Initial Submission Research Articles

Abnormalities Of 12p Are Associated With High-Risk Acute Myeloid Leukemia: A Children's Oncology Group Report

IntroductionAbnormalities of 12p are relatively rare in acute myeloid leukemia (AML), but are of particular interest because ETV6, an ETS family transcription factor that frequently acts as a tumor suppressor, maps to 12p13. In pediatric AML the recurrent t(7;12)(q36;p13) has been recognized in addition to other heterogeneous 12p abnormalities which results in the rearrangement or deletion of ETV6. Recently, a Medical Research Council study found that AML patients with 12p abnormalities have a poor prognosis. To date, abnormalities of 12p have been categorized as standard cytogenetic risk in Children's Oncology Group (COG) AML trials, but there are limited data on their frequency, morphologic classification, and concomitant gene mutations or chromosome abnormalities. ObjectiveTo evaluate characteristics and prognostic significance of 12p abnormalities in AML in the COG trial AAML0531. MethodsAAML0531 is a recently completed COG trial that enrolled patients between 2006 and 2010. Central review of cytogenetics was conducted on 981 of 1070 enrolled patients (non-Down syndrome) with de novo AML. Abnormalities of 12p were classified into 3 groups: 1) the t(7;12) or variants thereof; 2) abnormalities of band 12p13 other than the t(7;12) that were confirmed or highly suggestive of ETV6 rearrangement (other ETV6R); and 3) abnormalities resulting in loss of the band 12p13 (ETV6Loss). The entire group of children with 12p abnormalities (N=32) as well as the three subgroups were compared with children (N=949) without 12p abnormalities, with respect to demographics, frequency of gene mutation, additional cytogenetic abnormalities and survival. ResultsAbnormalities of 12p were identified in 32 (3.3%) of patients. 8 patients had a t(7;12) after central review (6 were missed in the local laboratory's initial submission); 10 had otherETV6R, and 14 had ETV6Loss. The median age of the 12p group was significantly lower (median, 5.8; range, 0.2–18.2) than the non-12p group (median, 9.9; range, 0.003–29.8; P=.018). Notable was the very young age of patients with the t(7;12) (median, 0.6; range, 0.2–6.4; P=.004), with 88% <2 years. In the 12p group, there were no CEBPA mutations; 1 FLT3-ITD and 2 NPM1 mutations (in the other ETV6R and ETV6Loss groups). These frequencies of genetic mutations were not significantly different from those in the non-12p group. Patients with 12p abnormalities were significantly less likely to have associated low-risk cytogenetic abnormalities of inv(16) or t(8;21) compared to the non-12p group [t(8;21) 0% vs 15%, P = .016 and inv(16) 0% vs 11% , P=.041]. Further, the proportion of patients with t(9;11) was 0% in the t(7;12) group compared to 20%, 21% and 21% in the other ETV6R, ETV6Loss, and non-12p groups, respectively. Six of 8 patients with t(7;12) had +19 as a secondary abnormality which was absent in the other 12p groups. Six of 7 patients with ETV6Loss had complex karyotypes with >6 abnormalities, compared to 0% in the other 12p groups and 4% in the non-12p groups (P<.002). On the basis of karyotype classification strategy in AAML0531 no patient with 12p abnormalities was low risk, 29 were standard risk, and 3 were high risk [due to presence of -5/5q- or -7].The 12p abnormality group had a worse 3-year OS (28±17% vs. 69±3%, P<.001) and worse 3-year EFS (14±13% vs. 51±3%, P<.001) compared with the non-12p group. For those patients who achieved CR, the RR from end of induction 1 was 37±4% for non-12p vs. 83±40% for the 12p group (P<.001). 3-year OS was 54±40% for the t(7;12), 35±32% for the otherETV6R and 11%±19% for ETV6Loss (P<.03); 3- year EFS rates were 15±28%, 13±3%, and 14±19%, respectively (P>.1). ConclusionsPatients with abnormalities of 12p should be considered for categorization as high-risk with respect to cytogenetic stratification for AML. Given the subtle nature of the t(7;12) and other ETV6 rearrangements and their prognostic implications FISH for ETV6 is recommended upfront for the evaluation of any young patient with AML with a +19 as a secondary abnormality and in any patient suggestive of 12p deletion or rearrangement. Disclosures:No relevant conflicts of interest to declare.

Editorial

In the UK (as I write this in early June) we are approaching 60% of the population having had at least one COVID-19 vaccine and almost 50% of all adults fully vaccinated. But there are still major issues with differential vaccination rates in various communities and the even greater problem of very limited rollout of vaccines across the world. Until we achieve high rates of international vaccination, we will not be able to consider ourselves in a postpandemic situation. For our profession, the effect of the pandemic has been, and continues to be, significant. The initial ruling that the vaccine could not be offered to pregnant (or even breastfeeding) women exemplified the lack of drug research in these vulnerable populations, which has, over the years, led to most medicines being prescribed off-licence. We now have a very confused pregnant population fearful of COVID-19 but, for many, more fearful of the vaccine. The impact of the pandemic on waiting lists in gynaecology has brought us back to a position we have not seen since the 1990s. We are in the fortunate position at TOG of having a large number of articles accepted for publication; this means that there are currently delays between acceptance and publication, and we are having to choose our articles with even greater care than usual. Please carry on submitting proposals for articles but be aware that your proposal (or article) may be rejected at the time of initial submission or after the full article is reviewed. You will have noticed that we have published little in TOG on COVID-19. The Editorial Board decided that as our journal does not have the facility to offer fast turnaround of papers, in general we would not publish articles on coronavirus on the basis that they would be out of date by the time of publication. This edition of the journal, as ever, covers topics from across our speciality. We have a Commentary from Sambit Mukhopadhyay and Mala Arora discussing how doctors in South-East Asia can benefit from the new RCOG CPD programme. I encourage everyone to read this as it has relevance for all of us, independent of where we work. There is an excellent Review that will be useful not only for members of our profession but also for general practitioners (GPs) and others caring for women’s sexual health by Ritchie et al. on the potential benefits of intrauterine contraceptive devices. They discuss use in the nulliparous population (with increased insertion failure rate but the benefits of long acting contraception). There is an excellent accompanying infographic that can be viewed on TOG online. There are two articles of interest to the obstetric readership in particular. The article by Crosby et al. on diagnosis and management of venous thromboembolism (VTE) in pregnancy will be relevant to all of us. This article will help your understanding of the best way to diagnose VTE and current management including the use (or not) of inferior vena cava filters. For the specialist – and I hope of interest to the generalist – there is an article on the investigation and management of fetal anaemia. Morris et al. have written an article that will ensure we are all able to give our women knowledge-based advice as they go through these investigations and treatments. One of the distressing aspects of cancer in young people is the potential impact on fertility for the survivors. Hartington et al. have reviewed the options for fertility preservation in pre- and postpubertal girls and boys. I recommend this article to all those who are supporting these families, including paediatric oncologists and GPs who may be inquisitive but do not know where to source this information to help their patients. Over the last few years we have published numerous articles on the pros and cons of mesh in the management of prolapse and urinary incontinence. I am grateful to Krishnaswamy et al. on their article on non-mesh surgery for urinary incontinence, bringing together the options available in 2021. It covers the ‘rediscovery’ of the techniques and benefits of colposuspension and discusses the use of autologous fascial slings. We need to consider the training (and potentially retraining) needs of our workforce and the need for collection of data to ensure long-term effects are identified as early as possible. I am, as ever, grateful to my Editorial Board for the huge amount of work they do. I am sorry that Mohamed Mehasseb is leaving us after many years of hard work supporting TOG and I am delighted to welcome Rasiah Bharathan as our newest member of the Board.

Patient factors associated with time to medication receipt of oral anti-cancer drugs.

1519 Background: The past decade has seen a dramatic increase in the number of Food and Drug Administration approvals of oral anti-cancer drugs (OACDs). Most OACD prescriptions require coordination between providers, payers, specialty pharmacists, and financial assistance organizations, which can delay drug receipt. We evaluated median time to OACD receipt (TTR) from initial OACD prescription submission and assessed clinical and process-related factors associated with TTR. Methods: We prospectively collected data on all new OACD prescriptions for adult oncology patients at a large, urban outpatient cancer center from 1/1/2018 to 12/31/2019. We collected patient demographic, medical, and insurance data; prescription submission and delivery dates; and interactions with payers and financial assistance groups. TTR was defined as the number of days from OACD initial prescription to patient receipt of the drug. We estimated the median TTR across all patients and used multivariable logistic regression to identify factors associated with TTR above the median. Results: The cohort included 1080 patients who were prescribed 1269 new OACDs. Of these prescriptions, 84% (N=1069) were received, and 71% (N=896) required prior authorization. The median patient age was 66, 44% identified as Non-Hispanic White (White), 25% of patients had commercial insurance, 16% had Medicaid alone, and 58% had Medicare alone or in combination with another plan. The median TTR per patient was 7 days (IQR 0 – 142; 25% ≥ 14 days and 5% ≥ 30 days). In unadjusted analyses, insurance and race/ethnicity were associated with TTR. Compared with patients covered by Medicaid, those with Medicare and supplemental insurance (a partial, not free-standing plan) had nearly 2.5 times the odds of TTR &gt;7 days controlling for other factors. Race/ethnicity showed a trend toward longer TTR with Non-Hispanic Black (Black) patients having a longer TTR compared to White patients, controlling for other factors. We did not observe statistically significant effects of either comorbidity or prior authorization requirement on TTR. Conclusions: Though the majority of oncology patients prescribed OACDs receive the drug, 71% of prescriptions required prior authorization and a quarter of patients waited at least two weeks. Disparities in TTR are primarily driven by financial factors, specifically insurance type.[Table: see text]

The ‘Research in Progress’ article category

ASRHE has introduced a novel article category named ‘Research in Progress’. While the journal’s website provides a succinct definition of this category, initial submissions indicate that further guidance is required to highlight requirements and opportunities. The editors have decided to approach this challenge by constructing an audio editorial, recorded in a conversational format, allowing for multiple voices and nuances to come across.&#x0D; Important aspects of Research in Progress lie in facilitating publication of tentative results, sharing of research approaches and discussion of research designs. The editors emphasize the need for a strong research foundation, as in literature grounding or careful research question design, and open and honest discussion of successes and failures. Research in Progress is strongly placed to invite collaborations and authors are reminded to be explicit in specifying how they want to work with others to take research forward. The editorial also addresses the situation of research students and how a Research in Progress article might sit alongside thesis writing.&#x0D; Research in Progress is a developing article category. The editors invite assistance from the higher education research community in shaping this category.

CSF: Formative Feedback in Autograding

Autograding systems are being increasingly deployed to meet the challenges of teaching programming at scale. Studies show that formative feedback can greatly help novices learn programming. This work extends an autograder, enabling it to provide formative feedback on programming assignment submissions. Our methodology starts with the design of a knowledge map, which is the set of concepts and skills that are necessary to complete an assignment, followed by the design of the assignment and that of a comprehensive test suite for identifying logical errors in the submitted code. Test cases are used to test the student submissions and learn classes of common errors. For each assignment, we train a classifier that automatically categorizes errors in a submission based on the outcome of the test suite. The instructor maps the errors to corresponding concepts and skills and writes hints to help students find their misconceptions and mistakes. We apply this methodology to two assignments in our Introduction to Computer Science course and find that the automatic error categorization has a 90% average accuracy. We report and compare data from two semesters, one semester when hints are given for the two assignments and one when hints are not given. Results show that the percentage of students who successfully complete the assignments after an initial erroneous submission is three times greater when hints are given compared to when hints are not given. However, on average, even when hints are provided, almost half of the students fail to correct their code so that it passes all the test cases. The initial implementation of the framework focuses on the functional correctness of the programs as reflected by the outcome of the test cases. In our future work, we will explore other kinds of feedback and approaches to automatically generate feedback to better serve the educational needs of the students.

Pragmatism as Transcendental Philosophy, Part 2: Peirce on God and Personality

Pragmatism as Transcendental Philosophy, Part 2: Peirce on God and Personality

Editorial Policy

Editorial Policy

Facilitating Timely Institutional Review Board Review: Common Issues and Recommendations.

Review of clinical research by institutional review boards (IRBs) is integral to the protection of human subjects and necessary for the conduct of legal and ethical research. Because such review is time and resource intensive, it is critical to identify common issues that contribute to delayed review and approval of research. Hence, the aim of this quality improvement project was to identify factors associated with long delays in IRB approval and identify potential strategies to streamline the review process. In collaboration with the human subjects research protection program at a large academic health center in the northeastern United States, we conducted a content analysis of minutes of convened IRB meetings for every new protocol (initial submission) approved between January and September 2019 that required greater than or equal to two full board reviews prior to approval (n = 33). We also examined characteristics of new protocols that were reviewed less than twice at convened meetings during the same time frame (n = 244). Using χ2 or Fisher's exact tests, the characteristics of protocols with multiple reviews by the convened IRBs were compared with those protocol submissions reviewed by the convened IRBs only once. Three factors significantly associated with increased delays were researcher conflict of interest (30% vs. 12%, respectively, p < .01), need for radiation safety evaluation (36% vs. 20%, respectively, p = .03), and protocols that were clinical trials (73% vs. 60%, respectively, p < .01). Other factors associated with delayed IRB approval were excessive technical jargon (93.94%, n = 31), inadequate description of data security or inability to meet data security requirements of the institution (75.76%, n = 25), protocol design affecting patient safety (57.58%, n = 19), and lack of clarity regarding compensation and payment or study duration (n = 18, 54.54% each). Approaches to mitigate delays in approval and increase the efficiency and efficacy of the IRB process are recommended.

Editorial Policy

Editorial Policy

The effect of peer review on the improvement of rejected manuscripts

ABSTRACT Peer review is intended to improve the quality and clarity of scientific reports. Upon rejection, authors receive suggestions from knowledgeable field experts. It is unclear whether authors take full advantage of the peer review process to improve their work before publication in another journal. We identified all actionable suggestions in rejection letters of 250 randomly selected manuscripts from a prominent orthopedic journal in 2012. We searched PubMed and Google Scholar and compared the published text to the initial submission to determine if reviewer suggestions were addressed. Two hundred (80%) of the 250 rejected manuscripts were published in another journal by July 2018. Among the 609 substantive actionable queries, 205 (34%) were addressed in the published manuscripts. The suggestions most frequently addressed were in the title and abstract (48%). Our findings suggest that authors often disregard advice from peer reviewers after rejection. Authors may regard the peer review process as particular to a journal rather than a process to optimize dissemination of useful, accurate knowledge in any media. Specialty journalsmight consider collaborating by using a single manuscript submission site that allows peer reviews to be transferred to the next journal, which helps holding authors accountable for making the suggested changes.

Infant and Child Development: A journal for open, transparent and inclusive science from prenatal through emerging adulthood

<i>Infant and Child Development</i>: A journal for open, transparent and inclusive science from prenatal through emerging adulthood

Special Issue Call for Papers: Ethics in Mathematics

The Journal of Humanistic Mathematics is pleased to announce a call for papers for a special issue on Ethics in Mathematics. Please send your abstract submissions via email to the guest editors by September 1, 2021. Initial submission of complete manuscripts is due December 1, 2021. The issue is currently scheduled to appear in July 2022.

Mining Electronic Health Records to Promote the Reach of Digital Interventions for Cancer Prevention Through Proactive Electronic Outreach: Protocol for the Mixed Methods OptiMine Study.

BackgroundDigital behavior change interventions have demonstrated effectiveness for smoking cessation and reducing alcohol intake, which ultimately reduce cancer risk. Leveraging electronic health records (EHR) to identify at-risk patients and increasing the reach of digital interventions through proactive electronic outreach provide a novel approach that may increase the number of individuals who engage with evidence-based treatment.ObjectiveThis study aims to increase the reach of digital behavior change interventions by implementing a proactive electronic message system for smoking cessation and alcohol reduction among a large, at-risk population identified through an acute hospital EHR.MethodsThis protocol describes a 3-phase, mixed-methods implementation study to assess the acceptability, feasibility, and reach of a proactive electronic message system to digital interventions using a hospital’s EHR system to identify eligible patients. In Phase 1, we will conduct focus group discussions with patients and hospital staff to assess the overall acceptability of the electronic message system. In Phase 2, we will conduct a descriptive analysis of the patient population in the hospital EHR regarding target risk behaviors and other person-level characteristics to determine the project’s feasibility and potential reach. In Phase 3, we will send proactive messages to patients identified as smokers or risky drinkers. Messages will encourage and provide access to behavior change mobile apps via an embedded link; the primary outcome will be the proportion of participants who click on the link to access information about the apps.ResultsAt the time of initial protocol submission, data collection was complete, but analysis had not begun. This study was funded by Cancer Research UK from April 2019 to March 2020. Health Research Authority approval was granted in June 2019.ConclusionsIncreasing the reach of digital behavior change interventions can improve population health by reducing the burden of preventable death and disease.International Registered Report Identifier (IRRID)DERR1-10.2196/23669

Help scientists save time for research by minimizing editorial requirements for initial manuscript submission

The new EASE campaign, aimed at further simplification of submission processes in science journals by means of an improved version 3.1 of the EASE Quick-Check Table, is now promoted worlwide. Volunteers have already translated the table into Dutch, German, Korean, Romanian, Slovenian, Spanish, and Turkish, while Bosnian and Polish translations will be finished soon. Volunteers who would like to translate the English version into other languages should first contact EASE Secretary to avoid duplication. We hope that our new campaign will help to increase the efficiency of scientific communication worldwide, which is crucial now. The initial extra effort of journal editors is worth it, as the optimization of manuscript submission is likely to minimize the number of manuscript revisions and may also aid in limiting the spread of COVID-19, thanks to faster publication of crucial research findings.

PDB63 Reimbursement Strategies of First-in-Class Drugs for Type 2 Diabetes Mellitus in Health Technology Assessment in Australia: A Qualitative Review

To gain insights into reimbursement strategies of first-in-class anti-diabetic drugs reflected in public summary documents (PSDs) by the Pharmaceutical Benefits Advisory Committee (PBAC) in Australia. A qualitative review was conducted on PSDs for exenatide, sitagliptin and dapagliflozin. Both initial and re-submissions were reviewed. No further reviews were performed once the indications proposed in the initial submission were recommended. Key information was extracted using a standardized data extraction form and summarized by narrative synthesis. All retrieved submissions were focused on combination therapies. All three drugs in combination with metformin (MET) and/or sulfonylurea (SU) were recommended eventually following an average of 2.3 attempts. Indirect comparisons were generally adopted to assess the comparative effectiveness and safety. In initial submissions, thiazolidinediones was nominated as the main comparator for sitagliptin and exenatide, whereas sitagliptin being the comparator for dapagliflozin. HbA1c reduction was the primary endpoint across all comparisons with a non-inferiority margin of 0.3% - 0.4% agreed by the PBAC. Cost-minimization analyses (CMA) were mainly employed except that cost-utility analyses were applied in the first two submissions for exenatide. All initial submissions were deemed to have high uncertainties with respect to comparative effectiveness, and exenatide was further characterized with high uncertainties in cost-effectiveness and safety concerns. These uncertainties were addressed in resubmissions by providing additional clinical evidence and adopting the comparator and the CMA approach suggested by the PBAC. All submissions estimated a net cost to the government of less than $10 million in Year 5 post listing. Furthermore, PBAC suggested a risk-sharing agreement to manage the potential usage beyond the listing of dapagliflozin to assure its nil net cost to the government. The selection of comparator(s) and the robustness of clinical and economic evaluation should be emphasized by the sponsors. Cost neutral and appropriate risk-sharing agreements may facilitate positive recommendations.

Evaluation of Arai etal.: What Can Differences across Daughter Cells Tell Us about Stem Cell Renewal?

One snapshot of the peer review process for "Machine learning of hematopoietic stem cell divisions from paired daughter cell expression profiles reveals effects of aging on self-renewal" (Arai etal., 2020).

Deciding to post a manuscript preprint

Deciding to post a manuscript preprint

Improving oncology biosimilar launches in the EU, the USA, and Japan: an updated Policy Review from the Southern Network on Adverse Reactions

The EU, the USA, and Japan account for the majority of biological pharmacotherapy use worldwide. Biosimilar regulatory approval pathways were authorised in the EU (2006), in Japan (2009), and in the USA (2015), to facilitate approval of biological drugs that are highly similar to reference products and to encourage market competition. Between 2007 and 2020, 33 biosimilars for oncology were approved by the European Medicines Agency (EMA), 16 by the US Food and Drug Administration (FDA), and ten by the Japan Pharmaceuticals and Medical Devices Agency (PMDA). Some of these approved applications were initially rejected because of manufacturing concerns (four of 36 [11%] with the EMA, seven of 16 [44%] with the FDA, none of ten for the PMDA). Median times from initial regulatory submission before approval of oncology biosimilars were 1·5 years (EMA), 1·3 years (FDA), and 0·9 years (PMDA). Pharmacists can substitute biosimilars for reference biologics in some EU countries, but not in the USA or Japan. US regulation prohibits substitution, unless the biosimilar has been approved as interchangeable, a designation not yet achieved for any biosimilar in the USA. Japan does not permit biosimilar substitution, as prescribers must include the product name on each prescription and that specific product must be given to the patient. Policy Reviews published in 2014 and 2016 in The Lancet Oncology focused on premarket and postmarket policies for oncology biosimilars before most of these drugs received regulatory approval. In this Policy Review from the Southern Network on Adverse Reactions, we identify factors preventing the effective launch of oncology biosimilars. Introduction to the market has been more challenging with therapeutic than for supportive care oncology biosimilars. Addressing region-specific competition barriers and educational needs would improve the regulatory approval process and market launches for these biologics, therefore expanding patient access to these products in the EU, the USA, and Japan.

Pan-Canadian learning outcomes in chemistry: a national snapshot

Science, technology, engineering, and mathematics (STEM) students have, for generations, chosen university Bachelor of Science (B.Sc.) programs for themselves with little or no information about what they may get out of those programs, except as implicitly communicated within the culture and curriculum. However, in Canada, B.Sc. programs typically must explicitly state their program outcomes, at least in their initial submission to their respective provincial ministries of post-secondary education. We undertook a survey of all Canadian institutions’ B.Sc. programs in chemistry to provide a national snapshot of the values and priorities encompassed in institutional delivery of these programs. Our results show a definite preference for knowledge over other learning domains, particularly in translational skills, chemistry, science, and the laboratory. Alignment with provincial degree-level expectations, mostly standardized across Canada, is discussed as well.

Peer review declaration

All papers published in this volume of IOP Conference Series: Earth and Environmental Science have been peer reviewed through processes administered by the Editors. Reviews were conducted by expert referees to the professional and scientific standards expected of a proceedings journal published by IOP Publishing.• Type of peer review: Single-blind• Conference submission management system: http://submission.chinarock.csrme.com/UserCentral/Index/Login• Number of submissions received: 722• Number of submissions sent for review: 722• Number of submissions accepted: 321• Acceptance Rate (Number of Submissions Accepted / Number of Submissions Received X 100): 44.46• Average number of reviews per paper: 2.1• Total number of reviewers involved: 524• Any additional info on review process: The review process consists of two rounds. During the first round of review, at least two reviewers were assigned for each initial submission. The revised papers were sent out for a second-round review subjected to the initial comments from the reviewers as well as the quality evaluated by the guest editors. The papers were finally accepted subjected to the satisfactory of both the reviewers and guest editors.• Contact person for queries:Dr. Xin Huang (Associate Professor), Tongji University, Shanghai, ChinaEmail: xhuang@tongji.edu.cnPhone: +86-17702118387