mechanistic understanding of MgR activity that can be harnessed as a powerful RNA analytical tool that will open up a new venue for RNA 2′-O-methylations research in biological and clinical samples.
Nearest-neighbour transition-state analysis for nucleic acid kinetics
Authors: Rejali Nick A , Ye Felix D , Zuiter Aisha M , Keller Caroline C , Wittwer Carl T
Published: March 2021

We used stopped-flow to monitor hypochromicity for 43 oligonucleotide duplexes to study nucleic acid kinetics and extract transition-state parameters for association and dissociation. Reactions were performed in 1.0 M NaCl (for literature comparisons) and 2.2 mM MgCl2 (PCR conditions). Dissociation kinetics depended on sequence, increased exponentially with temperature, and transition-state parameters inversely correlated to thermodynamic parameters (r = −0.99). Association had no consistent enthalpic component, varied little with temperature or sequence, and poorly correlated to thermodynamic parameters (r = 0.28). Average association rates decreased 78% in MgCl2 compared to NaCl while dissociation was relatively insensitive to ionic conditions. A nearest-neighbour kinetic model for dissociation predicted rate constants within 3-fold of literature values (n = 11). However, a nearest-neighbour model for association appeared overparameterized and inadequate for predictions. Kinetic predictions were used to simulate published high-speed (<1 min) melting analysis and extreme (<2 min) PCR experiments. Melting simulations predicted apparent melting temperatures increase on average 2.4°C when temperature ramp rates increased from 0.1 to 32°C/s, compared to 2.8°C reported in the literature. PCR simulations revealed that denaturation kinetics are dependent on the thermocycling profile. Simulations overestimated annealing efficiencies at shorter annealing times and suggested that polymerase interactions contribute to primer-template complex stability at extension temperatures.
The effect of grape interventions on cognitive and mental performance in healthy participants and those with mild cognitive impairment: a systematic review of randomized controlled trials
Authors: Bird Rachel Jayne , Hoggard Nigel , Aceves-Martins Magaly
Published: March 2021

Context

The prevalence of cognitive and mental health disorders are growing, and existing drug therapies do not treat the underlying cause. Grapes are a flavonoid-rich soft fruit and may therefore be beneficial to cognitive and mental health.

Objective

To systematically review evidence from randomized controlled trials investigating the acute and chronic effects of grape interventions on measures of cognition and mood in healthy participants and those with mild cognitive impairment.

Data Sources

MEDLINE, The Cochrane Library and EMBASE were searched.

Data Extraction and Analysis

Eight studies met the inclusion criteria: one considered acute interventions, 6 assessed chronic effects, and one assessed acute and chronic effects of grapes. The chronic studies found improvements in some cognitive domains (eg, memory, motor skills, or executive function). Acute studies found no consistent effect on memory but saw improvements in reaction time.

Conclusions

Differences in study design, dosages, and outcome tests hindered between-study comparison. Even so, the results across studies show that grapes can enhance some aspects of cognition, after both acute and chronic interventions.

Systematic Review Registration

PROSPERO registration no. CRD42020193062.
The impact of tryptophan supplementation on sleep quality: a systematic review, meta-analysis, and meta-regression
Authors: Sutanto Clarinda N , Loh Wen Wei , Kim Jung Eun
Published: March 2021

Context

L-tryptophan (Trp) has been documented to aid sleep, but a systematic compilation of its effect on sleep quality is still limited.

Objective

We assessed the effect of Trp supplementation on sleep quality via meta-analysis and meta-regression. The effects of daily Trp dose (<1 g and ≥1 g) were also assessed.

Data sources

A database search was done in PubMed, Medline (Ovid), Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Cochrane and a total of 18 articles were collected.

Data extraction

Extracted data from 4 articles were also analyzed using random-effect meta-analysis and meta-regression. Standardized mean difference (SMD) was used in meta-analysis.

Data analysis

Results from the study suggested that Trp supplementation can shorten wake after sleep onset (−81.03 min/g, P = 0.017; SMD, −1.08 min [95%CI, −1.89 to −0.28]). In addition, the group receiving ≥1 g Trp supplementation had a shorter wake after sleep onset than the group with Trp < 1g supplementation (Trp <1 g vs Trp ≥1 g: 56.55 vs 28.91 min; P = 0.001). However, Trp supplementation did not affect other sleep components.

Conclusion

Trp supplementation, especially at ≥1 g can help improve sleep quality.
Signatures of large-scale cold fronts in the optically-selected merging cluster HSC J085024+001536
Authors: Tanaka Keigo , Fujimoto Ryuichi , Okabe Nobuhiro , Mitsuishi Ikuyuki , Akamatsu Hiroki , Ota Naomi , Oguri Masamune , Nishizawa Atsushi J
Published: March 2021

We represent a joint X-ray, weak-lensing, and optical analysis of the optically-selected merging cluster, HSC J085024+001536, from the Subaru HSC-SSP survey. Both the member galaxy density and the weak-lensing mass map show that the cluster is composed of south-east and north-west components. The two-dimensional weak-lensing analysis shows that the south-east component is the main cluster, and the sub-cluster and main cluster mass ratio is $0.32^{+0.75}_{-0.23}$. The north-west sub-cluster is offset by ∼700 kpc from the main cluster center, and their relative line-of-sight velocity is ∼1300 km s−1 from spectroscopic redshifts of member galaxies. The X-ray emission is concentrated around the main cluster, while the gas mass fraction within a sphere of 1′ radius of the sub-cluster is only $f_{\mathrm{gas}}=4.0^{+2.3}_{-3.3}\%$, indicating that the sub-cluster gas was stripped by ram pressure. An X-ray residual image shows three arc-like excess patterns, of which two are symmetrically located at ∼550 kpc from the X-ray morphological center, and the other is close to the X-ray core. The excess close to the sub-cluster has a cold-front feature where dense-cold gas and thin-hot gas contact. The two outer excesses are tangentially elongated about ∼450–650 kpc, suggesting that the cluster is merged with a non-zero impact parameter. Overall features revealed by the multi-wavelength datasets indicate that the cluster is at the second impact or later. Since the optically-defined merger catalog is unbiased for merger boost of the intracluster medium, X-ray follow-up observations will pave the way to understand merger physics at various phases.
Newly approved IV acetaminophen in Canada: Switching from oral to IV acetaminophen. Is IV worth the price difference? A systematic review
Authors: Ulrich Maxime , Chamberland Martine , Bertoldi Christel , Garcia-Bournissen Facundo , Kleiber Niina
Published: March 2021

Context

The use of intravenous acetaminophen leads to meaningful health cost increases for paediatric institutions. Therefore, strict criteria for intravenous acetaminophen administration are needed.

Objective

To undertake a systematic review of available evidence comparing oral versus intravenous acetaminophen use in children.

Method

A systematic literature search was conducted on five databases. All prospective interventional studies comparing intravenous to oral acetaminophen in patients <18 years old were included. Data collection and analysis were done according to PRISMA guidelines.

Results

Among 6,417 retrieved abstracts, 29 full-text articles were assessed of which 3 were retained. (1) Pharmacokinetic: Oral bioavailability (72% with a high inter-individual variability) was reported in 47 stable patients in a paediatric intensive care unit. (2) Analgesia: In a double-blind randomized controlled trial of 45 children, no difference in analgesia was found between oral and intravenous administration after cleft palate repair. (3) Fever: In an open-label prospective observational study of 200 children, temperature decreased faster after intravenous than oral administration but was similar 4 hours later.

Conclusions

Available data are insufficient to guide clinicians with a rational choice of route of administration. Oral bioavailability should be studied in paediatric populations outside the intensive care unit. Despite the widespread use of intravenous acetaminophen, there is little evidence to suggest that it improves analgesia compared to the oral formulation. Similarly, fever weans faster but whether this translates into any meaningful clinical outcome is unknown. The lack of data plus the significantly higher costs of intravenous acetaminophen should motivate further research.
Central Neuropathic Pain in Multiple Sclerosis Is Associated with Impaired Innocuous Thermal Pathways and Neuronal Hyperexcitability
Authors: Rivel Michal , Achiron Anat , Dolev Mark , Stern Yael , Zeilig Gabi , Defrin Ruth
Published: March 2021

Objective

About one-third of patients with multiple sclerosis (MS) suffers from chronic and excruciating central neuropathic pain (CNP). The mechanism underlying CNP in MS is not clear, since previous studies are scarce and their results are inconsistent. Our aim was to determine whether CNP in MS is associated with impairment of the spinothalamic-thalamocortical pathways (STTCs) and/or increased excitability of the pain system.

Design

The study was cross-sectional

Setting

The study was conducted at a general hospital

Participants

Participants were 47 MS patients with CNP, 42 MS patients without CNP and 32 healthy controls.

Methods

Sensory testing included the measurement of temperature, pain, and touch thresholds and the thermal grill illusion for evaluating STTCs function and hyperpathia and allodynia as indicators of hyperexcitability. CNP was characterized using interviews and questionnaires.

Results

The CNP group had higher cold and warm thresholds (P < 0.01), as well as higher thermal grill illusion perception thresholds (P < 0.05), especially in painful body regions compared with controls, whereas touch and pain thresholds values were normal. The CNP group also had a significantly greater prevalence of hyperpathia and allodynia. Regression analysis revealed that whereas presence of CNP was associated with a higher cold threshold, CNP intensity and the number of painful body regions were associated with allodynia and hyperpathia, respectively.

Conclusions

CNP in MS is characterized by a specific impairment of STTC function, the innocuous thermal pathways, and by pain hyperexcitability. Whereas CNP presence is associated with STTC impairment, its severity and extent are associated with pain hyperexcitability. Interventions that reduce excitability level may therefore mitigate CNP severity.