bluuebunny/crossref_metadata_2025 huggingface dataset:
Agreement of Computerized QT and QTc Interval Measurements Between Both Bedside and Expert Nurses Using Electronic Calipers
Authors: Ho Karolina , Ganesh Gopika K. , Prasad Shelvin , Hoffmann Thomas J. , Larsen Amy , Sandoval Cass , Berger Sarah , Schell-Chaple Hildy , Badilini Fabio , Mackin Lynda A. , Pelter Michele M.
Published: October 2023

Background

In hospitalized patients, QT/QTc (heart rate corrected) prolongation on the electrocardiogram (ECG) increases the risk of torsade de pointes. Manual measurements are time-consuming and often inaccurate. Some bedside monitors automatically and continuously measure QT/QTc; however, the agreement between computerized versus nurse-measured values has not been evaluated.

Objective

The aim of this study was to examine the agreement between computerized QT/QTc and bedside and expert nurses who used electronic calipers.

Methods

This was a prospective observational study in 3 intensive care units. Up to 2 QT/QTc measurements (milliseconds) per patient were collected. Bland-Altman test was used to analyze measurement agreement.

Results

A total of 54 QT/QTc measurements from 34 patients admitted to the ICU were included. The mean difference (bias) for QT comparisons was as follows: computerized versus expert nurses, −11.04 ± 4.45 milliseconds (95% confidence interval [CI], −2.3 to −19.8; P = .016), and computerized versus bedside nurses, −13.72 ± 6.70 (95% CI, −0.70 to −26.8; P = .044). The mean bias for QTc comparisons was as follows: computerized versus expert nurses, −12.46 ± 5.80 (95% CI, −1.1 to −23.8; P = .035), and computerized versus bedside nurses, −18.49 ± 7.90 (95% CI, −3.0 to −33.9; P = .022).

Conclusion

Computerized QT/QTc measurements calculated by bedside monitor software and measurements performed by nurses were in close agreement; statistically significant differences were found, but differences were less than 20 milliseconds (on-half of a small box), indicating no clinical significance. Computerized measurements may be a suitable alternative to nurse-measured QT/QTc. This could reduce inaccuracies and nurse burden while increasing adherence to practice recommendations. Further research comparing computerized QT/QTc from bedside monitoring to standard 12-lead electrocardiogram in a larger sample, including non-ICU patients, is needed.
Autoimmune hepatitis recurrence after liver transplantation: “Les jeux sont faits”
Authors: Chouik Yasmina , Corpechot Christophe , Francoz Claire , De Martin Eleonora , Guillaud Olivier , Abergel Armand , Altieri Mario , Barbier Louise , Besch Camille , Chazouillères Olivier , Conti Filomena , Dharancy Sébastien , Durand François , Duvoux Christophe , Gugenheim Jean , Hardwigsen Jean , Hilleret Marie-Noëlle , Houssel-Debry Pauline , Kamar Nassim , Minello Anne , Neau-Cransac Martine , Pageaux Georges-Philippe , Radenne Sylvie , Roux Olivier , Saliba Faouzi , Samuel Didier , Vanlemmens Claire , Woehl-Jaegle Marie-Lorraine , Leroy Vincent , Duclos-Vallée Jean-Charles , Dumortier Jérôme
Published: October 2023

Autoimmune hepatitis (AIH) may recur after liver transplantation (LT). The aims of this study were to evaluate the incidence and risk factors for recurrent autoimmune hepatitis (rAIH). A multicenter retrospective French nationwide study, including all patients aged ≥16 transplanted for AIH, with at least 1 liver biopsy 1 year after LT, was conducted between 1985 and 2018. Risk factors for rAIH were identified using a multivariate Cox regression model. Three hundred and forty-four patients were included (78.8% women) with a median age at LT of 43.6 years. Seventy-six patients (22.1%) developed recurrence in a median time of 53.6 months (IQR, 14.1–93.2). Actuarial risk for developing rAIH was 41.3% 20 years after LT. In multivariate analysis, the strongest risk factor for rAIH was cytomegalovirus D+/R− mismatch status (HR=2.0; 95% CI: 1.1–3.6; p=0.03), followed by associated autoimmune condition. Twenty-one patients (27.6% of rAIH patients) developed liver graft cirrhosis after rAIH. Independent risk factors for these severe forms of rAIH were young age at LT, IgG levels >20.7 g/L, and LT in the context of (sub)fulminant hepatitis. Immunosuppression, especially long-term maintenance of corticosteroid therapy, was not significantly associated with rAIH. Recurrence of AIH after LT is frequent and may lead to graft loss. Recurrence is more frequent in young patients with active disease at the time of LT, yet systematic corticosteroid therapy does not prevent it.
The Kvetch
Authors: Yager Joel , Kay Jerald
Published: October 2023

Clinicians often encounter patients whose presentations are characterized by long lists of complaints about their biological, psychological, interpersonal, and social conditions. The problems on which the complaints are based are variably reality-based and variably modifiable. Some of these patients display chronic complaining as a core, distinguishing feature. Accordingly, the aims of this article are to consider excesses of chronic complaining as psychiatric phenomena, explore possible pathogenetic contributions, describe approaches for treating conditions marked by clinically pertinent chronic complaining, and suggest areas for future research. Based on clinical observations enhanced by selective narrative literature review, we delineate and differentiate four groups of patients: 1) situational complainers; 2) chronic complainers due to unidentified medical problems; 3) mood-induced chronic complainers; and 4) personality-driven pan-dimensional chronic complainers. The last-mentioned group consists of help-seeking versus help-rejecting subtypes, the latter including a subset we designate as malignant chronic complainers. Strategies for managing these patients begin with detailed assessment of all complaints, ascertaining reality-based contributions to the complaints, including those initiated by patients themselves. Management approaches use specific biopsychosocial techniques based on patient-centered particulars. Psychotherapeutic strategies center on compassionate, empathic witnessing. Specific tactics include attending to unresolved grief and trauma, behavioral activation, cognitive and narrative restructuring and reframing methods, mentalizing and imaginal approaches, and psychodynamic methods including attention to attachment issues and transference. Sources of countertransference reactions to these patients should be identified and can be addressed. The many questions raised by these patients' presentations merit further research.
Continuity Strategies for Long-Stay PICU Patients: Consensus Statements From the Lucile Packard Foundation PICU Continuity Panel
Authors: Edwards Jeffrey D. , Wocial Lucia D. , Madrigal Vanessa N. , Moon Michelle M. , Ramey-Hunt Cheryl , Walter Jennifer K. , Baird Jennifer D. , Leland Brian D.
Published: October 2023

OBJECTIVES:

To develop consensus statements on continuity strategies using primary intensivists, primary nurses, and recurring multidisciplinary team meetings for long-stay patients (LSPs) in PICUs.

PARTICIPANTS:

The multidisciplinary Lucile Packard Foundation PICU Continuity Panel comprising parents of children who had prolonged PICU stays and experts in several specialties/professions that care for children with medical complexity in and out of PICUs.

DESIGN/METHODS:

We used modified RAND Delphi methodology, with a comprehensive literature review, Delphi surveys, and a conference, to reach consensus. The literature review resulted in a synthesized bibliography, which was provided to panelists. We used an iterative process to generate draft statements following panelists’ completion of four online surveys with open-ended questions on implementing and sustaining continuity strategies. Panelists were anonymous when they voted on revised draft statements. Agreement of 80% constituted consensus. At a 3-day virtual conference, we discussed, revised, and re-voted on statements not reaching or barely reaching consensus. We used Grading of Recommendations Assessment, Development, and Evaluation to assess the quality of the evidence and rate the statements’ strength. The Panel also generated outcome, process, and balancing metrics to evaluate continuity strategies.

RESULTS:

The Panel endorsed 17 consensus statements in five focus areas of continuity strategies (Eligibility Criteria, Initiation, Standard Responsibilities, Resources Needed to Implement, Resources Needed to Sustain). The quality of evidence of the statements was low to very low, highlighting the limited evidence and the importance of panelists’ experiences/expertise. The strength of the statements was conditional. An extensive list of potential evaluation metrics was generated.

CONCLUSIONS:

These expert/parent-developed consensus statements provide PICUs with novel summaries on how to operationalize, implement, and sustain continuity strategies for LSP, a rapidly growing, vulnerable, resource-intensive population in PICUs.
Proprotein convertase subtisilin/kexin 9 levels decline with hepatitis C virus therapy in people with HIV/hepatitis C virus and correlate with inflammation
Authors: Gandhi Malini M. , Nguyen Kim-Lien , Lake Jordan E. , Liao Diana , Khodabakhshian Aleen , Guerrero Mario , Shufelt Chrisandra L. , Bairey Merz C. Noel , Jordan Wilbert C. , Daar Eric S. , Bhattacharya Debika , Chew Kara W.
Published: October 2023

Background:

Proprotein convertase subtisilin/kexin 9 (PCSK9) raises low-density lipoprotein cholesterol (LDL-C) levels and is associated with inflammation, which is elevated in HIV and hepatitis C virus (HCV) infection. We compared PCSK9 levels in people with co-occurring HIV and HCV (HIV/HCV) vs. HIV alone, and evaluated the impact of HCV direct-acting antiviral (DAA) therapy on PCSK9.

Design:

A prospective, observational cohort study.

Methods:

Thirty-five adults with HIV/HCV and 37 with HIV alone were evaluated, all with HIV virologic suppression and without documented cardiovascular disease. Circulating PCSK9 and inflammatory biomarkers were measured at baseline and following HCV treatment or at week 52 (for HIV alone) and compared using Wilcoxon tests and Spearman correlations.

Results:

At baseline, PCSK9 trended higher in HIV/HCV vs. HIV alone (307 vs. 284 ng/ml, P = 0.06). Twenty-nine participants with HIV/HCV completed DAA therapy with sustained virologic response. PCSK9 declined from baseline to posttreatment 1 (median 7.3 weeks after end of therapy [EOT]) and posttreatment 2 (median 43.5 weeks after EOT), reaching levels similar to HIV alone; median within-person reduction was -60.5 ng/ml (P = 0.003) and -55.6 ng/ml (P = 0.02), respectively. Decline in PCSK9 correlated with decline in soluble (s)E-selectin and sCD163 (r = 0.64, P = 0.002; r = 0.58, P = 0.008, respectively), but not with changes in LDL-C or other biomarkers. No significant change in PCSK9 occurred in the HIV alone group over 52 weeks.

Conclusion:

PCSK9 declined with DAA therapy in participants with HIV/HCV, correlating with declines in several inflammatory biomarkers but not LDL-C. Elevated PCSK9 with HCV may be linked to particular HCV-associated inflammatory pathways more so than cholesterol homeostasis.
Lower endoscopy, early-onset, and average-onset colon cancer among Medicaid beneficiaries with and without HIV
Authors: Joshu Corinne E. , Calkins Keri L. , Rudolph Jacqueline E. , Xu Xiaoqiang , Wentz Eryka , Coburn Sally B. , Kaur Maneet , Pirsl Filip , Moore Richard D. , Lau Bryan
Published: October 2023

Background:

Studies suggest a lower colorectal cancer (CRC) risk and lower or similar CRC screening among people with HIV (PWH) compared with the general population. We evaluated the incidence of lower endoscopy and average-onset (diagnosed at ≥50) and early-onset (diagnosed at <50) colon cancer by HIV status among Medicaid beneficiares with comparable sociodemographic factors and access to care.

Methods:

We obtained Medicaid Analytic eXtract (MAX) data from 2001 to 2015 for 14 states. We included 41 727 243 and 42 062 552 unique individuals with at least 7 months of continuous eligibility for the endoscopy and colon cancer analysis, respectively. HIV and colon cancer diagnoses and endoscopy procedures were identified from inpatient and other nondrug claims. We used Cox proportional hazards regression models to assess endoscopy and colon cancer incidence, controlling for age, sex, race/ethnicity, calendar year and state of enrollment, and comorbidities conditions.

Results:

Endoscopy and colon cancer incidence increased with age in both groups. Compared with beneficiaries without HIV, PWH had an increased hazard of endoscopy; this association was strongest among those 18–39 years [hazard ratio: 1.85, 95% confidence interval (95% CI) 1.77–1.92] and attenuated with age. PWH 18–39 years also had increased hazard of early-onset colon cancer (hazard ratio: 1.66, 95% CI:1.05–2.62); this association was attenuated after comorbidity adjustment. Hazard ratios were null among all beneficiaries less than 50 years of age. PWH had a lower hazard of average-onset colon cancer compared with those without HIV (hazard ratio: 0.79, 95% CI: 0.66–0.94).

Conclusion:

PWH had a higher hazard of endoscopy, particularly at younger ages. PWH had a lower hazard of average-onset colon cancer. Early-onset colon cancer was higher among the youngest PWH but not associated with HIV overall.
Factors associated with insulin resistance in a longitudinal study of Ugandan youth with and without HIV
Authors: Dirajlal-Fargo Sahera , Strah Monika , Ailstock Kate , Sattar Abdus , Karungi Christine , Nazzinda Rashidah , Funderburg Nicholas , Kityo Cissy , Musiime Victor , McComsey Grace A.
Published: October 2023

Prospective investigations from sub-Saharan Africa on metabolic complications in youth with perinatally acquired HIV (PHIV) are lacking. We investigated the changes in insulin resistance in Ugandan PHIV on ART and uninfected controls and their relationship with inflammation, HIV, and cardiovascular disease (CVD) risk factors.

Participants 10–18 years of age were included in a prospective study performed in Kampala, Uganda. We compared baseline and changes in insulin resistance (by HOMA-IR) and in markers of inflammation at baseline and 96 weeks. PHIVs were on ART with HIV-1 RNA level 400 copies/ml or less. Generalized Estimating Equation models were used to assess associations between HOMA-IR, and demographic as well as inflammatory markers.

Of the 197 participants recruited at baseline (101 PHIV, 96 HIV-negative), 168 (89 PHIV, 79 HIV-negative) had measurements at 96 weeks. At baseline, median (Q1, Q3) age was 13 years (11,15), 53.5% were women, median CD4+ cell counts were 988 cells/μl (631, 1310). At baseline, HOMA-IR was significantly higher in PHIV than in controls (P = 0.03). HOMA-IR did not significantly change by week 96 in either group, and at 96 weeks, was similar between groups (P = 0.15). HOMA-IR was not associated with any inflammatory markers, or any specific ART. In longitudinal analysis, age and Tanner stage remained associated with higher HOMA-IR throughout the study period, after adjusting for HIV status.

In this longitudinal cohort of virally suppressed PHIV in Uganda, PHIV have decreased insulin sensitivity compared to controls, however this difference does not persist through adolescence. ART and immune activation do not appear to affect glucose homeostasis in this population.
Impact of a livelihood intervention on gender roles and relationship power among people with HIV
Authors: Sheira Lila A. , Wekesa Pauline , Cohen Craig R. , Weke Elly , Frongillo Edward A. , Mocello A. Rain , Dworkin Shari L. , Burger Rachel L. , Weiser Sheri D. , Bukusi Elizabeth A.
Published: October 2023

Objective:

To evaluate the impact of an agricultural livelihood intervention on gender role conflict and sexual relationship power among people with HIV (PWH) in western Kenya.

Design:

Study participants were enrolled in Shamba Maisha, a cluster randomized controlled trial of an agricultural intervention conducted among PWH across 16 health facilities during 2016–2020. Intervention participants received a water pump, seeds, and agricultural and financial training; control participants received standard of HIV care.

Methods:

We assessed men's views on masculinity and gender roles via the validated gender role conflict score (GRCS; range 18–78, higher = greater gender role conflict). We measured gender power imbalances among women via the validated Sexual Relationship Power Scale (SRPS), which combines subscales of relationship control and decision-making dominance (range 1–4, higher = female holds more power). We compared changes over the study period by arm using longitudinal multilevel difference-in-difference linear regression models accounting for clustering of facilities using the intention-to-treat cohort.

Results:

We enrolled 720 participants (366 intervention, 354 control); 2-year retention was 94%. Median age was 40 and approximately 55% of participants were female. Among men, after 24-months the decrease in GRCS scores was 4.3 points greater in the intervention than the control arm (P < 0.001). Among women, the intervention resulted in 0.25 points greater increase in the SRPS compared to the control arm (P < 0.001).

Conclusions:

Shamba Maisha resulted in less gender role conflict in men and greater sexual relationship power for women. Agricultural livelihood interventions may be a powerful tool to improve gender power imbalances, which may subsequently mitigate poverty and food insecurity.
iNaturalist is an open science resource for ecological genomics by enabling rapid and tractable records of initial observations of sequenced biological samples
Authors: Goldberg Jay Keche
Published: October 2023

The rapidly growing body of publicly available sequencing data for rare species and/or wild-caught samples is accelerating the need for detailed records of the samples used to generate datasets. Many already published datasets are unlikely to ever be reused, not due to problems with the data themselves, but due to their questionable or unverifiable origins. In this paper, I present iNaturalist—a pre-existing citizen science platform that allows people to post photo observations of organisms in nature—as a tool that allows genomics researchers to rapidly publish observations of samples used to generate sequencing datasets. This practice aligns with the values of the open science movement, and I also discuss how iNaturalist, along with other online resources, can be used to create an open genomics pipeline that enables future replication studies and ensures the value of genomics datasets to future research.
Genome-wide identification of ATP-binding cassette transporter B subfamily, focusing on its structure, evolution and rearrangement in ciliates
Authors: Zhang Xue , Zhao Yan , Zheng Weibo , Nan Bei , Fu Jinyu , Qiao Yu , Zufall Rebecca A. , Gao Feng , Yan Ying
Published: October 2023

ATP-binding cassette subfamily B (ABCB) has been implicated in various essential functions such as multidrug resistance, auxin transport and heavy metal tolerance in animals and plants. However, the functions, the genomic distribution and the evolutionary history have not been characterized systematically in lower eukaryotes. As a lineage of highly specialized unicellular eukaryotes, ciliates have extremely diverse genomic features including nuclear dimorphism. To further understand the genomic structure and evolutionary history of this gene family, we investigated the ABCB gene subfamily in 11 ciliates. The results demonstrate that there is evidence of substantial gene duplication, which has occurred by different mechanisms in different species. These gene duplicates show consistent purifying selection, suggesting functional constraint, in all but one species, where positive selection may be acting to generate novel function. We also compare the gene structures in the micronuclear and macronuclear genomes and find no gene scrambling during genome rearrangement, despite the abundance of such scrambling in two of our focal species. These results lay the foundation for future analyses of the function of these genes and the mechanisms responsible for their evolution across diverse eukaryotic lineages.
Tyrosyl-DNA phosphodiesterase 1 (TDP1) and SPRTN protease repair histone 3 and topoisomerase 1 DNA–protein crosslinks
in vivo
Authors: Anticevic Ivan , Otten Cecile , Vinkovic Luka , Jukic Luka , Popovic Marta
Published: October 2023

DNA–protein crosslinks (DPCs) are frequent and damaging DNA lesions that affect all DNA transactions, which in turn can lead to the formation of double-strand breaks, genomic instability and cell death. At the organismal level, impaired DPC repair (DPCR) is associated with cancer, ageing and neurodegeneration. Despite the severe consequences of DPCs, little is known about the processes underlying repair pathways at the organism level. SPRTN is a protease that removes most cellular DPCs during replication, whereas tyrosyl-DNA phosphodiesterase 1 repairs one of the most abundant enzymatic DPCs, topoisomerase 1-DPC (TOP1-DPC). How these two enzymes repair DPCs at the organism level is currently unknown. We perform phylogenetic, syntenic, structural and expression analysis to compare tyrosyl-DNA phosphodiesterase 1 (TDP1) orthologues between human, mouse and zebrafish. Using the zebrafish animal model and human cells, we demonstrate that TDP1 and SPRTN repair endogenous, camptothecin- and formaldehyde-induced DPCs, including histone H3- and TOP1-DPCs. We show that resolution of H3-DNA crosslinks depends on upstream proteolysis by SPRTN and subsequent peptide removal by TDP1 in RPE1 cells and zebrafish embryos, whereas SPRTN and TDP1 function in different pathways in the repair of endogenous TOP1-DPCs and total DPCs. Furthermore, we have found increased TDP2 expression in TDP1-deficient cells and embryos. Understanding the role of TDP1 in DPCR at the cellular and organismal levels could provide an impetus for the development of new drugs and combination therapies with TOP1-DPC inducing drugs.
Museomics unveil systematics, diversity and evolution of Australian cycad-pollinating weevils
Authors: Hsiao Yun , Oberprieler Rolf G. , Zwick Andreas , Zhou Yu-Lingzi , Ślipiński Adam
Published: October 2023

Weevils have been shown to play significant roles in the obligate pollination of Australian cycads. In this study, we apply museomics to produce a first molecular phylogeny estimate of the Australian cycad weevils, allowing an assessment of their monophyly, placement and relationships. Divergence dating suggests that the Australian cycad weevils originated from the Late Oligocene to the Middle Miocene and that the main radiation of the cycad-pollinating groups occurred from the Middle to the Late Miocene, which is congruent with the diversification of the Australian cycads, thus refuting any notion of an ancient ciophilous system in Australia. Taxonomic studies reveal the existence of 19 Australian cycad weevil species and that their associations with their hosts are mostly non-species-specific. Co-speciation analysis shows no extensive co-speciation events having occurred in the ciophilous system of Australian cycads. The distribution pattern suggests that geographical factors, rather than diversifying coevolution, constitute the overriding process shaping the Australian cycad weevil diversity. The synchronous radiation of cycads and weevil pollinators is suggested to be a result of the post-Oligocene diversification common in Australian organisms.
Lacticaseibacillus huelsenbergensis sp. nov., isolated from grass silage and corn silage
Authors: Grabner F. Monika , Grabner H. Monika , Schein Hermine , Weidenholzer Elisabeth , Busche Tobias , Rückert-Reed Christian , Buchebner-Jance Marlene
Published: October 2023

Two rod-shaped, facultative anaerobic, Gram-stain-positive lactic acid bacteria were isolated from corn silage and grass silage. They were characterized using a polyphasic approach and designated as HO 1656T and HO 0673. Analysis of 16S rRNA gene sequence of both strains indicated that they belong to the

Lacticaseibacillus

group. The most closely related species,

Lacticaseibacillus casei

DSM 20011T and

Lacticaseibacillus zeae

DSM 20178T, have digital DNA–DNA hybridization (dDDH) values of 63.9 and 53.4%, respectively, with the novel strains. In contrast, the dDDH value between strains HO 1656T and HO 0673 is 99.3 %, clearly showing that these two isolated strains belong to the same species. According to analysis of the housekeeping genes (dnaK, mutL and pheS), both strains form a distinct cluster within the

Lacticaseibacillus

group. Strains HO 0673 and HO 1656T could produce acid from d-arabinose, adonitol, ribose, rhamnose, dulcitol, sorbitol, turanose, l-fucose and l-arabitol, unlike their nearest phylogenetic neighbour

L. casei

DSM 20011T. The major cellular fatty acids of both strains are C16 : 0 and C18 : 1 ω9c. The G+C content of the genomic DNA of both strains is 48.0 mol%. Thus, strains HO 1656T and HO 0673 represent a novel species based on their chemotaxonomic, phenotypic and phylogenetic characteristics. The name Lacticaseibacillus huelsenbergensis sp. nov. is proposed with the type strain HO 1656T (=DSM 115425T=NCIMB 15466T).
Microbial Primer: Multidrug efflux pumps
Authors: Siasat Pauline Ann , Blair Jessica M. A.
Published: October 2023

Multidrug efflux pumps are molecular machines that sit in the bacterial cell membrane and pump molecules out from either the periplasm or cytoplasm to outside the cell. While involved in a variety of biological roles, they are primarily known for their contribution to antibiotic resistance by limiting the intracellular accumulation of antimicrobial compounds within bacteria. These transporters are often overexpressed in clinical isolates, leading to multidrug-resistant phenotypes. Efflux pumps are classified into several families based on their structure and understanding the characteristics of each family is important for the development of novel therapies to restore antibiotic potency.
Longitudinal associations of sustained low or high income and income variability with incident cardiovascular disease in individuals with type 2 diabetes: a retrospective population-based cohort study
Authors: Park Yong-Moon Mark , Baek Jong Ha , Lee Hong Seok , Elfassy Tali , Brown Clare C. , Schootman Mario , Narcisse Marie-Rachelle , Ko Seung-Hyun , McElfish Pearl A. , Thomsen Michael R. , Amick Benjamin C. , Lee Seong-Su , Han Kyungdo
Published: October 2023

Background and Aims

Longitudinal change in income is crucial in explaining cardiovascular health inequalities, but there is limited evidence for cardiovascular disease (CVD) risk associated with income dynamics over time among individuals with type 2 diabetes (T2D).

Methods

Using a nationally representative sample from the Korean Health Insurance Service database, 1,528,108 adults with T2D aged 30-64 years and no history of CVD were enrolled between 2009-2012 (mean follow-up of 7.3 years). Using monthly health insurance premiums information, income levels were assessed annually for 4 years before the baseline year. Income variability was defined as the intraindividual standard deviation of the percent change in income across 5 years. The primary outcome was a composite event of incident fatal and nonfatal CVD (myocardial infarction, stroke, and heart failure) using insurance claims. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated after adjusting for potential confounders.

Results

Sustained low income (i.e., lowest income quartile) over 5 years was associated with increased CVD risk (HRn=5yearsvs.n=0years1.38, 95% CI 1.35-1.41; Ptrend<0.0001), whereas sustained high income (i.e., highest income quartile) was associated with decreased CVD risk (HR 0.71n=5yearsvs.n=0years95% CI 0.70-0.72; Ptrend<0.0001). High-income variability was associated with increased CVD risk (HRhighestvs.lowestquartile1.25, 95% CI 1.22-1.27; Ptrend<0.001). Individuals who experienced an income decline across 5 years leading up to baseline had increased CVD risk, particularly in a decrease to the lowest income level (i.e., Medical Aids beneficiaries), regardless of initial income status. Sensitivity analyses, including potential mediators, such as lifestyle-related factors and obesity, supported the results.

Conclusions

Among non-elderly Korean adults with T2D, sustained low income, higher income variability, and income declines were associated with increased CVD risk. Our findings highlight the need to understand better the mechanisms by which income dynamics impact CVD risk among individuals with T2D.
Epigenetic age and socioeconomic status contribute to racial disparities in cognitive and functional aging between Black and White older Americans
Authors: Yannatos Isabel , Stites Shana D. , Boen Courtney , Xie Sharon X. , Brown Rebecca T. , McMillan Corey T.
Published: October 2023

Epigenetic age, a biological aging marker measured by DNA methylation, is a potential mechanism by which social factors drive disparities in age-related health. Epigenetic age gap is the residual between epigenetic age measures and chronological age. Previous studies showed associations between epigenetic age gap and age-related outcomes including cognitive capacity and performance on some functional measures, but whether epigenetic age gap contributes to disparities in these outcomes is unknown. We use data from the Health and Retirement Study to examine the role of epigenetic age gap in racial disparities in cognitive and functional outcomes and consider the role of socioeconomic status (SES). Epigenetic age measures are GrimAge or Dunedin Pace of Aging methylation (DPoAm). Cognitive outcomes are cross-sectional score and two-year change in Telephone Interview for Cognitive Status (TICS). Functional outcomes are prevalence and incidence of limitations performing Instrumental Activities of Daily Living (IADLs). We find, relative to White participants, Black participants have lower scores and greater decline in TICS, higher prevalence and incidence rates of IADL limitations, and higher epigenetic age gap. Age- and gender-adjusted analyses reveal that higher GrimAge and DPoAm gap are both associated with worse cognitive and functional outcomes and mediate 6-11% of racial disparities in cognitive outcomes and 19-39% of disparities in functional outcomes. Adjusting for SES attenuates most DPoAm associations and most mediation effects. These results support that epigenetic age gap contributes to racial disparities in cognition and functioning and may be an important mechanism linking social factors to disparities in health outcomes.
The role of socio-economic disparities in the relative success of SARS-CoV-2 variants in New York City in early 2021
Authors: Vasylyeva Tetyana I. , Havens Jennifer L. , Wang Jade C. , Luoma Elizabeth , Hassler Gabriel W. , Amin Helly , Di Lonardo Steve , Taki Faten , Omoregie Enoma , Hughes Scott , Wertheim Joel O.
Published: October 2023

Background

Socio-economic disparities were associated with disproportionate viral incidence between neighborhoods of New York City (NYC) during the first wave of SARS-CoV-2. We investigated how these disparities affected the co-circulation SARS-CoV-2 variants during the second wave in NYC.

Methods

We tested for correlation between the prevalence, in late 2020/early 2021, of Alpha, Iota, Iota with E484K mutation (Iota-E484K), and B.1-like genomes and pre-existing immunity (seropositivity) in NYC neighborhoods. In the context of varying seroprevalence we described socio-economic profiles of neighborhoods and performed migration and lineage persistence analyses using a Bayesian phylogeographical framework.

Findings

Seropositivity was greater in areas with high poverty and a larger proportion of Black and Hispanic or Latino residents. Seropositivity was positively correlated with the proportion of Iota-E484K and Iota genomes, and negatively correlated with the proportion of Alpha and B.1-like genomes. The proportion of persisting Alpha lineages declined over time in locations with high seroprevalence, whereas the proportion of persisting Iota-E484K lineages remained the same in high seroprevalence areas.

Interpretation

During the second wave, the geographic variation of standing immunity, due to disproportionate disease burden during the first wave of SARS-CoV-2 in NYC, allowed for the immune evasive Iota-E484K variant, but not the more transmissible Alpha variant, to circulate in locations with high pre-existing immunity.

Funding

We acknowledge funding from the National Institutes of Health and the Centers for Disease Control and Prevention.
HPV detection patterns in young women from the PAPCLEAR longitudinal study: implications for HPV screening policies
Authors: Beneteau Thomas , Groc Soraya , Murall Carmen Lia , Boué Vanina , Elie Baptiste , Tessandier Nicolas , Bernat Claire , Bonneau Marine , Foulongne Vincent , Graf Christelle , Grasset Sophie , Rahmoun Massilva , Segondy Michel , Tribout Vincent , Reynes Jacques , Selinger Christian , Boulle Nathalie , Bravo Ignacio G. , Sofonea Mircea T. , Alizon Samuel
Published: October 2023

Objectives

HPV infections are ubiquitous. For most infections, we lose track of the presence of the virus in host in less than three years after the start of infection. The mechanisms regulating the persistence of HPV infection are still partially understood. In this work, we focus on incident HPV detection in young women and we characterise the dynamics of these infections and evaluate the effect of genotype and host socio-economic factors on the duration of HPV detection and time between detection.

Methods

We investigated human papillomavirus (HPV) genotype detection patterns in 182 young women in Montpellier, France. We relied on SPF10-LiPA25 screening assay for the simultaneous de-tection of 25 HPV genotypes. We used survival analysis tools with frailty effects to investigate the contribution of viral and host factors to variations in the time of HPV detectability, time of first incident detection, and time before re-detection.

Results

Women of the PAPCLEAR cohort experienced numerous positive HPV events, including frequent redetection of the same genotype. We retrieve classical results that HR-genotypes are detected for longer duration than LR-genotypes. HR-genotypes were also more liekly to be detected than LR-genotypes during the follow-up. The number of lifetime sexual partner was strongly associated with increased risk of new positive detection while vaccination was related to a lower risk of displaying incident infections. Covariates related to socio-economic difficulties were associated with longer duration of HPV positivity.

Conclusions

Young women display numerous event of HPV detection, with frequent codetections of multiple genotypes at the same time and redetection of the same type after periods of no detection. These new detection are almost certainly the result of new acquisition from sexual partners, with little evidence of re-emergence of latent infections. A better characterisation of transient infections might help unveil doubts and misconception on HPV physiopathology, favouring adherence to preventive policies.
Multi-modal transcriptomic analysis unravels enrichment of hybrid epithelial/mesenchymal state and enhanced phenotypic heterogeneity in basal breast cancer
Authors: Sahoo Sarthak , Ramu Soundharya , Nair Madhumathy G , Pillai Maalavika , San Juan Beatriz P , Milioli Heloisa Zaccaron , Mandal Susmita , Naidu Chandrakala M , Mavatkar Apoorva D , Subramaniam Harini , Neogi Arpita G , Chaffer Christine L , Prabhu Jyothi S , Somarelli Jason A , Jolly Mohit Kumar
Published: October 2023

Intra-tumoral phenotypic heterogeneity promotes tumor relapse and therapeutic resistance and remains an unsolved clinical challenge. It manifests along multiple phenotypic axes and decoding the interconnections among these different axes is crucial to understand its molecular origins and to develop novel therapeutic strategies to control it. Here, we use multi-modal transcriptomic data analysis – bulk, single-cell and spatial transcriptomics – from breast cancer cell lines and primary tumor samples, to identify associations between epithelial-mesenchymal transition (EMT) and luminal-basal plasticity – two key processes that enable heterogeneity. We show that luminal breast cancer strongly associates with an epithelial cell state, but basal breast cancer is associated with hybrid epithelial/mesenchymal phenotype(s) and higher phenotypic heterogeneity. These patterns were inherent in methylation profiles, suggesting an epigenetic crosstalk between EMT and lineage plasticity in breast cancer. Mathematical modelling of core underlying gene regulatory networks representative of the crosstalk between the luminal-basal and epithelial-mesenchymal axes recapitulate and thus elucidate mechanistic underpinnings of the observed associations from transcriptomic data. Our systems-based approach integrating multi-modal data analysis with mechanism-based modeling offers a predictive framework to characterize intra-tumor heterogeneity and to identify possible interventions to restrict it.
Glioblastoma initiation, migration, and cell types are regulated by core bHLH transcription factors ASCL1 and OLIG2
Authors: Myers Bianca L. , Brayer Kathryn J. , Paez-Beltran Luis E. , Keith Matthew S. , Suzuki Hideaki , Newville Jessie , Anderson Rebekka H. , Lo Yunee , Mertz Conner M. , Kollipara Rahul , Borromeo Mark D. , Bachoo Robert M. , Johnson Jane E. , Vue Tou Yia
Published: October 2023

Glioblastomas (GBMs) are highly aggressive, infiltrative, and heterogeneous brain tumors driven by complex driver mutations and glioma stem cells (GSCs). The neurodevelopmental transcription factors ASCL1 and OLIG2 are co-expressed in GBMs, but their role in regulating the heterogeneity and hierarchy of GBM tumor cells is unclear. Here, we show that oncogenic driver mutations lead to dysregulation of ASCL1 and OLIG2, which function redundantly to initiate brain tumor formation in a mouse model of GBM. Subsequently, the dynamic levels and reciprocal binding of ASCL1 and OLIG2 to each other and to downstream target genes then determine the cell types and degree of migration of tumor cells. Single-cell RNA sequencing (scRNA-seq) reveals that a high level of ASCL1 is key in defining GSCs by upregulating a collection of ribosomal protein, mitochondrial, neural stem cell (NSC), and cancer metastasis genes – all essential for sustaining the high proliferation, migration, and therapeutic resistance of GSCs.
Bile Acids Serve As Endogenous Antagonists Of The Leukemia Inhibitory Factor (LIF) Receptor in Oncogenesis
Authors: Di Giorgio Cristina , Morretta Elva , Lupia Antonio , Bellini Rachele , Massa Carmen , Urbani Ginevra , Bordoni Martina , Marchianò Silvia , Rapacciuolo Pasquale , Finamore Claudia , Sepe Valentina , Monti Maria Chiara , Moraca Federica , Natalizi Nicola , Graziosi Luigina , Distrutti Eleonora , Biagioli Michele , Catalanotti Bruno , Donini Annibale , Zampella Angela , Fiorucci Stefano
Published: October 2023

The leukemia inhibitory factor (LIF) is member of IL-6 family of cytokines involved immune regulation, morphogenesis and oncogenesis. In cancer tissues, LIF binds a heterodimeric receptor (LIFR), formed by a LIFRβ subunit and glycoprotein(gp)130, promoting epithelial mesenchymal transition and cell growth. Bile acids are cholesterol metabolites generated at the interface of host metabolism and the intestinal microbiota. Here we demonstrated that bile acids serve as endogenous antagonist to LIFR in oncogenesis. The tissue characterization of bile acids content in non-cancer and cancer biopsy pairs from gastric adenocarcinomas (GC) demonstrated that bile acids accumulate within cancer tissues, with glyco-deoxycholic acid (GDCA) functioning as negative regulator of LIFR expression. In patient-derived organoids (hPDOs) from GC patients, GDCA reverses LIF-induced stemness and proliferation. In summary, we have identified the secondary bile acids as the first endogenous antagonist to LIFR supporting a development of bile acid-based therapies in LIF-mediated oncogenesis.
Physical activity regulates the immune response to breast cancer by a hematopoietic stem cell-autonomous mechanism
Authors: Khair Lyne , Hayes Katherine , Tutto Amanda , Samant Amruta , Ferreira Lindsay , Nguyen Tammy T. , Brehm Michael , Messina Louis M.
Published: October 2023

Physical activity is a modifiable lifestyle factor that is associated with a decreased risk for the development of breast cancer. While the exact mechanisms for the reduction in cancer risk due to physical activity are largely unknown, it is postulated that the biological reduction in cancer risk is driven by improvements in inflammation and immune function with exercise. Hematopoietic stem cells (HSCs) are the progenitor for all of the cells of the immune system and are involved in cancer immunosurveillance through differentiation into cytotoxic cell population. In this study, we investigate the role of physical activity (PA) in a spontaneously occurring model of breast cancer over time, with a focus on tumor incidence, circulating and tumor-infiltrating immune cells as well gene expression profiles of tumors and hematopoietic stem cells. Furthermore, we show that, in addition to a direct effect of PA on the immune cells of tumor-bearing mice, PA reduces the oxidative stress in HSCs of wildtype and tumor-bearing mice, and by doing so, alters the differentiation of the HSCs towards T cells in order to enhance cancer immunosurveillance.
Three distinct gamma oscillatory networks within cortical columns in macaque monkeys’ area V1
Authors: Drebitz Eric , Rausch Lukas-Paul , Gil Esperanza Domingo , Kreiter Andreas K.
Published: October 2023

A fundamental property of the neocortex is its columnar organization in many species. Generally, neurons of the same column share stimulus preferences and have strong anatomical connections across layers. These features suggest that neurons within a column operate as one unified network. Other features, like the different patterns of input and output connections of neurons located in separate layers and systematic differences in feature tuning, hint at a more segregated and possibly flexible functional organization of neurons within a column. To distinguish between these views of columnar processing, we conducted laminar recordings in macaques’ area V1 while they performed a demanding attention task. We found three separate regions with strong gamma oscillatory current source density (CSD) signals, one each in the supragranular, granular, and infragranular laminar domains. Their characteristics differed significantly in terms of their dominant gamma frequency and attention-dependent modulation of their gramma power and gamma frequency. In line, spiking activity in the supragranular, infragranular, and upper part of the granular domain exhibited strong phase coherence with their domain’s CSD signals but showed much weaker coherence with the other domains’ CSD signals. These results indicate that columnar processing involves a certain degree of independence between neurons in the three laminar domains, consistent with the assumption of multiple, separate intracolumnar ensembles. Such a functional organization offers various possibilities for dynamic network configuration, indicating that neurons in a column are not restricted to operate as one unified network. Thus, the findings open interesting new possibilities for future concepts and investigations on flexible, dynamic cortical ensemble formation and selective information processing.
Development of properly-polarized trophoblast stem cell-derived organoids to model early human pregnancy
Authors: Zhou J , Sheridan MA , Tian Y , Dahlgren KJ , Messler M , Peng T , Ezashi T , Schulz LC , Ulery BD , Roberts RM , Schust DJ
Published: October 2023

The development of human trophoblast stem cells (hTSC) and stem cell-derived trophoblast organoids has enabled investigation of placental physiology and disease and early maternal-fetal interactions during a stage of human pregnancy that previously had been severely restricted. A key shortcoming in existing trophoblast organoid methodologies is the non-physiologic position of the syncytiotrophoblast (STB) within the inner portion of the organoid, which neither recapitulates placental villous morphologyin vivonor allows for facile modeling of STB exposure to the endometrium or the contents of the intervillous space. Here we have successfully established properly-polarized human trophoblast stem cell (hTSC)-sourced organoids with STB forming on the surface of the organoid. These organoids can also be induced to give rise to the extravillous trophoblast (EVT) lineage with HLA-G+migratory cells that invade into an extracellular matrix-based hydrogel. Compared to previous hTSC organoid methods, organoids created by this method more closely mimic the architecture of the developing human placenta and provide a novel platform to study normal and abnormal human placental development and to model exposures to pharmaceuticals, pathogens and environmental insults.

Motivation

Human placental organoids have been generated to mimic physiological cell-cell interactions. However, those published models derived from human trophoblast stem cells (hTSCs) or placental villi display a non-physiologic “inside-out” morphology.In vivo, the placental villi have an outer layer of syncytialized cells that are in direct contact with maternal blood, acting as a conduit for gas and nutrient exchange, and an inner layer of progenitor, single cytotrophoblast cells that fuse to create the syncytiotrophoblast layer. Existing “inside-out” models put the cytotrophoblast cells in contact with culture media and substrate, making physiologic interactions between syncytiotrophoblast and other cells/tissues and normal and pathogenic exposures coming from maternal blood difficult to model. The goal of this study was to develop an hTSC-derived 3-D human trophoblast organoid model that positions the syncytiotrophoblast layer on the outside of the multicellular organoid.

Graphical abstract
Cryo-EM structure of the CBC-ALYREF complex
Authors: Clarke Bradley P. , Angelos Alexia E. , Mei Menghan , Hill Pate S. , Xie Yihu , Ren Yi
Published: October 2023

In eukaryotes, RNAs transcribed by RNA Pol II are modified at the 5’ end with a 7-methylguanosine (m7G) cap, which is recognized by the nuclear cap binding complex (CBC). The CBC plays multiple important roles in mRNA metabolism including transcription, splicing, polyadenylation, and export. It promotes mRNA export through direct interaction with a key mRNA export factor, ALYREF, which in turn links the TRanscription and EXport (TREX) complex to the 5’ end of mRNA. However, the molecular mechanism for CBC mediated recruitment of the mRNA export machinery is not well understood. Here, we present the first structure of the CBC in complex with an mRNA export factor, ALYREF. The cryo-EM structure of CBC-ALYREF reveals that the RRM domain of ALYREF makes direct contact with both the NCBP1 and NCBP2 subunits of the CBC. Comparing CBC-ALYREF with other cellular complexes containing CBC and/or ALYREF components provides insights into the coordinated events during mRNA transcription, splicing, and export.