bluuebunny/crossref_metadata_2025 huggingface dataset:
Case report: A case of duodenal adenocarcinoma achieving significantly long survival treating with immune checkpoint inhibitors and chemotherapy without positive biomarkers
Authors: Chen Xian , Zhou Rui , Li Yong , Qu Xin , Qu Yan-chun , Li Wen-zhu , Ye Yong-song , Liu Li-rong , Zhu Yan-juan , Zhang Hai-bo
Published: December 2022

Small bowel adenocarcinoma (SBA), particularly duodenal adenocarcinoma (DA), is a rare gastrointestinal cancer with a dismal prognosis. Data on SBA treatments are limited, and the therapeutic strategy remains uncertain. Currently, chemotherapy is the most used treatment; however, it has a poor median progression-free survival (mPFS) of no more than five months in the second-line setting. We report a case with DA that responded well to the immune checkpoint inhibitor (ICI) tislelizumab plus irinotecan in the second-line treatment. To our knowledge, this is the first report of administering ICIs plus chemotherapy to SBA. Despite the absence of microsatellite instability-high (MSI-H) and high tumor mutational burden (TMB), the patient with TP53/KRAS mutation achieved a significantly long PFS of 17 months, and the benefit is still ongoing. The mechanism of this remarkable efficacy might be associated with an increase in tumor immunogenicity after chemotherapy. The current study presents a promising effect of ICIs plus chemotherapy on SBA, affirming the need to investigate the clinical value of this combination in SBA and the underlying mechanism behind it.
Impact of SARS-CoV-2 vaccination on systemic immune responses in people living with HIV
Authors: Bessen Clara , Plaza-Sirvent Carlos , Simsek Agit , Bhat Jaydeep , Marheinecke Corinna , Urlaub Doris , Bonowitz Petra , Busse Sandra , Schumann Sabrina , Blanco Elena Vidal , Skaletz-Rorowski Adriane , Brockmeyer Norbert H. , Overheu Oliver , Reinacher-Schick Anke , Faissner Simon , Watzl Carsten , Pfaender Stephanie , Potthoff Anja , Schmitz Ingo
Published: December 2022

Despite the development of vaccines, which protect healthy people from severe and life-threatening Covid-19, the immunological responses of people with secondary immunodeficiencies to these vaccines remain incompletely understood. Here, we investigated the humoral and cellular immune responses elicited by mRNA-based SARS-CoV-2 vaccines in a cohort of people living with HIV (PLWH) receiving anti-retroviral therapy. While antibody responses in PLWH increased progressively after each vaccination, they were significantly reduced compared to the HIV-negative control group. This was particularly noteworthy for the Delta and Omicron variants. In contrast, CD4+ Th cell responses exhibited a vaccination-dependent increase, which was comparable in both groups. Interestingly, CD4+ T cell activation negatively correlated with the CD4 to CD8 ratio, indicating that low CD4+ T cell numbers do not necessarily interfere with cellular immune responses. Our data demonstrate that despite the lower CD4+ T cell counts SARS-CoV-2 vaccination results in potent cellular immune responses in PLWH. However, the reduced humoral response also provides strong evidence to consider PLWH as vulnerable group and suggests subsequent vaccinations being required to enhance their protection against COVID-19.
Soluble mediators of innate immunity in annelids and bivalve mollusks: A mini-review
Authors: Canesi Laura , Auguste Manon , Balbi Teresa , Prochazkova Petra
Published: December 2022

Annelids and mollusks, both in the superphylum of Lophotrochozoa (Bilateria), are important ecological groups, widespread in soil, freshwater, estuarine, and marine ecosystems. Like all invertebrates, they lack adaptive immunity; however, they are endowed with an effective and complex innate immune system (humoral and cellular defenses) similar to vertebrates. The lack of acquired immunity and the capacity to form antibodies does not mean a lack of specificity: invertebrates have evolved genetic mechanisms capable of producing thousands of different proteins from a small number of genes, providing high variability and diversity of immune effector molecules just like their vertebrate counterparts. This diversity allows annelids and mollusks to recognize and eliminate a wide range of pathogens and respond to environmental stressors. Effector molecules can kill invading microbes, reduce their pathogenicity, or regulate the immune response at cellular and systemic levels. Annelids and mollusks are “typical” lophotrochozoan protostome since both groups include aquatic species with trochophore larvae, which unite both taxa in a common ancestry. Moreover, despite their extensive utilization in immunological research, no model systems are available as there are with other invertebrate groups, such as Caenorhabditis elegans or Drosophila melanogaster, and thus, their immune potential is largely unexplored. In this work, we focus on two classes of key soluble mediators of immunity, i.e., antimicrobial peptides (AMPs) and cytokines, in annelids and bivalves, which are the most studied mollusks. The mediators have been of interest from their first identification to recent advances in molecular studies that clarified their role in the immune response.
Simultaneous editing of TCR, HLA-I/II and HLA-E resulted in enhanced universal CAR-T resistance to allo-rejection
Authors: Li Wuling , Zhu Xiuxiu , Xu Yanmin , Chen Jun , Zhang Hongtao , Yang Zhi , Qi Yanan , Hong Juan , Li Yunyan , Wang Guixue , Shen Junjie , Qian Cheng
Published: December 2022

Introduction

The major challenge for universal chimeric antigen receptor T cell (UCAR-T) therapy is the inability to persist for a long time in patients leading to inferior efficacy clinically. The objective of this study was to design a novel UCAR-T cell that could avoid the occurrence of allo-rejection and provide effective resistance to allogeneic Natural Killer (NK) cell rejection, together with the validation of its safety and efficacy ex vivo and in vivo.

Methods

We prepared T-cell receptor (TCR), Human leukocyte antigen (HLA)-I/II triple-edited (TUCAR-T) cells and evaluated the anti-tumor efficacy ex vivo and in vivo. We measured the resistance of exogenous HLA-E expressing TUCAR-T (ETUCAR-T) to NK rejection by using an enhanced NK. Furthermore, we established the safety and efficacy of this regimen by treating Nalm6 tumor-bearing mice with a repeated high-dose infusion of ETUCAR-T. Moreover, we analyzed the effects of individual gene deficiency CAR-T on treated mice and the changes in the transcriptional profiles of different gene-edited T cells via RNA-Seq.

Results

Data showed that HLA-II editing didn’t impair the anti-tumor efficacy of TUCAR-T ex vivo and in vivo and we found for the first time that HLA-II deficiency could facilitate the persistence of CAR-T. Contrastively, as the most commonly eliminated target in UCAR-T, TCR deficiency was found to be a key disadvantageous factor for the shorter-term anti-tumor efficacy in vivo. Our study demonstrated ETUCAR-T could effectively resist allogeneic NK rejection ex vivo and in vivo.

Discussion

Our research provided a potential and effective strategy for promoting the persistence of UCAR-T cells in clinical application. And it reveals the potential key factors of the poor persistence of UCAR-T along with new insights for future development.
Viral infectious diseases severity: co-presence of transcriptionally active microbes (TAMs) can play an integral role for disease severity
Authors: Yadav Aanchal , Pandey Rajesh
Published: December 2022

Humans have been challenged by infectious diseases for all of their recorded history, and are continually being affected even today. Next-generation sequencing (NGS) has enabled identification of, i) culture independent microbes, ii) emerging disease-causing pathogens, and iii) understanding of the genome architecture. This, in turn, has highlighted that pathogen/s are not a monolith, and thereby allowing for the differentiation of the wide-ranging disease symptoms, albeit infected by a primary pathogen. The conventional ‘one disease - one pathogen’ paradigm has been positively revisited by considering limited yet important evidence of the co-presence of multiple transcriptionally active microbes (TAMs), potential pathogens, in various infectious diseases, including the COVID-19 pandemic. The ubiquitous microbiota presence inside humans gives reason to hypothesize that the microbiome, especially TAMs, contributes to disease etiology. Herein, we discuss current evidence and inferences on the co-infecting microbes particularly in the diseases caused by the RNA viruses - Influenza, Dengue, and the SARS-CoV-2. We have highlighted that the specific alterations in the microbial taxonomic abundances (dysbiosis) is functionally connected to the exposure of primary infecting pathogen/s. The microbial presence is intertwined with the differential host immune response modulating differential disease trajectories. The microbiota-host interactions have been shown to modulate the host immune responses to Influenza and SARS-CoV-2 infection, wherein the active commensal microbes are involved in the generation of virus-specific CD4 and CD8 T-cells following the influenza virus infection. Furthermore, COVID-19 dysbiosis causes an increase in inflammatory cytokines such as IL-6, TNF-α, and IL-1β, which might be one of the important predisposing factors for severe infection. Through this article, we aim to provide a comprehensive view of functional microbiomes that can have a significant regulatory impact on predicting disease severity (mild, moderate and severe), as well as clinical outcome (survival and mortality). This can offer fresh perspectives on the novel microbial biomarkers for stratifying patients for severe disease symptoms, disease prevention and augmenting treatment regimens.
Novel insight into miRNA biology and its role in the pathogenesis of systemic lupus erythematosus
Authors: Luo Baiwei , Zhou Kaixia , Liufu Yingcong , Huang Xia , Zeng Huiqiong , Zhang Zhaoyang
Published: December 2022

MicroRNAs(miRNAs) have emerged as key regulators that control and influence gene expression as well as multiple biological processes depending on their potential binding sites in human-protein coding genes and other unconventional patterns, including coding for peptides, activating Toll-like receptors as a ligand, and other manners. Accumulating evidence has demonstrated that microRNA expression is tightly regulated during phases of development, differentiation, and effector functions of immune cells, immunological disorders of systemic lupus erythematosus (SLE). This review outlines the biogenesis of miRNAs and their unconventional functions as well as underlying cellular and molecular mechanisms. It then summarizes our current knowledge about how the biogenesis of miRNAs is regulated. Moreover, an overview was provided concerning the role of abnormal expression of miRNAs in lupus immune cells. In particular, we will shed some light on the recent advances in the role of miRNAs and exosome-derived miRNAs in immunological and epigenetic pathways in the pathogenesis of SLE.
Single-cell transcriptomics reveals cell type–specific immune regulation associated with anti-NMDA receptor encephalitis in humans
Authors: Jiang Yushu , Dai Shuhua , Jia Linlin , Qin Lingzhi , Zhang Milan , Liu Huiqin , Wang Xiaojuan , Pang Rui , Zhang Jiewen , Peng Gongxin , Li Wei
Published: December 2022

Introduction

Anti-N-methyl-D-aspartate receptor encephalitis (anti-NMDARE) is a rare autoimmune disease, and the peripheral immune characteristics associated with anti-NMDARE antibodies remain unclear.

Methods

Herein, we characterized peripheral blood mononuclear cells from patients with anti-NMDARE and healthy individuals by single-cell RNA sequencing (scRNA-seq).

Results

The transcriptional profiles of 129,217 cells were assessed, and 21 major cell clusters were identified. B-cell activation and differentiation, plasma cell expansion, and excessive inflammatory responses in innate immunity were all identified. Patients with anti-NMDARE showed higher expression levels of CXCL8, IL1B, IL6, TNF, TNFSF13, TNFSF13B, and NLRP3. We observed that anti-NMDARE patients in the acute phase expressed high levels of DC_CCR7 in human myeloid cells. Moreover, we observed that anti-NMDARE effects include oligoclonal expansions in response to immunizing agents. Strong humoral immunity and positive regulation of lymphocyte activation were observed in acute stage anti-NMDARE patients.

Discussion

This high-dimensional single-cell profiling of the peripheral immune microenvironment suggests that potential mechanisms are involved in the pathogenesis and recovery of anti-NMDAREs.
Tropical cyclone Wind Pump induced chlorophyll-a enhancement in the South China Sea: A comparison of the open sea and continental shelf
Authors: Li Ying , Tang Danling
Published: December 2022

The continental shelf and open sea region have different ocean physical and environmental responses to tropical cyclones (TC). The present study firstly compared the grid-based maximum response (GMR) of sea surface chlorophyll a (Chl-a) to TCs Wind Pump between the continental shelf (depths 50-200m) and open sea (depths>200 m) region in the South China Sea (SCS) during 1998-2020, using multiple-satellite data. For all TC events, the average Chl-a increases by 0.13 mg/m3. The comparisons between the pre- and post-TC periods show that Chl-a increases by 0.18 mg/m3 (115%) in the continental shelf and 0.07 mg/m3 (57%) in the open sea region, respectively. In both areas, TC-induced Chl-a enhancement (Chl_en) strongly depends on TC maximum wind speed and translation speed. The strong and fast-moving TCs and weak and slow-moving TCs both induce the maximum Chl_en in the continental shelf region. While in the open sea, the maximum Chl_en was induced by the strong and slow-moving TCs. Overall, our results reveal that the TC wind pump’s effects on Chl-a enhancement are stronger in the continental shelf region than in the open sea.
Transcriptional responses indicate acclimation to prolonged deoxygenation in the coral Stylophora pistillata
Authors: Kvitt Hagit , Malik Assaf , Ben-Tabou de-Leon Smadar , Shemesh Eli , Lalzar Maya , Gruber David F. , Rosenfeld Hanna , Shi Tuo , Mass Tali , Tchernov Dan
Published: December 2022

The current decrease in oceanic dissolved oxygen is a widespread and pressing problem that raises concern as to how marine biota in general, and coral reefs in particular will be affected. However, the molecular response underlying tolerance of corals to prolonged severe deoxygenation where acclimation to hypoxia can accrue is not yet known. Here, we investigated the effect of two weeks of continuous exposure to conditions of extreme deoxygenation, not hitherto exerted under laboratory conditions (~ 0.35 mg L−1 dissolved oxygen), on the physiology and the diurnal gene expression of the coral, Stylophora pistillata. Deoxygenation had no physiologically significant effect on tissue loss, calcification rates, symbiont numbers, symbiont chlorophyll-a content and symbiont photosynthesis rate. However, deoxygenation evoked a significant transcriptional response that was much stronger at night, showing an acute early response followed by acclimation after two weeks. Acclimation included increased mitochondria DNA copy numbers, possibly increasing energy production. Gene expression indicated that the uptake of symbiosis-derived components was increased together with a decrease in nematocyst formation, suggesting that prolonged deoxygenation could enhance the corals’ need for symbiosis-derived components and reduces its predation abilities. Coral orthologs of the conserved hypoxia pathway, including oxygen sensors, hypoxia-inducible factor (HIF) and its target genes were differentially expressed in a similar temporal sequence as observed in other metazoans including other species of corals. Overall, our studies show that by utilizing highly conserved and coral–specific response mechanisms, S. pistillata can acclimate to deoxygenation and possibly survive under climate change-driven oceanic deoxygenation. On the other hand, the critical importance of algal symbionts in this acclimation suggests that any environmental perturbations that disrupt such symbiosis might negatively affect the ability of corals to withstand ocean oxygen depletion.
Peptide self-assembled nanomedicine induces antitumor immunity by blocking the PD-1/PD-L1 axis
Authors: Huang Tao , Sun Xianfu , Meng Xiaocao , Chen Mengdie , Li Yapeng , Du Shengnan , Qi Yingqiu , Ge Hong
Published: December 2022

The development of immune checkpoint inhibitors (ICIs) revolutionizes cancer treatment, which has been applied in the treatment of several kinds of malignancies in the clinic. Due to their specific affinity and controllable cost, the emerging peptide-based ICI therapeutics have attracted great attention. However, peptide-based drugs generally show poor bioavailability and a short in vivo half-life. Peptide-based nanomedicine is a promising approach to increase the efficacy of therapeutic peptides. In this work, an amphiphilic peptide based on the reported D-peptide for ICIs has been developed. The constructed amphiphilic peptide can self-assemble into a stable nanostructure (noted as CD-NPs). The prepared CD-NPs have a spherical shape with a hydrodynamic size of about 35 nm. In vivo studies show that the prepared nanomedicine can effectively inhibit tumor growth in 4T1 tumor-bearing mice. Moreover, we found that the CD-NPs increase the infiltration of effector T cells and natural killer cells as well as the immune cytokines in the tumor tissues, implying that they activated the immune response for antitumor activity. Finally, no obvious changes in the major organs, tissues, or the body weight caused by the nanomedicine can be observed, demonstrating their good biocompatibility. Taken together, this study provides a basic idea for designing a novel peptide-based nanomedicine for enhanced antitumor efficacy by enhancing the blockade of ICIs and activating the immune response.
Efficacy of high-flow nasal oxygenation compared with laryngeal mask airway in children undergoing ambulatory oral surgery under deep sedation: A randomized controlled non-inferiority trial
Authors: Ran Longkuan , Huang Guijin , Yao Ying , Wu Yujia , Zhang Chao , Wang Yan , Yu Cong
Published: December 2022

Background

High-flow nasal oxygenation (HFNO) has been suggested as an alternative oxygenation method during procedural sedation. This randomized, non-inferiority trial evaluated the safety and efficacy of HFNO compared with laryngeal mask airway (LMA) in pediatric ambulatory oral surgery under deep sedation.

Methods

In total, 120 children aged 2–7 years (weight: 10–30 kg) were equally assigned into two groups, namely, HFNO with propofol total intravenous anesthesia infusion (HFNO-IV) or LMA with propofol total intravenous anesthesia infusion (LMA-IV). The primary objective was to monitor carbon dioxide (CO2) accumulation during perioperative surgery. Secondary objectives included monitoring transcutaneous oxygen saturation, grade exposure to the surgical field, perioperative adverse events, or other events. The predefined non-inferiority margin was 7 mmHg. During the COVID-19 pandemic, a novel WeChat applet was implemented to gather follow-up data after discharge.

Results

Non-inferiority could be declared for HFNO relative to LMA (mean difference in transcutaneous CO2 (TcCO2) = −1.4 mmHg, 95% CI: −2.9, 0.1 mmHg; P > 0.05). The pre-surgical TcCO2 of the HFNO-IV group (45.4 ± 4.5 mmHg) was similar to that of the LMA-IV group (44.0 ± 3.5 mmHg), within the clinically acceptable normal range. All the children maintained SpO2 levels of >97%. The surgical field exposure score of the HFNO group was significantly better than that of the LMA group. There was no significant difference between the two groups regarding risk or adverse events.

Conclusion

HFNO was not inferior to LMA for maintaining oxygenation and ventilation in patients undergoing pediatric ambulatory oral surgery under deep sedation under strict isolation from the oral cavity to the upper airway.
The increasing incidence and high body mass index-related burden of gallbladder and biliary diseases–A results from global burden of disease study 2019
Authors: Liu Shuhua , Yi Maolin , Qin Juanjuan , Lei Fang , Lin Lijin , Li Yi , Zhuo Ming , Liu Weifang , Huang Xuewei , Cai Jingjing , Zhang Xiaojing , Zhang Peng , Ji Yanxiao , Ye Junming , Li Hongliang
Published: December 2022

Background

Gallbladder and biliary diseases are common gastrointestinal conditions associated with huge socioeconomic costs and are considered risk factors for cardiovascular diseases and digestive system cancers. The prevalence and incidence of gallbladder and biliary diseases have not received enough attention from 1990 to 2019. Several non-communicable diseases were associated with the incidence of gallbladder and biliary diseases. It is necessary to clarify the change in the incidence and disability burden of gallbladder and biliary diseases worldwide.

Methods

Data on high body mass index (BMI)-related disease burden and incidence, years of life lost prematurely, and years lived with disability (YLDs) due to gallbladder and biliary diseases were obtained from the Global Burden of Disease 2019. The estimated annual percentage change was calculated to qualify the gallbladder and biliary disease burden change.

Results

The global age-standardized incidence rate has increased from 585.35 per 100,000 (95% UI: 506.05–679.86) in 1990 to 634.32 per 100,000 (95% UI: 540.21–742.93) in 2019. And the increase in incidence was positively correlated with rising high BMI-related summary exposure value. The high BMI-related YLDs of gallbladder and biliary diseases have increased worldwide over time. Globally, the 25–49 age group suffered a rapid rise in incidence and high BMI attributable to the YLDs rate of gallbladder and biliary diseases.

Conclusion

The global incidence and high BMI-related YLDs of gallbladder and biliary diseases remain prominent to increase over the past 30 years. Notably, the incidence and high BMI-related YLDs among people aged 25–49 years have rapidly increased over time. Therefore, high BMI should be emphasized in strategic priorities for controlling gallbladder and biliary diseases.
Characteristics of dust mite sublingual immunotherapy-associated adverse events in the early phase
Authors: Chen Ming , Lin Lin , Yan Maoxiao , Xu Chong , Chai Ruonan
Published: December 2022

Background

Few studies reported the characteristics of house dust mite (HDM) sublingual immunotherapy (SLIT) adverse events (AEs) during early phase treatment. The aim of this prospective study was mainly to explore the characteristics of AEs in allergic rhinitis (AR) patients during 6 months of HDM SLIT.

Methods

A total of 242 patients with AR were enrolled in this study. Telephone follow-up and administration were conducted in the every week of the first month, the third month, and the sixth month of SLIT treatment. Furthermore, the early efficacy, AEs, and compliance were analyzed in our study.

Results

Overall, 70.25% (170/242) of the AR patients completed the study, while 29.75% (72/242) of the AR patients failed to complete the whole 6 months of SLIT treatment process. On the whole, symptoms improved in 87.65% (149/170) of patients including 34.12% (58/170) well-controlled and 53.53% (91/170) partially controlled. The correlation analysis results showed that the treatment effect was negatively correlated with the age (r = −0.1614, P = 0.0355). The AEs mainly occurred in the first month, comprised of local rashes, gastrointestinal reactions, and itching of mouth and tongue. Subgroup analysis in the first month showed the itching of mouth and tongue, gastrointestinal reactions, fatigue, and other AEs in ≥14 years old group (14–65 years old, n = 42) were significant differences when compared with that in the <14 years old group (4–13 years old, n = 128, all P < 0.05). In the study, the main reasons for terminated immunotherapy were drug inaccessibility, loss of follow-up and long course of treatment.

Conclusion

Patients with AR who received HDM SLIT revealed an early efficacy after 6 months, with AEs mostly occurred in the first month.
Case report: Successful treatment with the combined therapy of interferon-alpha 2b and anlotinib in a patient with advanced hepatic epithelioid hemangioendothelioma
Authors: Liu Xiaolei , Zhou Ruiquan , Si Shuang , Liu Liguo , Yang Shiwei , Han Dongdong , Tan Haidong
Published: December 2022

Hepatic epithelioid hemangioendothelioma (HEH) is a very rare tumor originating from vascular endothelial cells, with unpredictable malignancy. At present, there is no standard treatment protocol yet established. Both surgical resection and liver transplantation have been reported to be effective treatments for HEH; however, multiple intrahepatic lesions or extrahepatic metastasis make these procedures unsuitable to most patients. Systematic therapy has also been investigated, but the results are undetermined due to the limited cases. Interferon-alpha 2b (IFN-a 2b) has also been used for the treatment of HEH. Based on our previous study, the rate of tumor regression with IFN-a 2b monotherapy was more than 50%. Here, we reported a patient with advanced HEH, who achieved a partial response with the combined therapy of anlotinib and IFN-a 2b. The tumor stayed stable for 2 years with anlotinib monotherapy and regressed 3 months after the combined therapy of anlotinib and IFN-a 2b. The synergistic effect of combined therapy with anlotinib and IFN-a 2b provided promising guidance for future clinical study.
Role of complement activation in anti-neutrophil cytoplasmic antibody-associated glomerulonephritis
Authors: Kojima Tadasu , Oda Takashi
Published: December 2022

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is an autoimmune disease characterized by necrotizing inflammation of small or medium vessels, causing ANCA associated glomerulonephritis (AAGN). AAGN is defined as pauci-immune glomerulonephritis with no or little immune deposition; hence, activation of the complement system in AAV was overlooked until recently. However, many studies in mice and humans have revealed a crucial role for complement system activation in the development of AAGN. Circulating and urinary detection of various complement components associated with AP activation, which have been broadly correlated with the clinical activity of AAGN, has been reported and may be useful for predicting renal outcome at the time of diagnosis and setting up personalized treatments. Moreover, recent investigations have suggested the possible contribution of the complement classical or lectin pathway activation in the development of AAGN. Thus, as therapeutic options targeting complement components are making rapid strides, the primary complement pathway involved in AAGN disease progression remains to be elucidated: this will directly impact the development of novel therapeutic strategies with high specificity and reduced side effects. This review summarizes and discusses the most recent evidence on the crucial roles of the complement system in the development of AAGN and possible therapeutic strategies that target complement components for disease management.
Current status of stem cell treatments and innovative approaches for stress urinary incontinence
Authors: Seval Mehmet Murat , Koyuncu Kazibe
Published: December 2022

Stem cells are capable of self-renewal, differentiation, and the promotion of the release of chemokines and progenitor cells essential for tissue regeneration. Stem cells have the potential to develop into specialized cells if given the right conditions, to self-renew and maintain themselves, to generate a large number of new differentiated cells if injured, and to either generate new tissues or repair existing ones. In the last decade, it has become clear that treating lower urinary tract dysfunction with the patient's own adult stem cells is an effective, root-cause method. Regenerative medicine is predicated on the idea that a damaged rhabdosphincter can be repaired, leading to enhanced blood flow and improved function of the sphincter's exterior (striated) and internal (smooth) muscles. Stem cell therapy has the potential to cure stress urinary incontinence according to preclinical models. In contrast, stem cell treatment has not been licensed for routine clinical usage. This article reviews the current state of stem cell for stres urinary incontinence research and recommends future avenues to facilitate practical uses of this potential therapy modality.
Challenges and solutions for transforming health ecosystems in low- and middle-income countries through artificial intelligence
Authors: López Diego M. , Rico-Olarte Carolina , Blobel Bernd , Hullin Carol
Published: December 2022

Background

Recent studies demonstrate the potential of Artificial Intelligence to support diagnosis, mortality assessment, and clinical decisions in low-and-middle-income countries (LMICs). However, explicit evidence of strategies to overcome the particular challenges for transformed health systems in these countries does not exist.

Objective

The present study undertakes a review of research on the current status of artificial intelligence (AI) to identify requirements, gaps, challenges, and possible strategies to strengthen the large, complex, and heterogeneous health systems in LMICs.

Design

After introducing the general challenges developing countries face, the methodology of systematic reviews and the meta-analyses extension for scoping reviews (PRISMA-ScR) is introduced according to the preferred reporting items. Scopus and Web of Science databases were used to identify papers published between 2011–2022, from which we selected 151 eligible publications. Moreover, a narrative review was conducted to analyze the evidence in the literature about explicit evidence of strategies to overcome particular AI challenges in LMICs.

Results

The analysis of results was divided into two groups: primary studies, which include experimental studies or case studies using or deploying a specific AI solution (n= 129), and secondary studies, including opinion papers, systematic reviews, and papers with strategies or guidelines (n= 22). For both study groups, a descriptive statistical analysis was performed describing their technological contribution, data used, health context, and type of health interventions. For the secondary studies group, an in-deep narrative review was performed, identifying a set of 40 challenges gathered in eight different categories: data quality, context awareness; regulation and legal frameworks; education and change resistance; financial resources; methodology; infrastructure and connectivity; and scalability. A total of 89 recommendations (at least one per challenge) were identified.

Conclusion

Research on applying AI and ML to healthcare interventions in LMICs is growing; however, apart from very well-described ML methods and algorithms, there are several challenges to be addressed to scale and mainstream experimental and pilot studies. The main challenges include improving the quality of existing data sources, training and modeling AI solutions based on contextual data; and implementing privacy, security, informed consent, ethical, liability, confidentiality, trust, equity, and accountability policies. Also, robust eHealth environments with trained stakeholders, methodological standards for data creation, research reporting, product certification, sustained investment in data sharing, infrastructures, and connectivity are necessary.

Systematic review registration

[https://rb.gy/frn2rz].
Mobile colistin resistance (MCR), extended-spectrum beta-lactamase (ESBL) and multidrug resistance monitoring in Escherichia coli (commensal and pathogenic) in pig farming: need of harmonized guidelines and clinical breakpoints
Authors: García Vanesa , García-Meniño Isidro , Gómez Verónica , Jiménez-Orellana Miguel , Méndez Antonio , Aguarón Alvaro , Roca Elisabet , Mora Azucena
Published: December 2022

Current data on antimicrobial resistance in pig production is essential for the follow-up strategic programs to eventually preserve the effectiveness of last-resort antibiotics for humans. Here, we characterized 106 Escherichia coli recovered in routine diagnosis (2020–2022) from fecal sample pigs, belonging to 74 Spanish industrial farms, affected by diarrhea. The analysis of virulence-gene targets associated with pathotypes of E. coli, determined 64 as pathogenic and 42 as commensal. Antimicrobial susceptibility testing (AST) performed by minimal inhibitory concentration (MIC) assay, was interpreted by applying breakpoints/cut-off values from the different standards EUCAST/TECOFF 2022, CLSI VET ED5:2020, and CASFM VET2020. Comparisons taking EUCAST as reference exhibited moderate to high correlation except for enrofloxacin, neomycin, and florfenicol. Of note, is the lack of clinical breakpoints for antibiotics of common use in veterinary medicine such as cefquinome, marbofloxacin, or florfenicol. AST results determined multidrug resistance (MDR) to ≥3 antimicrobial categories for 78.3% of the collection, without significant differences in commensal vs pathogenic isolates. Plasmid-mediated mobile colistin resistance gene (mcr) was present in 11.3% of 106 isolates, all of them pathogenic. This means a significant decrease compared to our previous data. Furthermore, 21.7% of the 106 E. coli were ESBL-producers, without differences between commensal and pathogenic isolates, and mcr/ESBL genes co-occurred in 3 isolates. Phylogenetic characterization showed a similar population structure (A, B1, C, D, and E), in both commensal and pathogenic E. coli, but with significant differences for B1, C, and E (38.1 vs 20.3%; 19 vs 1.6%; and 7.1 vs 25%, respectively). Additionally, we identified one B2 isolate of clone O4:H5-B2-ST12 (CH13-223), positive for the uropathogenic (UPEC) status, and in silico predicted as human pathogen. We suggest that a diagnosis workflow based on AST, detection of mcr and ESBL genes, and phylogenetic characterization, would be a useful monitoring tool under a “One-Health” perspective.
Metagenomic-based surveillance systems for antibiotic resistance in non-clinical settings
Authors: Pillay Stephanie , Calderón-Franco David , Urhan Aysun , Abeel Thomas
Published: December 2022

The success of antibiotics as a therapeutic agent has led to their ineffectiveness. The continuous use and misuse in clinical and non-clinical areas have led to the emergence and spread of antibiotic-resistant bacteria and its genetic determinants. This is a multi-dimensional problem that has now become a global health crisis. Antibiotic resistance research has primarily focused on the clinical healthcare sectors while overlooking the non-clinical sectors. The increasing antibiotic usage in the environment – including animals, plants, soil, and water – are drivers of antibiotic resistance and function as a transmission route for antibiotic resistant pathogens and is a source for resistance genes. These natural compartments are interconnected with each other and humans, allowing the spread of antibiotic resistance via horizontal gene transfer between commensal and pathogenic bacteria. Identifying and understanding genetic exchange within and between natural compartments can provide insight into the transmission, dissemination, and emergence mechanisms. The development of high-throughput DNA sequencing technologies has made antibiotic resistance research more accessible and feasible. In particular, the combination of metagenomics and powerful bioinformatic tools and platforms have facilitated the identification of microbial communities and has allowed access to genomic data by bypassing the need for isolating and culturing microorganisms. This review aimed to reflect on the different sequencing techniques, metagenomic approaches, and bioinformatics tools and pipelines with their respective advantages and limitations for antibiotic resistance research. These approaches can provide insight into resistance mechanisms, the microbial population, emerging pathogens, resistance genes, and their dissemination. This information can influence policies, develop preventative measures and alleviate the burden caused by antibiotic resistance.
Next-generation sequencing of a combinatorial peptide phage library screened against ubiquitin identifies peptide aptamers that can inhibit the in vitro ubiquitin transfer cascade
Authors: Lisowska Małgorzata , Lickiss Fiona , Gil-Mir Maria , Huart Anne-Sophie , Trybala Zuzanna , Way Luke , Hernychova Lenka , Krejci Adam , Muller Petr , Krejcir Radovan , Zhukow Igor , Jurczak Przemyslaw , Rodziewicz-Motowidło Sylwia , Ball Kathryn , Vojtesek Borivoj , Hupp Ted , Kalathiya Umesh
Published: December 2022

Defining dynamic protein–protein interactions in the ubiquitin conjugation reaction is a challenging research area. Generating peptide aptamers that target components such as ubiquitin itself, E1, E2, or E3 could provide tools to dissect novel features of the enzymatic cascade. Next-generation deep sequencing platforms were used to identify peptide sequences isolated from phage-peptide libraries screened against Ubiquitin and its ortholog NEDD8. In over three rounds of selection under differing wash criteria, over 13,000 peptides were acquired targeting ubiquitin, while over 10,000 peptides were selected against NEDD8. The overlap in peptides against these two proteins was less than 5% suggesting a high degree in specificity of Ubiquitin or NEDD8 toward linear peptide motifs. Two of these ubiquitin-binding peptides were identified that inhibit both E3 ubiquitin ligases MDM2 and CHIP. NMR analysis highlighted distinct modes of binding of the two different peptide aptamers. These data highlight the utility of using next-generation sequencing of combinatorial phage-peptide libraries to isolate peptide aptamers toward a protein target that can be used as a chemical tool in a complex multi-enzyme reaction.
Insights into the role of long non-coding RNAs in DNA methylation mediated transcriptional regulation
Authors: Yang Zhen , Xu Feng , Teschendorff Andrew E. , Zhao Yi , Yao Lei , Li Jian , He Yungang
Published: December 2022

DNA methylation is one of the most important epigenetic mechanisms that governing regulation of gene expression, aberrant DNA methylation patterns are strongly associated with human malignancies. Long non-coding RNAs (lncRNAs) have being discovered as a significant regulator on gene expression at the epigenetic level. Emerging evidences have indicated the intricate regulatory effects between lncRNAs and DNA methylation. On one hand, transcription of lncRNAs are controlled by the promoter methylation, which is similar to protein coding genes, on the other hand, lncRNA could interact with enzymes involved in DNA methylation to affect the methylation pattern of downstream genes, thus regulating their expression. In addition, circular RNAs (circRNAs) being an important class of noncoding RNA are also found to participate in this complex regulatory network. In this review, we summarize recent research progress on this crosstalk between lncRNA, circRNA, and DNA methylation as well as their potential functions in complex diseases including cancer. This work reveals a hidden layer for gene transcriptional regulation and enhances our understanding for epigenetics regarding detailed mechanisms on lncRNA regulatory function in human cancers.
Correlations among peripheral blood markers, white matter hyperintensity, and cognitive function in patients with non-disabling ischemic cerebrovascular events
Authors: Li Binghan , Du Bingying , Gu Zhengsheng , Wu Chenghao , Tan Yuhao , Song Chenrui , Xu Yawen , Yin Ge , Gao Xin , Wang Weisen , Sun Xu , Bi Xiaoying
Published: December 2022

Background

Both inflammation and cerebral white matter injury are closely associated with vascular cognitive impairment (VCI). The aim of this study was to analyze the correlation between peripheral serological markers, white matter injury, and cognitive function in patients with non-disabling ischemic cerebrovascular events (NICE); to identify potential biological markers for the diagnosis and prediction of VCI; and to provide a basis for the early diagnosis and intervention of VCI.

Methods

We collected clinical data, along with demographic and medical history data, from 151 NICE patients. Fasting venous blood samples were collected. Based on the Montreal Cognitive Assessment (MoCA) after admission, we divided the patients into normal cognitive function (NCF) and VCI groups, and then classified them into mild white matter hyperintensity (mWMH) and severe white matter hyperintensity (sWMH) based on Fazekas scores. The differences in serological marker levels were compared between the cognitive function groups and the white matter hyperintensity groups. Binary logistic regression models and receiver operating characteristic curves were used to analyze the diagnostic predictive value of serological markers for VCI in patients with NICE and in the white matter hyperintensity subgroups.

Results

Among 151 patients with NICE, 95 were male and 56 were female. Lymphocyte count (OR = 0.405, p = 0.010, 95% CI [0.201, 0.806]), red blood cell count (OR = 0.433, p = 0.010, 95% CI [0.228, 0.821]), and hemoglobin level (OR = 0.979, p = 0.046, 95% CI [0.958, 0.999]) were protective factors for cognitive function in patients with NICE. The sWMH group had a higher age, granulocyte/lymphoid ratio (NLR), and neutrophil percentage but a lower MoCA score, hemoglobin level, and lymphocyte count than the mWMH group. In the mWMH group, lymphocyte count (AUC = 0.713, p = 0.003, 95% CI [0.593, 0.833]) had an acceptable predictive value for the diagnosis of VCI, whereas white blood cell count (AUC = 0.672, p = 0.011, 95% CI [0.545, 0.799]), red blood cell count (AUC = 0.665, p = 0.014, 95% CI [0.545, 0.784]), and hemoglobin level (AUC = 0.634, p = 0.047, 95% CI [0.502, 0.765]) had marginal predictive value for the diagnosis of VCI. In the sWMH group, no significant differences were found in serological markers between the NCF and VCI groups.

Conclusion

Lymphocyte count, red blood cell count, and hemoglobin level were independent protective factors for cognitive function in patients with NICE; they can be used as potential biological markers to distinguish VCI in patients with NICE and are applicable to subgroups of patients with mWMH.
Design and dynamic analysis of jumping wheel-legged robot in complex terrain environment
Authors: Guo Tiezheng , Liu Jinhui , Liang Haonan , Zhang Yitong , Chen Wei , Xia Ximing , Wang Meiqing , Wang Zhiming
Published: December 2022

Wheel-legged robots have fast and stable motion characteristics on flat roads, but there are the problems of poor balance ability and low movement level in special terrains such as rough roads. In this paper, a new type of wheel-legged robot with parallel four-bar mechanism is proposed, and the linear quadratic regulator (LQR) controller and fuzzy proportion differentiation (PD) jumping controller are designed and developed to achieve stable motion so that the robot has the ability to jump over obstacles and adapt to rough terrain. The amount of energy released by the parallel four-bar linkage mechanism changes with the change of the link angle, and the height of the jump trajectory changes accordingly, which improves the robot’s ability to overcome obstacles facing vertical obstacles. Simulations and real scene tests are performed in different terrain environments to verify obstacle crossing capabilities. The simulation results show that, in the pothole terrain, the maximum height error of the two hip joint motors is 2 mm for the obstacle surmounting method of the adaptive retractable wheel-legs; in the process of single leg obstacle surmounting, the maximum height error of the hip joint motors is only 6.6 mm. The comparison of simulation data and real scene experimental results shows that the robot has better robustness in moving under complex terrains.
Functional comorbidities and brain tissue changes before and after lung transplant in adults
Authors: Vandiver Matthew Scott , Roy Bhaswati , Mahmud Fahim , Lavretsky Helen , Kumar Rajesh
Published: December 2022

Background

Adults undergoing lung transplant, as a lifesaving treatment for end stage lung disease, exhibit high levels of peri-operative neurocognitive dysfunction in multiple domains, including delirium, cognition, and autonomic deficits. These complications impact healthcare costs, quality of life, and patient outcomes. Post-operative symptoms likely result from loss of brain tissue integrity in sites mediating such regulatory functions. Our aim in this study was to examine peri-operative neurocognitive dysfunction and brain tissue changes after lung transplant in adults.

Methods

We retrospectively examined the UCLA lung transplant database to identify 114 lung transplant patients with pre-operative clinical and neurocognitive data. Of 114 patients, 9 lung transplant patients had pre- and post-transplant brain magnetic resonance imaging. Clinical and neurocognitive data were summarized for all subjects, and brain tissue volume changes, using T1-weighted images, before and after transplant were examined. T1-weighted images were partitioned into gray matter (GM)-tissue type, normalized to a common space, smoothed, and the smoothed GM-volume maps were compared between pre- and post-transplant (paired t-tests; covariate, age; SPM12, p < 0.005).

Results

Increased comorbidities, including the diabetes mellitus (DM), hypertension, kidney disease, and sleep disordered breathing, as well as higher rates of neurocognitive dysfunction were observed in the lung transplant patients, with 41% experiencing post-operative delirium, 49% diagnosed with a mood disorder, and 25% of patients diagnosed with cognitive deficits, despite incomplete documentation. Similarly, high levels of delirium, cognitive dysfunction, and mood disorder were noted in a subset of patients used for brain MRI evaluation. Significantly decreased GM volumes emerged in multiple brain regions, including the frontal and prefrontal, parietal, temporal, bilateral anterior cingulate and insula, putamen, and cerebellar cortices.

Conclusion

Adults undergoing lung transplant often show significant pre-operative comorbidities, including diabetes mellitus, hypertension, and chronic kidney disease, as well as neurocognitive dysfunction. In addition, patients with lung transplant show significant brain tissue changes in regions that mediate cognition, autonomic, and mood functions. The findings indicate a brain structural basis for many enhanced post-operative symptoms and suggest a need for brain tissue protection in adults undergoing lung transplant to improve health outcomes.