bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multivariate meta-analysis of critical care meta-analyses: a meta-epidemiological study
Authors: Moran John L. 
Published: July 2021

Abstract
Background
Meta-analyses typically consider multiple outcomes and report univariate effect sizes considered as independent. Multivariate meta-analysis (MVMA) incorporates outcome correlation and synthesises direct evidence and related outcome estimates within a single analysis. In a series of meta-analyses from the critically ill literature, the current study contrasts multiple univariate effect estimates and their precision with those derived from MVMA.

Methods
A previous meta-epidemiological study was used to identify meta-analyses with either one or two secondary outcomes providing sufficient detail to structure bivariate or tri-variate MVMA, with mortality as primary outcome. Analysis was performed using a random effects model for both odds ratio (OR) and risk ratio (RR); borrowing of strength (BoS) between multivariate outcome estimates was reported. Estimate comparisons, β coefficients, standard errors (SE) and confidence interval (CI) width, univariate versus multivariate, were performed using Lin’s concordance correlation coefficient (CCC).

Results
In bivariate meta-analyses, for OR (n = 49) and RR (n = 48), there was substantial concordance (≥ 0.69) between estimates; but this was less so for tri-variate meta-analyses for both OR (n = 25; ≥ 0.38) and RR (≥ -0.10; n = 22). A variable change in the multivariate precision of primary mortality outcome estimates compared with univariate was present for both bivariate and tri-variate meta-analyses and for metrics. For second outcomes, precision tended to decrease and CI width increase for bivariate meta-analyses, but was variable in the tri-variate. For third outcomes, precision increased and CI width decreased. In bivariate meta-analyses, OR coefficient significance reversal, univariate versus MVMA, occurred once for mortality and 6 cases for second outcomes. RR coefficient significance reversal occurred in 4 cases; 2 were discordant with OR. For tri-variate OR meta-analyses reversal of coefficient estimate significance occurred in two cases for mortality, nine cases for second and 7 cases for third outcomes. In RR meta-analyses significance reversals occurred for mortality in 2 cases, 6 cases for second and 3 cases for third; there were 7 discordances with OR. BoS was greater in trivariate MVMAs compared with bivariate and for OR versus RR.

Conclusions
MVMA would appear to be the preferred solution to multiple univariate analyses; parameter significance changes may occur. Analytic metric appears to be a determinant.
Need of care in interpreting Google Trends-based COVID-19 infodemiological study results: potential risk of false-positivity
Authors: Sato Kenichiro , Mano Tatsuo , Iwata Atsushi , Toda Tatsushi 
Published: July 2021

Abstract
Background
Google Trends (GT) is being used as an epidemiological tool to study coronavirus disease (COVID-19) by identifying keywords in search trends that are predictive for the COVID-19 epidemiological burden. However, many of the earlier GT-based studies include potential statistical fallacies by measuring the correlation between non-stationary time sequences without adjusting for multiple comparisons or the confounding of media coverage, leading to concerns about the increased risk of obtaining false-positive results. In this study, we aimed to apply statistically more favorable methods to validate the earlier GT-based COVID-19 study results.

Methods
We extracted the relative GT search volume for keywords associated with COVID-19 symptoms, and evaluated their Granger-causality to weekly COVID-19 positivity in eight English-speaking countries and Japan. In addition, the impact of media coverage on keywords with significant Granger-causality was further evaluated using Japanese regional data.

Results
Our Granger causality-based approach largely decreased (by up to approximately one-third) the number of keywords identified as having a significant temporal relationship with the COVID-19 trend when compared to those identified by Pearson or Spearman’s rank correlation-based approach. “Sense of smell” and “loss of smell” were the most reliable GT keywords across all the evaluated countries; however, when adjusted with their media coverage, these keyword trends did not Granger-cause the COVID-19 positivity trends (in Japan).

Conclusions
Our results suggest that some of the search keywords reported as candidate predictive measures in earlier GT-based COVID-19 studies may potentially be unreliable; therefore, caution is necessary when interpreting published GT-based study results.
What is a prevention visit? A qualitative study of a structured approach to prevention and screening – the BETTER WISE project
Authors: Sopcak N. , Fernandes C. , O’Brien M. A. , Ofosu D. , Wong M. , Wong T. , Kebbe M. , Manca D. 
Published: July 2021

Abstract
Background
This qualitative study is a sub-component of BETTER WISE, a comprehensive and structured approach that proactively addresses chronic disease prevention, screening, and cancer survivorship, including screening for poverty and addressing lifestyle risks for patients aged 40 to 65. Patients (n = 527) from 13 primary care clinics (urban, rural, and remote) in Alberta, Ontario, and Newfoundland & Labrador, Canada agreed to participate in the study and were invited to a one-hour prevention visit delivered by a Prevention Practitioner (PP) as part of BETTER WISE. We identified the key components of a BETTER WISE prevention visit based on patients’ and primary care providers’ perspectives.

Methods
Primary care providers (PPs, physicians and their staff) participated in 14 focus groups and 19 key informant interviews to share their perspectives on the BETTER WISE project. Of 527 patients who agreed to participate in the study and were invited for a BETTER WISE prevention visit with a PP, we received 356 patient feedback forms. We also collected field notes and memos and employed thematic analysis using a constant comparative method focusing on the BETTER WISE prevention visit.

Results
We identified four key themes related to a BETTER WISE prevention visit: 1) Creating a safe environment and building trust with patients: PPs provided sufficient time and a safe space for patients to share what was important to them, including their concerns related to poverty, alcohol consumption, and mental health, topics that were often not shared with physicians; 2) Providing personalized health education: PPs used the BETTER WISE tools to provide patients with a personalized overview of their health status and eligible screening; 3) Non-judgmental empowering of patients: Instead of directing patients on what to do, PPs evoked patients’ preferences and helped them to set goals (if desired); and 4) Integrating care for patients: PPs clarified information from patients’ charts and surveys with physicians and helped patients to navigate resources within and outside of the primary care team.

Conclusions
The results of this study underscore the importance of personalized, trusting, non-judgmental, and integrated relationships between primary care providers and patients to effectively address chronic disease prevention, screening, and cancer survivorship as demonstrated by the BETTER WISE prevention visits.

Trial registration
This qualitative study is a sub-component of the BETTER WISE pragmatic, cRCT, trial registration ISRCTN21333761 (date of registration 19/12/2016)
Mobile intraoperative CT-assisted frameless stereotactic biopsies achieved single-millimeter trajectory accuracy for deep-seated brain lesions in a sample of 7 patients
Authors: Bichsel Oliver , Oertel Markus F. , Stieglitz Lennart H. 
Published: July 2021

Abstract
Background
Brain biopsies are crucial diagnostic interventions, providing valuable information for treatment and prognosis, but largely depend on a high accuracy and precision. We hypothesized that through the combination of neuronavigation-based frameless stereotaxy and MRI-guided trajectory planning with intraoperative CT examination using a mobile unit, one can achieve a seamlessly integrated approach yielding optimal target accuracy.

Methods
We analyzed a total of 7 stereotactic biopsy trajectories for a variety of deep-seated locations and different patient positions. After rigid head fixation, an intraoperative pre-procedural scan using a mobile CT unit was performed for automatic image fusion with the planning MRI images and a peri-procedural scan with the biopsy cannula in situ for verification of the definite target position. We then evaluated the radial trajectory error.

Results
Intraoperative scanning, surgery, computerized merging of MRI and CT images as well as trajectory planning were feasible without difficulties and safe in all cases. We achieved a radial trajectory deviation of 0.97 ± 0.39 mm at a trajectory length of 60 ± 12.3 mm (mean ± standard deviation). Repositioning of the biopsy cannula due to inaccurate targeting was not required.

Conclusion
Intraoperative verification using a mobile CT unit in combination with frameless neuronavigation-guided stereotaxy and pre-operative MRI-based trajectory planning was feasible, safe and highly accurate. The setting enabled single-millimeter accuracy for deep-seated brain lesions and direct detection of intraoperative complications, did not depend on a dedicated operating room and was seamlessly integrated into common stereotactic procedures.
Association of emergence of new mutations in circulating tumuor DNA during chemotherapy with clinical outcome in metastatic colorectal cancer
Authors: Jia Ning , Chang Lianpeng , Gao Xin , Shi Xiaohua , Dou Xuelin , Guan Mei , Shao Yajuan , Li Ningning , Cheng Yuejuan , Ying Hongyan , Sun Zhao , Zhou Yanping , Zhao Lin , Zhou Jianfeng , Bai Chunmei 
Published: July 2021

Abstract
Background
The understanding of molecular changes in mCRC during treatment could be used to personalise therapeutic strategies. The aim of our study was to explore the association of circulating tumour DNA (ctDNA) with clinical outcome in metastatic colorectal cancer (mCRC).

Methods
Sequential patients with mCRC receiving standard first-line chemotherapy were included prospectively. Both plasma ctDNA and serum CEA were assessed in samples obtained before treatment and after 4 cycles of chemotherapy (C4). Computed tomography (CT) scans were carried out at baseline and post-C4 (8–10 weeks) and were assessed using Response Evaluation Criteria In Solid Tumours version 1.1 (RECIST v1.1). Target-capture deep sequencing with a panel covering 1021 genes was performed to detected somatic mutations in ctDNA.

Results
A total of 20 patients were prospectively included and treated with either leucovorin, fluorouracil, and oxaliplatin (FOLFOX) (15/20) or leucovorin, fluorouracil, and irinotecan (FOLFIRI) (5/20). Median follow-up was 6.9 months (range 1.6–26.6). Somatic mutations for baseline ctDNA analysis were identified in 85% (17/20) of the patients. Mutation variations of ctDNA after chemotherapy were tested in 16/20 (80.0%) of the patients. In multivariate analyses, a high baseline molecular tumour burden index (mTBI) in ctDNA was associated with a higher risk of disease progression, as well as emergence of new mutations in ctDNA during chemotherapy. Patients with newly detected mutations had shorter progression-free survival (PFS) compared to those without (median 3.0 versus 7.3 months; hazard ratio (HR), 5.97; 95% confidence interval (CI), 0.70–50.69; P = 0.0003). Fold changes in mTBI from baseline to post-C4 were obtained in 80.0% (16/20) of the patients, which were also related to PFS. Patients with fold reduction in mTBI above 0.8-fold had longer PFS compared to those below (median 9.3 versus 4.1 months; HR, 4.51; 95% CI, 1.29–15.70; P = 0.0008).

Conclusions
Newly detected mutations in ctDNA during treatment might potentially be associated with clinical outcome in mCRC and may provide important clinical information.
A systematic review and meta-analysis of nab-paclitaxel mono-chemotherapy for metastatic breast cancer
Authors: Lu Haili , Zha Siluo , Zhang Wei , Wang Qiang , Jiang Daozhen , Xu Xinyun , Zheng Xiangmin , Qiu Ming , Shan Chengxiang 
Published: July 2021

Abstract
Background
Although various clinical trials and real-life studies have tried to explore the value of nab-paclitaxel mono-chemotherapy for metastatic breast cancer (MBC), the safety and efficacy of nab-paclitaxel remain unclear which need to be systematically evaluated.

Methods
Electronic searches for prospective clinical trials evaluating nab-paclitaxel monotherapy for MBC were performed. Requisite data were extracted, integrated and analysed from the included studies according to the different study designs using systematic review and meta-analysis. Meta-regression and subgroup analysis were further performed to explore the potential risk factors affecting each individual outcome of interest following nab-paclitaxel monotherapy.

Results
Twenty-two studies with 3287 MBC patients were included. A total of 1685 MBC patients received nab-paclitaxel as first-line therapy, 640 patients as further-line therapy, and 962 patients as mixed-line therapy. A total of 1966 MBC patients (60.40%) received nab-paclitaxel weekly, 1190 patients (36.56%) received nab-paclitaxel triweekly and 99 patients (3.04%) received nab-paclitaxel biweekly. The overall incidence rates of all-grade neutropenia, leukopenia, peripheral sensory neuropathy, and fatigue were 52% (95% CI, 38–66%, I2 = 98.97%), 58% (95% CI, 43–73%, I2 = 97.72%), 58% (95% CI, 48–68%, I2 = 97.17%), and 49% (95% CI, 41–56%, I2 = 94.39%), respectively. The overall response rate (ORR) was 40% (95% CI, 35–45%, I2 = 98.97%), and the clinical benefit rate (CBR) was 66% (95% CI, 59–73%, I2 = 98.97%) following nab-paclitaxel monotherapy. The median progression-free survival (PFS) was 7.64 months (95% CI, 6.89–8.40 months, I2 = 92.3%), and the median overall survival (OS) was 24.51 months (95% CI, 21.25–27.78 months, I2 = 92.7%). Treatment line, human epidermal growth factor receptor-2(Her-2)-negative status and dosage were found to be sources of heterogeneity among the included studies. According to the meta-regression and subgroup analysis, grade 3/4 neutropenia occurred less frequently in Her-2-negative patients than in the entire population (P = 0.046). Patients who received first-line nab-paclitaxel monotherapy showed a higher ORR (P = 0.006) and longer PFS (P = 0.045). Efficacy outcomes were not affected by the administration schedule. However, within the same schedule, patients appeared to have a superior ORR (P = 0.044) and longer PFS (P = 0.03) with an increasing dosage of nab-paclitaxel administered.

Conclusions
The benefits brought by nab-paclitaxel mono-chemotherapy in the treatment of MBC are considerable while the harm is generally manageable. Further study and validation are needed to figure out the roles which the dosage, schedule and other factors play actually in nab-paclitaxel chemotherapy.
The mutational profile of immune surveillance genes in diagnostic and refractory/relapsed DLBCLs
Authors: Nesic Marijana , Sønderkær Mads , Brøndum Rasmus Froberg , El-Galaly Tarec Christoffer , Pedersen Inge Søkilde , Bøgsted Martin , Dybkær Karen 
Published: July 2021

AbstractBackgroundDiffuse large B-cell lymphoma (DLBCL) is the most frequent lymphoid neoplasm among adults,and approximately 30–40% of patients will experience relapse while 5–10% will suffer from primary refractory disease caused by different mechanisms, including treatment-induced resistance. For refractory and relapsed DLBCL (rrDLBCL) patients, early detection and understanding of the mechanisms controlling treatment resistance are of great importance to guide therapy decisions. Here, we have focused on genetic variations in immune surveillance genes in diagnostic DLBCL (dDLBCL) and rrDLBCL patients to elaborate on the suitability of new promising immunotherapies.MethodsBiopsies from 30 dDLBCL patients who did not progress or relapse during follow up and 17 rrDLBCL patients with refractory disease or who relapsed during follow up were analyzed by whole-exome sequencing, including matched individual germline samples to include only somatic genetic variants in downstream analysis of a curated list of 58 genes involved in major immune surveillance pathways.ResultsMore than 70% of both dDLBCLs and rrDLBCLs harbored alterations in immune surveillance genes, but rrDLBCL tumor samples have a lower number of genes affected compared to dDLBCL tumor samples. Increased gene mutation frequencies in rrDLBCLs were observed in more than half of the affected immune surveillance genes than dDLBCLs.ConclusionGenetic variants in the antigen-presenting genes affect a higher number of rrDLBCL patients supporting an important role for these genes in tumor progression and development of refractory disease and relapse.
Factors motivating smoking cessation: a cross-sectional study in a lower-middle-income country
Authors: Martins Russell Seth , Junaid Muhammad Umer , Khan Muhammad Sharjeel , Aziz Namrah , Fazal Zoha Zahid , Umoodi Mariam , Shah Fatima , Khan Javaid Ahmed 
Published: July 2021

Abstract
Introduction
Only one-quarter of smokers in Pakistan attempt to quit smoking, and less than 3% are successful. In the absence of any literature from the country, this study aimed to explore factors motivating and strategies employed in successful smoking cessation attempts in Pakistan, a lower-middle-income country.

Methods
A survey was carried out in Karachi, Pakistan, amongst adult (≥ 18 years) former smokers (individuals who had smoked ≥100 cigarettes in their lifetime but who had successfully quit smoking for > 1 month at the time of survey). Multivariable logistic regression, with number of quit attempts (single vs. multiple) as the dependent variable, was performed while adjusting for age, sex, monthly family income, years smoked, cigarettes/day before quitting, and having suffered from a smoking-related health problem.

Results
Out of 330 former smokers, 50.3% quit successfully on their first attempt with 62.1% quitting “cold turkey”. Only 10.9% used a cessation aid (most commonly nicotine replacement therapy: 8.2%). Motivations for quitting included self-health (74.5%), promptings by one’s family (43%), and family’s health (14.8%). Other social pressures included peer-pressure to quit smoking (31.2%) and social avoidance by non-smokers (22.7%). Successful smoking cessation on one’s first attempt was associated with being married (OR: 4.47 [95% CI: 2.32–8.61]), employing an abrupt cessation mode of quitting (4.12 [2.48–6.84]), and telling oneself that one has the willpower to quit (1.68 [1.04–2.71]).

Conclusion
In Pakistan, smoking cessation is motivated by concern for self-health and family’s health, family’s support, and social pressures. Our results lay a comprehensive foundation for the development of smoking-cessation interventions tailored to the population of the country.

Implications
Little is known about the patterns and strategies employed by smokers who are attempting to quit smoking, especially in lower-middle-income countries like Pakistan. Likewise, there are very few smoking cessation programs designed to assist in quitting. Our study will allow for a better understanding of the culture-specific motivating factors and strategies that most contributed to successful quit attempts. Based on these results, evidence based smoking cessation interventions can be developed tailored to the socioeconomic demographic of our country and region, including smoking cessation clinics and public outreach and media campaigns highlighting key elements of successful smoking cessation.
The efficacy of virtual distance training of intensive therapy and anaesthesiology among fifth-year medical students during the COVID-19 pandemic: a cross-sectional study
Authors: Kovács Enikő , Kállai András , Fritúz Gábor , Iványi Zsolt , Mikó Vivien , Valkó Luca , Hauser Balázs , Gál János 
Published: July 2021

Abstract
Background
The coronavirus disease (COVID-19) brought several challenges in medical education. The aim of our study was to investigate whether virtual distance trainings (VDT) organized during the COVID-19 pandemic at our university were effective in replacing in-person bed-side education in intensive therapy and anaesthesiology among fifth-year medical students, both from students’ and instructors’ perspectives.

Methods
This was a cross-sectional study consisting of three parts: a 20-item students’ questionnaire filled out by students participating in VDT, a 22-item instructors’ questionnaire filled out by instructors taking part in virtual distance education and a 20-item knowledge test completed by students participating in VDT, as well as by students visiting bed-side trainings (BT) during the same semester, before COVID-19 pandemic. The questionnaires focused on effectiveness, content, self-preparedness, technical background and interactivity of VDT. Instructors’ and students’ responses given to the common questions, as well as the knowledge test results were compared. Mann-Whitney U test was used for group comparisons and binary logistic regression was performed to analyze the influence of previous health-care experience on students’ feeling of self-preparedness.

Results
One hundred thirthen students (response rate {RR}: 68%) and 29 instructors (RR: 97%) filled out the questionnaires. The majority of students found our VDT useful and effective; however, a considerable number of participants felt disadvantaged by taking VDT instead of BT sessions and would recommend keeping virtual distance education methods combined with BT. Instructors found VDT overall effective and deemed the transfer of their knowledge satisfactory; however, they described worse interactivity and contact with students during virtual sessions compared to in-person teaching. Instructors showed a clearer consensus that VDT should not replace BT in the future, while students’ answers were more divided in this regard. Previous health-care experience did not influence students’ feeling of self-preparedness.
One hundred and twenty-seven students (56 after VDT {RR: 34%}; 71 after BT {RR: 67%}) completed the end-of-semester knowledge test. Students attending VDT performed better than students visiting BT (median score VDT:83.5 vs BT:77.3; p = 0.015).

Conclusions
Virtual distance learning incorporating virtual practice sessions was effective in maintaining continuous education of intensive therapy and anaesthesiology among fifth-year medical students during the COVID-19 outbreak.