bluuebunny/crossref_metadata_2025 huggingface dataset:
Governance of Interorganizational Projects: A Process-Based Approach Applied to a Latin American–European Case
Authors: Fernandes Elieti Biques , Wegner Douglas , Möllering Guido
Published: March 2023

This article proposes a theoretical–conceptual model that describes how the governance of collaborative interorganizational projects (IOPs) develops over time. The model is based on empirical insights from a process-based study, which reveals that IOP governance relies on key partners as holders of a project’s capacity for specialization, centralization, coordination, and control over time. The results also show that trust and interpersonal relationships are essential elements for effective governance and the generation of relational rents. Moreover, relational factors help compensate for the destabilization of the governance configuration in case of unexpected events. These insights contribute to a theory of successful IOP management as a matter of dynamic governance.
Circulating SARS-CoV-2+ megakaryocytes are associated with severe viral infection in COVID-19
Authors: Fortmann Seth D. , Patton Michael J. , Frey Blake F. , Tipper Jennifer L. , Reddy Sivani B. , Vieira Cristiano P. , Hanumanthu Vidya Sagar , Sterrett Sarah , Floyd Jason L. , Prasad Ram , Zucker Jeremy D. , Crouse Andrew B. , Huls Forest , Chkheidze Rati , Li Peng , Erdmann Nathaniel B. , Harrod Kevin S. , Gaggar Amit , Goepfert Paul A. , Grant Maria B. , Might Matthew
Published: March 2023

Several independent lines of evidence suggest that megakaryocytes are dysfunctional in severe COVID-19. Herein, we characterized peripheral circulating megakaryocytes in a large cohort of inpatients with COVID-19 and correlated the subpopulation frequencies with clinical outcomes. Using peripheral blood, we show that megakaryocytes are increased in the systemic circulation in COVID-19, and we identify and validate S100A8/A9 as a defining marker of megakaryocyte dysfunction. We further reveal a subpopulation of S100A8/A9+ megakaryocytes that contain severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protein and RNA. Using flow cytometry of peripheral blood and in vitro studies on SARS-CoV-2–infected primary human megakaryocytes, we demonstrate that megakaryocytes can transfer viral antigens to emerging platelets. Mechanistically, we show that SARS-CoV-2–containing megakaryocytes are nuclear factor κB (NF-κB)-activated, via p65 and p52; express the NF-κB–mediated cytokines interleukin-6 (IL-6) and IL-1β; and display high surface expression of Toll-like receptor 2 (TLR2) and TLR4, canonical drivers of NF-κB. In a cohort of 218 inpatients with COVID-19, we correlate frequencies of megakaryocyte subpopulations with clinical outcomes and show that SARS-CoV-2–containing megakaryocytes are a strong risk factor for mortality and multiorgan injury, including respiratory failure, mechanical ventilation, acute kidney injury, thrombotic events, and intensive care unit admission. Furthermore, we show that SARS-CoV-2+ megakaryocytes are present in lung and brain autopsy tissues from deceased donors who had COVID-19. To our knowledge, this study offers the first evidence implicating SARS-CoV-2+ peripheral megakaryocytes in severe disease and suggests that circulating megakaryocytes warrant investigation in inflammatory disorders beyond COVID-19.
Melanocortin/MC5R axis regulates the proliferation of hematopoietic stem cells in mice after ionizing radiation injury
Authors: Chen Naicheng , Quan Yong , Chen Mo , Lu Yukai , Yang Lijing , Wang Song , Chen Fang , Xu Yang , Shen Mingqiang , Zeng Hao , Chen Shilei , Wang Fengchao , Wang Junping , Hu Mengjia
Published: March 2023

Hematopoietic stem cells (HSCs) possess great self-renewal and multidirectional differentiation abilities, which contribute to the continuous generation of various blood cells. Although many intrinsic and extrinsic factors have been found to maintain HSC homeostasis, the precise regulation of hematopoiesis under stress conditions is poorly understood. In this study, we show that melanocortin receptor 5 (MC5R) is abundantly expressed in hematopoietic stem progenitor cells (HSPCs). Using an MC5R knockout mouse model, we observed that it is not essential for steady-state hematopoiesis. Interestingly, the levels of α-melanocyte stimulating hormone (α-MSH), an important subtype of melanocortin, were elevated in the serum and bone marrow, and the expression of MC5R was upregulated in HSPCs from mice after irradiation. MC5R deficiency aggravates irradiation-induced myelosuppression because of impaired proliferation and reconstitution of HSCs. Further investigation revealed that the melanocortin/MC5R axis regulates the proliferation of HSCs by activating the PI3K/AKT and MAPK pathways. More importantly, α-MSH treatment can significantly accelerate hematopoietic recovery in irradiated mice. In conclusion, our data demonstrate that the melanocortin/MC5R axis plays a crucial role in regulating HSC proliferation under stress, thus providing a promising strategy to promote hematopoietic regeneration when suffering from injury.
MicroRNA-Transcription factor regulatory networks in the early strobilar development of Echinococcus granulosus protoscoleces
Authors: Mohammadi Mohammad Ali , Mansouri Mehdi , Derakhshani Ali , Rezaie Masoud , Borhani Mehdi , Nasibi Saeid , Mousavi Seyed Mohammad , Afgar Ali , Macchiaroli Natalia , Rosenzvit Mara C. , Harandi Majid Fasihi
Published: March 2023

Background

Echinococcus granulosus sensu lato has a complex developmental biology with a variety of factors relating to both intermediate and final hosts. To achieve maximum parasite adaptability, the development of the cestode is dependent on essential changes in transcript regulation. Transcription factors (TFs) and miRNAs are known as master regulators that affect the expression of downstream genes through a wide range of metabolic and signaling pathways. In this study, we aimed to develop a regulatory miRNA-Transcription factor (miRNA-TF) network across early developmental stages of E. granulosus protoscoleces by performing in silico analysis, and to experimentally validate TFs expression in protoscoleces obtained from in vitro culture, and from in vivo experiments.

Results

We obtained list of 394 unique E. granulosus TFs and matched them with 818 differentially expressed genes which identified 41 predicted TFs with differential expression. These TFs were used to predict the potential targets of 31 differentially expressed miRNAs. As a result, eight miRNAs and eight TFs were found, and the predicted network was constructed using Cytoscape. At least four miRNAs (egr-miR-124a, egr-miR-124b-3p, egr-miR-745-3p, and egr-miR-87-3p) and their corresponding differentially expressed TFs (Zinc finger protein 45, Early growth response protein 3, Ecdysone induced protein 78c and ETS transcription factor elf 2) were highlighted in this investigation. The expression of predicted differentially expressed TFs obtained from in vitro and in vivo experiments, were experimentally validated by quantitative polymerase chain reaction. This confirmed findings of RNA-seq data.

Conclusion

miRNA-TF networks presented in this study control some of the most important metabolic and signaling pathways in the development and life cycle of E. granulosus, providing a potential approach for disrupting the early hours of dog infection and preventing the development of the helminth in the final host.
Nutrient availability of roughages in isocaloric and isonitrogenous diets alters the bacterial networks in the whole gastrointestinal tract of Hu sheep
Authors: Li Yuqi , Gao Jian , Xue Yihan , Sun Ruolin , Sun Xiaoni , Sun Zhanying , Liu Suozhu , Tan Zhankun , Zhu Weiyun , Cheng Yanfen
Published: March 2023

Background

The nutrient availability of roughages could affect the dietary utilization efficiency of ruminants even in isocaloric and isonitrogenous diets. Here, we analyzed the bacterial composition and their metabolic pathways in the gastrointestinal tracts (GITs) of Hu sheep fed with wheat straw (WS) instead of alfalfa (AL) in isocaloric and isonitrogenous diets, trying to explore the reasons from the perspective of GITs bacterial network structure changes.

Results

We employed 16S rRNA gene sequencing in combination with the Kruskal–Wallis test, Spearman correlation analysis, and other statistical methods to describe the microbiota composition in the GITs of Hu sheep. The results showed after the roughage was replaced from AL to WS, the most positive response occurred in the rumen microbiota, resulting in a more obvious microbiological and functional redundancy phenomenon. Whereas extended biogeographic studies of the GITs bacterial community found opposite results for the hindgut microbiota and metabolism networks compared to the forestomach. The abundance of fiber-degrading bacteria such as Prevotella, Oscillospiraceae NK4A214 group, and Treponema was significantly increased in GITs, but low-efficiency crude fiber degradation inhibited energy use efficiency, the pentose phosphate pathway, gluconeogenesis, and volatile acid synthesis. In addition, dietary shifting from AL to WS decreased the abundance of beneficial bacteria such as the Lachnospiraceae NK3A20 group and Alistipes, thereby enhancing the underlying inflammatory response.

Conclusions

These findings suggest that feeding untreated WS affected the structure and function of the bacterial network in the GITs due to limited total digestible nutrients, and in particular increases the complexity of the rumen bacterial network, and limit the abundance of bacteria involved in the crude fiber degradation in the hindgut.
PRIMIS: design of a pivotal, randomized, phase 3 study evaluating the safety and efficacy of the nonsteroidal farnesoid X receptor agonist cilofexor in noncirrhotic patients with primary sclerosing cholangitis
Authors: Trauner Michael , Chung Chuhan , Sterling Kate , Liu Xiangyu , Lu Xiaomin , Xu Jun , Tempany-Afdhal Clare , Goodman Zachary D. , Färkkilä Martti , Tanaka Atsushi , Trivedi Palak , Kowdley Kris V. , Bowlus Christopher L. , Levy Cynthia , Myers Robert P.
Published: March 2023

Background

Primary sclerosing cholangitis (PSC) is a chronic progressive liver disease leading to biliary fibrosis and cirrhosis. Cilofexor is a nonsteroidal farnesoid X receptor agonist that demonstrated significant improvements in liver biochemistry and markers of cholestasis in patients with PSC in a phase 2 study. We describe here the rationale, design, and implementation of the phase 3 PRIMIS trial, the largest placebo-controlled trial in PSC.

Methods

Adults with large-duct PSC without cirrhosis are randomized 2:1 to receive oral cilofexor 100 mg once daily or placebo for up to 96 weeks during the blinded phase. Patients completing the blinded phase are eligible to receive open-label cilofexor 100 mg daily for up to 96 weeks. The primary objective is to evaluate whether cilofexor reduces the risk of fibrosis progression compared with placebo. Liver biopsy is performed at screening and Week 96 of the blinded phase for histologic assessment of fibrosis. The primary endpoint—chosen in conjunction with guidance from the U.S. Food and Drug Administration—is the proportion of patients with ≥ 1-stage increase in fibrosis according to Ludwig histologic classification at week 96. Secondary objectives include evaluation of changes in liver biochemistry, serum bile acids, liver fibrosis assessed by noninvasive methods, health-related quality of life, and safety of cilofexor.

Conclusion

The phase 3 PRIMIS study is the largest randomized, double-blind, placebo-controlled trial in PSC to date and will allow for robust evaluation of the efficacy and safety of cilofexor in noncirrhotic patients with large-duct PSC.

Trial Registration: ClinicalTrials.gov NCT03890120; registered 26/03/2019.
The differences in drug resistance between drug-resistant tuberculosis patients with and without diabetes mellitus in northeast China: a retrospective study
Authors: Pan Yuanping , Yu Yingying , Yi Yaohui , Dou Xiaofeng , Lu Jiachen , Zhou Ling
Published: March 2023

Background

Diabetes mellitus (DM) and drug-resistant tuberculosis (DR-TB) are serious global public health problems. This study aimed to explore the differences in drug resistance between DR-TB patients with and without DM. Risk factors for developing multidrug-resistant tuberculosis (MDR-TB) were also investigated among DR-TB patients.

Methods

The patient’s basic demographic,　clinical characteristics, and drug susceptibility testing (DST) data were collected from the Chinese Disease Control Information System. Descriptive statistics were used to estimate the frequency and proportion of included variables. Categorical variables were compared using the Chi-square test or Fisher’s exact test. Chi-square tests for trends were used to determine changes and trends in MDR-TB and pre-extensively drug-resistantTB (pre-XDR-TB) patterns over time. Univariate and multivariate logistic regression analysis was used to explore the risk factors of MDR-TB.

Results

Compared with DR-TB patients with DM, DR-TB patients without DM had significantly higher rates of mono-resistant streptomycin (SM) and any resistance to kanamycin (KM), but significantly lower rates of any resistance to protionamide (PTO) and mono-resistance to levofloxacin (LFX), and pre-XDR-TB (P<0.05). The proportion of resistance to other anti-TB drugs was not statistically different between the DR-TB with and without DM. Among DR-TB patients without and with DM, the proportion of patients with MDR-TB and pre-XDR-TB patterns showed a significant downward trend from 2016 to 2021 (P<0.05). Among DR-TB patients without DM, male, previously treated DR-TB cases, and immigration were risk factors for MDR-TB (P<0.05). In DR-TB patients with DM, a negative sputum smear is a risk factor for MDR-TB (P<0.05).

Conclusion

There was no statistical difference in resistance patterns between DR-TB with and without DM, except in arbitrary resistance to PTO and KM, mono-resistant SM and LFX, and pre-XDR-TB. Great progress has been made in the prevention and control of MDR-TB and pre-XDR-TB. However, DR-TB patients with and without DM differ in their risk factors for developing MDR-TB.
Role of self-management program based on 5A nursing model in quality of life among patients undergoing hemodialysis: a Randomized Clinical Trial
Authors: Keivan Sahar , Shariati Abdolali , Miladinia Mojtaba , Haghighizadeh Mohammad Hosein
Published: March 2023

Introduction

Various nursing models are usually employed to achieve self-management and improve the quality of life in chronic conditions. Given its person-based characteristics, the 5 A nursing model can improve the quality of life of hemodialysis patients.

Purpose

This study aimed to determine the role of a self-management program based on the 5 A nursing model in the quality of life of patients undergoing hemodialysis.

Materials and methods

This clinical trial was conducted on hemodialysis patients in Iran. Random sampling was adopted to assign 60 patients to intervention and control groups. After the participants completed a demographic questionnaire and the Kidney Disease Quality of Life–Short Form (KDQOL–SF), routine measures were taken in the control group. However, the 5 A nursing model was implemented in the intervention group for three months. The self-care program was executed in face-to-face sessions or via phone calls and SMSs. After three months, the quality of life was measured again in both groups.

Findings

There were significant differences after the intervention between the intervention and control groups in specific dimensions of quality of life, such as cognitive functions, symptoms, sleep, dialysis, social support, and renal complications (P < 0.05). The two groups also had significant differences in the general scores of quality of life (P < 0.05).

Conclusion

The 5 A self-management intervention as a person-based model could improve self-care in hemodialysis patients. Nurses can implement this model to mitigate care costs, enhance interventions, and improve patients’ quality of life.

Trial registration

Iranian Registry of Clinical Trials (IRCT20211103052955N1; 19/11/2021).
The level of serum albumin is associated with renal prognosis and renal function decline in patients with chronic kidney disease
Authors: Cheng Tong , Wang Xiaoyu , Han Yong , Hao Jianbing , Hu Haofei , Hao Lirong
Published: March 2023

Objective

The study’s purpose is to explore the link of serum albumin on renal progression in patients with chronic kidney disease (CKD).

Methods

This study was a secondary analysis of a prospective cohort study in which a total of 954 participants were non-selectively and consecutively collected from the research of CKD-ROUTE in Japan between November 2010 and December 2011. We evaluated the association between baseline ALB and renal prognosis (initiation of dialysis or 50% decline in eGFR from baseline) and renal function decline (annual eGFR decline) using the Cox proportional-hazards and linear regression models, respectively. We performed a number of sensitivity analyses to ensure the validity of the results. In addition, we performed subgroup analyses.

Results

The included patients had a mean age of (66.86 ± 13.41) years, and 522 (69.23%) were male. The mean baseline ALB and eGFR were (3.89 ± 0.59) g/dL and (33.43 ± 17.97) ml/min/1.73 m2. The annual decline in eGFR was 2.65 mL/min/1.73 m2/year. 218 (28.9%) individuals experienced renal prognosis during a median follow-up period of 36.0 months. The baseline ALB was inversely linked with renal prognosis (HR = 0.61, 95%CI: 0.45, 0.81) and renal function decline (β = -1.41, 95%CI: -2.11, -0.72) after controlling for covariates. The renal prognosis and ALB had a non-linear connection, with ALB’s inflection point occurring at 4.3 g/dL. Effect sizes (HR) were 0.42 (0.32, 0.56) and 6.11 (0.98, 38.22) on the left and right sides of the inflection point, respectively. There was also a non-linear relationship between ALB and renal function decline, and the inflection point of ALB was 4.1 g/dL. The effect sizes(β) on the left and right sides of the inflection point were -2.79(-3.62, -1.96) and 0.02 (-1.97, 1.84), respectively.

Conclusion

This study shows a negative and non-linear association between ALB and renal function decline as well as renal prognosis in Japanese CKD patients. When ALB is lower than 4.1 g/dL, ALB decline was closely related to poor renal prognosis and renal function decline. From a therapeutic point of view, reducing the decline in ALB makes sense for delaying CKD progression.
Changing attitudes towards HIV testing and treatment among three generations of men in Cameroon: a qualitative analysis using the Fogg Behavior Model
Authors: Katirayi Leila , Tchendjou Patrice , Tchounga Boris , Mbunka Muhamed , Wicks Madison , Conserve Donaldson F.
Published: March 2023

Introduction

Men are less likely than women to test for HIV and promptly initiate antiretroviral treatment, resulting in advanced HIV disease and increased mortality rates among them.

Methods

In-depth interviews were conducted with men and leaders in the west and central regions of Cameroon. Men were recruited from existing community groups and stratified by age: 21–30 years, 31–40 years, and 41 years and older. Community leaders were recommended by the community dialogue structure chairman. Interviews were conducted using a semi-structured guide in English or French, depending on the participant’s preference. Transcripts were coded in the MAXQDA v.12 software and analyzed using thematic analysis and by age group. The Fogg Behavior Model was used to gain a deeper understanding of the different perceptions across all age groups.

Results

Younger men (21–30 years) were generally more accepting of HIV testing, as it had become normative behavior. Although financial barriers could limit access, free testing was mentioned as a prompt to initiate HIV testing. The middle age men (31–40 years) had the most concerns about HIV testing interrupting their work day and recommended increasing testing locations and hours. The older men (41 + years) were the least motivated to get tested, citing worries about the impact on their social standing within the community. All age groups reported being motivated to begin treatment if they were found to be HIV-positive.

Participants also provided insights regarding community HIV testing and treatment messaging. Younger and older men preferred to hear directly from qualified health professionals, but younger men noted that social media, radio, and TV could be utilized. Middle age men also identified TV and radio as effective mediums, if door-to-door messaging was not an option.

Conclusions

The study highlights important considerations when planning future information-sharing activities for HIV testing and treatment. Since lived experiences differ across generations and societal roles continue to change, not only should the content of messages differ among the generations, but the means of communication must also be considered to ensure the messages are conveyed through a trusted source.
A qualitative exploration into the presence of TB stigmatization across three districts in South Africa
Authors: DeSanto Daniel , Velen Kavindhran , Lessells Richard , Makgopa Sewele , Gumede Dumile , Fielding Katherine , Grant Alison D , Charalambous Salome , Chetty-Makkan Candice M
Published: March 2023

Background

Tuberculosis (TB) stigma is a barrier to active case finding and delivery of care in fighting the TB epidemic. As part of a project exploring different models for delivery of TB contact tracing, we conducted a qualitative analysis to explore the presence of TB stigma within communities across South Africa.

Methods

We conducted 43 in-depth interviews with 31 people with TB and 12 household contacts as well as five focus group discussions with 40 ward-based team members and 11 community stakeholders across three South African districts.

Results

TB stigma is driven and facilitated by fear of disease coupled with an understanding of TB/HIV duality and manifests as anticipated and internalized stigma. Individuals are marked with TB stigma verbally through gossip and visually through symptomatic identification or when accessing care in either TB-specific areas in health clinics or though ward-based outreach teams. Individuals’ unique understanding of stigma influences how they seek care.

Conclusion

TB stigma contributes to suboptimal case finding and care at the community level in South Africa. Interventions to combat stigma, such as community and individual education campaigns on TB treatment and transmission as well as the training of health care workers on stigma and stigmatization are needed to prevent discrimination and protect patient confidentiality.
Structural features on quantitative chest computed tomography of patients with maximal mid-expiratory flow impairment in a normal lung function population
Authors: Yang Yuling , Ge Haiyan , Lu Jinjuan , Huang Xuemei , Wang Kun , Jin Liang , Qi Lin , Li Ming
Published: March 2023

Background

Maximal mid-expiratory flow (MMEF) is an earlier predictor of chronic obstructive pulmonary disease (COPD) development than forced expiratory volume in 1 s (FEV1). Changes of lung structure in patients with MMEF impairment only is still not clear. Therefore, this study aimed to investigate the structural features of patients with decreased MMEF by quantitative computed tomography (QCT) and develop a predictive model for predicting patients with reduced MMEF in normal lung function population.

Methods

In this study, 131 patients with normal spirometry results and available volumetric chest CT images were enrolled and divided into the reduced MMEF group (FEV1/forced expiratory vital capacity (FEV1/FVC) > 0.7, FEV1% predictive values (FEV1%pred) > 80%, MMEF%pred < 80%, n = 52) and the normal MMEF group (FEV1/FVC > 0.7, FEV1%pred > 80%, MMEF%pred ≥ 80%, n = 79). The emphysema, small airway disease and medium-size airway parameters were measured by a commercial software. The differences were investigated in clinical features, spirometrical parameters and QCT parameters between the two groups. A nomogram model was constructed based on the results of the multivariable logistic regression model. Spearman’s correlation coefficients were calculated between QCT measurements and spirometrical parameters.

Results

There were more males in reduced MMEF group than normal group (P < 0.05). Lung parenchyma parameter (PRMEmph) and airway-related parameters (functional small airway disease (PRMfSAD), luminal area of fifth- and sixth- generation airway (LA5, LA6) were significantly different between the reduced MMEF group and the normal group (20.2 ± 17.4 vs 9.4 ± 6.7, 3.4 ± 3.5 vs 1.9 ± 2.0, 12.2 ± 2.5 vs 13.7 ± 3.4, 7.7 ± 2.4 vs 8.9 ± 2.8, respectively, all P < 0.01). After multivariable logistical regression, only sex (odds ratio [OR]: 2.777; 95% confidence interval [CI]:1.123–3.867), PRMfSAD (OR:1.102, 95%CI:1.045–1.162) and LA6 (OR:0.650, 95%CI:0.528–0.799) had significant differences between the two groups (P < 0.05) and a model incorporating with the three indicators was constructed (area under curve, 0.836). Correlation analysis showed MMEF%pred had mild to moderate correlation with airway-related measurements.

Conclusion

In normal lung function population, patients with reduced MMEF have potential medium-size and small airway changes, and MMEF%pred is significantly associated with airway-related CT parameters. The nomogram incorporating with sex, PRMfSAD and LA6 has good predictive value and offers more objective evidences in a group with reduced MMEF.
Low dissolved oxygen supply functions as a global regulator of the growth and metabolism of Aurantiochytrium sp. PKU#Mn16 in the early stages of docosahexaenoic acid fermentation
Authors: Liu Lu , Zhu Xingyu , Ye Huike , Wen Yingying , Sen Biswarup , Wang Guangyi
Published: March 2023

Background

Thraustochytrids accumulate lipids with a high content of docosahexaenoic acid (DHA). Although their growth and DHA content are significantly affected by the dissolved oxygen (DO) supply, the role of DO on the transcriptional regulation of metabolism and accumulation of intracellular metabolites remains poorly understood. Here we investigate the effects of three different DO supply conditions (10%, 30%, and 50%) on the fed-batch culture of the Aurantiochytrium PKU#Mn16 strain to mainly reveal the differential gene expressions and metabolite profiles.

Results

While the supply of 10% DO significantly reduced the rates of biomass and DHA production in the early stages of fermentation, it achieved the highest amounts of biomass (56.7 g/L) and DHA (6.0 g/L) on prolonged fermentation. The transcriptome analyses of the early stage (24 h) of fermentation revealed several genes involved in the central carbon, amino acid, and fatty acid metabolism, which were significantly downregulated at a 10% DO level. The comparative metabolomics results revealed the accumulation of several long-chain fatty acids, amino acids, and other metabolites, supporting the transcriptional regulation under the influence of a low oxygen supply condition. In addition, certain genes involved in antioxidative systems were downregulated under 10% DO level, suggesting a lesser generation of reactive oxygen species that lead to oxidative damage and fatty acid oxidation.

Conclusions

The findings of this study suggest that despite the slow growth and metabolism in the early stage of fermentation of Aurantiochytrium sp. PKU#Mn16, a constant supply of low dissolved oxygen can yield biomass and DHA content better than that with high oxygen supply conditions. The critical information gained in this study will help to further improve DHA production through bioprocess engineering strategies.
Machine learning-based clustering to identify the combined effect of the DNA fragmentation index and conventional semen parameters on in vitro fertilization outcomes
Authors: Peng Tianwen , Liao Chen , Ye Xin , Chen Zhicong , Li Xiaomin , Lan Yu , Fu Xin , An Geng
Published: March 2023

Background

Previous studies have demonstrated an association between male sperm quality and assisted reproduction outcomes, focusing on the effects of individual parameters and reaching controversial conclusions. The WHO 6th edition manual highlights a new semen assay, the sperm DNA fragmentation index, for use after routine semen examination. However, the combined effect of the sperm DNA fragmentation index (DFI) and routine semen parameters remains largely unknown.

Methods

We assessed the combined effect of the sperm DFI and conventional semen parameters on single fresh conventional IVF outcomes for infertile couples from January 1, 2017, to December 31, 2020. IVF outcomes were obtained from the cohort database follow-up records of the Clinical Reproductive Medicine Management System of the Third Affiliated Hospital of Guangzhou Medical University. An unsupervised K-means clustering method was applied to classify participants into several coexposure pattern groups. A multivariate logistic regression model was used for statistical analysis.

Results

A total of 549 live births among 1258 couples occurred during the follow-up period. A linear exposure–response relationship was observed among the sperm DFI, sperm motility, and IVF outcomes. In multivariable adjustment, increased sperm DFI values and decreased sperm motility and semen concentration levels were associated with reduced odds of favourable IVF outcomes. Four coexposure patterns were generated based on the sperm DFI and the studied semen parameters, as follows: Cluster 1 (low sperm DFI values and high sperm motility and semen concentration levels), Cluster 2 (low sperm DFI values and moderate sperm motility and semen concentration levels), Cluster 3 (low sperm DFI values and low sperm motility and semen concentration levels) and Cluster 4 (high sperm DFI values and low sperm motility and semen concentration levels). Compared with those in Cluster 1, participants in Cluster 3 and Cluster 4 had lower odds of a live birth outcome, with odds ratios (95% confidence intervals [CIs]) of 0.733 (0.537, 0.998) and 0.620 (0.394, 0.967), respectively.

Conclusions

When combined with low sperm DFI values, there was no significant difference between high or moderate sperm concentration and motility levels, and both were associated with favourable IVF outcomes. Low sperm parameter levels, even when DFI values remain low, may still lead to poor IVF outcomes. Participants with high sperm DFI values and low sperm motility and semen concentration levels had the worst outcomes. Our findings offer a novel perspective for exploring the joint effects of sperm DFI and routine semen parameter values.
LncRNA HAGLR silencing inhibits IL-1β-induced chondrocytes inflammatory injury via miR-130a-3p/JAK1 axis
Authors: Zuo Yunzhou , Xiong Changjun , Gan Xuewen , Xie Wei , Yan Xiaokang , Chen Yanzhao , Li Xugui
Published: March 2023

Background

Osteoarthritis (OA), the most common form of arthritis, is accompanied by destruction of articular cartilage, development of osteophyte and sclerosis of subchondral bone. This study aims to explore whether lncRNA HAGLR can play a role in OA, and further clarify the potential mechanism.

Material and methods

StarBase and luciferase reporter assay were applied for predicting and confirming the interaction between lncRNA HAGLR, miR-130a-3p and JAK1. The levels of lncRNA HAGLR and miR-130a-3p were analyzed using quantitative reverse transcription PCR (qRT-PCR). The proliferation, cytotoxicity and apoptosis of CHON-001 cells were evaluated by MTT, lactate dehydrogenase assay (LDH) and Flow cytometry (FCM) analysis, respectively. Moreover, expression of cleaved Caspase3 protein were determined by Western blot assay. The release of inflammatory factors (TNF-α, IL-8, and IL-6) was detected by ELISA.

Results

lncRNA HAGLR directly targets miR-130a-3p. Level of lncRNA HAGLR was substantially higher and miR-130a-3p level was memorably lower in IL-1β stimulated CHON-001 cells than that in Control group. Furthermore, lncRNA HAGLR silencing alleviated IL-1β induce chondrocyte inflammatory injury, as evidenced by increased cell viability, reduced LDH release, decreased apoptotic cells, inhibited cleaved-Caspase3 expression, and reduced secretion of secretion of inflammatory factors. However, miR-130a-3p-inhibitor reversed these findings. We also found miR-130a-3p directly targeted JAK1 and negatively regulated JAK1 expression in CHON-001 cells. In addition, JAK1-plasmid reversed the effects of miR-130a-3p mimic on IL-1β-induced chondrocytes inflammatory injury.

Conclusion

Silencing of lncRNA HAGLR alleviated IL-1β-stimulated CHON-001 cells injury through miR-130a-3p/JAK1 axis, revealing lncRNA HAGLR may be a valuable therapeutic target for OA therapy.
Neurobiological effects of gallic acid: current perspectives
Authors: Bhuia Md. Shimul , Rahaman Md. Mizanur , Islam Tawhida , Bappi Mehedi Hasan , Sikder Md. Iqbal , Hossain Kazi Nadim , Akter Fatama , Al Shamsh Prottay Abdullah , Rokonuzzman Md. , Gürer Eda Sönmez , Calina Daniela , Islam Muhammad Torequl , Sharifi-Rad Javad
Published: March 2023

Gallic acid (GA) is a phenolic molecule found naturally in a wide range of fruits as well as in medicinal plants. It has many health benefits due to its antioxidant properties. This study focused on finding out the neurobiological effects and mechanisms of GA using published data from reputed databases. For this, data were collected from various sources, such as PubMed/Medline, Science Direct, Scopus, Google Scholar, SpringerLink, and Web of Science. The findings suggest that GA can be used to manage several neurological diseases and disorders, such as Alzheimer’s disease, Parkinson’s disease, strokes, sedation, depression, psychosis, neuropathic pain, anxiety, and memory loss, as well as neuroinflammation. According to database reports and this current literature-based study, GA may be considered one of the potential lead compounds to treat neurological diseases and disorders. More preclinical and clinical studies are required to establish GA as a neuroprotective drug.
A positive feedback loop driven by fibronectin and IL-1β sustains the inflammatory microenvironment in breast cancer
Authors: Tunali Gurcan , Yanik Hamdullah , Ozturk Suleyman Can , Demirkol-Canli Secil , Efthymiou Georgios , Yilmaz Kerim Bora , Van Obberghen-Schilling Ellen , Esendagli Gunes
Published: March 2023

Inflammatory alterations of the extracellular matrix shape the tumor microenvironment and promote all stages of carcinogenesis. This study aims to determine the impact of cellular fibronectin on inflammatory facets of tumor-associated macrophages (TAMs) in breast cancer. Cellular fibronectin (FN) harboring the alternatively spliced extra domain A (FN-EDA) was determined to be a matrix component produced by the triple-negative breast cancer (TNBC) cells. High levels of FN-EDA correlated with poor survival in breast cancer patients. The proinflammatory cytokine IL-1β enhanced the expression of cellular fibronectin including FN-EDA. TAMs were frequently observed in the tumor areas rich in FN-EDA. Conditioned media from TNBC cells induced the differentiation of CD206+CD163+ macrophages and stimulated the STAT3 pathway, ex vivo. In the macrophages, the STAT3 pathway enhanced FN-EDA-induced IL-1β secretion and NF-κB signaling. In conclusion, our data indicate a self-reinforcing mechanism sustained by FN-EDA and IL-1β through NF-κB and STAT3 signaling in TAMs which fosters an inflammatory environment in TNBC.
Sex differences in fetal intracranial volumes assessed by in utero MR imaging
Authors: Griffiths Paul D. , Jarvis Deborah , Mooney Cara , Campbell Michael J.
Published: March 2023

Background

The primary aim of the study is to test the null hypothesis that there are no statistically significant differences in intracranial volumes between male and female fetuses. Furthermore, we have studied the symmetry of the cerebral hemispheres in the cohort of low-risk fetuses.

Methods

200 normal fetuses between 18 and 37 gestational weeks (gw) were included in the cohort and all had in utero MR, consisting of routine and 3D-volume imaging. The surfaces of the cerebral ventricles, brain and internal table of the skull were outlined manually and volume measurements were obtained of ventricles (VV), brain parenchyma (BPV), extraaxial CSF spaces (EAV) and the total intracranial volume (TICV). The changes in those values were studied over the gestational range, along with potential gender differences and asymmetries of the cerebral hemispheres.

Results

BPV and VV increased steadily from 18 to 37 gestational weeks, and as a result TICV also increased steadily over that period. TICV and BPV increased at a statistically significantly greater rate in male relative to female fetuses after 24gw. The greater VV in male fetuses was apparent earlier, but the rate of increase was similar for male and female fetuses. There was no difference between the genders in the left and right hemispherical volumes, and they remained symmetrical over the age range measured.

Conclusions

We have described the growth of the major intracranial compartments in fetuses between 18 and 37gw. We have shown a number of statistically different features between male and female fetuses, but we have not detected any asymmetry in volumes of the fetal cerebral hemispheres.
Reference intervals for cd, hg, Mn and Pb in the general children population (3–14 years) of Kinshasa, Democratic Republic of Congo (DRC) between June 2019 and June 2020
Authors: Tuakashikila Y. M. , Mata H. M. , Kabamba M. M. , Malumba A. M. , Tuakuila J. K.
Published: March 2023

The reference intervals (RIs), proposed by the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) and the International Union of Pure and Applied Chemistry (IUPAC), were derived for Cd, Hg, Mn and Pb in the blood and urine of the children population living in Kinshasa (n = 200, aged 3–14 years with 97 girls). Levels of metals were measured using coupled plasma mass (ICP-MS). In blood, the proposed RIs [P5-P95 (GM)] were 0.022–1.112 μg/L (0.074), 35.69–144.50 μg/L (71.43), 0.060 to 1.161 μg/L (0.208) and 6.597–15.740 μg/L (9.882) for Cd, Pb, Hg and Mn, respectively. Urinary levels [(P5-P95 (GM)] were 0.082–1.530 μg/L (0.366) for Cd, 1.827–18.500 μg/L (5.458) for Pb, 0.323–1.953 μg/L (0.709) for Hg and 0.070 to 1.703 μg/L (0.186) for Mn. As compared to the CDC updated blood Pb reference value (35 μg/L), Pb levels remain higher of public health concern. Cd and Mn levels were similar to those found in the same city in 2015 and databases involving non-occupationally exposed populations from other countries. Hg levels significantly lower than those found in the same city in 2015, probably due to exclusion criteria of metal exposure applying in the present survey (occupationally exposed to the studied metals, smoking habits, amalgam tooth fillings, fish consumption habit more than one time per week, etc.). These background metal exposures will be useful for future occupational and/or environmental surveys as well as undertaking a reliable regulation of chemical exposure in Kinshasa via a national HBM program.
‘Learning and growing together’: exploring consumer partnerships in a PhD, an ethnographic study
Authors: Cox Ruth , Molineux Matthew , Kendall Melissa , Tanner Bernadette , Miller Elizabeth
Published: March 2023

Background

Consumer and community involvement (CCI) in health research is increasingly recognised as best practice and is closely linked with calls for epistemic justice and more transparent university collaborations with consumers. Given doctoral candidates play a key role in the future of co-production, examination of consumer partnerships in PhDs is important. This study aimed to describe and evaluate consumer partnerships in a PhD from the perspective of the consumer co-researchers, the PhD candidate, and the academic supervisors including optimal approaches, impacts, and benefits and challenges.

Methods

This prospective, co-produced ethnographic study was conducted over 33 months. Data collection included field notes, a monthly online log of partnership experiences and time spent, interviews or a focus group every six months, and a PhD student reflexive diary. Qualitative data were analysed using reflexive thematic analysis.

Results

The student, two academics, and four consumer co-researchers were involved. A mean of 11.10 h per month were spent on CCI. The student spent the most time (mean 15.86 h per month). Preparation for dissemination of findings was the most frequent partnership activity. The two overarching themes emphasised that a PhD promotes a rich partnership ethos with the student at the centre and that the partnership was a worthwhile but challenging process. The four sub-themes highlighted that developing a collegial and supportive environment with regular meetings combined with a multi-faceted and responsive co-learning approach were core to success. Additionally, there were benefits for individuals, research processes and outcomes, and for driving change in consumer-academic research partnerships. Recruiting to and forming the partnership, maintaining the collaboration through inevitable changes and challenges, and an ethical and supportive closure of the research team were critical.

Conclusions

This longitudinal ethnographic study demonstrated that doctoral research can create a rich ethos for research and knowledge co-production which evolved over time. Equalising power dynamics through relationship building and co-learning was critical. Additionally, a focus on supportively ending the partnership was essential, and CCI may reduce PhD student isolation and procrastination. Enhanced university incentivisation of co-production in health research is recommended to address gaps in consumer remuneration and student support.
Efficacy and Safety of Trastuzumab as a Single Agent in First-Line Treatment of HER2-Overexpressing Metastatic Breast Cancer
Authors: Vogel Charles L. , Cobleigh Melody A. , Tripathy Debu , Gutheil John C. , Harris Lyndsay N. , Fehrenbacher Louis , Slamon Dennis J. , Murphy Maureen , Novotny William F. , Burchmore Michael , Shak Steven , Stewart Stanford J. , Press Michael
Published: March 2023

PURPOSE

To evaluate the efficacy and safety of first-line, single-agent trastuzumab in women with HER2-overexpressing metastatic breast cancer.

PATIENTS AND METHODS

One hundred fourteen women with HER2-overexpressing metastatic breast cancer were randomized to receive first-line treatment with trastuzumab 4 mg/kg loading dose, followed by 2 mg/kg weekly, or a higher 8 mg/kg loading dose, followed by 4 mg/kg weekly.

RESULTS

The objective response rate was 26% (95% confidence interval [CI], 18.2% to 34.4%), with seven complete and 23 partial responses. Response rates in 111 assessable patients with 3+ and 2+ HER2 overexpression by immunohistochemistry (IHC) were 35% (95% CI, 24.4% to 44.7%) and none (95% CI, 0% to 15.5%), respectively. The clinical benefit rates in assessable patients with 3+ and 2+ HER2 overexpression were 48% and 7%, respectively. The response rates in 108 assessable patients with and without HER2 gene amplification by fluorescence in situ hybridization (FISH) analysis were 34% (95% CI, 23.9% to 45.7%) and 7% (95% CI, 0.8% to 22.8%), respectively. Seventeen (57%) of 30 patients with an objective response and 22 (51%) of 43 patients with clinical benefit had not experienced disease progression at follow-up at 12 months or later. The most common treatment-related adverse events were chills (25% of patients), asthenia (23%), fever (22%), pain (18%), and nausea (14%). Cardiac dysfunction occurred in two patients (2%); both had histories of cardiac disease and did not require additional intervention after discontinuation of trastuzumab. There was no clear evidence of a dose-response relationship for response, survival, or adverse events.

CONCLUSION

Single-agent trastuzumab is active and well tolerated as first-line treatment of women with metastatic breast cancer with HER2 3+ overexpression by IHC or gene amplification by FISH.
Association Between Age- and Sex-Specific Body Mass Index Percentile and Multiple Intubation Attempts: A Retrospective Cohort Analysis
Authors: Chhabada Surendrasingh , Skinner Chelsea , Kopac Orkun , Castro Pilar , Mascha Edward J. , Wang Dong , Gama de Abreu Marcelo , Turan Alparslan , Sessler Daniel I. , Ruetzler Kurt
Published: March 2023

BACKGROUND:

Obesity distorts airways and slightly complicates intubations in adults, but whether obesity complicates pediatric intubations remains unclear. We, therefore, tested the primary hypothesis that increasing age- and sex-specific body mass index (BMI) percentile is associated with difficult intubation, defined as >1 intubation attempt.

METHODS:

We conducted a retrospective analysis of pediatric patients between 2 and 18 years of age who had noncardiac surgery with oral endotracheal intubation. We assessed the association between BMI percentile and difficult intubation, defined as >1 intubation attempt, using a confounder-adjusted multivariable logistic regression model. Secondarily, we assessed whether the main association depended on preoperative substantial airway abnormality status or age group.

RESULTS:

A total of 9339 patients were included in the analysis. Median [quartiles] age- and sex-specific BMI percentile was 70 [33, 93], and 492 (5.3%) patients had difficult intubation. There was no apparent association between age- and sex-specific BMI percentile and difficult intubation. The estimated odds ratio (OR) for having difficult intubation for a 10-unit increase in BMI percentile was 0.98 (95% confidence interval [CI], 0.95–1.005) and was consistent across the 3 age groups of early childhood, middle childhood, and early adolescence (interaction P = .53). Patients with preoperative substantial airway abnormalities had lower odds of difficult intubation per 10-unit increase in BMI percentile, with OR (95% CI) of 0.83 (0.70–0.98), P = .01.

CONCLUSIONS:

Age- and sex-specific BMI percentile was not associated with difficult intubation in children between 2 and 18 years of age. As in adults, obesity in children does not much complicate intubation.