bluuebunny/crossref_metadata_2025 huggingface dataset:
The invasion depth measurement of bladder cancer using T2-weighted magnetic resonance imaging
Authors: Liu Yang , Zheng Haojie , Xu Xiaopan , Zhang Xi , Du Peng , Liang Jimin , Lu Hongbing
Published: December 2020

Background

Invasion depth is an important index for staging and clinical treatment strategy of bladder cancer (BCa). The aim of this study was to investigate the feasibility of segmenting the BCa region from bladder wall region on MRI, and quantitatively measuring the invasion depth of the tumor mass in bladder lumen for further clinical decision-making. This retrospective study involved 20 eligible patients with postoperatively pathologically confirmed BCa. It was conducted in the following steps: (1) a total of 1159 features were extracted from each voxel of both the certain cancerous and wall tissues with the T2-weighted (T2W) MRI data; (2) the support vector machine (SVM)-based recursive feature elimination (RFE) method was implemented to first select an optimal feature subset, and then develop the classification model for the precise separation of the cancerous regions; (3) after excluding the cancerous region from the bladder wall, the three-dimensional bladder wall thickness (BWT) was calculated using Laplacian method, and the invasion depth of BCa was eventually defined by the subtraction of the mean BWT excluding the cancerous region and the minimum BWT of the cancerous region.

Results

The segmented results showed a promising accuracy, with the mean Dice similarity coefficient of 0.921. The “soft boundary” defined by the voxels with the probabilities between 0.1 and 0.9 could demonstrate the overlapped region of cancerous and wall tissues. The invasion depth calculated from proposed segmentation method was compared with that from manual segmentation, with a mean difference of 0.277 mm.

Conclusion

The proposed strategy could accurately segment the BCa region, and, as the first attempt, realize the quantitative measurement of BCa invasion depth.
Synergistic health effects of air pollution, temperature, and pollen exposure: a systematic review of epidemiological evidence
Authors: Anenberg Susan C. , Haines Shannon , Wang Elizabeth , Nassikas Nicholas , Kinney Patrick L.
Published: December 2020

Background

Exposure to heat, air pollution, and pollen are associated with health outcomes, including cardiovascular and respiratory disease. Studies assessing the health impacts of climate change have considered increased exposure to these risk factors separately, though they may be increasing simultaneously for some populations and may act synergistically on health.

Our objective is to systematically review epidemiological evidence for interactive effects of multiple exposures to heat, air pollution, and pollen on human health.

Methods

We systematically searched electronic literature databases (last search, April 29, 2019) for studies reporting quantitative measurements of associations between at least two of the exposures and mortality from any cause and cardiovascular and respiratory morbidity and mortality specifically. Following the Navigation Guide systematic review methodology, we evaluated the risk of bias of individual studies and the overall quality and strength of evidence.

Results

We found 56 studies that met the inclusion criteria. Of these, six measured air pollution, heat, and pollen; 39 measured air pollution and heat; 10 measured air pollution and pollen; and one measured heat and pollen. Nearly all studies were at risk of bias from exposure assessment error. However, consistent exposure-response across studies led us to conclude that there is overall moderate quality and sufficient evidence for synergistic effects of heat and air pollution. We concluded that there is overall low quality and limited evidence for synergistic effects from simultaneous exposure to (1) air pollution, pollen, and heat; and (2) air pollution and pollen. With only one study, we were unable to assess the evidence for synergistic effects of heat and pollen.

Conclusions

If synergistic effects between heat and air pollution are confirmed with additional research, the health impacts from climate change-driven increases in air pollution and heat exposure may be larger than previously estimated in studies that consider these risk factors individually.
The associations between p,p’-DDE levels and plasma levels of lipoproteins and their subclasses in an elderly population determined by analysis of lipoprotein content
Authors: Jugan Juliann , Lind P. Monica , Salihovic Samira , Stubleski Jordan , Kärrman Anna , Lind Lars , La Merrill Michele A.
Published: December 2020

Background

Lipoproteins at aberrant levels are known to play a role in cardiovascular disease. The metabolite of the insecticide dichlorodiphenyltrichloroethane (DDT), p,p’-dichlorodiphenyldichloroethylene (p,p’-DDE), physically associates with lipids and accumulates in adipose tissue. Little is known about which lipoproteins associate with p,p’-DDE. An association between p,p’-DDE exposure and altered levels of circulating lipids was assessed in a large human cohort using a detailed analysis of lipoprotein content.

Methods

Plasma samples were collected from the subset of 75-year old Swedes in the Prospective Investigation of the Vasculature of Uppsala Seniors (PIVUS) cohort who were not prescribed lipid lowering medication (n = 571). p,p’-DDE concentrations in plasma were measured using high-throughput solid phase extraction and gas chromatography-high resolution mass spectrometry. Analysis of plasma lipoprotein content was performed with nuclear magnetic resonance spectroscopy.

Results

Detectable levels of p,p’-DDE were found in the plasma samples of all subjects. Elevated p,p’-DDE levels were associated with increased concentrations of lipoproteins of all diameters, with the exception of high density lipoprotein (HDL) of diameters between 14.3 nm–10.9 nm. Of the lipoprotein constituents, triglycerides were most uniformly associated with elevated p,p’-DDE across lipoproteins. p,p’-DDE was furthermore associated with apolipoprotein B, but not apolipoprotein A1.

Conclusions

The positive associations observed between each lipoprotein class and elevated p,p’-DDE support previous data suggesting that p,p’-DDE interacts with lipoproteins within plasma. It is speculated that both physio-chemical and biological mechanisms may explain why p,p’-DDE does not uniformly associate with lipids across lipoproteins.
Respiratory microbiome profiles differ by recent hospitalization and nursing home residence in patients on mechanical ventilation
Authors: Baek Min-gyung , Woo Seong Ji , Kim Nam Eun , Baek Chaeyun , Won Sungho , Kim Youngmi , Lee Jae Jun , Yi Hana , Hong Ji Young
Published: December 2020

Background

Healthcare-associated pneumonia (HCAP) is a heterogeneous disease. We redefined nursing-home- and hospital-associated infections (NHAI) group by revising existing HCAP risk factors. The NHAI group comprised nursing home residents with a poor functional status, or recent (past 90 days) hospitalization or recent (past 180 days) antibiotic therapy. Our aim was to determine whether respiratory microbiota profiles are related to newly defined NHAI group in critically ill patients on mechanical ventilation.

Methods

The 180 endotracheal aspirates (ETAs) from 60 mechanically ventilated ICU patients (NHAI group, n = 24; non-NHAI group, n = 36) were prospectively collected on days 1, 3 and 7 in a university hospital. The bacterial community profiles of the ETAs were explored by 16S rRNA gene sequencing. A phylogenetic-tree-based microbiome association test (TMAT), generalized linear mixed models (GLMMs), the Wilcoxon test and the reference frame method were used to analyze the association between microbiome abundance and disease phenotype.

Results

The relative abundance of the genusCorynebacteriumwas significantly higher in the pneumonia than in the non-pneumonia group. The microbiome analysis revealed significantly lower α-diversity in the NHAI group than in the non-NHAI group. In the analysis of β-diversity, the structure of the microbiome also differed significantly between the two groups (weighted UniFrac distance, Adonis,p < 0.001). The abundance ofCorynebacteriumwas significantly higher, and the relative abundances ofGranulicatella, Staphylococcus, StreptococcusandVeillonellawere significantly lower, in the NHAI group than in the non-NHAI group.

Conclusions

The microbiota signature of the ETAs distinguished between patients with and without risk factors for NHAI. The lung microbiome may serve as a therapeutic target for NHAI group.
Risk factors for severe COVID-19 in middle-aged patients without comorbidities: a multicentre retrospective study
Authors: Wang Peng , Sha Jing , Meng Mei , Wang Cuiyan , Yao Qingchun , Zhang Zhongfa , Sun Wenqing , Wang Xingguang , Qie Guoqiang , Bai Xue , Liu Keke , Chu Yufeng
Published: December 2020

Background

Information regarding characteristics and risk factors of COVID-19 amongst middle-aged (40–59 years) patients without comorbidities is scarce.

Methods

We therefore conducted this multicentre retrospective study and collected data of middle-aged COVID-19 patients without comorbidities at admission from three designated hospitals in China.

Results

Among 119 middle-aged patients without comorbidities, 18 (15.1%) developed into severe illness and 5 (3.9%) died in hospital. ARDS (26, 21.8%) and elevated D-dimer (36, 31.3%) were the most common complications, while other organ complications were relatively rare. Multivariable regression showed increasing odds of severe illness associated with neutrophil to lymphocyte ratio (NLR, OR, 11.238; 95% CI 1.110–1.382; p < 0.001) and D-dimer greater than 1 µg/ml (OR, 16.079; 95% CI 3.162–81.775; p = 0.001) on admission. The AUCs for the NLR, D-dimer greater than 1 µg/ml and combined NLR and D-dimer index were 0.862 (95% CI, 0.751–0.973), 0.800 (95% CI 0.684–0.915) and 0.916 (95% CI, 0.855–0.977), respectively. SOFA yielded an AUC of 0.750 (95% CI 0.602–0.987). There was significant difference in the AUC between SOFA and combined index(z = 2.574, p = 0.010).

Conclusions

More attention should be paid to the monitoring and early treatment of respiratory and coagulation abnormalities in middle-aged COVID-19 patients without comorbidities. In addition, the combined NLR and D-dimer higher than 1 μg/ml index might be a potential and reliable predictor for the incidence of severe illness in this specific patient with COVID-19, which could guide clinicians on early classification and management of patients, thereby relieving the shortage of medical resource. However, it is warranted to validate the reliability of the predictor in larger sample COVID-19 patients.
Analysis of ALS-related proteins during herpes simplex virus-2 latent infection
Authors: Cabrera Jorge Rubén , Rodríguez-Izquierdo Ignacio , Jiménez José Luis , Muñoz-Fernández María Ángeles
Published: December 2020

Background

Genetics have provided hints on potential molecular pathways involved in neurodegenerative diseases (NDD). However, the number of cases caused exclusively by genetic alterations is low, suggesting an important contribution of environmental factors to NDDs. Among these factors, viruses like herpes simplex viruses (HSV-2), capable of establishing lifelong infections within the nervous system (NS), are being proposed to have a role in NDDs. Despite promising data, there is a significant lack of knowledge on this and an urgent need for more research.

Methods

We have set up a mouse model to study HSV latency and its associated neuroinflammation in the spinal cord. The goal of this model was to observe neuroinflammatory changes caused by HSV latent infections, and if those changes were similar to alterations observed in the spinal cord of amyotrophic lateral sclerosis (ALS) patients.

Results

In infected spinal cords, we have observed a strong leukocyte infiltration and a severe alteration of microglia close to motor neurons. We have also analyzed ALS-related proteins: we have not found changes in TDP-43 and Fus in neurons, but interestingly, we have found decreased protein levels of C9orf72, of which coding gene is severely altered in some familial forms of ALS and is critical for microglia homeostasis.

Conclusions

Latent infection of HSV in the spinal cord showed altered microglia and leukocyte infiltration. These inflammatory features resembled to those observed in the spinal cord of ALS patients. No changes mimicking ALS neuropathology, such as TDP-43 cytoplasmic inclusions, were found in infected spinal cords, but a decrease in protein levels of C9orf72 was observed. Then, further studies should be required to determine whether HSV-2 has a role in ALS.
Hemagglutinin stalk-based monoclonal antibody elicits broadly reactivity against group 1 influenza A virus
Authors: Huang Jingjin , Huang Nan , Fan Menglu , Zhao Lingcai , Luo Yan , Ding Pingyun , Tian Miao , Liu Qingzheng , Guo Yanna , Zhao Jinhua , Zheng Yiqing , Zhang Haitao , Ping Jihui
Published: December 2020

Background

Influenza virus remains a continuous and severe threat to public health worldwide, and its prevention and treatment have always been a major international issue. Because of its ability to evade immune surveillance through rapid antigenic drift and antigenic shift, broad-spectrum vaccines seem increasingly important.

Methods

A mAb named 3C12 from an immortalized hybrid cell was generated via immunizing mice with HA2 protein from A/chicken/Anhui/BRI99/2016 (AH/BRI99/16, H9N2) generated by prokaryotic expression. Then, its broad-spectrum activity was analyzed by WB and IFA. Next, the minimal linear epitope was identified via analyzing the reaction of a series of HA truncations with 3C12. Finally, the protective effects of 3C12 were evaluated in vitro and in vivo infection experiments.

Results

The mAb could react with the viruses of subtypes H1, H2, H5, H8, H9, H12, H13, H16, and HA protein of H18 in group 1, but failed to react with viruses in group 2. The minimal linear epitope targeted by the mAb was 433NAELLVL439 in full length of HA and localized in the C-helix region of HA2 (residue 95-101, HA2 numbering). What’s more, the mAb 3C12 inhibited H1, H2, H5, H8, H9, H12, H13 and H16 virus-replication in vitro and also has shown effectiveness in preventing and treating disease in mice challenged with lethal dose of AH/BRI99/16 (H9N2) virus in vivo. These results suggested that the broadly reactive anti-HA stem mAb 3C12 exhibited prophylactic and therapeutic efficacy.

Conclusions

Here, we have demonstrated that the linear epitope identified in this study could be a novel target for developing broad-spectrum influenza diagnostics or vaccine design, and the HA2-based monoclonal antibody is indeed a promising strategy for broad-spectrum protection against seasonal and pandemic influenza viruses.
Physicochemical characterization and genotoxicity of the broad class of carbon nanotubes and nanofibers used or produced in U.S. facilities
Authors: Fraser Kelly , Kodali Vamsi , Yanamala Naveena , Birch M. Eileen , Cena Lorenzo , Casuccio Gary , Bunker Kristin , Lersch Traci L. , Evans Douglas E. , Stefaniak Aleksandr , Hammer Mary Ann , Kashon Michael L. , Boots Theresa , Eye Tracy , Hubczak John , Friend Sherri A. , Dahm Matthew , Schubauer-Berigan Mary K. , Siegrist Katelyn , Lowry David , Bauer Alison K. , Sargent Linda M. , Erdely Aaron
Published: December 2020

Background

Carbon nanotubes and nanofibers (CNT/F) have known toxicity but simultaneous comparative studies of the broad material class, especially those with a larger diameter, with computational analyses linking toxicity to their fundamental material characteristics was lacking. It was unclear if all CNT/F confer similar toxicity, in particular, genotoxicity. Nine CNT/F (MW #1–7 and CNF #1–2), commonly found in exposure assessment studies of U.S. facilities, were evaluated with reported diameters ranging from 6 to 150 nm. All materials were extensively characterized to include distributions of physical dimensions and prevalence of bundled agglomerates. Human bronchial epithelial cells were exposed to the nine CNT/F (0–24 μg/ml) to determine cell viability, inflammation, cellular oxidative stress, micronuclei formation, and DNA double-strand breakage. Computational modeling was used to understand various permutations of physicochemical characteristics and toxicity outcomes.

Results

Analyses of the CNT/F physicochemical characteristics illustrate that using detailed distributions of physical dimensions provided a more consistent grouping of CNT/F compared to using particle dimension means alone. In fact, analysis of binning of nominal tube physical dimensions alone produced a similar grouping as all characterization parameters together. All materials induced epithelial cell toxicity and micronuclei formation within the dose range tested. Cellular oxidative stress, DNA double strand breaks, and micronuclei formation consistently clustered together and with larger physical CNT/F dimensions and agglomerate characteristics but were distinct from inflammatory protein changes. Larger nominal tube diameters, greater lengths, and bundled agglomerate characteristics were associated with greater severity of effect. The portion of tubes with greater nominal length and larger diameters within a sample was not the majority in number, meaning a smaller percentage of tubes with these characteristics was sufficient to increase toxicity. Many of the traditional physicochemical characteristics including surface area, density, impurities, and dustiness did not cluster with the toxicity outcomes.

Conclusion

Distributions of physical dimensions provided more consistent grouping of CNT/F with respect to toxicity outcomes compared to means only. All CNT/F induced some level of genotoxicity in human epithelial cells. The severity of toxicity was dependent on the sample containing a proportion of tubes with greater nominal lengths and diameters.
Results of repeat manipulation under ultrasound-guided cervical nerve root block with corticosteroid and local anaesthetic injection for recurrence of frozen shoulder
Authors: Oshiro Tatsuki , Yagi Masayoshi , Harada Kazuki , Park Kieun
Published: December 2020

Background

This study aimed to evaluate the clinical results of a repeat manipulation under ultrasound-guided cervical nerve root block (MUC) with corticosteroid and local anaesthetic injection for recurrence of idiopathic frozen shoulder after MUC.

Methods

A consecutive series of 42 shoulders in 39 patients with idiopathic frozen shoulder underwent MUC. All patients were assessed according to the American Shoulder Elbow Surgeon (ASES) score and shoulder range of motion (ROM) both before MUC and at 1 year thereafter. If patients continued to have pain and limited ROM at 3 months after the procedure, they were offered a repeat MUC. Such patients were also assessed before the procedure and at 3 months and 1 year thereafter.

Results

The initial MUC was successful in 31 shoulders (single group). Repeat MUC was required in 11 shoulders (repeat group). Patients in the single group showed significant improvement in ROM and ASES score at 1 year after the procedure (p < 0.001); similarly, patients in the repeat group had significant improvement in ROM and ASES score at 3 months and 1 year after the procedure (p < 0.001). Patients in the repeat group had had significantly more severely limited ROM (p < 0.01) and decreased ASES score (p < 0.001) before the procedure compared with those in the single group.

Conclusions

A repeat MUC with corticosteroid and local anaesthetic injection is a valuable option before proceeding to surgery for recurrence of idiopathic frozen shoulder. When there is severely limited ROM and decreased ASES score before the MUC, a repeat MUC may be necessary, which would require the patient’s informed consent.

Trial registration

Retrospectively registered
Prevalence and association of anxiety and depression among orthopaedic trauma inpatients: a retrospective analysis of 1994 cases
Authors: Yang Yun , Tang Ting-ting , Chen Mei-ru , Xiang Mao-ying , Li Ling-li , Hou Xiao-ling
Published: December 2020

Background

Patients with traumatic injuries are often accompanied by emotional disorders, which seriously impede functional gains. The objective of this study was to identify the prevalence and risk factors associated with underlying anxiety and depression in orthopaedic trauma patients.

Methods

From July 2015 to December 2017, all orthopaedic trauma patients were included in the retrospective study. Patients with conditions that might affect cognitive impairment were excluded from the study. Basic demographic data were collected. All patients were screened for emotional disorders on admission using a simple questionnaire called “Huaxi Emotional-Distress Index” (HEI). Bivariate analyses and logistic regression were used to identify the factors associated with a HEI score of > 8.

Results

One hundred and sixty-two patients (8.1%) had a HEI score of > 8. About 1.0% of enrolled patients had severe emotional disorders (HEI score ≥ 17). The reasons caused by emotional disorders in patients with orthopaedic trauma were a higher Injury Severity Score (ISS), a higher visual analogue score (VAS) and type of surgery. On logistic regression, marital status was a protective factor for emotional disorders, while VAS and ISS were the risk factors for emotional disorders.

Conclusions

Although a significantly low percentage of orthopaedic trauma patients in our setting have emotional disorders, traumatic orthopaedic surgeons still need to pay attention to the risk of emotional disorders and integrate effective screening tools into clinical practice to screen for these factors and stratify emotional disorders. Appropriate targeted psychological intervention and treatment should be adopted according to the stratification of emotional disorders.
The Stoppa combined with iliac fossa approach for the treatment of both-column acetabular fractures
Authors: Yang Yun , Zou Chang , Fang Yue
Published: December 2020

Background

At present, the choice of surgical approach for both-column fractures is still controversial. The purpose of this study was to explore the efficacy of the Stoppa combined with iliac fossa (S+IF) approach in the treatment of both-column fractures.

Methods

In this retrospective case series, 76 patients were included in the study from 2014 to 2018. They were divided into two groups according to the surgical approaches. The differences of intraoperative blood loss, operative time, quality of reduction, clinical outcome, and perioperative complications were compared between the two groups.

Results

All patients had undergone the IL approach or the S+IF approach. The average operative time was 156.2 min (110~210 min) in group I and 126.5 min (80~180 min) in group II (P < 0.001). The average blood loss in group I was 784.1 ml, while the average blood loss in group II was 625.3 ml (P = 0.007). According to Matta’s criteria, 28 cases obtained anatomic reduction and 12 cases got imperfect reduction in group I; 21 cases obtained anatomic reduction and 7 cases got imperfect reduction in group II (P > 0.05). The clinical outcome (excellent to good) was 66% in group I versus 69% in group II (P > 0.05). The complication rates were 18.2% in group I and 12.5% in group II (P > 0.05).

Conclusions

As a minimally invasive surgical approach, the S+IF approach is a valuable alternative to the IL approach for the treatment of both-column acetabular fractures if these two anterior approaches can achieve fracture exposure, reduction, and fixation.
The effects of seaward distance on above and below ground carbon stocks in estuarine mangrove ecosystems
Authors: de Jong Cleyndert Georgia , Cuni-Sanchez Aida , Seki Hamidu A. , Shirima Deo D. , Munishi Pantaleo K. T. , Burgess Neil , Calders Kim , Marchant Robert
Published: December 2020

Background

Mangrove forests have gained recognition for their potential role in climate change mitigation due to carbon sequestration in live trees, and carbon storage in the sediments trapped by mangrove tree roots and pneumatophores. Africa hosts about 19% of the world’s mangroves, yet relatively few studies have examined the carbon stocks of African mangroves. The available studies report considerable differences among sites and amongst the different pools of carbon stocks. None considered the effects of seaward distance. We present details of AGC and SOC carbon stocks for Lindi in Tanzania, and focus on how these values differ with increasing seaward distance and, how our results compare to those reported elsewhere across Africa.

Results

AGC ranged between 11 and 55 Mg C ha−1, but was not significantly affected by seaward distance. SOC for 0–1 m depth ranged from 154 to 484, with a mean of 302 Mg C ha−1. SOC was significantly negatively correlated with seaward distance. Mangrove type (estuarine/oceanic), soil erosion, soil depth may explain these differences We note important methodological differences in previous studies on carbon stocks in mangroves in Africa.

Conclusion

This study indicates that seaward distance has an important effect on SOC stocks in the Lindi region of Tanzania. SOC should be fully incorporated into national climate change mitigation policies. Studies should report seaward distance and to describe the type of mangrove stand to make results easily comparable across sites and to assess the true value of Blue Carbon in Africa. We recommend focusing on trees > 10 cm diameter for AGC, and sampling soils to at least 1 m depth for SOC, which would provide a more complete assessment of the potentially considerable mangrove carbon store.
Effective therapeutic interventions for Australian adolescents using alcohol and/or other drugs: a scoping review
Authors: Martin Jennifer , Liddell Marg , Roberts Susan , Greenwood Emily
Published: December 2020

Background

There are a variety of residential and community service models of therapeutic interventions for people using substances. The focus of much of the currently available research is on adult populations with relatively little known about effective therapeutic interventions for adolescents. The aim of this paper is to identify the most effective therapeutic interventions for Australian adolescents using substances by conducting a systematic scoping literature review.

Methods

We followed the PRISMA guidelines to conduct a systematic scoping review that included searches of nine electronic databases (EMBASE, MEDLINE, EBSCO Host, APA PsycNet, SocIndex, Social Science Abstracts, Proquest Central Informit) and grey literature searches of government department and alcohol and other drugs peak body and service provider websites, Google Scholar and the Cochrane library.

Results

A total of 21 studies were identified. These studies included biological, psychological, social and technological therapeutic interventions targeted at different population groups and different substances. The review findings are limited and should considered with caution due to the inability to disaggregate the combinations of interventions provided and the low quality of most of the studies included.

Conclusions

This scoping review highlights the paucity of quality research on effective therapeutic interventions for Australian adolescents using substances. This is primarily due to the available studies not controlling for all of the therapeutic interventions provided. While there is an evidence-base for some of these interventions, others such as encounter groups and journaling require further and more substantive research for use with adolescents. This is necessary to enable informed service design and delivery decision-making and fiscal accountability.
Comparative analysis, applications, and interpretation of electronic health record-based stroke phenotyping methods
Authors: Thangaraj Phyllis M. , Kummer Benjamin R. , Lorberbaum Tal , Elkind Mitchell S. V. , Tatonetti Nicholas P.
Published: December 2020

Background

Accurate identification of acute ischemic stroke (AIS) patient cohorts is essential for a wide range of clinical investigations. Automated phenotyping methods that leverage electronic health records (EHRs) represent a fundamentally new approach cohort identification without current laborious and ungeneralizable generation of phenotyping algorithms. We systematically compared and evaluated the ability of machine learning algorithms and case-control combinations to phenotype acute ischemic stroke patients using data from an EHR.

Materials and methods

Using structured patient data from the EHR at a tertiary-care hospital system, we built and evaluated machine learning models to identify patients with AIS based on 75 different case-control and classifier combinations. We then estimated the prevalence of AIS patients across the EHR. Finally, we externally validated the ability of the models to detect AIS patients without AIS diagnosis codes using the UK Biobank.

Results

Across all models, we found that the mean AUROC for detecting AIS was 0.963 ± 0.0520 and average precision score 0.790 ± 0.196 with minimal feature processing. Classifiers trained with cases with AIS diagnosis codes and controls with no cerebrovascular disease codes had the best average F1 score (0.832 ± 0.0383). In the external validation, we found that the top probabilities from a model-predicted AIS cohort were significantly enriched for AIS patients without AIS diagnosis codes (60–150 fold over expected).

Conclusions

Our findings support machine learning algorithms as a generalizable way to accurately identify AIS patients without using process-intensive manual feature curation. When a set of AIS patients is unavailable, diagnosis codes may be used to train classifier models.
Natural killer cell-based immunotherapy for acute myeloid leukemia
Authors: Xu Jing , Niu Ting
Published: December 2020

Despite considerable progress has been achieved in the treatment of acute myeloid leukemia over the past decades, relapse remains a major problem. Novel therapeutic options aimed at attaining minimal residual disease-negative complete remission are expected to reduce the incidence of relapse and prolong survival. Natural killer cell-based immunotherapy is put forward as an option to tackle the unmet clinical needs. There have been an increasing number of therapeutic dimensions ranging from adoptive NK cell transfer, chimeric antigen receptor-modified NK cells, antibodies, cytokines to immunomodulatory drugs. In this review, we will summarize different forms of NK cell-based immunotherapy for AML based on preclinical investigations and clinical trials.
Chimeric antigen receptor-engineered natural killer cells for cancer immunotherapy
Authors: Yilmaz Ahmet , Cui Hanwei , Caligiuri Michael A. , Yu Jianhua
Published: December 2020

Natural killer (NK) cells are a critical component of the innate immune system. Chimeric antigen receptors (CARs) re-direct NK cells toward tumor cells carrying corresponding antigens, creating major opportunities in the fight against cancer. CAR NK cells have the potential for use as universal CAR cells without the need for human leukocyte antigen matching or prior exposure to tumor-associated antigens. Exciting data from recent clinical trials have renewed interest in the field of cancer immunotherapy due to the potential of CAR NK cells in the production of “off-the-shelf” anti-cancer immunotherapeutic products. Here, we provide an up-to-date comprehensive overview of the recent advancements in key areas of CAR NK cell research and identify under-investigated research areas. We summarize improvements in CAR design and structure, advantages and disadvantages of using CAR NK cells as an alternative to CAR T cell therapy, and list sources to obtain NK cells. In addition, we provide a list of tumor-associated antigens targeted by CAR NK cells and detail challenges in expanding and transducing NK cells for CAR production. We additionally discuss barriers to effective treatment and suggest solutions to improve CAR NK cell function, proliferation, persistence, therapeutic effectiveness, and safety in solid and liquid tumors.
Alternative splicing in endothelial cells: novel therapeutic opportunities in cancer angiogenesis
Authors: Di Matteo Anna , Belloni Elisa , Pradella Davide , Cappelletto Ambra , Volf Nina , Zacchigna Serena , Ghigna Claudia
Published: December 2020

Alternative splicing (AS) is a pervasive molecular process generating multiple protein isoforms, from a single gene. It plays fundamental roles during development, differentiation and maintenance of tissue homeostasis, while aberrant AS is considered a hallmark of multiple diseases, including cancer. Cancer-restricted AS isoforms represent either predictive biomarkers for diagnosis/prognosis or targets for anti-cancer therapies. Here, we discuss the contribution of AS regulation in cancer angiogenesis, a complex process supporting disease development and progression. We consider AS programs acting in a specific and non-redundant manner to influence morphological and functional changes involved in cancer angiogenesis. In particular, we describe relevant AS variants or splicing regulators controlling either secreted or membrane-bound angiogenic factors, which may represent attractive targets for therapeutic interventions in human cancer.
Mitophagy promotes sorafenib resistance through hypoxia-inducible ATAD3A dependent Axis
Authors: Wu Hong , Wang Tao , Liu Yiqiang , Li Xin , Xu Senlin , Wu Changtao , Zou Hongbo , Cao Mianfu , Jin Guoxiang , Lang Jinyi , Wang Bin , Liu Baohua , Luo Xiaolin , Xu Chuan
Published: December 2020

Background

The identification of novel targets for recovering sorafenib resistance is pivotal for Hepatocellular carcinoma (HCC) patients. Mitophagy is the programmed degradation of mitochondria, and is likely involved in drug resistance of cancer cells. Here, we identified hyperactivated mitophagy is essential for sorafenib resistance, and the mitophagy core regulator gene ATAD3A (ATPase family AAA domain containing 3A) was down regulated in hypoxia induced resistant HCC cells. Blocking mitophagy may restore the sorafenib sensitivity of these cells and provide a new treatment strategy for HCC patients.

Methods

Hypoxia induced sorafenib resistant cancer cells were established by culturing under 1% O2with increasing drug treatment. RNA sequencing was conducted in transfecting LM3 cells with sh-ATAD3A lentivirus. Subsequent mechanistic studies were performed in HCC cell lines by manipulating ATAD3A expression isogenically where we evaluated drug sensitivity, molecular signaling events. In vivo study, we investigated the combined treatment effect of sorafenib and miR-210-5P antagomir.

Results

We found a hyperactivated mitophagy regulating by ATAD3A-PINK1/PARKIN axis in hypoxia induced sorafenib resistant HCC cells. Gain- and loss- of ATAD3A were related to hypoxia-induced mitophagy and sorafenib resistance. In addition, ATAD3A is a functional target of miR-210-5p and its oncogenic functions are likely mediated by increased miR-210-5P expression. miR-210-5P was upregulated under hypoxia and participated in regulating sorafenib resistance. In vivo xenograft assay showed that miR-210-5P antagomir combined with sorafenib abrogated the tumorigenic effect of ATAD3A down-regulation in mice.

Conclusions

Loss of ATAD3A hyperactivates mitophagy which is a core event in hypoxia induced sorafenib resistance in HCC cells. Targeting miR-210-5P-ATAD3A axis is a novel therapeutic target for sorafenib-resistant HCC.
Rhenium N-heterocyclic carbene complexes block growth of aggressive cancers by inhibiting FGFR- and SRC-mediated signalling
Authors: Domenichini Alice , Casari Ilaria , Simpson Peter V. , Desai Nima Maheshkumar , Chen Lingfeng , Dustin Christopher , Edmands Jeanne S. , van der Vliet Albert , Mohammadi Moosa , Massi Massimiliano , Falasca Marco
Published: December 2020

Background

Platinum-based anticancer drugs have been at the frontline of cancer therapy for the last 40 years, and are used in more than half of all treatments for different cancer types. However, they are not universally effective, and patients often suffer severe side effects because of their lack of cellular selectivity. There is therefore a compelling need to investigate the anticancer activity of alternative metal complexes. Here we describe the potential anticancer activity of rhenium-based complexes with preclinical efficacy in different types of solid malignancies.

Methods

Kinase profile assay of rhenium complexes. Toxicology studies using zebrafish. Analysis of the growth of pancreatic cancer cell line-derived xenografts generated in zebrafish and in mice upon exposure to rhenium compounds.

Results

We describe rhenium complexes which block cancer proliferation in vitro by inhibiting the signalling cascade induced by FGFR and Src. Initially, we tested the toxicity of rhenium complexes in vivo using a zebrafish model and identified one compound that displays anticancer activity with low toxicity even in the high micromolar range. Notably, the rhenium complex has anticancer activity in very aggressive cancers such as pancreatic ductal adenocarcinoma and neuroblastoma. We demonstrate the potential efficacy of this complex via a significant reduction in cancer growth in mouse xenografts.

Conclusions

Our findings provide a basis for the development of rhenium-based chemotherapy agents with enhanced selectivity and limited side effects compared to standard platinum-based drugs.
Criteria for referral of pediatric SARS-CoV-2 infection: a real-life experience in the pandemic era
Authors: Montagnani Carlotta , Venturini Elisabetta , L’Erario Manuela , Tersigni Chiara , Bortone Barbara , Bianchi Leila , Menegazzo Francesca , Indolfi Giuseppe , Chiappini Elena , Galli Luisa
Published: December 2020

A practical guidance on the management of children with COVID-19 to insure homogeneous criteria for referral to a higher-level facility, according to the disease severity, is pivotal in the pandemic era. A panel of experts in pediatric infectious diseases and intensive care at the tertiary-care Meyer Children’s University Hospital, Florence, Italy, issued a practical document shared with Tuscany hospitals. The rationale was to target the referral for those children at risk of requiring an intensive support, since the above mentioned hospital has the pediatric intensive care unit. Overall, 378 patients between 0 and 19 years of age were diagnosed with COVID-19 infection in the Tuscany region with 24 (6.3%) hospitalizations. Only three children were centralized to Meyer Children’s University Hospital according to reported criteria. Considering that appropriate referral criteria have been associated with reduced mortality in other conditions, our document might be useful to improve outcomes of children with COVID-19.
A neonatal cluster of novel coronavirus disease 2019: clinical management and considerations
Authors: Olivini Nicole , Calò Carducci Francesca Ippolita , Santilli Veronica , De Ioris Maria Antonietta , Scarselli Alessia , Alario Dario , Geremia Caterina , Lombardi Mary Haywood , Marabotto Caterina , Mariani Rosanna , Papa Raffaele Edo , Peschiaroli Emanuela , Scrocca Raffaella , Sinibaldi Serena , Smarrazzo Andrea , Stella Pietro , Bernardi Stefania , Chiurchiù Sara , Pansa Paola , Romani Lorenza , Michaela Carletti , Concato Carlo , De Rose Domenico Umberto , Salvatori Gugliemo , Rossi Paolo , Villani Alberto , Dotta Andrea , D’Argenio Patrizia , Campana Andrea
Published: December 2020

Background

Lately, one of the major clinical and public health issues has been represented by Coronavirus disease of 2019 (COVID-19) during pregnancy and the risk of transmission of the infection from mother to child. Debate on perinatal management and postnatal care is still ongoing, principally questioning the option of the joint management of mother and child after birth and the safety of breastfeeding. According to the available reports, neonatal COVID-19 appears to have a horizontal transmission and seems to be paucisymptomatic or asymptomatic, compared to older age groups. The aim of this work is to describe a cluster of neonatal COVID-19 and discuss our experience, with reference to current evidence on postnatal care and perinatal management.

Methods

This is a retrospective observational case series of five mother-child dyads, who attended the Labor and Delivery Unit of a first-level hospital in Italy, in March 2020. Descriptive statistics for continuous variables consisted of number of observations, mean and the range of the minimum and maximum values.

Results

Five women and four neonates tested positive for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). In one case, the mother-child dyad was separated and the neonate remained negative on two consecutive tests. Two positive neonates developed symptoms, with a predominant involvement of the gastrointestinal tract. Blood tests were unremarkable, except for a single patient who developed mild neutropenia. No complications occurred.

Conclusions

We agree that the decision on whether or not to separate a positive/suspected mother from her child should be made on an individual basis, taking into account the parent’s will, clinical condition, hospital logistics and the local epidemiological situation. In conformity with literature, in our study, affected neonates were asymptomatic or paucisymptomatic. Despite these reassuring findings, a few cases of severe presentation in the neonatal population have been reported. Therefore, we agree on encouraging clinicians to monitor the neonates with a suspected or confirmed infection.
Standardized visual EEG features predict outcome in patients with acute consciousness impairment of various etiologies
Authors: Müller Michael , Rossetti Andrea O. , Zimmermann Rebekka , Alvarez Vincent , Rüegg Stephan , Haenggi Matthias , Z’Graggen Werner J. , Schindler Kaspar , Zubler Frédéric
Published: December 2020

Background

Early prognostication in patients with acute consciousness impairment is a challenging but essential task. Current prognostic guidelines vary with the underlying etiology. In particular, electroencephalography (EEG) is the most important paraclinical examination tool in patients with hypoxic ischemic encephalopathy (HIE), whereas it is not routinely used for outcome prediction in patients with traumatic brain injury (TBI).

Method

Data from 364 critically ill patients with acute consciousness impairment (GCS ≤ 11 or FOUR ≤ 12) of various etiologies and without recent signs of seizures from a prospective randomized trial were retrospectively analyzed. Random forest classifiers were trained using 8 visual EEG features—first alone, then in combination with clinical features—to predict survival at 6 months or favorable functional outcome (defined as cerebral performance category 1–2).

Results

The area under the ROC curve was 0.812 for predicting survival and 0.790 for predicting favorable outcome using EEG features. Adding clinical features did not improve the overall performance of the classifier (for survival: AUC = 0.806,p = 0.926; for favorable outcome: AUC = 0.777,p = 0.844). Survival could be predicted in all etiology groups: the AUC was 0.958 for patients with HIE, 0.955 for patients with TBI and other neurosurgical diagnoses, 0.697 for patients with metabolic, inflammatory or infectious causes for consciousness impairment and 0.695 for patients with stroke. Training the classifier separately on subgroups of patients with a given etiology (and thus using less training data) leads to poorer classification performance.

Conclusions

While prognostication was best for patients with HIE and TBI, our study demonstrates that similar EEG criteria can be used in patients with various causes of consciousness impairment, and that the size of the training set is more important than homogeneity of ACI etiology.
Randomized controlled multicentre study of albumin replacement therapy in septic shock (ARISS): protocol for a randomized controlled trial
Authors:   on behalf of SepNet - Critical Care Trials Group, Sakr Yasser , Bauer Michael , Nierhaus Axel , Kluge Stefan , Schumacher Ulricke , Putensen Christian , Fichtner Falk , Petros Sirak , Scheer Christian , Jaschinski Ulrich , Tanev Ivan , Jacob David , Weiler Norbert , Schulze P. Christian , Fiedler Fritz , Kapfer Barbara , Brunkhorst Frank , Lautenschlaeger Ingmar , Wartenberg Katja , Utzolino Stefan , Briegel Josef , Moerer Onnen , Bischoff Petra , Zarbock Alexander , Quintel Michael , Gattinoni Luciano
Published: December 2020

Background

Albumin is a key regulator of fluid distribution within the extracellular space and has several properties beyond its oncotic activity. The accumulating evidence suggests that supplementation of albumin may provide survival advantages only when the insult is severe as in patients with septic shock.

Methods/design

The randomized controlled multicentre study of albumin replacement therapy in septic shock (ARISS) investigates whether the replacement with albumin and the maintenance of its serum levels of at least 30 g/l for 28 days improve survival in patients with septic shock compared to resuscitation and volume maintenance without albumin. Adult patients (≥ 18 years) with septic shock are randomly assigned within a maximum of 24 h after the onset of septic shock after obtaining informed consents to treatment or control groups. Patients assigned to the treatment group receive a 60-g loading dose of human albumin 20% over 2–3 h. Serum albumin levels are maintained at least at 30 g/l in the ICU for a maximum of 28 days following randomization using 40–80 g human albumin 20% infusion. The control group is treated according to the usual practice with crystalloids as the first choice for the resuscitation and maintenance phase of septic shock. The primary endpoint is 90 days mortality and secondary endpoints include 28-day, 60-day, ICU, and in-hospital mortality, organ dysfunction/failure, total amount of fluid administration and total fluid balance in the ICU, and lengths of ICU and hospital stay. In total, 1412 patients need to be analysed, 706 per group. For the sample size estimation, a 15% reduction in 90-day mortality is assumed, i.e. an absolute reduction of 7.5% points to 42.5% (relative risk 1.18). Assuming a dropout rate of 15%, a total of 1662 patients need to be allocated.

Discussion

The results of the clinical trial may influence the treatment of patients with septic shock. The expected improvement in patient survival may result in a reduction in the resources currently used in the treatment of these patients and in the socioeconomic burden of this disease.

Trial registration

ClinicalTrials.gov NCT03869385. Registration on 18 July 2019. Protocol version: Final 3.0.
Therapeutic potential of oxadiazole or furadiazole containing compounds
Authors: Siwach Ankit , Verma Prabhakar Kumar
Published: December 2020

As we know that, Oxadiazole or furadi azole ring containing derivatives are an important class of heterocyclic compounds. A heterocyclic five-membered ring that possesses two carbons, one oxygen atom, two nitrogen atoms, and two double bonds is known as oxadiazole. They are derived from furan by the replacement of two methylene groups (= CH) with two nitrogen (-N =) atoms. The aromaticity was reduced with the replacement of these groups in the furan ring to such an extent that it shows conjugated diene character. Four different known isomers of oxadiazole were existed such as 1,2,4-oxadiazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole & 1,3,4-oxadiazole. Among them, 1,3,4-oxadiazoles & 1,2,4-oxadiazoles are better known and more widely studied by the researchers due to their broad range of chemical and biological properties. 1,3,4-oxadiazoles have become important synthons in the development of new drugs. The derivatives of the oxadiazole nucleus (1,3,4-oxadiazoles) show various biological activities such as antibacterial, anti-mycobacterial, antitumor, anti-viral and antioxidant activity, etc. as reported in the literature. There are different examples of commercially available drugs which consist of 1,3,4-oxadiazole ring such as nitrofuran derivative (Furamizole) which has strong antibacterial activity, Raltegravir as an antiviral drug and Nesapidil drug is used in anti-arrhythmic therapy. This present review summarized some pharmacological activities and various kinds of synthetic routes for 2, 5-disubstituted 1,3,4-oxadiazole, and their derived products.