bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiac magnetic field map topology quantified by Kullback–Leibler entropy identifies patients with clinically suspected myocarditis
Authors: Pille M. , Gapelyuk A. , Berg K. , Bannasch S. , Mockler J. , Park L.-S. , Park J.-W. , Wessel N.
Published: November 2023

Background

Myocarditis is a condition that can have severe adverse outcomes and lead to sudden cardiac death if remaining undetected. This study tested the capability of cardiac magnetic field mapping to detect patients with clinically suspected myocarditis. This could open up the way for rapid, non-invasive, and cost-effective screening of suspected cases before a gold standard assessment via endomyocardial biopsy.

Methods

Historical cardiac magnetic field maps (n = 97) and data from a state-of-the-art magnetocardiography device (n = 30) were analyzed using the Kullback–Leibler entropy (KLE) for dimensionality reduction and topological quantification. Linear discriminant analysis was used to discern between patients with ongoing myocarditis and healthy controls.

Results

The STT segment of a magnetocardiogram, i.e., the section between the end of the S wave and the end of the T wave, was best suited to discern both groups. Using a 250-ms excerpt from the onset of the STT segment gave a reliable classification between the myocarditis and control group for both historic data (sensitivity: 0.83, specificity: 0.85, accuracy: 0.84) and recent data (sensitivity: 0.69, specificity: 0.88, accuracy: 0.80) using the KLE to quantify the topology of the cardiac magnetic field map.

Conclusion

The implementation based on KLE can reliably distinguish between clinically suspected myocarditis patients and healthy controls. We implemented an automatized feature selection based on LDA to replace the observer-dependent manual thresholding in previous studies.
Simultaneous assessment of mechanical and electrical function in Langendorff-perfused ex-vivo mouse hearts
Authors: Louradour Julien , Ottersberg Rahel , Segiser Adrian , Olejnik Agnieszka , Martínez-Salazar Berenice , Siegrist Mark , Egle Manuel , Barbieri Miriam , Nimani Saranda , Alerni Nicolò , Döring Yvonne , Odening Katja E. , Longnus Sarah
Published: November 2023

Background

The Langendorff-perfused ex-vivo isolated heart model has been extensively used to study cardiac function for many years. However, electrical and mechanical function are often studied separately—despite growing proof of a complex electro-mechanical interaction in cardiac physiology and pathology. Therefore, we developed an isolated mouse heart perfusion system that allows simultaneous recording of electrical and mechanical function.

Methods

Isolated mouse hearts were mounted on a Langendorff setup and electrical function was assessed via a pseudo-ECG and an octapolar catheter inserted in the right atrium and ventricle. Mechanical function was simultaneously assessed via a balloon inserted into the left ventricle coupled with pressure determination. Hearts were then submitted to an ischemia-reperfusion protocol.

Results

At baseline, heart rate, PR and QT intervals, intra-atrial and intra-ventricular conduction times, as well as ventricular effective refractory period, could be measured as parameters of cardiac electrical function. Left ventricular developed pressure (DP), left ventricular work (DP-heart rate product) and maximal velocities of contraction and relaxation were used to assess cardiac mechanical function. Cardiac arrhythmias were observed with episodes of bigeminy during which DP was significantly increased compared to that of sinus rhythm episodes. In addition, the extrasystole-triggered contraction was only 50% of that of sinus rhythm, recapitulating the “pulse deficit” phenomenon observed in bigeminy patients. After ischemia, the mechanical function significantly decreased and slowly recovered during reperfusion while most of the electrical parameters remained unchanged. Finally, the same electro-mechanical interaction during episodes of bigeminy at baseline was observed during reperfusion.

Conclusion

Our modified Langendorff setup allows simultaneous recording of electrical and mechanical function on a beat-to-beat scale and can be used to study electro-mechanical interaction in isolated mouse hearts.
Comparing the clinical and singleton neonatal outcomes in male infertility patients with Oligoasthenospermia, OA, or NOA following fresh ICSI-ET using different sources of sperm
Authors: Xu Jianmin , Yang Qingling , Chen Wenhui , Jiang Yuqing , Shen Zhaoyang , Wang Huan , Sun Yingpu
Published: November 2023

Objective

To investigate clinical and singleton newborn outcomes in fresh cycles of embryo transfer after intracytoplasmic sperm injection (ICSI-ET) with diverse sperm sources (ejaculate, epididymis, and testis) in patients with Oligoasthenospermia, obstructive azoospermia (OA) or non-obstructive azoospermia (NOA).

Methods

Patients who received fresh ICSI-ET for the first time at the First Affiliated Hospital of Zhengzhou University Reproductive Medicine Center between June 2011 and June 2021 were selected for this 10-year retrospective cohort analysis. After propensity score matching, only 1630 cycles were included in the investigation of ICS-ET clinical and singleton newborn outcomes in patients with Oligoasthenospermia, OA, and NOA using sperm from diverse sperm sources.

Result(s)

After propensity score matching, our data revealed a negligible difference in baseline and cycle parameters among groups. In patients with Oligoasthenospermia and OA, different sperm sources do not appear to influence clinical pregnancy rates and live birth rates, nor do they influence newborn outcomes, such as newborn weight, premature birth rate, and neonatal sex ratio in singleton births, except for OA patients who use epididymal sperm having higher low birth weight (LBW) rates in singleton pregnancies than those who use testicular sperm. In addition, clinical pregnancy rates, live birth rates, singleton gestation birth weights, premature birth rates, and neonatal sex ratios were similar between patients with Oligoasthenospermia, OA, and NOA using testicular sperm.

Conclusion(s)

Regardless of the type of male infertility (Oligoasthenospermia, OA, NOA) or sperm sources (ejaculate, epididymis, testis), a successful ICSI-ET procedure can result in similar clinical and neonatal outcomes, such as clinical pregnancy rate, live birth rate, abortion rate, neonatal birth weight and sex ratio of singleton pregnancies.
Impact of diabetes itself and glycemic control status on tuberculosis
Authors: Meng Fanqi , Lan Lijuan , Wu Guihui , Ren Xiaoxia , Yuan Xiaoyan , Yang Ming , Chen Qing , Peng Xiaoli , Liu Dafeng
Published: November 2023

Objectives

To explore the impact of diabetes itself and glycemic control status on tuberculosis (TB).

Methods

A total of 3393 patients with TB and diabetes mellitus (DM) who were hospitalized in the Public Health Clinical Center of Chengdu from January 1, 2019, to December 31, 2021, were retrospectively included and divided into three groups according to baseline glycemic control status: two groups according to glycemic status at discharge, two groups according to cavity occurrence, three groups according to sputum results, and three groups according to lesion location. The influencing factors and the differences in cavity occurrence, sputum positivity and lesion location among different glycemic control groups or between different glycemic status groups were analyzed.

Results

In this TB with DM cohort, most of the subjects were male, with a male to female ratio of 4.54:1, most of them were 45-59 years old, with an average age of 57.44 ± 13.22 years old. Among them, 16.8% (569/3393) had cavities, 52.2% (1770/3393) were sputum positive, 30.4% (1030/3393) had simple intrapulmonary lesions, 68.1% (2311/3393) had both intra and extrapulmonary lesions, only 15.8% (537/3393) had good glycemic control,16.0% (542/3393) and 68.2% (2314/3393) had fair and poor glycemic control, respectively. Compared with the non-cavity group, the sputum-negative group and the extrapulmonary lesion group, the cavity group, sputum-positive group, intrapulmonary lesion group and the intra and extrapulmonary lesion group all had higher fasting plasma glucose (FPG) and glycosylated hemoglobin A 1c (HbA1c) and lower good glycemic control rates at admission (all P<0.001). Another aspect, compared with the good glycemic control group, the poor glycemic control group had a higher cavity occurrence rate, sputum positive rate, and greater proportion of intrapulmonary lesions. Moreover, FPG and HbA1c levels and poor glycemic control were significantly positively correlated with cavity occurrence, sputum positivity, and intrapulmonary lesions and were the main risk factors for TB disease progression. On the other hand, cavity occurrence, sputum positivity, and intrapulmonary lesions were also main risk factors for hyperglycemia and poor glycemic control.

Conclusion

Diabetes itself and glycemic control status could impact TB disease. Good glycemic control throughout the whole process is necessary for patients with TB and DM to reduce cavity occurrence and promote sputum negative conversion and lesion absorption.
Fecal short chain fatty acids modify therapeutic effects of sleeve gastrectomy
Authors: Shen Chongrong , Chen Yanru , Wang Qiaoling , Sun Yingkai , Lin Huibin , Ni Mengshan , Chen Yufei , Zhang Ling , Jin Jiabin , Ying Xiayang , Zou Yuyao , Wang Xiaolin , Ye Yaorui , Yuan Miaomiao , Yin Nan , Cao Zhiwen , Zhang Yifei , Gu Weiqiong , Wang Weiqing , Ning Guang , Wang Jiqiu , Zhao Shaoqian , Hong Jie , Liu Ruixin
Published: November 2023

Aims

We aimed to investigate changes of fecal short chain fatty acids (SCFAs) and their association with metabolic benefits after sleeve gastrectomy (SG). Specifically, whether pre-surgery SCFAs modify surgical therapeutic effects was determined.

Methods

62 participants with measurements of fecal SCFAs and metabolic indices before and 1, 3, 6 months after SG were included. Changes of fecal SCFAs and their association with post-surgery metabolic benefits were calculated. Then, participants were stratified by medians of pre-surgery fecal SCFAs and modification effects of pre-surgery fecal SCFAs on surgical therapeutic effects were investigated, through calculating interaction of group by surgery.

Results

Fecal SCFAs were markedly changed by SG. Changes of propionate and acetate were positively correlated with serum triglycerides and total cholesterol, respectively. Notably, high pre-surgery fecal hexanoate group showed a better effect of SG treatment on lowering body weight (P=0.01), BMI (P=0.041) and serum triglycerides (P=0.031), and low pre-surgery fecal butyrate had a better effect of SG on lowering ALT (P=0.003) and AST (P=0.019).

Conclusion

Fecal SCFAs were changed and correlated with lipid profiles improvement after SG. Pre-surgery fecal hexanoate and butyrate were potential modifiers impacting metabolic benefits of SG.
The causal relationship between sarcopenic obesity factors and benign prostate hyperplasia
Authors: Rao Xuezhi , Xu Zhijie , Zhang Jingchun , Zhou Jiaxiang , Huang Jian , Toh Zhanhao , Zheng Ruwen , Zhou Zhiyu
Published: November 2023

Background

Both benign prostatic hyperplasia (BPH) and sarcopenic obesity (SO) are common conditions among older adult/adults males. The prevalent lifestyle associated with SO is a significant risk factor for the development of BPH. Therefore, we investigated the causal relationship between SO factors and BPH.

Method

The instrumental variables for SO factors were selected using the inverse variance-weighted method, which served as the primary approach for Mendelian randomization analysis to assess the causal effect based on summary data derived from genome-wide association studies of BPH.

Result

The increase in BMR (OR = 1.248; 95% CI = (1.087, 1.432); P = 0.002) and ALM (OR = 1.126; 95% CI = (1.032, 1.228); P = 0.008) was found to be associated with an elevated risk of BPH. However, no genetic causality between fat-free mass distribution, muscle mass distribution, and BPH was observed.

Conclusion

Our findings indicate that a genetic causal association between BMR, ALM and BPH. BMR and ALM are risk factors for BPH. The decrease in BMR and ALM signified the onset and progression of SO, thus SO is a protective factor for BPH.
The role of retinoic acid receptor-related orphan receptors in skeletal diseases
Authors: Zhang Yifan , Ma Jun , Bao Xingfu , Hu Min , Wei Xiaoxi
Published: November 2023

Bone homeostasis, depending on the balance between bone formation and bone resorption, is responsible for maintaining the proper structure and function of the skeletal system. As an important group of transcription factors, retinoic acid receptor-related orphan receptors (RORs) have been reported to play important roles in bone homeostasis by regulating the transcription of target genes in skeletal cells. On the other hand, the dysregulation of RORs often leads to various skeletal diseases such as osteoporosis, rheumatoid arthritis (RA), and osteoarthritis (OA). Herein, we summarized the roles and mechanisms of RORs in skeletal diseases, aiming to provide evidence for potential therapeutic strategies.
Flow visualization by means of 3D thermography on yawing wind turbines
Authors: Fischer Andreas , Parrey Ann-Marie , Balaresque Nicholas , von Freyberg Axel
Published: November 2023

Thermographic flow visualization is an established tool for analyzing the actual flow behavior of real wind turbines in operation. While the laminar-turbulent flow transition as well as the beginning of flow separation can be localized in the thermographic image of a rotor blade, the corresponding positions on the 3d rotor blade surface are not yet known. To compensate the disturbing cross-influence of the wind turbine motion such as the yawing on the projected chord position of an identified flow feature, a geometric mapping algorithm of the 2d thermographic image on the 3d rotor blade is presented. With no geometric mapping, a significant error can occur depending on the camera location and orientation with respect to the location and orientation of the wind turbine. For the considered example, the maximal chord position error occurs for flow features at a relative chord location between 30% and 40%. If the yaw angle changes between ±30° and no correction is applied, the position error amounts up to ±17% of the chord length when the blade is observed above the nacelle. This example illustrates the necessity for an error correction. After its verification, the geometric mapping approach is applied on a thermographic image series from a field measurement campaign on a yawing wind turbine. For this purpose, the yaw angle is additionally measured with a laser scanner. In comparison with no geometric mapping, the corrected flow visualization of the laminar-turbulent transition during yawing reveals the actual mean chord location that is 20% of the chord length larger, a shift of the chord location that is almost one order of magnitude larger, and a chordwise location increase instead of a decrease. As a result, the geometry mapping is therefore considered applicable to advance thermographic flow visualization for the analysis of flow dynamics on yawing and pitching wind turbines, and in future even during one rotor revolution.
Scheduling of the HVAC system in a real commercial building considering equipment cycling and rebound effects
Authors: Faddel Samy , Sun Qun Zhou , Tian Guanyu , Parlato Alex
Published: November 2023

Commercial buildings consume a large portion of energy and the heating, ventilation, and air conditioning (HVAC) system is the major contributor to this high consumption. Though there are many reported works on the optimal scheduling of HVAC systems, practical considerations such as equipment cycling and possible rebound effects are rarely considered. This paper provides insights into the optimal scheduling of the HVAC system in an actual 3-floor commercial building where the cycling and rebound effects are addressed in the optimization. The experimental results prove that energy cost reduction can be achieved while ensuring temperature comfort and longer life expectancy of the HVAC. The results also show that considering the cycling and rebounds will affect the potential cost reduction.
Forecasting urban carbon emissions using an Adaboost-STIRPAT model
Authors: Kong Depeng , Dai Zheng , Tang Jiayue , Zhang Hong
Published: November 2023

Solving outstanding environmental issues, reducing carbon emissions, and promoting green development are necessary ways to achieve carbon neutrality and carbon peak goals. It is also an important issue faced by society today. This paper uses the Kaya identity combined with the logarithmic mean Divisia index (LMDI) decomposition method to analyze the factors affecting carbon emissions, and uses the Pearson correlation coefficient to screen out eight highly correlated features to construct an extended STIRPAT model. In order to further improve the accuracy of the model in predicting carbon emissions, this paper introduces the Adaboost algorithm from machine learning to enhance the STIRPAT model. Finally, scenario analysis is used to predict and analyze carbon emissions in Shandong Province from 2020 to 2050. The results show that: 1) The main factors affecting urban carbon emissions from 1998 to 2019 are economic growth effects, followed by energy structure effects and energy consumption effects. 2) Under three different development scenarios, Shandong Province can achieve carbon peak between 2030–2035, but there are differences in peaking time and peak values.
Avoided wildfire impact modeling with counterfactual probabilistic analysis
Authors: Thompson Matthew P. , Carriger John F.
Published: November 2023

Assessing the effectiveness and measuring the performance of fuel treatments and other wildfire risk mitigation efforts are challenging endeavors. Perhaps the most complicated is quantifying avoided impacts. In this study, we show how probabilistic counterfactual analysis can help with performance evaluation. We borrow insights from the disaster risk mitigation and climate event attribution literature to illustrate a counterfactual framework and provide examples using ensemble wildfire simulations. Specifically, we reanalyze previously published fire simulation data from fire-prone landscapes in New Mexico, USA, and show applications for post-event analysis as well as pre-event evaluation of fuel treatment scenarios. This approach found that treated landscapes likely would have reduced fire risk compared to the untreated scenarios. To conclude, we offer ideas for future expansions in theory and methods.
Identification and validation of N6-methyladenosine (m6A)-related lncRNAs signature for predicting the prognosis of laryngeal carcinoma, especially for smoking patients
Authors: Chen Yuqing , Chen Chenyu , Gao Gufeng , Zeng Chaojun , Chen Zhifeng , Lin Gongbiao , Yao Guangnan , Nian Shenqing , Chen Xihang , Weng Simin , Gu Xi , Lin Chang
Published: November 2023

Laryngeal cancer (LC), a highly fatal tumor in the head and neck region, has been the focus of research in recent years. The study of LC has primarily focused on the role of long non-coding RNAs (lncRNAs) in regulating gene expression, as they have emerged as pivotal factors in this biological process. Additionally, a reversible RNA modification called N6-methyladenosine (m6A) has been observed to have a significant impact on gene expression as well. The purpose of this research is to investigate the impact of m6A-related lncRNAs on the prognosis of laryngeal squamous cell carcinoma (LSCC). Specifically, this investigation analyzed the m6A-related regulators’ patterns of expression and mutation, encompassing a total of 15 regulators. Drawing upon the expression levels of prognostic m6A-regulated lncRNAs, two distinct lncRNA clusters were identified. Further analysis revealed differentially expressed lncRNAs between these clusters. In addition to studying the expression of lncRNAs, the researchers also examined the distribution of clinical characteristics and the tumor microenvironment (TME) in relation to the identified lncRNA clusters. This provided valuable insights into potential associations between lncRNA expression patterns and the clinical features of LSCC. Through the establishment of a risk model associated with lncRNAs, we were able to further investigate their clinical features, prognosis, and immune status. Additionally, we conducted a separate analysis of LINC00528, a lncRNA associated with smoking, examining its expression, overall survival time, correlated mRNAs, and conducting enrichment of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), as well as determining the sensitivity of related drugs. RT-qPCR results also indicated an increase in LINC00528 expression among smoking LSCC patients. The findings suggest that a high expression level of LINC00528 in LSCC patients may lead to a more favorable prognosis, providing new insights for the management and treatment of LSCC patients, particularly those with high expression of LINC00528. Overall, this research sheds light on the prognostic impact of m6A-regulated lncRNAs in LSCC. The implications of these findings for the advancement of innovative therapeutic approaches for LSCC patients are noteworthy.
Does human homology reduce the potential immunogenicity of non-antibody scaffolds?
Authors: De Groot Anne S. , Khan Sundos , Mattei Aimee E. , Lelias Sandra , Martin William D.
Published: November 2023

Biologics developers are moving beyond antibodies for delivery of a wide range of therapeutic interventions. These non-antibody modalities are often based on ‘natural’ protein scaffolds that are modified to deliver bioactive sequences. Both human-derived and non-human-sourced scaffold proteins have been developed. New types of “non-antibody” scaffolds are still being discovered, as they offer attractive alternatives to monoclonals due to their smaller size, improved stability, and ease of synthesis. They are believed to have low immunogenic potential. However, while several human-sourced protein scaffolds have not been immunogenic in clinical studies, this may not predict their overall performance in other therapeutic applications. A preliminary evaluation of their potential for immunogenicity is warranted. Immunogenicity risk potential has been clearly linked to the presence of T “helper” epitopes in the sequence of biologic therapeutics. In addition, tolerogenic epitopes are present in some human proteins and may decrease their immunogenic potential. While the detailed sequences of many non-antibody scaffold therapeutic candidates remain unpublished, their backbone sequences are available for review and analysis. We assessed 12 example non-antibody scaffold backbone sequences using our epitope-mapping tools (EpiMatrix) for this perspective. Based on EpiMatrix scoring, their HLA DRB1-restricted T cell epitope content appears to be lower than the average protein, and sequences that may act as tolerogenic epitopes are present in selected human-derived scaffolds. Assessing the potential immunogenicity of scaffold proteins regarding self and non-self T cell epitopes may be of use for drug developers and clinicians, as these exciting new non-antibody molecules begin to emerge from the preclinical pipeline into clinical use.
Zinc deficiency impairs axonal regeneration and functional recovery after spinal cord injury by modulating macrophage polarization via NF-κB pathway
Authors: Kijima Ken , Ono Gentaro , Kobayakawa Kazu , Saiwai Hirokazu , Hara Masamitsu , Yoshizaki Shingo , Yokota Kazuya , Saito Takeyuki , Tamaru Tetsuya , Iura Hirotaka , Haruta Yohei , Kitade Kazuki , Utsunomiya Takeshi , Konno Daijiro , Edgerton V. Reggie , Liu Charles Y. , Sakai Hiroaki , Maeda Takeshi , Kawaguchi Kenichi , Matsumoto Yoshihiro , Okada Seiji , Nakashima Yasuharu
Published: November 2023

Background

Spinal cord injury (SCI) is a devastating disease that results in permanent paralysis. Currently, there is no effective treatment for SCI, and it is important to identify factors that can provide therapeutic intervention during the course of the disease. Zinc, an essential trace element, has attracted attention as a regulator of inflammatory responses. In this study, we investigated the effect of zinc status on the SCI pathology and whether or not zinc could be a potential therapeutic target.

Methods

We created experimental mouse models with three different serum zinc concentration by changing the zinc content of the diet. After inducing contusion injury to the spinal cord of three mouse models, we assessed inflammation, apoptosis, demyelination, axonal regeneration, and the number of nuclear translocations of NF-κB in macrophages by using qPCR and immunostaining. In addition, macrophages in the injured spinal cord of these mouse models were isolated by flow cytometry, and their intracellular zinc concentration level and gene expression were examined. Functional recovery was assessed using the open field motor score, a foot print analysis, and a grid walk test. Statistical analysis was performed using Wilcoxon rank-sum test and ANOVA with the Tukey-Kramer test.

Results

In macrophages after SCI, zinc deficiency promoted nuclear translocation of NF-κB, polarization to pro-inflammatory like phenotype and expression of pro-inflammatory cytokines. The inflammatory response exacerbated by zinc deficiency led to worsening motor function by inducing more apoptosis of oligodendrocytes and demyelination and inhibiting axonal regeneration in the lesion site compared to the normal zinc condition. Furthermore, zinc supplementation after SCI attenuated these zinc-deficiency-induced series of responses and improved motor function.

Conclusion

We demonstrated that zinc affected axonal regeneration and motor functional recovery after SCI by negatively regulating NF-κB activity and the subsequent inflammatory response in macrophages. Our findings suggest that zinc supplementation after SCI may be a novel therapeutic strategy for SCI.
Development and characterization of narsoplimab, a selective MASP-2 inhibitor, for the treatment of lectin-pathway–mediated disorders
Authors: Dudler Thomas , Yaseen Sadam , Cummings W. Jason
Published: November 2023

Introduction

Overactivation of the lectin pathway of complement plays a pathogenic role in a broad range of immune-mediated and inflammatory disorders; mannan-binding lectin-associated serine protease-2 (MASP-2) is the key effector enzyme of the lectin pathway. We developed a fully human monoclonal antibody, narsoplimab, to bind to MASP-2 and specifically inhibit lectin pathway activation. Herein, we describe the preclinical characterization of narsoplimab that supports its evaluation in clinical trials.

Methods and results

ELISA binding studies demonstrated that narsoplimab interacted with both zymogen and enzymatically active forms of human MASP-2 with high affinity (KD 0.062 and 0.089 nM, respectively) and a selectivity ratio of >5,000-fold relative to closely related serine proteases C1r, C1s, MASP-1, and MASP-3. Interaction studies using surface plasmon resonance and ELISA demonstrated approximately 100-fold greater binding affinity for intact narsoplimab compared to a monovalent antigen binding fragment, suggesting an important contribution of functional bivalency to high-affinity binding. In functional assays conducted in dilute serum under pathway-specific assay conditions, narsoplimab selectively inhibited lectin pathway-dependent activation of C5b-9 with high potency (IC50 ~ 1 nM) but had no observable effect on classical pathway or alternative pathway activity at concentrations up to 500 nM. In functional assays conducted in 90% serum, narsoplimab inhibited lectin pathway activation in human serum with high potency (IC50 ~ 3.4 nM) whereas its potency in cynomolgus monkey serum was approximately 10-fold lower (IC50 ~ 33 nM). Following single dose intravenous administration to cynomolgus monkeys, narsoplimab exposure increased in an approximately dose-proportional manner. Clear dose-dependent pharmacodynamic responses were observed at doses >1.5 mg/kg, as evidenced by a reduction in lectin pathway activity assessed ex vivo that increased in magnitude and duration with increasing dose. Analysis of pharmacokinetic and pharmacodynamic data revealed a well-defined concentration-effect relationship with an ex vivo EC50 value of approximately 6.1 μg/mL, which was comparable to the in vitro functional potency (IC50 33 nM; ~ 5 μg/mL).

Discussion

Based on these results, narsoplimab has been evaluated in clinical trials for the treatment of conditions associated with inappropriate lectin pathway activation, such as hematopoietic stem cell transplantation-associated thrombotic microangiopathy.
Factors determining antenatal care utilization among mothers of deceased perinates in Ethiopia
Authors: Tesfay Neamin , Kebede Mandefro , Asamene Negga , Tadesse Muse , Begna Dumesa , Woldeyohannes Fitsum
Published: November 2023

Introduction

Receiving adequate antenatal care (ANC) had an integral role in improving maternal and child health outcomes. However, several factors influence the utilization of ANC from the individual level up to the community level factors. Thus, this study aims to investigate factors that determine ANC service utilization among mothers of deceased perinate using the proper count regression model.

Method

Secondary data analysis was performed on perinatal death surveillance data. A total of 3,814 mothers of deceased perinates were included in this study. Hurdle Poisson regression with a random intercept at both count-and zero-part (MHPR.ERE) model was selected as a best-fitted model. The result of the model was presented in two ways, the first part of the count segment of the model was presented using the incidence rate ratio (IRR), while the zero parts of the model utilized the adjusted odds ratio (AOR).

Result

This study revealed that 33.0% of mothers of deceased perinates had four ANC visits. Being in advanced maternal age [IRR = 1.03; 95CI: (1.01–1.09)], attending primary level education [IRR = 1.08; 95 CI: (1.02–1.15)], having an advanced education (secondary and above) [IRR = 1.14; 95 CI: (1.07–1.21)] and being resident of a city administration [IRR = 1.17; 95 CI: (1.05–1.31)] were associated with a significantly higher frequency of ANC visits. On the other hand, women with secondary and above education [AOR = 0.37; 95CI: (0.26–0.53)] and women who live in urban areas [AOR = 0.42; 95 CI: (0.33–0.54)] were less likely to have unbooked ANC visit, while women who resided in pastoralist regions [AOR = 2.63; 95 CI: (1.02–6.81)] were more likely to have no ANC visit.

Conclusion

The uptake of ANC service among mothers having a deceased perinate was determined by both individual (maternal age and educational status) and community (residence and type of region) level factors. Thus, a concerted effort is needed to improve community awareness through various means of communication by targeting younger women. Furthermore, efforts should be intensified to narrow down inequalities observed in ANC service provision due to the residence of the mothers by availing necessary personnel and improving the accessibility of service in rural areas.
Vertical variation of bacterial production and potential role in oxygen loss in the southern Bay of Bengal
Authors: Ye Wenqi , Ma Xiao , Liu Chenggang , Ye Ruijie , Priyadarshani W. N. C. , Jayathilake Ruchi , Weerakoon Ashoka , Wimalasiri Udeshika , Dissanayake P. A. K. N. , Pathirana Gayan , Iroshanie R. G. A. , Zhu Yuanli , Li Zhongqiao , Wang Bin , Shou Lu , Ran Lihua , Zhou Feng , Chen Jianfang , Du Ping
Published: November 2023

Marine environments wherein long-term microbial oxygen consumption exceeds oxygen replenishment can be associated with oxygen minimum zones (OMZ). The Bay of Bengal OMZ (BOB-OMZ) is one of the most intense OMZs globally. To assess the contribution of bacterial oxygen consumption to oxygen loss in BOB-OMZ, we measured bacterial production (BP), temperature, salinity, and dissolved oxygen (DO) in the whole water column. We then compared the estimated bacterial oxygen demand (BOD) with diapycnal oxygen supply (DOS) at depths of 50–200 m in the southern BOB in January 2020. The average BP was 3.53 ± 3.15 μmol C m−3 h−1 in the upper 200 m of four stations, which was lower than those reported in other tropical waters. The vertical distribution of BP differed between the open ocean and nearshore areas. In the open ocean, temperature and DO were the most important predictors for BP in the whole water column. In the nearshore areas, when DO increased sharply from the suboxic state, extremely high BP occurred at 200 m. The average estimated BOD/DOS could reach up to 153% at depths of 50–200 m, indicating advection and anticyclonic eddies probably are important DO replenishment pathways in the BOB.
Phylogenetic classification of natural product biosynthetic gene clusters based on regulatory mechanisms
Authors: Rodriguez-Sanchez Alberto C. , Gónzalez-Salazar Luz A. , Rodriguez-Orduña Lorena , Cumsille Ándres , Undabarrena Agustina , Camara Beatriz , Sélem-Mojica Nelly , Licona-Cassani Cuauhtemoc
Published: November 2023

The natural products (NPs) biosynthetic gene clusters (BGCs) represent the adapting biochemical toolkit for microorganisms to thrive different microenvironments. Despite their high diversity, particularly at the genomic level, detecting them in a shake-flask is challenging and remains the primary obstacle limiting our access to valuable chemicals. Studying the molecular mechanisms that regulate BGC expression is crucial to design of artificial conditions that derive on their expression. Here, we propose a phylogenetic analysis of regulatory elements linked to biosynthesis gene clusters, to classify BGCs to regulatory mechanisms based on protein domain information. We utilized Hidden Markov Models from the Pfam database to retrieve regulatory elements, such as histidine kinases and transcription factors, from BGCs in the MIBiG database, focusing on actinobacterial strains from three distinct environments: oligotrophic basins, rainforests, and marine environments. Despite the environmental variations, our isolated microorganisms share similar regulatory mechanisms, suggesting the potential to activate new BGCs using activators known to affect previously characterized BGCs.
Identification of five novel SCN1A variants
Authors: Zeng Baitao , Zhang Haoyi , Lu Qing , Fu Qingzi , Yan Yang , Lu Wan , Ma Pengpeng , Feng Chuanxin , Qin Jiawei , Luo Laipeng , Yang Bicheng , Zou Yongyi , Liu Yanqiu
Published: November 2023

Background

Epilepsy is characterized by recurrent unprovoked seizures. Mutations in the voltage-gated sodium channel alpha subunit 1 (SCN1A) gene are the main monogenic cause of epilepsy. Type and location of variants make a huge difference in the severity of SCN1A disorder, ranging from the mild phenotype (genetic epilepsy with febrile seizures plus, GEFS+) to the severe phenotype (developmental and epileptic encephalopathies, DEEs). Dravet Syndrome (DS) is an infantile-onset DEE, characterized by drug-resistant epilepsy and temperature sensitivity or febrile seizures. Genetic test results reveal SCN1A variants are positive in 80% DS patients and DS is mainly caused by de novo variants.

Methods

Trio-whole exome sequencing (WES) was used to detect variants which were associated with clinical phenotype of five probands with epilepsy or twitching. Then, Sanger sequencing was performed to validate the five novel SCN1A variants and segregation analysis. After analyzing the location of five SCN1A variants, the pathogenic potential was assessed.

Results

In this study, we identified five novel SCN1A variants (c.4224G > C, c.3744_3752del, c.209del, c.5727_5734delTTTAAAACinsCTTAAAAAG and c.5776delT) as the causative variants. In the five novel SCN1A variants, four were de novo and the remaining one was inherited. All novel variants would be classified as “pathogenic” or “likely pathogenic.”

Conclusion

The five novel SCN1A variants will enrich the SCN1A mutations database and provide the corresponding reference data for the further genetic counseling.
Altered motor learning and coordination in mouse models of autism spectrum disorder
Authors: Cording Katherine R. , Bateup Helen S.
Published: November 2023

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with increasing prevalence. Over 1,000 risk genes have now been implicated in ASD, suggesting diverse etiology. However, the diagnostic criteria for the disorder still comprise two major behavioral domains - deficits in social communication and interaction, and the presence of restricted and repetitive patterns of behavior (RRBs). The RRBs associated with ASD include both stereotyped repetitive movements and other motor manifestations including changes in gait, balance, coordination, and motor skill learning. In recent years, the striatum, the primary input center of the basal ganglia, has been implicated in these ASD-associated motor behaviors, due to the striatum’s role in action selection, motor learning, and habit formation. Numerous mouse models with mutations in ASD risk genes have been developed and shown to have alterations in ASD-relevant behaviors. One commonly used assay, the accelerating rotarod, allows for assessment of both basic motor coordination and motor skill learning. In this corticostriatal-dependent task, mice walk on a rotating rod that gradually increases in speed. In the extended version of this task, mice engage striatal-dependent learning mechanisms to optimize their motor routine and stay on the rod for longer periods. This review summarizes the findings of studies examining rotarod performance across a range of ASD mouse models, and the resulting implications for the involvement of striatal circuits in ASD-related motor behaviors. While performance in this task is not uniform across mouse models, there is a cohort of models that show increased rotarod performance. A growing number of studies suggest that this increased propensity to learn a fixed motor routine may reflect a common enhancement of corticostriatal drive across a subset of mice with mutations in ASD-risk genes.
Central vein stenosis in hemodialysis vascular access: clinical manifestations and contemporary management strategies
Authors: Echefu Gift , Stowe Ifeoluwa , Lukan Abdulkareem , Sharma Gaurav , Basu-Ray Indranill , Guidry London , Schellack Jon , Kumbala Damodar
Published: November 2023

Central venous stenosis is a significant and frequently encountered problem in managing hemodialysis (HD) patients. Venous hypertension, often accompanied by severe symptoms, undermines the integrity of the hemodialysis access circuit. In central venous stenosis, dialysis through an arteriovenous fistula is usually inefficient, with high recirculation rates and prolonged bleeding after dialysis. Central vein stenosis is a known complication of indwelling intravascular and cardiac devices, such as peripherally inserted central catheters, long-term cuffed hemodialysis catheters, and pacemaker wires. Hence, preventing this challenging condition requires minimization of central venous catheter use. Endovascular interventions are the primary approach for treating central vein stenosis. Percutaneous angioplasty and stent placement may reestablish vascular function in cases of elastic and recurrent lesions. Currently, there is no consensus on the optimal treatment, as existing management approaches have a wide range of patency rates.
Immune monitoring of allograft status in kidney transplant recipients
Authors: Han Hwarang S. , Lubetzky Michelle L.
Published: November 2023

Kidney transplant patients require careful management of immunosuppression to avoid rejection while minimizing the risk of infection and malignancy for the best long-term outcome. The gold standard for monitoring allograft status and immunosuppression adequacy is a kidney biopsy, but this is invasive and costly. Conventional methods of allograft monitoring, such as serum creatinine level, are non-specific. Although they alert physicians to the need to evaluate graft dysfunction, by the time there is a clinical abnormality, allograft damage may have already occurred. The development of novel and non-invasive methods of evaluating allograft status are important to improving graft outcomes. This review summarizes the available conventional and novel methods for monitoring allograft status after kidney transplant. Novel and less invasive methods include gene expression, cell-free DNA, urinary biomarkers, and the use of artificial intelligence. The optimal method to manage patients after kidney transplant is still being investigated. The development of less invasive methods to assess allograft function has the potential to improve patient outcomes and allow for a more personalized approach to immunosuppression management.
Mechanical thrombectomy for symptomatic stent thrombosis after carotid artery stenting
Authors: Fan You-Min , Liu Han-Yang , Xue Yu-Yang
Published: November 2023

Background

As there is still no consensus on the treatment of carotid stent thrombosis (CST), we would like to describe our experience with the revascularization of CST by mechanical thrombectomy.

Methods

We retrospectively studied patients who underwent mechanical thrombectomy after CST at Xuzhou Municipal First People’s Hospital and Xuzhou Central Hospital between January 2020 and November 2022. The results of the procedures, complications, and clinical and imaging follow-up were recorded.

Results

A total of six patients were included in this study. The stenosis grade before stent implantation was ≥85% in all patients, and the stenosis length ranged from 7 to 20 mm. Patients experienced CST within 6 days to 45 months after carotid artery stenting (CAS); the median admission on the National Institutes of Health Stroke Scale (NIHSS) at CST was 12 (range 8–25). Mechanical thrombectomy was successfully performed in all patients. There was no periprocedural death, and the modified Rankin Scale (mRS) at the 3-month follow-up was 0–2. All patients showed recovery from their neurological deficits.

Conclusion

The treatment of symptomatic CST with mechanical thrombectomy resulted in satisfactory clinical outcomes. This regimen could be effective and safe, and future prospective and randomized studies are warranted.
Lowered oxidative capacity in spinal muscular atrophy, Jokela type; comparison with mitochondrial muscle disease
Authors: Ratia Nadja , Palu Edouard , Lantto Hanna , Ylikallio Emil , Luukkonen Ritva , Suomalainen Anu , Auranen Mari , Piirilä Päivi
Published: November 2023

Introduction

Spinal muscular atrophy, Jokela type (SMAJ) is a rare autosomal dominantly hereditary form of spinal muscular atrophy caused by a point mutation c.197G>T in CHCHD10. CHCHD10 is known to be involved in the regulation of mitochondrial function even though patients with SMAJ do not present with multiorgan symptoms of mitochondrial disease. We aimed to characterize the cardiopulmonary oxidative capacity of subjects with SMAJ compared to healthy controls and patients with mitochondrial myopathy.

Methods

Eleven patients with genetically verified SMAJ, 26 subjects with mitochondrial myopathy (MM), and 28 healthy volunteers underwent a cardiopulmonary exercise test with lactate and ammonia sampling. The effect of the diagnosis group on the test results was analysed using a linear model.

Results

Adjusted for sex, age, and BMI, the SMAJ group had lower power output (p < 0.001), maximal oxygen consumption (VO2 max) (p < 0.001), and mechanical efficiency (p < 0.001) compared to the healthy controls but like that in MM. In the SMAJ group and healthy controls, plasma lactate was lower than in MM measured at rest, light exercise, and 30 min after exercise (p ≤ 0.001–0.030) and otherwise lactate in SMAJ was lower than controls and MM, in longitudinal analysis p = 0.018. In MM, the ventilatory equivalent for oxygen was higher (p = 0.040), and the fraction of end-tidal CO2 lower in maximal exercise compared to healthy controls (p = 0.023) and subjects with SMAJ.

Conclusion

In cardiopulmonary exercise test, subjects with SMAJ showed a similar decrease in power output and oxidative capacity as subjects with mitochondrial myopathy but did not exhibit findings typical of mitochondrial disease.
Tumor cell cytoplasmic metallothionein expression associates with differential tumor immunogenicity and prognostic outcome in high-grade serous ovarian carcinoma
Authors: Mairinger Elena , Wessolly Michael , Buderath Paul , Borchert Sabrina , Henrich Larissa , Mach Pawel , Steinborn Julia , Kimming Rainer , Jasani Bharat , Schmid Kurt Werner , Bankfalvi Agnes , Mairinger Fabian Dominik
Published: November 2023

Background

The underlying mechanism of high T-cell presence as a favorable prognostic factor in high-grade serous ovarian carcinoma (HGSOC) is not yet understood. In addition to immune cells, various cofactors are essential for immune processes. One of those are metallothioneins (MTs), metal-binding proteins comprising various isoforms. MTs play a role in tumor development and drug resistance. Moreover, MTs influence inflammatory processes by regulating zinc homeostasis. In particular, T-cell function and polarization are particularly susceptible to changes in zinc status. The aim of the present study was to investigate a possible role of MT-mediated immune response and its association with prognostic outcome in ovarian cancer.

Methods

A retrospective study was conducted on a clinically well-characterized cohort of 24 patients with HGSOC treated at the University Hospital of Essen. Gene expression patterns for anti-cancer immunogenicity-related targets were performed using the NanoString nCounter platform for digital gene expression analysis with the appurtenant PanCancer Immune Profiling panel, consisting of 770 targets and 30 reference genes. Tumor-associated immunohistochemical MT protein expression was evaluated using a semi-quantitative four-tier Immunohistochemistry (IHC) scoring.

Results

MT immunoexpression was detected in 43% (10/23) of all HGSOC samples. MT immunoexpression levels showed a significant association to survival, leading to prolonged progression-free and overall survival in positively stained tumors. Furthermore, T-cell receptor signaling gene signature showed a strong activation in MT-positive tumors. Activated downstream signaling cascades resulting in elevated interferon-gamma expression with a shift in the balance between T helper cells (TH1 and TH2) could be observed in the MT-positive subgroup. In addition, a higher expression pattern of perforin and several granzymes could be detected, overall suggestive of acute, targeted anti-cancer immune response in MT-positive samples.

Conclusion

This is the first study combining broad, digital mRNA screening of anti-tumor immune response–associated genes and their relation to MT-I/II in ovarian cancer. MT overexpression is associated with molecular characteristics of an anti-cancer immune response and is a strong prognostic marker in ovarian HGSOC. The observed immune cell activation associated with tumor MT expression comprises but is not limited to T cells and natural killer cells.