bluuebunny/crossref_metadata_2025 huggingface dataset:
Sex-disaggregated analysis of acute kidney injury in hospitalized children with sickle cell anemia in Uganda
Authors: Weckman Andrea , McDonald Chloe R. , Naggayi Shubaya K. , Soranno Danielle E. , Conroy Andrea L. , Batte Anthony
Published: June 2024

In this study, we report an increased risk of developing acute kidney injury (AKI) during hospitalization, worsening AKI, and death among females with sickle cell anemia (SCA) hospitalized with an acute pain crisis compared with males. The sex differences in AKI were not explained by socioeconomic differences, severity of pain, or disease severity among females compared with males. Together, these data suggest that female children with SCA may be at increased risk of AKI.
Release of ATP in the lung evoked by inhalation of irritant gases in rats
Authors: Chan Nai-Ju , Chen Yueh-Yin , Hsu Chun-Chun , Lin You Shuei , Zakeri Maxwell , Kim Seonwook , Khosravi Mehdi , Lee Lu-Yuan
Published: June 2024

Extracellular adenosine triphosphate (ATP) is a contributing factor and signaling molecule of airway inflammation. This study demonstrated for the first time that the ATP release in the lung was markedly elevated after acute inhalation challenges of three common industrial air pollutants; the order of the response magnitude was chlorine > sulfur dioxide > ammonia. These findings provided new information and improved our understanding of the adverse pulmonary effects caused by accidental inhalation exposures to these irritant gases.
Flow interruption compared to forced oscillatory maneuvers and esophageal balloon/pneumotachography for measurement of respiratory resistance in the horse
Authors: Mazan Melissa R. , Simotas Christopher , Coons Thomas , Barrow Brian , Bedenice Daniela , Minuto Jill , Wendell Kristen , Deveney Edward F.
Published: June 2024

We developed and document for the first time the use of flow interruption for the rapid and noninvasive measurement of resistance in equine patients and demonstrated short- and long-term stability and accuracy in comparison with the reference methods.
Muscle-derived microRNAs correlated with thigh lean mass gains during progressive resistance training in older adults
Authors: O’Bryan Samia M. , Lavin Kaleen M. , Graham Zachary A. , Drummer Devin J. , Tuggle S. Craig , Van Keuren-Jensen Kendall , Reiman Rebecca , Alsop Eric , Kadakia Madhavi P. , Craig Michael P. , Zhang Jin , Bamman Marcas M.
Published: June 2024

In this work, we identified a set of microRNAs correlated with thigh lean mass gains in a group of older adults. To our knowledge, this is the first time these microRNAs have been identified as novel predictive biomarkers correlating with lean mass gains in aging adults. As biomarkers, these may help interventionalists identify older individuals that are positively responding to an exercise intervention.
Similar endothelium-dependent vascular responses to intermittent hypoxia in young and older adults
Authors: Stray-Gundersen Sten , Wojan Frank , Tanaka Hirofumi , Lalande Sophie
Published: June 2024

The objective of this study was to determine the impact of age on the vascular response to intermittent hypoxia. Eight 4-min bouts of hypoxia at a targeted oxygen saturation of 80% induced a brachial artery vasodilation in both young and older adults, indicating that age does not influence the vasodilatory response to intermittent hypoxia. Intermittent hypoxia did not acutely affect brachial artery flow-mediated dilation in young or older adults.
Histological Evaluation of Internal Dental Resorption: An Analysis of a Cohort of 50 Cases
Authors: Puentes-Morelos Tania , Simancas-Escorcia Víctor , Tarón-Dunoyer Arnulfo , Ardila Carlos M. , Díaz-Caballero Antonio
Published: June 2024

Objective. This study aimed to perform a histological evaluation of teeth diagnosed with internal root resorption. Materials and Methods. A descriptive study involved the examination of 50 human teeth extracted due to an unfavorable prognosis for retention in the oral cavity. Teeth were preserved in 10% buffered formalin and subsequently subjected to the decalcification process. Masson–Goldner staining was applied for comprehensive histological assessment. Results. In all the 50 teeth examined, resorption gaps within the dentin tissue were identified, accompanied by the presence of reparative cells in the vicinity of these cavities. Marked structural loss and dentin fragmentation were evident, with regions exhibiting fissures and an absence of dentinal tubules. Conclusions. The histological evaluation of 50 teeth diagnosed with internal dental resorption revealed significant structural alterations, including resorption lacunae, the presence of multinucleated osteoclast‐like cells, and reparative connective tissue. These findings highlight the complex and multifaceted nature of internal dental resorption. These histological insights provide a deeper understanding of the pathological processes involved in internal dental resorption and underscore the necessity for early detection and intervention to mitigate tooth loss and preserve dental health.
Meta‐Analysis of the Therapeutic Effects of Stem Cell‐Derived Extracellular Vesicles in Rodent Models of Hemorrhagic Stroke
Authors: Wang Conglin , Yan Bo , Liao Pan , Chen Fanglian , Lei Ping
Published: June 2024

Background. Stem cell‐derived extracellular vesicles (SCEVs) have emerged as a potential therapy for hemorrhagic stroke. However, their effects are not fully understood. The aim of this study was to comprehensively evaluate the effects of SCEVs therapy in rodent models of hemorrhagic stroke, including subarachnoid hemorrhage (SAH) and intracerebral hemorrhage (ICH). Materials and Methods. We conducted a comprehensive search of PubMed, EMBASE, and Web of Science until May 2023 to identify studies investigating the effects of SCEVs therapy in rodent models of ICH. The functional outcomes were assessed using neurobehavioral scores. Standardized mean differences (SMDs) and confidence intervals (CIs) were calculated using a random‐effects model. Three authors independently screened the articles based on inclusion and exclusion criteria. All statistical analyses were performed using Revman 5.3 and Stata 17.0. Results. Twelve studies published between 2018 and 2023 met the inclusion criteria. Our results showed that SCEVs therapy improved neurobehavioral scores in the rodent SAH model (SMD = −3.49, 95% CI: −4.23 to −2.75; p < 0.001). Additionally, SCEVs therapy improved the chronic neurobehavioral scores of the rodent ICH model (SMD = 2.38, 95% CI: 0.36–4.40; p = 0.02) but did not have a significant impact on neurobehavioral scores in the acute and subacute phases. Significant heterogeneity was observed among the studies, and further stratification and sensitivity analyses failed to identify the source of heterogeneity. Conclusions. Our findings suggest that SCEVs therapy may improve neurofunctional behavior after hemorrhagic stroke and provide important insights into the design of preclinical trials.
Complete Transection of the Abdominal Wall Secondary to Being a Rear Seat‐Belted Passenger
Authors: Zuberi Jamshed , Masoudpoor Yousef , Saladziute Severija , Morel Emma , Garcia Daniel , Khetan Diya , Tutal Erem , Becker Natasha , Park Peter , Bonne Stephanie
Published: June 2024

Garrett and Braunstein introduced the concept of the “seat belt sign” in motor vehicle collision (MVC) victims. They defined this as abdominal wall bruising from a lap belt. These signs of trauma are not uncommon. However, “seat belt syndrome,” a pattern of musculoskeletal and internal organ injuries resulting from deceleration forces exerted by the safety device is rarely seen. Here, we illustrate a case of traumatic closed rupture of the rectus abdominis muscle secondary to seat belt injury. This potential injury is important to recognize and our case will illustrate the need for careful imaging review and clinical assessment to identify associated intra‐abdominal injuries.
Cyclophosphamide Pharmacogenomic Variation in Cancer Treatment and Its Effect on Bioactivation and Pharmacokinetics
Authors: El-Serafi Ibrahim , Steele Sinclair
Published: June 2024

Cyclophosphamide (Cy) is a prodrug that is mainly bioactivated by cytochrome P450 (CYP) 2B6 enzyme. Several other enzymes are also involved in its bioactivation and affect its kinetics. Previous studies have shown the effect of the enzymes’ genetic polymorphisms on Cy kinetics and its clinical outcome. These results were controversial primarily because of the involvement of several interacting enzymes in the Cy metabolic pathway, which can also be affected by several clinical factors as well as other drug interactions. In this review article, we present the effect of CYP2B6 polymorphisms on Cy kinetics since it is the main bioactivating enzyme, as well as discussing all previously reported enzymes and clinical factors that can alter Cy efficacy. Additionally, we present explanations for key Cy side effects related to the nature and site of its bioactivation. Finally, we discuss the role of busulphan in conditioning regimens in the Cy metabolic pathway as a clinical example of drug‐drug interactions involving several enzymes. By the end of this article, our aim is to have provided a comprehensive summary of Cy pharmacogenomics and the effect on its kinetics. The utility of these findings in the development of new strategies for Cy personalized patient dose adjustment will aid in the future optimization of patient specific Cy dosages and ultimately in improving clinical outcomes. In conclusion, CYP2B6 and several other enzyme polymorphisms can alter Cy kinetics and consequently the clinical outcomes. However, the precise quantification of Cy kinetics in any individual patient is complex as it is clearly under multifactorial genetic control. Additionally, other clinical factors such as the patient’s age, diagnosis, concomitant medications, and clinical status should also be considered.
Methods for Predicting Speed of Sound in Fatty Acid Ethyl Esters and Ethylic Biodiesels Using Gibbs Energy Additivity
Authors: Sirimongkolgal Natakron , Amornkitbamrung Mana , Phankosol Suriya
Published: June 2024

The speed of sound has a considerable influence on the parameters of fuel injection. It depends on the link between the fatty acid ethyl ester and the molecular structure and temperature. This study presents Gibbs energy additivity methods for predicting the speed of sound in saturated or unsaturated fatty acids, ethyl ester, or an ethylic biodiesel based on either (1) the number of carbon atoms (z) and number of double bonds (nd) of the fatty acid or (2) the saponification number (SN) and iodine value (IV) of the fatty acid. The proposed equations are straightforward to apply, and the estimated speed of sound values of pure fatty acid ethyl esters and ethylic biodiesels at various temperatures match the reported values well. Estimation using the proposed method is possible without knowing the sound speed of each fatty acid ethyl ester component in biodiesel.
Circular RNA CircZNF644 Facilitates Circulating Follicular Helper T Cells Response in Patients with Graves’ Disease
Authors: Liu Yingzhao , Wang Xuehua , Xu Juan , Xu Qian , Xing Jie , Zou Junli , Wang Shengjun , Peng Huiyong
Published: June 2024

Aberrant accumulation of circulating follicular helper T cells (cTfh) has been found in the peripheral blood mononuclear cells (PBMCs) of Graves’ disease (GD) patients. However, the underlying mechanism that contributes to the imbalance of cTfh cells remains unknown. Previously, studies described a GD‐related circular RNAs (circRNAs)‐circZNF644 that might be associated with cTfh cells. This study aimed to investigate the role of circZNF644 on cTfh cells in GD patients. Here, we found that circZNF644 was highly stable expression in the PBMCs of GD patients, which was positively correlated with the serum levels of TSH receptor autoantibodies (TRAb). Knockdown of circZNF644 caused a reduction of the proportion of cTfh cells in vitro. Mechanistically, circZNF644 served as a ceRNA for miR‐29a‐3p to promote ICOS expression, resulting in increased cTfh cells. In the PBMCs of GD patients, circZNF644 expression was positively correlated with ICOS expression and the percentage of cTfh cells, but negatively related to miR‐29a‐3p expression. Additionally, a strong relationship between circZNF644 and IL‐21 was revealed in GD patients, and silencing of circZNF644 inhibited IL‐21 expression. Our study elucidated that elevated expression of circZNF644 is a key feature in the development of GD and may contribute to the pathogenic role of cTfh cells in GD.
Facts and Hopes in the Systemic Therapy of Biliary Tract Carcinomas
Authors: Lamarca Angela , Macarulla Teresa
Published: June 2024

Biliary tract cancers (BTC) are a heterogeneous group of cancers that continue to present a particularly poor prognosis. BTC treatment is rapidly evolving yet facing many challenges to improve patient outcomes and maximize benefit from treatment. Only a minority of patients are diagnosed with early-stage disease and are suitable for curative resection. Current surgical strategies are limited by a high relapse rate, and despite extensive efforts focused on adjuvant strategies, the development of more effective adjuvant strategies remains a challenge. In addition, the role of locoregional strategies, liver transplant, and neoadjuvant treatment remains unclear. Systemic treatment in the advanced setting is based on three main pillars: first, cytotoxic chemotherapy options; second, the addition of immunotherapy to chemotherapy; and third, targeted therapies. The role of targeted therapies is oriented by many promising targets, including IDH1 mutations, FGFR2 fusions, BRAF-V600E mutations, and HER2 amplifications. The aim of this review is to provide an overview of current facts and future hopes in the management of BTC, including an overview of the unmet need, and particularly focus on systemic therapies.
Maximizing Treatment Opportunities: Assessing Protocol Waivers’ Impact on Safety and Outcome in the Drug Rediscovery Protocol
Authors: van Berge Henegouwen Jade M. , Zeverijn Laurien J. , Geurts Birgit S. , Hoes Louisa R. , van der Wijngaart Hanneke , van der Noort Vincent , Huitema Alwin D.R. , de Vos Filip Y.F. , Grünberg Katrien , Bloemendal Haiko J. , Verheul Henk M.W. , Voest Emile E. , Gelderblom Hans
Published: June 2024

Purpose:

Although eligibility criteria are essential in trial design, overly restrictive criteria contribute to low accrual and limited generalizability. To enhance trial inclusivity, there has been growing interest in broadening eligibility criteria, especially for patients with advanced or treatment-refractory disease. Yet, the impact on patient safety remains uncertain. In the Drug Rediscovery Protocol (DRUP), protocol exceptions are frequently requested and occasionally granted. Here we describe the impact of these waivers on treatment safety and efficacy.

Experimental Design:

DRUP is a multicenter, nonrandomized clinical basket trial treating patients with therapy-refractory cancer with molecularly targeted and immunotherapies outside their registered indications (NCT02925234). Here, all granted waivers were revised, analyzed in terms of safety and efficacy outcome, and comparedwithoutcomes of includedpatientswho didnot receive awaiver.

Results:

Between September 1, 2016, and September 1, 2021, protocol waivers were granted for 82 patients (8%) of 1,019 included patients in DRUP. Most waivers (45%) were granted for general- or drug-related eligibility criteria; other categories were out-of-window testing, treatment, and testing exceptions. Serious adverse event rate was similar between patients who received a waiver (pW) and patients who did not (pNW): 39% vs. 41%, respectively (P = 0.81). The clinical benefit (either objective response or stable disease ≥ 16 weeks) rate of pW was 40% versus 33% in pNW (P = 0.43).

Conclusions:

Safety and clinical benefit were preserved in patients for whom a waiver was granted. These data support a more personalized approach in assessing eligibility criteria, especially in trials with widely used and approved drugs accruing patients without other treatment options.

See related commentary by Waqar and Govindan, p. 3655
A Dual-Armed Oncolytic Virus Shows Clinical Efficacy in Advanced Solid Cancers
Authors: Silva-Pilipich Noelia , Smerdou Cristian
Published: June 2024

An oncolytic adenovirus armed with tumor necrosis factor-α and interleukin-2 was tested in patients with advanced solid tumors. Antitumor effects were observed in both treated and non-treated lesions, leading to long-term survival in some patients. This clinical trial shows the potential of oncolytic virotherapy for patients refractory to standard therapies.

See related article by Pakola et al., p. 3715
Effects of an Intervention to Improve Evidence-Based Care for People With Diabetes and Cardiovascular Disease Across Sex, Race, and Ethnicity Subgroups: Insights From the COORDINATE-Diabetes Trial
Authors: Tannu Manasi , Kaltenbach Lisa , Pagidipati Neha J. , McGuire Darren K. , Aroda Vanita R. , Pop-Busui Rodica , Kondamudi Nitin , Al-Khalidi Hussein R. , Lopes Renato D. , Cavender Matthew A. , Nelson Adam J. , Kirk Julienne , Lingvay Ildiko , Magwire Melissa , Richardson Caroline Regina , Webb Laura , Leyva Monica , Pandey Ambarish , Washington Alana , Pak Jonathan , Gaynor Tanya , Khan Waqar , Weston Patrick , Granger Christopher B. , Green Jennifer
Published: June 2024

BACKGROUND:

Results from the COORDINATE-Diabetes trial (Coordinating Cardiology Clinics Randomized Trial of Interventions to Improve Outcomes - Diabetes) demonstrated that a multifaceted, clinic-based intervention increased prescription of evidence-based medical therapies to participants with type 2 diabetes and atherosclerotic cardiovascular disease. This secondary analysis assessed whether intervention success was consistent across sex, race, and ethnicity.

METHODS:

COORDINATE-Diabetes, a cluster randomized trial, recruited participants from 43 US cardiology clinics (20 randomized to intervention and 23 randomized to usual care). The primary outcome was the proportion of participants prescribed all 3 groups of evidence-based therapy (high-intensity statin, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, and sodium-glucose cotransporter-2 inhibitor or glucagon-like peptide 1 receptor agonist) at last trial assessment (6 to 12 months). In this prespecified analysis, mixed-effects logistic regression models were used to assess the outcome by self-reported sex, race, and ethnicity in the intervention and usual care groups, with adjustment for baseline characteristics, medications, comorbidities, and site location.

RESULTS:

Among 1045 participants with type 2 diabetes and atherosclerotic cardiovascular disease, the median age was 70 years, 32% were female, 16% were Black, and 9% were Hispanic. At the last trial assessment, there was an absolute increase in the proportion of participants prescribed all 3 groups of evidence-based therapy in women (36% versus 15%), Black participants (41% versus 18%), and Hispanic participants (46% versus 18%) with the intervention compared with usual care, with consistent benefit across sex (male versus female;
P
interaction
=0.44), race (Black versus White;
P
interaction
=0.59), and ethnicity (Hispanic versus Non-Hispanic;
P
interaction
= 0.78).

CONCLUSIONS:

The COORDINATE-Diabetes intervention successfully improved delivery of evidence-based care, regardless of sex, race, or ethnicity. Widespread dissemination of this intervention could improve equitable health care quality, particularly among women and minority communities who are frequently underrepresented in clinical trials.

REGISTRATION:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT03936660.
Warm Hearts, Happy Lodgings: How Peer-To-Peer Accommodation Micro-Entrepreneurs Can Foster Sharing Citizenship Behavior
Authors: Liu Yue , Li Fangxuan (Sam) , Zhang Guojie , Zhang Jingru
Published: June 2024

In response to the call for elucidating the catalyst of consumer citizenship behavior in micro-entrepreneurship, this study explores the determinants of “sharing citizenship behavior” (SCB) within the peer-to-peer (P2P) accommodation environment from the host perspective. Particularly, it emphasizes the role of well-being (encompassing both the hedonic and eudaimonic forms) and the influence of “trait gratitude” (TG), all within the framework of the broaden-and-build theory. This research explains the mediating effects of both hedonic well-being and eudaimonic well-being (EWB), revealing multiple positive correlations among TG, well-being, and the SCB of guests. It also uncovers the moderating role of price fairness on the link between TG and EWB. It provides valuable insights for P2P accommodation micro-entrepreneurs on the SCB and the well-being of their guests.
Achieving adherence to positive airway pressure in commercial drivers using an employer-mandated remote management programme
Authors: Kneeland Elizabeth , Ali Nadia , Maislin David G. , Chang Yoon Hee , Epelboim Joyce , Keenan Brendan T. , Pack Allan I.
Published: June 2024

Background

Obstructive sleep apnoea (OSA) is common in commercial drivers, and associated with increased risk of crashes if untreated, making diagnosis and effective treatment crucial in this population.

Study design and methods

This is a retrospective summary of a clinical programme based on telemedicine and remote treatment monitoring developed with a national trucking company to screen new hires in the USA for OSA and implement positive airway pressure (PAP) management. New hires were informed of the programme and consented as part of their employment. Drivers who did not comply with the evaluation or with PAP after diagnosis were removed from driving commercial vehicles by the company or did not pursue further employment.

Results

A total of 975 drivers were enrolled. Among screened drivers, 35.5% were cleared without a sleep study, 15.0% were cleared following a sleep study (apnoea–hypopnoea index (AHI) <5 events·h−1), 22.1% had mild OSA (AHI 5–15) and 27.4% had moderate–severe OSA (AHI ≥15). Those with moderate–severe OSA were more obese (body mass index 36.2±6.3 kg·m−2) and had more comorbidities. Of 269 drivers starting PAP, 160 (59.5%) maintained participation in a care management programme, 80 (29.7%) resigned or were terminated, 23 (8.6%) were cleared to discontinue PAP and six (2.2%) were complex cases requiring transfer of care. Illustrating effectiveness, those that maintained participation had excellent PAP adherence (5.27±1.61 h·night−1; 88.5±12.9% days used; 79.7±17.7% days used ≥4 h).

Interpretation

Remote assessment of OSA and PAP management in commercial drivers is feasible and effective. This approach has wide-ranging applications, particularly in populations and areas with a lack of sleep medicine providers.
Assessing post-COVID-19 respiratory dynamics: a comprehensive analysis of pulmonary function, bronchial hyperresponsiveness and bronchodilator response
Authors: Huang Chun-Yao , Wu Yao-Kuang , Yang Mei-Chen , Huang Kuo-Liang , Su Wen-Lin , Huang Yi-Chih , Chih-Wei Wu , Tzeng I-Shiang , Lan Chou-Chin
Published: June 2024

Background

Coronavirus disease 2019 (COVID-19) has a considerable impact on the global healthcare system. Individuals who have recovered from COVID often experience chronic respiratory symptoms that affect their daily lives. This study aimed to assess respiratory dynamics such as airway hyperresponsiveness (AHR) and bronchodilator response in post-COVID patients.

Methods

This study included 282 adults with respiratory symptoms who underwent provocation tests. The demographic details, clinical symptoms and medical histories were recorded. Baseline spirometry, methacholine challenge tests (MCT) and post-bronchodilator spirometry were performed. Patients were divided into the following four groups: Group 1: non-COVID-19 and negative MCT; Group 2: post-COVID-19 and negative MCT; Group 3: non-COVID-19 and positive MCT; and Group 4: post-COVID-19 and positive MCT.

Results

Most post-COVID-19 patients (43.7%) experienced AHR, and wheezing was more common. Patients in Group 4 exhibited increased intensities of dyspnoea, cough and wheezing with the lowest pulmonary function test (PFT) parameters at baseline. Moreover, significant decreases in PFT parameters after the MCT were observed in these patients. Although the prevalence of a low forced expiratory volume in 1 s to forced vital capacity ratio (<70%) was initially 2% in Group 4, it increased to 29% after MCT. No significant differences in allergic history or underlying diseases were observed between the groups.

Conclusions

These findings provide comprehensive insights into the AHR and respiratory symptoms of post-COVID-19 individuals, highlighting the characteristics and potential exacerbations in patients with positive MCT results. This emphasises the need of MCT to address respiratory dynamics in post-COVID-19 individuals.
The noninvasive ventilation outcomes score in patients requiring NIV for COPD exacerbation without prior evidence of airflow obstruction
Authors: Lane Nicholas D. , Hartley Tom M. , Steer John , Bourke Stephen C.
Published: June 2024

Introduction

Exacerbation of COPD complicated by respiratory acidaemia is the commonest indication for noninvasive ventilation (NIV). The NIV outcomes (NIVO) score offers the best estimate of survival for those ventilated. Unfortunately, two-thirds of cases of COPD are unrecognised, and patients may present without COPD having been confirmed by spirometry.

Methods

In the 10-centre NIVO validation study there was no pre-admission spirometry in 111 of 844 consecutive patients (termed “clinical diagnosis” patients). We compared the performance of the NIVO, DECAF and CURB-65 scores for in-hospital mortality in the clinical diagnosis cohort. Usual clinical practice was not influenced, but confirmation of COPD in the year following discharge was captured.

Results

In the clinical diagnosis cohort, in-hospital mortality was 19.8% and rose incrementally across the NIVO risk categories, consistent with the NIVO validation cohort. NIVO showed good discrimination in the clinical diagnosis cohort: area under the receiver operating curve 0.724,versus0.79 in the NIVO validation cohort. At 1 year after discharge, 41 of 89 clinical diagnosis patients had undertaken diagnostic spirometry; 33 of 41 had confirmation of airflow obstruction (forced expiratory volume in 1 s/(forced) vital capacity <0.7), meaning the diagnosis of COPD was incorrect in 19.5% of cases.

Discussion

These data support the use of the NIVO score in patients with a “clinical diagnosis” of COPD. NIVO can help guide shared decision-making, assess risk-adjusted outcomes by centre and challenge prognostic pessimism. Accurate diagnosis is critical to ensure that acute and long-term treatment is optimised; this study highlights failings in the follow-up of such patients.
Lipomatous hypertrophy of the interatrial septum: a distinct adipose tissue type in COPD?
Authors: Lacaita Pietro G. , Kindl Benedikt , Plank Fabian , Beyer Christoph , Bilgeri Valentin , Barbieri Fabian , Senoner Thomas , Dichtl Wolfgang , Tancevski Ivan , Swoboda Michael , Luger Anna , Deeg Johannes , Widmann Gerlig , Feuchtner Gudrun M.
Published: June 2024

Objective

Lipomatous hypertrophy of the interatrial septum (LHIS) is a distinct section of epicardial adipose tissue. However, its association with COPD is poorly documented.

Methods

Patients undergoing coronary computed tomography angiography (CTA) for clinical indications were recruited retrospectively and screened for LHIS and COPD. LHIS density and the coronary artery disease profile were quantified by CTA: stenosis severity (coronary artery disease radiological reporting system (CADRADS)), coronary artery calcium (CAC) and high-risk plaque (HRP). COPD patients with LHIS were matched for age and sex, the major cardiovascular risk factors (CVRFs), and compared to controls.

Results

The prevalence of LHIS in all 5466 patients was 5.9%. 151 (72.6%) of 208 patients with COPD had LHIS. LHIS density in COPD patients was higher (−10.93 HUversus−21.1 HU; p<0.001), despite body mass index (BMI) (28.8versus27.01 kg·m−2; p=0.002) being lower. LHIS density was lower in obese (BMI >30 kg·m−2) patients (20.4versus13.6 HU; p=0.02). BMI was inversely correlated with LHIS density (BetaR −0.031; 95% CI: −0.054– −0.008; p=0.007). LHIS density was associated with COPD, but not with BMI on multivariate models. CAC and coronary stenosis severity (CADRADS and >50% stenosis) were not different (p=0.106, p=0.156 and p=0.350, respectively). HRPs were observed more frequently in COPD patients with severe Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages ≥2 (32.3%versus20.1%; p=0.044), but not when adding mild GOLD stages.

Conclusions

The prevalence of LHIS in COPD patients is high (72.6%), and the adipose tissue density is higher, indicating a higher brown fat component. In obese, patients LHIS density is lower and declines along with BMI. Coronary stenosis severity and calcium were not different; however HRPs were more frequent in severe COPD.
Decoding the impact of the placebo response in clinical trials for chronic cough
Authors: Zhang Mengru , Zhang Bangyu , Morice Alyn H.
Published: June 2024

Chronic cough is a prevalent and challenging condition, with limited treatment options available. The interpretation of clinical trial results for antitussive drugs is complicated by the presence of the placebo response, which can confound outcomes and impede regulatory approval. This review aims to explore the impact of the placebo response on clinical trials for cough medications and elucidate the underlying mechanisms involved. The multifaceted nature of antitussive effects, including pharmacological, psychological/neurobiological and nonspecific effects, is discussed. Additionally, potential solutions to address the placebo response in future cough medication development, such as strategic study design, appropriate choice of end-points and meticulous patient selection, are proposed. More progress to harness this issue is urgently needed.
USP38 exacerbates pressure overload-induced left ventricular electrical remodeling
Authors: Pan Yucheng , Xiao Zheng , Yang Hongjie , Kong Bin , Meng Hong , Shuai Wei , Huang He
Published: June 2024

Background

Ubiquitin-specific protease 38 (USP38), belonging to the USP family, is recognized for its role in controlling protein degradation and diverse biological processes. Ventricular arrhythmias (VAs) following heart failure (HF) are closely linked to ventricular electrical remodeling, yet the specific mechanisms underlying VAs in HF remain inadequately explored. In this study, we examined the impact of USP38 on VAs in pressure overload-induced HF.

Methods

Cardiac-specific USP38 knockout mice, cardiac-specific USP38 transgenic mice and their matched control littermates developed HF induced by aortic banding (AB) surgery. After subjecting the mice to AB surgery for a duration of four weeks, comprehensive investigations were conducted, including pathological analysis and electrophysiological assessments, along with molecular analyses.

Results

We observed increased USP38 expression in the left ventricle of mice with HF. Electrocardiogram showed that the USP38 knockout shortened the QRS interval and QTc, while USP38 overexpression prolonged these parameters. USP38 knockout decreased the susceptibility of VAs by shortening action potential duration (APD) and prolonging effective refractory period (ERP). In addition, USP38 knockout increased ion channel and Cx43 expression in ventricle. On the contrary, the increased susceptibility of VAs and the decreased expression of ventricular ion channels and Cx43 were observed with USP38 overexpression. In both in vivo and in vitro experiments, USP38 knockout inhibited TBK1/AKT/CAMKII signaling, whereas USP38 overexpression activated this pathway.

Conclusion

Our data indicates that USP38 increases susceptibility to VAs after HF through TBK1/AKT/CAMKII signaling pathway, Consequently, USP38 may emerge as a promising therapeutic target for managing VAs following HF.
Allele-specific binding variants causing ChIP-seq peak height of histone modification are not enriched in expression QTL annotations
Authors: Ghoreishifar Mohammad , Chamberlain Amanda J. , Xiang Ruidong , Prowse-Wilkins Claire P. , Lopdell Thomas J. , Littlejohn Mathew D. , Pryce Jennie E. , Goddard Michael E.
Published: June 2024

Background

Genome sequence variants affecting complex traits (quantitative trait loci, QTL) are enriched in functional regions of the genome, such as those marked by certain histone modifications. These variants are believed to influence gene expression. However, due to the linkage disequilibrium among nearby variants, pinpointing the precise location of QTL is challenging. We aimed to identify allele-specific binding (ASB) QTL (asbQTL) that cause variation in the level of histone modification, as measured by the height of peaks assayed by ChIP-seq (chromatin immunoprecipitation sequencing). We identified DNA sequences that predict the difference between alleles in ChIP-seq peak height in H3K4me3 and H3K27ac histone modifications in the mammary glands of cows.

Results

We used a gapped k-mer support vector machine, a novel best linear unbiased prediction model, and a multiple linear regression model that combines the other two approaches to predict variant impacts on peak height. For each method, a subset of 1000 sites with the highest magnitude of predicted ASB was considered as candidate asbQTL. The accuracy of this prediction was measured by the proportion where the predicted direction matched the observed direction. Prediction accuracy ranged between 0.59 and 0.74, suggesting that these 1000 sites are enriched for asbQTL. Using independent data, we investigated functional enrichment in the candidate asbQTL set and three control groups, including non-causal ASB sites, non-ASB variants under a peak, and SNPs (single nucleotide polymorphisms) not under a peak. For H3K4me3, a higher proportion of the candidate asbQTL were confirmed as ASB when compared to the non-causal ASB sites (P < 0.01). However, these candidate asbQTL did not enrich for the other annotations, including expression QTL (eQTL), allele-specific expression QTL (aseQTL) and sites conserved across mammals (P > 0.05).

Conclusions

We identified putatively causal sites for asbQTL using the DNA sequence surrounding these sites. Our results suggest that many sites influencing histone modifications may not directly affect gene expression. However, it is important to acknowledge that distinguishing between putative causal ASB sites and other non-causal ASB sites in high linkage disequilibrium with the causal sites regarding their impact on gene expression may be challenging due to limitations in statistical power.
penalizedclr: an R package for penalized conditional logistic regression for integration of multiple omics layers
Authors: Djordjilović Vera , Ponzi Erica , Nøst Therese Haugdahl , Thoresen Magne
Published: June 2024

Background

The matched case–control design, up until recently mostly pertinent to epidemiological studies, is becoming customary in biomedical applications as well. For instance, in omics studies, it is quite common to compare cancer and healthy tissue from the same patient. Furthermore, researchers today routinely collect data from various and variable sources that they wish to relate to the case–control status. This highlights the need to develop and implement statistical methods that can take these tendencies into account.

Results

We present an R package , that provides an implementation of the penalized conditional logistic regression model for analyzing matched case–control studies. It allows for different penalties for different blocks of covariates, and it is therefore particularly useful in the presence of multi-source omics data. Both L1 and L2 penalties are implemented. Additionally, the package implements stability selection for variable selection in the considered regression model.

Conclusions

The proposed method fills a gap in the available software for fitting high-dimensional conditional logistic regression models accounting for the matched design and block structure of predictors/features. The output consists of a set of selected variables that are significantly associated with case–control status. These variables can then be investigated in terms of functional interpretation or validation in further, more targeted studies.
Investigating diversity and similarity between CBM13 modules and ricin-B lectin domains using sequence similarity networks
Authors: De Coninck Tibo , Gippert Garry P. , Henrissat Bernard , Desmet Tom , Van Damme Els J.M.
Published: June 2024

Background

The CBM13 family comprises carbohydrate-binding modules that occur mainly in enzymes and in several ricin-B lectins. The ricin-B lectin domain resembles the CBM13 module to a large extent. Historically, ricin-B lectins and CBM13 proteins were considered completely distinct, despite their structural and functional similarities.

Results

In this data mining study, we investigate structural and functional similarities of these intertwined protein groups. Because of the high structural and functional similarities, and differences in nomenclature usage in several databases, confusion can arise. First, we demonstrate how public protein databases use different nomenclature systems to describe CBM13 modules and putative ricin-B lectin domains. We suggest the introduction of a novel CBM13 domain identifier, as well as the extension of CAZy cross-references in UniProt to guard the distinction between CAZy and non-CAZy entries in public databases. Since similar problems may occur with other lectin families and CBM families, we suggest the introduction of novel CBM InterPro domain identifiers to all existing CBM families. Second, we investigated phylogenetic, nomenclatural and structural similarities between putative ricin-B lectin domains and CBM13 modules, making use of sequence similarity networks. We concluded that the ricin-B/CBM13 superfamily may be larger than initially thought and that several putative ricin-B lectin domains may display CAZyme functionalities, although biochemical proof remains to be delivered.

Conclusions

Ricin-B lectin domains and CBM13 modules are associated groups of proteins whose database semantics are currently biased towards ricin-B lectins. Revision of the CAZy cross-reference in UniProt and introduction of a dedicated CBM13 domain identifier in InterPro may resolve this issue. In addition, our analyses show that several proteins with putative ricin-B lectin domains show very strong structural similarity to CBM13 modules. Therefore ricin-B lectin domains and CBM13 modules could be considered distant members of a larger ricin-B/CBM13 superfamily.
Mining biosynthetic gene clusters in Paenibacillus genomes to discover novel antibiotics
Authors: Kim Man Su , Jeong Da-Eun , Jang Jun-Pil , Jang Jae-Hyuk , Choi Soo-Keun
Published: June 2024

Background

Bacterial antimicrobial resistance poses a severe threat to humanity, necessitating the urgent development of new antibiotics. Recent advances in genome sequencing offer new avenues for antibiotic discovery. Paenibacillus genomes encompass a considerable array of antibiotic biosynthetic gene clusters (BGCs), rendering these species as good candidates for genome-driven novel antibiotic exploration. Nevertheless, BGCs within Paenibacillus genomes have not been extensively studied.

Results

We conducted an analysis of 554 Paenibacillus genome sequences, sourced from the National Center for Biotechnology Information database, with a focused investigation involving 89 of these genomes via antiSMASH. Our analysis unearthed a total of 848 BGCs, of which 716 (84.4%) were classified as unknown. From the initial pool of 554 Paenibacillus strains, we selected 26 available in culture collections for an in-depth evaluation. Genomic scrutiny of these selected strains unveiled 255 BGCs, encoding non-ribosomal peptide synthetases, polyketide synthases, and bacteriocins, with 221 (86.7%) classified as unknown. Among these strains, 20 exhibited antimicrobial activity against the gram-positive bacterium Micrococcus luteus, yet only six strains displayed activity against the gram-negative bacterium Escherichia coli. We proceeded to focus on Paenibacillus brasilensis, which featured five new BGCs for further investigation. To facilitate detailed characterization, we constructed a mutant in which a single BGC encoding a novel antibiotic was activated while simultaneously inactivating multiple BGCs using a cytosine base editor (CBE). The novel antibiotic was found to be localized to the cell wall and demonstrated activity against both gram-positive bacteria and fungi. The chemical structure of the new antibiotic was elucidated on the basis of ESIMS, 1D and 2D NMR spectroscopic data. The novel compound, with a molecular weight of 926, was named bracidin.

Conclusions

This study outcome highlights the potential of Paenibacillus species as valuable sources for novel antibiotics. In addition, CBE-mediated dereplication of antibiotics proved to be a rapid and efficient method for characterizing novel antibiotics from Paenibacillus species, suggesting that it will greatly accelerate the genome-based development of new antibiotics.
Expression and significance of Fractalkine/CX3CL1 in MPO-AAV-associated glomerulonephritis rats
Authors: Ma Junxue , Wang Junjie , Kang Hongli , Ma Ruiying , Zhu Zhengxi
Published: June 2024

Objective

To investigate the expression and significance of Fractalkine (CX3CL1, FKN) in serum and renal tissue of myeloperoxidase and anti-neutrophil cytoplasmic antibody associated vasculitis (MPO-AAV) rats.

Methods

Thirty Wistar-Kyoto (WKY) rats were randomly divided into: Control group, MPO-AAV group (400 µg/kg MPO mixed with Freund’s complete adjuvant i.p), MPO-AAV + Anti-FKN group (400 µg/kg MPO mixed with Freund’s complete adjuvant i.p), anti-FKN group (1 µg/ rat /day, i.p) after 6 weeks. MPO-AAV associated glomerulonephritis model was established by intraperitoneal injection of MPO + Freund’s complete adjuvant with 10 mice in each group. The concentration of MPO-ANCA and FKN in serum was detected by Enzyme-linked immunosorbent assay (ELISA). Hematoxylin-eosin (HE) staining was used to detect pathological changes of kidney tissue. Western blot and immunofluorescence staining were used to detect the expression and localization of FKN protein in kidney tissue. Renal function test indicators: 24-hour urinary protein (UAER), blood urea nitrogen (BUN), serum creatinine (Scr). The expression levels of p65NF-κB and IL-6 was detected by Immunohistochemical assays.

Results

Compared with the control group, the serum MPO-ANCA antibody expression level in the MPO-AAV group was significantly increased (P < 0.01), and the contents of UAER, BUN and Scr were significantly up-regulated at 24 h (P < 0.01). Compared with the control group, the glomeruli in the MPO-AAV group had different degrees of damage, infiltration of inflammatory cell, and membrane cell hyperplasia and renal tubule edema. Compared with the control group, rats in the MPO-AAV group had significantly higher levels of FKN in serum and renal tissues (P < 0.01), and high expression of p65NF-κB and IL-6 in renal tissues (P < 0.01) (P < 0.05), whereas anti-FKN reversed the expression of the above factors. In MPO-AAV renal tissue, FKN was mainly expressed in the cytoplasm of renal tubular epithelial cells and glomerular podocytes. In addition, the contents of 24 h UAER, BUN and Scr of renal function in MPO-AAV rats were significantly decreased (P < 0.01) and the damage of renal tissue was significantly ameliorated after the administration of antagonistic FKN.

Conclusion

FKN may play a key role in the pathogenesis of MPO-AAV associated glomerulonephritis.
Sex-specific implications of inflammation in covert cerebral small vessel disease
Authors: Chen Bo-An , Lee Wei-Ju , Meng Lin-Chieh , Lin Yi-Chin , Chung Chih-Ping , Hsiao Fei-Yuan , Chen Liang-Kung
Published: June 2024

Background

The relationship between inflammation and covert cerebral small vessel disease (SVD) with regards to sex difference has received limited attention in research. We aim to unravel the intricate associations between inflammation and covert SVD, while also scrutinizing potential sex-based differences in these connections.

Methods

Non-stroke/dementia-free study population was from the I-Lan longitudinal Aging Study. Severity and etiology of SVD were assessed by 3T-MRI in each participant. Systemic and vascular inflammatory-status was determined by the circulatory levels of high-sensitivity C-reactive protein (hsCRP) and homocysteine, respectively. Sex-specific multivariate logistic regression to calculate odds ratios (ORs) and interaction models to scrutinize women-to-men ratios of ORs (RORs) were used to evaluate the potential impact of sex on the associations between inflammatory factors and SVD.

Results

Overall, 708 participants (62.19 ± 8.51 years; 392 women) were included. Only women had significant associations between homocysteine levels and covert SVD, particularly in arteriosclerosis/lipohyalinosis SVD (ORs[95%CI]: 1.14[1.03–1.27] and 1.15[1.05–1.27] for more severe and arteriosclerosis/lipohyalinosis SVD, respectively). Furthermore, higher circulatory levels of homocysteine were associated with a greater risk of covert SVD in women compared to men, as evidenced by the RORs [95%CI]: 1.14[1.01–1.29] and 1.14[1.02–1.28] for more severe and arteriosclerosis/lipohyalinosis SVD, respectively. No significant associations were found between circulatory hsCRP levels and SVD in either sex.

Conclusion

Circulatory homocysteine is associated with covert SVD of arteriosclerosis/lipohyalinosis solely in women. The intricacies underlying the sex-specific effects of homocysteine on SVD at the preclinical stage warrant further investigations, potentially leading to personalized/tailored managements.

Trial registration

Not applicable.