bluuebunny/crossref_metadata_2025 huggingface dataset:
Gaucher disease in a patient with membranoproliferative glomerulonephritis: case report
Authors: Liang Mengjun , Zhu Shiyan , Liu Shaoqin , Chen Jianquan , Li Danni , Luo Chengzhi , Wang Xiaowen , Jiang Zongpei
Published: September 2023

Background

Gaucher disease (GD) is a rare autosomal recessive inherited, lysosomal storage disoder that involves liver, spleen, lung, bone, bone marrow even central nervous. However, GD associated membranoproliferative glomerulonephritis (MPGN) is seldom reported.

Case presentation

Here we described a case of 35-year-old man suffering from GD with hepatosplenomegaly, ascites, bone destruction, myelofibrosis and MPGN. Renal biopsy revealed MPGN and Gaucher cells presented in the glomeruli capillaries. β-glucosidase activity was 1.95nmol/1 h/mg and gene detection demonstrated that one homozygous pathogenic variant Leu483Pro in GBA. He received the treatment of oral prednisone and mycophenolate mofetil and his ascites and renal outcomes had been significantly improved.

Conclusions

Therapy of prednisone and mycophenolate mofetil may be an optional choice for patients with Gaucher disease who have no opportunity to use enzyme treatment.
Posterior reversible encephalopathy syndrome (PRES) associated with SARS-CoV-2 infection in a patient under maintenance haemodialysis: a case report
Authors: Shimamoto Yuki , Sasaki Hirohito , Kasuno Kenji , Watanabe Yuki , Sakashita Sayumi , Nishikawa Sho , Nishimori Kazuhisa , Morita Sayu , Nishikawa Yudai , Kobayashi Mamiko , Fukushima Sachiko , Enomoto Soichi , Takahashi Naoki , Hamano Tadanori , Sakamaki Ippei , Iwasaki Hiromichi , Iwano Masayuki
Published: September 2023

Background

Endothelial dysfunction is common in patients undergoing chronic haemodialysis, and is a major cause of posterior reversible encephalopathy syndrome (PRES). Recently, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been shown to cause endothelial dysfunction by infecting vascular endothelial cells. Several cases of neurological complications in patients without kidney dysfunction, and only a few cases in patients with chronic kidney disease, have been reported in the literature. However, no previous report has yet described PRES associated with SARS-CoV-2 infection among patients undergoing maintenance dialysis.

Case presentation

A 54-year-old woman undergoing maintenance haemodialysis was admitted to our hospital for status epilepticus. She had developed end-stage kidney disease (ESKD) secondary to diabetic nephropathy. Seven days prior to admission, she had developed fever and was diagnosed with COVID-19. Subsequently her blood pressure increased from 160/90 mmHg to 190/100 mmHg. On admission, she presented with severe hypertension (> 220/150 mmHg), unconsciousness, and epilepticus. CT tomography revealed no signs of brain haemorrhage. Cranio-spinal fluid (CSF) examination revealed no signs of encephalitis, and CSF polymerase chain reaction (PCR) for SARS-CoV-2 was negative. MRI findings revealed focal T2/FLAIR hyperintensity in the bilateral parietooccipital regions, leading to the diagnosis of PRES. Deep sedation and strict blood pressure control resulted in a rapid improvement of her symptoms, and she was discharged without sequelae.

Conclusions

We report the first case of PRES associated with SARS-CoV-2 infection in a patient undergoing maintenance haemodialysis. Patients undergoing maintenance haemodialysis are at high risk of PRES because of several risk factors. SARS-CoV-2 infection causes direct invasion of endothelial cells by binding to angiotensin-converting enzyme 2 (ACE2), initiating cytokine release, and hypercoagulation, leading to vascular endothelial cell injury and increased vascular leakage. In the present case, SARS-CoV-2 infection possibly be associated with the development of PRES.
Identification of characteristics predictive of long-term survival with durvalumab or durvalumab plus tremelimumab in metastatic urothelial carcinoma
Authors: Alt Marie , Stecca Carlos , Lin Yian , Kazeem Gbenga , Goluboff Erik T. , Sridhar Srikala S.
Published: September 2023

Background

This retrospective analysis of data from clinical trials in metastatic urothelial carcinoma (mUC) was conducted to determine baseline patient characteristics associated with long-term survival (LTS) following treatment with immune checkpoint inhibitors.

Methods

Data for this analysis were from patients with platinum-refractory mUC who received durvalumab or durvalumab plus tremelimumab in phase 1/2 studies. The primary outcome measure was LTS. Patients were categorised as overall survival (OS) ≥ 2 years (from first dose) or OS < 2 years. A univariable analysis assessed independent associations with LTS and multivariable logistic regression was employed including each variable with P ≤ 0.05 as covariates.

Results

Among 360 patients, 88 (24.4%) had OS ≥ 2 years and 272 (75.6%) had OS < 2 years. In univariable analysis, several baseline characteristics and laboratory measurements were associated with LTS including sex, ECOG PS, PD-L1 expression, prior surgery, time from initial diagnosis, lymph node-only involvement, visceral disease, haemoglobin level, absolute neutrophil count, neutrophil–lymphocyte ratio and lactate dehydrogenase level. In multivariable analysis, LTS was significantly associated with ECOG PS, PD-L1 expression, haemoglobin level and absolute neutrophil count.

Conclusions

Several baseline clinical characteristics and laboratory measurements were associated with LTS for patients with platinum-refractory mUC treated with durvalumab or durvalumab plus tremelimumab.
The development and productivity of a measure for identifying low language abilities in children aged 24–36 months
Authors: Law James , Charlton Jenna , Wilson Philip , Rush Robert , Gilroy Vicky , McKean Cristina
Published: September 2023

Background

Accurate early identification of children with low language ability is important but existing measures generally have low sensitivity. This remains an area of concern for preventive and public health services. This study aimed to create and evaluate a measure of child language, communication and related risks which can be used by community health nurses to accurately identify children with low language aged 24–30 months.

Methods

The Early Language Identification Measure (ELIM) was developed and comprised five measurement sections, each measuring different aspects of development combined into a single measure. This was tested blind against a reference standard language measure, the Preschool Language Scale-5 (PLS-5), at the universal 24–30-month health visitor review in England. The threshold for likely low language was the tenth centile or below on the PLS-5. The aim was to ascertain the performance of the five individual sections in the scale, and consider the optimum combination of sections, for predicting low language ability. Specificity, sensitivity, and positive and negative predictive values were reported for each of the five sections of the ELIM alone and in conjunction with each other. The performance for children from monolingual English-speaking families and those who spoke languages other than English were also considered separately.

Results

Three hundred and seventy-six children were assessed on both the ELIM identification measure and the PLS-5 with 362 providing complete data. While each section of the ELIM predicted low language ability, the optimal combination for predicting language outcome was the parent reported vocabulary checklist coupled with the practitioner observation of the child’s communication and related behaviours. This gave a sensitivity of 0·98 with a specificity of 0·63.

Conclusions

A novel measure has been developed which accurately identifies children at risk of low language, allowing clinicians to target resources efficiently and intervene early.
A case report and literature review on a rare subtype of triple-negative breast cancer in children
Authors: Shi Lexiang , Zhang Yinan , Wu Jingcheng , Li Jinping , Zhu Junzhao , Xu Youbo , Li Nie , Li Qin , Zhang Wanli
Published: September 2023

Background

Triple-negative breast cancer (TNBC) is a type of breast tumor with a poor prognosis because it lacks or expresses low levels of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2). TNBC is more common in middle-aged and older women, and cases of TNBC in children are rarely reported. This is the only case of childhood SBC in our hospital in more than 70 years, and the disease is extremely rare internationally. We analyzed and studied the disease and TNBC from both clinical and pathological aspects and found that SBC is very different from TNBC.

Case presentation

We report a case of secretory breast cancer (SBC), a subtype of TNBC, in an 8-year-old girl from our institution. The child presented with a single mass in the left breast only, with no skin rupture and no enlargement of the surrounding lymph nodes. The child underwent two surgeries and was followed up for one year with a good prognosis.

Conclusions

SBC is highly prevalent among the multiple pathological types of pediatric breast cancer. Almost all pediatric SBC patients are characterized by the ETV6-NTRK3 fusion gene, which has a good prognosis and a 10-year survival rate of more than 90% when compared with other TNBC subtypes. According to the patient, we performed local mass resection and a postoperative pathological diagnosis of SBC (a subtype of BL-TNBC). The TNBC case had a good prognosis and differed from basal TNBC in several aspects, including clinical presentation, treatment, and prognosis. It is necessary to exclude SBC from BL-type TNBC, enhance understanding of the disease, and individualize the treatment plan, so as to avoid medical errors.
The association between perceived social support and parenting self-efficacy among parents of children aged 0–8 years
Authors: Fierloos Irene N. , Windhorst Dafna A. , Fang Yuan , Hosman Clemens M. H. , Jonkman Harrie , Crone Matty R. , Jansen Wilma , Raat Hein
Published: September 2023

Strengthening social support has been recognized as a potentially effective strategy to enhance parenting self-efficacy, but empirical evidence is limited. This study examined the association between perceived social support and parenting self-efficacy.

Data of 647 parents of children aged 0–8 years, gathered in the CIKEO cohort study in the Netherlands, were analysed. Data were collected between October 2017 and December 2019. Multivariable linear regression models were used to examine the association between social support and parenting self-efficacy. The mean age of the participants was 33.8 years (SD = 4.9); 94.9% mothers. At the start of the study, 15.1% parents perceived low to moderate social support. Parents who experienced lower levels of social support at the start of the study reported lower parenting self-efficacy at follow-up (β: 0.13; 95% CI: 0.05, 0.21), independent of potential socio-demographic confounders. Experiencing an increase in perceived social support during the study period was associated with an increase in parenting self-efficacy (β: 0.15; 95% CI: 0.10, 0.21).

Our findings indicate perceived social support is associated with parenting self-efficacy among parents of children aged 0–8 years. Future longitudinal studies need to confirm our findings and may examine which social support interventions are effective in strengthening parenting self-efficacy.
Identification of determinant factors for crash severity levels occurred in Addis Ababa City, Ethiopia, from 2017 to 2020: using ordinal logistic regression model approach
Authors: Bekelcho Tariku , Olani Ararso Baru , Woldemeskel Asfawosen , Alemayehu Micheal , Guta Geleta
Published: September 2023

Background

Road traffic Injuries (RTI) are multifaceted occurrences determined by the combination of multiple factors. Also, severity levels of injuries from road traffic accidents are determined by the interaction of the composite factors. Even though most accidents are severe to fatal in developing countries, there is still a lack of extensive researches on crash severity levels and factors associated with these accidents. Hence, this study was intended to identify severity levels of road traffic injuries and determinant factors in Addis Ababa City, Ethiopia.

Methods

The study was conducted in Addis Ababa, the capital city of Ethiopia, using secondary data obtained from the Addis Ababa Police Commission office. The ordinal logistic regression model was used to investigate road traffic injury severity levels and factors worsening injury severity levels using the recorded dataset from October 2017 to July 2020.

Results

A total of 8458 car accidents were considered in the study, of which 15.1% were fatal, 46.7% severe, and 38.3% were slight injuries. The results of the ordinal logistic regression analysis estimation showed that being a commercial truck, college and above level educated driver, rollover crash, motorbike passengers, the crash day on Friday, and darkness were significantly associated factors with crash injury severity levels in the study area. On the contrary, driving experience (> 10 years), passenger of the vehicle, two-lane roads, and afternoon crashes were found to decrease the severity of road traffic injuries.

Conclusions

Road traffic injury reduction measures should include strict law enforcement in order to maintain road traffic rules especially among commercial truckers, motorcyclists, and government vehicle drivers. Also, it is better to train drivers to be more alert and conscious in their travels, especially on turning and handling their vehicles while driving.
An enigma of hypothyroidism and hyponatremia coexistence: a nationwide population-based retrospective study
Authors: Chu Chun-Hao , Chien Wu-Chien , Liu Chiung-Chen , Chung Chi-Hsiang , Chen Ying-Chuan , Kuo Feng-Chih , Fang Hung-Hsiang , Cheng Cheng-Yi , Ding Yi-Xuan , Tien Chiung-Hsi , Lin Chien-Ming
Published: September 2023

Introduction

Hypothyroidism is a rare and possible cause of hyponatremia. However, the clinical epidemiology and risk of mortality (ROM) when they coexist still remain elusive.

Objectives

We assessed the epidemiology and ROM among index patients with coexisting hypothyroidism and hyponatremia via a national population database.

Patients and methods

This retrospective cohort study utilized Taiwan’s National Health Insurance program database. Distributions of definite sociodemographic factors were analyzed. The annual incidence among the overall group and sex-subgroups was investigated. In addition, potential factors influencing the ROM were also evaluated.

Results

Of 4,549,226 patients from 1998 to 2015, a total of 3,140 index patients with concurrent hypothyroidism and hyponatremia were analyzed. The incidence rate increased tenfold from 1998 to 2015; average annual incidence rate was 174. Among the total participants, 57.1% were women; mean age was 72.6 ± 14.7 years and 88.8% were aged > 55 years. Although average length of stay (LOS) was 13.1 ± 15.4 days, the mortality group had significantly longer LOS than that in the survival group (12.9 days vs 22.2 days). Old age, catastrophic illness, cardiac dysrhythmia, and low hospital hierarchy were independent predictors of hospital mortality. The optimal LOS cutoff value for ROM prediction was 16 days. Index patients with LOS > 16 days increased ROM by 2.3-fold.

Conclusions

Coexistent hypothyroidism and hyponatremia is rare, although the incidence increased gradually. Factors influencing the ROM, such as old age, underlying catastrophic status, cardiac dysrhythmia, hospital hierarchy, and LOS should be considered in clinical care.
A qualitative evaluation of the national rollout of a diabetes prevention programme in England
Authors: Brunton Lisa , Soiland-Reyes Claudia , Wilson Paul
Published: September 2023

Background

The National Health Service Diabetes Prevention Programme (NHS DPP) was commissioned by NHS England in 2016 and rolled out in three ‘waves’ across the whole of England. It aims to help people with raised blood glucose levels reduce their risk of developing type 2 diabetes through behaviour change techniques (e.g., weight loss, dietary changes and exercise). An independent, longitudinal, mixed methods evaluation of the NHS DPP was undertaken. We report the findings from the implementation work package: a qualitative interview study with designated local leads, responsible for the local commissioning and implementation of the programme. The aim of the study was to explore how local implementation processes were enacted and adapted over time.

Methods

We conducted a telephone interview study across two time-points. Twenty-four semi-structured interviews with local leads across 19 sampled case sites were undertaken between October 2019 and January 2020 and 13 interviews with local leads across 13 sampled case sites were conducted between July 2020 and August 2020. Interviews aimed to reflect on the experience of implementation and explore how things changed over time.

Results

We identified four overarching themes to show how implementation was locally enacted and adapted across the sampled case sites: 1. Adapting to provider change; 2. Identification and referral; 3. Enhancing uptake in underserved populations; and 4. Digital and remote service options.

Conclusion

This paper reports how designated local leads, responsible for local implementation of the NHS DPP, adapted implementation efforts over the course of a changing national diabetes prevention programme, including how local leads adapted implementation during the COVID-19 pandemic. This paper highlights three main factors that influence implementation: the importance of facilitation, the ability (or not) to tailor interventions to local needs and the role of context in implementation.
Implementing quality management strategies improves clinical quality as a voluntary medical male circumcision program in Namibia matures: a process analysis
Authors: O’Bryan Gillian , Ensminger Alison , Billah Idel , Sithole Edwin , Nghatanga Magdaleena , Brandt Laura , Shepard Mark , Aupokolo Mekondjo , Mengistu Assegid Tassew , Forster Norbert , Zemburuka Brigitte , Mutandi Gram , Barnhart Scott , O’Malley Gabrielle , Feldacker Caryl
Published: September 2023

Background

Surgical voluntary medical male circumcision (VMMC) is a safe procedure; however, maintaining quality standards at scale, particularly during scale-up, is a challenge making ongoing quality management (QM) efforts essential. This study describes program quality measured by rates of adverse events (AEs) over four years of VMMC implementation in Namibia, compares AE rates over time, and discusses QM processes that contextualize AE trends and illustrate improvements in quality as the program matured. The International Training and Education Center for Health (I-TECH) assisted the Namibian Ministry of Health and Social Services (MoHSS) in expanding VMMC in three regions among boys and men over 10 years of age between January 2015 and September 2019.

Methods

A comprehensive package of QM strategies was implemented by multi-disciplinary onsite teams with support from national and international technical advisors. Retrospective routine MoHSS data from the VMMC register, client forms, and monthly AE reports were collected during implementation in the three regions to assess the impact of QM interventions on AEs and to calculate the proportion of clients who experienced AEs over time. The proportion of clients who experienced an AE over time was compared using a Cochran-Armitage test for trend.

Results

Between January 2015 and September 2019, 40,336 clients underwent VMMC and 593 (1.5%) clients experienced a post-operative AE in the three supported regions. The AE rate was highest in the first quarter of clinical service delivery in each region (January-March 2015 in Oshana and Zambezi, October-December 2017 in //Kharas) but declined over the implementation period as the program matured. This observed trend between program maturity and declining AE rates over time was significant (p < 0.001) when compared using a Cochran-Armitage test for trend.

Conclusions

As the I-TECH-supported VMMC program matured, QM measures were introduced and routinized, and clinical quality improved over time with the rate of AEs decreasing significantly over the implementation period. Applying systematic and continuous QM processes and approaches across the continuum of VMMC services and considering local context can contribute to increased clinical safety. QM measures that are established in more mature program sites can be quickly adopted to respond to quality issues in program expansion sites.
Interaction between phenylpropane metabolism and oil accumulation in the developing seed of Brassica napus revealed by high temporal-resolution transcriptomes
Authors: Yu Liangqian , Liu Dongxu , Yin Feifan , Yu Pugang , Lu Shaoping , Zhang Yuting , Zhao Hu , Lu Chaofu , Yao Xuan , Dai Cheng , Yang Qing-Yong , Guo Liang
Published: September 2023

Background

Brassica napus is an important oilseed crop providing high-quality vegetable oils for human consumption and non-food applications. However, the regulation between embryo and seed coat for the synthesis of oil and phenylpropanoid compounds remains largely unclear.

Results

Here, we analyzed the transcriptomes in developing seeds at 2-day intervals from 14 days after flowering (DAF) to 64 DAF. The 26 high-resolution time-course transcriptomes are clearly clustered into five distinct groups from stage I to stage V. A total of 2217 genes including 136 transcription factors, are specifically expressed in the seed and show high temporal specificity by being expressed only at certain stages of seed development. Furthermore, we analyzed the co-expression networks during seed development, which mainly included master regulatory transcription factors, lipid, and phenylpropane metabolism genes. The results show that the phenylpropane pathway is prominent during seed development, and the key enzymes in the phenylpropane metabolic pathway, including TT5, BAN, and the transporter TT19, were directly or indirectly related to many key enzymes and transcription factors involved in oil accumulation. We identified candidate genes that may regulate seed oil content based on the co-expression network analysis combined with correlation analysis of the gene expression with seed oil content and seed coat content.

Conclusions

Overall, these results reveal the transcriptional regulation between lipid and phenylpropane accumulation during B. napus seed development. The established co-expression networks and predicted key factors provide important resources for future studies to reveal the genetic control of oil accumulation in B. napus seeds.
Multi-omic insights into the formation and evolution of a novel shell microstructure in oysters
Authors: Bai Yitian , Liu Shikai , Hu Yiming , Yu Hong , Kong Lingfeng , Xu Chengxun , Li Qi
Published: September 2023

Background

Molluscan shell, composed of a diverse range of architectures and microstructures, is a classic model system to study the relationships between molecular evolution and biomineralized structure formation. The shells of oysters differ from those of other molluscs by possessing a novel microstructure, chalky calcite, which facilitates adaptation to the sessile lifestyle. However, the genetic basis and evolutionary origin of this adaptive innovation remain largely unexplored.

Results

We report the first whole-genome assembly and shell proteomes of the Iwagaki oyster Crassostrea nippona. Multi-omic integrative analyses revealed that independently expanded and co-opted tyrosinase, peroxidase, TIMP genes may contribute to the chalky layer formation in oysters. Comparisons with other molluscan shell proteomes imply that von Willebrand factor type A and chitin-binding domains are basic members of molluscan biomineralization toolkit. Genome-wide identification and analyses of these two domains in 19 metazoans enabled us to propose that the well-known Pif may share a common origin in the last common ancestor of Bilateria. Furthermore, Pif and LamG3 genes acquire new genetic function for shell mineralization in bivalves and the chalky calcite formation in oysters likely through a combination of gene duplication and domain reorganization.

Conclusions

The spatial expression of SMP genes in the mantle and molecular evolution of Pif are potentially involved in regulation of the chalky calcite deposition, thereby shaping the high plasticity of the oyster shell to adapt to a sessile lifestyle. This study further highlights neo-functionalization as a crucial mechanism for the diversification of shell mineralization and microstructures in molluscs, which may be applied more widely for studies on the evolution of metazoan biomineralization.
A phase 1 trial of fuzuloparib in combination with apatinib for advanced ovarian and triple-negative breast cancer: efficacy, safety, pharmacokinetics and germline BRCA mutation analysis
Authors: Liu Yaxin , Wang Wei , Yin Rutie , Zhang Youzhong , Zhang Yu , Zhang Keqiang , Pan Hongming , Wang Ke , Lou Ge , Li Guiling , Zhang Ruyan , Li Kun , Rao Jing , Zhang Ben , Wang Yuting , Wang Quanren , Gao Yunong , Li Huiping
Published: September 2023

Background

The effect of the combination of an anti-angiogenic agent with a poly (ADP-ribose) polymerase (PARP) inhibitor in cancer treatment is unclear. We assessed the oral combination of fuzuloparib, a PARP inhibitor, and apatinib, a VEGFR2 inhibitor for treating advanced ovarian cancer (OC) or triple-negative breast cancer (TNBC).

Methods

This dose-escalation and pharmacokinetics-expansion phase 1 trial was conducted in China. We used a standard 3 + 3 dose-escalation design, with 7 dose levels tested. Patients received fuzuloparib orally twice daily, and apatinib orally once daily. The study objectives were to determine the safety profile, recommended phase 2 dose (RP2D), pharmacokinetics, preliminary efficacy, and efficacy in relation to germline BRCA mutation (gBRCAmut).

Results

Fifty-two pre-treated patients were enrolled (30 OC/22 TNBC). 5 (9.6%) patients had complete response, 14 (26.9%) had partial response, and 15 (28.8%) had stable disease. Objective response rate (ORR) and disease control rate were 36.5% (95% CI 23.6–51.0) and 65.4% (95% CI 50.9–78.0), respectively. At the highest dose level of fuzuloparib 100 mg plus apatinib 500 mg, the ORR was 50.0% (4/8; 95% CI 15.7–84.3); this dose was determined to be the RP2D. Patients with gBRCAmut had higher ORR and longer median progression-free survival (PFS) than those with gBRCAwt, both in OC (ORR, 62.5% [5/8] vs 40.9% [9/22]; PFS, 9.4 vs 6.7 months) and TNBC (ORR, 66.7% [2/3] vs 15.8% [3/19]; PFS, 5.6 vs 2.8 months). Two dose-limiting toxicities occurred: grade 4 febrile neutropenia (fuzuloparib 100 mg plus apatinib 250 mg) and thrombocytopenia (fuzuloparib 100 mg plus apatinib 375 mg). Maximum tolerated dose was not reached. The most common treatment-related grade ≥ 3 toxicities in all patients were hypertension (19.2%), anaemia (13.5%), and decreased platelet count (5.8%). Exposure of apatinib increased proportionally with increasing dose ranging from 250 to 500 mg, when combined with fuzuloparib 100 mg.

Conclusions

Fuzuloparib plus apatinib had acceptable safety in patients with advanced OC or TNBC. Fuzuloparib 100 mg bid plus apatinib 500 mg qd was established as the RP2D. With the promising clinical activity observed, this combination is warranted to be further explored as a potential alternative to chemotherapy.

Trial registration

ClinicalTrials.gov, NCT03075462 (Mar. 9, 2017).
Integrating plasma proteomes with genome-wide association data for causal protein identification in multiple myeloma
Authors: Wang Qiangsheng , Shi Qiqin , Wang Zhenqian , Lu Jiawen , Hou Jian
Published: September 2023

Background

Multiple myeloma (MM) is a severely debilitating and fatal B-cell neoplastic disease. The discovery of disease-associated proteins with causal genetic evidence offers a chance to uncover novel therapeutic targets.

Methods

First, we comprehensively investigated the causal association between 2994 proteins and MM through two-sample mendelian randomization (MR) analysis using summary-level data from public genome-wide association studies of plasma proteome (N = 3301 healthy individuals) and MM (598 cases and 180,756 controls). Sensitivity analyses were performed for these identified causal proteins. Furthermore, we pursued the exploration of enriched biological pathways, prioritized the therapeutic proteins, and evaluated their druggability using the KEGG pathway analysis, MR-Bayesian model averaging analysis, and cross-reference with current databases, respectively.

Results

We identified 13 proteins causally associated with MM risk (false discovery rate corrected P < 0.05). Six proteins were positively associated with the risk of MM, including nicotinamide phosphoribosyl transferase (NAMPT; OR [95% CI]: 1.35 [1.18, 1.55]), tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (TIE1; 1.14 [1.06, 1.22]), neutrophil cytosol factor 2 (NCF2; 1.27 [1.12, 1.44]), carbonyl reductase 1, cAMP-specific 3',5'-cyclic phosphodiesterase 4D (PDE4D), platelet-activating factor acetylhydrolase IB subunit beta (PAFAH1B2). Seven proteins were inversely associated with MM, which referred to suppressor of cytokine signaling 3 (SOCS3; 0.90 [0.86, 0.94]), Fc-gamma receptor III-B (FCGR3B; 0.75 [0.65,0.86]), glypican-1 (GPC1; 0.69 [0.58,0.83]), follistatin-related protein 1, protein tyrosine phosphatase non-receptor type 4 (PTPN4), granzyme B, complement C1q subcomponent subunit C (C1QC). Three of the causal proteins, SOCS3, FCGR3B, and NCF2, were enriched in the osteoclast differentiation pathway in KEGG enrichment analyses while GPC1 (marginal inclusion probability (MIP):0.993; model averaged causal effects (MACE): − 0.349), NAMPT (MIP:0.433; MACE: − 0.113), and NCF2 (MIP:0.324; MACE:0.066) ranked among the top three MM-associated proteins according to MR-BMA analyses. Furthermore, therapeutics targeting four proteins are currently under evaluation, five are druggable and four are future breakthrough points.

Conclusions

Our analysis revealed a set of 13 novel proteins, including six risk and seven protective proteins, causally linked to MM risk. The discovery of these MM-associated proteins opens up the possibility for identifying novel therapeutic targets, further advancing the integration of genome and proteome data for drug development.
Effect of fermented dandelion on productive performance, meat quality, immune function, and intestinal microbiota of broiler chickens
Authors: Mao Jinju , Wang Yuan , Duan Ting , Yin Na , Dong Chenlin , Ren Xuerong , Liu Na , An Xiaoping , Qi Jingwei
Published: September 2023

Background

Dandelion has a great potential to be used as feed additive. Using microbial fermentation technology to degrade cell walls is conducive to enable better release of bioactive compounds of dandelion. This study intended to explore the effect of fermented dandelion (FD) on production performance, meat quality, immune function, and intestinal microbiota of broiler chickens. One-hundred and twenty 1-day-old male Arbor Acres broiler chickens were randomly allotted into three treatments: CON (basal diet, control), LFD and HFD (basal diet with 500 and 1000 mg/kg FD, respectively), with five replicates of eight birds each. The experiment lasted for 42 days.

Results

The results showed that birds in HFD group had increased ADG during 1–21 days (P < 0.05). On day 21, the bursa of Fabricius index of birds in LFD group was higher (P < 0.05), while the serum contents of IFN-γ and TNF-ɑ were lower in HFD group (P < 0.05). FD supplementation decreased the observed_species, shannon, chao1 and ace indexes (P < 0.05) as well as the abundance of Bacteroidota, Bacteroides, and Alistipes (P < 0.05). Birds in HFD group had higher abundance of Firmicutes and lower abundance of Verrucomicrobiota (P < 0.05). LFD group had lower abundance of unidentified_bacteria (P < 0.05). On day 42, the abdominal fat yield of HFD group was decreased (P < 0.05). Birds in LFD group had lower L* and b* values of breast muscle (P < 0.05), while higher spleen index. The CAT activities of breast muscle of FD groups were higher (P < 0.05).

Conclusion

In summary, dietary FD supplementation at 1000 mg/kg improved production performance and immune function and modulated microbiota composition in ileum of broiler chickens. FD can be supplemented in the diet to enhance performance and health of broiler chickens, of which 1000 mg/kg FD is more effective.
Mechanical stretch promotes apoptosis and impedes ciliogenesis of primary human airway basal stem cells
Authors: Lin Li-Qin , Zeng Hai-Kang , Luo Yu-Long , Chen Di-Fei , Ma Xiao-Qian , Chen Huan-Jie , Song Xin-Yu , Wu Hong-Kai , Li Shi-Yue
Published: September 2023

Background

Airway basal stem cells (ABSCs) have self-renewal and differentiation abilities. Although an abnormal mechanical environment related to chronic airway disease (CAD) can cause ABSC dysfunction, it remains unclear how mechanical stretch regulates the behavior and structure of ABSCs. Here, we explored the effect of mechanical stretch on primary human ABSCs.

Methods

Primary human ABSCs were isolated from healthy volunteers. A Flexcell FX-5000 Tension system was used to mimic the pathological airway mechanical stretch conditions of patients with CAD. ABSCs were stretched for 12, 24, or 48 h with 20% elongation. We first performed bulk RNA sequencing to identify the most predominantly changed genes and pathways. Next, apoptosis of stretched ABSCs was detected with Annexin V-FITC/PI staining and a caspase 3 activity assay. Proliferation of stretched ABSCs was assessed by measuringMKI67mRNA expression and cell cycle dynamics. Immunofluorescence and hematoxylin-eosin staining were used to demonstrate the differentiation state of ABSCs at the air-liquid interface.

Results

Compared with unstretched control cells, apoptosis and caspase 3 activation of ABSCs stretched for 48 h were significantly increased (p < 0.0001; p < 0.0001, respectively), andMKI67mRNA levels were decreased (p < 0.0001). In addition, a significant increase in the G0/G1 population (20.2%, p < 0.001) and a significant decrease in S-phase cells (21.1%, p < 0.0001) were observed. The ratio of Krt5+ABSCs was significantly higher (32.38% vs. 48.71%, p = 0.0037) following stretching, while the ratio of Ac-tub+cells was significantly lower (37.64% vs. 21.29%, p < 0.001). Moreover, compared with the control, the expression ofNKX2-1was upregulated significantly after stretching (14.06% vs. 39.51%, p < 0.0001). RNA sequencing showed 285 differentially expressed genes, among which 140 were upregulated and 145 were downregulated, revealing thatDDIAS, BIRC5, TGFBI, andNKX2-1may be involved in the function of primary human ABSCs during mechanical stretch. There was no apparent difference between stretching ABSCs for 24 and 48 h compared with the control.

Conclusions

Pathological stretching induces apoptosis of ABSCs, inhibits their proliferation, and disrupts cilia cell differentiation. These features may be related to abnormal regeneration and repair observed after airway epithelium injury in patients with CAD.
Yearly attained adherence to Mediterranean diet and incidence of diabetes in a large randomized trial
Authors: Martínez-González Miguel A. , Montero Pedro , Ruiz-Canela Miguel , Toledo Estefanía , Estruch Ramón , Gómez-Gracia Enrique , Li Jun , Ros Emilio , Arós Fernando , Hernáez Alvaro , Corella Dolores , Fiol Miquel , Lapetra José , Serra-Majem Lluis , Pintó Xavier , Cofán Montse , Sorlí José V. , Babio Nancy , Márquez-Sandoval Yolanda F. , Castañer Olga , Salas-Salvadó Jordi
Published: September 2023

Background

Several large observational prospective studies have reported a protection by the traditional Mediterranean diet against type 2 diabetes, but none of them used yearly repeated measures of dietary intake. Repeated measurements of dietary intake are able to improve subject classification and to increase the quality of the assessed relationships in nutritional epidemiology. Beyond observational studies, randomized trials provide stronger causal evidence. In the context of a randomized trial of primary cardiovascular prevention, we assessed type 2 diabetes incidence according to yearly repeated measures of compliance with a nutritional intervention based on the traditional Mediterranean diet.

Methods

PREDIMED (‘‘PREvención con DIeta MEDiterránea’’) was a Spanish trial including 7447 men and women at high cardiovascular risk. We assessed 3541 participants initially free of diabetes and originally randomized to 1 of 3 diets: low-fat diet (n = 1147, control group), Mediterranean diet supplemented with extra virgin olive (n = 1154) or Mediterranean diet supplemented with mixed nuts (n = 1240). As exposure we used actual adherence to Mediterranean diet (cumulative average), yearly assessed with the Mediterranean Diet Adherence Screener (scoring 0 to 14 points), and repeated up to 8 times (baseline and 7 consecutive follow-up years). This score was categorized into four groups: < 8, 8–< 10, 10– < 12, and 12–14 points. The outcome was new-onset type 2 diabetes.

Results

Multivariable-adjusted hazard ratios from time-varying Cox models were 0.80 (95% confidence interval, 0.70–0.92) per + 2 points in Mediterranean Diet Adherence Screener (linear trend p = .001), and 0.46 (0.25–0.83) for the highest (12–14 points) versus the lowest (< 8) adherence. This inverse association was maintained after additionally adjusting for the randomized arm. Age- and sex-adjusted analysis of a validated plasma metabolomic signature of the Mediterranean Diet Adherence Screener (constituted of 67 metabolites) in a subset of 889 participants also supported these results.

Conclusions

Dietary intervention trials should quantify actual dietary adherence throughout the trial period to enhance the benefits and to assist results interpretation. A rapid dietary assessment tool, yearly repeated as a screener, was able to capture a strong inverse linear relationship between Mediterranean diet and type 2 diabetes.

Trial registration ISRCTN35739639
High triglyceride-glucose (TyG) index is associated with poor prognosis of heart failure with preserved ejection fraction
Authors: Zhou Qing , Yang Jie , Tang Hongyi , Guo Zexuan , Dong Wenyue , Wang Yiting , Meng Xiangbin , Zhang Kuo , Wang Wenyao , Shao Chunli , Hua Xinwei , Tang Yi-Da
Published: September 2023

Background

The impact of insulin resistance on the prognosis of heart failure with preserved ejection fraction (HFpEF) remains unknown. This study aimed to investigate the association between the triglyceride-glucose (TyG) index, an easily calculated marker of insulin resistance, and the long-term prognosis of HFpEF.

Methods

A total of 823 patients with HFpEF were enrolled in the study. The TyG index was determined using the formula ln(fasting triglycerides [mg/dL] × fasting glucose [mg/dL]/2). The primary endpoint was all-cause death. The secondary endpoints were cardiovascular (CV) death and heart failure (HF) rehospitalization. Restricted cubic spline, multivariate Cox proportional hazard models, and competing risk models were used for analyses.

Results

During a median follow-up period of 3.16 years, 147 (17.8%) all-cause deaths, 139 (16.8%) CV deaths, and 222 (27.0%) HF rehospitalizations occurred. Restricted cubic spline analysis revealed a J-shaped association between the TyG index and the mortality and rehospitalization rates. In the multivariate Cox proportional hazard models, compared with those in the lowest TyG index tertile, patients in the highest tertile exhibited the greatest susceptibility to all-cause death (HR 1.53, 95% CI 1.19–1.98) and CV death (HR 1.52, 95% CI 1.19–1.96). In the competing risk model, a significant association between the TyG index and HF rehospitalization was observed (HR 1.31, 95% CI, 1.07–1.61).

Conclusion

A high TyG index is associated with an increased risk of mortality and rehospitalization in patients with HFpEF. The TyG index may serve as a promising prognostic marker for patients with HFpEF.
Refactoring the architecture of a polyketide gene cluster enhances docosahexaenoic acid production in Yarrowia lipolytica through improved expression and genetic stability
Authors: Dietrich Demian , Jovanovic-Gasovic Sofija , Cao Peng , Kohlstedt Michael , Wittmann Christoph
Published: September 2023

Background

Long-chain polyunsaturated fatty acids (LC-PUFAs), such as docosahexaenoic acid (DHA), are essential for human health and have been widely used in the food and pharmaceutical industries. However, the limited availability of natural sources, such as oily fish, has led to the pursuit of microbial production as a promising alternative. Yarrowia lipolytica can produce various PUFAs via genetic modification. A recent study upgraded Y. lipolytica for DHA production by expressing a four-gene cluster encoding a myxobacterial PKS-like PUFA synthase, reducing the demand for redox power. However, the genetic architecture of gene expression in Y. lipolytica is complex and involves various control elements, offering space for additional improvement of DHA production. This study was designed to optimize the expression of the PUFA cluster using a modular cloning approach.

Results

Expression of the monocistronic cluster with each gene under the control of the constitutive TEF promoter led to low-level DHA production. By using the minLEU2 promoter instead and incorporating additional upstream activating UAS1B4 sequences, 5' promoter introns, and intergenic spacers, DHA production was increased by 16-fold. The producers remained stable over 185 h of cultivation. Beneficially, the different genetic control elements acted synergistically: UAS1B elements generally increased expression, while the intron caused gene-specific effects. Mutants with UAS1B16 sequences within 2–8 kb distance, however, were found to be genetically unstable, which limited production performance over time, suggesting the avoidance of long repetitive sequence blocks in synthetic multigene clusters and careful monitoring of genetic stability in producing strains.

Conclusions

Overall, the results demonstrate the effectiveness of synthetic heterologous gene clusters to drive DHA production in Y. lipolytica. The combinatorial exploration of different genetic control elements allowed the optimization of DHA production. These findings have important implications for developing Y. lipolytica strains for the industrial-scale production of valuable polyunsaturated fatty acids.
Managing high-risk behaviours and challenges to prevent housing loss in permanent supportive housing: a rapid review
Authors: Kerman Nick , Kidd Sean A. , Mutschler Christina , Sylvestre John , Henwood Benjamin F. , Oudshoorn Abe , Marshall Carrie Anne , Aubry Tim , Stergiopoulos Vicky
Published: September 2023

Permanent supportive housing is an effective intervention for stably housing most people experiencing homelessness and mental illness who have complex support needs. However, high-risk behaviours and challenges are prevalent among this population and have the potential to seriously harm health and threaten housing tenures. Yet, the research on the relationship between high-risk issues and housing stability in permanent supportive housing has not been previously synthesized. This rapid review aimed to identify the housing-related outcomes of high-risk behaviours and challenges in permanent supportive housing settings, as well as the approaches used by agencies and residents to address them. A range of high-risk behaviours and challenges were examined, including risks to self (overdose, suicide/suicide attempts, non-suicidal self-injury, falls/fall-related injuries), and risks to multiple parties and/or building (fire-setting/arson, hoarding, apartment takeovers, physical/sexual violence, property damage, drug selling, sex trafficking). The search strategy included four components to identify relevant academic and grey literature: (1) searches of MEDLINE, APA PsycINFO, and CINAHL Plus; (2) hand searches of three journals with aims specific to housing and homelessness; (3) website browsing/searching of seven homelessness, supportive housing, and mental health agencies and networks; and (4) Advanced Google searches. A total of 32 articles were eligible and included in the review. Six studies examined the impacts of high-risk behaviours and challenges on housing tenancies, with overdose being identified as a notable cause of death. Twenty-six studies examined approaches and barriers to managing high-risk behaviours and challenges in PSH programs. These were categorized into eight types of approaches: (1) clinical, (2) relational/educational, (3) surveillant, (4) restrictive, (5) strategic, (6) design-based, (7) legal, and (8) self-defence. Consistent across all approaches was a lack of rigorous examination of their effectiveness. Further, some approaches that are legal, restrictive, surveillant, or strategic in nature may be used to promote safety, but may conflict with other program objectives, including housing stability, or resident empowerment and choice. Research priorities were identified to address the key evidence gaps and move toward best practices for preventing and managing high-risk behaviours and challenges in permanent supportive housing.
MicroRNA-125a-5p regulates the effect of Tregs on Th1 and Th17 through targeting ETS-1/STAT3 in psoriasis
Authors: Yan Kexiang , Zhang Fuxin , Ren Jie , Huang Qiong , Yawalkar Nikhil , Han Ling
Published: September 2023

Background

Psoriasis is an inflammatory disease mediated by helper T (Th)17 and Th1 cells. MicroRNA-125a (miR-125a) is reduced in the lesional skin of psoriatic patients. However, the mechanism by which miR-125a participates in psoriasis remains unclear.

Methods

The levels of miR-125a-5p and its downstream targets (ETS-1, IFN-γ, and STAT3) were detected in CD4+ T cells of healthy controls and psoriatic patients by quantitative real-time PCR (qRT-PCR). In vitro, transfection of miR-125a-5p mimics was used to analyze the effect of miR-125a-5p on the differentiation of Th17 cells by flow cytometry. Imiquimod (IMQ)-induced mouse model was used to evaluate the role of upregulating miR-125a-5p by intradermal injection of agomir-125a-5p in vivo.

Results

miR-125a-5p was downregulated in peripheral blood CD4+ T cells of psoriatic patients, which was positively associated with the proportion of regulatory T cells (Tregs) and negatively correlated with the Psoriasis Area and Severity Index (PASI) score. Moreover, the miR-125a-5p mimics promoted the differentiation of Tregs and downregulated the messenger RNA (mRNA) levels of ETS-1, IFN-γ, and STAT3 in murine CD4+ T cells. Furthermore, agomir-125a-5p alleviated psoriasis-like inflammation in an IMQ-induced mouse model by downregulating the proportion of Th17 cells.

Conclusions

miR-125a-5p may have therapeutic potential in psoriasis by restoring the suppressive function of Tregs on Th17 cells through targeting STAT3, and on Th1 cells indirectly through targeting ETS-1 and IFN-γ.
Influenza H7N9 virus disrupts the monolayer human brain microvascular endothelial cells barrier in vitro
Authors: Lei Yuxuan , Sun Ying , Wu Weihua , Liu Hui , Wang Xin , Shu Yuelong , Fang Shisong
Published: September 2023

Influenza H7N9 virus causes human infections with about 40% case fatality rate. The severe cases usually present with pneumonia; however, some present with central nervous system complications. Pneumonia syndrome is attributed to the cytokine storm after infection with H7N9, but the pathogenic mechanism of central nervous system complications has not been clarified. This study used immortalized human brain microvascular endothelial cells hCMEC/D3 to simulate the blood-brain barrier. It demonstrated that H7N9 virus could infect brain microvascular endothelial cells and compromise the blood-brain barrier integrity and permeability by down-regulating the expression of cell junction-related proteins, including claudin-5, occludin, and vascular endothelial (VE)-cadherin. These results suggested that H7N9 could infect the blood-brain barrier in vitro and affect its functions, which could be a potential mechanism for the pathogenesis of H7N9 viral encephalopathy.