Persistent Controversy Research Articles

Characterization of Survival Outcomes and Clinical and Molecular Modulators in Adult Patients with Core-Binding Factor Acute Myeloid Leukemia (CBF-AML) Treated with Hidac Consolidation: An Alliance Legacy Study

Introduction CBF-AML is a specific disease entity defined by the presence of either t(8;21)(q22q22)RUNX1-RUNX1T1, or inv(16)(p13.1q22) or t(16;16)(p13.1;q22) creating the CBFB-MYH11 fusion gene, and is associated with a relatively favorable prognosis. Yet, outcomes are variable and relapse occurs in ~50% of patients (pts). Whereas several clinical and molecular features have been suggested to modulate survival, consensus data are sparse. Moreover, there is persistent controversy about the optimal dose intensity of cytarabine consolidation, which complicates interpretation of correlative studies with respect to outcome associations. Thus, we analyzed outcomes of a large cohort of CBF-AML pts treated with high-dose cytarabine (HiDAC) consolidation with respect to cytogenetic subtypes and co-existing molecular features. We analyzed clinical and molecular characteristics and outcomes of 304 pts with CBF-AML aged 18-59 years [y; inv(16)/t(16;16), n=186; t(8;21), n=118] who were similarly treated and achieved a complete remission upon standard cytarabine/anthracycline induction followed by HiDAC on frontline Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology protocols between 1986-2016. All pts had centrally reviewed cytogenetics and samples from 136 pts underwent comprehensive molecular profiling of 80 AML-associated genes for association studies. Kaplan-Meier method was used to estimate probabilities of disease-free survival (DFS) and overall survival (OS), and the log-rank test evaluated differences between survival distributions. Cox proportional hazard regression analyses was used for DFS and OS univariable and multivariable modeling. Results Thirty-eight percent of pts relapsed and 69% were alive 5y after diagnosis (median OS): 12.5y with median follow-up of 8.6y. Outcomes of t(8;21) and inv(16)/t(16;16) AML were similar; relapse rates: 35% vs 40%, 5y OS rates, 64% vs 72%, respectively. Although outcome of pts with inv(16) was not significantly different from outcome of t(16;16) pts, the latter had, by trend, a superior DFS (5y rates, 75% vs 47%, P=0.07); their OS was not significantly different (5y rates, 81% vs 64%, P=0.24). As secondary cytogenetic abnormalities are common and impact on survival has yielded controversial results, we next analyzed the impact on outcomes of our pt cohort. None of the frequently observed secondary abnormalities [i.e., loss of X or Y chromosomes, +8, or del(9q) in t(8;21) pts and +22 or +8 in inv(16)/t(16;16) pts] affected the outcomes of CBF-AML pts we analyzed, which contrasts with some previous reports. The presence of a complex karyotype also did not negatively affect the favorable survival of CBF-AML pts. Next, we assessed the impact of recurrent gene mutations on pt outcomes. While KIT mutations have previously been shown to confer inferior survival, our data suggest that presence of a KIT mutation negatively affects DFS of both t(8;21) and inv(16)/t(16;16) AML pts [5y rates, t(8;21) 36% vs 67%, P= 0.03; inv(16)/t(16;16), 21% vs 61%, P<0.001], and also OS in inv(16)/t(16;16) pts (5y rates, 52% vs 74%, P=0.04). Co-existing FLT3-TKD mutations were almost exclusively found in inv(16)/t(16;16) in 16/18 cases. Though a negative prognostic impact of FLT3-TKD has been suggested, this was not found in our cohort (5y rates, DFS, 56% vs 55%, P=0.93; OS, 78% vs 68%, P=0.69). Furthermore, neither the presence of NRAS or KRAS mutations affected survival outcomes. In multivariable analyses for OS, a higher percentage of peripheral blood blasts was the only feature associated with inferior survival [HR, 1.14 (95% CI, 1.04-1.25), P=0.004]. Conclusions Our analysis of a large cohort of younger CBF-AML pts treated on frontline protocols with 7+3-based induction therapy and HiDAC consolidation, showed though these pts are considered favorable risk, they demonstrate varying long-term survival. Clinically, the presence of high blast count at time of diagnosis, was a strong adverse prognosticator for inferior survival. With respect to recurrent co-occurring cytogenetic aberrations or gene mutations, only KIT mutations associated with inferior survival in pts with t(8;21) and in those with inv(16)/t(16;16). Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org. Clinicaltrials.gov: NCT00048958(CALGB 8461), NCT00899223(CALGB 9665), NCT00900224(CALGB 20202) *co-senior authors

Risk stratification by 30-day prognostic factors of clinical outcomes after granulocyte transfusion in acute myeloid leukemia: A single-center retrospective study.

BackgroundGranulocyte transfusions (GTs) have been used to treat infections in neutropenic patients undergoing chemotherapy or hematopoietic stem cell transplantation. However, there is persistent controversy regarding their outcomes. We aimed to analyze accumulated clinical and laboratory data from patients with acute myeloid leukemia (AML) who underwent GT at our institution in the last 10 years to determine optimal parameters to estimate the GT effect. We hypothesized that patients grouped according to prognostic factors would have inconsistent clinical outcomes.Materials and methodsIn this single-center retrospective study, we collected medical records of 219 GT-treated patients diagnosed with AML from 2009 to 2019. Prognostic factors, including clinical and laboratory parameters, were assessed. Serial measurements of laboratory parameters before and after GT were collected, and the area under the curve of the white blood cells (AUC-WBC) was calculated using the trapezoidal method. A prognostic scoring system using 8 factors from multivariate analysis was analyzed. The primary outcome was survival at 30 days (D30) after GT initiation.ResultsThe 8 factors for the prognosis scoring system included secondary AML, mean AUC-WBC, prothrombin time, and levels of blood urea nitrogen (BUN), bilirubin, alanine aminotransferase (ALT), phosphorus, and lactate dehydrogenase (LDH). Patients were grouped into 4 risk groups (low, medium, high, and very high), and the D30 survival rates for each group were as follows: 87.6% (99/113), 55.9% (33/59), 21.1% (4/19), and 0% (0/19), respectively. Hematopoiesis, liver, and renal function affected the outcome. FLT3 mutation acted as a favorable factor for D30 survival.ConclusionsGT response in patients with AML seemed to be reflected by 8 score markers, and GT was significantly effective in the low-risk group. We suggest that it is important to evaluate the risk assessment of patients before GT to achieve better outcomes.

Adequate trials: How the search for a cure shaped leukemia diagnosis.

This article examines the relationship between diagnosis and therapy, focusing on the case of leukemia and cancer chemotherapy in the 1960s. This case, I argue, reinforces the need to study diagnoses from a social-science perspective, because the persistent controversy around leukemia classification was resolved by institutional restructuring introduced through clinical experimentation, rather than by techno-scientific advances. In an attempt to prove that chemical cancer therapy was possible, oncologists replaced the question 'Is this drug working?' with the question 'How can we make this drug work?' To create the conditions and criteria under which drugs could work, oncologists undertook the reclassification of cancers and patients, producing a new diagnostic style that reversed the roles of diagnosis and therapy. Experts gained and secured the power to classify not by solving existing problems, but by redefining what counts as a problem and what qualifies as a solution. Similarly, therapies can become transformative not only when they 'work', but when they work just well enough to mobilize resources and support. Theorizing these displacements, I develop the concept of 'adequate trials' in order to capture modes of innovation in which a deep commitment to give new technologies a 'fair chance' to succeed (i.e. an 'adequate trial') leads experts to redefine the tasks and goals of their field. To further our theoretical understanding of how rigid drug testing becomes malleable and conducive to normative change, I analyze the organizational, scientific, and jurisdictional conditions that gave rise to oncologists' practical orientations.

Elizabeth Taylor Greenfield's Mid-to-Late Career, Philanthropy, and Activism in Nineteenth-Century America

Elizabeth Taylor Greenfield's Mid-to-Late Career, Philanthropy, and Activism in Nineteenth-Century America

Following diversity through the university: On knowing and embodying a problem

Diversity is a widely shared concern within contemporary universities. Most diversity research focuses on what universities are saying and doing about diversity. Herein lies the assumption that researchers already know ‘the’ problem of diversity before studying it and that it stays the same during and after investigation. This article takes a different approach by following how diversity becomes a problem in a concrete academic setting. More specifically, we ask how conditions of knowledge production intervene with, transform, and contribute to what is known as the problem of diversity. We thereby demonstrate how diversity is made into multiple problems throughout a single setting. More importantly, we show how these problems never fully come to contain the controversy of diversity as epistemic troubles routinely (re)emerged. Indeed, our research provoked such troubles. As one of the researchers was recurringly understood as an embodiment of diversity, fieldwork itself elicited and shaped the persistent controversy of diversity.

Management and outcome of pancreatic trauma: a 6-year experience at a level I trauma center

Abstract Background Pancreatic trauma (PT) accounts for less than 1% of all trauma admissions. Occasionally, PT is undetected during the primary survey and becomes apparent only when complications arise. It occurs in up to 5% of blunt abdominal trauma cases and 12% of individuals with penetrating abdominal injuries. Management is determined by the status of the main pancreatic duct and associated injuries. Methods This was an ambispective study conducted at the Jai Prakash Narayan Apex Trauma Center, All India Institute of Medical Sciences, New Delhi, from January 2015 to December 2017 (retrospective), and January 2019 to December 2020 (prospective). In total, 113 patients with PT were included in this study. Results We analyzed the data of 113 patients with PT included in this study, of which males predominated (93.7%). Blunt PT was present in 101 patients (89.4%) and penetrating PT in 12 patients (10.6%). Half of the patients (51.3%) had the American Association for the Surgery of Trauma grade III PT, followed by grade II (18.6%), and grade I (15%). Of the total 113 patients, 68 (60.2%) were treated with operative management, and 45 (39.8%) with nonoperative management. Distal pancreatectomy, with or without splenectomy, was the most common procedure performed in our study, followed by drainage. There were 27 mortalities (23.8%) during the study period, of which 7 were directly related to PT and 20 were due to other organ-related sepsis and hemorrhagic shock. Conclusion Pancreatic trauma is rare but challenging for trauma surgeons, with persistent management controversies. Early diagnosis is important for favorable results; however, a delay in diagnosis has been associated with higher morbidity and mortality. Low-grade pancreatic injuries can be successfully managed nonoperatively, whereas high-grade pancreatic injuries require surgical intervention.

Healthcare Professionals' Understandings of the Definition and Determination of Death: A Scoping Review.

Background.During the 1950s, advances in critical care, and organ transplantation altered the relationship between organ failure and death. There has since been a shift away from traditional cardiocirculatory based to brain-based criteria of death, with resulting academic controversy, despite the practice being largely accepted worldwide. Our objective is to develop a comprehensive description of the current understandings of healthcare professionals regarding the meaning, definition, and determination of death.Methods.Online databases were used to identify papers published from 2003 to 2020. Additional sources were searched for conference proceedings and theses. Two reviewers screened papers using predefined inclusion and exclusion criteria. Complementary searches and review of reference lists complemented the final study selection. A data extraction instrument was developed to iteratively chart the results of the review. A qualitative approach was conducted to thematically analyze the data.Results.Seven thousand four hundred twenty-eight references were identified. In total, 75 papers met the inclusion criteria. Fourteen additional papers were added from complementary searches. Most were narratives (35%), quantitative investigations (21%), and reviews (18%). Identified themes included: (1) the historical evolution of brain death (BD), (2) persistent controversies about BD and death determination, (3) wide variability in healthcare professionals’ knowledge and attitudes, (4) critical need for BD determination revision.Conclusions.We concluded that although BD is widely accepted, there exists variation in healthcare providers’ understanding of its conceptual basis. Death determination remains a divisive issue among scholars. This review identified a need for increased opportunities for formal training on BD among healthcare providers.

Guadalupe Mountains National Park: An Environmental History of the Southwest Borderlands

The story of American national parks has long consisted of layered histories of ecological changes, social collisions, forceful dispossessions, and persistent controversies over conservation and preservation. Many historians have carved out helpful environmental and public history narratives of parklands in the West. Scholars have recently moved beyond these approaches to consider parks as regional and global borderlands to understand new relationships and conflicts between the ecological, the political, and the personal. Jeffrey P. Shepherd joins this effort with Guadalupe Mountains National Park by tracing the ways many of these factors intersect in national park mountain lands that have long been borderlands for environmental, social, and political relationships. Shepherd argues that the history of the Guadalupe Mountains National Park helps us better understand the ways “people interact with their natural environments: how they perceive and misperceive them, try to control and transform them, and in this case, how they ultimately decide to live with and in them” (p. vii).

Optimizing EEG Source Reconstruction with Concurrent fMRI-Derived Spatial Priors

Reconstructing EEG sources involves a complex pipeline, with the inverse problem being the most challenging. Multiple inversion algorithms are being continuously developed, aiming to tackle the non-uniqueness of this problem, which has been shown to be partially circumvented by including prior information in the inverse models. Despite a few efforts, there are still current and persistent controversies regarding the inversion algorithm of choice and the optimal set of spatial priors to be included in the inversion models. The use of simultaneous EEG-fMRI data is one approach to tackle this problem. The spatial resolution of fMRI makes fMRI derived spatial priors very convenient for EEG reconstruction, however, only task activation maps and resting-state networks (RSNs) have been explored so far, overlooking the recent, but already accepted, notion that brain networks exhibit dynamic functional connectivity fluctuations. The lack of a systematic comparison between different source reconstruction algorithms, considering potentially more brain-informative priors such as fMRI, motivates the search for better reconstruction models. Using simultaneous EEG-fMRI data, here we compared four different inversion algorithms (minimum norm, MN; low resolution electromagnetic tomography, LORETA; empirical Bayes beamformer, EBB; and multiple sparse priors, MSP) under a Bayesian framework (as implemented in SPM), each with three different sets of priors consisting of: (1) those specific to the algorithm; (2) those specific to the algorithm plus fMRI task activation maps and RSNs; and (3) those specific to the algorithm plus fMRI task activation maps and RSNs and network modules of task-related dFC states estimated from the dFC fluctuations. The quality of the reconstructed EEG sources was quantified in terms of model-based metrics, namely the expectation of the posterior probability P(model|data) and variance explained of the inversion models, and the overlap/proportion of brain regions known to be involved in the visual perception tasks that the participants were submitted to, and RSN templates, with/within EEG source components. Model-based metrics suggested that model parsimony is preferred, with the combination MSP and priors specific to this algorithm exhibiting the best performance. However, optimal overlap/proportion values were found using EBB and priors specific to this algorithm and fMRI task activation maps and RSNs or MSP and considering all the priors (algorithm priors, fMRI task activation maps and RSNs and dFC state modules), respectively, indicating that fMRI spatial priors, including dFC state modules, might contain useful information to recover EEG source components reflecting neuronal activity of interest. Our main results show that providing fMRI spatial derived priors that reflect the dynamics of the brain might be useful to map neuronal activity more accurately from EEG-fMRI. Furthermore, this work paves the way towards a more informative selection of the optimal EEG source reconstruction approach, which may be critical in future studies.

Multifaceted roles of IL-38 in inflammation and cancer

Interleukin (IL)-38 is the least well-understood cytokine of the IL-1 family. Since its discovery twenty years ago, numerous studies have linked IL-38 to diverse pathologies, especially in the context of autoimmune and inflammatory processes, while its role in cancer has been less explored. Broad anti-inflammatory effects have been reported for IL-38 in both in vitro and in vivo models, and, together with its homology to the IL-1 and IL-36 receptor antagonists, have raised expectations about its potential therapeutic utility. Data in human and mouse experimental systems support a negative regulatory role of IL-38 on the Th17 axis through effects on T cells and myeloid cells. Additional studies point to tolerogenic functions of IL-38, acting on dendritic cells and regulatory T cells, as well as to inhibition of pro-inflammatory macrophage activity. IL-38 further exhibits anti-inflammatory and tissue protective properties in epithelial and mesenchymal cells. However, published data also reveal variability and inconsistent dose-dependencies of these anti-inflammatory effects, as well as context-dependent pro-inflammatory properties of IL-38, and are difficult to interpret due to the high heterogeneity in the materials and experimental designs used across studies. In addition, it is still not clear which receptor(s) is/are fundamental for IL-38 signalling, and the biological impact of N-terminal processing of the protein remains to be clarified. In this review, we provide an overview of our current knowledge of IL-38 biology, discuss persistent controversies surrounding this cytokine, and highlight some questions to be addressed to facilitate progress towards a better understanding of its mechanisms of action.

Estrogen concentration and estrogen receptor-β expression in postmenopausal colon cancer considering patient/tumor background

A large number of studies have suggested an inhibitory role of estrogens against colorectal cancer (CRC), but persistent controversy exists. CRC characteristics are affected by sex, age, and tumor locus, suggesting the need for a systematic study considering these factors. The purpose of this study was to verify the difference in the pathobiological role of estrogens in CRC according to patient/tumor backgrounds. Surgical specimens from 116 postmenopausal women (≥ 70years/o, n = 74; < 70years/o, n = 42) were studied. Estrogen receptor-β (ER-β), the main ER in the colorectal epithelium, was immunohistochemically examined. The concentrations of estradiol (E2) and estrone (E1) were examined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). These factors were compared according to the tissue type (cancerous or non-cancerous), patients' age, tumor backgrounds (locus, histology, pathological stage, status of mismatch repair protein = MMR), and clinical outcome. ER-β-positivity, higher E2 concentration, deficient-MMR, and medullary/mucinous histology (Med/Muc) were closely related to right-sided tumors in women who were aged ≥ 70years /o (R-Ca ≥ 70) and also closely related to each other. ER-β reduction compared with non-cancerous counterparts was observed only in left-sided tumors of patients < 70years /o (L-Ca < 70), non-Med/Muc, or proficient-MMR tumors. The present results suggest that estrogens do not suppress, but rather promote, R-Ca ≥ 70, Med/Muc, or deficient-MMR tumors, whereas estrogens suppress L-Ca < 70, non-Med/Muc, or proficient-MMR tumors, confirming the difference in pathobiological role of estrogens in postmenopausal colon cancer according to the patients' age and tumor background. This may at least partly explain the controversy regarding the association between estrogens and CRC.

Evolution of the G Matrix under Nonlinear Genotype-Phenotype Maps.

AbstractThe G matrix is a statistical summary of the genetic basis of a set of traits and a central pillar of quantitative genetics. A persistent controversy is whether G changes slowly or quickly over time. The evolution of G is important because it affects the ability to predict, or reconstruct, evolution by selection. Empirical studies have found mixed results on how fast G evolves. Theoretical work has largely been developed under the assumption that the relationship between genetic variation and phenotypic variation-the genotype-phenotype map (GPM)-is linear. Under this assumption, G is expected to remain constant over long periods of time. However, according to developmental biology, the GPM is typically complex and nonlinear. Here, we use a GPM model based on the development of a multicellular organ to study how G evolves. We find that G can change relatively fast and in qualitative different ways, which we describe in detail. Changes can be particularly large when the population crosses between regions of the GPM that have different properties. This can result in the additive genetic variance in the direction of selection fluctuating over time and even increasing despite the eroding effect of selection.

Comfort Women: Impacts on Japan’s Relations with South Korea and The Philippines

The objective of this paper is to analyse how the issue of “comfort women” affects Japan’s relations with its neighboring countries, namely South Korea and the Philippines, using qualitative methods, and constructivism as the conceptual framework. “Comfort women” or “jugun ianfu” in Japanese, and “wianbu” in romanized Korean, is an euphemism used to describe young women from all across Asia who were forced to please the Japanese troops sexually during World War II. These young women were deceived, lured, or kidnapped and then confined in “comfort stations.” Initially, the Japanese government denied that they had systematically confined these so-called “comfort women” and distributed them to comfort stations to be sex slaves, and rejected demands for a formal apology and war reparations to the victims. This had outraged South Korea and the comfort women survivors. This paper suggests that Japan finally admitted its role in the establishment of comfort stations in 1993, and has been trying to make amends with these countries. The process of making amends remains a persistent controversy, with Japan seeking to turn over a new leaf and many South Koreans and Filipinos striving to not let the tragic history be forgotten.

“FUNCTIONAL OUTCOME OF CEMENTED VERSUS UNCEMENTED HEMIARTHROPLASTY IN FRACTURE NECK OF FEMUR", A COMPARATIVE STUDY.

Aim: To elucidate whether a specic type of hemiarthroplasty using an uncemented implant could yield the same clinical results as a hemiarthroplasty using a cemented implant for treatment of displaced femoral neck fractures in elderly people. Introduction: A femoral neck fracture is a most common injury which can lead to increased morbidity and mortality in elderly patients. Hemiarthroplasty, as an effective treatment,1 contributes to early ambulation and good functional recovery. However, there has been persistent controversy over whether cemented hemiarthroplasty (CH) or uncemented hemiarthroplasty (UCH) is preferable for elderly patients. Results: Concerning Harris hip score, results were equivalent for both cemented and uncemented hemiarthroplasty. There were no differences in the inability to walk, use of analgesics, and range of movements. Discussion: The primary functional outcome measure considering the factors like pain, range of movement at the hip joint, ambulatory status &amp; limp, based on modied Harris hip score after 1 year of follow up was equivalent between the two groups. No signicant statistical difference was noted. Conclusion: Both methodologies of hemiarthroplasties may be used with good results for displaced femoral neck fractures.

Fourteen Stations of Auxin.

Auxin has always been at the forefront of research in plant physiology and development. Since the earliest contemplations by Julius von Sachs and Charles Darwin, more than a century-long struggle has been waged to understand its function. This largely reflects the failures, successes, and inevitable progress in the entire field of plant signaling and development. Here I present 14 stations on our long and sometimes mystical journey to understand auxin. These highlights were selected to give a flavor of the field and to show the scope and limits of our current knowledge. A special focus is put on features that make auxin unique among phytohormones, such as its dynamic, directional transport network, which integrates external and internal signals, including self-organizing feedback. Accented are persistent mysteries and controversies. The unexpected discoveries related to rapid auxin responses and growth regulation recently disturbed our contentment regarding understanding of the auxin signaling mechanism. These new revelations, along with advances in technology, usher us into a new, exciting era in auxin research.

Combination of XGBoost Analysis and Rule-Based Method for Intrapartum Cardiotocograph Classification

PurposeThe two major components of a cardiotocograph (CTG) are uterine contraction (UC) and fetal heart rate (FHR) signals. CTG has been widely used to monitor fetal well-being in the past 50 years. The guideline provided by the National Institute of Child Health and Human Development (NICHD) classifies CTG patterns into three categories (I, II, and III) in evaluating the status of a fetus. However, manual interpretation of CTG is time-consuming and is subjected to inter-personal bias.MethodsIn this study, we combined the rule-based method and eXtreme Gradient Boosting (XGBoost) analysis in classifying CTG patterns. Because of the persistent controversies about the Category II of NICHD, XGBoost analysis was used to classify it into IIa and IIb. A total of 68 pregnant women were enrolled in this study.ResultsThree categories (I, II, and III) were consistent in both manual interpretation by clinicians and our algorithm across all categories, and the average Kappa was about 0.72. The probability of fetal distress (FD) was 28.8% and 71.2% in the categories IIa and IIb, respectively.ConclusionThese findings show the proposed method has the potential to provide a clinical assistant tool to monitor fetal well-being and has high potential to be an assistive and warning system to reduce the burden of medical staff.

Noncollapsibility, confounding, and sparse-data bias. Part 2: What should researchers make of persistent controversies about the odds ratio?

A previous note illustrated how the odds of an outcome have an undesirable property for risk summarization and communication: Noncollapsibility, defined as a failure of a group measure to represent a simple average of the measure over individuals or subgroups. The present sequel discusses how odds ratios amplify odds noncollapsibility and provides a basic numeric illustration of how noncollapsibility differs from confounding of effects (with which it is often confused). It also draws a connection of noncollapsibility to sparse-data bias in logistic, log-linear, and proportional-hazards regression.

Metabolic Adaptations to Weight Loss: Relative Changes in Resting Metabolic Rate and Energy Expenditure for Physical Activity and Association With Weight Loss Maintenance

Abstract Objectives There is persistent controversy over the extent to which different components of energy expenditure disproportionately decrease after weight loss and contribute to weight regain through decreased energy requirements. We conducted a secondary analysis of the CALERIE I study to test the hypothesis that decreased resting metabolic rate (RMR) and energy expenditure for physical activity (EEPA) after a 6-month calorie restriction intervention would predict weight regain at 12 months, with a greater decrease in RMR than EEPA. Methods Participants (n = 46) received all food and energy-containing beverages for 6 months. Outcome measures included total energy expenditure by doubly labeled water, RMR by indirect calorimetry, and body composition by BOD POD. Predictions for RMR and EEPA were derived from baseline linear regression models including age, sex, fat mass, and fat free mass. Baseline regression coefficients were used to calculate the predicted RMR and EEPA at 6 months. Residuals were calculated as the difference between measured and predicted values and were adjusted for body weight. The presence of metabolic adaptation was evaluated by a paired t-test comparing measured and predicted RMR at 6 months. Differences between 6-month RMR and EEPA residuals were evaluated by the same method. Linear regression was used to assess the association between 6-month residuals and weight loss maintenance (% weight change, 6 to 12 months). Results Mean weight loss was 6.9% at 6 months with 2.1% regain from 6 to 12 months. No adaptation in RMR was observed at 6 months (mean residual: 19 kcal; 95% confidence interval: −9, 48; P = 0.18). However, significant adaptation was observed in EEPA (mean residual: −199 kcal; −126, −272; P &amp;lt; 0.0001). In addition, the mean 6-month RMR residual was significantly greater than the mean 6-month EEPA residual (218 kcal; 133, 304; P &amp;lt; 0.0001). There was no significant association between 6-month RMR or EEPA residuals and weight regain at 12 months (P = 0.56, 0.34). Conclusions There was no measurable decrease in RMR with weight loss after adjusting for changes in fat free mass and fat mass, but there was a decrease in EEPA. Changes in RMR and EEPA with weight loss over 6 months did not predict weight regain at 12 months. Funding Sources Jean Mayer USDA Human Nutrition Research Center on Aging Doctoral Scholarship; USDA agreement #8050–51000-105–01S

Continuous Deep Sedation Until Death: First National Survey in France after the 2016 Law Promulgating It

ContextThe French parliament passed a groundbreaking law in 2016, opening a right for patients to access continuous and deep sedation until death (CDS) at the end of life, under conditions. Parliamentarians’ goal was to consolidate patients’ rights whilst avoiding legislating on medical aid in dying. ObjectivesTo conduct a first national retrospective survey on CDS to evaluate the number of CDS requested, proposed and performed in 2017 and to elicit qualitative data from physicians on the practice and on the terms used by patients to refer to CDS. MethodsEarly 2018, an online survey was sent to all French hospitals, nursing homes, hospital at homes services and general practitioners (GPs). Descriptive statistics and qualitative inductive content analysis were used to analyze the data and comments of respondents. ResultsThe qualitative data show that respondents generally approve the law on CDS as it sets a legal framework; nonetheless, there is a persistent controversy about CDS vs. euthanasia for some physicians in all settings. GPs reported limited access to midazolam and the difficulty in organizing multidisciplinary procedures as major constraints. In hospital settings in particular, differentiating CDS from other sedation practices is uneasy. All physicians reported patients use multiple elements of language to request CDS. ConclusionAfter the law was passed in France, CDS were requested, proposed and performed in all medical settings, in nursing homes, at home. The qualitative data presented here show the relevance of exploring physicians’ reflexive stances on this practice in different settings and within the context of a patient-physician relationship marked by a new patient's right. The study highlights the wide range of elements of language used by patients at the end of life, as understood by respondent physicians to mean a request for CDS and underscores the polymorphous meaning of CDS.

Initial optimal medical therapy with or without invasive strategy for stable coronary disease: a meta-analysis and systematic review.

There is a persistent controversy regarding the benefit and timing of angiography in patients with stable coronary artery disease (CAD). With this meta-analysis of randomized controlled trials (RCTs) the advantages of initial invasive strategy and medical therapy compared with only medical therapy. We conducted a literature search of the following databases Pubmed/MEDLINE, Cochrane Library and Embase. Data was collected from all the RCTs that compared early invasive approach with medical therapy alone in treating stable CAD which was conducted by two independent authors. Primary outcomes were all-cause mortality and myocardial infarction (MI), while the secondary outcomes included major adverse cardiovascular events (MACE), cardiovascular mortality, cardiovascular hospitalization, hospitalization due to unstable angina and revascularization events. The Mantel-Haenszel random-effects model was used to estimate risk ratios (RRs) and 95% confidence intervals (CIs). We included 15 RCTs (13 916 patients, mean age 63.1, 78.9% men). The early invasive strategy, compared with medical therapy alone, did not reveal a significant reduction in the incidence of all-cause mortality (RR, 0.94; 95% CI, 0.84-1.05, P = 0.30) or MI (RR, 0.93; 95% CI, 0.79-1.10, P = 0.42). Furthermore, the early invasive strategy did not reduce the incidence of cardiovascular mortality, cardiovascular hospitalization or the revascularization rate compared with medical therapy alone (P > 0.05). However, the incidence of MACE and hospitalization due to unstable angina were lower in patients treated with early invasive strategy (RR, 0.79; 95% CI, 0.63-0.99, P = 0.04), and (RR, 0.46; 95% CI, 0.32-0.67, P < 0.0001), respectively. Early invasive strategy with medical therapy did not reduce the incidence of all-cause mortality and MI when compared with medical therapy alone among patients with stable CAD with significant stenosis. However, there was a significant reduction in the incidence of MACE and hospitalization due to unstable angina in the early invasive group.