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Purpose: To identify therapeutic targets in ovarian clear cell carcinomas, a chemoresistant and aggressive type of ovarian cancer.Experimental Design: Twelve ovarian clear cell carcinoma cell lines were subjected to tiling path microarray comparative genomic hybridization and genome-wide expression profiling analysis. Regions of high-level amplification were defined and genes whose expression levels were determined by copy number and correlated with gene amplification were identified. The effects of inhibition of PPM1D were assessed using short hairpin RNA constructs and a small-molecule inhibitor (CCT007093). The prevalence of PPM1D amplification and mRNA expression was determined using chromogenic in situ hybridization and quantitative real-time reverse transcription-PCR in a cohort of pure ovarian clear cell carcinomas and on an independent series of unselected epithelial ovarian cancers.Results: Array-based comparative genomic hybridization analysis revealed regions of high-level amplification on 1q32, 1q42, 2q11, 3q24-q26, 5p15, 7p21-p22, 11q13.2-q13.4, 11q22, 17q21-q22, 17q23.2, 19q12-q13, and 20q13.2. Thirty-four genes mapping to these regions displayed expression levels that correlated with copy number gains/amplification. PPM1D had significantly higher levels of mRNA expression in ovarian clear cell carcinoma cell lines harboring gains/amplifications of 17q23.2. PPM1D inhibition revealed that PPM1D expression and phosphatase activity are selectively required for the survival of ovarian clear cell carcinoma cell lines with 17q23.2 amplification. PPM1D amplification was significantly associated with ovarian clear cell carcinoma histology (P = 0.0003) and found in 10% of primary ovarian clear cell carcinomas. PPM1D expression levels were significantly correlated with PPM1D gene amplification in primary ovarian clear cell carcinomas.Conclusion: Our data provide strong circumstantial evidence that PPM1D is a potential therapeutic target for a subgroup of ovarian clear cell carcinomas.

Supplementary Data from PPM1D Is a Potential Therapeutic Target in Ovarian Clear Cell Carcinomas

Racism left an indelible mark on Bernardine Lacey and her professional growth as a nurse, including roles as an educator, political advocate, researcher, clinician, and leader. This article uses oral history methods to detail, in Lacey's own words, experiences from her childhood and early in her education and career. Her story allows for an exploration of some of the difficult truths about racism, the culpable role of nursing in this history, and the impact of historical accounts on the profession's current inclusivity and diversity efforts.

Background: Previous studies have independently validated the prognostic relevance of residual cancer burden (RCB) after neoadjuvant chemotherapy. We used results from several independent cohorts in a pooled patient-level analysis to evaluate the relationship of RCB with long-term prognosis across different phenotypic subtypes of breast cancer, to assess generalisability in a broad range of practice settings. Methods: In this pooled analysis, 12 institutes and trials in Europe and the USA were identified by personal communications with site investigators. We obtained participant-level RCB results, and data on clinical and pathological stage, tumour subtype and grade, and treatment and follow-up in November, 2019, from patients (aged ≥18 years) with primary stage I–III breast cancer treated with neoadjuvant chemotherapy followed by surgery. We assessed the association between the continuous RCB score and the primary study outcome, event-free survival, using mixed-effects Cox models with the incorporation of random RCB and cohort effects to account for between-study heterogeneity, and stratification to account for differences in baseline hazard across cancer subtypes defined by hormone receptor status and HER2 status. The association was further evaluated within each breast cancer subtype in multivariable analyses incorporating random RCB and cohort effects and adjustments for age and pretreatment clinical T category, nodal status, and tumour grade. Kaplan-Meier estimates of event-free survival at 3, 5, and 10 years were computed for each RCB class within each subtype. Findings: We analysed participant-level data from 5161 patients treated with neoadjuvant chemotherapy between Sept 12, 1994, and Feb 11, 2019. Median age was 49 years (IQR 20–80). 1164 event-free survival events occurred during follow-up (median follow-up 56 months [IQR 0–186]). RCB score was prognostic within each breast cancer subtype, with higher RCB score significantly associated with worse event-free survival. The univariable hazard ratio (HR) associated with one unit increase in RCB ranged from 1·55 (95% CI 1·41–1·71) for hormone receptor-positive, HER2-negative patients to 2·16 (1·79–2·61) for the hormone receptor-negative, HER2-positive group (with or without HER2-targeted therapy; p

Agricultural productivity relies on synthetic nitrogen fertilizers, yet half of that reactive nitrogen is lost to the environment. There is an urgent need for alternative nitrogen solutions to reduce the water pollution, ozone depletion, atmospheric particulate formation, and global greenhouse gas emissions associated with synthetic nitrogen fertilizer use. One such solution is biological nitrogen fixation (BNF), a component of the complex natural nitrogen cycle. BNF application to commercial agriculture is currently limited by fertilizer use and plant type. This paper describes the identification, development, and deployment of the first microbial product optimized using synthetic biology tools to enable BNF for corn (Zea mays) in fertilized fields, demonstrating the successful, safe commercialization of root-associated diazotrophs and realizing the potential of BNF to replace and reduce synthetic nitrogen fertilizer use in production agriculture. Derived from a wild nitrogen-fixing microbe isolated from agricultural soils, Klebsiella variicola 137-1036 ("Kv137-1036") retains the capacity of the parent strain to colonize corn roots while increasing nitrogen fixation activity 122-fold in nitrogen-rich environments. This technical milestone was then commercialized in less than half of the time of a traditional biological product, with robust biosafety evaluations and product formulations contributing to consumer confidence and ease of use. Tested in multi-year, multi-site field trial experiments throughout the U.S. Corn Belt, fields grown with Kv137-1036 exhibited both higher yields (0.35 ± 0.092 t/ha ± SE or 5.2 ± 1.4 bushels/acre ± SE) and reduced within-field yield variance by 25% in 2018 and 8% in 2019 compared to fields fertilized with synthetic nitrogen fertilizers alone. These results demonstrate the capacity of a broad-acre BNF product to fix nitrogen for corn in field conditions with reliable agronomic benefits.

In some countries, pregnant women experience disproportionately high morbidity and mortality during infectious disease outbreaks due to a variety of gender-based factors and pregnancy-related immunological changes. Despite this, the interests of pregnant women have largely been absent from policies that guide the design of clinical trials and the deployment of vaccines in epidemic contexts. This review examines historic precedent for both excluding and including pregnant women in vaccine trials and considers the rights of pregnant women in epidemic crises. The latest research reveals that perceptions of risk and vulnerability of pregnant women in clinical research are beginning to change, resulting in modest policy and guideline amendments. A growing advocacy movement calling for “fair inclusion” has played an important role. Despite the global-scale and far-reaching implications of vaccine research policies, the current debate appears to reside primarily in disciplinary siloes across Western academic and policymaking spaces. Conceptual ambiguity of “risk,” the pervasive view of pregnant women as “vulnerable,” and competing ethical values that construct research protocols, globally, call for more explicit guidelines.

The problem of child labor is worse in Myanmar than nearly anywhere else in the world. Moreover, unlike in many other countries where this practice occurs, in Myanmar, child labor is conducted open...

The process of clinical diagnosis—from establishing the patient–physician relationship to gathering evidence, to performing, evaluating, interpreting, and allocating diagnostic tests, to settling upon a working explanation for the patient’s condition and pursuing a treatment plan, all the while avoiding the pitfalls of both overdiagnosis and underdiagnosis—is, arguably, the cornerstone of all of modern medicine. Via the discussion of actual case studies, this book shows that the process of clinical diagnosis, even in what might be considered to be ordinary or routine cases, is complex, fascinating, multifaceted, and involves considerations of logic, evidence, ethics, probability, and economics. Thus, the process of clinical diagnosis is about far more than just basic science. Here, as in all areas of medical practice, ethics is inextricably intertwined with evidence: Becoming a good diagnostician requires not only an understanding of probability theory and statistical analysis but also learning to listen to your patients, learning how to interpret the results of diagnostic tests by taking into account clinical considerations, learning how to manage and communicate diagnostic uncertainty in the clinical setting, understanding the potential reasons to conduct diagnostic tests or not, and being concerned with issues of diagnostic justice, while keeping in mind the concerns of the actual patient who is in front of you.

This chapter analyzes two examples, one from endocrinology and one from neuroscience, to show that undertreatment and overtreatment are major medical issues that are very much intertwined with the twin diagnostic problems of under- and overdiagnosis. If physicians do not correctly diagnose a disease (or if they miss it altogether), then there is very little hope that they will be able to treat it effectively. On the other hand, if physicians diagnose “disease” that does not cause suffering for the patient, then they might end up causing the patient harm from the subsequent overtreatment of the condition. Therefore, in addition to research on the causal basis of diseases, physicians also need to improve their diagnostic practices by carefully selecting the appropriate screening and/or diagnostic tests and by appealing to clinical findings to aid in interpretation of their results.

Via an analysis of the coronavirus disease 2019 pandemic, this chapter addresses the various uses of diagnostic testing that go beyond clinical patient care, such as the promotion of public health (via either prevention strategies or research studies). Furthermore, it addresses the question of what to do when diagnostic tests are scarce: For the physician, testing allocations should be made, in the first instance, on the basis of the needs of the individual patient, and societal concerns should be considered to be secondary. For a medical researcher, on the other hand, the priority is reversed: When acquisition of knowledge is the primary goal, considerations of individual patients and their care will necessarily be secondary.

This concluding chapter reiterates the point that being a good diagnostician requires not only an understanding of probability theory and statistical analysis but also learning to listen to your patients, learning how to interpret the results of diagnostic tests by taking into account clinical considerations, learning how to manage and communicate diagnostic uncertainty in the clinical setting, understanding the potential reasons to conduct diagnostic tests or not, and being concerned with issues of diagnostic justice while keeping in mind the concerns of the actual patient who is in front of you.

This chapter demonstrates how the process of clinical diagnosis requires first establishing a therapeutic alliance between the patient and the physician and then drawing on, and evaluating, both qualitative and quantitative forms of evidence. Although clinical diagnosis is a technical process that requires an understanding of scientific study design, probability theory, and statistical analysis, it is also relational because it starts with the relationship between the patient and the physician. In fact, very often, getting to a correct diagnosis directly depends on the way in which the physician navigates this relationship: If a physician is dismissive of the patient’s concerns, the physician risks cutting the patient off too quickly and possibly missing important pieces of evidence that could lead to a timely and accurate diagnosis.

Philosophers have been writing about the practice of medicine for some time, but relatively little has been written about the practice of clinical diagnosis or the issues of evidence, ethics, and justice involved in this process. This introduction sets the stage for the philosophical analysis that takes place in the rest of the book, which combines methods of current philosophy of science and philosophy of medicine to address both issues in diagnostic reasoning and diagnostic testing in the clinical setting.

Medical practice—from testing methods to diagnostic reasoning, treatment protocols, and prognostic evaluations—is often both complex and uncertain. Via an examination of three case studies, this chapter demonstrates that effective management of diagnostic uncertainty must begin with an ability to recognize and acknowledge it in routine cases in the clinical setting. However, even when diagnostic uncertainty is recognized, this alone is not enough for effective diagnostic practice: Once it is recognized, it must then also be clearly communicated to the patient. If these steps are taken in routine cases, then it will become automatic to do so in even the most complex situations, and diagnostic practice will be the better for it.

The process of diagnostic decision-making (DDM) can be very complex, and in all instances, it involves considerations of epistemology, ethics, probability, and economics. Furthermore, the process of DDM is patient-specific both in terms of qualitative evidence toward a diagnosis (e.g., information from the medical history) and in terms of quantitative evidence (e.g., pre- and post-test probabilities). Thus, learning to make diagnostic decisions requires at least a basic understanding of concepts in each of these fields as well as careful consideration on the part of both the physician and the patient as to how these considerations bear on the individual case at hand. In addition, it requires a commitment on the part of each to shared decision-making in the clinical context.

The United States (US) is facing a rapidly aging population that suffers from multiple chronic illnesses. To prepare nursing students to care for this increasingly complex, aging population nurse educators must develop curricula that incorporate both current technology and cutting-edge teaching pedagogies that facilitate development of real-time decision-making skills. Branching scenarios are simulations that mimic real-life; rapidly changing patient conditions unfold based on actual student decision-making. This challenges learners to adapt the nursing process based on subjective and objective assessments and utilize current technology to analyze multiple sources of patient data. As nursing students make decisions and act, the scenario branches, presenting them with immediate feedback on the outcomes. Branching simulation scenario designs incorporate multiple different mobile technologies with decision-support software that nursing students may access, such as real-time decision-support algorithms, evidence-based guidelines, telehealth, medication information resources, and electronic medical records (EMRs). Faculty at NYU Rory Meyers College of Nursing (NYU) have successfully incorporated mobile technology with decision-support software into branching simulations as a strategy to develop real-time clinical decision-making in the care of older adults with multiple chronic illnesses.

Diagnostic testing can be used for many purposes, including testing to facilitate the clinical care of individual patients, testing as an inclusion criterion for clinical trial participation, and both passive and active surveillance testing of the general population in order to facilitate public health outcomes, such as the containment or mitigation of an infectious disease. As such, diagnostic testing presents us with ethical questions that are, in part, already addressed in the literature on clinical care as well as clinical research (such as the rights of patients to refuse testing or treatment in the clinical setting or the rights of participants in randomized controlled trials to withdraw from the trial at any time). However, diagnostic testing, for the purpose of disease surveillance also raises ethical issues that we do not encounter in these settings, and thus have not been much discussed. In this paper we will be concerned with the similarities and differences between the ethical considerations in these three domains: clinical care, clinical research, and public health, as they relate to diagnostic testing specifically. Via an examination of the COVID-19 case we will show how an appeal to the concept of diagnostic justice helps us to make sense of the (at times competing) ethical considerations in these three domains., Dijagnostičko testiranje može se koristiti u mnoge svrhe, uključujući testiranje za olakšavanje kliničke skrbi pojedinačnih pacijenata, testiranje kao kriterij uključivanja za sudjelovanje u kliničkim ispitivanjima i pasivno i aktivno nadzorno testiranje opće populacije kako bi se olakšali ishodi javnog zdravlja, kao što su kao obuzdavanje ili ublažavanje zarazne bolesti. Kao takvo, dijagnostičko testiranje nam postavlja etička pitanja koja su dijelom već obrađena u literaturi o kliničkoj skrbi, kao i kliničkim istraživanjima (kao što su prava pacijenata da odbiju testiranje ili liječenje u kliničkom okruženju ili prava sudionika u randomiziranim kontroliranim ispitivanjima da se povuku iz ispitivanja u bilo kojem trenutku). Međutim, dijagnostičko testiranje, u svrhu nadzora bolesti, postavlja i etička pitanja s kojima se ne susrećemo u ovim okruženjima, pa se o njima nije puno raspravljalo. U ovom radu bavit ćemo se sličnostima i razlikama između etičkih razmatranja u ove tri domene: klinička skrb, klinička istraživanja i javno zdravstvo, jer se oni posebno odnose na dijagnostičko testiranje. Kroz ispitivanje slučaja COVID-19 pokazat ćemo kako nam pozivanje na pojam dijagnostičke pravde pomaže da shvatimo (ponekad suparnička) etička razmatranja u ove tri domene.

Purpose The goal of sentinel lymph node biopsy is to establish the presence or absence of cancer cells in regional axillary nodes. The number of sentinel nodes harvested from each patient varies. The aim of this study was to determine what factors influence the number of sentinel nodes excised at sentinel node biopsy. Methods Data from 426 patients with breast cancer who underwent sentinel lymph node biopsy at the Edinburgh Breast Unit by 10 different experienced breast surgeons were included in this analysis. Univariate and multivariable statistical analysis was performed. Results In the multivariate analysis the number of sentinel nodes biopsied varied significantly between operating surgeon (p p p Conclusions This study shows that the surgeon plays a pivotal and significant role in determining the numbers of sentinel nodes removed by sentinel lymph node biopsy. Surgeons should monitor their own data on the average numbers of sentinel nodes they remove. Some surgeons may not be removing sufficient numbers of sentinel nodes to maintain a low false negative rate for this procedure.

ObjectivesThe primary objective of this study was to ascertain the reasons for emergency department (ED) attendance among patients with a history of atrial fibrillation (AF).DesignAppropriate ED attendance was defined by the requirement for an electrical or chemical cardioversion and/or an attendance resulting in hospitalisation or administration of intravenous medications for ventricular rate control. Quantitative and qualitative responses were recorded and analysed using descriptive statistics and content analysis, respectively. Random effects logistic regression was performed to estimate the OR of inappropriate ED attendance based on clinically relevant patient characteristics.ParticipantsParticipants ≥18 years with a documented history of AF were approached in one of eight centres partaking in the study across Canada (Ontario, Nova Scotia, Alberta and British Columbia).ResultsOf the 356 patients enrolled (67±13, 45% female), the majority (271/356, 76%) had inappropriate reasons for presentation and did not require urgent ED treatment. Approximately 50% of patients(172/356, 48%) were driven to the ED due to symptoms, while the remainder presented on the basis of general fear or anxiety (67/356, 19%) or prior medical advice (117/356, 33%). Random effects logistic regression analysis showed that patients with a history of congestive heart failure were significantly more likely to seek urgent care for appropriate reasons (p=0.03). Likewise, symptom-related concerns for ED presentation were significantly less likely to result in inappropriate visitation (p=0.02). When patients were surveyed on alternatives to ED care, the highest proportion of responses among both groups was in favour of specialised rapid assessment outpatient clinics (186/356, 52%). Qualitative content analysis confirmed these results.ConclusionsImproved education focused on symptom management and alleviating disease-related anxiety as well as the institution of rapid access arrhythmias clinics may reduce the need for unnecessary healthcare utilisation in the ED and subsequent hospitalisation.Trial registration numberNCT03127085

In early December 2019 a cluster of cases of pneumonia of unknown cause was identified in Wuhan, a city of 11 million persons in the People’s Republic of China. Further investigation revealed these cases to result from infection with a newly identified coronavirus, initially termed 2019-nCoV and subsequently SARS-CoV-2. The infection moved rapidly through China, spread to Thailand and Japan, extended into adjacent countries through infected persons travelling by air, eventually reaching multiple countries and continents. Similar to such other coronaviruses as those causing the Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS), the new coronavirus was reported to spread via natural aerosols from human-to-human. In the early stages of this epidemic the case fatality rate is estimated to be approximately 2%, with the majority of deaths occurring in special populations. Unfortunately, there is limited experience with coronavirus infections during pregnancy, and it now appears certain that pregnant women have become infected during the present 2019-nCoV epidemic. In order to assess the potential of the Wuhan 2019-nCoV to cause maternal, fetal and neonatal morbidity and other poor obstetrical outcomes, this communication reviews the published data addressing the epidemiological and clinical effects of SARS, MERS, and other coronavirus infections on pregnant women and their infants. Recommendations are also made for the consideration of pregnant women in the design, clinical trials, and implementation of future 2019-nCoV vaccines.

Lamotrigine (LTG) is associated with the potential for a life-threatening rash (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis). The incidence has been linked to rapid titration and an interaction with valproic acid that can increase the level of LTG. Providers often have difficulty discriminating between serious versus benign rashes, and the package insert recommends discontinuing the medication at the first sign of a rash. Therefore, many patients end up being taken off LTG when it may have been effective for them. We present a case where LTG is reintroduced with a faster initial titration than what is noted in the literature after development of a rash. This case is also unique in that the patient had been on LTG for years prior to emergence of the rash and demonstrates that retrials can be successful.

Background: The Ontario MedsCheck program was introduced in April 2007, with enhancements to strengthen the program made in October 2016. Previous literature has characterized patients who received the service before the enhancements and described the experiences of community pharmacists and physicians, but the experiences of participants in the enhanced MedsCheck program and those of hospital pharmacists and pharmacy technicians have not been explored. Objectives: This study was designed to describe and compare the demographic and clinical characteristics of patients admitted to Sunnybrook Health Sciences Centre (SHSC) who had received a MedsCheck before and after the program enhancements of 2016. The study also aimed to describe the experiences of patients, hospital pharmacists, and pharmacy technicians with the MedsCheck program. Methods: Chart reviews were completed to identify and characterize patients who had received a MedsCheck and were admitted to SHSC between March and May 2016 (retrospective cohort) and between March and May 2017 (prospective cohort). Patients were interviewed and focus groups were conducted with pharmacy staff to explore their experiences with the MedsCheck program. Results: MedsChecks had been performed for 321 (14.5%) of 2216 patients in the retrospective cohort and 172 (6.8%) of 2547 patients in the prospective cohort, an absolute decline of 7.7% after the 2016 enhancements. Patient characteristics were similar between the 2 cohorts. Patients’ experiences were varied, but because of low enrolment in the interview process (n = 3), it was difficult to identify and summarize common themes. The analysis of focus groups involving pharmacy staff (n = 27 participants) revealed that the benefits of MedsChecks depended on quality and access, and also identified common barriers and oppor -tunities for future enhancements. Conclusions: Patient interviews revealed the features of the program that patients valued. Pharmacy staff identified several benefits and barriers encountered when using MedsChecks. These findings can guide clinicians in optimal application of the current MedsCheck program and can inform subsequent program revisions. RESUME Contexte : En avril 2007, l’Ontario a introduit le programme MedsCheck assorti d’ameliorations visant a renforcer le programme elabore en octobre 2016. La documentation anterieure decrivait l’experience des patients rece-vant le service ainsi que celle des pharmaciens et des medecins communau-taires avant les ameliorations, mais les experiences des participants au programme MedsCheck ameliore ainsi que celles des techniciens en pharmacie et des pharmaciens d’hopitaux n’avaient toutefois pas ete etudiees. Objectifs : Cette etude a ete concue pour decrire et comparer les caracteristiques demographiques et cliniques des patients admis au Sunnybrook Health Sciences Centre (SHSC) qui ont recu un MedsCheck avant et apres les ameliorations apportees au programme de 2016. L’etude vise egalement a decrire les experiences qu’ont faites les patients, les pharmaciens d’hopitaux et les techniciens en pharmacie avec le programme MedsCheck ameliore. Methodes : Des examens de graphiques ont permis d’identifier et de caracteriser les patients admis au SHSC entre mars et mai 2016 (cohorte retrospective) et entre mars et mai 2017 (cohorte prospective), ayant recu un MedsCheck. Les patients ont ete interroges et des groupes de discussion avec le personnel de pharmacie ont ete organises pour etudier les experiences qu’ils ont faites avec le programme MedsCheck. Resultats : Des MedsChecks ont ete effectues aupres de 321 patients (14,5 %) sur les 2216 dans la cohorte retrospective, et de 172 patients (6,8 %) sur les 2547 dans la cohorte prospective : une diminution de 7,7 % apres les ameliorations apportees en 2016. Les caracteristiques des patients etaient similaires dans les deux cohortes. Les experiences des patients etaient variees, mais la faible inscription au processus d’entretien (n = 3) n’a pas permis de determiner et de resumer les themes communs. L’analyse des groupes de discussion comprenant des membres du personnel de pharmacie (n = 27 participants) a revele que les avantages du programme MedsChecks dependaient de la qualite de l’information fournie par le programme et de l’acces a cette information, et elle a aussi permis de cibler les obstacles courants et des possibilites d’ameliorations futures. Conclusions : Les entretiens avec les patients ont revele les caracteristiques du programme que les patients appreciaient. Le personnel de pharmacie a releve plusieurs avantages et quelques obstacles lies a l’utilisation du programme MedsChecks. Ces resultats peuvent faciliter l’application optimale du programme MedsCheck actuel par les cliniciens et orienter les revisions ulterieures.

i?½ 2016 The Author(s) Philosophy Compass i?½ 2016 John Wiley & Sons Ltd Increasing philosophical attention is being directed to the rapidly growing discipline of evidence-based medicine (EBM). Philosophical discussions of EBM, however, remain narrowly focused on randomization, mechanisms, and the sociology of EBM. Other aspects of EBM have been all but ignored, including (a) the nature of clinical reasoning and the question of whether it can be standardized; (b) the application of EBM principles to the logic, value, and ethics of diagnosis and prognosis; (c) evidence synthesis (systematic reviews and meta-analyses); and (d) the nature and ethics of placebo controls. Philosophical analysis in each of these areas has the potential to enhance the discussion of EBM methodology and practice.

Although much has been written on the role of randomized controlled trials and mechanistic reasoning in the evaluation of therapeutic treatments, philosophers of medicine have not yet turned their attention to the question of how diagnostic tests and procedures should be evaluated. I aim to begin to fill this gap by examining each of the following questions: What is the best way to determine the accuracy of a diagnostic test? What is the best way to determine the clinical effectiveness of a diagnostic test? Can an accurate diagnostic test be considered medically valuable even if it is not clinically effective? I argue that while diagnostic accuracy is a minimum requirement for both clinical effectiveness and medical value, accuracy and effectiveness are not sufficient for determining the value of a diagnostic test, because diagnostic value extends beyond patient outcomes.

Background: Achieving a pathologic complete response (pCR) has been shown on the patient level to predict excellent long-term event-free survival outcomes. Residual cancer burden (RCB) quantifies the extent of residual disease for patients who did not achieve pCR. We have previously observed in the I-SPY 2 TRIAL that while metastatic events outside the central nervous system (CNS) were dramatically reduced in the setting of pCR, the incidence of CNS metastasis remained similar across RCB classes, raising the possibility that these CNS events may be independent of response in the breast. In this study, we evaluate the type and sites of recurrences by RCB in a large pooled dataset, which allows for analysis within subtype, to validate these findings. Methods: 5161 patients pooled across 12 institutions/trials with available RCB and event-free survival (EFS) data were included in this analysis. EFS was calculated as the interval between treatment initiation, and locoregional recurrence, distant recurrence or death from any cause; patients without event are censored at time of last follow-up. The median follow-up is 4.6 years. We summarized the EFS event type, further sub-dividing the distant recurrence events (DR) by their site of relapse (CNS-only, CNS and other sites, Non-CNS). We used a competing risk (Fine-Gray) model to assess which of these site-specific relapses differ between RCB classes and estimated the cumulative incidence of CNS-only and non-CNS events at 5 years. Analyses were performed across the entire study population and within HR/HER2 defined subtypes. Results: Among the 5161 subjects, there were 1164 EFS events, including 92 (7.9%) local recurrences (without distant recurrence and/or death) and 1072 distant recurrence-free survival (DRFS) events. Among the DRFS events, 158 patients died without a distant recurrence. 914 experienced distant recurrences, including 90 (9.8%) with CNS-only, 145 (15.9%) with CNS and other sites, 664 (72.6%) with non-CNS distant recurrence; 15 (1.6%) patients had missing recurrence site information. Table 1 summarizes the cumulative incidence of CNS-only and non-CNS recurrence at 5 years and the proportion of CNS-only recurrences among DR events by RCB class overall and within each HR/HER2 subtypes. The incidence of CNS-only recurrences was low and similar across RCB classes. In contrast, the incidence of non-CNS recurrences increases with increasing RCB. As a result, CNS-only recurrences are proportionally higher within the RCB-0 and RCB-I than in the RCB-II and RCB-III groups, largely because of the low DR event rate and relative low frequency of non-CNS recurrence events within the RCB-0 and RCB-I classes. Overall, 27% of the recurrences in the setting of pCR (RCB-0) are due to CNS-only recurrences.Conclusions: Consistent with previous studies, our large pooled analysis confirmed that CNS-only recurrences are uncommon but appear similar across RCB groups, independent of response, suggesting that the CNS is a treatment sanctuary site. In contrast, non-CNS recurrence rates increase as RCB increases. These findings suggest that inclusion of CNS-only recurrences as an outcome event may impact the association between neoadjuvant therapy response and long-term outcomes in the context of current therapies. Novel therapies that cross the blood brain barrier will be needed to impact CNS recurrence rates. Table 1: Cumulative Incidence of CNS Only and non-CNS Distant Recurrences at 5 years and proportion of CNS-only events among DR eventsRCB Class0IIIIIIpOverall (5161)N16766622017806Cum. Inc. CNS Only2%2%2%1%0.627Cum. Inc. Non-CNS3%6%16%27% Citation Format: Sonal Shad, Marieke van der Noordaa, Marie Osdoit, Diane de Croze, Anne-Sophie Hamy, Marick Lae, Fabien Reyal, Miguel Martin, María Del Monte-Millán, Sara López-Tarruella, I-SPY 2 TRIAL Consortium, Judy C Boughey, Matthew P Goetz, Tanya Hoskin, Rebekah Gould, Vicente Valero, Gabe Sonke, Tessa G Steenbruggen, Maartje van Seijen, Jelle Wesseling, John Bartlett, Stephen Edge, Mi-Ok Kim, Jean Abraham, Carlos Caldas, Helena Earl, Elena Provenzano, Stephen-John Sammut, David Cameron, Ashley Graham, Peter Hall, Lorna Mackintosh, Fan Fang, Andrew K Godwin, Kelsey Schwensen, Priyanka Sharma, Angela DeMichele, Janet Dunn, Louise Hiller, Larry Hayward, Jeremy Thomas, Kimberly Cole, Lajos Pusztai, Laura Van't Veer, Fraser Symmans, Laura Esserman, Christina Yau. Site of recurrence after neoadjuvant therapy: A multi-center pooled analysis [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD13-02.

Oral feeds pose a challenge for congenital diaphragmatic hernia (CDH) infants. Tube feed (TF) supplementation may be required to support the achievement of normal growth. The aim of this study was to determine the duration and factors associated with TF use in CDH infants at our institution.A single centre retrospective chart review was performed for CDH-born infants who underwent repair between 2000 to 2013 (REB #1000053124). Patient demographics, perinatal management, and feeding status of infants with at least 1-year follow-up were reviewed.Of 160 CDH infants, 32 (20%) were discharged on partial or complete TF, and an additional 5 (3.1%) patients started TF post discharge. CDH infants with TF were more likely to have initial arterial blood pH 7.25, patch repair, ECMO support, and prolonged ICU stay (p 0.05). Time to TF discontinuation did not differ significantly between those partially or fully TF at discharge. Twelve patients (33.3%) remained TF at their last known follow-up.High risk CDH patients are likely to require TF to support their nutritional intake. Parents and caregivers need to be informed and properly supported. Long-term monitoring of CDH patient oral intake, growth, and development will be required.Level III Retrospective Study.

Maternal dietary habits influence maternal and foetal health, representing a pathway for intervention to maximise pregnancy outcomes. Advice on energy intake is provided on a trimester basis, with no additional calories required in the first trimester and an additional 340 kcal∙d-1 and 452 kcal∙d-1 needed for the second and third trimesters. Energy intake depends on pre-gravid body mass index (BMI); underweight women are recommended an increase of 150, 200 and 300 kcal∙d-1 during the first, second and third trimester, normal weight women an increase of 0, 350 and 500 kcal∙d-1 and obese women an increase of 0, 450 and 350 kcal∙day-1. The recommendations for carbohydrate and protein intake are 175 g∙d-1 and 0.88-1.1 g∙kgBM∙d−1, with no change to fat intake. The number of pre-gravid obese women is rising; therefore, we need to regulate weight in women of childbearing age and limit gestational weight gain to within the recommended ranges [overweight women 6.8–11.3 kg and obese women 5.0–9.1 kg]. This can be achieved using nutritional interventions, as dietary changes have been shown to help with gestational weight management. As pregnancy has been identified as a risk factor for the development of obesity, normal weight women should gain 11.5-16.0 kg during pregnancy. Whilst some research has shown that dietary interventions help to regulate gestational weight gain and promote postpartum weight loss to some extent, future research is needed to provide safe and effective guidelines to maximise these effects, whist benefitting maternal and foetal health.

To evaluate the outcomes and learning curve of fenestrated and branched endovascular repair (F/BEVAR) of thoracoabdominal aneurysms.Endovascular aneurysm repair has reduced morbidity and mortality compared with open surgical repair. However, application to thoracoabdominal aneurysm repair remains limited by procedural complexity and device availability.Fifty patients treated in a prospective, nonrandomized, single-center Investigational Device Exemption (IDE) study between January 2014 and July 2017 were analyzed. Patients (mean age 75.6 ± 7.5 years; mean aneurysm diameter 67.3 ± 9.8 mm) underwent F/BEVAR of thoracoabdominal aneurysms (58% type IV; 42% type I-III) using custom-manufactured endografts. The experience was divided into 3 cohorts (Early: 1 to 17; Mid: 18 to 34; Late: 35 to 50) to evaluate learning curve effects on key process measures.F/BEVAR included 194 visceral arteries (average 3.9 per patient). Technical success was 99.5% (193/194 targeted arteries). Thirty-day major adverse events (MAEs) included 3 (6%) deaths, 1 (2%) new-onset dialysis, 3 (6%) paraparesis/paraplegia, and 2 (4%) strokes. One-year survival was 79 ± 7%. Comparing the Early and Late groups revealed reductions in procedure time (452 ± 74 vs 362 ± 53 minutes; P = 0.0001), fluoroscopy time (130 ± 40 vs 99 ± 27 minutes; P = 0.016), contrast administration (157 ± 73 vs 108 ± 38 mL; P = 0.028), and estimated blood loss (EBL; 1003 ± 933 vs 481 ± 317 mL; P = 0.042). Intensive care unit (ICU) and total length of stay (LOS) decreased from 4 ± 3 to 2 ± 1 days and from 7 ± 6 to 5 ± 2 days, respectively, but was not statistically significant.Use of F/BEVAR for treatment of thoracoabdominal aneurysms is safe and effective. During this early experience, there was a significant improvement in key process measures reflecting improvements in technique and physician learning over time.