bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiovascular risk associated with changes in anticholinergic load on four different scales: a registry-based cohort study of geriatric outpatients
Authors: Riis Johannes , Kragholm Kristian , Søndergaard Marc Meller , Clemmensen Silas , Hansen Lene Torp , Torp-Pedersen Christian , Melgaard Dorte
Published: July 2024

Background

Recent studies have shown that anticholinergic medications are associated with cardiovascular disease. Little is known about how discontinuation of anticholinergic medication affects this association. We investigated how baseline anticholinergic load and change in anticholinergic load associates with major adverse cardiovascular events (MACE) on four different scales.

Methods

We included all geriatric outpatients aged 65 and older in Denmark between January 2011 and December 2018. Data were sourced from Danish national registries. Anticholinergic drug exposure was assessed at first contact to the outpatient clinic (baseline) and changes were assessed at 180 days after outpatient contact. Anticholinergic scales were the CRIDECO Anticholinergic Load Scale, Anticholinergic Drugs Scale, Anticholinergic Cognitive Burden and a scale by the Danish Institute of Rational Pharmacotherapy. Multivariate analyses were conducted to investigate the 1- and 5-year risk of MACE by baseline anticholinergic load and changes in anticholinergic load after 180 days.

Results

We included a total of 64 378 patients in the analysis of baseline anticholinergic load and 54 010 patients remained after 180 days for inclusion in the analysis of change in anticholinergic load. At baseline the mean age was 81.7 year (SD 7.5) and 68% were women. Higher level of anticholinergic load on any scale associated with greater risk of MACE in a dose response pattern. There were no association between reduction in anticholinergic load and risk of MACE.

Conclusion

While anticholinergic load at baseline was associated with MACE, reducing anticholinergic load did not lower the risk of MACE indicating the association may not be causal.
Can metformin prevent cancer relative to sulfonylureas? A target trial emulation accounting for competing risks and poor overlap via double/debiased machine learning estimators
Authors: Xu Shenbo , Zheng Bang , Su Bowen , Finkelstein Stan Neil , Welsch Roy , Ng Kenney , Shahn Zach
Published: July 2024

There is mounting interest in the possibility that metformin, indicated for glycemic control in type 2 diabetes, has a range of additional beneficial effects. Randomized trials have shown that metformin prevents adverse cardiovascular events, and metformin use has also been associated with reduced cognitive decline and cancer incidence. In this paper, we dig more deeply into whether metformin prevents cancer by emulating target randomized trials comparing metformin to sulfonylureas as first-line diabetes therapy using data from the Clinical Practice Research Datalink, a UK primary-care database (1987-2018). We included 93 353 individuals with diabetes, no prior cancer diagnosis, no chronic kidney disease, and no prior diabetes therapy who initiated use of metformin (n = 79 489) or a sulfonylurea (n = 13 864). In our cohort, the estimated overlap-weighted additive separable direct effect of metformin compared with sulfonylureas on cancer risk at 6 years was −1 percentage point (95% CI, −2.2 to 0.1), which is consistent with metformin’s providing no direct protection against cancer incidence or substantial protection. The analysis faced 2 methodological challenges: (1) poor overlap and (2) precancer death as a competing risk. To address these issues while minimizing nuisance model misspecification, we develop and apply double/debiased machine learning estimators of overlap-weighted separable effects in addition to more traditional effect estimates.

This article is part of a Special Collection on Pharmacoepidemiology.
Risk factors for treatment of asymptomatic bacteriuria in a rural health system
Authors: Rang Miranda , Nasser Rana , Gabor Rachel , Whitfield Philip
Published: July 2024

Purpose

Asymptomatic bacteriuria is often inappropriately treated, leading to antimicrobial-related adverse events and contributing to antimicrobial resistance. This study examined the asymptomatic bacteriuria treatment rate at a rural Wisconsin health system and the patient-specific factors that may be influencing clinicians’ decisions to treat.

Methods

This is a retrospective descriptive report of patients admitted from January to May 2022 at 7 rural Wisconsin hospitals. Patients were included if they were a hospitalized adult with asymptomatic bacteriuria. Patients were excluded if they had a urinary tract abnormality, active infection, symptoms of a urinary tract infection, a planned urological surgery, or treatment or prophylaxis for a urinary tract infection within 72 hours of admission, were immunocompromised, or were transferred from an outside facility. Electronic and manual chart abstraction were used for data collection.

Results

Of 429 patients with a positive urine culture, 137 patients with asymptomatic bacteriuria were included in the study. The median age was 75 years, and most patients were female (80.3%). The treatment rate of asymptomatic bacteriuria was 78.1%, amounting to 393 days of unnecessary antimicrobial therapy. Symptoms of fatigue (P = 0.014) and altered mentation (P < 0.006) and urinalysis results of nitrite positivity (P = 0.026) and pyuria (P < 0.001) were each independently associated with antimicrobial treatment.

Conclusion

Despite guideline recommendations to avoid treatment of asymptomatic bacteriuria, treatment rates in rural hospitalized patients remain high. Nonspecific signs and symptoms of altered mentation and fatigue as well as laboratory findings of nitrite positivity and pyuria were factors associated with a decision to treat. Future stewardship efforts should speak to the poor specificity of these factors.
Intravenous push lacosamide: Successful implementation and patient outcomes across a health system
Authors: Spangler Julie R , Young Sarah , Carr Dustin R , Finoli Lauren
Published: July 2024

Purpose

Intravenous administration of the antiseizure medication lacosamide can be delayed given operational challenges related to short beyond-use-dating and controlled substance requirements. The purpose of this study was to describe the steps required to successfully transition from intravenous piggyback administration to intravenous push administration and demonstrate that workflow changes improved time to administration without compromising patient safety.

Methods

This multicenter study had 2 components; the first portion was a prospective description of the implementation and operationalization process, while the second was a retrospective cohort analysis comparing patients who received intravenous piggyback and intravenous push lacosamide. After the transition, the default administration route for adult patients for lacosamide doses of 400 mg or less was intravenous push. While the primary objective was to describe the implementation process, secondary objectives included comparison of time to administration and safety, using a composite and incidence of PR prolongation.

Results

Success in implementation and operationalization across a large health system was achieved by following a 6-month timeline. A total of 102 patients were included in the cohort study, with 869 individual administrations analyzed (519 intravenous piggyback and 350 intravenous push). Time from verification to administration was significantly decreased when comparing intravenous piggyback (median, 159 minutes) to intravenous push (median, 88 minutes) administrations (P = 0.008). No significant difference was found in the safety composite or PR prolongation.

Conclusion

Transitioning intravenous lacosamide administration from piggyback to push administration is feasible and decreases time from verification to administration without increased incidence of adverse effects.
Enhancing predictions of protein stability changes induced by single mutations using MSA-based language models
Authors: Cuturello Francesca , Celoria Marco , Ansuini Alessio , Cazzaniga Alberto
Published: July 2024

Motivation

Protein language models offer a new perspective for addressing challenges in structural biology, while relying solely on sequence information. Recent studies have investigated their effectiveness in forecasting shifts in thermodynamic stability caused by single amino acid mutations, a task known for its complexity due to the sparse availability of data, constrained by experimental limitations. To tackle this problem, we introduce two key novelties: leveraging a protein language model that incorporates Multiple Sequence Alignments to capture evolutionary information, and using a recently released mega-scale dataset with rigorous data preprocessing to mitigate overfitting.

Results

We ensure comprehensive comparisons by fine-tuning various pretrained models, taking advantage of analyses such as ablation studies and baselines evaluation. Our methodology introduces a stringent policy to reduce the widespread issue of data leakage, rigorously removing sequences from the training set when they exhibit significant similarity with the test set. The MSA Transformer emerges as the most accurate among the models under investigation, given its capability to leverage co-evolution signals encoded in aligned homologous sequences. Moreover, the optimized MSA Transformer outperforms existing methods and exhibits enhanced generalization power, leading to a notable improvement in predicting changes in protein stability resulting from point mutations.

Availability and implementation

Code and data at https://github.com/RitAreaSciencePark/PLM4Muts.
Genome-wide analysis and visualization of copy number with CNVpytor in igv.js
Authors: Panda Arijit , Suvakov Milovan , Thorvaldsdottir Helga , Mesirov Jill P , Robinson James T , Abyzov Alexej
Published: July 2024

Copy number variation (CNV) and alteration (CNA) analysis is a crucial component in many genomic studies and its applications span from basic research to clinic diagnostics and personalized medicine. CNVpytor is a tool featuring a read depth-based caller and combined read depth and B-allele frequency (BAF) based 2D caller to find CNVs and CNAs. The tool stores processed intermediate data and CNV/CNA calls in a compact HDF5 file—pytor file. Here, we describe a new track in igv.js that utilizes pytor and whole genome variant files as input for on-the-fly read depth and BAF visualization, CNV/CNA calling and analysis. Embedding into HTML pages and Jupiter Notebooks enables convenient remote data access and visualization simplifying interpretation and analysis of omics data.

Availability and implementation

The CNVpytor track is integrated with igv.js and available at https://github.com/igvteam/igv.js. The documentation is available at https://github.com/igvteam/igv.js/wiki/cnvpytor. Usage can be tested in the IGV-Web app at https://igv.org/app and also on https://github.com/abyzovlab/CNVpytor.
Medication use patterns in pregnant women with psoriasis: a nationwide study in Taiwan
Authors: Ou Chien-Hua , Kao Li-Ting , Yang Hui-Wen , Chiang Yi-Lin , Wen Yuan-Liang , To Sheng-Yin , Chen Yi-Hsien
Published: July 2024

Background

Psoriasis, an autoimmune skin condition, affects 2–4% of the global population, with significant prevalence among women of childbearing age. Pregnancy presents challenges in managing psoriasis because of hormonal changes and treatment safety concerns. Understanding treatment patterns in pregnant women is crucial, given limited real-world evidence.

Objectives

To explore the utilization patterns of medications among pregnant women diagnosed with psoriasis within real-world data, utilizing data sourced from a nationwide database in Taiwan.

Methods

This nationwide study utilized Taiwan's National Health Insurance (NHI) database and birth certificate application records. It included registered pregnant women diagnosed with psoriasis from 2005 to 2014. Medication usage was tracked 3 years before conception to 3 years after delivery. Medications were categorized based on Anatomical Therapeutic Chemical codes, and statistical analyses were conducted using SAS software.

Results

In total, 30 267 pregnant women with psoriasis were studied. In total, 11 651 (38.5%) mothers had received ≥ 1 prescription during follow-up (exposed group) and 61.5% (18 616) had never received medication (unexposed group). Demographics and comorbidities were similar between these two groups. Topical corticosteroids were the most prescribed treatment, followed by phototherapy, with systemic drugs and biologics less common. During the study period, 11 096 women with psoriasis had used topical corticosteroids, 3376 had used nonsteroidal topical agents, 218 had used systemic agents or biologics and 519 had received treatment with phototherapy. Medication usage declined during pregnancy, reaching its lowest in the third trimester but rebounded postpartum.

Conclusions

Psoriasis medications, systemic, biological or topical, were largely discontinued during pregnancy, sometimes up to 2 years before and extending postpartum. Research is needed to understand its impact on maternal and child health.
Pemphigus foliaceus: a patient’s perspective
Authors: Damani Namiz , Popli Urvi
Published: July 2024

A patient’s perspective on pemphigus foliaceus.
Topical sirolimus in dermatology: a systematic review
Authors: Afzal Usamah M , Alazemi Mohammad , Ali Omar , Ali Faisal R , Lear John T
Published: July 2024

Topical sirolimus is increasingly utilized off-licence to manage various dermatological conditions while avoiding typical adverse effects associated with systemic sirolimus. However, widespread use is limited by a highly heterogeneous evidence base of mixed quality. Our aim was to evaluate the current evidence base for the indications, efficacy and safety profile of topical sirolimus in dermatology. A literature search was conducted from 2005 to 4 July 2023, of English-language studies, with the following databases consulted: MEDLINE, PubMed, Embase, CENTRAL and EBSCO. Key words included ‘topical’, ‘rapamycin’, ‘sirolimus’ and ‘dermatology’. Data on drug efficacy, concentration, side-effects, cointerventions and follow-up were extracted. The search identified 202 studies, 71 of which met the inclusion criteria. Efficacy of topical sirolimus was demonstrated in facial angiofibromas (799 patients) compared with placebo across multiple randomized controlled trials, with a predominant concentration of 0.1%. Evidence was mixed for use of sirolimus in port-wine stains (61 patients), with evidence of effectiveness for combined sirolimus and pulsed-dye laser. Multiple case reports demonstrated clinical improvement with topical sirolimus in cutaneous vascular abnormalities (33 patients) at a higher concentration of 1%. Other applications of topical sirolimus were predominantly case reports, demonstrating generally favourable outcomes. Topical sirolimus was generally well tolerated; most reported adverse effects were localized irritation and pruritus. Ointment-based preparations and once-daily dosing appeared to confer a better side-effect profile. Most high-quality data pertain to the efficacy of topical sirolimus in treating facial angiofibromas in tuberous sclerosis. Outcomes are generally promising in other indications, with good tolerability, but data quality is mixed.
Precocious maturation and semi-multivoltine lifecycle in a subtropical grass lizard, Takydromus toyamai
Authors: Asato Hitomi , Toda Mamoru
Published: July 2024

There are many short-lived animals, but those displaying a lifecycle with more than one generation per year (multivoltine lifecycle) are rare among terrestrial vertebrates. The multivoltine lifecycle requires rapid growth and maturation and a long active season. Thus, small lizards in humid tropical or subtropical areas are candidates for multivoltine lifecycles. To test this prediction, we conducted a capture-mark-recapture study of a subtropical grass lizard, Takydromus toyamai, endemic to Miyako Islands, Japan. Juveniles grew very quickly, averaging 0.3 mm/day in the warm season, and attained sexual maturity at 2.5 months post-hatching. The breeding season was very long, and hatchlings emerged from May to November. The prolonged breeding season and rapid growth to maturity allowed some individuals to produce a second generation in their first year. Estimates of hatching date from growth rates indicated that many females that hatched in May–June became gravid 76–120 days after hatching and 122–165 days after oviposition of the eggs from which they hatched. Analyses of juvenile survivorship and month of hatching suggest that nearly half of breeding adults were members of multivoltine generations, although the 2 generations were not discrete. The species is short-lived, with only 16% of individuals surviving beyond 12 months, and few individuals reproduced in a second year. We refer to this condition as a “semi-multivoltine lifecycle.” Individuals that hatch late in the season defer reproduction until the following year and become founders of the next season’s cohort. This putative advantage of late-hatching individuals may have driven the evolution of this lifecycle.
Felt Age and Its Psychological Correlates in Dementia Spousal Caregiving Dyads: Findings From the IDEAL Programme
Authors: Sabatini Serena , Turner Shelbie G , Clare Linda
Published: July 2024

Objectives

Evidence suggests spouses influence each other’s subjective views on aging. Aligned with the Theory of Dyadic Illness Management, we investigated for the first time similarities in felt age (how old people feel relative to their chronological age) between people with dementia and their spousal caregivers, and how each partner’s felt age was related to psychological correlates in the other partner.

Methods

We used baseline (2014–2016) data from 1,001 people with dementia and their spousal caregivers who participated in the British Improving the experience of Dementia and Enhancing Active Life study. We ran linear regressions to analyze the extent to which the felt age of people with dementia and their caregivers were similar, and whether relationship quality was associated with the similarity. We utilized actor–partner interdependence models to analyze whether the felt age of people with dementia and their caregivers were associated with each other’s well-being, satisfaction with life, and self-efficacy.

Results

The felt age of people with dementia was associated with the felt age of their caregivers (β = 0.10; p = .001). Caregivers and people with dementia reported a more similar felt age when caregivers rated the caregiving relationship more positively (β = 0.07; p = .04). Caregivers' felt age was associated with well-being (β = 0.07; p = .02) and satisfaction with life (β = 0.06; p = .04), but not with self-efficacy, in people with dementia.

Discussion

Felt age in caregivers and people with dementia may be interwoven, and important psychological variables in people with dementia are related to caregivers' felt age. Findings offer empirical evidence on dementia caregiving dynamics and how family relationships are related to views on aging.
Intranasal M2SR (M2-Deficient Single Replication) Influenza Vaccine Induces Broadly Reactive Mucosal Antibody Production in Adults
Authors: Hill-Batorski Lindsay , Weiner Joshua A , Ackerman Margaret E , Hatta Yasuko , Hoft Daniel F , Herber Renee , Moser Michael J , Bilsel Pamuk
Published: July 2024

Intranasal H3N2 M2SR vaccine induced cross-reactive mucosal IgA antibodies against a panel of H3N2 hemagglutinins, ranging from 1968 to 2014, in adults independent of baseline immune status. The breadth extended to potential pandemic strain H7N9, presumably through the hemagglutinin stem.

Intranasal M2SR (M2-deficient single replication) influenza virus vaccine induces robust immune responses in animal models and humans. A high-throughput multiplexed platform was used to analyze hemagglutinin-specific mucosal antibody responses in adults after a single dose of H3N2 M2SR. Nasal swab specimens were analyzed for total and hemagglutinin-specific IgA. Significant dose-dependent increases in mucosal antibody responses to vaccine-matched and drifted H3N2 hemagglutinin were observed in persons vaccinated with M2SR regardless of baseline serum and mucosal immune status. These data suggest that M2SR induces broadly cross-reactive mucosal immune responses, which may provide better protection against drifted and newly emerging influenza strains.
Prepandemic Metabolic Correlates of Coronavirus Disease 2019 (COVID-19) Severity and Long COVID Incidence in People Living With HIV
Authors: Agrawal Priyesh , Giron Leila B , Singh Shalini , Haw Nel Jason , Goldman Aaron R , Elkaeid Mohamed , Macatangay Bernard , Palella Frank J , Alcaide Maria L , Moran Caitlin A , Kassaye Seble G , Erdmann Nathan , Chew Kara W , Floris-Moore Michelle , Chandran Aruna , Augenbraun Michael H , Sharma Anjali , Palmer Clovis , Landay Alan L , Peluso Michael J , Keshavarzian Ali , Brown Todd T , Tien Phyllis C , Abdel-Mohsen Mohamed
Published: July 2024

Host metabolic dysregulation, especially in tryptophan metabolism, is intricately linked to coronavirus disease 2019 (COVID-19) severity and its postacute sequelae (long COVID). People living with human immunodeficiency virus (HIV; PLWH) experience similar metabolic dysregulation and face an increased risk of developing long COVID. However, whether preexisting HIV-associated metabolic dysregulations contribute in predisposing PLWH to severe COVID-19 outcomes remains underexplored. Analyzing prepandemic samples from PLWH with documented postinfection outcomes, we found specific metabolic alterations, including increased tryptophan catabolism, predicting an elevated risk of severe COVID-19 and the incidence of long COVID. These alterations warrant further investigation for their potential prognostic and mechanistic significance in determining COVID-19 complications.
Control charts in healthcare quality monitoring: a systematic review and bibliometric analysis
Authors: Waqas Muhammad , Xu Song Hua , Hussain Sajid , Aslam Muhammad Usman
Published: July 2024

Control charts, used in healthcare operations to monitor process stability and quality, are essential for ensuring patient safety and improving clinical outcomes. This comprehensive research study aims to provide a thorough understanding of the role of control charts in healthcare quality monitoring and future perspectives by utilizing a dual methodology approach involving a systematic review and a pioneering bibliometric analysis. A systematic review of 73 out of 223 articles was conducted, synthesizing existing literature (1995–2023) and revealing insights into key trends, methodological approaches, and emerging themes of control charts in healthcare. In parallel, a bibliometric analysis (1990–2023) on 184 articles gathered from Web of Science and Scopus was performed, quantitatively assessing the scholarly landscape encompassing control charts in healthcare. Among 25 countries, the USA is the foremost user of control charts, accounting for 33% of all applications, whereas among 14 health departments, epidemiology leads with 28% of applications. The practice of control charts in health monitoring has increased by more than one-third during the last 3 years. Globally, exponentially weighted moving average charts are the most popular, but interestingly the USA remained the top user of Shewhart charts. The study also uncovers a dynamic landscape in healthcare quality monitoring, with key contributors, research networks, research hotspot tendencies, and leading countries. Influential authors, such as J.C. Benneyan, W.H. Woodall, and M.A. Mohammed played a leading role in this field. In-countries networking, USA–UK leads the largest cluster, while other clusters include Denmark–Norway–Sweden, China–Singapore, and Canada–South Africa. From 1990 to 2023, healthcare monitoring evolved from studying efficiency to focusing on conditional monitoring and flowcharting, with human health, patient safety, and health surveys dominating 2011–2020, and recent years emphasizing epidemic control, COronaVIrus Disease of 2019 (COVID-19) statistical process control, hospitals, and human health monitoring using control charts. It identifies a transition from conventional to artificial intelligence approaches, with increasing contributions from machine learning and deep learning in the context of Industry 4.0. New researchers and journals are emerging, reshaping the academic context of control charts in healthcare. Our research reveals the evolving landscape of healthcare quality monitoring, surpassing traditional reviews. We uncover emerging trends, research gaps, and a transition in leadership from established contributors to newcomers amidst technological advancements. This study deepens the importance of control charts, offering insights for healthcare professionals, researchers, and policymakers to enhance healthcare quality. Future challenges and research directions are also provided.
Establishment of epidemiological cut-off values for eravacycline, against Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Acinetobacter baumannii and Staphylococcus aureus
Authors: Jing Ran , Yi Qiao-Lian , Zhuo Chao , Kang Wei , Yang Qi-Wen , Yu Yun-Song , Zheng Bo , Li Yun , Hu Fu-Pin , Yang Yang , Lin Jie , Zhang Ge , Zhang Jing-Jia , Wang Tong , Li Jin , Zhuo Chu-Yue , Li Xue , Zhu Yun-Fan , Xu Ying-Chun
Published: July 2024

Objectives

To establish the epidemiology cut-off (ECOFF) values of eravacycline against Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Acinetobacter baumannii and Staphylococcus aureus, from a multi-centre study in China.

Methods

We collected 2500 clinical isolates from five hospitals in China from 2017 to 2020. The MICs of eravacycline were determined using broth microdilution. The ECOFF values of eravacycline against the five species commonly causing cIAIs were calculated using visual estimation and ECOFFinder following the EUCAST guideline.

Results

The MICs of eravacycline against all the strains were in the range of 0.004–16 mg/L. The ECOFF values of eravacycline were 0.5 mg/L for E. coli, 2 mg/L for K. pneumonia and E. cloacae, and 0.25 mg/L for A. baumannii and S. aureus, consistent with the newest EUCAST publication of eravacycline ECOFF values for the populations. No discrepancy was found between the visually estimated and 99.00% ECOFF values calculated using ECOFFinder.

Conclusions

The determined ECOFF values of eravacycline against the five species can assist in distinguishing wild-type from non-wild-type strains. Given its promising activity, eravacycline may represent a member of the tetracycline class in treating cIAIs caused by commonly encountered Gram-negative and Gram-positive pathogens.
A Multiplex Assay for Fast PIK3CA Hotspot Mutation Characterization in a Single Specimen by 3-Color Digital PCR Analysis
Authors: Helmijr Jean , Motta Gianmarco , Jongbloed Lisa , de Weerd Vanja , van Bergen Lotte , Verschoor Noortje , Stella Stefania , Beaufort Corine , Vigneri Paolo , Martens John W M , Wilting Saskia M , Jansen Maurice P H M
Published: July 2024

Background

Activating mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gene have been detected often in solid tumors. Targeted therapy for mutant PIK3CA is now available in the clinic, making molecular diagnostics pivotal. Our aim was to design a multiplex digital PCR (dPCR) assay to evaluate the 4 most common PIK3CA hotspot mutations simultaneously to characterize and quantify these in liquid biopsies.

Methods

A multiplex assay was developed to detect exon 9 p.E542K and p.E545K mutations, and exon 20 p.H1047L and p.H1047R mutations using the Stilla 3-color dPCR Naica system. The assay was evaluated on stock and pre-amplified DNA from cell lines with the above mutations as single and pooled samples, and on cell-free DNA (cfDNA) from healthy blood donors (HBDs) and breast cancer patients, to determine detection thresholds and diagnostic accuracy.

Results

The assay distinguished all 4 PIK3CA mutations in (cf)DNA, and also when dual mutations were present. Detection thresholds of stock and pre-amplified cfDNA samples were 0.11 and 0.40 copies/uL (cp/uL) for mutant copies concentration, and 0.003% and 0.68% for variant allele frequencies (VAFs), respectively. The assay confirmed the PIK3CA (mutation) status as defined by targeted next-generation sequencing (NGS) in 82 out of 96 patients that were mutant for PIK3CA, and in 11 out of 12 patients with wild-type PIK3CA.

Conclusions

Our designed multiplex dPCR assay detected PIK3CA mutations with high accuracy in stock and pre-amplified cfDNA. Furthermore, it is affordable and demands less cfDNA input when compared to available uniplex dPCR assays and NGS analyses.
Diagnostic accuracy of deep learning using speech samples in depression: a systematic review and meta-analysis
Authors: Liu Lidan , Liu Lu , Wafa Hatem A , Tydeman Florence , Xie Wanqing , Wang Yanzhong
Published: July 2024

Objective

This study aims to conduct a systematic review and meta-analysis of the diagnostic accuracy of deep learning (DL) using speech samples in depression.

Materials and Methods

This review included studies reporting diagnostic results of DL algorithms in depression using speech data, published from inception to January 31, 2024, on PubMed, Medline, Embase, PsycINFO, Scopus, IEEE, and Web of Science databases. Pooled accuracy, sensitivity, and specificity were obtained by random-effect models. The diagnostic Precision Study Quality Assessment Tool (QUADAS-2) was used to assess the risk of bias.

Results

A total of 25 studies met the inclusion criteria and 8 of them were used in the meta-analysis. The pooled estimates of accuracy, specificity, and sensitivity for depression detection models were 0.87 (95% CI, 0.81-0.93), 0.85 (95% CI, 0.78-0.91), and 0.82 (95% CI, 0.71-0.94), respectively. When stratified by model structure, the highest pooled diagnostic accuracy was 0.89 (95% CI, 0.81-0.97) in the handcrafted group.

Discussion

To our knowledge, our study is the first meta-analysis on the diagnostic performance of DL for depression detection from speech samples. All studies included in the meta-analysis used convolutional neural network (CNN) models, posing problems in deciphering the performance of other DL algorithms. The handcrafted model performed better than the end-to-end model in speech depression detection.

Conclusions

The application of DL in speech provided a useful tool for depression detection. CNN models with handcrafted acoustic features could help to improve the diagnostic performance.

Protocol registration

The study protocol was registered on PROSPERO (CRD42023423603).
Risk factors for breast cancer subtypes by race and ethnicity: a scoping review
Authors: Hurson Amber N , Ahearn Thomas U , Koka Hela , Jenkins Brittany D , Harris Alexandra R , Roberts Sylvia , Fan Sharon , Franklin Jamirra , Butera Gisela , Keeman Renske , Jung Audrey Y , Middha Pooja , Gierach Gretchen L , Yang Xiaohong R , Chang-Claude Jenny , Tamimi Rulla M , Troester Melissa A , Bandera Elisa V , Abubakar Mustapha , Schmidt Marjanka K , Garcia-Closas Montserrat
Published: July 2024

Background

Breast cancer consists of distinct molecular subtypes. Studies have reported differences in risk factor associations with breast cancer subtypes, especially by tumor estrogen receptor (ER) status, but their consistency across racial and ethnic populations has not been comprehensively evaluated.

Methods

We conducted a qualitative, scoping literature review using the Preferred Reporting Items for Systematic Reviews and Meta-analysis, extension for Scoping Reviews to investigate consistencies in associations between 18 breast cancer risk factors (reproductive, anthropometric, lifestyle, and medical history) and risk of ER-defined subtypes in women who self-identify as Asian, Black or African American, Hispanic or Latina, or White. We reviewed publications between January 1, 1990 and July 1, 2022. Etiologic heterogeneity evidence (convincing, suggestive, none, or inconclusive) was determined by expert consensus.

Results

Publications per risk factor ranged from 14 (benign breast disease history) to 66 (parity). Publications were most abundant for White women, followed by Asian, Black or African American, and Hispanic or Latina women. Etiologic heterogeneity evidence was strongest for parity, followed by age at first birth, postmenopausal body mass index, oral contraceptive use, and estrogen-only and combined menopausal hormone therapy. Evidence was limited for other risk factors. Findings were consistent across racial and ethnic groups, although the strength of evidence varied.

Conclusion

The literature supports etiologic heterogeneity by ER for some established risk factors that are consistent across race and ethnicity groups. However, in non-White populations evidence is limited. Larger, more comparable data in diverse populations are needed to better characterize breast cancer etiologic heterogeneity.
Effect of resistance training on physical function during chemotherapy in colon cancer
Authors: Brown Justin C , Yang Shengping , Compton Stephanie L E , Campbell Kristin L , Cespedes Feliciano Elizabeth M , Quinney Sara , Sternfeld Barbara , Caan Bette J , Meyerhardt Jeffrey A , Schmitz Kathryn H
Published: July 2024

Background

The decline of physical function during chemotherapy predicts poor quality of life and premature death. It is unknown if resistance training prevents physical function decline during chemotherapy in colon cancer survivors.

Methods

This multicenter trial randomly assigned 181 colon cancer survivors receiving postoperative chemotherapy to home-based resistance training or usual care control. Physical function outcomes included the short physical performance battery, isometric handgrip strength, and the physical function subscale of the Medical Outcomes Short-Form 36-item questionnaire. Mixed models for repeated measures quantified estimated treatment differences.

Results

At baseline, participants had a mean (SD) age of 55.2 (12.8) years; 67 (37%) were 60 years or older, and 29 (16%) had a composite short physical performance battery score of no more than 9. Compared with usual care control, resistance training did not improve the composite short physical performance battery score (estimated treatment difference = −0.01, 95% confidence interval [CI] = −0.32 to 0.31; P = .98) or the short physical performance battery scores for balance (estimated treatment difference = 0.01, 95% CI = −0.10 to 0.11; P = .93), gait speed (estimated treatment difference = 0.08, 95% CI = −0.06 to 0.22; P = .28), and sit-to-stand (estimated treatment difference = −0.08, 95% CI = −0.29 to 0.13; P = .46). Compared with usual care control, resistance training did not improve isometric handgrip strength (estimated treatment difference = 1.50 kg, 95% CI = −1.06 to 4.05; P = .25) or self-reported physical function (estimated treatment difference = −3.55, 95% CI = −10.03 to 2.94); P = .28). The baseline short physical performance battery balance score (r = 0.21, 95% CI = 0.07 to 0.35) and handgrip strength (r = 0.23, 95% CI = 0.09 to 0.36) correlated with chemotherapy relative dose intensity.

Conclusion

Among colon cancer survivors with relatively high physical functioning, random assignment to home-based resistance training did not prevent physical function decline during chemotherapy.

Clinical Trial Registration

NCT03291951.
Alternate bearing in ‘Hass’ avocado: fruit load-induced changes in bud auxin homeostasis are associated with flowering repression
Authors: Pochamreddy Madhuri , Haim Dor , Halon Eyal , Keinan Eti , Rai Avinash Chandra , Kamara Itzhak , Sadka Avi , Irihimovitch Vered
Published: July 2024

In ‘Hass’ avocado (Persea americana), fruit presence reduces next season flowering. Recent fruit tree studies proposed that heavy fruit load (HFL) generates an auxin (indole-3-acetic acid, IAA) signal in the buds that represses flowering. However, the nature of this signal remains unknown. Here, we investigated the effect of avocado HFL on bud IAA accumulation and flowering transition. We found that IAA–aspartate and IAA–glutamate conjugate levels were significantly higher in buds from fully loaded (‘on’) than low-loaded (‘off’) trees, hinting that free IAA levels were higher in the former. Expression analysis showed that coinciding with flowering reduction, HFL induced the floral repressor PaTFL1, and suggested that accumulation of IAA in buds as imposed by HFL was associated with its conjugation to aspartate and glutamate and resulted both from de novo IAA synthesis and from reduced IAA export. Accordingly, experiments involving radiolabelled [14C]IAA demonstrated that HFL reduced shoot basipetal IAA transport. Finally, we confirmed the negative effects of IAA on flowering, showing that IAA and polar auxin transport blocker (2,3,5-triiodobenzoic acid) treatments delayed ‘off’ trees’ inflorescence development, reducing their inflorescence axis and inducing PaTFL1 expression. Together, our data indicate that avocado HFL generates IAA signalling in buds that induces PaTFL1, leading to repression of inflorescence development.
Optical and H i observations of IC 443 and G189.6 + 3.3 in a complex environment
Authors: Bakış H , Paylı G , Aktekin E , Sano H , Sezer A
Published: July 2024

The supernova remnant (SNR) IC 443 is one of the best-studied Galactic SNRs at many wavelengths. It is interacting with a very complex environment, including the SNR G189.6 + 3.3 and H ii regions. In this paper, we report on observations of IC 443 and G189.6 + 3.3 using 1.5- and 1-m telescopes to better understand the nature of these SNRs in the optical band. We obtain H$\alpha$ images showing both filamentary and diffuse structures, and long-slit spectra from many locations, with Balmer and forbidden lines detected for IC 443 and G189.6 + 3.3. The [S ii]/ H$\alpha$ ratios confirm the SNR nature of G189.6 + 3.3. The ranges of our estimated electron density and pre-shock cloud density clearly indicate the complex structure surrounding IC 443 and G189.6 + 3.3. We also investigate the archival H i data and newly find some shell-like distributions of H i that are possibly associated with G189.6 $+$ 3.3.
How does dark matter stabilize disc galaxies?
Authors: Aditya K
Published: July 2024

The study presents a theoretical framework for understanding the role of dark matter on the stability of the galactic disc. We model the galaxy as a two-component system consisting of stars and gas in equilibrium with an external dark matter halo. We derive the equations governing the growth of perturbations and obtain a stability criterion that connects the potential of the dark matter halo and the gas fraction with the stability levels of the galaxy. We find that a two-component disc is more susceptible to the growth of gravitational instabilities than individual components, particularly as gas fractions increase. However, the external field, due to the dark matter halo, acts as a stabilizing agent and increases the net stability levels even in the presence of a cold gas component. We apply the stability criterion to models of the Milky Way, low surface brightness galaxies, and baryon-dominated cold rotating disc galaxies observed in the early universe. Our results show that the potential due to the dark matter halo plays a significant role in stabilizing nearby galaxies, such as the Milky Way, and low surface brightness galaxies, which would otherwise be prone to local gravitational instabilities. However, we find that the baryon-dominated cold disc galaxies observed in the early universe remain susceptible to the growth of local gravitational instabilities despite the stabilizing effect of the dark matter halo.
Adaptive Evolution of Two Distinct Adaptive Haplotypes of Neanderthal Origin at the Immunoglobulin Heavy-chain Locus in East Asian and European Populations
Authors: Ma Xixian , Lu Yan , Xu Shuhua
Published: July 2024

Immunoglobulins (Igs) have a crucial role in humoral immunity. Two recent studies have reported a high-frequency Neanderthal-introgressed haplotype throughout Eurasia and a high-frequency Neanderthal-introgressed haplotype specific to southern East Asia at the immunoglobulin heavy-chain (IGH) gene locus on chromosome 14q32.33. Surprisingly, we found the previously reported high-frequency Neanderthal-introgressed haplotype does not exist throughout Eurasia. Instead, our study identified two distinct high-frequency haplotypes of putative Neanderthal origin in East Asia and Europe, although they shared introgressed alleles. Notably, the alleles of putative Neanderthal origin reduced the expression of IGHG1 and increased the expression of IGHG2 and IGHG3 in various tissues. These putatively introgressed alleles also affected the production of IgG1 upon antigen stimulation and increased the risk of systemic lupus erythematosus. Additionally, the greatest genetic differentiation across the whole genome between southern and northern East Asians was observed for the East Asian haplotype of putative Neanderthal origin. The frequency decreased from southern to northern East Asia and correlated positively with the genome-wide proportion of southern East Asian ancestry, indicating that this putative positive selection likely occurred in the common ancestor of southern East Asian populations before the admixture with northern East Asian populations.
Analysis of bacterial transcriptome and epitranscriptome using nanopore direct RNA sequencing
Authors: Tan Lu , Guo Zhihao , Shao Yanwen , Ye Lianwei , Wang Miaomiao , Deng Xin , Chen Sheng , Li Runsheng
Published: July 2024

Bacterial gene expression is a complex process involving extensive regulatory mechanisms. Along with growing interests in this field, Nanopore Direct RNA Sequencing (DRS) provides a promising platform for rapid and comprehensive characterization of bacterial RNA biology. However, the DRS of bacterial RNA is currently deficient in the yield of mRNA-mapping reads and has yet to be exploited for transcriptome-wide RNA modification mapping. Here, we showed that pre-processing of bacterial total RNA (size selection followed by ribosomal RNA depletion and polyadenylation) guaranteed high throughputs of sequencing data and considerably increased the amount of mRNA reads. This way, complex transcriptome architectures were reconstructed for Escherichia coli and Staphylococcus aureus and extended the boundaries of 225 known E. coli operons and 89 defined S. aureus operons. Utilizing unmodified in vitro-transcribed (IVT) RNA libraries as a negative control, several Nanopore-based computational tools globally detected putative modification sites in the E. coli and S. aureus transcriptomes. Combined with Next-Generation Sequencing-based N6-methyladenosine (m6A) detection methods, 75 high-confidence m6A candidates were identified in the E. coli protein-coding transcripts, while none were detected in S. aureus. Altogether, we demonstrated the potential of Nanopore DRS in systematic and convenient transcriptome and epitranscriptome analysis.
Adenovirus small E1A directs activation of Alu transcription at YAP/TEAD- and AP-1-bound enhancers through interactions with the EP400 chromatin remodeler
Authors: Cantarella Simona , Vezzoli Marco , Carnevali Davide , Morselli Marco , Zemke Nathan R , Montanini Barbara , Daussy Coralie F , Wodrich Harald , Teichmann Martin , Pellegrini Matteo , Berk Arnold J , Dieci Giorgio , Ferrari Roberto
Published: July 2024

Alu retrotransposons, which form the largest family of mobile DNA elements in the human genome, have recently come to attention as a potential source of regulatory novelties, most notably by participating in enhancer function. Even though Alu transcription by RNA polymerase III is subjected to tight epigenetic silencing, their expression has long been known to increase in response to various types of stress, including viral infection. Here we show that, in primary human fibroblasts, adenovirus small e1a triggered derepression of hundreds of individual Alus by promoting TFIIIB recruitment by Alu-bound TFIIIC. Epigenome profiling revealed an e1a-induced decrease of H3K27 acetylation and increase of H3K4 monomethylation at derepressed Alus, making them resemble poised enhancers. The enhancer nature of e1a-targeted Alus was confirmed by the enrichment, in their upstream regions, of the EP300/CBP acetyltransferase, EP400 chromatin remodeler and YAP1 and FOS transcription factors. The physical interaction of e1a with EP400 was critical for Alu derepression, which was abrogated upon EP400 ablation. Our data suggest that e1a targets a subset of enhancer Alus whose transcriptional activation, which requires EP400 and is mediated by the e1a-EP400 interaction, may participate in the manipulation of enhancer activity by adenoviruses.
The critical role of the iron–sulfur cluster and CTC components in DOG-1/BRIP1 function in Caenorhabditis elegans
Authors: Li Xiao , Perdomo Ivette Maria Menendez , Rodrigues Alves Barbosa Victoria , Diao Catherine , Tarailo-Graovac Maja
Published: July 2024

FANCJ/BRIP1, initially identified as DOG-1 (Deletions Of G-rich DNA) in Caenorhabditis elegans, plays a critical role in genome integrity by facilitating DNA interstrand cross-link repair and resolving G-quadruplex structures. Its function is tightly linked to a conserved [4Fe–4S] cluster-binding motif, mutations of which contribute to Fanconi anemia and various cancers. This study investigates the critical role of the iron–sulfur (Fe–S) cluster in DOG-1 and its relationship with the cytosolic iron–sulfur protein assembly targeting complex (CTC). We found that a DOG-1 mutant, expected to be defective in Fe–S cluster binding, is primarily localized in the cytoplasm, leading to heightened DNA damage sensitivity and G-rich DNA deletions. We further discovered that the deletion of mms-19, a nonessential CTC component, also resulted in DOG-1 sequestered in cytoplasm and increased DNA damage sensitivity. Additionally, we identified that CIAO-1 and CIAO-2B are vital for DOG-1’s stability and repair functions but unlike MMS-19 have essential roles in C. elegans. These findings confirm the CTC and Fe–S cluster as key elements in regulating DOG-1, crucial for genome integrity. Additionally, this study advances our understanding of the CTC’s role in Fe–S protein regulation and development in C. elegans, offering a model to study its impact on multicellular organism development.
Intrinsic PARG inhibitor sensitivity is mimicked by TIMELESS haploinsufficiency and rescued by nucleoside supplementation
Authors: Coulson-Gilmer Camilla , Littler Samantha , Barnes Bethany M , Brady Rosie M , Anagho Holda A , Pillay Nisha , Dey Malini , Macmorland William , Bronder Daniel , Nelson Louisa , Tighe Anthony , Lin Wei-Hsiang , Morgan Robert D , Unwin Richard D , Nielsen Michael L , McGrail Joanne C , Taylor Stephen S
Published: July 2024

A subset of cancer cells are intrinsically sensitive to inhibitors targeting PARG, the poly(ADP-ribose) glycohydrolase that degrades PAR chains. Sensitivity is accompanied by persistent DNA replication stress, and can be induced by inhibition of TIMELESS, a replisome accelerator. However, the nature of the vulnerability responsible for intrinsic sensitivity remains undetermined. To understand PARG activity dependency, we analysed Timeless model systems and intrinsically sensitive ovarian cancer cells. We show that nucleoside supplementation rescues all phenotypes associated with PARG inhibitor sensitivity, including replisome speed and fork stalling, S-phase completion and mitotic entry, proliferation dynamics and clonogenic potential. Importantly nucleoside supplementation restores PARG inhibitor resistance despite the continued presence of PAR chains, indicating that sensitivity does not correlate with PAR levels. In addition, we show that inhibition of thymidylate synthase, an enzyme required for dNTP homeostasis, induces PARG-dependency. Together, these observations suggest that PARG inhibitor sensitivity reflects an inability to control replisome speed and/or maintain helicase-polymerase coupling in response to nucleotide imbalances.