bluuebunny/crossref_metadata_2025 huggingface dataset:
Supradiaphragmatic central venous catheter malposition detection using the parasternal long-axis echocardiographic view and dextrose 50% contrast solution: A pilot study
Authors: Che Rahim Mohd Jazman , Abdull Wahab Shaik Farid , Fauzi Mohd Hashairi , Nadarajan Chandran , Ab Hamid Siti Azrin
Published: October 2021

Background

Contrast-enhanced ultrasonography (CEUS) using saline was studied to detect supradiaphragmatic central venous catheter malposition. Commonly used echocardiographic views are apical 4-chamber (A4c) and subcostal views. However, this standard method is not feasible in certain situations. We explored the feasibility of the right ventricle inflow parasternal long axis (RVI-PLAX) echocardiographic view and dextrose 50% (D50%) contrast solution for detecting supradiaphragmatic central venous catheter malposition.

Method

This pilot study screened 60 patients who underwent ultrasound-guided supradiaphragmatic central venous catheter insertion. We compared the investigators' guidewire's J-tip detection, D50% rapid atrial swirl sign (RASS) findings on the RVI-PLAX view and the central venous catheter tip on chest radiograph. We also compared the mean capillary blood sugar level before and after the 5 ml D50% flush.

Results

No guidewire J-tips were detected from the RVI-PLAX view. The first and second investigators’ diagnosis of central venous catheter malposition detected on RVI-PLAX CEUS achieved an almost perfect agreement (κ = 1.0 (95% confidence interval (CI): 0.90 to 1.0), p < .0001). The RVI-PLAX CEUS was not able to detect two central venous catheter malpositions (one atrial malposition and one left brachiocephalic vein venous catheter malposition). The capillary blood sugar was significantly elevated (8.96 mmol/L vs. 9.75 mmol/L) after D50% flush ( p < 0.005) with no complications reported within 30 minutes after the D50% flush.

Conclusion

RVI-PLAX view should not be used for guidewire detection. CEUS using D50% and RVI-PLAX view are potentially useful tools in detecting central venous catheter malposition. Further studies comparing them with conventional methods are needed.
Quality-of-care comparison of stroke: The reliability and robustness of ranking by process or outcome measures
Authors: Li Jingkun , Qu Peng , Wang Chao , Li Xi , Hou Shuang , Liu Meina
Published: October 2021

Background and aim

Discussion on the most rational types of performance measures for care quality comparisons has received increasing attention. The important consideration is to what extent will the measure detect a genuine difference in the underlying quality. In this study, we aimed to compare the ranking of hospitals on the performance of individual indicators, composite scores (CS, that were calculated by the method of opportunity-based score on patient-level), and in-hospital outcome of acute ischemic stroke across hospitals, and determined the reliability and robustness of the three types of ranking.

Methods

We analyzed data from 15,090 patients diagnosed with acute ischemic stroke who were treated at 184 large tertiary hospitals from January 2014 to May 2017. We ranked the hospital effects of recombinant tissue plasminogen activator (rt-PA) and CS and independence (modified Rankin Scale ≤2) at discharge based on fixed- and random-effects regression models before and after case-mix adjustment. We assessed the time-robustness of the hospital effects and calculated the rankability by relating the uncertainty within the hospital and the total hospital variation “beyond chance.”

Results

After case-mix and reliability adjustment, we estimated that 84.03% of the variance in CS between hospitals was due to true quality differences. The uncertainty within hospitals caused a poor (49.51%) rankability in rt-PA and moderate rankability (63.34%) in independence at discharge. The hospital rankings of CS were more robust across years compared with rt-PA and independence.

Conclusions

Our data indicated that CS is the optimal measure to indicate the quality-of-care variation of acute ischemic stroke between hospitals.
Zanubrutinib monotherapy for relapsed or refractory non-germinal center diffuse large B-cell lymphoma
Authors: Yang Haiyan , Xiang Bing , Song Yuqin , Zhang Huilai , Zhao Weili , Zou Dehui , Lv Fangfang , Guo Wei , Liu Aichun , Li Caixia , Tan Ziwen , Liu Yang , Fu Lina , Guo Haiyi , Novotny William , Huang Jane , Li Yufu
Published: October 2021

The non-germinal center B-cell like (non-GCB) subtype of diffuse large B-cell lymphoma (DLBCL) has poor clinical outcomes. Bruton tyrosine kinase (BTK) inhibitors have established therapeutic activity in B-cell malignancies, with modest activity in DLBCL. Zanubrutinib, a potent and selective BTK inhibitor, was evaluated in patients with relapsed or refractory (R/R) non-GCB DLBCL. The BGB-3111-207 study (NCT03145064) was a multicenter single-arm phase 2 study. Patients received twice-daily oral zanubrutinib, 160 mg, until disease progression or unacceptable toxicity. The primary end point was the overall response rate (ORR). Secondary end points included progression-free survival (PFS) and duration of response (DOR). Overall survival (OS) was an exploratory end point. Forty-one patients were enrolled in China after having progressed or not responded to prior therapy. At data cutoff, 4 patients continued treatment with 37 discontinuations. The median follow-up was 6.8 months, the ORR was 29.3%, and the complete response rate was 17.1%. Median DOR, PFS, and OS were 4.5, 2.8, and 8.4 months, respectively. Adverse events (AEs) leading to treatment discontinuation were reported in 4 patients, and grade ≥ 3 AEs were reported in 48.8% of patients. Major hemorrhage, atrial fibrillation, and/or flutter were not observed. Zanubrutinib demonstrated modest antitumor activity in non-GCB DLBCL, like other BTK inhibitors, as well as a safety profile consistent with previous studies. Through retrospective biomarker testing, potential antitumor activity was observed in patients with both CD79B and MYD88 mutations, who have inferior outcomes to immunochemotherapy. Future studies of zanubrutinib in R/R non-GCB DLBCL will focus on developing mechanism-based treatment combinations and biomarker-driven patient selection.
Anti-CD25 radioimmunotherapy with BEAM autologous hematopoietic cell transplantation conditioning in Hodgkin lymphoma
Authors: Herrera Alex F. , Palmer Joycelynne , Adhikarla Vikram , Yamauchi Dave , Poku Erasmus K. , Bading James , Yazaki Paul , Dandapani Savita , Mei Matthew , Chen Robert , Cao Thai , Karras Nicole , McTague Pamela , Nademanee Auayporn , Popplewell Leslie , Sahebi Firoozeh , Shively John E. , Simpson Jennifer , Smith D. Lynne , Song Joo , Spielberger Ricardo , Tsai Ni-Chun , Thomas Sandra H. , Forman Stephen J. , Colcher David , Wu Anna M. , Wong Jeffrey , Smith Eileen
Published: October 2021

High-risk relapsed or refractory (R/R) classical Hodgkin lymphoma (HL) is associated with poor outcomes after conventional salvage therapy and autologous hematopoietic cell transplantation (AHCT). Post-AHCT consolidation with brentuximab vedotin (BV) improves progression-free survival (PFS), but with increasing use of BV early in the treatment course, the utility of consolidation is unclear. CD25 is often expressed on Reed-Sternberg cells and in the tumor microenvironment in HL, and we hypothesized that the addition of 90Y-antiCD25 (aTac) to carmustine, etoposide, cytarabine, melphalan (BEAM) AHCT would be safe and result in a transplantation platform that is agnostic to prior HL-directed therapy. Twenty-five patients with high-risk R/R HL were enrolled in this phase 1 dose-escalation trial of aTac-BEAM. Following an imaging dose of 111In-antiCD25, 2 patients had altered biodistribution, and a third developed an unrelated catheter-associated bacteremia; therefore, 22 patients ultimately received therapeutic 90Y-aTac-BEAM AHCT. No dose-limiting toxicities were observed, and 0.6 mCi/kg was deemed the recommended phase 2 dose, the dose at which the heart wall would not receive >2500 cGy. Toxicities and time to engraftment were similar to those observed with standard AHCT, though 95% of patients developed stomatitis (all grade 1-2 per Bearman toxicity scale). Seven relapses (32%) were observed, most commonly in patients with ≥3 risk factors. The estimated 5-year PFS and overall survival probabilities among 22 evaluable patients were 68% and 95%, respectively, and non-relapse mortality was 0%. aTac-BEAM AHCT was tolerable in patients with high-risk R/R HL, and we are further evaluating the efficacy of this approach in a phase 2 trial. This trial was registered at www.clinicaltrials.gov as #NCT01476839.
Assessment of romiplostim immunogenicity in pediatric patients in clinical trials and in a global postmarketing registry
Authors: Bowers Charles , Mytych Daniel T. , Lawrence Tatiana , Wang Kejia , Barger Troy E. , Eisen Melissa , Bennett Carolyn M. , Tarantino Michael D.
Published: October 2021

Development of first-generation thrombopoietins (TPOs) was halted due to antibodies that neutralized endogenous TPO, causing protracted thrombocytopenia in some patients. The second-generation TPO receptor agonist romiplostim, having no homology to TPO, was developed to circumvent potential immunogenicity. We examined the development of binding and neutralizing antibodies to romiplostim and TPO among pediatric patients with primary immune thrombocytopenia (ITP) in 5 clinical trials and a global postmarketing registry. In the trials, 25 of 280 (8.9%) patients developed anti-romiplostim binding antibodies. The first positive result was detected 67 weeks (median) after romiplostim treatment was initiated. The median romiplostim dose was 8 µg/kg, and the median platelet count was 87 × 109/L. Most patients who developed anti-romiplostim binding antibodies (18 of 25 [72%]) had ≥90% of platelet assessments showing a response. Anti-romiplostim neutralizing antibodies developed in 8 of 280 (2.9%) patients. The development of anti-romiplostim neutralizing antibodies was unrelated to the romiplostim dose, and most patients who developed the antibodies (7 of 8 [88%]) had platelet response. Nine of 279 (3.2%) patients developed anti-TPO binding antibodies, and 1 (0.4%) developed transient anti-TPO neutralizing antibodies. In 8 patients who developed anti-romiplostim neutralizing antibodies, no TPO cross-reactivity was observed. In the postmarketing registry, 3 of 19 (15.8%) patients developed anti-romiplostim binding antibodies; 1 (5.3%) patient developed anti-romiplostim neutralizing antibodies. These results suggest that immunogenicity to romiplostim occurs infrequently in pediatric patients with ITP and is generally not associated with loss of platelet response or other negative clinical sequelae.
GATA2 deficiency phenotype associated with tandem duplication of GATA2 and overexpression of GATA2-AS1
Authors: Singh Preeti , Heer Maninder , Resteu Anastasia , Mikulasova Aneta , Reza Mojgan , Largeaud Laëtitia , Dufrechou Stéphanie , Prade Naïs , Dickinson Rachel E. , Bustamante Jacinta , Neven Bénédicte , Bigley Venetia , Delabesse Eric , Rico Daniel , Pasquet Marlène , Collin Matthew
Published: October 2021

A 3-year-old girl of nonconsanguineous healthy parents presented with cervical and mediastinal lymphadenopathy due to Mycobacterium fortuitum infection. Routine blood analysis showed normal hemoglobin, neutrophils, and platelets but profound mononuclear cell deficiency (monocytes < 0.1 × 109/L; B cells 78/μL; NK cells 48/μL). A 548 902-bp region containing GATA2 was sequenced by targeted capture and deep sequencing. This revealed a de novo 187-kb duplication of the entire GATA2 locus, containing a maternally inherited copy number variation deletion of 25 kb (GRCh37: esv2725896 and nsv513733). Many GATA2-associated phenotypes have been attributed to amino acid substitution, frameshift/deletion, loss of intronic enhancer function, or aberrant splicing. Gene deletion has been described, but other structural variation has not been reported in the germline configuration. In this case, duplication of the GATA2 locus was paradoxically associated with skewed diminished expression of GATA2 messenger RNA and loss of GATA2 protein. Chimeric RNA fusion transcripts were not detected. A possible mechanism involves increased transcription of the anti-sense long noncoding RNA GATA2-AS1 (RP11-472.220), which was increased several fold. This case further highlights that evaluation of the allele count is essential in any case of suspected GATA2-related syndrome.
TheCADM1tumor suppressor gene is a major candidate gene in MDS with deletion of the long arm of chromosome 11
Authors: Lafage-Pochitaloff Marina , Gerby Bastien , Baccini Véronique , Largeaud Laetitia , Fregona Vincent , Prade Naïs , Juvin Pierre-Yves , Jamrog Laura , Bories Pierre , Hébrard Sylvie , Lagarde Stéphanie , Mansat-De Mas Véronique , Dovey Oliver M. , Yusa Kosuke , Vassiliou George S. , Jansen Joop H. , Tekath Tobias , Rombaut David , Ameye Geneviève , Barin Carole , Bidet Audrey , Boudjarane John , Collonge-Rame Marie-Agnès , Gervais Carine , Ittel Antoine , Lefebvre Christine , Luquet Isabelle , Michaux Lucienne , Nadal Nathalie , Poirel Hélène A. , Radford-Weiss Isabelle , Ribourtout Bénédicte , Richebourg Steven , Struski Stéphanie , Terré Christine , Tigaud Isabelle , Penther Dominique , Eclache Virginie , Fontenay Michaela , Broccardo Cyril , Delabesse, Eric
Published: October 2021

Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis leading to peripheral cytopenias and in a substantial proportion of cases to acute myeloid leukemia. The deletion of the long arm of chromosome 11, del(11q), is a rare but recurrent clonal event in MDS. Here, we detail the largest series of 113 cases of MDS and myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) harboring a del(11q) analyzed at clinical, cytological, cytogenetic, and molecular levels. Female predominance, a survival prognosis similar to other MDS, a low monocyte count, and dysmegakaryopoiesis were the specific clinical and cytological features of del(11q) MDS. In most cases, del(11q) was isolated, primary and interstitial encompassing the 11q22-23 region containing ATM, KMT2A, and CBL genes. The common deleted region at 11q23.2 is centered on an intergenic region between CADM1 (also known as Tumor Suppressor in Lung Cancer 1) and NXPE2. CADM1 was expressed in all myeloid cells analyzed in contrast to NXPE2. At the functional level, the deletion of Cadm1 in murine Lineage-Sca1+Kit+ cells modifies the lymphoid-to-myeloid ratio in bone marrow, although not altering their multilineage hematopoietic reconstitution potential after syngenic transplantation. Together with the frequent simultaneous deletions of KMT2A, ATM, and CBL and mutations of ASXL1, SF3B1, and CBL, we show that CADM1 may be important in the physiopathology of the del(11q) MDS, extending its role as tumor-suppressor gene from solid tumors to hematopoietic malignancies.
Non-coding RNA in raw and commercially processed milk and putative targets related to growth and immune-response
Authors: Shome S. , Jernigan R. L. , Beitz D. C. , Clark S. , Testroet E. D.
Published: October 2021

Background

Bovine milk contains extracellular vesicles (EVs) that play a role in cellular communication, acting in either an autocrine, paracrine, or an exocrine manner. The unique properties of the EVs protect the cargo against degradation. We profiled the ncRNAs (non-coding RNA) present in the EVs from seven dairy products - raw whole milk, heat-treated skim milk, homogenized heat-treated skim milk, pasteurized homogenized skim milk, pasteurized heavy whipping cream, sweet cream buttermilk and cultured buttermilk with four replicates each, obtained at different processing steps from a commercial dairy plant. EVs and their cargo were extracted by using a validated commercial kit that has been shown to be efficient and specific for EVs. Further, to find the annotation of ncRNAs, we probed bovine and other organism repositories(such as miRBase, miRTarBase, Ensemble) to find homolog ncRNA annotation in case the annotations of ncRNA are not available in Bos Taurus database.

Results

Specifically, 30 microRNAs (miRNAs), were isolated throughout all the seven milk samples, which later when annotated with their corresponding 1546 putative gene targets have functions associated with immune response and growth and development. This indicates the potential for these ncRNAs to beneficially support mammary health and growth for the cow as well as neonatal gut maturation. The most abundant miRNAs were bta-miR-125a and human homolog miR-718 based on the abundance values of read count obtained from the milk samples.bta-miR-125a is involved in host bacterial and viral immune response, and human homolog miR-718 is involved in the regulation of p53, VEGF, and IGF signaling pathways, respectively.

Sixty-two miRNAs were up-regulated and 121 miRNAs were down-regulated throughout all the milk samples when compared to raw whole milk. In addition, our study explored the putative roles of other ncRNAs which included 88 piRNAs (piwi-interacting RNA), 64 antisense RNAs, and 105 lincRNAs (long-intergenic ncRNAs) contained in the bovine exosomes.

Conclusion

Together, the results indicate that bovine milk contains significant numbers of ncRNAs with putative regulatory targets associated with immune- and developmental-functions important for neonatal bovine health, and that processing significantly affects the ncRNA expression values; but statistical testing of overall abundance(read counts) of all miRNA samples suggests abundance values aren’t much affected. This can be attributed to the breakage of exosomal vesicles during the processing stages. It is worth noting, however, that these gene regulatory targets are putative, and further evidence could be generated through experimental validation.
Are morbidity and mortality estimates from randomized controlled trials externally valid? A comparison of outcomes among infants enrolled into an RCT or a cohort study in Botswana
Authors: Thivalapill Neil , Lockman Shahin , Powis Kathleen , Zash Rebecca , Leidner Jean , Ajibola Gbolahan , Mmalane Mompati , Makhema Joseph , Shapiro Roger L.
Published: October 2021

Background

The external validity of the randomized controlled trial (RCT) refers to the extent to which the results of the RCT apply to the relevant, non-trial population and is impacted by its eligibility criteria, its organization, and its delivery of the intervention. Here, we compared the outcomes of mortality and hospitalization between an RCT and a cohort study that concurrently enrolled HIV-exposed uninfected (HEU) newborns in Botswana.

Methods

The Mpepu Study (the RCT) was a clinical trial which determined that co-trimoxazole (CTX) provided no survival benefit for HEUs, allowing both arms of the RCT to be used. The Maikaelelo study (the cohort study) was a prospective observational study that enrolled HEU newborns with telephone follow-up and no in-person visits. Rates of death and hospitalization in the pooled population, were modeled using cox-proportional hazards models for time to death or time to first hospitalization, with study setting (RCT vs. cohort study) as an independent variable. The causal effect of study setting on morbidity and mortality was obtained through a treatment effects approach.

Results

In total, 4,010 infants were included; 1,306 were enrolled into the cohort study and 2,704 were enrolled into the RCT. No significant differences in mortality were observed between the two study settings (HR: 1.28, 95% CI: 0.76, 2.13), but RCT participants had a lower risk of hospitalization (HR: 0.72, 95% CI: 0.58, 0.89) that decreased with age. However, RCT participants had a higher risk of hospitalization within the first six months of life. The causal risk difference in hospitalizations attributable to the RCT setting was -0.03 (95% CI: -0.05, -0.01).

Conclusions

Children in an RCT with rigorous application of national standard of care guidelines experienced a significantly lower risk of hospitalization than children participating in a cohort study that did not alter clinical care. Future research is needed to further investigate outcome disparities when real-world results fail to mirror those achieved in a clinical trial.

Trial registration

The Mpepu Trial was funded by the U.S. National Institutes of Health (No. NCT01229761) and the Maikaelelo Study was funded primarily by the U.S. Centers for Disease Control and Prevention (32AI007433-21).
Predictive P-score for treatment ranking in Bayesian network meta-analysis
Authors: Rosenberger Kristine J. , Duan Rui , Chen Yong , Lin Lifeng
Published: October 2021

Background

Network meta-analysis (NMA) is a widely used tool to compare multiple treatments by synthesizing different sources of evidence. Measures such as the surface under the cumulative ranking curve (SUCRA) and the P-score are increasingly used to quantify treatment ranking. They provide summary scores of treatments among the existing studies in an NMA. Clinicians are frequently interested in applying such evidence from the NMA to decision-making in the future. This prediction process needs to account for the heterogeneity between the existing studies in the NMA and a future study.

Methods

This article introduces the predictive P-score for informing treatment ranking in a future study via Bayesian models. Two NMAs were used to illustrate the proposed measure; the first assessed 4 treatment strategies for smoking cessation, and the second assessed treatments for all-grade treatment-related adverse events. For all treatments in both NMAs, we obtained their conventional frequentist P-scores, Bayesian P-scores, and predictive P-scores.

Results

In the two examples, the Bayesian P-scores were nearly identical to the corresponding frequentist P-scores for most treatments, while noticeable differences existed for some treatments, likely owing to the different assumptions made by the frequentist and Bayesian NMA models. Compared with the P-scores, the predictive P-scores generally had a trend to converge toward a common value of 0.5 due to the heterogeneity. The predictive P-scores’ numerical estimates and the associated plots of posterior distributions provided an intuitive way for clinicians to appraise treatments for new patients in a future study.

Conclusions

The proposed approach adapts the existing frequentist P-score to the Bayesian framework. The predictive P-score can help inform medical decision-making in future studies.
GoodReports: developing a website to help health researchers find and use reporting guidelines
Authors: Struthers Caroline , Harwood James , de Beyer Jennifer Anne , Dhiman Paula , Logullo Patricia , Schlüssel Michael
Published: October 2021

Background

Th EQUATOR Network improves the quality and transparency in health research, primarily by promoting awareness and use of reporting guidelines. In 2018, the UK EQUATOR Centre launched GoodReports.org, a website that helps authors find and use reporting guidelines. This paper describes the tool’s development so far. We describe user experience and behaviour of using GoodReports.org both inside and outside a journal manuscript submission process. We intend to use our findings to inform future development and testing of the tool.

Methods

We conducted a survey to collect data on user experience of the GoodReports website. We cross-checked a random sample of 100 manuscripts submitted to a partner journal to describe the level of agreement between the tool’s checklist recommendation and what we would have recommended. We compared the proportion of authors submitting a completed reporting checklist alongside their manuscripts between groups exposed or not exposed to the GoodReports tool. We also conducted a study comparing completeness of reporting of manuscript text before an author received a reporting guideline recommendation from GoodReports.org with the completeness of the text subsequently submitted to a partner journal.

Results

Seventy percent (423/599) of survey respondents rated GoodReports 8 or more out of 10 for usefulness, and 74% (198/267) said they had made changes to their manuscript after using the website. We agreed with the GoodReports reporting guideline recommendation in 84% (72/86) of cases. Of authors who completed the guideline finder questionnaire, 14% (10/69) failed to submit a completed checklist compared to 30% (41/136) who did not use the tool. Of the 69 authors who received a GoodReports reporting guideline recommendation, 20 manuscript pairs could be reviewed before and after use of GoodReports. Five included more information in their methods section after exposure to GoodReports. On average, authors reported 57% of necessary reporting items before completing a checklist on GoodReports.org and 60% after.

Conclusion

The data suggest that reporting guidance is needed early in the writing process, not at submission stage. We are developing GoodReports by adding more reporting guidelines and by creating editable article templates. We will test whether GoodReports users write more complete study reports in a randomised trial targeting researchers starting to write health research articles.
Employing multiple synchronous outcome samples per subject to improve study efficiency
Authors: A’Hern Roger P.
Published: October 2021

Background

Accuracy can be improved by taking multiple synchronous samples from each subject in a study to estimate the endpoint of interest if sample values are not highly correlated. If feasible, it is useful to assess the value of this cluster approach when planning studies. Multiple assessments may be the only method to increase power to an acceptable level if the number of subjects is limited.

Methods

The main aim is to estimate the difference in outcome between groups of subjects by taking one or more synchronous primary outcome samples or measurements. A summary statistic from multiple samples per subject will typically have a lower sampling error. The number of subjects can be balanced against the number of synchronous samples to minimize the sampling error, subject to design constraints. This approach can include estimating the optimum number of samples given the cost per subject and the cost per sample.

Results

The accuracy improvement achieved by taking multiple samples depends on the intra-class correlation (ICC). The lower the ICC, the greater the benefit that can accrue. If the ICC is high, then a second sample will provide little additional information about the subject’s true value. If the ICC is very low, adding a sample can be equivalent to adding an extra subject. Benefits of multiple samples include the ability to reduce the number of subjects in a study and increase both the power and the available alpha. If, for example, the ICC is 35%, adding a second measurement can be equivalent to adding 48% more subjects to a single measurement study.

Conclusion

A study’s design can sometimes be improved by taking multiple synchronous samples. It is useful to evaluate this strategy as an extension of a single sample design. An Excel workbook is provided to allow researchers to explore the most appropriate number of samples to take in a given setting.
Short-term aspirin and statin chemoprophylaxis did not reduce the risk of developing advanced adenomatous polyps in Black patients
Authors: Renelus Benjamin D. , Dixit Devika , Nguyen Phuong T. , Njoku Kingsley K. , Patel Parth B. , Pintor-Jimenez Katiria , Yan Fengxia , Buscaglia Jonathan M. , Woods Kevin E. , Jamorabo Daniel S.
Published: October 2021

Background

Chemoprevention of colorectal neoplasia with aspirin and statins is under-investigated in Black patients. Since Black patients suffer disproportionately from colon cancer incidence and mortality compared to other populations, we investigated the utility of aspirin and statin in reducing advanced adenomatous polyp (AAP) risk in Black patients.

Methods

We carried out a retrospective cohort study of screening colonoscopies performed at a large urban academic center from 1/1/2011 through 12/31/2019. We analyzed self-identified Black patients with > 1 colonoscopy and no personal history of either inflammatory bowel disease or colon cancer syndromes. Our primary endpoint was first AAP development after index colonoscopy among Black patients taking both aspirin and a statin compared to those taking one or neither medication. We used multivariate logistic regression modeling to investigate our outcomes.

Results

We found data on chemoprophylaxis use in 560 patients. The mean observation period between index colonoscopy and AAP identification was 4 years. AAP developed in 106/560 (19%) of our cohort. We found no difference in AAP risk among Black patients taking both chemoprevention medications compared to partial or no chemoprophylaxis (20% vs 18% respectively, p = 0.49). This finding remained after adjusting for age, body mass index, and tobacco use (odds ratio 1.04, 95% CI 0.65–1.67; p = 0.87).

Conclusions

Short-term aspirin-statin chemoprevention did not reduce the risk of AAP development in our cohort of Black patients. Larger and long-term prospective investigations are needed to investigate the utility of chemoprophylaxis in this population.

Trial Registration: Not applicable.
Tryptophan metabolism induced by TDO2 promotes prostatic cancer chemotherapy resistance in a AhR/c-Myc dependent manner
Authors: Li Fan , Zhao Zhenyu , Zhang Zongbiao , Zhang Yan , Guan Wei
Published: October 2021

Background

Tumor cells exhibit enhanced metabolism of nutrients to satisfy the demand of sustained proliferation in vivo. Seminal reports have presented evidence that tryptophan (Trp) metabolic reprogramming induced by aberrant indoleamine 2,3-dioxygenases could promote tumor development in several cancer types. However, the underlying mechanism of Trp metabolism associated tumor progression is not fully understood.

Materials and methods

Prostatic cell lines LNCaP and VCaP were purchased from the Cell Bank of the Chinese Academy of Sciences (China). Human prostatic tumor tissue samples were obtained from the Tongji Hospital. Female NOD-SCID mice (6 ~ 8 weeks) were purchased from Huafukang Co. (China) and raised in SPF room. Commercial kits and instruments were used for cell apoptosis analysis, real-time PCR, western blotting, ELISA analysis and other experiments.

Result

Comparing the tumor tissues from prostatic cancer patients, we found elevated expression of tryptophan 2, 3-dioxygenase 2 (TDO2), and elevated Trp metabolism in chemo-resistant tumor tissues. In vitro, overexpression of TDO2 significantly promoted the Trp metabolism in prostatic cancer cell lines LNCaP and VCap, resulting in the multidrug resistance development. Mechanistically, we demonstrated that Trp metabolite kynurenine (Kyn) promoted the upregulation and nuclear translocation of transcription factor aryl hydrocarbon receptor (AhR). Subsequently, AhR collaborated with NF-κB to facilitate the activation of c-Myc. In turn, c-Myc promoted the up-regulation of ATP-binding cassette (ABC) transporters and Trp transporters, thereby contributing to chemoresistance and strengthened Trp metabolism in prostatic cancer. Interrupt of Trp/TDO2/Kyn/AhR/c-Myc loop with c-Myc inhibitor Mycro-3 efficiently suppressed the chemoresistance and improved the outcome of chemotherapy, which described a new strategy in clinical prostatic cancer treatment.

Conclusion

Our study demonstrates that elevated TOD2 expression promoted Trp metabolism and metabolite Kyn production, thus resulting in the activation of AhR/c-Myc/ABC-SLC transporters signaling pathway. Interrupt of Trp metabolism/c-Myc loop efficiently suppressed the drugs resistance induced by TDO2, which represented potential target to improve the outcome in drug-resistant prostatic cancer treatment.
Correction to: Differences in myoelectric activity of the lumbar muscles between recurrent and chronic low back pain: a cross-sectional study
Authors: Balasch-Bernat Mercè , Willems Tine , Danneels Lieven , Meeus Mira , Goubert Dorien
Published: October 2021

An amendment to this paper has been published and can be accessed via the original article.
The healthy behaviours and COVID-19 mortality among Iranian women: a case–control study
Authors: Pourfarzi Farhad , Rahim Pouran Shima , Dargahi Abdollah , Karami Chiman , Fouladi Nasrin , Zandian Hamed , Zahirian Moghadam Telma
Published: October 2021

Background

Women are among the susceptible groups to Coronavirus disease-19 (COVID-19) in Ardabil, north-west of Iran, despite the current global status. The underlying causes of high incidence and fatality rate of women in Ardabil are not fully understood. Hence, this study aimed to investigate the healthy behaviours in women of Ardabil and its relationship with COVID-19 mortality.

Methods

We conducted a case–control study to compare the adherence to health protocols and behaviours with respect to COVID-19 between the infected (261 patients) and healthy (515 persons) women. Health protocols and behaviours such as using mask, gloves, disinfectants, history of travelling and contacting, and attending various gatherings and places during the COVID-19 pandemic along with demographic variables were defined as independent variables, and COVID-19 death rate was defined as the dependent variable. Multivariable logistic regression methods were used to explore the risk factors associated with COVID-19 mortality.

Results

Chi-square and Fisher tests showed significant differences between infected and healthy women in terms of history of contact and traveling (p < 0.05), wearing mask (p < 0.001), going to work place (p < 0.001), and attend public gatherings (p = 0.038). Multivariable logistic regression disclosed that the age group over 80 years: 8.97 times (95% CI 2.27–29.85), women with underlying chronic diseases: 4.14 times (95% CI 1.61–10.64), and obese women: 3.01 times (95% CI 1.04–6.03) were more likely to die from COVID-19 than other women.

Conclusion

Considering the high incidence and mortality rate in Ardabil women due to COVID-19 and the corresponding health behavioural factors, special emphasis should be given to the increase of women awareness on the importance of healthy behaviours, diet, and life-style.
Constitutive TDO2 expression promotes liver cancer progression by an autocrine IL-6 signaling pathway
Authors: Wu Zhengzhong , Yan Leye , Lin Junqing , Ke Kun , Yang Weizhu
Published: October 2021

Background

Increased tryptophan (Trp) metabolism by indoleamine 2,3-dioxygenase (IDO)/tryptophan 2,3-dioxygenase (TDO) represents one of the most studied pathways for immunosuppression in tumor tissues. However, the pro-tumor effects induced by Trp metabolism remain controversial.

Methods

The paraffin sections of tumor tissues were obtained from patients with liver cancer and examined by immunohistochemical staining to investigate the role of Trp metabolic enzymes. To further confirm the pro-tumor effects induced by TDO2, we established TDO2 overexpression SMC-7721 and HepG2 liver cancer cell lines, and western blotting, cell proliferation, and colony formation were evaluated. Meanwhile, liver cancer subcutaneous mice models were established, and the tumorigenic rates of SMC-7721 cells, tumor volume and survival of bearing mice were calculated. In addition, the survival data of liver cancer patients from The Cancer Genome Atlas (TCGA) database were downloaded to analyze the effect of TDO2 expression on the survival of patients with liver cancer.

Results

Here, we showed that constitutive TDO2 expression gave rise to liver cancer through upregulation of Trp metabolism. And the TDO2 expression was positively correlated with the poor prognosis in liver cancer patients. TDO2 expression in tumor cells accounted for the release of kynurenine (Kyn), which activated aryl hydrocarbon receptor (AhR) to promote liver cancer cells proliferation. Mechanistically, we found that AhR expression contributed to the secretion of Interleukin-6 (IL-6), thereby promoting tumor cells proliferation through the STAT3 and NF-kB/TIM4 signals. Interrupt of AhR signals by PDM2 revealed improved outcomes in subcutaneous tumor-bearing mice.

Conclusions

Together, our study showed that the TDO2/Kyn/AhR/IL-6 signaling pathway was a novel mechanism underlying the malignancy of liver cancer, and suggested that AhR signals might be a valuable therapeutic target for tumor therapy.
Purification of native histidine-rich protein 2 (nHRP2) from Plasmodium falciparum culture supernatant, infected RBCs, and parasite lysate
Authors: Singh Balwan , McCaffery Jessica N. , Kong Amy , Ah Yong , Wilson Scott , Chatterjee Sayan , Tomar Deepak , Aidoo Michael , Udhayakumar Venkatachalam , Rogier Eric
Published: October 2021

Background

Despite the widespread use of histidine-rich protein 2 (HRP2)-based rapid diagnostic tests (RDTs), purified native HRP2 antigen is not standardly used in research applications or assessment of RDTs used in the field.

Methods

This report describes the purification of native HRP2 (nHRP2) from the HB3 Plasmodium falciparum culture strain. As this culture strain lacks pfhrp3 from its genome, it is an excellent source of HRP2 protein only and does not produce the closely-related HRP3. The nHRP2 protein was isolated from culture supernatant, infected red blood cells (iRBCs), and whole parasite lysate using nickel-metal chelate chromatography. Biochemical characterization of nHRP2 from HB3 culture was conducted by SDS-PAGE and western blotting, and nHRP2 was assayed by RDT, ELISA, and bead-based immunoassay.

Results

Purified nHRP2 was identified by SDS-PAGE and western blot as a − 60 kDa protein that bound anti-HRP-2 monoclonal antibodies. Mouse anti-HRP2 monoclonal antibody was found to produce high optical density readings between dilutions of 1:100 and 1:3,200 by ELISA with assay signal observed up to a 1:200,000 dilution. nHRP2 yield from HB3 culture by bead-based immunoassay revealed that both culture supernatant and iRBC lysate were practical sources of large quantities of this antigen, producing a total yield of 292.4 µg of nHRP2 from two pooled culture preparations. Assessment of nHRP2 recognition by RDTs revealed that Carestart Pf HRP2 and HRP2/pLDH RDTs detected purified nHRP2 when applied at concentrations between 20.6 and 2060 ng/mL, performing within a log-fold dilution of commercially-available recombinant HRP2. The band intensity observed for the nHRP2 dilutions was equivalent to that observed for P. falciparum culture strain dilutions of 3D7 and US06 F Nigeria XII between 12.5 and 1000 parasites/µL.

Conclusions

Purified nHRP2 could be a valuable reagent for laboratory applications as well as assessment of new and existing RDTs prior to their use in clinical settings. These results establish that it is possible to extract microgram quantities of the native HRP2 antigen from HB3 culture and that this purified protein is well recognized by existing monoclonal antibody lines and RDTs.

Graphical Abstract
Generating evidence on the use of Image and performance enhancing drugs in the UK: results from a scoping review and expert consultation by the Anabolic Steroid UK network
Authors: McVeigh Jim , Hearne Evelyn , Boardley Ian , Bates Geoff , Hope Vivian , Ralphs Rob , Van Hout Marie Claire
Published: October 2021

Background

The use of anabolic androgenic steroids (AAS) and associated image and performance enhancing drugs (IPEDs) is now a global phenomenon. There is a need to develop evidence to support the development of interventions to prevent the commencement of use, to minimise the potential harms or to support those in their cessation of use. While the United Kingdom (UK) is no exception to this issue, its public health and legislative response to the phenomenon differs to other countries and requires the examination of research specific to the UK. Therefore, a scoping review has been conducted to examine the recent relevant literature to help inform the development and evaluation of effective interventions to reduce the harmful use of IPEDs.

Methods

A comprehensive search strategy was developed for multiple bibliographic databases, supported by and iterative citation searching process and complimented by expert input from the Anabolic Steroid UK Network. Research conducted by or UK academics or within the UK were eligible, if published in the previous five years.

Results

In total 87 eligible outputs were identified, including 26 review articles, 25 qualitative papers and 24 quantitative papers. together with small numbers of clinical studies/case reports (6) and commentaries/correspondence (6). The most common topics of research were public health, treatment and harm reduction (41), followed by studies focusing on epidemiology, sub-groups of people using IPEDs and motivations for use (34). The studies illustrated the diverse populations of people who use a range of enhancement drugs including concomitant psychoactive drug use. A number of papers focused on blood borne viruses and associated issues, while others reported on the uptake of needle and syringe programmes. No effectiveness evaluations related to any aspect of treatment, harm reduction or other intervention were published during study period.

Conclusion

There is a need for the development of effectiveness evaluations of current interventions and any future service provision for people using image and performance enhancing drugs. While there have been no studies of this nature to date, this review illustrates the rich data that has been gathered through diverse methodologies, that will assist in the development of future effectiveness evaluations.
MiR-144-3p inhibits gastric cancer progression and stemness via directly targeting GLI2 involved in hedgehog pathway
Authors: Lu Yixun , Zhang Benlong , Wang Baohua , Wu Di , Wang Chuang , Gao Yunhe , Liang Wenquan , Xi Hongqing , Wang Xinxin , Chen Lin
Published: October 2021

Background

Gastric cancer (GC) is the fifth most commonly diagnosed cancer worldwide. Due to the dismal prognosis, identifying novel therapeutic targets in GC is urgently needed. Evidences have shown that miRNAs played critical roles in the regulation of tumor initiation and progression. GLI family zinc finger 2 (GLI2) has been reported to be up-regulated and facilitate cancer progression in multiple malignancies. In this study, we focused on identifying GLI2-targeted miRNAs and clarifying the underlying mechanism in GC.

Methods

Paired fresh gastric cancer tissues were collected from gastrectomy patients. GLI2 and miRNAs expression were detected in gastric cancer tissues and cell lines. Bioinformatics analysis was used to predict GLI2-targeted miRNAs and dual-luciferase reporter assay was applied for target verification. CCK-8, clone formation, transwell and flow cytometry were carried out to determine the proliferation, migration, invasion and cell cycle of gastric cancer cells. Tumorsphere formation assay and flow cytometry were performed to detail the stemness of gastric cancer stem cells (GCSCs). Xenograft models in nude mice were established to investigate the role of the miR-144-3p in vivo.

Results

GLI2 was frequently upregulated in GC and indicated a poor survival. Meanwhile, miR-144-3p was downregulated and negatively correlated with GLI2 in GC. GLI2 was a direct target gene of miR-144-3p. MiR-144-3p overexpression inhibited proliferation, migration and invasion of gastric cancer cells. Enhanced miR-144-3p expression inhibited tumorsphere formation and CD44 expression of GCSCs. Restoration of GLI2 expression partly reversed the suppressive effect of miR-144-3p. Xenograft assay showed that miR-144-3p could inhibit the tumorigenesis of GC in vivo.

Conclusions

MiR-144-3p was downregulated and served as an essential tumor suppressor in GC. Mechanistically, miR-144-3p inhibited gastric cancer progression and stemness by, at least in part, regulating GLI2 expression.
Comprehensive analysis of oncogenic fusions in mismatch repair deficient colorectal carcinomas by sequential DNA and RNA next generation sequencing
Authors: Wang Jing , Li Ruiyu , Li Junjie , Yi Yuting , Liu Xiaoding , Chen Jingci , Zhang Hui , Lu Junliang , Li Cami , Wu Huanwen , Liang Zhiyong
Published: October 2021

Background

Colorectal carcinoma (CRC) harboring oncogenic fusions has been reported to be highly enriched in mismatch repair deficient (dMMR) tumors with MLH1 hypermethylation (MLH1me+) and wild-type BRAF and RAS. In this study, dMMR CRCs were screened for oncogene fusions using sequential DNA and RNA next generation sequencing (NGS).

Results

Comprehensive analysis of fusion variants, genetic profiles and clinicopathological features in fusion-positive dMMR CRCs was performed. Among 193 consecutive dMMR CRCs, 39 cases were identified as MLH1me+BRAF/RAS wild-type. Eighteen fusion-positive cases were detected by DNA NGS, all of which were MLH1me+ and BRAF/RAS wild-type. RNA NGS was sequentially conducted in the remaining 21 MLH1me+BRAF/RAS wild-type cases lacking oncogenic fusions by DNA NGS, and revealed four additional fusions, increasing the proportion of fusion-positive tumors from 46% (18/39) to 56% (22/39) in MLH1me+BRAF/RAS wild-type dMMR cases. All 22 fusions were found to involve RTK-RAS pathway. Most fusions affected targetable receptor tyrosine kinases, including NTRK1(9/22, 41%), NTRK3(5/22, 23%), ALK(3/22, 14%), RET(2/22, 9%) and MET(1/22, 5%), whilst only two fusions affected mitogen-activated protein kinase cascade components BRAF and MAPK1, respectively. RNF43 was identified as the most frequently mutated genes, followed by APC, TGFBR2, ATM, BRCA2 and FBXW7. The vast majority (19/22, 86%) displayed alterations in key WNT pathway components, whereas none harbored additional mutations in RTK-RAS pathway. In addition, fusion-positive tumors were typically diagnosed in elder patients and predominantly right-sided, and showed a significantly higher preponderance of hepatic flexure localization (P < 0.001) and poor differentiation (P = 0.019), compared to fusion-negative MLH1me+ CRCs.

Conclusions

We proved that sequential DNA and RNA NGS was highly effective for fusion detection in dMMR CRCs, and proposed an optimized practical fusion screening strategy. We further revealed that dMMR CRCs harboring oncogenic fusion was a genetically and clinicopathologically distinctive subgroup, and justified more precise molecular subtyping for personalized therapy.
Moving for safety: a qualitative analysis of affected communities’ evacuation response during the 2014 Mayon Volcano eruption
Authors: Martinez-Villegas Ma. Mylene , Solidum Renato U. , Saludadez Jean A. , Pidlaoan Abigail C. , Lamela Ruben C.
Published: October 2021

This study looks at the 2014 Mayon Volcano eruption to identify possible factors that contribute to the actions that people (local authorities/officials, community leaders, and residents) take during an eruptive period. We used qualitative analysis to examine interviews of people who experienced the August–December 2014 Mayon Volcano unrest, to determine the nature of people’s understanding of hazards and risks, their decision-making, and response process. The thematic analysis shows that residents reacted to the information given to them in several ways- they evacuated when ordered (mandatory), chose not to evacuate for various reasons (e.g. they did not believe they are in danger citing experiences, inconvenience in evacuation sites, etc.), and evacuated even when not ordered to (voluntary). The local officials and community leaders were asked about their views on the possible reasons or motivations as to why residents would evacuate, and common themes that emerged were fear emanating from the experience of past eruptions, obeying the order to evacuate because it is the law, and order from provincial authorities (setting aside personal opinion on the state of the volcano based on experiential knowledge), and the potential to receive relief goods for those who are economically in need. This paper also looks at the challenges to local officials when an eruptive episode occurs- but the event falls short of the expected typical explosive behavior from the volcano. This study argues for people’s experiential knowledge as an important factor in shaping views about hazards and risks that leads to the decision-making of individuals and its importance in risk communication strategies.