bluuebunny/crossref_metadata_2025 huggingface dataset:
Bacillus integrative plasmid system combining a synthetic gene circuit for efficient genetic modifications of undomesticated Bacillus strains
Authors: Kim Man Su , Jeong Da-Eun , Choi Soo-Keun
Published: December 2022

Background

Owing to CRISPR-Cas9 and derivative technologies, genetic studies on microorganisms have dramatically increased. However, the CRISPR-Cas9 system is still difficult to utilize in many wild-type Bacillus strains owing to Cas9 toxicity. Moreover, less toxic systems, such as cytosine base editors, generate unwanted off-target mutations that can interfere with the genetic studies of wild-type strains. Therefore, a convenient alternative system is required for genetic studies and genome engineering of wild-type Bacillus strains. Because wild-type Bacillus strains have poor transformation efficiencies, the new system should be based on broad-host-range plasmid-delivery systems.

Results

Here, we developed a Bacillus integrative plasmid system in which plasmids without the replication initiator protein gene (rep) of Bacillus are replicated in a donor Bacillus strain by Rep proteins provided in trans but not in Bacillus recipients. The plasmids were transferred to recipients through a modified integrative and conjugative element, which is a wide host range plasmid-delivery system. Genetic mutations were generated in recipients through homologous recombination between the transferred plasmid and the genome. The system was improved by adding a synthetic gene circuit for efficient screening of the desired mutations by double crossover recombination in recipient strains. The improved system exhibited a mutation efficiency of the target gene of approximately 100% in the tested wild-type Bacillus strains.

Conclusion

The Bacillus integrative plasmid system developed in this study can generate target mutations with high efficiency when combined with a synthetic gene circuit in wild-type Bacillus strains. The system is free of toxicity and unwanted off-target mutations as it generates the desired mutations by traditional double crossover recombination. Therefore, our system could be a powerful tool for genetic studies and genome editing of Cas9-sensitive wild-type Bacillus strains.
Choice of health providers and health-seeking behaviour among forest goer population in Myanmar: findings from a cross-sectional household survey
Authors: Thet May Me , Khaing Myat Noe Thiri , Zin Su Su , Thein Si Thu , Tesfazghi Kemi
Published: December 2022

Background

In Myanmar, malaria still poses a significant burden for vulnerable populations particularly forest goers even though impressive progress has been made over the past decade. Limited evidence existed related to forest goers’ health-seeking behaviour and factors that drive decision making for providers’ choice to support national malaria programmes towards elimination. In response to that, this research is conducted to identify who they preferred and what are the factors associated with providers’ choice in malaria febrile illness and Rapid Diagnostic Testing (RDT).

Methods

A cross-sectional study applying quantitative household survey was completed with 479 forest goer households in 20 malaria endemic townships across Myanmar. The household data was collected with the types of providers that they consulted for recent and previous febrile episodes. To identify the factors associated with providers’ choices, univariate and multivariate multinomial logistic regressions were done using Stata version 14.1. Statistical significance was set as p = 0.05.

Results

A total of 307 individuals experienced fever within one month and 72.3% sought care from providers. Also, a total of 509 forest goers reported that they had a previous febrile episode and 62.6% received care from a provider. Furthermore, 56.2% said that they had RDT testing during these previous febrile illnesses. They consulted public facilities and public health staff, private facilities, private and semi-private providers, community health volunteers or workers in their residing village and those located outside their villages but majority preferred those within their villages. On multivariate analyses, second richest quintile (public, RRR = 12.9) (semi-private, RRR = 17.9), (outside, RRR = 8.4) and access to 4 and above nearby providers (public, RRR = 30.3) (semi-private, RRR = 1.5) (outside, RRR = 0.5) were found to be significantly associated with provider choice for recent fever episode. Similar findings were also found for previous febrile illness and RDT testing among forest goers.

Conclusions

It was highlighted in this study that in forest goer households, they preferred nearby providers and the decision to choose providers seemed to be influenced by their access to number of nearby providers and socio-economic status when they sought care from a provider regardless of fever occurrence location. It was important that the national programmes considere involving these nearby providers in elimination efforts.
Longitudinal single-cell analysis of a patient receiving adoptive cell therapy reveals potential mechanisms of treatment failure
Authors: Qu Rihao , Kluger Yuval , Yang Junchen , Zhao Jun , Hafler David A. , Krause Diane S. , Bersenev Alexey , Bosenberg Marcus , Hurwitz Michael , Lucca Liliana , Kluger Harriet M.
Published: December 2022

Adoptive cell therapy (ACT) using tumor infiltrating lymphocytes (TIL) is being studied in multiple tumor types. However, little is known about clonal cell expansion in vitro and persistence of the ACT product in vivo. We performed single-cell RNA and T-Cell Receptor (TCR) sequencing on serial blood and tumor samples from a patient undergoing ACT, who did not respond. We found that clonal expansion varied during preparation of the ACT product, and only one expanded clone was preserved in the ACT product. The TCR of the preserved clone which persisted and remained activated for five months was previously reported as specific for cytomegalovirus and had upregulation of granzyme family genes and genes associated with effector functions (HLA-DQB1, LAT, HLA-DQA1, and KLRD1). Clones that contracted during TIL preparation had features of exhaustion and apoptosis. At disease progression, all previously detected clonotypes were detected. New clonotypes appearing in blood or tumor at disease progression were enriched for genes associated with cytotoxicity or stemness (FGFBP2, GNLY, GZMH, GZMK, IL7R, SELL and KLF2), and these might be harnessed for alternative cellular therapy or cytokine therapy. In-depth single-cell analyses of serial samples from additional ACT-treated patients is warranted, and viral- versus tumor-specificity should be carefully analyzed.
Factors associated with the speed and scope of diffusion of COVID-19 therapeutics in a nationwide healthcare setting: a mixed-methods investigation
Authors: La Jennifer , Fillmore Nathanael R. , Do Nhan V. , Brophy Mary , Monach Paul A. , Branch-Elliman Westyn
Published: December 2022

Background

The global COVID-19 pandemic is an opportunity to evaluate factors associated with high levels of adoption of different therapeutics in a real-world setting. The aim of this nationwide, retrospective cohort study was to evaluate the diffusion and adoption of novel therapeutics with an emerging evidence basis and to identify factors that influenced physicians’ treatment decisions.

Methods

Cohort creation: A cohort of Veteran patients with a microbiologically confirmed diagnosis of SARS-CoV2 were identified, and cases were classified by disease severity (outpatient, inpatient with mild and severe disease, intensive care unit ICU]). After classification of disease severity, the proportion of cases (outpatients) and admissions (inpatients) in each category receiving each type of medication were plotted as a function of time. Identification of milestones and guidance changes: Key medications used for the management of COVID-19 milestones in the release of primary research results in various forms (e.g. via press release, preprint or publication in a traditional medical journal), policy events and dates of key guidelines were identified and plotted as a timeline. After a timeline was created, time points were compared to changes in medication use, and factors potentially impacting the magnitude (i.e. proportion of patients who received the treatment) and the speed (i.e. the slope of the change in use) of practice changes were evaluated.

Results

Dexamethasone and remdesivir, the first two medications with clinical trial data to support their use, underwent the most rapid, complete and sustained diffusion and adoption; the majority of practice changes occurred after press releases and preprints were available and prior to guideline changes, although some additional uptake occurred following guideline updates. Medications that were not “first in class”, that were identified later in the pandemic, and that had higher perceived risk had slower and less complete uptake regardless of the strength and quality of the evidence supporting the intervention.

Conclusions

Our findings suggest that traditional and social media platforms and preprint releases were major catalysts of practice change, particularly prior to the identification of effective treatments. The “first available treatment in class” impact appeared to be the single most important factor determining the speed and scope of diffusion.
Long-term survivors demonstrate superior quality of life after haploidentical stem cell transplantation to matched sibling donor transplantation
Authors: Zhang Xiaoyu , Wang Jiao , Liu Yuqiu , Liu Jie , Wang Bei , Zhang Qiuhui , Guan Wei , Zhang Huijuan , Xu Li , Liu Guiying , Zhang Ping , He Yi , Feng Sizhou , Han Mingzhe , Li Changping , Jiang Erlie , Xie Wenjun
Published: December 2022

Background

It has been well-documented that haplo-identical hematopoietic stem cell transplantation (HID-HSCT) can provide outcomes comparable to conventional matched sibling donor (MSD) HSCT, however, little is known about the effects on quality of life (QoL) in long-term survivors. This study is to investigate the differences in longitudinal performance of QoL between HID and MSD HSCT using a comprehensive assessment system.

Methods

This prospective study enrolled consecutive patients who had received allogenic-HSCT (allo-HSCT) between January 2018 and December 2019 in our center. All patients were informed to complete QoL questionnaires including the Mos 36-Item Short-Form Health Survey (SF-36) and the Functional Assessment of Cancer Therapy Bone Marrow Transplant (FACT-BMT, version 4), using an online applet, before transplantation and at scheduled time points after transplantation. The linear mixed-effects model was used to analyze the variation trend of different dimensions of both SF-36 and FACT-BMT with different follow-up times.

Results

Of the 425 participants, recipients of HID and MSD who survived more than 1 year (n = 230) were included in the final analysis of QoL (median age [range]: 36, [15, 66]). The 3 year overall survival (OS) of HID and MSD was 82.42% and 86.46%, respectively. QoL was assessed using both SF-36 and FACT-BMT and there was longitudinal recovery with clinical significance in the cohort. Compared to MSD-HSCT patients, HID-HSCT recipients demonstrated superior QoL performance in some subscales describing physical and mental wellness. Specifically, the difference in physical performance is more remarkable using FACT-BMT whereas that in mental wellness is more significant using SF36. In the subsequent stratified analysis, patients with a history of aGVHD or CMV reactivation demonstrated inferior QoL.

Conclusions

Long-term survivors of HID HSCT achieved better QoL in some sub-scales compared to MSD HSCT. In addition, SF-36 and FACT-BMT demonstrated different performance thus combination of both improved capacity of the evaluation system.
Models of microglia depletion and replenishment elicit protective effects to alleviate vascular and neuronal damage in the diabetic murine retina
Authors: Church Kaira A. , Rodriguez Derek , Vanegas Difernando , Gutierrez Irene L. , Cardona Sandra M. , Madrigal José L. M. , Kaur Tejbeer , Cardona Astrid E.
Published: December 2022

Microglia, the resident phagocytes of the retina, are believed to influence the development of retinopathy, but their exact contributions to vascular integrity and neuronal loss are unknown. Therefore, utilizing two models of microglia depletion, we aimed to deplete and repopulate microglia to clarify the contribution of microglia to neuronal loss and vascular damage in the diabetic retina in an STZ-induced model of hyperglycemia. Here, we report that 2 weeks exposure to diphtheria toxin (DTx) in diabetic CX3CR1CreER:R26iDTR transgenic mice induced a 62% increase in Iba1+ microglia associated with an increase in TUJ1+ axonal density and prevention of NeuN+RBPMS+ neuronal loss. Conversely, diabetic PBS controls exhibited robust TUJ1+ axonal and NeuN+RBPMS+ neuronal loss compared to non-diabetic controls. A 2-week recovery period from DTx was associated with a 40% reduction in angiogenesis and an 85% reduction in fibrinogen deposition into the diabetic retina in comparison to diabetic PBS-treated controls. Analysis of microglia morphology and marker expression revealed that following a 2-week recovery period microglia displayed a P2RY12+Ly6C– phenotype and high transformation index (TI) values complimented by a ramified-surveillant morphology closely resembling non-diabetic controls. In contrast, diabetic PBS-treated control mice displayed P2RY12+Ly6C+ microglia, with a 50% reduction in TI values with an amoeboid morphology. To validate these observations were due to microglia depletion, we used PLX-5622 to assess vascular and neuronal damage in the retinas of diabetic mice. Confocal microscopy revealed that PLX-5622 also induced an increase in TUJ1+ axonal density and prevented fibrinogen extravasation into the diabetic retina. mRNAseq gene expression analysis in retinal isolates revealed that PLX-5622-induced microglia depletion and repopulation induced a downregulation in genes associated with microglial activation and phagocytosis, B2m, Cx3cr1, and Trem2, and complement-associated synaptic pruning, C1qa, C1qb, and C1qc. Although the levels of microglia depletion induced with DTx in the CX3CR1CreER:R26iDTR model and those induced with the CSF-1R antagonists are distinct, our results suggest that microglia depletion and replenishment is neuroprotective by inducing the proliferation of a homeostatic microglia pool that supports neuronal and vascular integrity.
Blood and cerebrospinal fluid flow oscillations measured with real-time phase-contrast MRI: breathing mode matters
Authors: Laganà Maria Marcella , Di Tella Sonia , Ferrari Francesca , Pelizzari Laura , Cazzoli Marta , Alperin Noam , Jin Ning , Zacà Domenico , Baselli Giuseppe , Baglio Francesca
Published: December 2022

Background

Cervical blood and cerebrospinal fluid (CSF) flow rates can be quantified with Phase-contrast (PC) MRI, which is routinely used for clinical studies. Previous MRI studies showed that venous and CSF flow alterations are linked to various pathological conditions. Since it is well known that, besides the heart beating, the thoracic pump influences the blood and CSF dynamics, we studied the effect of different respiration modes on blood and CSF flow rates using a real-time (RT)-PC prototype.

Methods

Thirty healthy volunteers were examined with a 3 T scanner. A RT-PC sequence was acquired at the first cervical level to quantify the flow rates of internal carotid arteries, internal jugular veins (IJVs) and CSF. Each RT-PC acquisition was repeated three times, while the subjects were asked to breathe in three different ways for 60 s each: freely (F), with a constant rate (PN) and with deep and constant respiration rate (PD). The average flow rates were computed, they were removed from the respective signals and integrated in the inspiratory and expiratory phases (differential volumes). Finally, the power spectral density was computed for each detrended flow rate. High- and very-high frequency peaks were identified on the spectra while their frequencies were compared to the respiratory and cardiac frequencies estimated using a thoracic belt and a pulse oximeter. The area under the spectra was computed in four 0.5 Hz-wide ranges, centered on the high-frequency peak, on very-high frequency peak and its 2nd and 3rd harmonics, and then they were normalized by the flow rate variance. The effect of breathing patterns on average flow rates, on systolic and diastolic peaks, and on the normalized power was tested. Finally, the differential volumes of inspiration were compared to those of expiration.

Results

The frequencies of the high- and very-high spectral peaks corresponded to the respiratory and cardiac frequencies. The average flow rate progressively decreased from F to PN to PD breathing, and the cardiac modulations were less predominant especially for the IJVs. The respiratory modulation increased with PD breathing. The average volumes displaced in the inspiratory phases were not significantly different from those of the expiratory one.

Conclusions

The spectral analyses demonstrated higher respiratory modulations in PD compared to free breathing, even prevailing the cardiac modulation in the IJVs, showing an increment of the thoracic pump affecting the flow rate shape.
Analysis and mapping of global research publications on shift work (2012–2021)
Authors: Sweileh Waleed M.
Published: December 2022

Background

The main objective of the study was to identify research trends, collaboration patterns, and the most impactful publications in the field of shift work.

Methods

Documents published in scientific journals indexed in the Scopus database on shift work were retrieved and analyzed using the title/abstract search methodology. The study period was from January 1st, 2012, to December 31st, 2021.

Results

Two thousand three hundred twenty-eight documents were retrieved with an h-index of 71 and an average number of 4.5 authors per document. The cumulative number of publications showed a linear growth pattern, while that of citations showed an exponential pattern. The most frequent author keywords, excluding keywords related to shift work, were sleep, fatigue, and nursing. The average annual growth rate was 4.3, and the average doubling time was 3.2. No significant correlation was found between the number of publications and national income among prolific countries. Cross-country research collaboration was weak while the degree of author-author collaboration was relatively high. The Chronobiology International journal was the most prolific, while Harvard University was the most active institution in the field of shift work.

Conclusions

Given the volume and the negative health impact of shift work, better human resource management is needed to create safer and healthier working schedules.
Pseudo high-frequency boosts the generalization of a convolutional neural network for cassava disease detection
Authors: Zhang Jiayu , Qi Chao , Mecha Peter , Zuo Yi , Ben Zongyou , Liu Haolu , Chen Kunjie
Published: December 2022

Frequency is essential in signal transmission, especially in convolutional neural networks. It is vital to maintain the signal frequency in the neural network to maintain the performance of a convolutional neural network. Due to destructive signal transmission in convolutional neural network, signal frequency downconversion in channels results into incomplete spatial information. In communication theory, the number of Fourier series coefficients determines the integrity of the information transmitted in channels. Consequently, the number of Fourier series coefficients of the signals can be replenished to reduce the information transmission loss. To achieve this, the ArsenicNetPlus neural network was proposed for signal transmission modulation in detecting cassava diseases. First, multiattention was used to maintain the long-term dependency of the features of cassava diseases. Afterward, depthwise convolution was implemented to remove aliasing signals and downconvert before the sampling operation. Instance batch normalization algorithm was utilized to keep features in an appropriate form in the convolutional neural network channels. Finally, the ArsenicPlus block was implemented to generate pseudo high-frequency in the residual structure. The proposed method was tested on the Cassava Datasets and compared with the V2-ResNet-101, EfficientNet-B5, RepVGG-B3g4 and AlexNet. The results showed that the proposed method performed $$95.93\%$$

95.93
%

in terms of accuracy, 1.2440 in terms of loss, and $$95.94\%$$

95.94
%

in terms of the F1-score, outperforming the comparison algorithms.
Equine-assisted services for individuals with substance use disorders: a scoping review
Authors: Diaz Liam , Gormley Mirinda Ann , Coleman Ashley , Sepanski Abby , Corley Heather , Perez Angelica , Litwin Alain H.
Published: December 2022

The implementation of equine-assisted services (EAS) during treatment for psychological disorders has been frequently documented; however, little is known about the effect of EAS on outcomes for populations with substance use disorder (SUD). The purpose of this scoping review was to synthesize existing literature reporting the effects of EAS when incorporated into SUD treatment. This review followed guidelines in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist for scoping reviews. A search of four databases (MEDLINE/PubMed, PsycINFO, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Academic OneFile) identified studies reporting quantitative and/or qualitative data for an EAS intervention that was implemented among a population receiving treatment for and/or diagnosed with SUD. Of 188 titles, 71 underwent full-text assessment and six met inclusion criteria. Three additional articles were identified through other sources. Quantitative data suggested a potential positive effect of EAS on SUD treatment retention and completion as well as participants’ mental health; however, studies were limited by small sample sizes. Qualitative data indicated that in addition to participants developing bonds with the horses and perceiving EAS as welcomed breaks from traditional treatment, they experienced increased self-efficacy, positive emotional affect, and SUD treatment motivation. Due to methodological limitations and an overall dearth of available studies, the effectiveness of EAS as adjuncts to SUD treatment is inconclusive. Additional research is necessary before supporting broad implementation of EAS as adjuncts to SUD treatment.
Dosimetric evaluation of bone marrow sparing in proton radiotherapy for cervical cancer guided by MR functional imaging
Authors: Qin Xiaohang , Gong Guanzhong , Wang Lizhen , Su Ya , Yin Yong
Published: December 2022

Background

To segment the pelvic active bone marrow (PABM) using magnetic resonance (MR) functional imaging and investigate the feasibility and dosimetric characteristics of cervical cancer proton radiotherapy for active bone marrow (ABM) sparing.

Methods

We collected CT and MR simulation images of 33 patients with cervical cancer retrospectively. The PBM was contoured on the MRI FatFrac images; the PBM was divided into high-active bone marrow (ABM-high) and low-active bone marrow based on the fat content of the PBM. Four radiotherapy plans were created for each patient, which included intensity-modulated photon therapy (IMRT), bone marrow sparing IMRT (IMRT-BMS), intensity-modulated proton therapy (IMPT), and bone marrow sparing IMPT (IMPT-BMS). The dosimetric differences among the four plans were compared.

Results

The ABM-high volume in the enrolled patients accounted for 45.2% of the total ABM volume. The target coverage was similar among the four radiotherapy plans. IMRT-BMS, IMPT, and IMPT-BMS reduced the Dmean of ABM-high by 16.6%, 14.2%, and 44.5%, respectively, compared to the Dmean of IMRT (p < 0.05). IMPT-BMS had the best protective effect on the bone marrow. Compared to IMRT, the volume of ABM-high receiving an irradiation dose of 5–40 Gy decreased by 10.2%, 36.8%, 58.8%, 67.4%, 64.9%, and 44.5%, respectively (p < 0.001).

Conclusions

The MR functional imaging technique helped in the grading and segmentation of PABM. MR functional image-guided proton radiotherapy for cervical cancer can achieve optimal BMS.
Automatic assessment of knee osteoarthritis severity in portable devices based on deep learning
Authors: Yang Jianfeng , Ji Quanbo , Ni Ming , Zhang Guoqiang , Wang Yan
Published: December 2022

Background

For knee osteoarthritis, the commonly used radiology severity criteria Kellgren–Lawrence lead to variability among surgeons. Most existing diagnosis models require preprocessed radiographs and specific equipment.

Methods

All enrolled patients diagnosed with KOA who met the criteria were obtained from **** Hospital. This study included 2579 images shot from posterior–anterior X-rays of 2,378 patients. We used RefineDet to train and validate this deep learning-based diagnostic model. After developing the model, 823 images of 697 patients were enrolled as the test set. The whole test set was assessed by up to 5 surgeons and this diagnostic model. To evaluate the model’s performance we compared the results of the model with the KOA severity diagnoses of surgeons based on K-L scales.

Results

Compared to the diagnoses of surgeons, the model achieved an overall accuracy of 0.977. Its sensitivity (recall) for K-L 0 to 4 was 1.0, 0.972, 0.979, 0.983 and 0.989, respectively; for these diagnoses, the specificity of this model was 0.992, 0.997, 0.994, 0.991 and 0.995. The precision and F1-score were 0.5 and 0.667 for K-L 0, 0.914 and 0.930 for K-L 1, 0.978 and 0.971 for K-L 2, 0.981 and 0.974 for K-L 3, and 0.988 and 0.985 for K-L 4, respectively. All K-L scales perform AUC > 0.90. The quadratic weighted Kappa coefficient between the diagnostic model and surgeons was 0.815 (P < 0.01, 95% CI 0.727–0.903). The performance of the model is comparable to the clinical diagnosis of KOA. This model improved the efficiency and avoided cumbersome image preprocessing.

Conclusion

The deep learning-based diagnostic model can be used to assess the severity of KOA in portable devices according to the Kellgren–Lawrence scale. On the premise of improving diagnostic efficiency, the results are highly reliable and reproducible.
Identifying adult hypophosphatasia in the rheumatology unit
Authors: Feurstein Julia , Behanova Martina , Haschka Judith , Roetzer Katharina , Uyanik Gökhan , Hadzimuratovic Benjamin , Witsch-Baumgartner Martina , Schett Georg , Zwerina Jochen , Kocijan Roland
Published: December 2022

Background

The most frequent manifestation in adult hypophosphatasia (HPP) is musculoskeletal pain. The unspecific nature of its clinical presentation may prevent correct diagnosis. The aim of the study was to assess the prevalence of ALPL mutations in adult patients treated in rheumatological outpatient facilities with evident musculoskeletal symptoms typical for HPP.

Methods

Over a period of 10 years 9,522 patients were screened in the rheumatology outpatient clinic of the Hanusch hospital Vienna. Serum ALP levels ≤ 40 U/L were found in 524 patients. After screening for secondary causes, 73 patients were invited for clinical evaluation. Genetic testing was performed in 23 patients with suspected HPP. Logistic regression models with Firth penalisation were used to estimate the unadjusted and BMI-adjusted association of each clinical factor with HPP.

Results

Mutations in the ALPL gene were observed in 57% of genetically screened patients. Arthralgia, fractures, and pain were the leading symptoms in individuals with ALPL mutation. Chondrocalcinosis (OR 29.12; 95% CI 2.02–1593.52) and dental disease (OR 8.33; 95% CI 0.93–143.40) were associated with ALPL mutation, independent of BMI. Onset of symptoms in patients with ALPL mutation was at 35.1 (14.3) years, with a mean duration from symptoms to diagnosis of 14.4 (8.1) years. Bone mineral density (BMD) and trabecular bone score (TBS) as well as bone turnover markers were not indicative for HPP or ALPL mutation.

Conclusion

HPP can mimic rheumatologic diseases. Thus, HPP should be considered as a possible diagnosis in adult patients presenting with musculoskeletal pain of unknown origin in rheumatology outpatient clinics. In patients with persistently low ALP serum levels and unclear musculoskeletal pain, HPP as the underlying cause has to be considered.
RETRACTED ARTICLE: ANGPTL4 functions as an oncogene through regulation of the ETV5/CDH5/AKT/MMP9 axis to promote angiogenesis in ovarian cancer
Authors: Liu Yinping , Yang Rui , Zhang Yan , Zhu Yaping , Bao Wei
Published: December 2022

Background

Angiopoietin-like 4 (ANGPTL4) is highly expressed in a variety of neoplasms and promotes cancer progression. Nevertheless, the mechanism of ANGPTL4 in ovarian cancer (OC) metastasis remains unclear. This study aimeds to explore whether ANGPTL4 regulates OC progression and elucidate the underlying mechanism.

Methods

ANGPTL4 expression in clinical patient tumor samples was determined by immunohistochemistry (IHC) and high-throughput sequencing. ANGPTL4 knockdown (KD) and the addition of exogeneous cANGPTL4 protein were used to investigate its function. An in vivo xenograft tumor experiment was performed by intraperitoneal injection of SKOV3 cells transfected with short hairpin RNAs (shRNAs) targeting ANGPTL4 in nude mice. Western blotting and qRT-PCR were used to detect the levels of ANGPTL4, CDH5, p-AKT, AKT, ETV5, MMP2 and MMP9 in SKOV3 and HO8910 cells transfected with sh-ANGPTL4 or shRNAs targeting ETV5.

Results

Increased levels of ANGPTL4 were associated with poor prognosis and metastasis in OC and induced the angiogenesis and metastasis of OC cells both in vivo and in vitro. This tumorigenic effect was dependent on CDH5, and the expression levels of ANGPTL4 and CDH5 in human OC werepositively correlated. In addition, CDH5 activated p-AKT, and upregulated the expression of MMP2 and MMP9. We also found that the expression of ETV5 was upregulated by ANGPTL4, which could bind the promoter region of CDH5, leading to increased CDH5 expression.

Conclusion

Our data indicated that an increase in the ANGPTL4 level results in increased ETV5 expression in OC, leading to metastasis via activation of the CDH5/AKT/MMP9 signaling pathway.
Machine learning for the real-time assessment of left ventricular ejection fraction in critically ill patients: a bedside evaluation by novices and experts in echocardiography
Authors: Varudo Rita , Gonzalez Filipe A. , Leote João , Martins Cristina , Bacariza Jacobo , Fernandes Antero , Michard Frederic
Published: December 2022

Background

Machine learning algorithms have recently been developed to enable the automatic and real-time echocardiographic assessment of left ventricular ejection fraction (LVEF) and have not been evaluated in critically ill patients.

Methods

Real-time LVEF was prospectively measured in 95 ICU patients with a machine learning algorithm installed on a cart-based ultrasound system. Real-time measurements taken by novices (LVEFNov) and by experts (LVEFExp) were compared with LVEF reference measurements (LVEFRef) taken manually by echo experts.

Results

LVEFRef ranged from 26 to 80% (mean 54 ± 12%), and the reproducibility of measurements was 9 ± 6%. Thirty patients (32%) had a LVEFRef < 50% (left ventricular systolic dysfunction). Real-time LVEFExp and LVEFNov measurements ranged from 31 to 68% (mean 54 ± 10%) and from 28 to 70% (mean 54 ± 9%), respectively. The reproducibility of measurements was comparable for LVEFExp (5 ± 4%) and for LVEFNov (6 ± 5%) and significantly better than for reference measurements (p < 0.001). We observed a strong relationship between LVEFRef and both real-time LVEFExp (r = 0.86, p < 0.001) and LVEFNov (r = 0.81, p < 0.001). The average difference (bias) between real time and reference measurements was 0 ± 6% for LVEFExp and 0 ± 7% for LVEFNov. The sensitivity to detect systolic dysfunction was 70% for real-time LVEFExp and 73% for LVEFNov. The specificity to detect systolic dysfunction was 98% both for LVEFExp and LVEFNov.

Conclusion

Machine learning-enabled real-time measurements of LVEF were strongly correlated with manual measurements obtained by experts. The accuracy of real-time LVEF measurements was excellent, and the precision was fair. The reproducibility of LVEF measurements was better with the machine learning system. The specificity to detect left ventricular dysfunction was excellent both for experts and for novices, whereas the sensitivity could be improved.

Trial registration: NCT05336448. Retrospectively registered on April 19, 2022.
circ-Iqsec1 induces bone marrow-derived mesenchymal stem cell (BMSC) osteogenic differentiation through the miR-187-3p/Satb2 signaling pathway
Authors: Fan Lixia , Yang Kaiyun , Yu Ruixuan , Hui Houde , Wu Wenliang
Published: December 2022

Background

Bone marrow-derived mesenchymal stem cells (BMSCs) are general progenitor cells of osteoblasts and adipocytes and they are characterized as a fundamental mediator for bone formation. The current research studied the molecular mechanisms underlying circRNA-regulated BMSC osteogenic differentiation.

Methods

Next-generation sequencing (NGS) was employed to study abnormal circRNA and mRNA expression in BMSCs before and after osteogenic differentiation induction. Bioinformatics analysis and luciferase reporting analysis were employed to confirm correlations among miRNA, circRNA, and mRNA. RT-qPCR, ALP staining, and alizarin red staining illustrated the osteogenic differentiation ability of BMSCs.

Results

Data showed that circ-Iqsec1 expression increased during BMSC osteogenic differentiation. circ-Iqsec1 downregulation reduced BMSC osteogenic differentiation ability. The present investigation discovered that Satb2 played a role during BMSC osteogenic differentiation. Satb2 downregulation decreased BMSC osteogenic differentiation ability. Bioinformatics and luciferase data showed that miR-187-3p linked circ-Iqsec1 and Satb2. miR-187-3p downregulation or Satb2 overexpression restored the osteogenic differentiation capability of BMSCs post silencing circ-Iqsec1 in in vivo and in vitro experiments. Satb2 upregulation restored osteogenic differentiation capability of BMSCs post miR-187-3p overexpression.

Conclusion

Taken together, our study found that circ-Iqsec1 induced BMSC osteogenic differentiation through the miR-187-3p/Satb2 signaling pathway.
The impact of hospital price and quality transparency tools on healthcare spending: a systematic review
Authors: Chen Jinyang , Miraldo Marisa
Published: December 2022

Background

Global spending on health was continuing to rise over the past 20 years. To reduce the growth rates, alleviate information asymmetry, and improve the efficiency of healthcare markets, global health systems have initiated price and quality transparency tools in the hospital industry in the last two decades.

Objective 

The objective of this review is to synthesize whether, to what extent, and how hospital price and quality transparency tools affected 1) the price of healthcare procedures and services, 2) the payments of consumers, and 3) the premium of health insurance plans bonding with hospital networks.

Methods

A literature search of EMBASE, Web of Science, Econlit, Scopus, Pubmed, CINAHL, and PsychINFO was conducted, from inception to Oct 31, 2021. Reference lists and tracked citations of retrieved articles were hand-searched. Study characteristics were extracted, and included studies were scored through a risk of bias assessment framework. This systematic review was reported according to the PRISMA guidelines and registered in PROSPERO with registration No. CRD42022319070.

Results

Of 2157 records identified, 18 studies met the inclusion criteria. Near 40
percent of studies focused on hospital quality transparency tools, and more than 90 percent of studies were from the US. Hospital price transparency reduced the price of laboratory and imaging tests except for office-visit services. Hospital quality transparency declined the level or growth rates of healthcare spending, while it adversely and significantly raised the price of healthcare services and consumers’ payment in higher-ranked or rated facilities, which was referred to as the reputation premium in the healthcare industry. Hospital quality transparency not only leveraged private insurers bonding with a higher-rated hospital network to increase premiums, but also induced their anticipated pricing behaviors.

Conclusion

Hospital price and quality transparency was not effective as expected. Future research should explore the understudied consequences of hospital quality transparency programs, such as the reputation/rating premium and its policy intervention.
Transcriptomic analysis of spleen B cell revealed the molecular basis of bursopentin on B cell differentiation
Authors: Zhang Ze , Cai Jiaxi , Hao Shanshan , Li Chenfei , Chen Jiajing , Li Tongtong , Feng Xiuli
Published: December 2022

The bursa of Fabricius, the acknowledged humoral immune organ unique to birds, plays a vital role in B cell development. Bursopentin (BP5) derived from the bursa is reported to induce the development and formation of B cells. However, the mechanism of BP5 on B cell differentiation is still unclear. In this paper, total B lymphocytes from mice immunized with H9N2 subtype AIV vaccine were stimulated with BP5. The results show that BP5 at the experimental dosages promoted B cell differentiation, including the total B cells, activated B cells, differentiated B cells, mature B cells and plasma cells. Then, the in vivo immune experiment proved that the percentages of activated and differentiated B cells from mice immunized with AIV vaccine and 0.25 mg/mL BP5 were increased. To investigate the molecular mechanism of BP5 on B cell differentiation, the gene expression profiles of B cells purified from the spleen cells of mice immunized with AIV vaccine and BP5 were detected following RNA sequencing technology. The results show that BP5 at 0.05 and 0.25 mg/mL induced the enrichment of various biological functions, and stimulated five common significant enrichment pathways in B cells from the immunized mice. Additionally, 120 and 59 differentially expressed genes (DEG) represented transcriptional factors in B cells following 0.05 and 0.25 mg/mL BP5 immunization, respectively. In summary, these results suggest that BP5 regulates various gene expression involved in regulation of B cell development, which provides the knowledge required for additional studies on B cell differentiation in response to bursal-derived peptides and also provides an important experimental basis for improving vaccine immunity.
Pathogenicity of highly pathogenic avian influenza H5N8 subtype for herring gulls (Larus argentatus): impact of homo- and heterosubtypic immunity on the outcome of infection
Authors: Tarasiuk Karolina , Kycko Anna , Knitter Małgorzata , Świętoń Edyta , Wyrostek Krzysztof , Domańska-Blicharz Katarzyna , Bocian Łukasz , Meissner Włodzimierz , Śmietanka Krzysztof
Published: December 2022

To improve understanding of the pathobiology of highly pathogenic avian influenza virus (HPAIV) infections in wild birds, pathogenicity and transmissibility of HPAIV H5N8 subtype clade 2.3.4.4b was evaluated in ~ 8-week-old herring gulls (Larus argentatus) divided into 3 groups: naïve birds (group A), birds previously exposed to low pathogenic avian influenza virus (LPAIV) H5N1 (group B) and LPAIV H13N6 (group C). The HPAIV H5N8 virus was highly virulent for naïve gulls, that showed early morbidity, high mortality, a broad spectrum of clinical signs, including violent neurological disorders, systemic distribution of the virus in organs accompanied by high level of shedding and transmission to contact birds. Pre-exposure to homologous and heterologous LPAIV subtypes conferred only partial protection: we observed increased survival rate (statistically significant only in group B), nervous signs, pantropic distribution of virus in organs, shedding (significantly reduced in gulls of group C in the early phase of disease and asymptomatic shedding in the late phase), transmission to contact gulls (more pronounced in group B) and near-complete seroconversion in survivors. Histopathological and immunohistochemical results indicate virus tropism for the neural, respiratory and myocardial tissues. In conclusion, we demonstrate that HPAIV H5N8 clade 2.3.4.4b is highly virulent and lethal for fully susceptible herring gulls and that pre-exposure to homo- and heterosubtypic LPAIV only partially modulates the disease outcome.
An artificial intelligence-enabled ECG algorithm for identifying ventricular premature contraction during sinus rhythm
Authors: Chang Sheng-Nan , Tseng Yu-Heng , Chen Jien-Jiun , Chiu Fu-Chun , Tsai Chin-Feng , Hwang Juey-Jen , Wang Yi-Chih , Tsai Chia-Ti
Published: December 2022

Background

Ventricular premature complex (VPC) is a common arrhythmia in clinical practice. VPC could trigger ventricular tachycardia/fibrillation or VPC-induced cardiomyopathy in susceptible patients. Existing screening methods require prolonged monitoring and are limited by cost and low yield when the frequency of VPC is low. Twelve-lead electrocardiogram (ECG) is low cost and widely used. We aimed to identify patients with VPC during normal sinus rhythm (NSR) using artificial intelligence (AI) and machine learning-based ECG reading.

Methods

We developed AI-enabled ECG algorithm using a convolutional neural network (CNN) to detect the ECG signature of VPC presented during NSR using standard 12-lead ECGs. A total of 2515 ECG records from 398 patients with VPC were collected. Among them, only ECG records of NSR without VPC (1617 ECG records) were parsed.

Results

A total of 753 normal ECG records from 387 patients under NSR were used for comparison. Both image and time-series datasets were parsed for the training process by the CNN models. The computer architectures were optimized to select the best model for the training process. Both the single-input image model (InceptionV3, accuracy: 0.895, 95% confidence interval [CI] 0.683–0.937) and multi-input time-series model (ResNet50V2, accuracy: 0.880, 95% CI 0.646–0.943) yielded satisfactory results for VPC prediction, both of which were better than the single-input time-series model (ResNet50V2, accuracy: 0.840, 95% CI 0.629–0.952).

Conclusions

AI-enabled ECG acquired during NSR permits rapid identification at point of care of individuals with VPC and has the potential to predict VPC episodes automatically rather than traditional long-time monitoring.
Monitoring PD-L1 Expression on Circulating Tumor–Associated Cells in Recurrent Metastatic Non–Small-Cell Lung Carcinoma Predicts Response to Immunotherapy With Radiation Therapy
Authors: Moran Jillian A. , Adams Daniel L. , Edelman Martin J. , Lopez Pablo , He Jianzhong , Qiao Yawei , Xu Ting , Liao Zhongxing , Gardner Kirby P. , Tang Cha-Mei , Lin Steven H.
Published: December 2022

PURPOSE

Current diagnostic methods to determine programmed death 1 (PD-1) receptor and its ligand (PD-L1)/PD-1 immunotherapy (immune checkpoint inhibitor [ICI]) efficacy in recurrent or metastatic non–small-cell lung carcinoma (rmNSCLC) are imprecise. Although previously shown that patients with high tumor PD-L1 (≥ 50%) demonstrate clinical benefit in the form of disease reduction and improved survival, patients with low PD-L1 (< 50%) sometimes benefit from treatment. Since the PD-L1/PD-1 pathway is dynamic, monitoring PD-L1 levels during treatment may be more accurate than a static baseline tumor biopsy; however, rebiopsying the primary or metastatic disease is rarely feasible. Liquid biopsies that measure the upregulation of PD-L1 on tumor-associated cells (TACs), ie, cancer-associated macrophage-like cells and circulating tumor cells, have been performed, but their predictive value for ICI therapy efficacy is unknown.

MATERIALS AND METHODS

We initiated a single-blind prospective study to evaluate TAC PD-L1 expression changes in rmNSCLC from blood samples before (T0) and after (T1) treatment with ICI (ICI, n = 41) or without ICI (no ICI, n = 41). Anonymized blood was filtered to isolate TACs, which were then quantified for high/low PD-L1 expression. Progression-free survival (PFS) or overall survival (OS) hazard ratios (HRs) were evaluated at 18 and 24 months by censored univariate analysis.

RESULTS

Increased TAC PD-L1 expression between T0 and T1 in patients who were not treated with ICI had no relationship with PFS or OS. However, increased TAC PD-L1 expression between T0 and T1 in patients treated with ICI had significantly better PFS (HR, 3.49; 95% CI, 1.5 to 8.3; P = .0091) and OS (HR, 3.058; 95% CI, 1.2 to 7.9; P = .0410).

CONCLUSION

Blood-based monitoring of dynamic changes in PD-L1 in TACs appears to identify patients with rmNSCLC who may benefit from ICI.
Effect of an Intermittent Calorie-restricted Diet on Type 2 Diabetes Remission: A Randomized Controlled Trial
Authors: Yang Xiao , Zhou Jiali , Shao Huige , Huang Bi , Kang Xincong , Wu Ruiyu , Bian Fangzhou , Hu Minghai , Liu Dongbo
Published: December 2022

Context

The 2021 consensus report on the definition and interpretation of remission of type 2 diabetes (T2D) has been released. Although intermittent fasting diets (IF) are becoming very popular, no studies have investigated their benefit in diabetes remission.

Objective

The present study examined the effectiveness of IF in diabetes remission and potential remission durability.

Methods

Participants between ages 38 and 72 years with a duration of T2D of 1 to 11 years, a body mass index (BMI) of 19.1 to 30.4, 66.7% male, and antidiabetic agent use and/or insulin injection were randomly allocated at a ratio of 1:1 to the Chinese Medical Nutrition Therapy (CMNT) or control group. The primary outcome was diabetes remission, defined as a stable glycated hemoglobin A1c (HbA1c) level of less than 48 mmol/mol (< 6.5%) for at least 3 months after discontinuing all antidiabetic medications. The secondary outcomes included HbA1c level, fasting blood glucose level, blood pressure, weight, quality of life, and medication costs. We conducted a 12-month follow-up to assess the continuation of remission.

Results

On completing the 3-month intervention plus 3-month follow-up, 47.2% (17/36) of participants achieved diabetes remission in the CMNT group, whereas only 2.8% (1/36) of individuals achieved remission in the control group (odds ratio 31.32; 95% CI, 2.39-121.07; P < 0.0001). The mean body weight of participants in the CMNT group was reduced by 5.93 kg (SD 2.47) compared to 0.27 kg (1.43) in the control group. After the 12-month follow-up, 44.4% (16/36) of the participants achieved sustained remission, with an HbA1c level of 6.33% (SD 0.87). The medication costs of the CMNT group were 77.22% lower than those of the control group (60.4/month vs 265.1/month).

Conclusion

This study demonstrated the clinical efficacy of CMNT in achieving diabetes remission for at least 1 year.