bluuebunny/crossref_metadata_2025 huggingface dataset:
Reflux, Barrett’s Esophagus, and Esophageal Adenocarcinoma After Bariatric Surgery
Authors: Medina Benjamin , Molena Daniela
Published: January 2022

We present the case of a patient who developed esophageal adenocarcinoma after a previous laparoscopic sleeve gastrectomy. Bariatric surgery has emerged as the most effective treatment option for weight loss and obesity-related diseases; however, sleeve gastrectomy promotes gastroesophageal reflux and leads to Barrett’s esophagus in a substantial portion of patients. The natural history of Barrett’s esophagus in these patients is unknown, and active surveillance is recommended until the incidence of dysplasia and adenocarcinoma in this population is clarified. Management options for these patients include conversion to Roux-en-Y gastric bypass. Although esophagectomy in patients who have previously undergone sleeve gastrectomy may require an alternative conduit, the remnant stomach can be used in carefully selected patients. Here, we review the different weight loss procedures, their effect on gastroesophageal reflux disease and Barrett’s esophagus, and the treatment options for patients with esophageal cancer after sleeve gastrectomy. We report the use of preoperative coil embolization as a means of vascular preconditioning before successful use of a gastric conduit.
Timing of high-dose methotrexate CNS prophylaxis in DLBCL: a multicenter international analysis of 1384 patients
Authors: Wilson Matthew R. , Eyre Toby A. , Kirkwood Amy A. , Wong Doo Nicole , Soussain Carole , Choquet Sylvain , Martinez-Calle Nicolás , Preston Gavin , Ahearne Matthew , Schorb Elisabeth , Moles-Moreau Marie-Pierre , Ku Matthew , Rusconi Chiara , Khwaja Jahanzaib , Narkhede Mayur , Lewis Katharine L. , Calimeri Teresa , Durot Eric , Renaud Loïc , Øvlisen Andreas Kiesbye , McIlroy Graham , Ebsworth Timothy J. , Elliot Johnathan , Santarsieri Anna , Ricard Laure , Shah Nimish , Liu Qin , Zayac Adam S. , Vassallo Francesco , Lebras Laure , Roulin Louise , Lombion Naelle , Manos Kate , Fernandez Ruben , Hamad Nada , Lopez-Garcia Alberto , O'Mahony Deirdre , Gounder Praveen , Forgeard Nathalie , Lees Charlotte , Agbetiafa Kossi , Strüßmann Tim , Htut Thura Win , Clavert Aline , Scott Hamish , Guidetti Anna , Barlow Brett R. , Tchernonog Emmanuelle , Smith Jeffery , Miall Fiona , Fox Christopher P. , Cheah Chan Y. , El Galaly Tarec Christoffer , Ferreri Andrés J. M. , Cwynarski Kate , McKay Pamela
Published: January 2022

Prophylactic high-dose methotrexate (HD-MTX) is often used for diffuse large B-cell lymphoma (DLBCL) patients at high risk of central nervous system (CNS) relapse, despite limited evidence demonstrating efficacy or the optimal delivery method. We conducted a retrospective, international analysis of 1384 patients receiving HD-MTX CNS prophylaxis either intercalated (i-HD-MTX) (n = 749) or at the end (n = 635) of R-CHOP/R-CHOP-like therapy (EOT). There were 78 CNS relapses (3-year rate 5.7%), with no difference between i-HD-MTX and EOT: 5.7% vs 5.8%, P = .98; 3-year difference: 0.04% (−2.0% to 3.1%). Conclusions were unchanged on adjusting for baseline prognostic factors or on 6-month landmark analysis (n = 1253). In patients with a high CNS international prognostic index (n = 600), the 3-year CNS relapse rate was 9.1%, with no difference between i-HD-MTX and EOT. On multivariable analysis, increasing age and renal/adrenal involvement were the only independent risk factors for CNS relapse. Concurrent intrathecal prophylaxis was not associated with a reduction in CNS relapse. R-CHOP delays of ≥7 days were significantly increased with i-HD-MTX vs EOT, with 308 of 1573 (19.6%) i-HD-MTX treatments resulting in a delay to subsequent R-CHOP (median 8 days). Increased risk of delay occurred in older patients when delivery was later than day 10 in the R-CHOP cycle. In summary, we found no evidence that EOT delivery increases CNS relapse risk vs i-HD-MTX. Findings in high-risk subgroups were unchanged. Rates of CNS relapse in this HD-MTX-treated cohort were similar to comparable cohorts receiving infrequent CNS prophylaxis. If HD-MTX is still considered for certain high-risk patients, delivery could be deferred until R-CHOP completion.
Cumulative incidence of subsequent malignancy after allo-HCT conditioned with or without low-dose total body irradiation
Authors: Nunez Lina , Abedin Tasnima , Naqvi Syed , Shen Hua , Chaudhry Ahsan , Bellerby Scott , Savoie Lynn , Daly Andrew , Shafey Mona , Duggan Peter , Storek Jan , Jamani Kareem
Published: January 2022

Subsequent malignancies (SMs) present a significant burden of morbidity and are a common cause of late mortality in survivors of allogeneic hematopoietic cell transplant (allo-HCT). Previous studies have described total body irradiation (TBI) as a risk factor for the development of SMs in allo-HCT survivors. However, most studies of the association between TBI and SM have examined high-dose TBI regimens (typically ≥600 cGy), and thus little is known about the association between low-dose TBI regimens and risk of SMs. Our goal, therefore, was to compare the cumulative incidence of SMs in patients of Alberta, Canada, who received busulfan/fludarabine alone vs busulfan/fludarabine plus 400 cGy TBI. Of the 674 included patients, 49 developed a total of 56 malignancies at a median of 5.9 years’ posttransplant. The cumulative incidence of SMs at 15 years’ post-HCT in the entire cohort was 11.5% (95% confidence interval [CI], 8.5-15.6): 13.4% (95% CI, 9.1-19.3) in the no-TBI group and 10.8% (95% CI, 6.6-17.4) in the TBI group. In the multivariable model, TBI was not associated with SMs, whereas there was an association with number of pre-HCT cycles of chemotherapy. The standardized incidence ratio for the entire cohort, compared with the age-, sex-, and calendar year–matched general population, was 1.75. allo-HCT conditioning that includes low-dose TBI does not seem to increase risk of SMs compared with chemotherapy-alone conditioning.
Circulating microvesicles and exosomes in small cell lung cancer by quantitative proteomics
Authors: Pedersen Shona , Jensen Katrine Papendick , Honoré Bent , Kristensen Søren Risom , Pedersen Camilla Holm , Szejniuk Weronika Maria , Maltesen Raluca Georgiana , Falkmer Ursula
Published: January 2022

Background

Early detection of small cell lung cancer (SCLC) crucially demands highly reliable markers. Growing evidence suggests that extracellular vesicles carry tumor cell-specific cargo suitable as protein markers in cancer. Quantitative proteomic profiling of circulating microvesicles and exosomes can be a high-throughput platform for discovery of novel molecular insights and putative markers. Hence, this study aimed to investigate proteome dynamics of plasma-derived microvesicles and exosomes in newly diagnosed SCLC patients to improve early detection.

Methods

Plasma-derived microvesicles and exosomes from 24 healthy controls and 24 SCLC patients were isolated from plasma by either high-speed- or ultracentrifugation. Proteins derived from these extracellular vesicles were quantified using label-free mass spectrometry and statistical analysis was carried out aiming at identifying significantly altered protein expressions between SCLC patients and healthy controls. Furthermore, significantly expressed proteins were subjected to functional enrichment analysis to identify biological pathways implicated in SCLC pathogenesis.

Results

Based on fold change (FC) ≥ 2 or ≤ 0.5 and AUC ≥ 0.70 (p < 0.05), we identified 10 common and 16 and 17 unique proteins for microvesicles and exosomes, respectively. Among these proteins, we found dysregulation of coagulation factor XIII A (Log2 FC =  − 1.1, p = 0.0003, AUC = 0.82, 95% CI: 0.69–0.96) and complement factor H-related protein 4 (Log2 FC = 1.2, p = 0.0005, AUC = 0.82, 95% CI; 0.67–0.97) in SCLC patients compared to healthy individuals. Our data may indicate a novel tumor-suppressing role of blood coagulation and involvement of complement activation in SCLC pathogenesis.

Conclusions

In comparing SCLC patients and healthy individuals, several differentially expressed proteins were identified. This is the first study showing that circulating extracellular vesicles may encompass specific proteins with potential diagnostic attributes for SCLC, thereby opening new opportunities as novel non-invasive markers.
Mutational landscape and in silico structure models of SARS-CoV-2 spike receptor binding domain reveal key molecular determinants for virus-host interaction
Authors: Nelson-Sathi Shijulal , Umasankar P. K. , Sreekumar E. , Nair R. Radhakrishnan , Joseph Iype , Nori Sai Ravi Chandra , Philip Jamiema Sara , Prasad Roshny , Navyasree K. V. , Ramesh Shikha , Pillai Heera , Ghosh Sanu , Santosh Kumar T. R. , Pillai M. Radhakrishna
Published: January 2022

Background

SARS-CoV-2, the causative agent of COVID-19 pandemic is a RNA virus prone to mutations. Formation of a stable binding interface between the Receptor Binding Domain (RBD) of SARS-CoV-2 Spike (S) protein and Angiotensin-Converting Enzyme 2 (ACE2) of host is pivotal for viral entry. RBD has been shown to mutate frequently during pandemic. Although, a few mutations in RBD exhibit enhanced transmission rates leading to rise of new variants of concern, most RBD mutations show sustained ACE2 binding and virus infectivity. Yet, how all these mutations make the binding interface constantly favourable for virus remain enigmatic. This study aims to delineate molecular rearrangements in the binding interface of SARS-CoV-2 RBD mutants.

Results

Here, we have generated a mutational and structural landscape of SARS-CoV-2 RBD in first six months of the pandemic. We analyzed 31,403 SARS-CoV-2 genomes randomly across the globe, and identified 444 non-synonymous mutations in RBD that cause 49 distinct amino acid substitutions in contact and non-contact amino acid residues. Molecular phylogenetic analysis suggested independent emergence of RBD mutants. Structural mapping of these mutations on the SARS-CoV-2 Wuhan reference strain RBD and structural comparison with RBDs from bat-CoV, SARS-CoV, and pangolin-CoV, all bound to human or mouse ACE2, revealed several changes in the interfacial interactions in all three binding clusters. Interestingly, interactions mediated via N487 residue in cluster-I and Y449, G496, T500, G502 residues in cluster-III remained largely unchanged in all RBD mutants. Further analysis showed that these interactions are evolutionarily conserved in sarbecoviruses which use ACE2 for entry. Importantly, despite extensive changes in the interface, RBD-ACE2 stability and binding affinities were maintained in all the analyzed mutants. Taken together, these findings reveal how SARS-CoV-2 uses its RBD residues to constantly remodel the binding interface.

Conclusion

Our study broadly signifies understanding virus-host binding interfaces and their alterations during pandemic. Our findings propose a possible interface remodelling mechanism used by SARS-CoV-2 to escape deleterious mutations. Future investigations will focus on functional validation of in-silico findings and on investigating interface remodelling mechanisms across sarbecoviruses. Thus, in long run, this study may provide novel clues to therapeutically target RBD-ACE2 interface for pan-sarbecovirus infections.
Cardiac physiology and metabolic gene expression during late organogenesis among F. heteroclitus embryo families from crosses between pollution-sensitive and -resistant parents
Authors: Bozinovic Goran , Feng Zuying , Shea Damian , Oleksiak Marjorie F.
Published: January 2022

Background

The teleost fish Fundulus heteroclitus inhabit estuaries heavily polluted with persistent and bioaccumulative chemicals. While embryos of parents from polluted sites are remarkably resistant to toxic sediment and develop normally, embryos of parents from relatively clean estuaries, when treated with polluted sediment extracts, are developmentally delayed, displaying deformities characteristic of pollution-induced embryotoxicity. To gain insight into parental effects on sensitive and resistant phenotypes during late organogenesis, we established sensitive, resistant, and crossed embryo families using five female and five male parents from relatively clean and predominantly PAH-polluted estuaries each, measured heart rates, and quantified individual embryo expression of 179 metabolic genes.

Results

Pollution-induced embryotoxicity manifested as morphological deformities, significant developmental delays, and altered cardiac physiology was evident among sensitive embryos resulting from crosses between females and males from relatively clean estuaries. Significantly different heart rates among several geographically unrelated populations of sensitive, resistant, and crossed embryo families during late organogenesis and pre-hatching suggest site-specific adaptive cardiac physiology phenotypes relative to pollution exposure. Metabolic gene expression patterns (32 genes, 17.9%, at p < 0.05; 11 genes, 6.1%, at p < 0.01) among the embryo families indicate maternal pollutant deposition in the eggs and parental effects on gene expression and metabolic alterations.

Conclusion

Heart rate differences among sensitive, resistant, and crossed embryos is a reliable phenotype for further explorations of adaptive mechanisms. While metabolic gene expression patterns among embryo families are suggestive of parental effects on several differentially expressed genes, a definitive adaptive signature and metabolic cost of resistant phenotypes is unclear and shows unexpected sensitive-resistant crossed embryo expression profiles. Our study highlights physiological and metabolic gene expression differences during a critical embryonic stage among pollution sensitive, resistant, and crossed embryo families, which may contribute to underlying resistance mechanisms observed in natural F. heteroclitus populations living in heavily contaminated estuaries.
The evolution of insect visual opsin genes with specific consideration of the influence of ocelli and life history traits
Authors: Guignard Quentin , Allison Jeremy D. , Slippers Bernard
Published: January 2022

Background

Visual opsins are expressed in the compound eyes and ocelli of insects and enable light detection. Three distinct phylogenetic groups of visual opsins are found in insects, named long (LW), short (SW) and ultraviolet (UV) wavelength sensitive opsins. Recently, the LW group was found to be duplicated into the LW2b and the LW2a opsins. The expression of LW2b opsins is ocelli specific in some insects (e.g., bees, cricket, scorpion flies), but the gene was not found in other orders possessing three or less ocelli (e.g., dragonflies, beetles, moths, bugs). In flies, two LW2b homologs have been characterised, with one expressed in the ocelli and the other in the compound eyes. To date, it remains unclear which evolutionary forces have driven gains and losses of LW opsins in insects. Here we take advantage of the recent rapid increase in available sequence data (i.e., from insect genomes, targeted PCR amplification, RNAseq) to characterize the phylogenetic relationships of 1000 opsin sequences in 18 orders of Insects. The resulting phylogeny discriminates between four main groups of opsins, and onto this phylogeny we mapped relevant morphological and life history traits.

Results

Our results demonstrate a conserved LW2b opsin only present in insects with three ocelli. Only two groups (Brachycera and Odonata) possess more than one LW2b opsin, likely linked to their life history. In flies, we hypothesize that the duplication of the LW2b opsin occurred after the transition from aquatic to terrestrial larvae. During this transition, higher flies (Brachycera) lost a copy of the LW2a opsin, still expressed and duplicated in the compound eyes of lower flies (Nematocera). In higher flies, the LW2b opsin has been duplicated and expressed in the compound eyes while the ocelli and the LW2b opsin were lost in lower flies. In dragonflies, specialisation of flight capabilities likely drove the diversification of the LW2b visual opsins.

Conclusion

The presence of the LW2b opsin in insects possessing three ocelli suggests a role in specific flight capabilities (e.g., stationary flight). This study provides the most complete view of the evolution of visual opsin genes in insects yet, and provides new insight into the influence of ocelli and life history traits on opsin evolution in insects.
Development and evaluation of a meat mitochondrial metagenomic (3MG) method for composition determination of meat from fifteen mammalian and avian species
Authors: Jiang Mei , Xu Shu-Fei , Tang Tai-Shan , Miao Li , Luo Bao-Zheng , Ni Yang , Kong Fan-De , Liu Chang
Published: January 2022

Background

Bioassessment and biomonitoring of meat products are aimed at identifying and quantifying adulterants and contaminants, such as meat from unexpected sources and microbes. Several methods for determining the biological composition of mixed samples have been used, including metabarcoding, metagenomics and mitochondrial metagenomics. In this study, we aimed to develop a method based on next-generation DNA sequencing to estimate samples that might contain meat from 15 mammalian and avian species that are commonly related to meat bioassessment and biomonitoring.

Results

In this project, we found the meat composition from 15 species could not be identified with the metabarcoding approach because of the lack of universal primers or insufficient discrimination power. Consequently, we developed and evaluated a meat mitochondrial metagenomics (3MG) method. The 3MG method has four steps: (1) extraction of sequencing reads from mitochondrial genomes (mitogenomes); (2) assembly of mitogenomes; (3) mapping of mitochondrial reads to the assembled mitogenomes; and (4) biomass estimation based on the number of uniquely mapped reads. The method was implemented in a python script called 3MG. The analysis of simulated datasets showed that the method can determine contaminant composition at a proportion of 2% and the relative error was < 5%. To evaluate the performance of 3MG, we constructed and analysed mixed samples derived from 15 animal species in equal mass. Then, we constructed and analysed mixed samples derived from two animal species (pork and chicken) in different ratios. DNAs were extracted and used in constructing 21 libraries for next-generation sequencing. The analysis of the 15 species mix with the method showed the successful identification of 12 of the 15 (80%) animal species tested. The analysis of the mixed samples of the two species revealed correlation coefficients of 0.98 for pork and 0.98 for chicken between the number of uniquely mapped reads and the mass proportion.

Conclusion

To the best of our knowledge, this study is the first to demonstrate the potential of the non-targeted 3MG method as a tool for accurately estimating biomass in meat mix samples. The method has potential broad applications in meat product safety.
Association of hyperchloremia with all-cause mortality in patients admitted to the surgical intensive care unit: a retrospective cohort study
Authors: Song Keke , Yang Tingting , Gao Wei
Published: January 2022

Background

Serum chloride (Cl−) is one of the most essential extracellular anions. Based on emerging evidence obtained from patients with kidney or heart disease, hypochloremia has been recognized as an independent predictor of mortality. Nevertheless, excessive Cl− can also cause death in severely ill patients. This study aimed to investigate the relationship between hyperchloremia and high mortality rate in patients admitted to the surgical intensive care unit (SICU).

Methods

We enrolled 2131 patients from the Multiparameter Intelligent Monitoring in Intensive Care III database version 1.4 (MIMIC-III v1.4) from 2001 to 2012. Selected SICU patients were more than 18 years old and survived more than 72 h. A serum Cl− level ≥ 108 mEq/L was defined as hyperchloremia. Clinical and laboratory variables were compared between hyperchloremia (n = 664) at 72 h post-ICU admission and no hyperchloremia (n = 1467). The Locally Weighted Scatterplot Smoothing (Lowess) approach was utilized to investigate the correlation between serum Cl- and the thirty-day mortality rate. The Cox proportional-hazards model was employed to investigate whether serum chlorine at 72 h post-ICU admission was independently related to in-hospital, thirty-day and ninety-day mortality from all causes. Kaplan-Meier curve of thirty-day and ninety-day mortality and serum Cl− at 72 h post-ICU admission was further constructed. Furthermore, we performed subgroup analyses to investigate the relationship between serum Cl− at 72 h post-ICU admission and the thirty-day mortality from all causes.

Results

A J-shaped correlation was observed, indicating that hyperchloremia was linked to an elevated risk of thirty-day mortality from all causes. In the multivariate analyses, it was established that hyperchloremia remained a valuable predictor of in-hospital, thirty-day and ninety-day mortality from all causes; with adjusted hazard ratios (95% CIs) for hyperchloremia of 1.35 (1.02 ~ 1.77), 1.67 (1.28 ~ 2.19), and 1.39 (1.12 ~ 1.73), respectively. In subgroup analysis, we observed hyperchloremia had a significant interaction with AKI (P for interaction: 0.017), but there were no interactions with coronary heart disease, hypertension, and diabetes mellitus (P for interaction: 0.418, 0.157, 0.103, respectively).

Conclusion

Hyperchloremia at 72 h post-ICU admission and increasing serum Cl− were associated with elevated mortality risk from all causes in severely ill SICU patients.
Comparison of GRACE and TIMI risk scores in the prediction of in-hospital and long-term outcomes among East Asian non-ST-elevation myocardial infarction patients
Authors: Yanqiao Lu , Shen Lan , Yutong Miao , Linghong Shen , Ben He
Published: January 2022

Background

Risk stratification in non-ST segment elevation myocardial infarction (NSTEMI) determines the intervention time. Limited study compared two risk scores, the Thrombolysis in Myocardial Infarction (TIMI) and Global Registry of Acute Coronary Events (GRACE) risk scores in the current East Asian NSTEMI patients.

Methods

This retrospective observational study consecutively collected patients in a large academic hospital between 01/01 and 11/01/2017 and followed for 4 years. Patients were scored by TIMI and GRACE scores on hospital admission. In-hospital endpoints were defined as the in-hospital composite event, including mortality, re-infarction, heart failure, stroke, cardiac shock, or resuscitation. Long-term outcomes were all-cause mortality and cardiac mortality in 4-year follow-up.

Results

A total of 232 patients were included (female 29.7%, median age 67 years), with a median follow-up of 3.7 years. GRACE score grouped most patients (45.7%) into high risk, while TIMI grouped the majority (61.2%) into medium risk. Further subgrouping the TIMI medium group showed that half (53.5%) of the TIMI medium risk population was GRACE high risk (≥ 140). Compared to TIMI medium group + GRACE < 140 subgroup, the TIMI medium + GRACE high-risk (≥ 140) subgroup had a significantly higher in-hospital events (39.5% vs. 9.1%, p < 0.05), long-term all-cause mortality (22.2% vs. 0% p < 0.001) and cardiac death (11.1% vs. 0% p = 0.045) in 4-year follow-up. GRACE risk scores showed a better predictive ability than TIMI risk scores both for in-hospital and long-term outcomes. (AUC of GRACE vs. TIMI, In-hospital: 0.82 vs. 0.62; long-term mortality: 0.89 vs. 0.68; long-term cardiac mortality: 0.91 vs. 0.67, all p < 0.05). Combined use of the two risk scores reserved both the convenience of scoring and the predictive accuracy.

Conclusion

GRACE showed better predictive accuracy than TIMI in East Asian NSTEMI patients in both in-hospital and long-term outcomes. The sequential use of TIMI and GRACE scores provide an easy and promising discriminative tool in predicting outcomes in NSTEMI East Asian patients.
Reporting of abstracts in studies that used routinely collected data for exploring drug treatment effects: a cross-sectional survey
Authors: Liu Mei , Wang Wen , Wang Mingqi , He Qiao , Li Ling , Li Guowei , He Lin , Zou Kang , Sun Xin
Published: January 2022

Background

In recent years, studies that used routinely collected data (RCD), such as electronic medical records and administrative claims, for exploring drug treatment effects, including effectiveness and safety, have been increasingly published. Abstracts of such studies represent a highly attended source for busy clinicians or policy-makers, and are important for indexing by literature database. If less clearly presented, they may mislead decisions or indexing. We thus conducted a cross-sectional survey to systematically examine how the abstracts of such studies were reported.

Methods

We searched PubMed to identify all observational studies published in 2018 that used RCD for assessing drug treatment effects. Teams of methods-trained collected data from eligible studies using pilot-tested, standardized forms that were developed and expanded from “The reporting of studies conducted using observational routinely collected health data statement for pharmacoepidemiology” (RECORD-PE) statement. We used descriptive analyses to examine how authors reported data source, study design, data analysis, and interpretation of findings.

Results

A total of 222 studies were included, of which 118 (53.2%) reported type of database used, 17 (7.7%) clearly reported database linkage, and 140 (63.1%) reported coverage of data source. Only 44 (19.8%) studies stated a predefined hypothesis, 127 (57.2%) reported study design, 140 (63.1%) reported statistical models used, 142 (77.6%) reported adjusted estimates, 33 (14.9%) mentioned sensitivity analyses, and 39 (17.6%) made a strong claim about treatment effect. Studies published in top 5 general medicine journals were more likely to report the name of data source (94.7% vs. 67.0%) and study design (100% vs. 53.2%) than those in other journals.

Conclusions

The under-reporting of key methodological features in abstracts of RCD studies was common, which would substantially compromise the indexing of this type of literature and prevent the effective use of study findings. Substantial efforts to improve the reporting of abstracts in these studies are highly warranted.
Development of a data classification system for preterm birth cohort studies: the RECAP Preterm project
Authors: Bamber Deborah , Collins Helen E. , Powell Charlotte , Gonçalves Gonçalo Campos , Johnson Samantha , Manktelow Bradley , Ornelas José Pedro , Lopes João Correia , Rocha Artur , Draper Elizabeth S.
Published: January 2022

Background

The small sample sizes available within many very preterm (VPT) longitudinal birth cohort studies mean that it is often necessary to combine and harmonise data from individual studies to increase statistical power, especially for studying rare outcomes. Curating and mapping data is a vital first step in the process of data harmonisation. To facilitate data mapping and harmonisation across VPT birth cohort studies, we developed a custom classification system as part of the Research on European Children and Adults born Preterm (RECAP Preterm) project in order to increase the scope and generalisability of research and the evaluation of outcomes across the lifespan for individuals born VPT.

Methods

The multidisciplinary consortium of expert clinicians and researchers who made up the RECAP Preterm project participated in a four-phase consultation process via email questionnaire to develop a topic-specific classification system. Descriptive analyses were calculated after each questionnaire round to provide pre- and post- ratings to assess levels of agreement with the classification system as it developed. Amendments and refinements were made to the classification system after each round.

Results

Expert input from 23 clinicians and researchers from the RECAP Preterm project aided development of the classification system’s topic content, refining it from 10 modules, 48 themes and 197 domains to 14 modules, 93 themes and 345 domains. Supplementary classifications for target, source, mode and instrument were also developed to capture additional variable-level information. Over 22,000 individual data variables relating to VPT birth outcomes have been mapped to the classification system to date to facilitate data harmonisation. This will continue to increase as retrospective data items are mapped and harmonised variables are created.

Conclusions

This bespoke preterm birth classification system is a fundamental component of the RECAP Preterm project’s web-based interactive platform. It is freely available for use worldwide by those interested in research into the long term impact of VPT birth. It can also be used to inform the development of future cohort studies.
The effect of BKV reactivation on cytokines behavior in kidney transplanted patients
Authors: Rahimi Zahra , Yaghobi Ramin , Afshari Afsoon , Roozbeh Jamshid , Mokhtari Mohammad Javad , Hosseini Ali Malek
Published: January 2022

Background

BK virus associated nephropathy (BKVAN) is one of the common causes of graft loss among kidney transplanted recipients (KTRs). The current treatment for BKV nephropathy is decreasing the immunosuppressive regimen in KTRs. Interleukin-27 (IL-27) is a multifunctional cytokine that might be the front-runner of an important pathway in this regard. Therefore, in current study it is tried to evaluate the changes in the expression level of IL-27 and some related molecules, resulting from BKV reactivation in KTR patients.

Methods

EDTA-treated blood samples were collected from all participants. Patients were divided into two groups, 31 kidney transplant recipients with active and 32 inactive BKV infection, after being monitored by Real time PCR (Taq-Man) in plasma. Total of 30 normal individuals were considered as healthy control group. Real time PCR (SYBR Green) technique is used to determine the expression level of studied genes.

Results

The results of gene expression comparisons showed that the expression level of IL-27, IFN-γ, TNF-α, TNFR2 and IRF7 genes was significantly higher in inactive group in comparison to active group. The expression level of TLR4 was lower in both active and inactive groups in comparison to control group. ROC curve analysis showed that IL-27 and IRF7 are significantly different amongst other studied genes. Finally, the analyses revealed that the expression level of most of the studied genes (except for TNF-α and TLR4) have significant correlation with viral load.

Conclusions

Our findings revealed that IL-27, IFN-γ, TNF-α, TNFR2 and IRF7 expression level is higher in inactive group and TLR4 expression level is lower in patients’ groups in comparison to control group. Also, ROC curve analysis showed IL-27 and IRF7 can significantly differentiate studied groups (BKV active vs. inactive). Therefore, these results might help elucidating the pattern in charge of BKV reactivation in kidney transplanted patients.
Digital gene expression analysis of NSCLC-patients reveals strong immune pressure, resulting in an immune escape under immunotherapy
Authors: Wessolly Michael , Stephan-Falkenau Susann , Streubel Anna , Wiesweg Marcel , Borchert Sabrina , Mairinger Elena , Kollmeier Jens , Reis Henning , Bauer Torsten , Schmid Kurt Werner , Mairinger Thomas , Schuler Martin , Mairinger Fabian D.
Published: January 2022

Background

Immune checkpoint inhibitors (ICIs) are currently one of the most promising therapy options in the field of oncology. Although the first pivotal ICI trial results were published in 2011, few biomarkers exist to predict their therapy outcome. PD-L1 expression and tumor mutational burden (TMB) were proven to be sometimes-unreliable biomarkers. We have previously suggested the analysis of processing escapes, a qualitative measurement of epitope structure alterations under immune system pressure, to provide predictive information on ICI response. Here, we sought to further validate this approach and characterize interactions with different forms of immune pressure.

Methods

We identified a cohort consisting of 48 patients with advanced non-small cell lung cancer (NSCLC) treated with nivolumab as ICI monotherapy. Tumor samples were subjected to targeted amplicon-based sequencing using a panel of 22 cancer-associated genes covering 98 mutational hotspots. Altered antigen processing was predicted by NetChop, and MHC binding verified by NetMHC. The NanoString nCounter® platform was utilized to provide gene expression data of 770 immune-related genes. Patient data from 408 patients with NSCLC were retrieved from The Cancer Genome Atlas (TCGA) as a validation cohort.

Results

The two immune escape mechanisms of PD-L1 expression (TPS score) (n = 18) and presence of altered antigen processing (n = 10) are mutually non-exclusive and can occur in the same patient (n = 6). Both mechanisms have exclusive influence on different genes and pathways, according to differential gene expression analysis and gene set enrichment analysis, respectively. Interestingly, gene expression patterns associated with altered processing were enriched in T cell and NK cell immune activity. Though both mechanisms influence different genes, they are similarly linked to increased immune activity.

Conclusion

Pressure from the immune system will lay the foundations for escape mechanisms, leading to acquisition of resistance under therapy. Both PD-L1 expression and altered antigen processing are induced similarly by pronounced immunoactivity but in different context. The present data help to deepen our understanding of the underlying mechanisms behind those immune escapes.
Blood routine risk factors for coronary artery aneurysm in infants younger than 8 months with Kawasaki disease
Authors: Haiyan Ge , Jianming Lai , Suqian Tong , Dong Qu , Shuang Liu , Jin Zhang
Published: January 2022

Objective

The aims of this study were to characterize the evolution of routine blood values within the first 10 days of illness and coronary artery outcome in infants < 8 months with Kawasaki disease (KD) and to identify risk factors for coronary artery aneurysm (CAA).

Methods

Laboratory data, clinical features and coronary artery outcomes from 78 infants < 8 months old and 86 patients between 8 months and 7 years old were retrospectively analyzed. Logistic regression analysis was conducted to evaluate the potential risk factors for CAA.

Results

Infants < 8 months old were more likely to present with incomplete KD (37.2% vs 4.7%, P < 0.001), erythema and induration at the BCG inoculation site (24.4% vs 3.5%, P < 0.001) and CAA (47.4% vs 15.1%, P < 0.001) even with timely diagnosis and treatment with intravenous immunoglobulin (IVIG) compared with patients ≥8 months old. Clinical feature related to diagnostic criteria for KD including bilateral conjunctival injection, oral changes, unilateral cervical lymphadenopathy and extremity changes were less common in the younger group. During the acute phase, the percentage neutrophils and neutrophil to lymphocyte ratio [NLR] peaked on median illness day 3, followed by white blood cell (WBC) and CRP on median illness day 4, hemoglobin on median illness day 7 and platelet count on median illness day 9. CAA occurred on median illness day 6 and regressed on median illness day 28. Multivariate logistic regression analysis revealed that the peak percentage neutrophils (odds ratio [OR] per 0.1: 1.597, 95% confidence interval [CI]: 1.041–2.452, P = 0.032) and the peak platelet count (OR per 10 × 109/L: 1.029, 95% CI: 1.004–1.055, P = 0.024) were independent risk factors for CAA. Hemoglobin on the 5th day was associated with persistent CAA at 1 year after KD onset.

Conclusion

Factors associated with CAA include a high peak percentage neutrophils, increased peak platelet count, and reduced hemoglobin within 4–6 days during the acute phase of KD. Therefore, this population should receive primary therapy with IVIG and adjunctive anti-inflammatory medications.
An informed approach to the development of primary care pediatric firearm safety messages
Authors: Fuzzell Lindsay N. , Dodd Sherry , Hu Sisi , Hinnant Amanda , Lee Sungkyoung , Cameron Glen , Garbutt Jane M.
Published: January 2022

Background

Firearm ownership is prevalent in the US and many children spend time in areas where firearms are not stored safely. The AAP recommends firearm safety counseling at pediatric well-visits.

Methods

We developed and tested six contextual messages to promote safe firearm storage based on: absence of harm, collective appeal to understanding child behavior, pediatrician’s authority, evidence-based, fear appeal, and general safety considerations. One hundred four parents who keep firearms at home were recruited from Amazon Mechanical Turk Prime and viewed video messages and reported behavioral intentions and emotional reactions following each message.

Results

All six contextual messages were perceived as important and believable and increased parents’ intentions to follow safety advice provided, but also elicited negative emotions. The authority message elicited more negative emotions and resulted in lower intentions to follow safe storage advice.

Conclusions

Including firearm messages with other child safety advice merits further evaluation. Authority messages should be avoided.
A novel circ_MACF1/miR-942-5p/TGFBR2 axis regulates the functional behaviors and drug sensitivity in gefitinib-resistant non-small cell lung cancer cells
Authors: Fan Daping , Yang Yue , Zhang Wei
Published: January 2022

Background

Resistance to gefitinib remains a major obstacle for the successful treatment of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. In this paper, we studied the precise actions of circular RNA (circRNA) microtubule actin crosslinking factor 1 (circ_MACF1) in gefitinib resistance.

Methods

We established gefitinib-resistant NSCLC cells (PC9/GR and A549/GR). The levels of circ_MACF1, microRNA (miR)-942-5p, and transforming growth factor beta receptor 2 (TGFBR2) were gauged by quantitative real-time PCR (qRT-PCR) or western blot. Subcellular fractionation and Ribonuclease R (RNase R) assays were done to characterize circ_MACF1. Cell survival, proliferation, colony formation, apoptosis, migration, and invasion were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), 5-Ethynyl-2’-Deoxyuridine (EdU), colony formation, flow cytometry, and transwell assays, respectively. Dual-luciferase reporter assays were used to verify the direct relationship between miR-942-5p and circ_MACF1 or TGFBR2. The xenograft assays were used to assess the role of circ_MACF1 in vivo.

Results

Circ_MACF1 was down-regulated in A549/GR and PC9/GR cells. Overexpression of circ_MACF1 repressed proliferation, migration, invasion, and promoted apoptosis and gefitinib sensitivity of A549/GR and PC9/GR cells in vitro, as well as inhibited tumor growth under gefitinib in vivo. Circ_MACF1 directly targeted miR-942-5p, and miR-942-5p mediated the regulatory effects of circ_MACF1. TGFBR2 was identified as a direct and functional target of miR-942-5p. Circ_MACF1 modulated TGFBR2 expression through miR-942-5p.

Conclusion

Our findings demonstrated that circ_MACF1 regulated cell functional behaviors and gefitinib sensitivity of A549/GR and PC9/GR cells at least partially by targeting miR-942-5p to induce TGFBR2 expression.
Risk factor analysis and nomogram for predicting in-hospital mortality in ICU patients with sepsis and lung infection
Authors: Ren Yinlong , Zhang Luming , Xu Fengshuo , Han Didi , Zheng Shuai , Zhang Feng , Li Longzhu , Wang Zichen , Lyu Jun , Yin Haiyan
Published: January 2022

Background

Lung infection is a common cause of sepsis, and patients with sepsis and lung infection are more ill and have a higher mortality rate than sepsis patients without lung infection. We constructed a nomogram prediction model to accurately evaluate the prognosis of and provide treatment advice for patients with sepsis and lung infection.

Methods

Data were retrospectively extracted from the Medical Information Mart for Intensive Care (MIMIC-III) open-source clinical database. The definition of Sepsis 3.0 [10] was used, which includes patients with life-threatening organ dysfunction caused by an uncontrolled host response to infection, and SOFA score ≥ 2. The nomogram prediction model was constructed from the training set using logistic regression analysis, and was then internally validated and underwent sensitivity analysis.

Results

The risk factors of age, lactate, temperature, oxygenation index, BUN, lactate, Glasgow Coma Score (GCS), liver disease, cancer, organ transplantation, Troponin T(TnT), neutrophil-to-lymphocyte ratio (NLR), and CRRT, MV, and vasopressor use were included in the nomogram. We compared our nomogram with the Sequential Organ Failure Assessment (SOFA) score and Simplified Acute Physiology Score II (SAPSII), the nomogram had better discrimination ability, with areas under the receiver operating characteristic curve (AUROC) of 0.743 (95% C.I.: 0.713–0.773) and 0.746 (95% C.I.: 0.699–0.790) in the training and validation sets, respectively. The calibration plot indicated that the nomogram was adequate for predicting the in-hospital mortality risk in both sets. The decision-curve analysis (DCA) of the nomogram revealed that it provided net benefits for clinical use over using the SOFA score and SAPSII in both sets.

Conclusion

Our new nomogram is a convenient tool for accurate predictions of in-hospital mortality among ICU patients with sepsis and lung infection. Treatment strategies that improve the factors considered relevant in the model could increase in-hospital survival for these ICU patients.
Healthcare providers’ perception of advance care planning for patients with critical illnesses in acute-care hospitals: a cross-sectional study
Authors: Yamamoto Kanako , Yonekura Yuki , Nakayama Kazuhiro
Published: January 2022

Background

In acute-care hospitals, patients treated in an ICU for surgical reasons or sudden deterioration are treated in an outpatient ward, ICU, and other multiple departments. It is unclear how healthcare providers are initiating advance care planning (ACP) for such patients and assisting them with it. The purpose of this study is to clarify healthcare providers’ perceptions of the ACP support provided to patients receiving critical care in acute-care hospitals.

Methods

A cross-sectional study was conducted using questionnaires. In this study, 400 acute-care hospitals with ICUs in Japan were randomly selected, and 1490 subjects, including intensivists, surgeons, ICU nurses, surgical floor nurses, and surgical outpatient nurses, participated. Survey items examined whether ICU patients received ACP support, the participants’ degree of confidence in providing ACP support, the patients’ treatment preferences, and the decision-making process, and whether any discussion was conducted on change of values.

Results

Responses were obtained from 598 participants from 157 hospitals, 41.4% of which reportedly supported ACP provision to ICU patients. The subjects with the highest level of ACP understanding were surgeons (45.8%), and differences in understanding were observed across specialties (P < 0.001). Among the respondents, physicians and nurses expressed high levels of confidence in providing ACP support to patients requiring critical care. However, 15.2% of all the subjects mentioned that they would not attempt to resuscitate the patients. In addition, 25.7% of the participants handed over patients’ values to other departments or hospitals, whereas 25.3% handed over the decision-making process.

Conclusions

Among the participating hospitals, 40% provided ACP support to patients receiving critical care. The low number is possibly because support providers lack understanding of the content of patients’ ACP or about how to support and use ACP. Second, it is sometimes too late to start providing ACP support after ICU admission. Third, healthcare providers differ in their perception of ACP, widely considered an ambiguous concept. Finally, in acute-care hospitals with different healthcare settings, it is necessary to confirm and integrate the changes in feelings and thoughts of patients.
The relationship between genetic variants associated with primary ovarian insufficiency and lipid profile in women recruited from MASHAD cohort study
Authors: Mirinezhad Mohammad Reza , Ghazizadeh Hamideh , Aghsizadeh Maliheh , Zamiri Bidary Mohammad , Naghipour Alireza , Hasanzadeh Elahe , Yaghooti-Khorasani Mahdiyeh , Ebrahimi Dabagh Ali , Moghadam Mohammad Reza Shadmand Foumani , Sheikh Andalibi Nazanin , Naseri Far Zeynab , Esmaily Habibollah , Ferns Gordon A. , Hamzehloei Tayebeh , Pasdar Alireza , Ghayour-Mobarhan Majid
Published: January 2022

Background and aim

Primary Ovarian Insufficiency (POI) is defined by the occurrence of menopause before the age of 40 years. It is often associated with cardiovascular disease (CVD). The purpose of this study was to explore the relationship between POI-associated genotypes cardiometabolic disorder risk factors.

Methods

One hundred seventeen women with POI and one hundred eighty-three healthy women without POI were recruited in this study. DNA was extracted and analyzed using ASO-PCR or Tetra ARMS-PCR. Lipid profiles were also assessed.

Results

Multivariate logistic regression analysis showed that individuals with GG vs. TT genotype of the rs1046089 SNP were more likely to have a higher serum LDL (p = 0.03) compared to the control group. There was also a significant association between low serum HDL and rs2303369 and rs4806660 SNP genotypes in the POI group. In the POI group, the percentage of those with high total cholesterol was lower in those with a CC genotype compared to those with a TT genotype (p = 0.03).

Conclusion

Some SNPs reported to be associated with POI appear to be independently associated with dyslipidemia. These results may be helpful to identify subjects with POI who may be susceptible to CVD.
Discovery and identification of potential anti-melanogenic active constituents of Bletilla striata by zebrafish model and molecular docking
Authors: Luo Yiyuan , Wang Juan , Li Shuo , Wu Yue , Wang Zhirui , Chen Shaojun , Chen Hongjiang
Published: January 2022

Background

Bletilla striata is the main medicine of many skin whitening classic formulas in traditional Chinese medicine (TCM) and is widely used in cosmetic industry recently. However, its active ingredients are still unclear and its fibrous roots are not used effectively. The aim of the present study is to discover and identify its potential anti-melanogenic active constituents by zebrafish model and molecular docking.

Methods

The antioxidant activities were evaluated by 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity, 2,2′-azino-bis-(3-ethylbenthiazoline-6-sulphonic acid) (ABTS) radical scavenging activity and ferric reducing antioxidant power (FRAP) assay. The anti-melanogenic activity was assessed by tyrosinase inhibitory activity in vitro and melanin inhibitory in zebrafish. The chemical profiles were performed by ultra-high-performance liquid chromatography combined with quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS). Meanwhile, the potential anti-melanogenic active constituents were temporary identified by molecular docking.

Results

The 95% ethanol extract of B. striata fibrous roots (EFB) possessed the strongest DPPH, ABTS, FRAP and tyrosinase inhibitory activities, with IC50 5.94 mg/L, 11.69 mg/L, 6.92 mmol FeSO4/g, and 58.92 mg/L, respectively. In addition, EFB and 95% ethanol extract of B. striata tuber (ETB) significantly reduced the melanin synthesis of zebrafish embryos in a dose-dependent manner. 39 chemical compositions, including 24 stilbenoids were tentatively identified from EFB and ETB. Molecular docking indicated that there were 83 (including 60 stilbenoids) and 85 (including 70 stilbenoids) compounds exhibited stronger binding affinities toward tyrosinase and adenylate cyclase.

Conclusion

The present findings supported the rationale for the use of EFB and ETB as natural skin-whitening agents in pharmaceutical and cosmetic industries.