bluuebunny/crossref_metadata_2025 huggingface dataset:
Identifying and ranking causal biochemical biomarkers for breast cancer: a Mendelian randomisation study
Authors: Tang Sonja N. , Zuber Verena , Tsilidis Konstantinos K.
Published: November 2022

Background

Only a few of the 34 biochemical biomarkers measured in the UK Biobank (UKB) have been associated with breast cancer, with many associations suffering from possible confounding and reverse causation. This study aimed to screen and rank all UKB biochemical biomarkers for possible causal relationships with breast cancer.

Methods

We conducted two-sample Mendelian randomisation (MR) analyses on ~420,000 women by leveraging summary-level genetic exposure associations from the UKB study (n = 194,174) and summary-level genetic outcome associations from the Breast Cancer Association Consortium (n = 228,951). Our exposures included all 34 biochemical biomarkers in the UKB, and our outcomes were overall, oestrogen-positive, and oestrogen-negative breast cancer. We performed inverse-variance weighted MR, weighted median MR, MR-Egger, and MR-PRESSO for 30 biomarkers for which we found multiple instrumental variables. We additionally performed multivariable MR to adjust for known risk factors, bidirectional MR to investigate reverse causation, and MR Bayesian model averaging to rank the significant biomarkers by their genetic evidence.

Results

Increased genetic liability to overall breast cancer was robustly associated with the following biomarkers by decreasing importance: testosterone (odds ratio (OR): 1.12, 95% confidence interval (CI): 1.04–1.21), high-density lipoprotein (HDL) cholesterol (OR: 1.08, 95% CI: 1.04–1.13), insulin-like growth factor 1 (OR: 1.08, 95% CI: 1.02–1.13), and alkaline phosphatase (ALP) (OR: 0.93, 95% CI: 0.89–0.98).

Conclusions

Our findings support a likely causal role of genetically predicted levels of testosterone, HDL cholesterol, and IGF-1, as well as a novel potential role of ALP in breast cancer aetiology. Further studies are needed to understand full disease pathways that may inform breast cancer prevention.
Homogenizing effect of PEEP on tidal volume distribution during neurally adjusted ventilatory assist: study of an animal model of acute respiratory distress syndrome
Authors: Widing Hannes , Chiodaroli Elena , Liggieri Francesco , Mariotti Paola Sara , Hallén Katarina , Perchiazzi Gaetano
Published: November 2022

Background

The physiological response and the potentially beneficial effects of positive end-expiratory pressure (PEEP) for lung protection and optimization of ventilation during spontaneous breathing in patients with acute respiratory distress syndrome (ARDS) are not fully understood. The aim of the study was to compare the effect of different PEEP levels on tidal volume distribution and on the ventilation of dependent lung region during neurally adjusted ventilatory assist (NAVA).

Methods

ARDS-like lung injury was induced by using saline lavage in 10 anesthetized and spontaneously breathing farm-bred pigs. The animals were ventilated in NAVA modality and tidal volume distribution as well as dependent lung ventilation were assessed using electric impedance tomography during the application of PEEP levels from 0 to 15 cmH20, in steps of 3 cmH20. Tidal volume distribution and dependent fraction of ventilation were analysed using Wilcoxon signed rank test. Furthermore, airway, esophageal and transpulmonary pressure, as well as airway flow and delivered volume, were continuously measured during the assisted spontaneous breathing.

Results

Increasing PEEP improved oxygenation and re-distributed tidal volume. Specifically, ventilation distribution changed from a predominant non-dependent to a more even distribution between non-dependent and dependent areas of the lung. Dependent fraction of ventilation reached 47 ± 9% at PEEP 9 cmH20. Further increasing PEEP led to a predominant dependent ventilation.

Conclusion

During assisted spontaneous breathing in this model of induced ARDS, PEEP modifies the distribution of ventilation and can achieve a homogenizing effect on its spatial arrangement. The study indicates that PEEP is an important factor during assisted spontaneous breathing and that EIT can be of valuable interest when titrating PEEP level during spontaneous breathing, by indicating the most homogeneous distribution of gas volumes throughout the PEEP spectrum.
Derivation and external validation of a simple prediction rule for the development of respiratory failure in hospitalized patients with influenza
Authors: Ayuso Blanca , Lalueza Antonio , Arrieta Estibaliz , Romay Eva María , Marchán-López Álvaro , García-País María José , Folgueira Dolores , Gude María José , Cueto Cecilia , Serrano Antonio , Lumbreras Carlos
Published: November 2022

Background

Influenza viruses cause seasonal epidemics worldwide with a significant morbimortality burden. Clinical spectrum of Influenza is wide, being respiratory failure (RF) one of its most severe complications. This study aims to elaborate a clinical prediction rule of RF in hospitalized Influenza patients.

Methods

A prospective cohort study was conducted during two consecutive Influenza seasons (December 2016–March 2017 and December 2017–April 2018) including hospitalized adults with confirmed A or B Influenza infection. A prediction rule was derived using logistic regression and recursive partitioning, followed by internal cross-validation. External validation was performed on a retrospective cohort in a different hospital between December 2018 and May 2019.

Results

Overall, 707 patients were included in the derivation cohort and 285 in the validation cohort. RF rate was 6.8% and 11.6%, respectively. Chronic obstructive pulmonary disease, immunosuppression, radiological abnormalities, respiratory rate, lymphopenia, lactate dehydrogenase and C-reactive protein at admission were associated with RF. A four category-grouped seven point-score was derived including radiological abnormalities, lymphopenia, respiratory rate and lactate dehydrogenase. Final model area under the curve was 0.796 (0.714–0.877) in the derivation cohort and 0.773 (0.687–0.859) in the validation cohort (p < 0.001 in both cases). The predicted model showed an adequate fit with the observed results (Fisher’s test p > 0.43).

Conclusion

we present a simple, discriminating, well-calibrated rule for an early prediction of the development of RF in hospitalized Influenza patients, with proper performance in an external validation cohort. This tool can be helpful in patient’s stratification during seasonal Influenza epidemics.
Time trends of cardiovascular risk management in type 1 diabetes - nationwide analyses of real-life data
Authors: Amadid Hanan , Clemmensen Kim Katrine Bjerring , Vistisen Dorte , Persson Frederik , Jørgensen Marit Eika
Published: November 2022

Background

Individuals diagnosed with and treated for type 1 diabetes (T1D) have increased risk of micro- and macrovascular disease and excess mortality. Improving cardiovascular (CV) risk factors in individuals with T1D is known to reduce diabetes- related CV complications.

Aim

To examine time trends in CV risk factor levels and CV-protective treatment patterns. Additionally, examine incidence rates of diabetes-related CV complications in relation to exposure CV-protective treatment.

Methods

We analysed records from 41,630 individuals with T1D, registered anytime between 1996 and 2017 in a nationwide diabetes register. We obtained CV risk factor measurements (2010–2017), CV-protective drug profiles (1996–2017) and CV complication history (1977–2017) from additional nationwide health registers.

Results

From 2010 to 2017 there were decreasing levels of HbA1c, LDL-C, and blood pressure. Decreasing proportion of smokers, individuals with glycaemic dysregulation (HbA1c ≥ 58 mmol/mol), dyslipidaemia (LDL-C > 2.6 mmol/l), and hypertension (≥ 140/85 mmHg). Yet, one fifth of the T1D population by January 1st, 2017 was severely dysregulated (HbA1c > 75 mmol/mol). A slight increase in levels of BMI and urinary albumin creatinine ratio and a slight decrease in estimated glomerular filtration rate (eGFR) levels was observed. By January 1st, 2017, one fourth of the T1D population had an eGFR < 60 ml/min/1.73 m2. The proportion of the T1D population redeeming lipid-lowering drugs (LLDs) increased from 5% in 2000 to 30% in 2010 followed by a plateau and then a decline. The proportion of the T1D population redeeming antihypertensive drugs (AHDs) increased from 28% in 1996 to 42% in 2010 followed by a tendency to decline. Use of LLDs was associated with lower incidence of micro- and macrovascular complications, while use of AHDs had higher incidence of CVD and CKD, when compared to non-use and discontinued use, respectively.

Conclusion

Improvements were seen in CV risk factor control among individuals with T1D in Denmark between 2010 and 2017. However, there is clearly a gap between current clinical guidelines and clinical practice for CV risk management in T1D. Action is needed to push further improvements in CV risk control to reduce CVD and the related excess mortality.
The hero of American and Polish nations: a molecular look at Thaddeus Kosciuszko’s cause of death suggests a contribution of endocarditis caused by Cutibacterium acnes infection
Authors: Witt Michał , Tokarski Miron , Ziętkiewicz Ewa , Lebioda Arleta , Szczypek Maria , Falkowski Wojciech , Mrozowski Przemysław , Kulak Teresa , Sobieszczańska Małgorzata , Mrugalska-Banaszak Magdalena , Jurek Tomasz , Dobosz Tadeusz
Published: November 2022

The remains of the heart tissue of Thaddeus Kosciuszko have been investigated as the possible cause of disease and death of the hero of Polish and American nations. Three specimens, DNA isolated from scrappings of wax surface, from the surface of a wooden plate, and from the linen cloth that have had contact with the object were subjected to nanosequencing. From the first two, among all reads identified, only one classified as Propionibacterium acnes (synonymous current name Cutibacterium acnes), had a purported clinical significance. The observed identity between the P. acnes sequences and reference was 89–90% consistent with the hypothesis that the identified reads represent the ancient P. acnes DNA (aDNA), which underwent fragmentation and sequence changes caused by its long-time presence in the environmental conditions conducive to degradation. We present a reasonable and entirely new hypothesis that the analyzed samples could reflect the presence of the bacteria in the original Kosciuszko’s heart tissue and that the process of C. acnes infection was progressing inside the organ (endocarditis), not on its surface (pericarditis) leading to rapid deterioration of health and eventually death. We again point out that normal skin and mucosal membranes commensal, a causative agent of common skin acne, may be associated with various severe organ infections posing a threat to health and life.
Machine learning for data integration in human gut microbiome
Authors: Li Peishun , Luo Hao , Ji Boyang , Nielsen Jens
Published: November 2022

Recent studies have demonstrated that gut microbiota plays critical roles in various human diseases. High-throughput technology has been widely applied to characterize the microbial ecosystems, which led to an explosion of different types of molecular profiling data, such as metagenomics, metatranscriptomics and metabolomics. For analysis of such data, machine learning algorithms have shown to be useful for identifying key molecular signatures, discovering potential patient stratifications, and particularly for generating models that can accurately predict phenotypes. In this review, we first discuss how dysbiosis of the intestinal microbiota is linked to human disease development and how potential modulation strategies of the gut microbial ecosystem can be used for disease treatment. In addition, we introduce categories and workflows of different machine learning approaches, and how they can be used to perform integrative analysis of multi-omics data. Finally, we review advances of machine learning in gut microbiome applications and discuss related challenges. Based on this we conclude that machine learning is very well suited for analysis of gut microbiome and that these approaches can be useful for development of gut microbe-targeted therapies, which ultimately can help in achieving personalized and precision medicine.
Tiliroside suppresses triple-negative breast cancer as a multifunctional CAXII inhibitor
Authors: Han Rui , Yang Hongxing , Ling Changquan , Lu Lingeng
Published: November 2022

Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by poor prognosis, early recurrence, and the lack of durable chemotherapy responses and specific targeted treatments. In this preclinical study, we examines Tiliroside (TS, C30H26O13), as one of the major compounds of Tribulus terrestris L. which has been used as an alternative therapy in clinic practice of breast cancer treatment, for its therapeutic use in TNBC. The association between CAXII expression level and survival probability of TNBC patients, and the difference of CAXII expression level between TNBC and normal samples were evaluated by using publicly accessible databases. To determine the anticancer efficacy of TS on TNBC cells, cell proliferation, wound healing, cell invasion, and 3D spheroid formation assays were performed and excellent anticancer activities of TS were displayed. Mouse models further demonstrated that TS significantly reduced the tumor burden and improved survival rate. The properties of TS as a novel CAXII inhibitor have also been evaluated by CAXII activity assay, pHi, pHe and lactate level assay. Further RT-PCR and Caspase-3 activity analyses also revealed the positive regulating effects of TS on E2F1,3/Caspase-3 axis in TNBC cells cultured in 2D or 3D systems. The findings indicate that TS suppresses TNBC progression as a potential novel CAXII inhibitor in preclinical experiments, which warrants further investigation on its therapeutic implications.
Immune modulating nanoparticles for the treatment of ocular diseases
Authors: Fang Lianfei , Liu Jin , Liu Zeyang , Zhou Huifang
Published: November 2022

Ocular diseases are increasingly influencing people’s quality of life. Complicated inflammatory mechanisms involved in the pathogenic process of ocular diseases make inflammation-targeting treatment a potential therapeutic approach. The limited efficacy of conventional anti-inflammatory therapeutic strategies, caused by various objective factors, such as complex ocular biological barriers, and subjective factors, such as poor compliance, are promoting the development of new therapeutic methods. With the advantages of considerable tissue permeability, a controllable drug release rate, and selective tissue targeting ability, nanoparticles have successfully captured researchers’ attention and have become a research hotspot in treating ocular diseases. This review will focus on the advantages of nanosystems over traditional therapy, the anti-inflammation mechanisms of nanoparticles, and the anti-inflammatory applications of nanoparticles in different ocular diseases (ocular surface diseases, vitreoretinopathy, uveal diseases, glaucoma, and visual pathway diseases). Furthermore, by analyzing the current situation of nanotherapy and the challenges encountered, we hope to inspire new ideas and incentives for designing nanoparticles more consistent with human physiological characteristics to make progress based on conventional treatments. Overall, some progress has been made in nanoparticles for the treatment of ocular diseases, and nanoparticles have rather broad future clinical translation prospects.
A carbon monoxide releasing metal organic framework nanoplatform for synergistic treatment of triple-negative breast tumors
Authors: Cong Yiyang , Sun Bo , Hu Jianlun , Li Xiaoyang , Wang Yanan , Zhang Jingyi , Yang Dongzhi , Lu Weifei , Ding Zhi , Wang Xiaofeng , Hong Hao
Published: November 2022

Background

Carbon monoxide (CO) is an important signaling molecule participating in multiple biological functions. Previous studies have confirmed the valuable roles of CO in cancer therapies. If the CO concentration and distribution can be controlled in tumors, new cancer therapeutic strategy may be developed to benefit the patient survival.

Results

In this study, a UiO-67 type metal–organic framework (MOF) nanoplatform was produced with cobalt and ruthenium ions incorporated into its structure (Co/Ru-UiO-67). Co/Ru-UiO-67 had a size range of 70–90 nm and maintained the porous structure, with cobalt and ruthenium distributed uniformly inside. Co/Ru-UiO-67 was able to catalyze carbon dioxide into CO upon light irradiation in an efficient manner with a catalysis speed of 5.6 nmol/min per 1 mg Co/Ru-UiO-67. Due to abnormal metabolic properties of tumor cells, tumor microenvironment usually contains abundant amount of CO2. Co/Ru-UiO-67 can transform tumor CO2 into CO at both cellular level and living tissues, which consequently interacts with relevant signaling pathways (e.g. Notch-1, MMPs etc.) to adjust tumor microenvironment. With proper PEGylation (pyrene-polyacrylic acid-polyethylene glycol, Py-PAA-PEG) and attachment of a tumor-homing peptide (F3), functionalized Co/Ru-UiO-67 could accumulate strongly in triple-negative MDA-MB-231 breast tumors, witnessed by positron emission tomography (PET) imaging after the addition of radioactive zirconium-89 (89Zr) into Co-UiO-67. When applied in vivo, Co/Ru-UiO-67 could alter the local hypoxic condition of MDA-MB-231 tumors, and work synergistically with tirapazamine (TPZ).

Conclusion

This nanoscale UiO-67 MOF platform can further our understanding of CO functions while produce CO in a controllable manner during cancer therapeutic administration.

Graphical Abstract
Intensity-adjustable pain management with prolonged duration based on phase-transitional nanoparticles-assisted ultrasound imaging-guided nerve blockade
Authors: Qiao Bin , Song Xinye , Zhang Weiyi , Xu Ming , Zhuang Bowen , Li Wei , Guo Huanling , Wu Wenxin , Huang Guangliang , Zhang Minru , Xie Xiaoyan , Zhang Nan , Luan Yong , Zhang Chunyang
Published: November 2022

Background

The lack of a satisfactory strategy for postoperative pain management significantly impairs the quality of life for many patients. However, existing nanoplatforms cannot provide a longer duration of nerve blockage with intensity-adjustable characteristics under imaging guidance for clinical applications.

Results

To overcome this challenge, we proposed a biocompatible nanoplatform that enables high-definition ultrasound imaging-guided, intensity-adjustable, and long-lasting analgesia in a postoperative pain management model in awake mice. The nanoplatform was constructed by incorporating perfluoropentane and levobupivacaine with red blood cell membranes decorated liposomes. The fabricated nanoplatform can achieve gas-producing and can finely escape from immune surveillance in vivo to maximize the anesthetic effect. The analgesia effect was assessed from both motor reactions and pain-related histological markers. The findings demonstrated that the duration of intensity-adjustable analgesia in our platform is more than 20 times longer than free levobupivacaine injection with pain relief for around 3 days straight. Moreover, the pain relief was strengthened by repeatable ultrasound irradiation to effectively manage postoperative pain in an intensity-adjustable manner. No apparent systemic and local tissue injury was detected under different treatments.

Conclusion

Our results suggest that nanoplatform can provide an effective strategy for ultrasound imaging-guided intensity-adjustable pain management with prolonged analgesia duration and show considerable transformation prospects.
Self-injecting non-prescribed substances into vascular access devices: a case study of one health system’s ongoing journey from clinical concern to practice and policy response
Authors: Chase Jocelyn , Nicholson Melissa , Dogherty Elizabeth , Garrod Emma , Hill Jocelyn , Brar Rupinder , Weaver Victoria , Connors William J.
Published: November 2022

Background

Overdose-associated deaths and morbidity related to substance use is a global public health emergency with devastating social and economic costs. Complications of substance use are most pronounced among people who inject drugs (PWID), particularly infections, resulting in increased risk of hospitalization. PWID often require intravenous access for medical treatments such as antibiotics; however, vascular access may be limited due to the impacts of long-term self-venipuncture. While vascular access devices including peripherally inserted central catheters (PICCs) allow reliable and sustained routes of administration for indicated therapies, the use of PICCs among PWID presents unique challenges. The incidence and risks associated with self-injecting non-prescribed substances into vascular access devices (SIVAD) is one such concern for which there is limited evidence and absence of formal practice guidance.

Case presentation

We report the experience of a multidisciplinary team at a health organization in Vancouver, Canada, working to characterize the incidence, patient and healthcare provider perspectives, and overall impact of SIVAD. The case study of SIVAD begins with a patient’s perspective, including patient rationale for SIVAD, understanding of risks and the varying responses given by healthcare providers following disclosure of SIVAD. Using the limited literature available on the subject, we summarize the intersection of SIVAD and substance use and outline known and anticipated health risks. The case study is further contextualized by experience from a Vancouver in-hospital Overdose Prevention Site (OPS), where 37% of all individual visits involve SIVAD. The case study concludes by describing the systematic process by which local clinical guidance for SIVAD harm reduction was developed with stakeholder engagement, medical ethics consultation, expert consensus guideline development and implementation with staff education and planned research evaluation.

Conclusion

SIVAD is encountered with enough frequency in an urban healthcare setting in Vancouver, Canada, to warrant an organizational approach. This case study aims to enhance appreciation of SIVAD as a common and complex clinical issue with anticipated health risks. The authors conclude that using a harm reduction lens for SIVAD policy and research can provide benefit to clinicians and patients by offering a clear and a consistent healthcare response to this common issue.
Impact of antiretroviral therapy (ART) duration on ART adherence among men who have sex with men (MSM) living with HIV in Jinan of China
Authors: Jiao Kedi , Liao Meizhen , Liu Guangmei , Bi Yanmei , Zhao Xiuhong , Chen Qian , Ma Jing , Yan Yu , Cheng Chunxiao , Li Yijun , Jia Wenwen , Wang Lina , Cao Yanwen , Zhao Zhonghui , Yang Xuan , Meng Jing , Li Jianzhuo , Li Xinrui , Wang Chunmei , Kang Dianmin , Ma Wei
Published: November 2022

Background

Consistent and complete adherence is considered an essential requirement for patients on antiretroviral therapy (ART). This study aimed to evaluate the impact of ART duration on ART adherence, identify the trend of complete adherence, and compare the factors associated with ART adherence between short-term and long-term ART group among men who have sex with men (MSM) living with HIV in Jinan of China.

Methods

MSM living with HIV aged 18 or above and currently on ART were recruited from October to December 2020 using convenience sampling. Univariate and multivariable logistic regressions were used to evaluate the impact of ART duration on adherence and compare factors associated with ART adherence between subgroups. The Mann–Kendall test was used to identify the trend of complete adherence.

Results

A total of 585 participants were included in analysis, consisting of 352 on short-term ART (ART initiation ≤ 3 years) and 233 on long-term ART (ART initiation > 3 years). Significant difference of complete ART adherence between short-term and long-term ART group was detected (79.8% vs. 69.1%, P = 0.003). Multivariable analysis showed that men with longer ART duration were less likely to report complete ART adherence (AOR = 0.88, 95% CI 0.81–0.95). A descending trend of complete adherence was identified (Z = 1.787, P = 0.037). Alcohol use and lack of medication reminders were barriers to complete adherence for both of the subgroups.

Conclusions

Sustained efforts to encourage maintaining adherence for a lifetime are necessary, especially for those on long-term ART. Future interventions should be tailored to subgroups with different ART duration and individuals with specific characteristics.
Introducing new plan evaluation indices for prostate dose painting IMRT plans based on apparent diffusion coefficient images
Authors: Moradi Saman , Hashemi Bijan , Bakhshandeh Mohsen , Banaei Amin , Mofid Bahram
Published: November 2022

Background

Dose painting planning would be more complicated due to different levels of prescribed doses and more complex evaluation with conventional plan quality indices considering uniform dose prescription. Therefore, we tried to introduce new indices for evaluating the dose distribution conformity and homogeneity of treatment volumes based on the tumoral cell density and relative volumes of each lesion in prostate IMRT.

Methods

CT and MRI scans of 20 male patients having local prostate cancer were used for IMRT DP planning. Apparent diffusion coefficient (ADC) images were imported to a MATLAB program to identify lesion regions based on ADC values automatically. Regions with ADC values lower than 750 mm2/s and regions with ADC values higher than 750 and less than 1500 mm2/s were considered CTV70Gy (clinical tumor volume with 70 Gy prescribed dose), and CTV60Gy, respectively. Other regions of the prostate were considered as CTV53Gy. New plan evaluation indices based on evaluating the homogeneity (IOE(H)), and conformity (IOE(C)) were introduced, considering the relative volume of each lesion and cellular density obtained from ADC images. These indices were compared with conventional homogeneity and conformity indices and IOEs without considering cellular density. Furthermore, tumor control probability (TCP) was calculated for each patient, and the relationship of the assessed indices were evaluated with TCP values.

Results

IOE (H) and IOE (C) with considering cellular density had significantly lower values compared to conventional indices and IOEs without considering cellular density. (P < 0.05). TCP values had a stronger relationship with IOE(H) considering cell density (R2 = -0.415), and IOE(C) without considering cell density (R2 = 0.624).

Conclusion

IOE plan evaluation indices proposed in this study can be used for evaluating prostate IMRT dose painting plans. We suggested to consider cell densities in the IOE(H) calculation formula and it’s appropriate to calculate IOE(C) without considering cell density values.
Fluid balance and renal replacement therapy initiation strategy: a secondary analysis of the STARRT-AKI trial
Authors: Wald Ron , Kirkham Brian , daCosta Bruno R. , Ghamarian Ehsan , Adhikari Neill K. J. , Beaubien-Souligny William , Bellomo Rinaldo , Gallagher Martin P. , Goldstein Stuart , Hoste Eric A. J. , Liu Kathleen D. , Neyra Javier A. , Ostermann Marlies , Palevsky Paul M. , Schneider Antoine , Vaara Suvi T. , Bagshaw Sean M.
Published: November 2022

Background

Among critically ill patients with acute kidney injury (AKI), earlier initiation of renal replacement therapy (RRT) may mitigate fluid accumulation and confer better outcomes among individuals with greater fluid overload at randomization.

Methods

We conducted a pre-planned post hoc analysis of the STandard versus Accelerated initiation of Renal Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial. We evaluated the effect of accelerated RRT initiation on cumulative fluid balance over the course of 14 days following randomization using mixed models after censoring for death and ICU discharge. We assessed the modifying effect of baseline fluid balance on the impact of RRT initiation strategy on key clinical outcomes. Patients were categorized in quartiles of baseline fluid balance, and the effect of accelerated versus standard RRT initiation on clinical outcomes was assessed in each quartile using risk ratios (95% CI) for categorical variables and mean differences (95% CI) for continuous variables.

Results

Among 2927 patients in the modified intention-to-treat analysis, 2738 had available data on baseline fluid balance and 2716 (92.8%) had at least one day of fluid balance data following randomization. Over the subsequent 14 days, participants allocated to the accelerated strategy had a lower cumulative fluid balance compared to those in the standard strategy (4509 (− 728 to 11,698) versus 5646 (0 to 13,151) mL, p = 0.03). Accelerated RRT initiation did not confer greater 90-day survival in any of the baseline fluid balance quartiles (quartile 1: RR 1.11 (95% CI 0.92 to 1.34), quartile 2: RR 1.03 (0.87 to 1.21); quartile 3: RR 1.08 (95% CI 0.91 to 1.27) and quartile 4: RR 0.87 (95% CI 0.73 to 1.03), p value for trend 0.08).

Conclusions

Earlier RRT initiation in critically ill patients with AKI conferred a modest attenuation of cumulative fluid balance. Nonetheless, among patients with greater fluid accumulation at randomization, accelerated RRT initiation did not have an impact on all-cause mortality.

Trial registration: ClinicalTrials.gov number, https://clinicaltrials.gov/ct2/show/NCT02568722, registered October 6, 2015.
m6A RNA methylation impairs gene expression variability and reproductive thermotolerance in Arabidopsis
Authors: Wang Ling , Zhuang Haiyan , Fan Wenwen , Zhang Xia , Dong Haihong , Yang Hongxing , Cho Jungnam
Published: November 2022

Heat-imposed crop failure is often attributed to reduced thermotolerance of floral tissues; however, the underlying mechanism remains unknown. Here, we demonstrate that m6A RNA methylation increases in Arabidopsis flowers and negatively regulates gene expression variability. Stochastic gene expression provides flexibility to cope with environmental stresses. We find that reduced transcriptional fluctuation is associated with compromised activation of heat-responsive genes. Moreover, disruption of an RNA demethylase AtALKBH10B leads to lower gene expression variability, suppression of heat-activated genes, and strong reduction of plant fertility. Our work proposes a novel role for RNA methylation in the bet-hedging strategy of heat stress response.
Illuminating links between cis-regulators and trans-acting variants in the human prefrontal cortex
Authors: Liu Shuang , Won Hyejung , Clarke Declan , Matoba Nana , Khullar Saniya , Mu Yudi , Wang Daifeng , Gerstein Mark
Published: November 2022

Background

Neuropsychiatric disorders afflict a large portion of the global population and constitute a significant source of disability worldwide. Although Genome-wide Association Studies (GWAS) have identified many disorder-associated variants, the underlying regulatory mechanisms linking them to disorders remain elusive, especially those involving distant genomic elements. Expression quantitative trait loci (eQTLs) constitute a powerful means of providing this missing link. However, most eQTL studies in human brains have focused exclusively on cis-eQTLs, which link variants to nearby genes (i.e., those within 1 Mb of a variant). A complete understanding of disease etiology requires a clearer understanding of trans-regulatory mechanisms, which, in turn, entails a detailed analysis of the relationships between variants and expression changes in distant genes.

Methods

By leveraging large datasets from the PsychENCODE consortium, we conducted a genome-wide survey of trans-eQTLs in the human dorsolateral prefrontal cortex. We also performed colocalization and mediation analyses to identify mediators in trans-regulation and use trans-eQTLs to link GWAS loci to schizophrenia risk genes.

Results

We identified ~80,000 candidate trans-eQTLs (at FDR<0.25) that influence the expression of ~10K target genes (i.e., “trans-eGenes”). We found that many variants associated with these candidate trans-eQTLs overlap with known cis-eQTLs. Moreover, for >60% of these variants (by colocalization), the cis-eQTL’s target gene acts as a mediator for the trans-eQTL SNP's effect on the trans-eGene, highlighting examples of cis-mediation as essential for trans-regulation. Furthermore, many of these colocalized variants fall into a discernable pattern wherein cis-eQTL’s target is a transcription factor or RNA-binding protein, which, in turn, targets the gene associated with the candidate trans-eQTL. Finally, we show that trans-regulatory mechanisms provide valuable insights into psychiatric disorders: beyond what had been possible using only cis-eQTLs, we link an additional 23 GWAS loci and 90 risk genes (using colocalization between candidate trans-eQTLs and schizophrenia GWAS loci).

Conclusions

We demonstrate that the transcriptional architecture of the human brain is orchestrated by both cis- and trans-regulatory variants and found that trans-eQTLs provide insights into brain-disease biology.
Whole-exome sequencing identifies novel protein-altering variants associated with serum apolipoprotein and lipid concentrations
Authors: Sandholm Niina , Hotakainen Ronja , Haukka Jani K. , Jansson Sigfrids Fanny , Dahlström Emma H. , Antikainen Anni A. , Valo Erkka , Syreeni Anna , Kilpeläinen Elina , Kytölä Anastasia , Palotie Aarno , Harjutsalo Valma , Forsblom Carol , Groop Per-Henrik ,   on behalf of the FinnDiane Study Group
Published: November 2022

Background

Dyslipidemia is a major risk factor for cardiovascular disease, and diabetes impacts the lipid metabolism through multiple pathways. In addition to the standard lipid measurements, apolipoprotein concentrations provide added awareness of the burden of circulating lipoproteins. While common genetic variants modestly affect the serum lipid concentrations, rare genetic mutations can cause monogenic forms of hypercholesterolemia and other genetic disorders of lipid metabolism. We aimed to identify low-frequency protein-altering variants (PAVs) affecting lipoprotein and lipid traits.

Methods

We analyzed whole-exome (WES) and whole-genome sequencing (WGS) data of 481 and 474 individuals with type 1 diabetes, respectively. The phenotypic data consisted of 79 serum lipid and apolipoprotein phenotypes obtained with clinical laboratory measurements and nuclear magnetic resonance spectroscopy.

Results

The single-variant analysis identified an association between the LIPC p.Thr405Met (rs113298164) and serum apolipoprotein A1 concentrations (p=7.8×10−8). The burden of PAVs was significantly associated with lipid phenotypes in LIPC, RBM47, TRMT5, GTF3C5, MARCHF10, and RYR3 (p<2.9×10−6). The RBM47 gene is required for apolipoprotein B post-translational modifications, and in our data, the association between RBM47 and apolipoprotein C-III concentrations was due to a rare 21 base pair p.Ala496-Ala502 deletion; in replication, the burden of rare deleterious variants in RBM47 was associated with lower triglyceride concentrations in WES of >170,000 individuals from multiple ancestries (p=0.0013). Two PAVs in GTF3C5 were highly enriched in the Finnish population and associated with cardiovascular phenotypes in the general population. In the previously known APOB gene, we identified novel associations at two protein-truncating variants resulting in lower serum non-HDL cholesterol (p=4.8×10−4), apolipoprotein B (p=5.6×10−4), and LDL cholesterol (p=9.5×10−4) concentrations.

Conclusions

We identified lipid and apolipoprotein-associated variants in the previously known LIPC and APOB genes, as well as PAVs in GTF3C5 associated with LDLC, and in RBM47 associated with apolipoprotein C-III concentrations, implicated as an independent CVD risk factor. Identification of rare loss-of-function variants has previously revealed genes that can be targeted to prevent CVD, such as the LDL cholesterol-lowering loss-of-function variants in the PCSK9 gene. Thus, this study suggests novel putative therapeutic targets for the prevention of CVD.
Repeated cardiopulmonary performance measurements in young competitive handball players with and without SARS-CoV-2 infection
Authors: Lässing Johannes , Kwast S. , Bischoff C. , Hölldobler N. , Vondran M. , Falz R. , Busse M.
Published: November 2022

Background

The SARS-CoV-2 virus and its long-term consequences in adolescents have a global impact on upcoming medical issues. The aim of this study was to investigate the effects of a SARS-CoV-2 infection on cardiorespiratory parameters in young athletes.

Methods

In a cohort study involving repeated measurements during a six-month period, cardiorespiratory parameters were assessed in infected (SCoV) and non-infected (noSCoV) athletes. We evaluated handball players (17.2 ± 1.0 years) via performance diagnostics and a specific examination after a SARS-CoV-2 infection or without.

Results

We observed no significant differences between the two groups at the first visit. But between the first and second visit, the SCoV group’s maximum power output was significantly lower than the noSCoV group’s (− 48.3 ± 12.5; p ≤ 0.01 vs. − 15.0 ± 26.0 W; p = 0.09). At the second visit, lung diffusion capacity (DLCO/VA, %predicted) did not differ between groups (111.6 ± 11.5 vs. 116.1 ± 11.8%; p = 0.45). HR during comparative stress showed no group differences. The SCoV group’s mean oxygen uptake during incremental exercise was lower (Two-way-ANOVA: 1912 vs. 2106 ml; p ≤ 0.01; mean difference: − 194 ml; 95% CI − 317 to − 71); we also noted a significantly lower stroke volume course during exercise (Two-way-ANAOVA: 147.5 vs. 169.5 ml; mean difference: − 22 ml; p ≤ 0.01; 95% CI − 34.2 to − 9.9). The probability of premature ventricular complexes after a SARS-CoV-2 infection yielded an odds ratio of 1.6 (95% CI 0.24–10.81).

Conclusions

The physical performance of young athletes infected with SARS-CoV-2 was impaired. This decreased performance is probably due to cardiac and/or peripheral deconditioning. Studies with larger cohorts are needed to make more profound conclusions.
Daytime fluctuations of endurance performance in young soccer players: a randomized cross-over trial
Authors: Fiedler Janis , Altmann Stefan , Chtourou Hamdi , Engel Florian A. , Neumann Rainer , Woll Alexander
Published: November 2022

Objectives

Fluctuations of physical performance and biological responses during a repetitive daily 24-h cycle are known as circadian rhythms. These circadian rhythms can influence the optimal time of day for endurance performance and related parameters which can be crucial in a variety of sports disciplines. The current study aimed to evaluate the daytime variations in endurance running performance in a 3.000-m field run and endurance running performance, blood lactate levels, and heart rate in an incremental treadmill test in adolescent soccer players.

Results

In this study, 15 adolescent male soccer players (age: 18.0 ± 0.6 years) performed a 3.000-m run and an incremental treadmill test at 7:00–8:00 a.m. and 7:00–8:00 p.m. in a randomized cross-over manner. No significant variations after a Bonferroni correction were evident in endurance running performance, perceived exertion, blood lactate levels, and heart rates between the morning and the evening. Here, the largest effect size was observed for maximal blood lactate concentration (9.15 ± 2.18 mmol/l vs. 10.64 ± 2.30 mmol/l,p = .110, ES = 0.67). Therefore, endurance running performance and physiological responses during a field-based 3.000-m run and a laboratory-based test in young male soccer players indicated no evidence for daytime variations.
Subclinical binge eating symptoms in early adolescence and its preceding and concurrent factors: a population-based study
Authors: Derks Ivonne P. M. , Harris Holly A. , Staats Soundry , Gaillard Romy , Dieleman Gwen C. , Llewellyn Clare H. , Swanson Sonja A. , Jansen Pauline W.
Published: November 2022

Objective

Binge eating, loss of control eating and overeating often develop during late childhood or early adolescence. Understanding the presentation of binge eating as early as symptoms manifest and its preceding and concurrent factors is essential to hamper the development of eating disorders. This study examined the prevalence, concurrent and preceding factors (e.g. compensatory behaviors, emotional and behavioral problems) of subclinical binge eating symptoms in early adolescence.

Methods

Data from the population-based Generation R Study were used (n = 3595). At 10 years and 14 years, preceding and concurrent factors including eating behaviors, body dissatisfaction, emotional and behavioral problems and body composition were assessed. At 14 years, 3595 adolescents self-reported on binge eating symptoms in the past 3 months and were categorized into four groups: no symptoms (n = 3143, 87.4%), overeating only (n = 121, 3.4%), loss of control (LOC) eating only (n = 252, 7.0%) or binge eating (i.e. both, n = 79, 2.2%).

Results

In total, 452 (12.6%) young adolescents reported subclinical binge eating symptoms. Those who reported LOC eating and binge eating showed most compensatory behaviors (e.g. hide or throw away food, skipping meals). Concurrent emotional and behavioral problems, body dissatisfaction, more emotional-, restrained- and uncontrolled eating, and a higher BMI were associated with subclinical binge eating symptoms. Preceding self-reported emotional and behavioral problems, body dissatisfaction, more restrained eating and higher BMI (both fat mass and fat-free mass) at 10 years were associated with LOC eating and binge eating, but not with overeating.

Discussion

Among young adolescents, subclinical binge eating symptoms were common. Considering the high prevalence of LOC eating, and the overlapping preceding and concurrent factors of LOC eating and binge eating compared to overeating, LOC eating seems to be a key symptom of binge eating in early adolescence.
blf and the drl cluster synergistically regulate cell fate commitment during zebrafish primitive hematopoiesis
Authors: Zhang Xue , Yang Yuxi , Wei Yuxuan , Zhao Qingshun , Lou Xin
Published: November 2022

Hematopoiesis is a highly coordinated process that generates all the body's blood cells, and perturbations in embryonic hematopoiesis may result in illnesses ranging from fetal anemia to various leukemias. Correct establishment of hematopoietic progenitor cell fate is essential for the development of adequate blood cell subpopulations, although regulators of cell fate commitment have not been fully defined. Here, we show that primary erythropoiesis and myelopoiesis in zebrafish embryos are synergistically regulated by blf and the drl cluster, as simultaneous depletion led to severe erythrocyte aplasia and excessive macrophage formation at the expense of neutrophil development. Integrative analysis of transcriptome- and genome-wide binding data revealed that blf and drl cluster genes are responsible for constraining the expression of vasculogenesis-promoting genes in the intermediate cell mass and monocytopoiesis-promoting genes in the rostral blood island. This indicates that blf and drl cluster genes act as determinants of the fate commitment of erythroid and myeloid progenitor cells. Furthermore, a rescue screen demonstrated that Zfp932 is a potential mammalian functional equivalent to zebrafish blf and drl cluster genes. Our data provide insight into conserved cell fate commitment mechanisms of primitive hematopoiesis.
Resurfacing defects from mycobacterial skin and soft tissue infections using thoracodorsal artery perforator free flaps
Authors: Wang Hyun , Lee Young Man , Kim Youn Hwan
Published: November 2022

Purpose: Skin and soft tissue infections (SSTIs) caused by mycobacteria are rare and difficult to diagnose and treat. Furthermore, systematic treatment protocols for mycobacterial SSTIs have not been established. This study introduces a strategy with radical resection and resurfacing using thoracodorsal artery perforator (TDAP) free flaps.Methods: From December 2013 to February 2022, 13 patients with mycobacterial SSTIs underwent radical resection and reconstruction using TDAP free flaps. Exact mapping of the lesion extent was performed preoperatively with magnetic resonance imaging. When the extent was limited to soft tissue, resection and reconstruction were performed in a single stage. However, in cases with bone or joint involvement, two-stage reconstruction was applied with radical resection and negative-pressure wound therapy followed by resurfacing with a flap. Complex defects formed after resection were filled with a musculocutaneous or chimeric flap. All patients were administered antimycobacterial medications.Results: Mycobacterial infection recurred in one patient; therefore, a total of 14 cases of reconstruction were performed. Reconstruction was performed with a TDAP free flap alone in 10 cases, with a chimeric flap in three cases, and with a musculocutaneous flap in one case. The flaps ranged in size from 7×5 cm2 to 25×12 cm2 (mean, 97.2 cm2). The mycobacterial species identified were Mycobacterium tuberculosis (n=8) and nontuberculous mycobacteria (n=5).Conclusion: For mycobacterial SSTIs, radical resection followed by resurfacing and reconstruction using TDAP free flaps can be an effective surgical treatment strategy.
Compressed Smooth Sparse Decomposition
Authors: Mou Shancong , Shi Jianjun
Published: November 2022

Image-based anomaly detection systems are of vital importance in various manufacturing applications. The resolution and acquisition rate of such systems are increasing significant in recent years under the fast development of image sensing technology. This enables the detection of tiny anomalies in real time. However, such a high resolution and a high acquisition rate of image data not only slow down the speed of image processing algorithms but also, increase data storage and transmission cost. To tackle this problem, we propose a fast and data-efficient method with theoretical performance guarantee that is suitable for sparse anomaly detection in images with a smooth background (smooth plus sparse signal). The proposed method, named compressed smooth sparse decomposition (CSSD), is a one-step method that unifies the compressive image acquisition- and decomposition-based image processing techniques. To further enhance its performance in a high-dimensional scenario, a Kronecker compressed smooth sparse decomposition (KronCSSD) method is proposed. Compared with traditional smooth and sparse decomposition algorithms, significant transmission cost reduction and computational speed boost can be achieved with negligible performance loss. Simulation examples and several case studies in various applications illustrate the effectiveness of the proposed framework.

History: Kwok-Leung Tsui served as the senior editor for this article.

Funding: This work is partially support by the National Science Foundation Division of Engineering Education and Centers [Grant 2052714].

Data Ethics & Reproducibility Note: The code capsule is available on Code Ocean at https://doi.org/10.24433/CO.6352310.v2 and in the e-Companion to this article (available at https://doi.org/10.1287/ijds.2022.0023 ).