bluuebunny/crossref_metadata_2025_split huggingface dataset:
Determination of human DNA replication origin position and efficiency reveals principles of initiation zone organisation
Authors: Guilbaud Guillaume , Murat Pierre , Wilkes Helen S , Lerner Leticia Koch , Sale Julian E , Krude Torsten 
Published: July 2022

AbstractReplication of the human genome initiates within broad zones of ∼150 kb. The extent to which firing of individual DNA replication origins within initiation zones is spatially stochastic or localised at defined sites remains a matter of debate. A thorough characterisation of the dynamic activation of origins within initiation zones is hampered by the lack of a high-resolution map of both their position and efficiency. To address this shortcoming, we describe a modification of initiation site sequencing (ini-seq), based on density substitution. Newly replicated DNA is rendered ‘heavy-light’ (HL) by incorporation of BrdUTP while unreplicated DNA remains ‘light-light’ (LL). Replicated HL-DNA is separated from unreplicated LL-DNA by equilibrium density gradient centrifugation, then both fractions are subjected to massive parallel sequencing. This allows precise mapping of 23,905 replication origins simultaneously with an assignment of a replication initiation efficiency score to each. We show that origin firing within early initiation zones is not randomly distributed. Rather, origins are arranged hierarchically with a set of very highly efficient origins marking zone boundaries. We propose that these origins explain much of the early firing activity arising within initiation zones, helping to unify the concept of replication initiation zones with the identification of discrete replication origin sites.
Identification of nucleobase chemical modifications that reduce the hepatotoxicity of gapmer antisense oligonucleotides
Authors: Yoshida Tokuyuki , Morihiro Kunihiko , Naito Yuki , Mikami Atsushi , Kasahara Yuuya , Inoue Takao , Obika Satoshi 
Published: July 2022

Abstract
Currently, gapmer antisense oligonucleotide (ASO) therapeutics are under clinical development for the treatment of various diseases, including previously intractable human disorders; however, they have the potential to induce hepatotoxicity. Although several groups have reported the reduced hepatotoxicity of gapmer ASOs following chemical modifications of sugar residues or internucleotide linkages, only few studies have described nucleobase modifications to reduce hepatotoxicity. In this study, we introduced single or multiple combinations of 17 nucleobase derivatives, including four novel derivatives, into hepatotoxic locked nucleic acid gapmer ASOs and examined their effects on hepatotoxicity. The results demonstrated successful identification of chemical modifications that strongly reduced the hepatotoxicity of gapmer ASOs. This approach expands the ability to design gapmer ASOs with optimal therapeutic profiles.
Short LNA-modified oligonucleotide probes as efficient disruptors of DNA G-quadruplexes
Authors: Chowdhury Souroprobho , Wang Jiayi , Nuccio Sabrina Pia , Mao Hanbin , Di Antonio Marco 
Published: July 2022

Abstract
G-quadruplexes (G4s) are well known non-canonical DNA secondary structures that can form in human cells. Most of the tools available to investigate G4-biology rely on small molecule ligands that stabilise these structures. However, the development of probes that disrupt G4s is equally important to study their biology. In this study, we investigated the disruption of G4s using Locked Nucleic Acids (LNA) as invader probes. We demonstrated that strategic positioning of LNA-modifications within short oligonucleotides (10 nts.) can significantly accelerate the rate of G4-disruption. Single-molecule experiments revealed that short LNA-probes can promote disruption of G4s with mechanical stability sufficient to stall polymerases. We corroborated this using a single-step extension assay, revealing that short LNA-probes can relieve replication dependent polymerase-stalling at G4 sites. We further demonstrated the potential of such LNA-based probes to study G4-biology in cells. By using a dual-luciferase assay, we found that short LNA probes can enhance the expression of c-KIT to levels similar to those observed when the c-KIT promoter is mutated to prevent the formation of the c-KIT1 G4. Collectively, our data suggest a potential use of rationally designed LNA-modified oligonucleotides as an accessible chemical-biology tool for disrupting individual G4s and interrogating their biological functions in cells.
RETRACTED: Changes in Tobacco Dependence and Association With Onset and Progression of Use by Product Type From Wave 1 to Wave 3 of the Population Assessment of Tobacco and Health (PATH) Study
Authors: Strong David R , Pierce John P , White Martha , Stone Matthew D , Abrams David B , Glasser Allison M , Wackowski Olivia A , Cummings K Michael , Hyland Andrew , Taylor Kristie , Edwards Kathryn C , Silveira Marushka L , Kimmel Heather L , Lambert Elizabeth Y , Compton Wilson M , Hull Lynn C , Niaura Raymond 
Published: July 2022

Abstract

Introduction
This study examined trajectories of tobacco dependence (TD) in relation to changes in tobacco product use and explored the effects of product-specific adding, switching, or discontinued use on dependence over time.

Aims and Methods
Data were analyzed from the first three waves of the Population Assessment of Tobacco and Health (PATH) Study, a nationally representative, longitudinal study of adults and youth in the United States. Data included 9556 Wave 1 (2013/2014) adult current established tobacco users who completed all three interviews and had established use at ≥2 assessments. Groups included cigarettes-only users, e-cigarettes-only users, cigars-only users, hookah-only users, any smokeless-only users, cigarette + e-cigarette dual users, and multiple product users. A validated 16-item scale assessed TD across product users.

Results
Wave 1 e-cigarette-only users’ who maintained exclusive e-cigarette use increased levels of TD through Wave 3 as did those who added or switched to another product. Wave 1 multiple product users’ TD decreased across waves. TD for all other Wave 1 user groups remained about the same. For Wave 1 cigarette-only smokers, switching to another product or moving to a pattern of no established use was associated with lower levels of TD than smokers whose use stayed the same. Movement to no established use of any tobacco product was consistently associated with lower TD for all other product users.

Conclusions
Except for Wave 1 e-cigarette-only users, TD among US tobacco product users was stable over time, with daily users less likely to vary from baseline.

Implications
The level of TD among most US tobacco users was stable over the first three waves of the PATH Study and trends in levels of TD were predominantly unrelated to changes in patterns of continued product use. Stable levels of TD suggest a population at persistent risk of health impacts from tobacco. Wave 1 e-cigarette users, including those maintaining exclusive e-cigarette use, experienced increasing levels of TD over time, perhaps because of increases in quantity or frequency of their e-cigarette product use or increasing efficiency of nicotine delivery over time.
What the Senses Cannot ‘Say’
Authors: Morgan Jonathan Brink 
Published: July 2022

AbstractSome have claimed that there are laws of appearance, i.e. in principle constraints on which types of sensory experiences are possible. Within a representationalist framework, these laws amount to restrictions on what a given experience can represent. I offer an in-depth defence of one such law and explain why prevalent externalist varieties of representationalism have trouble accommodating it. In light of this, I propose a variety of representationalism on which the spatial content of experience is determined by intrinsic features of conscious subjects. I conclude by considering an externalist-friendly reworking of my proposal, but suggest that the success of such a reworking is dubious.
Exploring Family Planning Perspectives Among Men Receiving Medications for Opioid Use Disorder: Implications for Service Development
Authors: Rinehart Deborah J. , Stowell Melanie , Barrett Kaeli , Langland Katie , Thomas-Gale Tara , Al-Tayyib Alia , O’Connell Ryan 
Published: July 2022

Objective
Studies have consistently found high rates of unintended pregnancy among women with substance use disorder. While research efforts have begun to focus on understanding needs and providing family planning services for women in treatment, few studies have included men. This has resulted in a gap in the literature regarding men’s reproductive health experiences and family planning desires.

Methodology
Between December 2019 and February 2020, we conducted semistructured qualitative interviews with adult men receiving medications for opioid use disorder at a safety-net healthcare system in Denver, Colorado. Interviews were recorded and analyzed using the Rapid Assessment Process.

Results
Fifteen men participated in an interview. Overall, men described feeling excluded from family planning education and services as well as from decision making with their partners. Participants desired knowledge and resources related to contraceptive methods, partner communication, and parenting. Additional themes included loss of autonomy around pregnancy decisions, the importance of fatherhood, and the importance of addressing family planning during recovery. Participants expressed interest in a family planning intervention but indicated that engaging men on this topic may be challenging.

Conclusions
Our findings suggest that men in treatment desire education and involvement in family planning. Participants endorsed access to a subject expert within the treatment environment, but engagement strategies that underscore topic relevance to men will be critical. Initiating a conversation involving education and service navigation in the treatment setting may be a promising strategy for engaging men in recovery in family planning and improving men’s access to needed services and resources.
Evaluating the Impact of Substance Use Disorder Resources on Outcomes of Persons Who Inject Drugs with Infections
Authors: Greenlee Sage B. , Kenney Rachel M. , Makowski Charles T. , Bulat Elizabeth , Brar Indira , Davis Susan L. 
Published: July 2022

Objective
The aim of the study is to evaluate the impact of inpatient substance use disorder (SUD) resources on outcomes of persons who inject stimulants and/or opioids (PWIDs) with infections.

Methods
This retrospective cohort evaluated PWIDs hospitalized from July 1, 2020, to May 31, 2021, and prescribed an antimicrobial course. The patients were compared based on inpatient implementation of SUD resources, including consultation of addiction medicine/behavioral health, implementation of an opioid withdrawal treatment protocol, or continuation/initiation of medications for opioid use disorder. The primary outcome was a composite of antibiotic completion, no unplanned discharge, and no 30-day readmission. Notable secondary outcomes included length of stay and presence of stigmatizing language in the electronic medical record.

Results
A total of 119 patients were analyzed—74 (62.2%) received SUD resources. The primary outcome was met by 43 patients with SUD resources implemented (58.1%) and 19 patients without resources (42.2%, P = 0.093). After adjustment for infection type, implementation of SUD resources (adjusted odds ratio, 2.593; 95% confidence interval, 1.162–5.789) was independently associated with primary outcome success. The patients who received SUD resources had a median length of stay of 7 days (4–13.3) compared with 4 days (2–6.5) in those without resources (P < 0.001). Stigmatizing language was present in 98% of patient electronic medical records.

Conclusions
Patient care provided to PWIDs with infections is optimized when SUD resources are implemented. This study further supports the necessity of improving SUD management when PWIDs are admitted to healthcare facilities.
Examining the Role of Nonsurgical Therapy in the Treatment of Geriatric Urinary Incontinence
Authors: Parker-Autry Candace , Neiberg Rebecca , Leng X. Iris , Matthews Catherine A. , Dumoulin Chantale , Kuchel George , Kritchevsky Stephen B. 
Published: July 2022

OBJECTIVE:
To examine the role of physical function impairments on the change in urinary incontinence (UI) symptoms after pelvic floor muscle training in older women.

METHODS:
This is a prospective cohort study of 70 community-dwelling participants, older than age 70 years, with at least moderate incontinence symptoms. A comprehensive pelvic floor and physical function assessment was done at baseline. Individualized pelvic floor muscle training prescriptions with behavioral management strategies to reduce incontinence episodes were provided for 12 weeks. Baseline physical function was determined using the SPPB (Short Physical Performance Battery). A total score of 9 or lower out of 12 indicated impaired physical function, and scores higher than 9 indicated normal physical function. A 3-day bladder diary established daily incontinence episodes. The between-group difference in the change in number of UI episodes, from baseline to 6 weeks, was our primary outcome. Descriptive analyses compared important demographic and clinical characteristics. Longitudinal mixed model linear regression analyses determined the change in incontinence episodes and estimates of improvement based on the presence of impaired physical function and adjusted for age, race, and body mass index (BMI).

RESULTS:
Participants' mean±SD age was 76.9±5.4 years, and 15.7% identified as African American, with no significant differences in age or race between groups. Participants with impaired physical function had higher mean±SD BMI (33.6±14.5 vs 27.4±5.8; P=.03) and more baseline incontinence episodes (4.5±2.9 vs 2.7±2.1 episodes per day; P=.005) than in women without functional impairment. After 6 weeks of pelvic floor exercises, the change in number of incontinence episodes per day was not different between participants with physical functional impairment compared with women with normal physical function (mean [95% CI] −1.2 [−2.0 to −0.5] vs −0.4 [−1.1 to 0.3], P=.31). Overall, after 12 weeks of pelvic floor muscle training, complete satisfaction with incontinence symptom improvement was low for both groups (41.8% with physical function impairments vs 44.8% with normal physical function; P=.90).

CONCLUSION:
Behavioral therapy including pelvic floor muscle training may not significantly decrease UI symptoms to a degree that is satisfactory in women who are older than 70 years and are seeking treatment for UI, regardless of the presence of physical function impairments.

CLINICAL TRIAL REGISTRATION:

ClinicalTrials.gov, NCT03057834.
Effect of Paracervical Block Volume on Pain Control for Dilation and Aspiration
Authors: Crouthamel Bonnie , Economou Nicole , Averbach Sarah , Rible Radhika , Kully Gennifer , Meckstroth Karen , Mody Sheila K. 
Published: July 2022

OBJECTIVE:
To compare pain scores during office dilation and aspiration between low-volume and high-volume paracervical block of the same dose.

METHODS:
We conducted a multi-site, randomized, single-blind, placebo-controlled trial from October 2018 to December 2020. We randomized participants presenting for office dilation and aspiration under minimal sedation stratified by procedural indication (induced abortion vs early pregnancy loss) to a 20-mL buffered 1% lidocaine paracervical block or a 40-mL buffered 0.5% lidocaine paracervical block, both with two units of vasopressin in a standardized technique. To detect a 15-mm or greater difference in pain at the time of cervical dilation with 80% power and a two-sided alpha of 0.05, a total of 104 participants was required. The study was also powered to detect a 20-mm or greater difference in pain at the time of cervical dilation within each stratum (induced abortion and early pregnancy loss). The primary outcome was pain with cervical dilation on a 100-mm visual analog scale in the overall cohort. Secondary outcomes included pain with cervical dilation within each stratum. We used a Wilcoxon rank-sum test to compare median pain scores between groups.

RESULTS:
We enrolled 114 participants. There was no difference in median pain scores between low-volume and high-volume groups during dilation (62 mm vs 59 mm, P=.94), aspiration (69.5 mm vs 70 mm, P=.47), postprocedure (25 mm vs 25 mm, P=.76), or overall (60 mm vs 60 mm, P=.23). Stratified by indication, there were no significant differences in scores at any time point between the low-volume and high-volume paracervical block groups. There was decreased overall pain in patients with induced abortion who received the higher volume paracervical block, though this did not reach statistical significance (67.5 mm vs 60.5 mm, P=.08). Pain during paracervical block administration was similar between groups (55 mm vs 45 mm, P=.24) and there was no difference in occurrence of side effects (P=.63).

CONCLUSION:
We found no difference in pain with cervical dilation among participants who received the low-volume compared with high-volume paracervical block when studied alone.

CLINICAL TRIAL REGISTRATION:
ClinicalTrials.gov, NCT03636451.
Umbilical Cord Collection and Drug Testing to Estimate Prenatal Substance Exposure in Utah
Authors: Smid Marcela C. , Allshouse Amanda A. , McMillin Gwendolyn A. , Nunez Kendyl , Cavin Tyler , Worden Joseph , Buchi Karen , Muniyappa Bhanu , Varner Michael W. , Cochran Gerald , Metz Torri D. 
Published: July 2022

OBJECTIVE:
Our primary objective was to estimate statewide prenatal substance exposure based on umbilical cord sampling. Our secondary objectives were to compare prevalence of prenatal substance exposure across urban, rural, and frontier regions, and to compare contemporary findings to those previously reported.

METHODS:
We performed a cross-sectional prevalence study of prenatal substance exposure, as determined by umbilical cord positivity for 49 drugs and drug metabolites, through the use of qualitative liquid chromatography-tandem mass spectrometry. All labor and delivery units in Utah (N=45) were invited to participate. Based on a 2010 study using similar methodology, we calculated that a sample size of at least 1,600 cords would have 90% power to detect 33% higher rate of umbilical cords testing positive for any substance. Deidentified umbilical cords were collected from consecutive deliveries at participating hospitals. Prevalence of prenatal substance exposure was estimated statewide and by rurality using weighted analysis.

RESULTS:
From November 2020 to November 2021, 1,748 cords (urban n=988, rural n=384, frontier n=376) were collected from 37 hospitals, representing 92% of hospitals that conduct 91% of births in the state. More than 99% of cords (n=1,739) yielded results. Statewide, 9.9% (95% CI 8.1–11.7%) were positive for at least one substance, most commonly opioids (7.0%, 95% CI 5.5–8.5%), followed by cannabinoid (11-nor-9-carboxy-delta-9-tetrahydrocannabinol [THC-COOH]) (2.5%, 95% CI 1.6–3.4%), amphetamines (0.9%, 95% CI 0.4–1.5), benzodiazepines (0.5%, 95% CI 0.1–0.9%), alcohol (0.4%, 95% CI 0.1–0.7%), and cocaine (0.1%, 95% CI 0–0.3%). Cord positivity was similar by rurality (urban=10.3%, 95% CI 8.3–12.3%, rural=7.1%, 95% CI 3.5–10.7%, frontier=9.2%, 95% CI 6.2–12.2%, P=.31) and did not differ by substance type. Compared with a previous study, prenatal exposure to any substance (6.8 vs 9.9%, P=.01), opioids (4.7 vs 7.0% vs 4.7%, P=.03), amphetamines (0.1 vs 0.9%, P=.01) and THC-COOH (0.5 vs 2.5%, P<.001) increased.

CONCLUSION:
Prenatal substance exposure was detected in nearly 1 in 10 births statewide.
Enhancing Skin Uptake of Topical Antioxidants With 1,440-nm Nonablative Fractional Diode Laser Pretreatment
Authors: Wang Jordan V. , Friedman Paul M. , Rodeberg Deirdre , Konda Adarsh , Parker Catherine , Geronemus Roy G. 
Published: July 2022

BACKGROUND
Energy-based devices, such as nonablative lasers, are a promising method to enhance the delivery and absorption of topically applied molecules.

OBJECTIVE
To characterize ex vivo uptake of common antioxidant topicals after pretreatment with a nonablative laser wavelength.

MATERIALS AND METHODS
Using donor human skin tissue, uptake of 3 topical antioxidants was analyzed (C E Ferulic with 15% l-ascorbic acid [15% vitamin C serum], Phloretin CF with ferulic acid [10% vitamin C serum], and Phyto+ [botanical serum]; SkinCeuticals, Dallas, TX; 2010 formulations) after pretreatment with a 1,440-nm nonablative fractional diode laser.

RESULTS
Pretreatment with the 1,440-nm laser enhanced uptake of 15% and 10% vitamin C serums by approximately 10 and 21 times, respectively, compared to controls. Laser pretreatment also enhanced uptake of botanical serum by approximately 6 times relative to controls. Permeation of vitamin C and botanical serums was also enhanced through laser pretreatment.

CONCLUSION
Nonablative laser pretreatment increased uptake and permeation of topical antioxidants. Optimizing treatment requires consideration of the device and treatment parameters as well as the properties of the topical formulation.
Effects of adjuvant Chinese patent medicine therapy on major adverse cardiovascular events in patients with coronary heart disease angina pectoris: a population-based retrospective cohort study
Authors: Liu Yijia , Li Zhu , Wang Xu , Ni Tongyao , Ma Mei , He Yuanyuan , Yang Rongrong , Luo Mingchi 
Published: July 2022

Abstract

Objective:
This study aimed to explore the effects of Chinese patent medicine (CPM) in reducing the incidence of major adverse cardiovascular events (MACE) in patients with coronary heart disease (CHD) angina pectoris and improving clinical effectiveness and provide evidence for its use as clinical adjuvant therapy.

Methods:
Twenty-eight thousand five hundred and seventeen patients hospitalized with CHD angina pectoris from 6 hospitals were divided into CPM group (n = 11,374) and non-CPM group (n = 17,143) to evaluate the incidence of MACE, including myocardial infarction, percutaneous coronary intervention, and coronary artery bypass grafting.

Results:
The incidence of MACE in the CPM group was lower than that in the non-CPM group. CPM therapy was an independent protective factor that reduced the overall risk of MACE [adjusted hazard ratio = 0.40, 95% confidence interval (0.33; 0.49)]. Patients in the CPM group who received one, two, or three types of CPM could benefit from adjuvant treatment with CPM, and taking more types of CPM was associated with a lower risk of MACE. In addition, the male population was better than the female population in taking CPM, and middle-aged people aged 55 to 64 were more suited to take CPM based on Western medicine.

Conclusions:
The use of CPM as adjuvant therapy can decrease the occurrence of MACE in patients with CHD angina pectoris, especially in men and middle-aged people, and the drug treatment plan should be optimized accordingly. However, this conclusion needs further verification by prospective cohort studies in the future.