bluuebunny/crossref_metadata_2025 huggingface dataset:
Anticancer drug-induced life-threatening ventricular arrhythmias: a World Health Organization pharmacovigilance study
Authors: Salem Joe-Elie , Nguyen Lee S , Moslehi Javid J , Ederhy Stéphane , Lebrun-Vignes Bénédicte , Roden Dan M , Funck-Brentano Christian , Gougis Paul
Published: May 2021

Aims

With the explosion of anticancer drugs, an emerging concern is the risk for drug-induced sudden death (SD) via ventricular arrhythmias (VA).

Methods and results

We used the international pharmacovigilance database VigiBase (n = 18 441 659 reports) to compare drug-induced long QT (diLQT, n = 18 123) and VA (n = 29 193) including torsade de pointes (TdP, n = 8163) reporting for 663 anticancer drugs vs. all other drugs until 01/01/2019. The analysis used the 95% lower-end credibility interval of the information component (IC025), an indicator for disproportionate Bayesian reporting; significant when IC025 >0. There were 2301 reports (13.8% fatal) for 40 anticancer drugs significantly associated with diLQT (with 27 also associated with VA or SD) and 9 drugs associated with VA without diLQT. Half of these (46.9%, 23/49) were associated with SD. Most (41%, 20/49) were kinase inhibitors, 8% (4/49) were hormonal therapies, 6% (3/49) were immunotherapies, 24% (12/49) were cytotoxics, and 20% (10/49) were miscellaneous. In VigiBase, reports of diLQT, TdP, or VA increased from 580 in the period 1967–83 to 15 070 in 2014–18 with the proportion related to anticancer drugs increasing from 0.9% (5/580) to 14.0% (2115/15 070) (P < 0.0001). Concordance between these VigiBase signals and data concerning diLQT and VA/TdP identified in CredibleMeds or US Food and Drug Administration (FDA) labels was moderate (κ = 0.47 and 0.40, P < 0.0001). Twenty-three drugs represent new signals, while 24 flagged by CredibleMeds or FDA had no signal in VigiBase. A three-level SD risk stratification relying on isolated long QT (low risk), associated with VA without SD (moderate risk), and VA with SD (high risk) is proposed.

Conclusion

This list of liable anticancer drugs may prove useful for physicians and regulatory authorities to re-evaluate cardiac monitoring requirements.

Clinical trial registration

NCT03530215.
Age Trends in Growth and Differentiation Factor-11 and Myostatin Levels in Healthy Men, and Differential Response to Testosterone, Measured Using Liquid Chromatography–Tandem Mass Spectrometry
Authors: Peng Liming , Gagliano-Jucá Thiago , Pencina Karol M , Krishnan Srinivasan , Li Zhuoying , Tracy Russell P , Jasuja Ravi , Bhasin Shalender
Published: May 2021

Background

Growth and differentiation factor (GDF)-11 controls embryonic development and has been proposed as an antiaging factor. GDF-8 (myostatin) inhibits skeletal muscle growth. Difficulties in accurately measuring circulating GDF-11 and GDF-8 have generated controversy.

Methods

We developed a liquid chromatography–tandem mass spectrometry (LC–MS/MS) method for simultaneous measurement of circulating GDF-8 and GDF-11 that employs denaturation, reduction, and alkylation; cation-exchange solid-phase extraction; tryptic digestion; followed by separation and quantification using 2 signature peptides for multiple reaction monitoring and C-terminal [13C615N4]-Arg peptides as internal standards. We evaluated age trends in serum GDF-11 and GDF-8 concentrations in community-dwelling healthy men, 19 years or older, and determined the effects of graded testosterone doses on GDF-8 and GDF-11 concentrations in healthy men in a randomized trial.

Results

The assay demonstrated linearity over a wide range, lower limit of quantitation 0.5 ng/mL for both proteins, and excellent precision, accuracy, and specificity (no detectable cross-reactivity of GDF-8 in GDF-11 assay or of GDF-11 in GDF-8 assay). Mean ± SD (median ± 1QR) GDF-8 and GDF-11 levels in healthy community-dwelling men, 19 years and older, were 7.2 ± 1.9 (6.8 ± 1.4) ng/mL. Neither GDF-8 nor GDF-11 levels were related to age or body composition. Testosterone treatment significantly increased serum GDF-8 but not GDF-11 levels.

Conclusions

The LC–MS/MS method for the simultaneous measurement of circulating total GDF-8 and GDF-11 demonstrates the characteristics of a valid assay. Testosterone treatment increased GDF-8 levels, but not GDF-11. Increase in GDF-8 levels by testosterone treatment, which increased muscle mass, suggests that GDF-8 acts as a chalone to restrain muscle growth.
Mobility of Older Adults: Gait Quality Measures Are Associated With Life-Space Assessment Scores
Authors: Suri Anisha , Rosso Andrea L , VanSwearingen Jessie , Coffman Leslie M , Redfern Mark S , Brach Jennifer S , Sejdić Ervin
Published: May 2021

Background

The relation of gait quality to real-life mobility among older adults is poorly understood. This study examined the association between gait quality, consisting of step variability, smoothness, regularity, symmetry, and gait speed, and the Life-Space Assessment (LSA).

Method

In community-dwelling older adults (N = 232, age 77.5 ± 6.6, 65% females), gait quality was derived from (i) an instrumented walkway: gait speed, variability, and walk ratio and (ii) accelerometer: signal variability, smoothness, regularity, symmetry, and time-frequency spatiotemporal variables during 6-minute walk. In addition to collecting LSA scores, cognitive functioning, walking confidence, and falls were recorded. Spearman correlations (speed as covariate) and random forest regression were used to assess associations between gait quality and LSA, and Gaussian mixture modeling (GMM) was used to cluster participants.

Results

Spearman correlations of ρ p = .11 (signal amplitude variability mediolateral [ML] axis), ρ p = .15 and ρ p = −.13 (symmetry anterior-posterior–vertical [AP–V] and ML–AP axes, respectively), ρ p = .16 (power V), and ρ = .26 (speed), all p <.05 and marginally related, ρ p = −.12 (regularity V), ρ p = .11 (smoothness AP), and ρ p = −.11 (step-time variability), all p <.1, were obtained. The cross-validated random forest model indicated good-fit LSA prediction error of 17.77; gait and cognition were greater contributors than age and gender. GMM indicated 2 clusters. Group 1 (n = 189) had better gait quality than group 2 (n = 43): greater smoothness AP (2.94 ± 0.75 vs 2.30 ± 0.71); greater similarity AP–V (.58 ± .13 vs .40 ± .19); lower regularity V (0.83 ± 0.08 vs 0.87 ± 0.10); greater power V (1.86 ± 0.18 vs 0.97 ± 1.84); greater speed (1.09 ± 0.16 vs 1.00 ± 0.16 m/s); lower step-time coefficient of variation (3.70 ± 1.09 vs 5.09 ± 2.37), and better LSA (76 ± 18 vs 67 ± 18), padjusted < .004.

Conclusions

Gait quality measures taken in the clinic are associated with real-life mobility in the community.
Assessing What Matters Most in Older Adults With Multicomplexity
Authors: Moye Jennifer , Driver Jane A , Owsiany Montgomery T , Chen Li Qing , Whitley Jessica Cruz , Auguste Elizabeth J , Paik Julie M
Published: May 2021

Background and Objectives

Abilities and activities that are often simultaneously valued may not be simultaneously achievable for older adults with multicomplexity. Because of this, the Geriatrics 5Ms framework prioritizes care on “what matters most.” This study aimed to evaluate and refine the What Matters Most—Structured Tool (WMM-ST).

Research Design and Methods

About 105 older adults with an average of 4 chronic conditions completed the WMM-ST along with open-ended questions from the Serious Illness Conversation Guide. Participants also provided demographic and social information, completed cognitive screening with the Telephone-Montreal Cognitive Assessment-Short and frailty screening with the Frail scale. Quantitative and qualitative analyses aimed to (a) describe values; (b) evaluate the association of patient characteristics with values; and (c) assess validity via the tool’s acceptability, educational bias, and content accuracy.

Results

Older adults varied in what matters most. Ratings demonstrated modest associations with social support, religiosity, cognition, and frailty, but not with age or education. The WMM-ST was rated as understandable (86%) and applicable to their current situation (61%) independent of education. Qualitative analyses supported the content validity of WMM-ST, while revealing additional content.

Discussion and Implications

It is possible to assess what matters most to older adults with multicomplexity using a structured tool. Such tools may be useful in making an abstract process clearer but require further validation in diverse samples.
Cell surface integrin α5ß1 clustering negatively regulates receptor tyrosine kinase signaling in colorectal cancer cells via glycogen synthase kinase 3
Authors: Starchenko Alina , Graves-Deal Ramona , Brubaker Douglas , Li Cunxi , Yang Yuping , Singh Bhuminder , Coffey Robert J , Lauffenburger Douglas A
Published: May 2021

As a key process within the tissue microenvironment, integrin signaling can influence cell functional responses to growth factor stimuli. We show here that clustering of integrin α5ß1 at the plasma membrane of colorectal cancer-derived epithelial cells modulates their ability to respond to stimulation by receptor tyrosine kinase (RTK)-activating growth factors EGF, NRG and HGF, through GSK3-mediated suppression of Akt pathway. We observed that integrin α5ß1 is lost from the membrane of poorly organized human colorectal tumors and that treatment with the integrin-clustering antibody P4G11 is sufficient to induce polarity in a mouse tumor xenograft model. While adding RTK growth factors (EGF, NRG and HGF) to polarized colorectal cancer cells induced invasion and loss of monolayer formation in 2D and 3D, this pathological behavior could be blocked by P4G11. Phosphorylation of ErbB family members as well as MET following EGF, NRG and HGF treatment was diminished in cells pretreated with P4G11. Focusing on EGFR, we found that blockade of integrin α5ß1 increased EGFR phosphorylation. Since activity of multiple downstream kinase pathways were altered by these various treatments, we employed computational machine learning techniques to ascertain the most important effects. Partial least-squares discriminant analysis identified GSK3 as a major regulator of EGFR pathway activities influenced by integrin α5ß1. Moreover, we used partial correlation analysis to examine signaling pathway crosstalk downstream of EGF stimulation and found that integrin α5ß1 acts as a negative regulator of the AKT signaling cascade downstream of EGFR, with GSK3 acting as a key mediator. We experimentally validated these computational inferences by confirming that blockade of GSK3 activity is sufficient to induce loss of polarity and increase of oncogenic signaling in the colonic epithelial cells.
Two Kinds of “Bad” Musical Performance: Musical and Moral Mistakes
Authors: London Justin
Published: May 2021

There are many ways in which a musical performance can be “bad,” but here the focus is on two: those performances that make you laugh, and those that make you angry. These forms of musical badness, however, are not primarily compositional deficits, but either (a) that the performer simply cannot competently deliver the music to their audience, inducing laughter, or (b) that the performer exhibits some form of disrespect, provoking anger. Such laughter or anger stems from failure of the expected relationship between a performer and their audience, that is, a social failure. After surveying a range of musical faults, the article examines the causes of laughter in general and in relation to some of examples of risible “bad” music. Similarly, the causes of social and moral anger in general are examined, and several cases of anger-inducing musical performances are presented. The article concludes with a consideration of the broader implications of these responses to “bad” music for theories of emotional expression in music, the relationship between aesthetic and moral judgments, and the centrality of musical performances as opposed to works in discussions of musical expression and value.
Ontogenetic changes in cheliped and uropod morphology of the symbiotic shrimp Stenalpheops anacanthus Miya, 1997 (Decapoda: Caridea: Alpheidae): implications for the taxonomy of the genus
Authors: Aldea Kristian Q , Henmi Yumi , Itani Gyo
Published: May 2021

We investigated collections of the alpheid shrimp Stenalpheops Miya, 1997, symbiotic in the burrows of gebiidean and axiidean shrimps, in Tokyo Bay, Japan to clarify ontogenetic changes in the diagnostic morphology of the cheliped and uropod. The uropod flaps were found only among the largest male shrimp, none among females. The number of articles of the uropod flap ranged from one to five, and uropod length was positively correlated with the length of the carapace. Furthermore, no chelae showing a subcheliped shape were found, while the angle of the propodus-pollex decreased with the development of the carapace. Ontogenetic changes in these characters support the view that the male cheliped is normal in S. anacanthus Miya, 1997 (subcheliped in S. crangonus Anker, Jeng & Chan, 2001), and the uropod flap is found only in the large males of S. anacanthus (in both males and females in S. crangonus).
Finding the missing piece of the puzzle: how NMCPs fit into the plant nuclear lamina
Authors: Graumann Katja
Published: May 2021

This article comments on:

Masuda K, Hikida R, Fujino K. 2021. The plant nuclear lamina proteins NMCP1 and NMCP2 form a filamentous network with lateral filament associations. Journal of Experimental Botany 72, 6190–6204.
Deep conservation of ribosome stall sites across RNA processing genes
Authors: Chyżyńska Katarzyna , Labun Kornel , Jones Carl , Grellscheid Sushma N , Valen Eivind
Published: May 2021

The rate of translation can vary depending on the mRNA template. During the elongation phase the ribosome can transiently pause or permanently stall. A pause can provide the nascent protein with the time to fold or be transported, while stalling can serve as quality control and trigger degradation of aberrant mRNA and peptide. Ribosome profiling has allowed for the genome-wide detection of such pauses and stalls, but due to library-specific biases, these predictions are often unreliable. Here, we take advantage of the deep conservation of protein synthesis machinery, hypothesizing that similar conservation could exist for functionally important locations of ribosome slowdown, here collectively called stall sites. We analyze multiple ribosome profiling datasets from phylogenetically diverse eukaryotes: yeast, fruit fly, zebrafish, mouse and human to identify conserved stall sites. We find thousands of stall sites across multiple species, with the enrichment of proline, glycine and negatively charged amino acids around conserved stalling. Many of the sites are found in RNA processing genes, suggesting that stalling might have a conserved role in RNA metabolism. In summary, our results provide a rich resource for the study of conserved stalling and indicate possible roles of stalling in gene regulation.
GeneMark-HM: improving gene prediction in DNA sequences of human microbiome
Authors: Lomsadze Alexandre , Bonny Christophe , Strozzi Francesco , Borodovsky Mark
Published: May 2021

Computational reconstruction of nearly complete genomes from metagenomic reads may identify thousands of new uncultured candidate bacterial species. We have shown that reconstructed prokaryotic genomes along with genomes of sequenced microbial isolates can be used to support more accurate gene prediction in novel metagenomic sequences. We have proposed an approach that used three types of gene prediction algorithms and found for all contigs in a metagenome nearly optimal models of protein-coding regions either in libraries of pre-computed models or constructed de novo. The model selection process and gene annotation were done by the new GeneMark-HM pipeline. We have created a database of the species level pan-genomes for the human microbiome. To create a library of models representing each pan-genome we used a self-training algorithm GeneMarkS-2. Genes initially predicted in each contig served as queries for a fast similarity search through the pan-genome database. The best matches led to selection of the model for gene prediction. Contigs not assigned to pan-genomes were analyzed by crude, but still accurate models designed for sequences with particular GC compositions. Tests of GeneMark-HM on simulated metagenomes demonstrated improvement in gene annotation of human metagenomic sequences in comparison with the current state-of-the-art gene prediction tools.
Performance and Operational Evaluation of the Access Bio CareStart Rapid Antigen Test in a High-Throughput Drive-Through Community Testing Site in Massachusetts
Authors: Pollock Nira R , Tran Kristine , Jacobs Jesica R , Cranston Amber E , Smith Sita , O’Kane Claire Y , Roady Tyler J , Moran Anne , Scarry Alison , Carroll Melissa , Volinsky Leila , Perez Gloria , Patel Pinal , Gabriel Stacey , Lennon Niall J , Madoff Lawrence C , Brown Catherine , Smole Sandra C
Published: May 2021

Background

To facilitate deployment of point-of-care testing for severe acute respiratory syndrome coronavirus 2, we evaluated the Access Bio CareStart COVID-19 Antigen test in a high-throughput, drive-through, free community testing site using anterior nasal (AN) swab reverse-transcription polymerase chain reaction (RT-PCR) for clinical testing.

Methods

Consenting symptomatic and asymptomatic children (≤18 years) and adults received dual AN swabs. CareStart testing was performed with temperature/humidity monitoring. All tests had 2 independent reads to assess interoperator agreement. Patients with positive CareStart results were called and instructed to isolate pending RT-PCR results. The paired RT-PCR result was the reference for sensitivity and specificity calculations.

Results

Of 1603 participants, 1245 adults and 253 children had paired RT-PCR/CareStart results and complete symptom data. Eighty-three percent of adults and 87% of children were asymptomatic. CareStart sensitivity/specificity were 84.8% (95% confidence interval [CI], 71.1–93.7)/97.2% (95% CI, 92.0–99.4) and 85.7% (95% CI, 42.1–99.6)/89.5% (95% CI, 66.9–98.7) in adults and children, respectively, within 5 days of symptoms. Sensitivity/specificity were 50.0% (95% CI, 41.0–59.0)/99.1% (95% CI, 98.3–99.6) in asymptomatic adults and 51.4% (95% CI, 34.4–68.1)/97.8% (95% CI, 94.5–99.4) in asymptomatic children. Sensitivity in all 234 RT-PCR-positive people was 96.3% with cycle threshold (Ct) ≤25, 79.6% with Ct ≤30, and 61.4% with Ct ≤35. All 21 false-positive CareStart tests had faint but normal bands. Interoperator agreement was 99.5%. Operational challenges included identification of faint test bands and inconsistent swab elution volumes.

Conclusions

CareStart had high sensitivity in people with Ct ≤25 and moderate sensitivity in symptomatic people overall. Specificity was unexpectedly lower in symptomatic versus asymptomatic people. Excellent interoperator agreement was observed, but operational challenges indicate that operator training is warranted.
First Experience Addressing the Prognostic Utility of Novel Urinary Biomarkers in Patients With COVID-19
Authors: Tantry Udaya S , Bliden Kevin P , Cho Alastair , Walia Naval , Dahlen Jeffrey R , Ens Gordon , Traianova Malina , Jerjian Christophe , Usman Abira , Gurbel Paul A
Published: May 2021

Urine 11-dehydro-thromboxane B2 (u11-dh-TxB2), 8-hydroxy-2’-deoxyguanosine (8-OHdG), and liver-type fatty acid binding protein levels (L-FABP) at the time of hospitalization were higher in coronavirus disease 2019 (COVID-19) patients with adverse events vs without events. Higher u11-dh-TxB2 and L-FABP levels were associated with longer hospitalization, more thrombotic events, and greater mortality, providing evidence for potential utility as early prognostic biomarkers for COVID-19.
Linkage Arguments For and Against Rights
Authors: Nickel James
Published: May 2021

This article is about relations of support and conflict within systems of fundamental legal rights—and the arguments for and against rights that those relations make possible. Justificatory linkage arguments defend controversial rights by claiming that they provide very useful support to the realisation of well-accepted rights. This article analyses such arguments in detail and discusses their structures, uses and pitfalls. It then shows that linkage arguments can be used not just to defend rights, but also to attack them. When rights conflict—whether severely or weakly, logically or practically—negative linkage arguments attacking them can be based on the trouble they make for other rights. Many examples of conflicts of rights are provided. Negative linkage arguments provide reasons for rejecting, repealing or trimming the criticised right. Such arguments are already in regular use, but their close relation to justificatory linkage arguments has not been recognised.
AV Dicey and the Making of Common Law Constitutionalism†
Authors: Loughlin Martin
Published: May 2021

The work of the mid-Victorian jurist, AV Dicey, has had a remarkable influence on British constitutional thought, not least in establishing the orthodox framework within which modern constitutional lawyers continue to work. That legal positivist framework has, however, recently been challenged by jurists advocating what is generally called common law constitutionalism. Accepting the core of sense in Dicey’s account, their objective has been to revise some of the jurisprudential underpinnings of his framework for the purpose of showing that the dominant characteristic of the British system is not sovereignty but legality. Mark Walters now builds on this revisionary work by offering a new historically informed study of Dicey’s Law of the Constitution, which is designed to show that the orthodox interpretation of Dicey as a legal positivist is itself misconceived. Walters argues that, properly understood, Dicey had a more nuanced appreciation of the relationship between sovereignty and legality than is commonly appreciated. This review article examines Walters’s exercise and assesses its contemporary significance.
A diagnostic challenge in an unresponsive refugee child improving with neurosurgery—a case report
Authors: Makris George , Papageorgiou Nefeli , Panagopoulos Dimitrios , Brubakk Katrin Glatz
Published: May 2021

An unresponsive paediatric patient may present a diagnostic challenge for health professionals, as rapid identification of the cause is needed to provide proper interventions. The following report details a challenging diagnosis of unresponsiveness in a refugee child. In the migratory context, observed unresponsiveness states are frequently attributed to psychologic factors, and overlapping psychiatric classifications (resignation syndrome, functional coma and catatonia) are common. Our patient fell into an unresponsive state for 6 months after witnessing a traumatic event. Diagnostic workup for multiple medical comorbidities led to surgical intervention for tethered cord syndrome. Shortly after that, the patient’s responsiveness improved, putting to question her condition’s underlying cause. This case highlights the need for a biopsychosocial approach in such cases, reflected in thorough clinical examination and diagnostic investigations. A multidisciplinary perspective and expertise proved crucial and may help in the rehabilitation of children in similar situations.
Case of an unreported genetic variant of salt losing 3-β-hydroxysteroid dehydrogenase deficiency
Authors: Alkhatib Einas H , Adams Stacie D , Miller Emily R
Published: May 2021

Salt losing 3-β-hydroxysteroid dehydrogenase deficiency (HSD3B2) is a rare form of congenital adrenal hyperplasia, seen in <0.5% of cases. We present a 7-year-old male diagnosed with HSD3B2 deficiency, not identified by state newborn screen, due to a novel variant identified in the HSD3B2 gene (c.694C > G; p.His232Asp). This patient was referred to pediatric endocrinology and pediatric biochemical genetics following a fourth hospitalization for emesis and electrolyte derangements including hyponatremia, hyperkalemia, ketoacidosis and hypoglycemia. Endocrinology evaluation yielded elevated 17-hydroxyprogesterone (17-OHP), 17-hydroxypregnenolone (17-OHPreg), dehydroepiandrosterone and adrenocorticotropic hormone (ACTH). ACTH stimulation test indicated flat response. Sequencing of the HSD3B2 revealed a pathogenic variant inherited in trans with the novel c.694C > G (p.His232Asp) variant. The patient was started on daily glucocorticoid and mineralocorticoid replacement and has since had no further adrenal crises.
DEPDC5 variant in focal cortical dysplasia: a case report and review of the literature
Authors: Jesus-Ribeiro Joana , Pereira Cristina , Robalo Conceição , Pereira Daniela J , Duro Diana , Ramos Fabiana , Freire António , Melo Joana B
Published: May 2021

Germline and 2-hit brain somatic variants in DEPDC5 gene, a negative regulator of the mammalian target of rapamycin (mTOR) pathway, are increasingly recognized in patients with focal cortical dysplasia (FCD). Next-generation targeted sequencing identified a heterozygous germline variant in DEPDC5 gene (c.3241A>C, p.Thr1081Pro), classified as of unknown significance, in a patient with clinical features compatible with DEPDC5 phenotype (FCD, focal epilepsy, attention-deficit/hyperactivity disorder and borderline intellectual functioning). This missense variant has previously been reported in two other epileptic patients. Although interpretation of missense variants remains a challenge, DEPDC5 variants in patients with FCD and epilepsy cannot be neglected. Null variants were the most frequently reported in FCD patients, but missense variants have been described as well. The recognition of DEPDC5 phenotype and the appropriate interpretation of the detected variants are essential, since it may have important treatment implications in the near future, namely the use of mTOR inhibitors.
Boosting automated sleep staging performance in big datasets using population subgrouping
Authors: Nasiri Samaneh , Clifford Gari D
Published: May 2021

Current approaches to automated sleep staging from the electroencephalogram (EEG) rely on constructing a large labeled training and test corpora by aggregating data from different individuals. However, many of the subjects in the training set may exhibit changes in the EEG that are very different from the subjects in the test set. Training an algorithm on such data without accounting for this diversity can cause underperformance. Moreover, test data may have unexpected sensor misplacement or different instrument noise and spectral responses. This work proposes a novel method to learn relevant individuals based on their similarities effectively. The proposed method embeds all training patients into a shared and robust feature space. Individuals who share strong statistical relationships and are similar based on their EEG signals are clustered in this feature space before being passed to a deep learning framework for classification. Using 994 patient EEGs from the 2018 Physionet Challenge (≈6,561 h of recording), we demonstrate that the clustering approach significantly boosts performance compared to state-of-the-art deep learning approaches. The proposed method improves, on average, a precision score from 0.72 to 0.81, a sensitivity score from 0.74 to 0.82, and a Cohen’s Kappa coefficient from 0.64 to 0.75 under 10-fold cross-validation.
Modeling the selective advantage of new amino acids on the hemagglutinin of H1N1 influenza viruses using their patient age distributions
Authors: Piantham Chayada , Ito Kimihito
Published: May 2021

In 2009, a new strain of H1N1 influenza A virus caused a pandemic, and its descendant strains are causing seasonal epidemics worldwide. Given the high mutation rate of influenza viruses, variant strains having different amino acids on hemagglutinin (HA) continuously emerge. To prepare vaccine strains for the next influenza seasons, it is an urgent task to predict which variants will be selected in the viral population. An analysis of 24,681 pairs of an amino acid sequence of HA of H1N1pdm2009 viruses and its patient age showed that the empirical fixation probability of new amino acids on HA significantly differed depending on their frequencies in the population, patient age distributions, and epitope flags. The selective advantage of a variant strain having a new amino acid was modeled by linear combinations of patients age distributions and epitope flags, and then the fixation probability of the new amino acid was modeled using Kimura’s formula for advantageous selection. The parameters of models were estimated from the sequence data and models were tested with four-fold cross validations. The frequency of new amino acids alone can achieve high sensitivity, specificity, and precision in predicting the fixation of a new amino acid of which frequency is more than 0.11. The estimated parameter suggested that viruses with a new amino acid having a frequency in the population higher than 0.11 have a significantly higher selective advantage compared to viruses with the old amino acid at the same position. The model considering the Z-value of patient age rank-sums of new amino acids predicted amino acid substitutions on HA with a sensitivity of 0.78, specificity of 0.86, and precision of 0.83, showing significant improvement compared to the constant selective advantage model, which used only the frequency of the amino acid. These results suggested that H1N1 viruses tend to be selected in the adult population, and frequency of viruses having new amino acids and their patient ages are useful to predict amino acid substitutions on HA.
Systemness Taps the Power of Interdependence in Healthcare
Authors: Stokes Charles D. , Brace Rod
Published: May 2021

While the term systemness has been used in the healthcare sector for decades, its definition varies from organization to organization. Still, the goals are consistent: to improve patient experience, lower costs, reduce risk, and provide insights into a wide range of care and management issues. Most health systems face similar challenges, such as margin enhancement, quality improvement, increased access, and fending off disruptive competition. Systemness is a way to address these challenges while improving the overall interdependence of the organization. Although embraced by and advantageous to healthcare organizations, systemness efforts often fail. The obstacles are surmountable when organizations thoroughly analyze the achievable scale of systemness, community resources, and current mindset regarding the good of the whole. Leaders must play a vital role in promoting systemness by providing education and a routine review of day-to-day organizational activities. Sometimes, systemness requires a change in leadership or an updating of leadership skills.

Organizations must recognize and assess their culture as it relates to principles of independence versus interdependence, and refocus clinical standardization through best-practice protocols and policies as COVID-19 affects the already-fractured healthcare sector. Fortunately, current and developing artificial intelligence, wearables, at-home testing, and improved technologies promise to provide a needed break for a contracting physician field and fatigued front line, and they present an opportunity for those organizations poised to meet the systemness challenge.
Critical issues in alliances between management partners and accountable care organizations
Authors: Murray Genevra F. , D'Aunno Thomas , Lewis Valerie A.
Published: May 2021

Background

Despite widespread engagement of accountable care organizations (ACOs) with management partners, little empirical evidence on these alliances exists to inform policymakers or payers. Management partners may be providing a valuable service in facilitating the transition to population health management. Alternately, in some cases, partners may be receiving high fees relative to the value of services provided.

Purpose

The aim of this study was to use qualitative data to identify motivations for and critical issues in alliances between ACOs and management partners.

Methodology/Approach

We used qualitative data collected from seven ACOs (193 semistructured interviews and observational data from 12 site visits) to characterize the alliances between management partners and providers in ACOs.

Results

We found that ACOs sought partners to provide financing, technical expertise, and risk bearing. Tensions in partnerships arose around resources (e.g., delivery on promised resources), control (e.g., who holds decision making authority), and values (e.g., commitment to safety net mission). Some partnerships persisted, whereas others dissolved. We found that there are two different underlying models of ACO–management partner alliances in our sample: (1) short-term partnerships aimed at organizational learning and (2) long-term partnerships based on complementarity.

Conclusion

Our results demonstrate how ACO alliances with management partners have unfolded as a kind of natural experiment in value-based payment reform. We expect that there is wide variation in quality, expertise, and delivery by management partners. Now multiple years into many of these alliances, we may address their value, strengths, and weaknesses from the perspective of providers as well as policy makers and payers.

Practice Implications

Accountable care organization providers must determine whether a management partner is the best solution to the challenges they face and, if so, which alliance model to pursue. Policymakers and payers should consider short- and long-term implications of ACO–management partner alliances, including considering changing the regulatory environment.
Could Dispositional Optimism Impair Panic Disorder and Depression Outcomes?
Authors: Rodrigues Michele F. , Vianna Ruan , Galdino Melyssa K. , Nardi Antonio Egídio , Appolinário José Carlos , Levitan Michelle N.
Published: May 2021

The objective of this study was to investigate potential correlates of dispositional optimism and quality of life in patients with depression and panic disorder. The study used a cross-sectional design. The analyzed sample consisted of 77 participants with panic disorder and 75 participants with depression attending two outpatient clinics at the Psychiatry Institute of the Federal University of Rio de Janeiro. Both groups presented similar impairments in optimism and quality of life. In the panic disorder group, optimism scores were significantly correlated with a decrease in anxiety and depression scores (r = 0.26 and r = 0.37, respectively); in the depression group, increases in optimism scores were significantly correlated with decreases in anxiety and depression scores (r = 0.23 and r = 0.3, respectively). The present study showed that high anxiety and depression are correlated with poor optimism and quality of life scores in panic disorder and depression groups. Thus, psychological treatments that can address these topics, besides acute symptoms, are crucial to the absolute recovery of patients.
Reflections on US Psychiatry
Authors: de Leon Jose
Published: May 2021

The medical model in psychiatry and descriptive psychopathology were established in Germany by Krapelin’s textbook and Jaspers’ General Psychopathology. In the United Kingdom, Mayer-Gross’ textbook synthesized both books, influencing US psychiatry. US psychiatrists from the World War II generation defeated the US academic psychoanalytic establishment by building three pillars: biological psychiatry (brought by Wortis), the psychopharmacology revolution, and the Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition (DSM-III). The psychopharmacology revolution included immigrants (e.g., Gershon), Cole’s marketing, and textbooks by Klein and Fink. The “neo-Kraepelinians” introduced the medical model in US psychiatry and defined 15 valid psychiatric disorders. Spitzer supervised DSM-III’s development. Its 1980 publication started the world dominance of US psychiatry and the multiplication of diagnoses. Major contributions by US psychiatrists include a) McHugh’s update of the Jaspersian approach, b) Fink’s inclusion of catatonia as a syndrome in DSM-5 (following Abrams and Taylor’s studies), and c) DSM-III's departure from the Jaspersian hierarchy of schizophrenia and affective symptoms.
Pediatric and Maternal Anxiety at First Visit to a Turkish Gastroenterology Clinic Compared to Anxiety Prior to Pediatric Endoscopy Procedure
Authors: Cam Sebahat
Published: May 2021

The aim of this study was the prospective comparison of pediatric and maternal anxiety at the first visit to a gastroenterology clinic with anxiety prior to a pediatric endoscopy procedure. A total of 101 children aged 4–18 years plus their mothers who were referred to an outpatient pediatric gastroenterology clinic were included in the first group. The second group consisted of 101 different children aged 4–18 years undergoing pediatric endoscopy. The Hospital Anxiety and Depression Scale (HADS) was administered to mothers. Visual analog scale scores were obtained from the children to measure anxiety. The demographic characteristics of the groups were similar. The mean HADS anxiety score was 3.83 in mothers of the first group. The same score was significantly higher as (6.96) in the mothers whose children underwent an endoscopy (p < .001). The comparison of the depression scores revealed significantly higher scores in the endoscopy group. Visual analog scale values of the children revealed remarkably higher anxiety scores in the endoscopy group. About 5% of mothers in the first group and almost half of the mothers in the endoscopy group developed remarkable anxiety (>8 HADS anxiety). The rate of significant depression (>8 HADS depression) was 2% and 17.82% in the first and second groups, respectively. The current prospective trial concluded that particularly anxiety is a major concern for mothers and children when endoscopy is required.
Eggs of extinct dwarf island emus retained large size
Authors: Hume Julian P. , Robertson Christian
Published: May 2021

Islands off southern Australia once harboured three subspecies of the mainland emu (
Dromaius novaehollandiae
), the smaller Tasmanian emu (
D. n. diemenensis
) and two dwarf emus, King Island emu (
D. n. minor
) and Kangaroo Island emu (
D. n. baudinianus
), which all became extinct rapidly after discovery by European settlers. Little was recorded about their life histories and only a few historical museum specimens exist, including a number of complete eggs from Tasmania and a unique egg from Kangaroo Island. Here, we present a detailed analysis of eggs of dwarf emus, including the first record of an almost complete specimen from King Island. Our results show that despite the reduction in size of all island emus, especially the King Island emu that averaged 44% smaller than mainland birds, the egg remained similar sized in linear measurements, but less in volume and mass, and seemingly had a slightly thinner eggshell. We provide possible reasons why these phenomena occurred.
Temporal stability of chimpanzee social culture
Authors: van Leeuwen Edwin J. C.
Published: May 2021

Culture is a hallmark of the human species, both in terms of the transmission of material inventions (e.g. tool manufacturing) and the adherence to social conventions (e.g. greeting mannerisms). While material culture has been reported across the animal kingdom, indications of social culture in animals are limited. Moreover, there is a paucity of evidencing cultural stability in animals. Here, based on a large dataset spanning 12 years, I show that chimpanzees adhere to arbitrary group-specific handclasp preferences that cannot be explained by genetics or the ecological environment. Despite substantial changes in group compositions across the study period, and all chimpanzees having several behavioural variants in their repertoires, chimpanzees showed and maintained the within-group homogeneity and between-group heterogeneity that are so characteristic of the cultural phenomenon in the human species. These findings indicate that human culture, including its arbitrary social conventions and long-term stability, is rooted in our evolutionary history.
Colorimetric sensing of cephradine through polypropylene glycol functionalized gold nanoparticles
Authors: Raja Daim Asif , Munir Fazeelah , Shah Muhammad Raza , Bhanger Muhammad Iqbal , Malik Muhammad Imran
Published: May 2021

The development of metal nanoparticle-based facile colorimetric assays for drugs and insecticides is an emerging area of current scientific research. In the present work, polypropylene glycol was used for stabilization of gold nanoparticles (AuNPs) in a simple one-pot two-phase process and subsequently employed it for the specific detection of cephradine (CPH). The characterization of the prepared PPG-AuNPs was conducted through various analytical techniques such as UV-visible spectrophotometry, Fourier transform infrared spectroscopy, atomic force microscopy (AFM), zeta potential and zetasizer techniques. As the major target of the study, the stabilized PPG-AuNPs were employed for colorimetric detection of CPH and other drugs. Typical wine-red colour of PPG-AuNPs disappeared immediately and surface plasmon resonance band quenched by addition of CPH in the presence of several other interferents (drugs and salts) and in real samples. PPG-AuNPs permitted efficient, selective, reliable and rapid determination in a concentration range of 0.01–120 mM with a detection limit (LoD) of 11.0 mM. The developed sensor has the potential to be used for fast scanning of pharmaceutical formulations for quantification of CPH at production facilities.
Locomotory behaviour of early tetrapods from Blue Beach, Nova Scotia, revealed by novel microanatomical analysis
Authors: Lennie Kendra I. , Manske Sarah L. , Mansky Chris F. , Anderson Jason S.
Published: May 2021

Evidence for terrestriality in early tetrapods is fundamentally contradictory. Fossil trackways attributed to early terrestrial tetrapods long predate the first body fossils from the Late Devonian. However, the Devonian body fossils demonstrate an obligatorily aquatic lifestyle. Complicating our understanding of the transition from water to land is a pronounced gap in the fossil record between the aquatic Devonian taxa and presumably terrestrial tetrapods from the later Early Carboniferous. Recent work suggests that an obligatorily aquatic habit persists much higher in the tetrapod tree than previously recognized. Here, we present independent microanatomical data of locomotor capability from the earliest Carboniferous of Blue Beach, Nova Scotia. The site preserves limb bones from taxa representative of Late Devonian to mid-Carboniferous faunas as well as a rich trackway record. Given that bone remodels in response to functional stresses including gravity and ground reaction forces, we analysed both the midshaft compactness profiles and trabecular anisotropy, the latter using a new whole bone approach. Our findings suggest that early tetrapods retained an aquatic lifestyle despite varied limb morphologies, prior to their emergence onto land. These results suggest that trackways attributed to early tetrapods be closely scrutinized for additional information regarding their creation conditions, and demand an expansion of sampling to better identify the first terrestrial tetrapods.
Dynamical symmetrization of the state of identical particles
Authors: Allahverdyan Armen E. , Hovhannisyan Karen V. , Petrosyan David
Published: May 2021

We propose a dynamical model for state symmetrization of two identical particles produced in spacelike-separated events by independent sources. We adopt the hypothesis that the pair of non-interacting particles can initially be described by a tensor product state since they are in principle distinguishable due to their spacelike separation. As the particles approach each other, a quantum jump takes place upon particle collision, which erases their distinguishability and projects the two-particle state onto an appropriately (anti-)symmetrized state. The probability density of the collision times can be estimated quasi-classically using the Wigner functions of the particles’ wavepackets, or derived from fully quantum mechanical considerations using an appropriately adapted time-of-arrival operator. Moreover, the state symmetrization can be formally regarded as a consequence of the spontaneous measurement of the collision time. We show that symmetric measurements performed on identical particles can in principle discriminate between the product and symmetrized states. Our model and its conclusions can be tested experimentally.
Symbiosis in the Cambrian: enteropneust tubes from the Burgess Shale co-inhabited by commensal polychaetes
Authors: Nanglu Karma , Caron Jean-Bernard
Published: May 2021

Thein situpreservation of animal behaviour in the fossil record is exceedingly rare, but can lead to unique macroecological and macroevolutionary insights, especially regarding early representatives of major animal clades. We describe a new complex ecological relationship from the middle Cambrian Burgess Shale (Raymond Quarry, Canada). More than 30 organic tubes were recorded with multiple enteropneust and polychaete worms preserved within them. Based on the tubicolous nature of fossil enteropneusts, we suggest that they were the tube builders while the co-preserved polychaetes were commensals. These findings mark, to our knowledge, the first record of commensalism within Annelida and Hemichordata in the entire fossil record. The finding of multiple enteropneusts sharing common tubes suggests that either the tubes represent reproductive structures built by larger adults, and the enteropneusts commonly preserved within are juveniles, or these enteropneusts were living as a pseudo-colony without obligate attachment to each other, and the tube was built collaboratively. While neither hypothesis can be ruled out, gregarious behaviour was clearly an early trait of both hemichordates and annelids. Further, commensal symbioses in the Cambrian may be more common than currently recognized.
Longer telomeres during early life predict higher lifetime reproductive success in females but not males
Authors: Heidinger Britt J. , Kucera Aurelia C. , Kittilson Jeff D. , Westneat David F.
Published: May 2021

The mechanisms that contribute to variation in lifetime reproductive success are not well understood. One possibility is that telomeres, conserved DNA sequences at chromosome ends that often shorten with age and stress exposures, may reflect differences in vital processes or influence fitness. Telomere length often predicts longevity, but longevity is only one component of fitness and little is known about how lifetime reproductive success is related to telomere dynamics in wild populations. We examined the relationships between telomere length beginning in early life, telomere loss into adulthood and lifetime reproductive success in free-living house sparrows (
Passer domesticus
). We found that females, but not males, with longer telomeres during early life had higher lifetime reproductive success, owing to associations with longevity and not reproduction per year or attempt. Telomeres decreased with age in both sexes, but telomere loss was not associated with lifetime reproductive success. In this species, telomeres may reflect differences in quality or condition rather than the pace of life, but only in females. Sexually discordant selection on telomeres is expected to influence the stability and maintenance of within population variation in telomere dynamics and suggests that any role telomeres play in mediating life-history trade-offs may be sex specific.