Nevin Manimala

Cancer Res. 2021 Jun 18:canres.3543.2020. doi: 10.1158/0008-5472.CAN-20-3543. Online ahead of print.

ABSTRACT

ENO1 (α-enolase) expression is significantly correlated with reduced survival and poor prognosis in many cancer types, including lung cancer. However, the function of ENO1 in carcinogenesis remains elusive. In this study, we found that high expression of ENO1 is present in metastatic lung cancer cell lines and malignant tumors and is associated with poor overall survival of lung cancer patients. Knockdown of ENO1 decreased cancer cell proliferation and invasiveness, whereas overexpression of ENO1 enhanced these processes. Moreover, ENO1 expression promoted tumor growth in orthotopic models and enhanced lung tumor metastasis in tail-vein injection models. These effects were mediated by upregulation of mesenchymal markers N-cadherin and vimentin and the epithelial-mesenchymal transition (EMT) regulator SLUG, along with concurrent downregulation of E-cadherin. Mechanistically, ENO1 interacted with hepatocyte growth factor receptor (HGFR) and activated HGFR and Wnt signaling via increased phosphorylation of HGFR and the Wnt co-receptor LRP5/6. Activation of these signaling axes decreased GSK-3β activity via Src-PI3K-AKT signaling and inactivation of the β-catenin destruction complex to ultimately upregulate SLUG and β-catenin. Additionally, we generated a chimeric anti-ENO1 monoclonal antibody (chENO1-22) that can decrease cancer cell proliferation and invasion. chENO1-22 attenuated cancer cell invasion by inhibiting ENO1-mediated GSK3β inactivation to promote SLUG protein ubiquitination and degradation. Moreover, chENO1-22 prevented lung tumor metastasis and prolonged survival in animal models. Taken together, these findings illuminate the molecular mechanisms underlying the function of ENO1 in lung cancer metastasis and supports the therapeutic potential of a novel antibody targeting ENO1 for treating lung cancer.

PMID:34145039 | DOI:10.1158/0008-5472.CAN-20-3543

BMJ Open. 2021 Jun 18;11(6):e051417. doi: 10.1136/bmjopen-2021-051417.

ABSTRACT

INTRODUCTION: The global COVID-19 pandemic continues to have wide-ranging implications for health, including psychological well-being. A growing corpus of research reviews has emerged on the topic of psychological resilience in the context of the pandemic. However, this body of work has not been systematically reviewed for its quality, nor with respect to findings on the effectiveness of tools and strategies for psychological resilience. To this end, a meta-review protocol is proposed with the following objectives: (1) identify review work on the topic of psychological resilience during COVID-19; (2) assess the quality of this review work using A MeaSurement Tool to Assess systematic Reviews; (3) assess the risk of bias in this work; (4) generate a narrative summary of the key points, strengths and weaknesses; (5) identify the psychological resilience strategies that have been reviewed; (6) identify how these strategies have been evaluated for their effectiveness; (7) identify what outcomes were measured and (8) summarise the findings on strategies for psychological resilience so far, providing recommendations, if possible.

METHODS AND ANALYSIS: A systematic meta-review will be conducted in accordance with the Preferred Reporting Items for Systematic Reviews for Protocols and Joanna Briggs Institute umbrella review guidelines. Electronic searches of general databases, especially Web of Science, Scopus and PubMed, will be conducted. Only results from January 2020 onwards will be considered, coinciding with the COVID-19 pandemic. Only results in English will be included. Descriptive statistics, thematic analysis and narrative summaries describing the nature of the reviewed work and evaluation of psychological resilience strategies will be carried out.

ETHICS AND DISSEMINATION: Ethical approval is not needed for systematic review protocols. The results of the meta-review will be published in an international peer-reviewed journal. The raw and summarised data will be shared in the journal or other open venues.

PROSPERO REGISTRATION NUMBER: CRD42021235288.

PMID:34145023 | DOI:10.1136/bmjopen-2021-051417

BMJ Open. 2021 Jun 18;11(6):e050948. doi: 10.1136/bmjopen-2021-050948.

ABSTRACT

INTRODUCTION: This research project addresses the lack of screening tools for the early detection of high-risk individuals for long-term care, through four individual studies.Study 1 investigates the predictive ability of the ‘Kihon Check List’, study 2 the ‘Cognitive Function instrument’ and EuroQol-5 Dimension (EQ-5D) and study 3 the ‘Cognitive Function instrument’ and EQ-5D as well as the ‘Frail Kenshin’ health check-up, for incident long-term care certification over a follow-up period of up to 4 years. This is the first large prospective study to evaluate the predictive ability of these tools for the outcome measure long-term care certification. The last subsection of this project study four aims to explore a mixed methods intervention for delaying the need for long-term care. This section is purely exploratory, looking for clues for further studies.

METHODS AND ANALYSIS: Baseline data have been collected through local government programs, as well as through postal self-reported questionnaires. The primary outcome variable for all studies is long-term care certification data. Statistical analysis will be carried out using Kaplan-Meier, Multiple Cox regression as well as logistic regression.

CONCLUSION: This project hopes to identify tools effective in predicting long-term care need. This will enable identification of citizens that are of higher risk for long-term care in the near future. This subset of high-risk individuals can in the future be addressed for extra support/intervention.

ETHICS AND DISSEMINATION: All studies have been approved by respective institutional ethical committees and the WHO ethical committee ERC.0002899. In addition, all studies conform to the provisions of the Declaration of Helsinki and are conducted in accordance with Japan’s ‘Ethical Guidelines for Medical and Health Research Involving Human Subjects’. All findings will be disseminated at conferences and published in peer-reviewed journals.

TRIAL REGISTRATION NUMBER: UMIN000023283.

PMID:34145022 | DOI:10.1136/bmjopen-2021-050948

BMJ Open. 2021 Jun 18;11(6):e049339. doi: 10.1136/bmjopen-2021-049339.

ABSTRACT

INTRODUCTION: A 2011 paper proposed a working taxonomy of implementation outcomes, their conceptual distinctions and a two-pronged research agenda on their role in implementation success. Since then, over 1100 papers citing the manuscript have been published. Our goal is to compare the field’s progress to the originally proposed research agenda, and outline recommendations for the next 10 years. To accomplish this, we are conducting the proposed scoping review.

METHODS AND ANALYSIS: Our approach is informed by Arksey and O’Malley’s methodological framework for conducting scoping reviews. We will adhere to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews. We first aim to assess the degree to which each implementation outcome has been investigated in the literature, including healthcare settings, clinical populations and innovations represented. We next aim to describe the relationship between implementation strategies and outcomes. Our last aim is to identify studies that empirically assess relationships among implementation and/or service and client outcomes. We will use a forward citation tracing approach to identify all literature that cited the 2011 paper in the Web of Science (WOS) and will supplement this with citation alerts sent to the second author for a 6-month period coinciding with the WOS citation search. Our review will focus on empirical studies that are designed to assess at least one of the identified implementation outcomes in the 2011 taxonomy and are published in peer-reviewed journals. We will generate descriptive statistics from extracted data and organise results by these research aims.

ETHICS AND DISSEMINATION: No human research participants will be involved in this review. We plan to share findings through a variety of means including peer-reviewed journal publications, national conference presentations, invited workshops and webinars, email listservs affiliated with our institutions and professional associations, and academic social media.

PMID:34145020 | DOI:10.1136/bmjopen-2021-049339

BMJ Open. 2021 Jun 18;11(6):e045656. doi: 10.1136/bmjopen-2020-045656.

ABSTRACT

OBJECTIVES: To validate and test the dimensionality of six constructs from the Workplace Integrated Safety and Health (WISH) assessment, an instrument that assesses the extent to which organisations implement integrated systems approaches for protecting and promoting worker health, safety and well-being, in a sample of nursing homes in the USA.

DESIGN: Validation of an assessment scale using data from a cross-sectional survey.

SETTING: Nursing homes certified by the Centers for Medicaid and Medicare services in three states of the USA: Ohio, California and Massachusetts.

PARTICIPANTS: 569 directors of nursing from nursing homes serving adults and with more than 30 beds participated in the study.

RESULTS: Graded response Item Response Theory (IRT) models showed that five out of six constructs were unidimensional based on balanced interpretation of model fit statistics-M2 or C2 with p value >0.05, Comparative Fit Index >0.95, lower bound of the root mean squared error of approximation 90% CI <0.06 and standardised root mean square residual <0.08. Overall measure and construct reliability ranged from acceptable to good. Category boundary location parameters indicated that items were most informative for respondents in lower range of latent scores (ie, β₁, β₂, β₃ typically below 0). A few items were recommended to be dropped from future administrations of the instrument based on empirical and substantive interpretation.

CONCLUSIONS: The WISH instrument has utility to understand to what extent organisations integrate protection and promotion of worker health, safety and well-being; however, it is most informative in organisations that present lower scores.

PMID:34145013 | DOI:10.1136/bmjopen-2020-045656

BMJ Open. 2021 Jun 18;11(6):e044242. doi: 10.1136/bmjopen-2020-044242.

ABSTRACT

OBJECTIVES: To develop and validate a rule-out prediction model for the risk of hospitalisation among patients with SARS-CoV-2 infection in the ambulatory setting to derive a simple score to determine outpatient follow-up.

DESIGN: Prospective cohort study.

SETTING: Swiss university hospital.

PARTICIPANTS: 1459 individuals with a positive result for SARS-CoV-2 infection between 2 March and 23 April 2020.

METHODS: We applied the rule of 10 events per variable to construct our multivariable model and included a maximum of eight covariates. We assessed the model performance in terms of discrimination and calibration and performed internal validation to estimate the statistical optimism of the final model. The final prediction model included age, fever, dyspnoea, hypertension and chronic respiratory disease. To develop the OUTCoV score, we assigned points for each predictor that were proportional to the coefficients of the regression equation. Sensitivity, specificity, positive and negative likelihood ratios were estimated, including positive and negative predictive values in different thresholds.

MAIN OUTCOME MEASURE: The primary outcome was COVID-19-related hospitalisation.

RESULTS: The OUTCoV score ranged from 0 to 7.5 points. The two threshold parameters with optimal rule-out and rule-in characteristics for the risk of hospitalisation were 3 and 5.5, respectively. Outpatients with a score <3 (997/1459; 68.3%) had no follow-up as at low risk of hospitalisation (1.8%; 95% CI 1.1 to 2.8). For a score ≥5.5 (20/1459; 1.4%), the hospitalisation risk was higher (30%; 95% CI 11.9 to 54.3).

CONCLUSIONS: The OUTCoV score allows to rule out two-thirds of outpatients with SARS-CoV-2 infection presenting a low hospitalisation risk and to identify those at high risk that require careful follow-up to assess the need for hospitalisation. The model provides a simple decision-making tool for an effective allocation of resources to maintain quality care for outpatient populations.

PMID:34145007 | DOI:10.1136/bmjopen-2020-044242

BMJ Open. 2021 Jun 18;11(6):e042376. doi: 10.1136/bmjopen-2020-042376.

ABSTRACT

OBJECTIVES: To assess the association between the Human Development Index (HDI) and covariates on the mortality-to-incidence ratio (MIR) of lips and oral cavity cancer (LOCC) in Mexico.

DESIGN: Ecological study.

SETTING: Data from 32 Mexican states for year 2019.

PARTICIPANTS: Data set of male and female populations from Mexico.

EXPOSURES: Socioeconomic conditions based on HDI and covariates related to healthcare system capacity (total health spending per capita, school dropout and ratio of medical personnel in direct contact with patients).

PRIMARY AND SECONDARY OUTCOME MEASURES: MIR of LOCC by state and sex was calculated from the Global Burden of Disease Study website for year 2019. Data for calculating HDI 2019 by state and covariates were obtained from the National Institute of Statistics and Geography. A multiple regression model was constructed to measure the effects of HDI and covariates on LOCC-MIR.

RESULTS: Among the states with the highest HDI (>0.780), Colima had the highest aged-standardised rates per 100.000 in men for incidence (5.026) and mortality (3.118). The greatest burden of the disease was found on men, with the highest Men:Women MIR in Colima (3.10) and Baja California Sur (2.73). The highest MIR (>0.65) was found among the states with the lowest HDI (Oaxaca and Chiapas). For each unit of increase of the HDI there was a decrease in the LOCC- MIR of -0.778, controlling for the covariates. The most suitable regression model explained the 57% (F (p): 0.000) of the variance.

CONCLUSIONS: Men were most affected by LOCC in Mexican states. The highest MIRs of LOCC were found in the states with the highest HDI. But a worse prognosis of the disease, expressed as a higher MIR, is expected in contexts with lower HDI in the country, even with lower MIRs.

PMID:34145006 | DOI:10.1136/bmjopen-2020-042376

J Neuroimaging. 2021 Jun 18. doi: 10.1111/jon.12896. Online ahead of print.

ABSTRACT

BACKGROUND AND PURPOSE: The aim of this study was to investigate the relationship between arterial morphological parameters and the rupture risk of anterior communicating artery (AComA) aneurysms.

METHODS: A hospital database was retrospectively reviewed to identify patients with AComA aneurysms. Morphologic parameters were evaluated on the 3-dimensional computed tomography angiograms. The patients were divided into two groups as ruptured and unruptured. Patient age, sex, morphological parameters such as aneurysm height and weight, neck diameter, aspect ratio (AR), size ratio (SR), bifurcation angle, aneurysm shape, and diameters of the artery were statistically compared between two groups.

RESULTS: Ninety-five AComA aneurysms were analyzed in this study (60 ruptured and 35 unruptured). The aneurysm neck size (p = .005) and the diameter of the A1 segment of the ipsilateral anterior cerebral artery (i-A1) were smaller in the ruptured group than in the unruptured group (p = .001), but AR (p = .001) was higher. The number of patients with irregular shape aneurysm were higher in the ruptured group (p = .006). There was no significant difference between the two groups in terms of age, sex, aneurysm height and weight, bifurcation angle, and SR. Univariate logistic regression analysis showed that i-A1 segment diameter (odds ratio [OR]: -2.070, confidence interval [CI]: 0.030-0.531, p = .005), aneurysm neck diameter (OR: -0.409, CI: 0.491-0.899, p = .008), irregular shape (OR: 1.197, CI: 1.382-7.929, p = .007), and AR (OR: 0.880, CI: 1.315-4.417, p = .004) were significantly correlated with ruptured status. Multivariate regression analysis demonstrated that aneurysm neck diameter (OR: -0.457, CI: 0.410-0.977, p = .039) was the only independent variable for rupture.

CONCLUSION: AComA aneurysm rupture is more likely to occur in aneurysms with smaller i-A1 segment diameter, smaller aneurysm neck diameter, irregular aneurysm shape, and higher AR. Aneurysm neck diameter may be a more important determinant for rupture prediction.

PMID:34143925 | DOI:10.1111/jon.12896

J Clin Endocrinol Metab. 2021 Jun 18:dgab449. doi: 10.1210/clinem/dgab449. Online ahead of print.

ABSTRACT

PURPOSE: European and French guidelines for ENSAT stage IV low tumor burden or indolent adrenocortical carcinoma (ACC) recommend combination of mitotane and locoregional treatments (LRT) in first-line. Nevertheless, the benefit of LRT combination with mitotane has never been evaluated in this selected group of patients.

METHODS: A retrospective chart review was performed from 2003-2018 of patients with stage IV ACC with ≤2 tumoral organs who received mitotane in our center. Primary endpoint was the delay between mitotane initiation and first systemic chemotherapy. Secondary endpoints were progression-free survival (PFS) and overall survival (OS) from mitotane initiation. Adjusted analyses were performed on the main prognostic factors.

RESULTS: Out of 79 included patients, 48 (61%) patients were female and median age at stage IVA diagnosis was 49.8 years (interquartile-range:38.8-60.0). Metastatic sites were mainly lungs (76%) and liver (48%). Fifty-eight (73%) patients received LRT including adrenal bed radiotherapy (14 patients, 18%), surgery (37 patients, 47%) and/or interventional radiology n(35,44%). Median time between mitotane initiation and first chemotherapy administration was 9 months (Interquartile-range:4-18). Median PFS1 (first tumor-progression) was 6.0 months (CI95%:4.5-8.6). Median OS was 46 months (CI95%:41-68). PFS1, PFS2 and OS were statistically longer in the mitotane plus LRT group compared to the mitotane-only group (Hazard ratio (HR)=0.39 (CI95%:0.22-0.68), HR=0.35 (CI95%:0.20-0.63) and HR=0.27 (CI95%:0.14-0.50) respectively). Ten (13%) patients achieved complete response, all from mitotane plus LRT group.

CONCLUSION: Our results endorse European and French guidelines for stage IV ACC with ≤2 tumor-organs and favor the combination of mitotane and LRT as first-line treatment. For the first time, a significant number of complete responses were observed. Prospective studies are expected to confirm these findings.

PMID:34143888 | DOI:10.1210/clinem/dgab449

Hum Reprod. 2021 Jun 18:deab148. doi: 10.1093/humrep/deab148. Online ahead of print.

ABSTRACT

STUDY QUESTION: Can sperm donation increase live birth rates following ICSI in advanced maternal age (AMA) patients?

SUMMARY ANSWER: Sperm donation increases the live birth rate in AMA ICSI cycles.

WHAT IS KNOWN ALREADY: In ICSI practice, sperm donation has been predominantly applied to overcome male infertility. The involvement of paternal age and lower sperm quality in the severe reduction in fertility observed in AMA patients remains to be clarified.

STUDY DESIGN, SIZE, DURATION: Retrospective multicenter cohort study including data generated between 2015 and 2019 from 755 ICSI cycles achieving a fresh embryo transfer, of which 337 were first homologous cycles (normozoospermic partner sperm and homologous oocytes) and 418 were first sperm donation cycles (donor sperm and homologous oocytes). The association of sperm origin (partner vs donor) with live birth was assessed by multivariate analysis in non-AMA (<37 years, n = 278) and AMA (≥37 years, n = 477) patients, separately, including in the model all variables previously found to be associated with live birth in a univariate analysis (number of MII oocytes recovered, number of embryos transferred, and maternal age). ICSI outcomes were compared between sperm donation and homologous cycles in overall, non-AMA and AMA patients.

PARTICIPANTS/MATERIALS, SETTING, METHODS: The study was conducted in three fertility clinics and included 755 Caucasian patients aged 24-42 years undergoing their first homologous or sperm donation ICSI cycle achieving a fresh embryo transfer.

MAIN RESULTS AND THE ROLE OF CHANCE: The multivariate analysis revealed that sperm donation was positively associated with the likelihood of a live birth independently of all other variables tested in AMA (P = 0.02), but not in non-AMA patients. Live birth, delivery, and miscarriage rates differed substantially between sperm donation and homologous AMA cycles; live birth and delivery rates were 70-75% higher (25.4% vs 14.5% and 22.5% vs 13.5%, respectively; P < 0.01), while miscarriage occurrence was less than half (18.0% vs 39.5%; P < 0.01) in sperm donation compared to homologous AMA cycles.

LIMITATIONS, REASONS FOR CAUTION: This study is limited by its retrospective nature, differences in patients profiles between sperm donation and homologous-control groups and varying proportion of donor cycles between fertility centers, although these variations have been controlled for in the statistical analysis.

WIDER IMPLICATIONS OF THE FINDINGS: The findings suggest that sperm donation increases live birth rates while reducing miscarriage occurrence in AMA patients, and thus may be a valid strategy to improve ICSI outcomes in this growing and challenging patient group.

STUDY FUNDING/COMPETING INTEREST(S): N/A.

TRIAL REGISTRATION NUMBER: N/A.

PMID:34143887 | DOI:10.1093/humrep/deab148