bluuebunny/crossref_metadata_2025 huggingface dataset:
Is metabolic syndrome a risk factor in hepatectomy? A meta-analysis with subgroup analysis for histologically confirmed hepatic manifestations
Authors: Murtha-Lemekhova Anastasia , Fuchs Juri , Feiler Svenja , Schulz Erik , Teroerde Miriam , Kalkum Eva , Klotz Rosa , Billeter Adrian , Probst Pascal , Hoffmann Katrin
Published: January 2022

Background

Metabolic syndrome (MetS) is a risk factor in surgery. MetS can progress to metabolic (dysfunction)-associated fatty liver disease (MAFLD), a vast-growing etiology of primary liver tumors which are major indications for liver surgery. The aim of this meta-analysis was to investigate the impact of MetS on complications and long-term outcomes after hepatectomy.

Methods

The protocol for this meta-analysis was registered at PROSPERO prior to data extraction. MEDLINE, Web of Science, and Cochrane Library were searched for publications on liver resections and MetS. Comparative studies were included. Outcomes encompassed postoperative complications, mortality, and long-term oncologic status. Data were pooled as odds ratio (OR) with a random-effects model. Risk of bias was assessed using the Quality in Prognostic Studies tool (QUIPS), and the certainty of the evidence was evaluated with GRADE. Subgroup analyses for patients with histopathologically confirmed non-alcoholic fatty liver disease (NAFLD) versus controls were performed.

Results

The meta-analyses included fifteen comparative studies. Patients with MetS suffered significantly more overall complications (OR 1.55; 95% CI [1.05; 2.29]; p=0.03), major complications (OR 1.97 95% CI [1.13; 3.43]; p=0.02; I2=62%), postoperative hemorrhages (OR 1.76; 95% CI [1.23; 2.50]; p=0.01) and infections (OR 1.63; 95% CI [1.03; 2.57]; p=0.04). There were no significant differences in mortality, recurrence, 1- or 5-year overall or recurrence-free survivals. Patients with histologically confirmed NAFLD did not have significantly more overall complications; however, PHLF rates were increased (OR 4.87; 95% CI [1.22; 19.47]; p=0.04). Recurrence and survival outcomes did not differ significantly. The certainty of the evidence for each outcome ranged from low to very low.

Conclusion

Patients with MetS that undergo liver surgery suffer more complications, such as postoperative hemorrhage and infection but not liver-specific complications—PHLF and biliary leakage. Histologically confirmed NAFLD is associated with significantly higher PHLF rates, yet, survivals of these patients are similar to patients without the MetS. Further studies should focus on identifying the tipping point for increased risk in patients with MetS-associated liver disease, as well as reliable markers of MAFLD stages and early markers of PHLF.

Trial registration

PROSPERO Nr: CRD42021253768
Alterations in chromatin accessibility during osteoblast and adipocyte differentiation in human mesenchymal stem cells
Authors: Liu Jianyun , Gan Lijun , Ma Baichen , He Shan , Wu Ping , Li Huiming , Xiong Jianjun
Published: January 2022

Although differential expression of genes is apparent during the adipogenic/osteogenic differentiation of marrow mesenchymal stem cells (MSCs), it is not known whether this is associated with changes in chromosomal structure. In this study, we used ATAC-sequencing technology to observe variations in chromatin assembly during the early stages of MSC differentiation. This showed significant changes in the number and distribution of chromosome accessibility at different time points of adipogenic/osteogenic differentiation. Sequencing of differential peaks indicated alterations in transcription factor motifs involved in MSC differentiation. Gene Ontology (GO) and pathway analysis indicated that changes in biological function resulted from the alterations in chromatin accessibility. We then integrated ATAC-seq and RNA-seq and found that only a small proportion of the overlapping genes were screened out from ATAC-seq and RNA-seq overlapping. Through GO and pathway analysis of these overlapped genes, we not only observed some known biological functions related to adipogenic/osteogenic differentiation but also noticed some unusual biological clustering during MSC differentiation. In summary, our work not only presents the landscape of chromatin accessibility of MSC during differentiation but also helps to further our understanding of the underlying mechanisms of gene expression in these processes.
Implications of fasting plasma glucose variability on the risk of incident peripheral artery disease in a population without diabetes: a nationwide population-based cohort study
Authors: Chung Hye Soo , Hwang Soon Young , Kim Jung A. , Roh Eun , Yoo Hye Jin , Baik Sei Hyun , Kim Nan Hee , Seo Ji A. , Kim Sin Gon , Kim Nam Hoon , Choi Kyung Mook
Published: January 2022

Background

Diabetes have been known as a traditional risk factor of developing peripheral artery disease (PAD). However, the study evaluating the impact of long-term glycemic variability on the risk of developing PAD is limited, especially in a general population without diabetes.

Methods

We included 152,931 individuals without diabetes from the Korean National Health Insurance Service–Health Screening Cohort. Fasting plasma glucose (FPG) variability was measured using coefficient variance (FPG-CV), standard deviation (FPG-SD), and variability independent of the mean (FPG-VIM).

Results

A total of 16,863 (11.0%) incident cases of PAD were identified during a median follow-up of 8.3 years. Kaplan–Meier curves showed a progressively increasing risk of PAD in the higher quartile group of FPG variability than in the lowest quartile group (log rank P < 0.001). Multivariable Cox proportional hazard analysis showed the hazard ratio for PAD prevalence as 1.11 (95% CI 1.07–1.16, P < 0.001) in the highest FPG-CV quartile than in the lowest FPG-CV quartile after adjusting for confounding variables, including mean FPG. Similar degree of association was shown in the FPG-SD and FPG-VIM. In sensitivity analysis, the association between FPG variability and the risk of developing PAD persisted even after the participants were excluded based on previously diagnosed diseases, including stroke, coronary artery disease, congestive heart failure, chronic kidney disease, or current smokers or drinkers. Subgroup analysis demonstrated that the effects of FPG variability on the risk of PAD were more powerful in subgroups of younger age, regular exercisers, and those with higher income.

Conclusions

Increased long-term glycemic variability may have a significant prognostic effect for incident PAD in individuals without diabetes.

Graphical
Abstract
ZMIZ2 promotes the development of triple-receptor negative breast cancer
Authors: Zou Xiaopan , Liu Yan , Di Jun , Wei Wei , Watanabe Nobumoto , Li Jiang , Li Xiaomeng
Published: January 2022

Background

Triple-receptor negative breast cancer (TNBC) is an aggressive breast tumor subtype that generally has a poor prognosis. This study aimed to investigate the role and regulatory mechanisms of Zinc finger MIZ-type containing 2 (ZMIZ2) in relation to TNBC.

Methods

Based on data from The Cancer Genome Atlas (TCGA), the expression of ZMIZ2 in different subtypes and its correlation with androgen receptor (AR) were analyzed, and a regulatory mechanism network was constructed. The expression and prognostic value of ZMIZ2 in clinical TNBC tissue samples were also investigated. Furthermore, in vitro studies were conducted to investigate the effects of ZMIZ2 knockdown on the malignant behaviors of TNBC cells and target gene expression.

Results

Based on TCGA data, ZMIZ2 was found to be significantly upregulated in TNBC tissues and its expression was negatively correlated with AR expression. Key relationships, such as the ZMIZ2-CCL5, ZMIZ2/AR-MCM3, ZMIZ2/AR-E2F4, and the ZMIZ2/AR-DHX38 were identified, which were enriched in NOD-like receptor signaling pathway/toll-like receptor signaling pathway, DNA replication, cell cycle, and spliceosome, respectively. Moreover, ZMIZ2 was upregulated in clinical breast cancer tissues and its high expression was correlated with the poor prognosis of TNBC patients. Furthermore, ZMIZ2 expression was increased in breast cancer cells, and a knockdown of ZMIZ2 inhibited MDA-MB-231 cell proliferation, migration, and invasion, induced cell cycle arrest in the G1 phase, and promoted cell apoptosis. Furthermore, ZMIZ2 knockdown inhibited the mRNA and protein expression of CCL5, MCM3, E2F4, and DHX38.

Conclusion

Our findings reveal that ZMIZ2 is upregulated in TNBC tissues and is associated with its poor prognosis. ZMIZ2 may promote TNBC progression by promoting the expression of its target genes and affecting the corresponding pathways. Consequently, ZMIZ2 may serve as a promising target for future TNBC treatments.
Antitumor responses in gastric cancer by targeting B7H3 via chimeric antigen receptor T cells
Authors: Sun Fengqiang , Yu Xiaomei , Ju Ruixue , Wang Zhanzhao , Wang Yuhui
Published: January 2022

Background

Gastric cancer (GC) has a poor prognosis and limited therapeutic options. As a new promising cancer therapeutic approach, chimeric antigen receptor (CAR)-T cells represent a potential GC treatment. We investigated the antitumor activity of CAR-T cells target-B7H3 in GC.

Methods

In our study, expression of B7H3 was examined in GC tissues and explored the tumoricidal potential of B7H3-targeting CAR-T cells in GC. B7H3-directed CAR-T cells with a humanized antigen-recognizing domain was generated. The anti-tumor effects of this CAR-T cell were finally investigated in vitro and in vivo.

Results

Our results show that B7H3-directed CAR-T cells efficiently killed GC tumor cells. In addition, we found that B7H3 is correlated with tumor cell stemness, and anti-B7H3 CAR-T can simultaneously target stem cell-like GC cells to improve the treatment outcome.

Conclusions

Our study indicates that B7H3 is an attractive target for GC therapy, and B7H3 has high potential for clinical application.
Evaluating the knowledge on microbiome and dysbiosis in allergic diseases among medical sciences students in Saudi Arabia
Authors: Alamri Aisha , AlKhater Suzan A.
Published: January 2022

Background

Microbiome science deals with the development of diseases that are derived from the interaction between the host immune system and microbes. Microbiome disturbance or dysbiosis has been increasingly recognized as an important contributor to the pathogenesis of allergic diseases. Thus, this field is pivotal in the management of allergic disorders. Despite the increasing prevalence of allergic disorders in Saudi Arabia, medical students lack knowledge of microbiome science. Therefore, this study aimed to assess the level of knowledge of medical sciences students on the human microbiome, dysbiosis, and management of the impaired microbiome with a focus on allergic diseases and asthma.

Methods

An online survey was designed, validated, and distributed to 100 final-year students and interns majoring in clinical nutrition, public health, and clinical laboratory sciences at a single university in Saudi Arabia. The study period was from November 2020 to January 2021.

Results

The overall knowledge of the human microbiome was adequate among the participants, but their understanding of dysbiosis and management of the impaired microbiome was low to moderate. Knowledge of dysbiosis management was significantly higher in students majoring in clinical nutrition than in those majoring in public health and clinical laboratory sciences.

Conclusions

Collectively, this study provides the first evidence that knowledge of specific domains of microbiome science among a cohort of medical sciences students in Saudi Arabia is insufficient. Large-scale studies are warranted to confirm these observations at a national level, and specific curriculum modifications are necessary to improve the knowledge of future healthcare professionals about clinical applications of microbiome science.
Increased use of knowledge translation strategies is associated with greater research impact on public health policy and practice: an analysis of trials of nutrition, physical activity, sexual health, tobacco, alcohol and substance use interventions
Authors: Wolfenden Luke , Mooney Kaitlin , Gonzalez Sharleen , Hall Alix , Hodder Rebecca , Nathan Nicole , Yoong Serene , Ditton Elizabeth , Sutherland Rachel , Lecathelinais Christophe , McCrabb Sam
Published: January 2022

Background

Greater use of knowledge translation (KT) strategies is recommended to improve the research impact of public health trials. The purpose of this study was to describe (1) the research impact of setting-based public health intervention trials on public health policy and practice; (2) the association between characteristics of trials and their research impact on public health policy and practice; and (3) the association between the use of KT strategies and research impacts on public health policy and practice.

Methods

We conducted a survey of authors of intervention trials targeting nutrition, physical activity, sexual health, tobacco, alcohol or substance use. We assessed the use of KT strategies aligned to domains of the Knowledge-To-Action Framework. We defined “research impact” on health policy and practice as any one or more of the following: citation in policy documents or announcements, government reports, training materials, guidelines, textbooks or court rulings; or endorsement by a (non)governmental organization; use in policy or practice decision-making; or use in the development of a commercial resource or service.

Results

Of the included trials, the authors reported that 65% had one or more research impacts. The most frequently reported research impact was citation in a policy document or announcement (46%). There were no significant associations between the effectiveness of the intervention, trial risk of bias, setting or health risk and trial impact. However, for every one unit increase in the total KT score (range 0–8), reflecting greater total KT activity, the odds of a health policy or practice research impact increased by approximately 30% (OR = 1.30, 95% CI: 1.02, 1.66; p = 0.031). Post hoc examination of KT domain scores suggests that KT actions focused on providing tailored support to facilitate program implementation and greater use of research products and tools to disseminate findings to end-users may be most influential in achieving impact.

Conclusions

Trials of public health interventions frequently have public health impacts, and the use of more comprehensive KT strategies may facilitate greater research impact.
Ceramide from sphingomyelin hydrolysis induces neuronal differentiation, whereas de novo ceramide synthesis and sphingomyelin hydrolysis initiate apoptosis after NGF withdrawal in PC12 Cells
Authors: Kagan Terri , Stoyanova Gloria , Lockshin Richard A. , Zakeri Zahra
Published: January 2022

Background

Ceramide, important for both neuronal differentiation and dedifferentiation, resides in several membranes, is synthesized in the endoplasmic reticulum, mitochondrial, and nuclear membranes, and can be further processed into glycosphingolipids or sphingomyelin. Ceramide may also be generated by hydrolysis of sphingomyelin by neutral or acidic sphingomyelinases in lysosomes and other membranes. Here we asked whether the differing functions of ceramide derived from different origins.

Methods

We added NGF to PC12 cells and to TrkA cells. These latter overexpress NGF receptors and are partially activated to differentiate, whereas NGF is required for PC12 cells to differentiate. We differentiated synthesis from hydrolysis by the use of appropriate inhibitors. Ceramide and sphingomyelin were measured by radiolabeling.

Results

When NGF is added, the kinetics and amounts of ceramide and sphingomyelin indicate that the ceramide comes primarily from hydrolysis but, when hydrolysis is inhibited, can also come from neosynthesis. When NGF is removed, the ceramide comes from both neosynthesis and hydrolysis.

Conclusion

We conclude that the function of ceramide depends heavily on its intracellular location, and that further understanding of its function will depend on resolving its location during changes of cell status.

Graphical Abstract
Liver-specific LINC01146, a promising prognostic indicator, inhibits the malignant phenotype of hepatocellular carcinoma cells both in vitro and in vivo
Authors: Ma Xiaoyun , Mo Meile , Tan Chao , Tan Jennifer Hui Juan , Huang Huishen , Liu Bihu , Huang Dongping , Liu Shun , Zeng Xiaoyun , Qiu Xiaoqiang
Published: January 2022

Background

Long non-coding RNAs (lncRNAs) are involved in the development of hepatocellular carcinoma (HCC). We aimed to investigate the function of LINC01146 in HCC.

Methods

The expression of LINC01146 in HCC tissues was explored via The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and was verified using quantitative real-time polymerase chain reaction (qRT–PCR) in our HCC cohort. Kaplan–Meier analysis was used to assess the relationship between LINC01146 and the prognosis of HCC patients. Cell Counting Kit 8, colony formation assays, Transwell assays, flow cytometric assays, and tumour formation models in nude mice were conducted to reveal the effects of LINC01146 on HCC cells both in vitro and in vivo. Bioinformatic methods were used to explore the possible potential pathways of LINC01146 in HCC.

Results

LINC01146 was significantly decreased in HCC tissues compared with adjacent normal tissues and was found to be related to the clinical presentations of malignancy and the poor prognosis of HCC patients. Overexpression of LINC01146 inhibited the proliferation, migration, and invasion of HCC cells in vitro, while promoting their apoptosis. In contrast, downregulation of LINC01146 exerted the opposite effects on HCC cells in vitro. In addition, overexpression of LINC01146 significantly inhibited tumour growth, while downregulation of LINC01146 promoted tumour growth in vivo. Furthermore, the coexpressed genes of LINC01146 were mainly involved in the “metabolic pathway” and “complement and coagulation cascade pathway”.

Conclusion

LINC01146 expression was found to be decreased in HCC tissues and associated with the prognosis of HCC patients. It may serve as a cancer suppressor and prognostic biomarker in HCC.
Modeling the determinant of time to age at first marriage among women in Ethiopia using Cox models with mixed effects
Authors: Gobena Molalign Gualu , Berelie Yebelay
Published: January 2022

Background

Time to age at first marriage of women is the duration of time until the age at which they started living with their first partner. Time to age at first marriage is widely considered a proxy indicator for the age at which women begin to be exposed to the risks inherent in sexual activity. The purpose is to model the determinant of time to age at first marriage among women in Ethiopia using Cox models with mixed effects.

Methods

The 2016 Ethiopian Demography and Health survey sample was selected using a two-stage cluster design. The data set in this study were obtained from the Demography and Health survey conducted in Ethiopia in 2016. In this study, we used Cox models with mixed effects.

Results

Of all 15,683 women aged 15–49 years, 11,405 (72.72%) were married with the median and mean age at first marriage 17 years and 18 years, respectively. Cox frailty survival model showed that residence, educational level, occupation, work status of women& head education level of households were the most significant factors whereas religion, access to media and wealth index of a household of women were not significant factors at 5% level of significance. The significant clustering effect showed that heterogeneity among the regions on age at first marriage was present.

Conclusions

The present study determined the duration of time until the age at first marriage and indicated relevant solutions for marriage-related problems of women aged 15–49 years in Ethiopia. Women residing in rural area of Ethiopia and had lower education level were married earlier. Therefore, programs to reduce the high rate of early marriage in Ethiopia should give attention to women education and women residing in rural area.
CHEK2 mutations and papillary thyroid cancer: correlation or coincidence?
Authors: Koen Kortbeek , Robin De Putter , Eline Naert
Published: January 2022

We report the case of a breast cancer survivor, diagnosed with an underlying CHEK2 c.1100delC heterozygosity, who developed a papillary thyroid cancer 5 years later. A CHEK2 c.1100delC (likely) pathogenic variant is associated with an increased risk of breast, prostate and colorectal cancer and therefore risk-specific screening will be offered. Current national and international screening guidelines do not recommend routine screening for thyroid cancer. Hence, we reviewed the literature to explore the possible association between a CHEK2 mutation and thyroid cancer. A weak association was found between the various CHEK2 mutations and papillary thyroid cancer. The evidence for an association with CHEK2 c.1100delC in particular is the least robust. In conclusion, there is insufficient evidence to warrant systematic thyroid screening in CHEK2 carriers.
AGAMEMNON: an Accurate metaGenomics And MEtatranscriptoMics quaNtificatiON analysis suite
Authors: Skoufos Giorgos , Almodaresi Fatemeh , Zakeri Mohsen , Paulson Joseph N. , Patro Rob , Hatzigeorgiou Artemis G. , Vlachos Ioannis S.
Published: January 2022

We introduce AGAMEMNON (https://github.com/ivlachos/agamemnon) for the acquisition of microbial abundances from shotgun metagenomics and metatranscriptomic samples, single-microbe sequencing experiments, or sequenced host samples. AGAMEMNON delivers accurate abundances at genus, species, and strain resolution. It incorporates a time and space-efficient indexing scheme for fast pattern matching, enabling indexing and analysis of vast datasets with widely available computational resources. Host-specific modules provide exceptional accuracy for microbial abundance quantification from tissue RNA/DNA sequencing, enabling the expansion of experiments lacking metagenomic/metatranscriptomic analyses. AGAMEMNON provides an R-Shiny application, permitting performance of investigations and visualizations from a graphics interface.
FIONA1 is an RNA N6-methyladenosine methyltransferase affecting Arabidopsis photomorphogenesis and flowering
Authors: Wang Chunling , Yang Junbo , Song Peizhe , Zhang Wei , Lu Qiang , Yu Qiong , Jia Guifang
Published: January 2022

Background

N6-methyladenosine (m6A) mRNA modification is essential for mammalian and plant viability. The U6 m6A methyltransferases in other species regulate S-adenosylmethionine (SAM) homeostasis through installing m6A in pre-mRNAs of SAM synthetases. However, U6 m6A methyltransferase has not been characterized in Arabidopsis and little is known about its role in regulating photomorphogenesis and flowering.

Results

Here we characterize that FIONA1 is an Arabidopsis U6 m6A methyltransferase that installs m6A in U6 snRNA and a small subset of poly(A)+RNA. Disruption ofFIONA1leads to phytochrome signaling-dependent hypocotyl elongation and photoperiod-independent early flowering. Distinct from mammalian METTL16 and worm METT-10, FIONA1 neither installs m6A in the mRNAs of Arabidopsis SAM synthetases nor affects their transcript expression levels under normal or high SAM conditions. We confirm that FIONA1 can methylate plant mRNA m6A motifs in vitro and in vivo. We further show that FIONA1 installs m6A in several phenotypic related transcripts, thereby affecting downstream mRNA stability and regulating phytochrome signaling and floral transition.

Conclusion

FIONA1 is functional as a U6 m6A methyltransferase in Arabidopsis, distinct from mammalian METTL16 and worm METT-10. Our results demonstrate that FIONA1-mediated m6A post-transcriptional regulation is an autonomous regulator for flowering and phytochrome signaling-dependent photomorphogenesis.
Paediatric Acute Respiratory Distress Syndrome Neuromuscular Blockade study (PAN-study): a phase IV randomised controlled trial of early neuromuscular blockade in moderate-to-severe paediatric acute respiratory distress syndrome
Authors: Rudolph Michelle W. , Slager Sjoerdtje , Burgerhof Johannes G. M. , van Woensel Job B.M. , Alffenaar Jan-Willem C. , Wösten - van Asperen Roelie M. , de Hoog Matthijs , IJland Marloes M. , Kneyber Martin C. J. ,   For the SKIC research consortium
Published: January 2022

Background

Paediatric acute respiratory distress syndrome (PARDS) is a manifestation of severe, life-threatening lung injury necessitating mechanical ventilation with mortality rates ranging up to 40–50%. Neuromuscular blockade agents (NMBAs) may be considered to prevent patient self-inflicted lung injury in PARDS patients, but two trials in adults with severe ARDS yielded conflicting results. To date, randomised controlled trials (RCT) examining the effectiveness and efficacy of NMBAs for PARDS are lacking. We hypothesise that using NMBAs for 48 h in paediatric patients younger than 5 years of age with early moderate-to-severe PARDS will lead to at least a 20% reduction in cumulative respiratory morbidity score 12 months after discharge from the paediatric intensive care unit (PICU).

Methods

This is a phase IV, multicentre, randomised, double-blind, placebo-controlled trial performed in level-3 PICUs in the Netherlands. Eligible for inclusion are children younger than 5 years of age requiring invasive mechanical ventilation with positive end-expiratory pressure (PEEP) ≥ 5 cm H2O for moderate-to-severe PARDS occurring within the first 96 h of PICU admission. Patients are randomised to continuous infusion of rocuronium bromide or placebo for 48 h. The primary endpoint is the cumulative respiratory morbidity score 12 months after PICU discharge, adjusted for confounding by age, gestational age, family history of asthma and/or allergy, season in which questionnaire was filled out, day-care and parental smoking. Secondary outcomes include respiratory mechanics, oxygenation and ventilation metrics, pulmonary and systemic inflammation markers, prevalence of critical illness polyneuropathy and myopathy and metrics for patient outcome including ventilator free days at day 28, length of PICU and hospital stay, and mortality

Discussion

This is the first paediatric trial evaluating the effects of muscular paralysis in moderate-to-severe PARDS. The proposed study addresses a huge research gap identified by the Paediatric Acute Lung Injury Consensus Collaborative by evaluating practical needs regarding the treatment of PARDS. Paediatric critical care practitioners are inclined to use interventions such as NMBAs in the most critically ill. This liberal use must be weighed against potential side effects. The proposed study will provide much needed scientific support in the decision-making to start NMBAs in moderate-to-severe PARDS.

Trial registration

ClinicalTrials.govNCT02902055. Registered on September 15, 2016.
Effect of acupuncture therapy combined with fluticasone propionate in the treatment of persistent allergic rhinitis: study protocol for a randomized controlled trial
Authors: Fan Qi , Feng Yixuan , Hou Yan , Wu Feihu , Zhang Wei , Nie Wenbin , Li Bin , Zhou Zhongyu , Fu Wenbin , Shi Lei , Sun Zhongren , Zhao Hong
Published: January 2022

Background

Allergic rhinitis (AR) is an immunoglobulin E (IgE)-mediated inflammatory response.

Persistent allergic rhinitis (PAR) is a subtype of AR, but the treatment of PAR is still a problem. Acupuncture is used as an alternative therapy for AR in clinical practice. The aim of this study is to evaluate the effectiveness of acupuncture therapy combined with fluticasone propionate nasal spray in comparison to fluticasone propionate nasal spray alone in the relief of symptoms for PAR.

Methods

This study is a multicenter, single-blind, randomized controlled trial. A total of 260 eligible patients will be randomly assigned into the treatment group or the control group. The treatment group will receive the nasal fluticasone propionate combined with acupuncture, and the control group will receive fluticasone propionate nasal spray alone for 6 weeks. The primary outcome is the change in the Reflective Total Nasal Symptom Score (rTNSS) from baseline to the end of treatment, and the Total Non Nasal Symptom Score (TNNSS), reflective total ocular symptom score (rTOSS), Rhinitis Quality of Life Questionnaire (RQLQ), use of antiallergic drugs, and the Rhinitis Control Assessment Test (RCAT) are used as secondary outcomes. The participants will be followed up for another 24 weeks after treatment.

Discussion

This clinical trial will be able to provide high level evidence on the acupuncture therapy combined with fluticasone propionate nasal spray in the treatment of PAR.

Trial registration

ISRCTN Registry, ID: ISRCTN44040506. Registered on 22 July 2020.
Cluster randomised, controlled, triple-blind trial assessing the efficacy of intranasally administered virus-neutralising bovine colostrum supplement in preventing SARS-CoV-2 infection in household contacts of SARS-CoV-2-positive individuals: a study protocol
Authors: Uusküla Anneli , Keis Aime , Toompere Karolin , Planken Anu , Rebrov Konstantin
Published: January 2022

The SARS-CoV-2 enters into the human body mainly through the nasal epithelial cells. Prevention of SARS-CoV-2 infection at the point of nasal entry is a novel strategy that has the potential to help contain the ongoing pandemic. BioBlock is a nasal spray of anti-SARS-CoV-2 preparation based on virus-neutralising antibodies prepared from colostrum from cows immunised with SARS-CoV-2 spike protein.

This triple-blind placebo-controlled cluster randomised parallel trial seeks to evaluate the efficacy of a BioBlock spray in the prevention and treatment of SARS-CoV-2 infection. Laboratory-confirmed COVID-19 cases and their household members will be randomly allocated to each of either the intervention (BioBlock nasal spray) or the placebo (nasal spray) arms. The intervention is a 14-day course of nasal spray used by index case and household contacts.

In most countries, those with confirmed or suspected infections are requisitioned to isolate at home, putting other members of their household at risk of infection. Therefore, in parallel to the need of household transmission prevention measures, households also present as a good model for infection transmission studies, allowing for the testing of several close contact transmission prevention study hypotheses. Our hope is that if the trial results are encouraging, this will provide new and additional COVID-19 prevention strategies.

Trial registration

ISRCTN48554326 Registered on June 14, 2021
Neonatal tetanus with good outcomes at a regional referral hospital in Eastern Uganda: a case report
Authors: Nakubulwa Clare , Opio Emmanuel , Alekat Gladys Sarah , Kibetenga Medrine , Alaroker Florence Olwedo Egwau
Published: January 2022

Background

Neonatal tetanus, though now rare in developed countries, is still a significant cause of mortality in developing countries. Mortality, which can be as high as 100% without medical intervention, can be reduced to less than 10% with intensive care. Low-resource settings still lack sophisticated intensive care that has been shown to improve outcomes in high-income countries. However, there are low-cost interventions that have been shown to improve outcomes such as the use of magnesium sulfate in the management of severe tetanus.

Case presentation

A 9-day-old term Itesot neonate presented to our facility with inability to breast feed, excessive crying, and stiffening of the body when touched that started on the fourth day of life. On admission, she had signs of respiratory distress, fever, and labile heart rate. A diagnosis of neonatal tetanus with autonomic dysfunction was made, and the neonate was started on diazepam and magnesium sulfate infusion. She showed remarkable improvement and was discharged after 24 days of inpatient care.

Conclusion

There is still need to improve case management modalities for neonatal tetanus in low-income settings to improve outcomes. This case report summarizes how adopting a low-cost treatment modality for neonatal tetanus resulted in good outcomes at a regional referral hospital in Eastern Uganda.
Primary biliary cholangitis first demonstrated in pregnancy: a case report
Authors: Melo Daniela , Areia Ana Luísa , Moura Paulo
Published: January 2022

Background

We present a case of primary biliary cholangitis diagnosed during pregnancy. Diagnosis of this entity in pregnancy is infrequent, and when everything seemed to point to a simple obstetric cholestasis, close attention to the details of the clinical history was required to raise suspicion of the true diagnosis.

Case presentation

We present a 37-year-old Portuguese Caucasian patient who complained of generalized pruritus and showed alteration in hepatic function tests with a cholestatic pattern. The first diagnostic hypothesis was intrahepatic cholestasis of pregnancy, and she began treatment with ursodeoxycholic acid, which resulted in slight improvement of cholestasis. Her pregnancy was also complicated with occlusive hemorrhagic placenta, and at 30 weeks she underwent emergency cesarean section due to heavy blood loss. However, careful observation of clinical and laboratory findings, postpartum evolution, and a multidisciplinary approach to the patient led to the probable diagnosis of primary biliary cholangitis.

Conclusions

Physiological changes during pregnancy can mimic chronic liver disease that can only be revealed at this stage, having an impact not only on the pregnancy but on the entire future of the woman.
Promise and challenges of clinical non-invasive T-cell tracking in the era of cancer immunotherapy
Authors: Gosmann Dario , Russelli Lisa , Weber Wolfgang A. , Schwaiger Markus , Krackhardt Angela M. , D’Alessandria Calogero
Published: January 2022

In the last decades, our understanding of the role of the immune system in cancer has significantly improved and led to the discovery of new immunotherapeutic targets and tools, which boosted the advances in cancer immunotherapy to fight a growing number of malignancies. Approved immunotherapeutic approaches are currently mainly based on immune checkpoint inhibitors, antibody-derived targeted therapies, or cell-based immunotherapies. In essence, these therapies induce or enhance the infiltration and function of tumor-reactive T cells within the tumors, ideally resulting in complete tumor eradication. While the clinical application of immunotherapies has shown great promise, these therapies are often accompanied either by a variety of side effects as well as partial or complete unresponsiveness of a number of patients. Since different stages of disease progression elicit different local and systemic immune responses, the ability to longitudinally interrogate the migration and expansion of immune cells, especially T cells, throughout the whole body might greatly facilitate disease characterization and understanding. Furthermore, it can serve as a tool to guide development as well as selection of appropriate treatment regiments. This review provides an overview about a variety of immune-imaging tools available to characterize and study T-cell responses induced by anti-cancer immunotherapy. Moreover, challenges are discussed that must be taken into account and overcome to use immune-imaging tools as predictive and surrogate markers to enhance assessment and successful application of immunotherapies.
Correction to: Open-access database of literature derived drug-related Torsade de Pointes cases
Authors: Krumpholz Laura , Wiśniowska Barbara , Polak Sebastian
Published: January 2022

An amendment to this paper has been published and can be accessed via the original article.
Combinatorial nanococktails via self-assembling lipid prodrugs for synergistically overcoming drug resistance and effective cancer therapy
Authors: Li Tongyu , Shi Weiwei , Yao Jie , Hu Jingyun , Sun Qiong , Meng Jing , Wan Jian , Song Haihan , Wang Hangxiang
Published: January 2022

Background

Combinatorial systemic chemotherapy is a powerful treatment paradigm against cancer, but it is fraught with problems due to the emergence of chemoresistance and additive systemic toxicity. In addition, coadministration of individual drugs suffers from uncontrollable pharmacokinetics and biodistribution, resulting in suboptimal combination synergy.

Methods

Toward the goal of addressing these unmet medical issues, we describe a unique strategy to integrate multiple structurally disparate drugs into a self-assembling nanococktail platform. Conjugation of a polyunsaturated fatty acid (e.g., linoleic acid) with two chemotherapies generated prodrug entities that were miscible with tunable drug ratios for aqueous self-assembly. In vitro and in vivo assays were performed to investigate the mechanism of combinatorial nanococktails in mitigating chemoresistance and the efficacy of nanotherapy.

Results

The coassembled nanoparticle cocktails were feasibly fabricated and further refined with an amphiphilic matrix to form a systemically injectable and PEGylated nanomedicine with minimal excipients. The drug ratio incorporated into the nanococktails was optimized and carefully examined in lung cancer cells to maximize therapeutic synergy. Mechanistically, subjugated resistance by nanococktail therapy was achieved through the altered cellular uptake pathway and compromised DNA repair via the ATM/Chk2/p53 cascade. In mice harboring cisplatin-resistant lung tumor xenografts, administration of the nanococktail outperformed free drug combinations in terms of antitumor efficacy and drug tolerability.

Conclusion

Overall, our study provides a facile and cost-effective approach for the generation of cytotoxic nanoparticles to synergistically treat chemoresistant cancers.
Ultrasonographic and macroscopic study of pregnancy in golden hamster
Authors: Keshavarz Mohammad Amin , Mogheiseh Asghar , Ahrari-Khafi Mohammad Saeed , Mahboobi Reza
Published: January 2022

Background

Hamster is widely used as an experimental model in the study of reproductive system. However, pregnancy diagnosis and aging always have been a challenge. ultrasonography have been used in diagnosis of pregnancy in some small laboratory animals, such as rabbits, rats, and mice. Current study describes use of trans-abdominal ultrasonography for pregnancy diagnosis and fetal age estimation in golden hamster. Furthermore, a macroscopic examination was performed to evaluate the embryonic vesicle diameter, crown-rump length, and fetal head diameter. Ten adult female golden hamsters were selected and maintained under controlled light conditions (14 h light/10 h darkness). The estrous cycle was synchronized using eCG and hCG. During estrous (18 h after hCG injection), the hamsters were naturally mated. After seven days of mating, the hamsters were examined daily for pregnancy diagnosis and aging with an ultrasound scanner equipped with an 8.5-MHZ linear probe. On each day of the experiment, at least one of the pregnant hamsters was euthanized and dissected for macroscopic fetal measurements using a digital caliper.

Results

The gestational sac and crown-rump length were identified and measured by ultrasonographicly on day 7 of pregnancy and head could be visible after day 10 of gestation. Statistical analysis revealed that the ultrasound estimation of gestational age was significantly correlated with the actual age of the fetus (r = 0.98; p < 0.05).

Conclusions

Real-time ultrasound can be used for the diagnosis of pregnancy and estimation of fetal age in golden hamster from day 7 of gestation.
Fault enhancement comparison among coherence enhancement, probabilistic neural networks, and convolutional neural networks in the Taranaki Basin area, New Zealand
Authors: Mora José P. , Bedle Heather , Marfurt Kurt J.
Published: January 2022

Fault identification is a critical component of seismic interpretation. During the past 25 years, coherence, curvature, and other seismic attributes sensitive to faults improved seismic interpretation, but human interaction is still required to generate a complete fault interpretation. Today, image enhancement of fault-sensitive attributes, multiattribute fault analysis using shallow learning, and deep-learning algorithms based on extensive training and convolutional neural networks (CNNs) are promising fault interpretation workflows. We have compared three workflows to test fault-detection capabilities; these include image enhancement, probabilistic neural networks (PNNs), and CNNs. We compared results to human-interpreted faults as our ground truth for a merged 3D seismic survey acquired in the Taranaki Basin, New Zealand. We extracted fault surfaces from the results of the workflows using them as seed points for an active contour method. Extracted faults are then compared to the human-interpreted surface using the Hausdorff distance. Data conditioning, including spectral balancing and structure-oriented filtering, improved the performance of all three workflows. Although all three approaches produce enhanced fault volumes, we find differences in fault location and different artifacts (mispredicted faults). Because all three methods exhibit “false positive” predictions, the enhanced multispectral coherence method produces faults and stratigraphic edges in the final image, including residual stair-step artifacts. In our implementation, PNN produces many salt-and-pepper artifacts through the resulting image, suggesting that we might need to include better training data or reduce the volume size to reduce the number of relevant classes to obtain an improved classification. The CNN algorithm is trained with synthetic data that provide rapid results, correctly identifying larger faults, but missing smaller faults and, in some cases, misclassifying mass-transport deposits and angular unconformities as being faults.
Propagation of instability fronts in modulationally unstable systems
Authors: Kamchatnov A. M. , Shaykin D. V.
Published: January 2022

We study the evolution of pulses propagating through focusing nonlinear media. A small disturbance of a smooth initial non-uniform pulse amplitude leads to formation of a region of strong nonlinear oscillations. We develop here an asymptotic method for finding the law of motion of the front of this region. The method is based on the conjecture that instability fronts propagate with the minimal group velocity of linear waves. To support this conjecture, at first we review several physical situations where this statement was obtained as a result of direct calculations. Then we generalize it to situations with a non-uniform flow and apply it to the focusing nonlinear Schrödinger equation for the particular cases of Talanov and Akhmanov-Sukhorukov-Khokhlov initial distributions. The approximate analytical results agree very well with the exact numerical solutions for these two problems.
Latent TGFβ-binding proteins 1 and 3 protect the larval zebrafish outflow tract from aneurysmal dilatation
Authors: Abrial Maryline , Basu Sandeep , Huang Mengmeng , Butty Vincent , Schwertner Asya , Jeffrey Spencer , Jordan Daniel , Burns Caroline E. , Burns C. Geoffrey
Published: January 2022

Aortic root aneurysm is a common cause of morbidity and mortality in Loeys-Dietz and Marfan syndromes, where perturbations in transforming growth factor beta (TGFβ) signaling play a causal or contributory role, respectively. Despite the advantages of cross-species disease modeling, animal models of aortic root aneurysm are largely restricted to genetically engineered mice. Here, we report that zebrafish devoid of the genes encoding latent-transforming growth factor beta-binding protein 1 and 3 (ltbp1 and ltbp3, respectively) develop rapid and severe aneurysm of the outflow tract (OFT), the aortic root equivalent. Similar to syndromic aneurysm tissue, the distended OFTs display evidence for paradoxical hyperactivated TGFβ signaling. RNA-sequencing revealed significant overlap between the molecular signatures of disease tissue from mutant zebrafish and a mouse model of Marfan syndrome. Moreover, chemical inhibition of TGFβ signaling in wild-type animals phenocopied mutants but chemical activation did not, demonstrating that TGFβ signaling is protective against aneurysm. Human relevance is supported by recent studies implicating genetic lesions in LTBP3 and, potentially, LTBP1 as heritable causes of aortic root aneurysm. Ultimately, our data demonstrate that zebrafish can now be leveraged to interrogate thoracic aneurysmal disease and identify novel lead compounds through small-molecule suppressor screens.

This article has an associated First Person interview with the first author of the paper.
Working to enhance the accessibility of Disease Models & Mechanisms
Authors: Hackett Rachel , Patton E. Elizabeth
Published: January 2022

Summary: The DMM Editor-in-Chief discusses the importance of accessibility to published research and outlines the implications of new Read & Publish agreements for the DMM community.
ALFY localizes to early endosomes and cellular protrusions to facilitate directional cell migration
Authors: Søreng Kristiane , Pankiv Serhiy , Bergsmark Camilla , Haugsten Ellen M. , Dahl Anette K. , de la Ballina Laura R. , Yamamoto Ai , Lystad Alf H. , Simonsen Anne
Published: January 2022

Cell migration is a complex process underlying physiological and pathological processes such as brain development and cancer metastasis. The autophagy-linked FYVE protein (ALFY; also known as WDFY3), an autophagy adaptor protein known to promote clearance of protein aggregates, has been implicated in brain development and neural migration during cerebral cortical neurogenesis in mice. However, a specific role of ALFY in cell motility and extracellular matrix adhesion during migration has not been investigated. Here, we reveal a novel role for ALFY in the endocytic pathway and in cell migration. We show that ALFY localizes to RAB5- and EEA1-positive early endosomes in a PtdIns(3)P-dependent manner and is highly enriched in cellular protrusions at the leading and lagging edge of migrating cells. We find that cells lacking ALFY have reduced attachment and altered protein levels and glycosylation of integrins, resulting in the inability to form a proper leading edge and loss of directional cell motility.
Novel stress granule-like structures are induced via a paracrine mechanism during viral infection
Authors: Iadevaia Valentina , Burke James M. , Eke Lucy , Moller-Levet Carla , Parker Roy , Locker Nicolas
Published: January 2022

To rapidly adapt to stresses such as infections, cells have evolved several mechanisms, which include the activation of stress response pathways and the innate immune response. These stress responses result in the rapid inhibition of translation and condensation of stalled mRNAs with RNA-binding proteins and signalling components into cytoplasmic biocondensates called stress granules (SGs). Increasing evidence suggests that SGs contribute to antiviral defence, and thus viruses need to evade these responses to propagate. We previously showed that feline calicivirus (FCV) impairs SG assembly by cleaving the scaffolding protein G3BP1. We also observed that uninfected bystander cells assembled G3BP1-positive granules, suggesting a paracrine response triggered by infection. We now present evidence that virus-free supernatant generated from infected cells can induce the formation of SG-like foci, which we name paracrine granules. They are linked to antiviral activity and exhibit specific kinetics of assembly-disassembly, and protein and RNA composition that are different from canonical SGs. We propose that this paracrine induction reflects a novel cellular defence mechanism to limit viral propagation and promote stress responses in bystander cells.