Different subtypes of eating disorders (ED) show dysfunctional eating behaviors such as overeating and/or restriction in response to emotions. Yet, systematic comparisons of all major EDs on emotional eating patterns are lacking. Furthermore, emotional eating correlates with body mass index (BMI), which also differs between EDs and thus confounds this comparison.n = 204) with restrictive (AN‐R) or binge‐purge anorexia nervosa (AN‐BP), bulimia nervosa (BN), or binge‐eating disorder (BED) completed a questionnaire assessing “negative emotional eating”  and “happiness eating.” ED groups were compared to BMI‐matched healthy controls  to exclude BMI as a confound.Interview‐diagnosed female ED patients (Within HCs, higher BMI was associated with higher negative emotional eating and lower happiness eating. AN‐R reported the lowest degree of negative emotional eating relative to other EDs and BMI‐matched HCs, and the highest degree of happiness eating relative to other EDs. The BN and BED groups showed higher negative emotional eating compared to BMI‐matched HCs. Patients with AN‐BP occupied an intermediate position between AN‐R and BN/BED and reported less happiness eating compared to BMI‐matched HCs.Negative emotional and happiness eating patterns differ across EDs. BMI‐independent emotional eating patterns distinguish ED subgroups and might be related to the occurrence of binge eating versus restriction. Hence, different types of emotional eating can represent fruitful targets for tailored psychotherapeutic interventions. While BN and BED might be treated with similar approaches, AN‐BP and AN‐R would need specific treatment modules.  Moreover, the contribution of mere over−/underweight to emotional eating of the different ED subgroups has not been sufficiently addressed thus far, despite clear evidence that BMI and emotional eating are correlated  requires a measurement instrument that taps into both “directions” of eating changes, that is, under‐ and overeating. We have recently developed the Salzburg Emotional Eating Scale (SEES) that differentiates between increased eating  and decreased eating  in response to emotions  individuals with elevated BMI was expected based on previous research , based on interview‐based diagnostics. In addition, we considered the role of BMI by also investigating weight‐related groups  and by selecting BMI‐matched healthy control groups for each ED subgroup. We separately examined the differences between ED groups on the four emotional eating subscales  of the SEES. Based on previous research, we hypothesized higher 22.1n = 28, normal weight n = 84, overweight n = 29, and obesity n = 31), patients with restrictive subtype AN , binge‐purge subtype AN , BN (n = 71), and BED (n = 36). All groups were partially recruited at the University of Salzburg, Austria (mostly HCs) as well as before and during inpatient treatment at the Schoen Clinic Roseneck, Germany (mostly ED groups). All participants were tested with a structured clinical interview  and were examined using continuous BMI scores. Exclusion criteria for HCs were a current or lifetime ED as revealed with the abovementioned interview. As a result, 44 individuals from originally 420 individuals who were screened for study participation were excluded because of several reasons .In total, 376 female participants were included in the present study, which was part of a larger project: healthy controls with regard to EDs , but not with regard to years of education .ED groups differed with regard to age  to 5  with a score of 3 indicating unchanged food intake. The scale differentiates between four emotional states, namely happiness , sadness , anger  and anxiety , derived from previous factor analyses  post‐hoc tests. To test the effect of BMI on SEES scores we calculated bivariate non‐parametric correlations within the HCs including individuals with underweight, normal weight, overweight and obesity. To differentiate the effect of BMI from ED psychopathology on emotional eating, auxiliary analyses provided BMI‐matched HCs for each ED group: All patients of the BN, respectively BED group, were matched with BMI‐similar HCs. In contrast, as both AN groups are defined by BMI and also showed BMIs in the life threatening range, we opted for a different approach: only for the auxiliary analyses were BMI criteria set to ≥16.00 kg/m3Descriptive data from the groups  can be seen in Table 3.1F = 15.3, p < .001, partial η2 = .186  or nonparametric: χ2(3) = 44.9, p < .001). As can be seen in Figure p = .020), BN  and BED .ED patient groups differed significantly on the SEES happiness eating scores  = 83.1, p < .001, partial η2 = .555  or nonparametric: χ2(3) = 105.7, p < .001). Sadness eating scores were lowest in AN‐R and increased to AN‐BP, BN, up to BED , BN  and BED . Additionally, AN‐BP significantly differed from BN  and BED .ED patient groups also differed significantly on the SEES sadness eating scores  = 47.8, p < .001, partial η2 = .418  or nonparametric: χ2(3) = 88.9, p < .001). Anger eating scores were lowest in AN‐R and increased to AN‐BP, BN, up to BED  and BED . Additionally, AN‐BP significantly differed from BN  and BED .ED patient groups further differed significantly on the SEES anger eating scores  = 36.9, p < .001, partial η2 = .356  or nonparametric: χ2(3) = 75.2, p < .001). Anxiety eating scores were lowest in AN‐R and increased to AN‐BP, BN, up to BED , BN  and BED . Additionally, AN‐BP significantly differed from BN  and BED .ED patient groups differed significantly on the SEES anxiety eating scores (3.5r(172) = −.294, p < .001 and positively with sadness eating, r(172) = .322, p < .001, anger eating, r(172) = .161, p = .034, and anxiety eating, r(172) = .264, p < .001 .As can be seen in Figure 4The aims of the present study were to characterize all relevant ED subgroups with regard to their emotional eating patterns (a), to examine whether and how BMI is related to various types of emotional eating (b), and to refine emotional eating by controlling for BMI differences between ED groups (c). The main findings of this study demonstrated significant differences between the EDs with increasing levels of negative emotional eating and decreasing levels of happiness eating from AN‐R, AN‐BP, BN to BED (a). In HCs higher BMI was associated with higher negative emotional eating and lower happiness eating (b). This demonstrated the necessity to control ED subgroup differences in emotional eating for BMI (c): Compared to weight‐matched healthy individuals, only the mild/moderate AN‐R group reported lower negative emotional eating (“negative undereating”) while the BN and the BED groups reported clearly higher negative emotional eating (“negative overeating”). The AN‐BP group reported lack of “happy overeating,” while the BED group further reported “happy undereating.”4.1Negative emotional eating was low in AN‐R and gradually increased in AN‐BP, BN to BED. Across groups, sadness seemed to contribute the most to such negative emotional overeating, in line with previous research using a sadness mood induction , patients with AN‐R and AN‐BP reported eating Patients with BN and BED did not differ with regard to negative emotional eating suggesting that the similarities of the two groups with regard to binge eating arise on a shared negative emotional eating background, while the compensation—seen only in BN—does not alter the emotional eating expression. This contrasts with research suggesting that specific emotions might be more important for triggering emotional eating in patients with purging behavior  may be more functional with regard to weight management compared to a style of “unhappy overeating” eating in these groups and emotional eating is not mainly influenced by BMI or the presence of compensatory behavior. By contrast, patients with AN‐R showed less negative emotional eating than their BMI‐matched HCs, suggesting that the symptomatic dietary restriction and not BMI seems to contribute to negative emotional (under)eating in this group. Interestingly, the AN‐BP group seemed most similar to BMI‐matched HCs, as they only differed with regard to happiness eating, potentially because their behavior is marked by binge eating and restrained eating at the same time. Hence, whereas BMI seems to be an important factor for negative emotional eating in healthy individuals, emotional eating in ED groups seems mainly to be related to binge eating on the one hand, restrained eating on the other, and not BMI.4.5Several strengths of the present study such as thorough interview diagnostics and mostly large sample sizes alongside with the inclusion of a large control group with a broad BMI range have to been seen in the context of some limitations. First, the present study used a psychometric, cross‐sectional design limiting the causal inference of the interpretation of the results. The SEES is a self‐report questionnaire that measures perceived alterations in food intake in response to emotions. Hence, the scale is susceptible to response and retrospective biases and several researchers argued that emotional eating questionnaires are not validly assessing real behavior (Bongers & Jansen, 4.6It has previously been argued that psychotherapeutic treatment should be tailored to the degree of emotional eating: Individuals with high emotional eating might especially profit from interventions improving emotion regulation skills or mindfulness (van Strien, The authors declare no conflict of interest.Appendix S1: Supporting informationClick here for additional data file.Appendix S2: Supporting informationClick here for additional data file.Appendix S3: Supporting informationClick here for additional data file.


In contrast, thromboembolic  and mortality  risks were significantly increased in underweight anticoagulated AF patients (BMI <18.5 kg/m2). In overweight and obese anticoagulated AF patients, the risks of major bleeding  and intracranial bleeding  were also significantly lower compared to normal BMI patients, while similar risks were observed in underweight and morbidly obese patients. This meta‐analysis demonstrated lower thromboembolic and mortality risks with increasing BMI. However, as this paradox was driven by results from randomized studies, while observational studies rendered more conflicting results, these seemingly protective effects should still be interpreted with caution.Although obesity is associated with the development and progression of atrial fibrillation (AF), an obesity paradox may be present, illustrated by seemingly protective effects of obesity on AF‐related outcomes. Body mass index (BMI) has an impact on outcomes in AF patients using oral anticoagulants. After searching Medline and Embase, meta‐analysis of results of four randomized and five observational studies demonstrated significantly lower risks of stroke or systemic embolism  and all‐cause mortality  in overweight, obese and morbidly obese anticoagulated AF patients (BMI 25 to <30, ≥30 and ≥40 kg/m A meta‐analysis investigates the impact of underweight, overweight (BMI 25 to <30 kg/m22),2),2),2),2)2)An extensive literature search was performed using the Medline and Embase databases see  by two iFor the meta‐analysis, results from Phase III RCTs  and longitudinal observational cohort studies examining the risk of stroke/SE, all‐cause mortality, major bleeding and intracranial bleeding in underweight, overweight, obese and Class II–III obese AF patients using oral anticoagulants  compared to normal BMI anticoagulated AF patients were selected, with the BMI subgroups categorized according to the WHO BMI classification.Up to February 1, 2021, 6553 articles were identified. Additional articles of interest were selected by screening the reference list of studies. If secondary analyses of Phase III RCTs did not report outcome data in specific BMI subgroups , the FDA (U.S. Food and Drug Administration) Advisory Committee briefing documents on regulatory submissions for drug approval of NOACs by the pharmaceutical company  were searched for the gray literature.2‐statistic. The risk of bias of studies included in the meta‐analysis was assessed using the quality assessment tool 'QUALSYST' from the “Standard Quality Assessment Criteria for Evaluating Primary Research Papers from a Variety of Fields” , patient characteristics , comparison , and the aforementioned outcomes of interest were extracted from the original publications,  Fields” .13 Fou Fields” .33.13.1.12) included in the ENGAGE AF‐TIMI 48 trialIn RCTs investigating oral anticoagulants in AF patients, lower thromboembolic risks have been observed with increasing BMI, corroborating the 'obesity paradox' . Indeed,However, in other observational studies, the impact of BMI on AF‐related outcomes was not or less clear, illustrating the general controversy regarding the topic. For example, obesity was associated with similar stroke,2 increase in BMI, although only 19% were OAC‐treated and analyses were not adjusted for confounders.In contrast, two observational studies illustrated worse outcomes in obese AF patients. A Croatian cohort study by Lucijanic et al. observed a significantly shorter time to stroke/SE in obese versus non‐obese AF patients.3.1.22DS2‐VASc score.In line with the impact on the thromboembolic risk, (morbid) obesity was associated with significantly lower all‐cause mortality risks compared to the normal BMI subgroup in the ARISTOTLE3.1.32 increase in BMI in a TaiwaneseAs opposed to the lower thromboembolic and mortality risks with increasing BMI, the impact on bleeding outcomes is less evident . SimilarConversely, significantly higher bleeding risks in obese versus normal BMI AF patients were observed in the Chinese MISSION‐AF study,In AF patients with low body weight (≤50–60 kg) compared to normal weight, worse thromboembolic and mortality outcomes have also been observed, while bleeding risks were mostly comparable  Phase III RCTs2) anticoagulated AF patients, the risk of stroke/SE was significantly higher in underweight (BMI <18.5 kg/m2) anticoagulated AF patients , whereas significantly lower risks were seen in overweight (BMI 25 to <30 kg/m²), obese (BMI ≥30 kg/m2) and morbidly obese (BMI ≥40 kg/m2) anticoagulated AF patients  , while significantly lower risks were demonstrated in overweight, obese and morbidly obese anticoagulated AF patients  Figures .Moreover, overweight and obese anticoagulated AF patients were associated with significantly lower major bleeding  and intracranial bleeding risks  compared to normal BMI AF patients, whereas similar major and intracranial bleeding risks were observed in underweight  and morbidly obese anticoagulated AF patients  Figures .2) (Similar trends were observed in anticoagulated AF patients with Class II obesity (BMI 35‐ < 40 kg/m2) . Moreove2) .2 62%) and Class II obese AF patients (I2 69%), and the risk of major bleeding in overweight (I2 64%) and morbidly obese AF patients (I2 88%), substantial heterogeneity was detected, probably caused by heterogeneous results from the included randomized studies. Indeed, overweight and Class II obese patients included in the ARISTOTLE trial2 81% and 80%, respectively), probably due to heterogeneous results of the included observational studies.No publication bias was suspected based on visual inspection of the funnel plots, although the interpretation may not have been reliable, as less than 10 studies were included in the meta‐analysis . All inc42) was associated with higher thromboembolic and mortality risks, which may be suggestive of a 'lean paradox.' This is in line with results in AF patients with low body weight of ≤60 kg compared to normal weight, illustrated by the meta‐analysis by Boonyawat et al.As a vivid debate is still ongoing whether or not (morbid) obesity has a protective effect on AF‐related outcomes, this meta‐analysis based on four randomized4.1Several considerations and hypotheses have been suggested in order to elucidate the apparent protective effect of obesity on AF‐related outcomes. First, cardiovascular risk factors  may have been tackled earlier in obese patients, resulting in faster and more intensive medical treatment.Second, the large metabolic reserves present in obese patients may help to cope with chronic diseases and help to survive complications or exacerbations.Third, inflammation  and activation of the renin‐angiotensin‐aldosterone system (expression of angiotensin‐II receptors which activate thromboxane A2 and induce IL‐6) promote a prothrombotic state in AF.Fourth, selection bias in randomized studies may have influenced results, illustrated by the difference in comorbidities and age between obese and normal BMI AF patients. Indeed, obese patients included in RCTs frequently had a better renal function and less prior stroke/SE, although the prevalence of hypertension and diabetes mellitus was higher.Lastly, in line with the fourth hypothesis, the observed worse outcomes in underweight versus normal BMI AF patients may have been the result of older age and a higher comorbidity burden, as underweight has been associated with frailty and chronic diseases in the elderly.4.22).Our systematic review and meta‐analysis have several strengths, such as the inclusion of both Phase III RCTs, characterized by detailed methodologies and well‐defined cohorts, and longitudinal observational cohort studies, which include large real‐world patient subgroups with long follow‐up. By pooling results, we have included large numbers of patients for each outcome, even in the subgroup of patients with underweight and morbid obesity, who were underrepresented in randomized studies. Moreover, we have only included patients based on the BMI, as a body weight of <60 kg or >120 kg does not necessarily correspond with underweight or morbid obesity, respectively (e.g., any person larger than 1.73 meters with a body weight of 120 kg has a BMI of <40 kg/mSeveral limitations should be mentioned complicating the comparability of included studies. First, classification of patients according to BMI differed between studies. For example, some studies categorized their patient cohorts according to the BMI tertiles5In conclusion, this meta‐analysis exploring the controversial 'obesity paradox' demonstrated lower thromboembolic and mortality risks with increasing BMI in anticoagulated AF patients. However, as this paradox was driven by results from randomized studies, while subsequent observational studies rendered more conflicting results, these seemingly protective effects should still be interpreted with caution.Maxim Grymonprez and Lies Lahousse contributed to the concept and design of the systematic review. Maxim Grymonprez and Andreas Capiau performed the literature search. Maxim Grymonprez performed the statistical analysis, interpretation and writing. Andreas Capiau, Tine L. De Backer, Stephane Steurbaut, Koen Boussery, and Lies Lahousse revised the systematic review critically. All authors contributed to the article and approved the submitted version.Appendix S1: Supporting informationClick here for additional data file.


BMI of 25 kg/m2 and below or 40 kg/m2 and above, were independent predictors of in‐hospital mortality in a multivariate analysis along with prior history of congestive heart failure and Deyo Comorbidity Index of ≥2. A U‐shaped relationship between the BMI and in‐hospital mortality was documented in patients hospitalized for an out of hospital sudden cardiac death in the United States in the recent years.While obesity has been shown to be associated with elevated risk for Sudden Cardiac Death (SCD), studies examining its effect on outcomes in SCD victims have shown conflicting results. We aimed to describe the body mass index (BMI) distribution in a nationwide cohort of patients admitted for an out of hospital SCD (OHSCD), and the relationship between BMI and in‐hospital mortality. We drew data from the U.S. National Inpatient Sample (NIS), to identify cases of OHSCD. Patients were divided into six groups based on their BMI . Socio‐demographic and clinical data were collected, mortality and length of stay were analyzed. Multivariate analysis was performed to identify predictors of mortality. Among a weighted total of 2330 hospitalizations for OHSCD in patients with documented BMI, the mean age was 62.3 ± 29 years, 52.4% were male and 62% were white. The overall rate of in‐hospital mortality was 69.3%. A U‐shaped relationship between the BMI and mortality was documented, as patients with 25 < BMI < 40 exhibited significantly lower mortality (60.7%) compared to the other BMI groups (75.2%),  Hippocrates recognized that “sudden death is more common in those who are naturally fat than in the lean”.2 admitted to the hospital following a sudden cardiac death.Sudden cardiac death (SCD) is responsible for about 50% of the mortality from cardiovascular disease in the United States and other developed countries.We aimed at describing the BMI distribution and baseline characteristics in a nationwide cohort of patients, admitted for an out of hospital sudden cardiac death (OHSCD) in the United States, and the relationship between BMI and in‐hospital mortality.22.1The data were drawn from the National Inpatient Sample (NIS), the Healthcare Cost and Utilization Project (HCUP), and Agency for Healthcare Research and Quality (AHRQ)The NIS is the largest collection of all‐payer data on inpatient hospitalizations in the United States. The dataset represents an approximate 20% stratified sample of all inpatient discharges from U.S. hospitals.For the purpose of this study, we obtained data for the years 2015 (last quarter) and 2016. International Classification of Diseases, 10th Revision, Clinical Modification (ICD‐10‐CM) was used from the last quarter of 2015 and thereafter for reporting diagnoses and procedures in the NIS database during the study period. For each index hospitalization, the database provides a principal discharge diagnosis and a maximum of 29 additional diagnoses, in addition to a maximum of 15 procedures. The reason we only included the data coded with ICD‐10 codes is that the ICD‐10 system includes individual codes for BMI values and ranges.2.2We identified patients 18 years of age or older with a primary diagnosis of sudden cardiac death based on ICD‐10‐CM codes I46.2, I46.8, or I46.9, who had one of the BMI, Z68.x, codes, among the secondary diagnoses. Of notice, these represented only the successfully resuscitated OHSCD patients, since those who were not successfully resuscitated in the field or died in the emergency departments, were not hospitalized. To have the “cleanest” possible data on patients admitted for successfully resuscitated out of hospital cardiac arrest, we avoided including patients with a secondary diagnosis of a cardiac arrest in our analysis due to the fact that these could represent patients who underwent an in‐hospital sudden cardiac death or had a prior history of cardiac arrest included as a secondary diagnosis.2, under‐weight group; Z68.20–25, BMI 20–25 kg/m2, normal‐weight group; Z68.26–30, BMI 26–30 kg/m2, over‐weight group; Z68.31–35, BMI 31–35 kg/m2, obese I group; Z68.36–39 kg/m2, BMI 36–39, obese II group; Z68.4, BMI ≥40 kg/m2, extremely obese group. In addition to analyzing the individual BMI subgroups mentioned above, we combined the overweigh, Obese I and Obese II groups to compare the outcomes of these patients to the combined group of all the underweight, normal weight and extremely obese patients.The following codes represent the six BMI subgroups we have created for our study: Z68.1, BMI ≤19 kg/mThe following patient demographics were collected from the database: age, sex, and race. Prior comorbidities were identified by measures from the AHRQ. For the purposes of calculating Deyo‐Charlson Comorbidity Index (Deyo‐CCI), additional comorbidities were identified from the database using ICD‐10‐CM codes. Deyo‐CCI is a modification of the Charlson Comorbidity Index, containing 17 comorbidity conditions with differential weights, with a total score ranging from 0 to 33. (Detailed information on Deyo‐CCI provided in the 2.3χ2) test and Wilcoxon Rank Sum test were used to compare categorical variables and continuous variables, respectively. The NIS provides discharge sample weights that are calculated within each sampling stratum as the ratio of discharges in the universe to discharges in the sample.p < .05 in our final multivariable regression model. For all analyses, we used SAS® software version 9.4  A p value <.05 was considered statistically significant.The chi‐square χ2 test an33.1A total of 466 hospitalizations for successfully resuscitated out of hospital sudden cardiac death patients across the United States during 2015 (last quarter) and 2016 were included in the analysis. After implementing the weighting method, these represented an estimated total of 2330 hospitalizations for OHSCD, in patients with documented BMI during the index hospitalization. The majority of patients (52.4%) were male and the mean age of the cohort was 62.3 ± 29 years.2). The data reveal that 16.3% of all hospitalizations for successfully resuscitated OHSCD included patients with a diagnosis of VT/VF and 9.2% of the patients were diagnosed with an acute myocardial infraction (STEMI or NSTEMI). Twelve percent of the patients underwent a percutaneous coronary angiography and 2.8% of the patients required percutaneous coronary intervention.As shown in Table 3.2p < .001). While about three quarters of the OHSCD patients (74.9%) across the country were obese (BMI > 30 kg/m2), the prevalence of obesity among the study population was highest in the Midwest (81.4%) and lowest in the West coast of the United States (68.3%), p < .001. Female predominance was documented in the obese II and the extremely obese groups. Younger age and higher prevalence of comorbidities including hypertension, diabetes and congestive heart failure were documented in the obese patients (Table p < .001).Baseline characteristics of the study population in the different BMI groups is presented in detail in Table 3.3p < .001 . In addition, BMI 26–30, BMI 31–35, BMI 36–39 (compared to BMI 20–25) and having BMI between 26 and 39 compared to the other groups combined (below 25 kg/m2 or above 40 kg/m2), decreased the risk for in‐hospital mortality . Personal history of hypertension and diabetes were found as predictors of improved outcomes in a univariate analysis, before adjusting for potential confounders. While admission with a diagnosis of STEMI or NSTEMI did not predict improved outcomes, the small proportion of patients who underwent coronary intervention (2.8%) were found to have lower mortality, Odds Ratio (OR) –0.21, 95% Confidence Interval (95% CI), (0.17–0.28). After adjusting for potential confounders, BMI below 25 kg/m2 or above 40 kg/m2, compared to BMI 26–39 kg/m2, remained an independent predictor of in‐hospital mortality in a multivariate analysis , while overweight patients did better  and obese had similar survival as normal weight patients.Some of the prior studies, investigating the relationship between BMI and survival after a sudden cardiac death, analyzed specific patient subgroups like post MI sudden cardiac death patientsOur goal was to assess the relationship between BMI and in‐hospital course and outcomes in a nationwide, general population of patients, hospitalized following a successfully resuscitated out of hospital cardiac death in the US, overcoming the potential “selection bias” in prior studies. We also aimed to better differentiate the different subgroups of patients suffering from obesity, dividing the obese patients into mild (30 < BMI≤35), moderate (35 < BMI < 40) and extremely obese (BMI ≥ 40) groups.The clinical characteristics of the patient population in this study were consistent with prior publications on SCD in regard to the median age and different comorbidities such as diabetes mellitus (DM), hypertension (HTN) and history of a myocardial infarction (MI).Our data revealed a U‐shaped relationship between the BMI and the in‐hospital mortality, while the over‐weight, obese I and obese II patient subgroups (BMI 26–39) exhibited significantly lower in‐hospital mortality. Several other studies have implied that the “obesity paradox”, described in various cardio‐vascular conditions such as acute myocardial infarction and heart failure, applies to patients admitted after a sudden cardiac death, showing a lower mortality in obese patients.As shown in Table Not surprisingly, patients in the higher BMI groups suffered from increased prevalence of cardiovascular risk factors such as DM and HTN. Some prior studies reported better outcomes in patients with hypertension,This association of obesity with favorable survival after OHSCD should not be interpreted as supporting weight gain. Elevated BMI has been proven over the years as an independent risk factor for various cardio‐vascular conditions such as ischemic heart disease, acute coronary syndrome, congestive heart failure, atrial and ventricular arrhythmia and sudden cardiac death.Our study should be interpreted in the context of several limitations. First, the NIS database is a retrospective administrative database that contains discharge‐level records and as such is susceptible to coding errors. Second, the lack of patient identifiers in the NIS database prevented us from using other outcome variables and mortality measures such as at 30 days. We could only capture events that occurred in the same index hospitalization. The NIS database also does not include detailed information about patients' clinical characteristics, medication, blood tests etc. Therefore, we cannot rule out residual confounding of the association we observed. These limitations are counterbalanced by the real world, nationwide nature of the data, lack of selection bias as well as absence of reporting bias introduced by selective publication of results from specialized centers.4.1A U‐shaped relationship between BMI and in‐hospital mortality was documented in patients hospitalized for out of hospital sudden cardiac death in the United States in the recent years. These findings support the existence of an “obesity paradox” in OHSCD, associated with improved in‐hospital survival.


Juvenile forms of parkinsonism are rare conditions with onset of bradykinesia, tremor and rigidity before the age of 21 years. These atypical presentations commonly have a genetic aetiology, highlighting important insights into underlying pathophysiology. Genetic defects may affect key proteins of the endocytic pathway and clathrin‐mediated endocytosis (CME), as in DNAJC6‐related juvenile parkinsonism.DNAJC6 parkinsonism‐dystonia and determine the functional consequences on auxilin and dopamine homeostasis.To report on a new patient cohort with juvenile‐onset Twenty‐five children with juvenile parkinsonism were identified from a research cohort of patients with undiagnosed pediatric movement disorders. Molecular genetic investigations included autozygosity mapping studies and whole‐exome sequencing. Patient fibroblasts and CSF were analyzed for auxilin, cyclin G–associated kinase and synaptic proteins.DNAJC6 mutations. All presented with neurodevelopmental delay in infancy, progressive parkinsonism, and neurological regression in childhood. 123I‐FP‐CIT SPECT (DaTScan) was performed in 3 patients and demonstrated reduced or absent tracer uptake in the basal ganglia. CSF neurotransmitter analysis revealed an isolated reduction of homovanillic acid. Auxilin levels were significantly reduced in both patient fibroblasts and CSF. Cyclin G–associated kinase levels in CSF were significantly increased, whereas a number of presynaptic dopaminergic proteins were reduced.We identified 6 patients harboring previously unreported, homozygous nonsense DNAJC6 is an emerging cause of recessive juvenile parkinsonism‐dystonia. DNAJC6 encodes the cochaperone protein auxilin, involved in CME of synaptic vesicles. The observed dopamine dyshomeostasis in patients is likely to be multifactorial, secondary to auxilin deficiency and/or neurodegeneration. Increased patient CSF cyclin G–associated kinase, in tandem with reduced auxilin levels, suggests a possible compensatory role of cyclin G–associated kinase, as observed in the auxilin knockout mouse. DNAJC6 parkinsonism‐dystonia should be considered as a differential diagnosis for pediatric neurotransmitter disorders associated with low homovanillic acid levels. Future research in elucidating disease pathogenesis will aid the development of better treatments for this pharmacoresistant disorder. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. Parkin, PINK1, and DJ‐1)ATP13A2, PLA2G6, FBXO7, SLC6A3, SLC39A14, and PANK2) have been described.SYNJ1DNAJC6,Classical Parkinson's disease (PD) is an age‐related neurodegenerative disorder, mainly affecting adults aged >50 years. Patients typically present with resting tremor, bradykinesia, rigidity, and postural instability. To date, a number of early‐onset genetic forms of PD  and pattern of cerebrospinal fluid (CSF) neurotransmitter metabolites. Furthermore, we utilized patient fibroblasts and CSF to investigate secondary effects on auxilin, cyclin G–associated kinase (GAK), and dopaminergic proteins.In this study, we report on 6 children from three families, presenting with juvenile parkinsonism‐dystonia associated with novel, biallelic A cohort of 232 children with undiagnosed movement disorders were recruited for research between 2012 and 2016 at UCL Great Ormond Street–Institute of Child Health . A subgroup of 25 patients were identified with juvenile parkinsonism, defined as onset of bradykinesia before 21 years of age, and at least one of the following signs: resting tremor, rigidity, and postural instability. All patients had detailed clinical assessment, undertaken by a movement disorder specialist. Review of (1) the clinical history, (2) features on neuroimaging, and (3) video recordings of the movement disorder at different time points was undertaken. Written informed consent was obtained from participating families, and the study was approved by the local ethics committees (Reference 13/LO/0168).In order to rule out a primary neurotransmitter disorder, where possible, patients had a routine diagnostic lumbar puncture for CSF neurotransmitter analysis. Using standardized protocols,DNAJC6 coverage of 30×, with minimum coverage 10× for 82% of the gene. WES data were probed for putative disease‐causing DNAJC6 mutations in the remaining 20 cases . This was undertaken through UCL Genomics (8 patients) and Wellcome Trust Sanger Institute (12 patients) within the Wellcome Trust UK10K Rare Diseases project, as previously reported.DNAJC6 mutations were identified, whole‐exome data were also probed for other genes associated with early‐onset dystonia‐parkinsonism , we prioritized two consanguineous families  for initial analysis. These families were investigated using an autozygosity mapping approach, given that the affected children were phenotypically similar and both families originated from the same region in Pakistan. Single‐nucleotide polymorphism (SNP) genotyping was performed as previously described.DNAJC6 sequence  was utilized to design primers, using Primer3 software (http://bioinfo.ut.ee/primer3/). Primers and polymerase chain reaction (PCR) amplification conditions are available on request. PCR products were cleaned up with MicroCLEAN (Web Scientific) and directly sequenced using Big Dye Terminator Cycle Sequencing System . Sequencing reactions were run on an ABI PRISM 3730 DNA Analyzer (Applied Biosystems Inc.) and analyzed with Chromas (http://www.technelysium.com.au/chromas.html).Sanger sequencing was used to confirm variants identified on WES and to establish familial segregation. A genomic Methods to assess protein expression in patient fibroblasts were as previously reported.Patients A‐III:1, A‐III:4, and B‐IV:4 underwent lumbar puncture for diagnostic CSF neurotransmitter analysis, and three CSF aliquots were snap frozen and stored at −80°C. Seven age‐matched control CSF samples were identified, from subjects without movement disorders on no medication. Patient and control CSF samples were immunoblotted for auxilin, GAK, and dopaminergic proteins as described previously.t test.Statistical analysis was performed using Prism software , with data tested for Gaussian distribution and compared by the Student https://www.ebi.ac.uk/ega/home), EGAS00001000128(UK10K RARE FIND). Details of statistical analysis can be shared upon request.All clinical and experimental data relevant to this study are contained within the article. For Families A, B, and C, there is no ethical approval in place for deposition of whole‐exome sequencing genomic data into a public repository. Genomic data from UK10K are available at the EGA European Genomen Phenome Archive  was identified both in A‐III:1 and B‐IV:2 on WES, located within the common region of homozygosity. No other pathogenic changes in previously reported genes causing juvenile parkinsonism‐dystonia phenotypes were identified from the WES data. Direct Sanger sequencing confirmed the homozygous c.766C>T mutation in all 5 affected patients, and familial segregation studies revealed that all parents were obligate carriers in both kindreds, with unaffected siblings either wild type or heterozygous for the identified variant  in a sixth unrelated patient (Patient C), which was confirmed on Sanger sequencing.WES performed in Patients A‐III:1 and B‐IV:2 revealed 23,365 and 23,549 variants, respectively. Given familial consanguinity and the autozygosity mapping results, targeted analysis for recessive pathogenic variants within the putative disease locus on chromosome 1 was undertaken. A single homozygous nonsense variant c.766C>T (p.R256*) in Patients A‐III:1, A‐III:4, and A‐III:5 are 3 affected children born to first‐cousin parents, currently 20, 12, and 10 years old , but nonprogressive over time. All siblings had early neurodevelopmental delay and moderate learning difficulties.l‐dopa, CSF HVA, and HVA:5‐HIAA ratio were low. Brain MRI showed evidence of right‐sided atrophy of the perisylvian region and right cerebellum by 19 years of age  showed absent uptake in the basal ganglia when compared to normal subjects  at 11 years showed profound reduction in tracer uptake in the basal ganglia  presented with fine motor difficulties at 8 years of age. They subsequently developed positional tremor, upper limb dystonic posturing, hypophonia, hypomimia, bradykinesia, cogwheel rigidity, and postural instability over 12 months  and 3. LPatients B‐IV:2 and B‐IV:4 are 2 affected girls, born to first‐cousin parents, and currently 28 and 19 years old. Both were born uneventfully following a normal pregnancy, presenting with early feeding difficulties, hypotonia, and delayed milestones by 6 months old. Both made slow developmental progress, achieving independent ambulation and spoken language by 3 years of age.l‐dopa , selegiline, rotigotine, and trihexyphenidyl. The younger sibling, B‐IV:4, presented at 7 years with gait deterioration, bradykinesia, and cogwheel rigidity. She lost independent ambulation and speech by 10 years (123I‐FP‐CIT SPECT (DaTScan) at 17 years showed profound reduction in tracer uptake in the basal ganglia  compared to controls (but not 5‐HIAA levels) in 3 patients  and a trend for increased GAK protein , vesicular monoamine transporter , dopamine transporter , and D2 receptor  imaging, CSF analysis, and immunoblotting suggest downstream dyshomeostasis of auxilin, GAK, and dopaminergic proteins in DNAJC6‐related disease.Juvenile parkinsonism attributed to DNAJC6‐parkinsonism have core clinical characteristics  was performed in 3 patients, demonstrating reduced tracer uptake in the basal ganglia, suggestive of impaired presynaptic dopamine uptake and striatonigral neurodegeneration. Postmortem studies have confirmed striatal dopamine deficiency in patients with parkinsonism.DNAJC6 patients. MRI brain imaging further corroborates this hypothesis; the mild generalized cerebral and/or cerebellar atrophy in 4 patients suggests that DNAJC6‐related disorders may also be associated with neuronal loss in other regions of the central nervous system.DNAJC6 mutations have been reported in early adult‐onset PD.All 6 cases fit the juvenile phenotype associated with this gene, though more recently, DNAJC6 are predicted to result in loss of protein function. To date, splice‐site variants,Homozygous and compound heterozygous mutations in DNAJC6 encodes for auxilin, a neuronally expressed J‐chaperone protein involved in the uncoating of clathrin‐coated vesiclesLRRK2,VMAT2,SNCA‐related disease.DNAJC6 mutations further corroborates the notion that auxilin is likely to have a central role in neurodevelopment, given its role in CME. In Drosophila, auxilin is crucial for Notch signaling, a developmental pathway that regulates neural stem‐cell proliferation, survival, renewal, and differentiation, as well as neuronal specification of dopaminergic neurons.DNAJC6 mutations, we studied auxilin and GAK protein levels in 2 patients using patient fibroblasts and CSF. Auxilin is a neuron‐specific protein, enriched in presynaptic terminals, whereas GAK is an ubiquituously expressed protein.DNAJC6 patients, partially compensating for auxilin reduction, as evident in the auxilin knockout mouse model.To investigate the downstream effects of DNAJC6 mutations may impact the dopaminergic system, we used patient CSF to analyze proteins involved in dopamine signaling and homeostasis. We observed that patient CSF had significantly reduced levels of VMAT, DAT, TH, and D2R when compared to controls. 123I‐FP‐CIT SPECT (DaTScan) imaging additionally provides in vivo evidence of impaired DAT function in DNAJC6 patients. VMAT and DAT are both synaptic transporters recycled through clathrin‐mediated endocytosis.DNAJC6 mutations thus may affect D2R protein levels and normal postsynaptic function. It is likely that presynaptic D2R autoreceptor function will also be affected, leading to aberrant TH regulation.Diagnostic CSF neurotransmitter analysis revealed that levels of the stable dopamine metabolite (HVA) were either below the age‐related reference ranges or close to the lower limit of normal in our patients, indicating impaired dopamine turnover. Indeed, CSF‐HVA levels and HVA:5‐HIAA ratios were comparable to those observed in TH deficiency, an inherited dopamine synthesis defect associated with central dopamine deficiency.DNAJC6‐associated parkinsonism are likely to be multifactorial. Another plausible explanation for the reduction in synaptic protein levels may be as a result of neurodegeneration secondary to defective chaperone function. Auxilin and other J‐chaperone proteins play a crucial role in regulating the folding and conformational change of proteins to maintain integrity in the neuron.DNAJB2, DNAJB6, DNAJC5, DNAJC6, DNAJC12, DNAJC13, DNAJC19, and DNAJC29) have been described.Overall, our findings suggest that the mechanisms governing DNAJC6 mutations associated with early neurodevelopmental delay, juvenile parkinsonism, and neurological regression in the second decade of life. We further demonstrate disturbance of dopamine homeostasis in patient‐derived CSF and report on a possible GAK‐mediated compensatory mechanism for auxilin deficiency. Mutations in DNAJC6 are rare, but a likely under‐recognized cause of parkinsonism‐dystonia in infants and children. Elucidating the genetic diagnosis has important implications for families given that early diagnosis negates the need for extensive invasive investigations, facilitates treatment strategies, and aids genetic counseling for future pregnancies. The early clinical features and CSF neurotransmitter signature observed in our patients can mimic primary neurotransmitter disorders, and DNAJC6 mutations should thus be considered as a differential diagnosis. We observed reduced auxilin and increased GAK protein levels, suggesting a possible compensatory role for GAK in this condition. Study of CSF synaptic proteins suggest downstream effects on dopamine synthesis, recycling, homeostasis, and signaling that may result from a combination of primary auxilin deficiency and neurodegeneration. Abnormal synaptic vesicle dynamics are increasingly recognized as a disease mechanism in neurodegenerative parkinsonian disorders, and future research into elucidating the pathogenesis of such conditions will no doubt assist the development of novel targeted treatments.In conclusion, we report on a cohort of patients with previously unreported (1) Research Project: A. Conception and Design; B. Acquisition of Data; C. Analysis and Interpretation of Data; (2) Manuscript: A. Writing of the First Draft, B. Review and Critique; 3) Other: A. Statistical Analysis  is also present when ambulant. He has difficulties in maintaining normal balance when he is standing.Click here for additional data file.Video 3 Patient A‐III:5. He has recently turned 10 years old. He has evidence of resting tremor and bradykinesia. No abnormal eye movements are present. The gait is mildly affected as he can run and walk, but has dystonic posturing of both hands. Improvement of dystonic posturing is seen upon running. He has trouble in trying to walk on a line, showing difficulties in maintaining balance.Click here for additional data file.Video 4 Patient B‐IV:2. She is now 27 years old. She has significant disability and is completely wheelchair bound. She is very hypomimic and has poor head control. She is able to understand simple commands, but she is extremely hypokinetic. She exhibits some sudden muscle contractions from both arms and legs. She has fixed distal deformities in her hands and feet, with dystonic postures. No signs of spasticity are present.Click here for additional data file.Video 5 Patient B‐IV:4. She is now 17 years old. She has poor head control. She is also very hypomimic. She can understand commands. She exhibits a clear tremor. She has episodic whole‐body shaking, almost always related to new situations when she is anxious or nervous. These episodes are short and rarely last for more than 1 minute. Bradykinesia is evident on finger‐finger testing. Cogwheel rigidity is more evident than in her older sister, B‐IV:2. Distal tremor from her left foot is shown.Click here for additional data file.Video 6 Patient C. Segment 1 demonstrates examination in the off state at age 14. There is moderate facial masking with prominent lower facial dystonia. She has moderate‐to‐severe dysarthria. Hand grasping, finger tapping, and foot tapping is moderately impaired bilaterally, left slightly greater than right. There is moderate generalized bradykinesia. Her gait is characterized by mildly reduced stride length, reduced bilateral arm swing, some festination, and a tendency to fall forward. Pull test is negative. Segment 2 illustrates examination in the off state at age 17, which shows progression from segment 1, taken 3 years earlier. She has marked anterocollis with more prominent lower facial dystonia. She is almost mute. She can follow some simple commands, but her movements are markedly bradykinetic with long latency to respond. She has prominent drooling. Finger‐to‐nose testing, hand grasping, and foot tapping reveal marked bradykinesia bilaterally. She requires assistance from one person to stand up from a chair and has a tendency to fall backward. She can take only a few steps very slowly, requiring assistance from other people.Click here for additional data file.FIG. S1 Brain MRI in patient A‐III:1. Patient A‐III:1: axial T2 and coronal FLAIR images at ages 12 and 19 years showing progressive right frontoparietal and perisylvian (black star) atrophy over time. There is also evidence of right cerebellar atrophy between the two studies (white arrow). FLAIR, fluid‐attenuated inversion recovery.Click here for additional data file.FIG. S2 Brain MRI in Patient B‐IV:4. Patient B‐IV:4: Sagittal T1 and axial T2 MR images at age 12 and 16 years show a subtle, but definite, global brain parenchymal volume loss over time, particularly in the posterior aspects of the cerebral hemispheres. The occipital horns of the lateral ventricles are, as a result, more dilated over time. There is also subtle cerebellar atrophy between the two studies as shown on the sagittal T1 images.Click here for additional data file.


Artemisia spp.) ecosystem, much of which has been fragmented or converted to non‐native grasslands via the cheatgrass‐fire cycle. Like many sagebrush obligates, greater sage‐grouse (Centrocercus urophasianus) depend upon sagebrush for food and cover and are affected by changes to this ecosystem. We investigated habitat selection by 28 male greater sage‐grouse during each of 3 years after a 113,000‐ha wildfire in a sagebrush steppe ecosystem in Idaho and Oregon. During the study period, seeding and herbicide treatments were applied for habitat restoration. We evaluated sage‐grouse responses to vegetation and post‐fire restoration treatments. Throughout the 3 years post‐fire, sage‐grouse avoided areas with high exotic annual grass cover but selected strongly for recovering sagebrush and moderately strongly for perennial grasses. By the third year post‐fire, they preferred high‐density sagebrush, especially in winter when sagebrush is the primary component of the sage‐grouse diet. Sage‐grouse preferred forb habitat immediately post‐fire, especially in summer, but this selection preference was less strong in later years. They also selected areas that were intensively treated with herbicide and seeded with sagebrush, grasses, and forbs, although these responses varied with time since treatment. Wildfire can have severe consequences for sagebrush‐obligate species due to loss of large sagebrush plants used for food and for protection from predators and thermal extremes. Our results show that management efforts, including herbicide application and seeding of plants, directed at controlling exotic annual grasses after a wildfire can positively affect habitat selection by sage‐grouse.Habitat loss is the most prevalent threat to biodiversity in North America. One of the most threatened landscapes in the United States is the sagebrush ( We investigated habitat selection by 28 male greater sage‐grouse during each of 3 years after a wildfire in Idaho and Oregon. Sage‐grouse avoided areas with high exotic annual grass cover but selected for recovering sagebrush, areas that were intensively treated with herbicide, and areas that were seeded with sagebrush, grasses, and forbs. Our results show that management efforts directed at controlling exotic annual grasses after a wildfire can positively affect habitat selection by sage‐grouse. The lower elevation limit for sagebrush steppe occurs along the eastern, northern, and northwestern boundaries of the burned area, where fire and exotic annual grasses have degraded the dominant salt desert habitat. The landscape has a long history of livestock utilization, which, in recent decades, has consisted of cattle (Bos taurus) and sheep (Ovis aries) grazing in spring or fall. Additional details of the wildfire and study area are described elsewhere , breeding (15 February–15 May), summer (16 May–31 August), and fall (1 September–30 November). Because each winter season incorporated a portion of two years, we grouped December locations with those from the following year . Finally, we removed all nighttime locations because we presumed that habitat selection by sage‐grouse might differ between day and night. In winter, we defined nighttime locations as those between sunset and sunrise. In all other seasons, we defined nighttime locations as those between sunset and 1 h before sunrise.2.3We evaluated sage‐grouse habitat use in the context of three types of environmental data: pre‐fire land cover, post‐fire vegetation, and post‐fire treatments. The first of these were 2012 (pre‐fire) land cover data derived from the Landscape Fire and Resource Management Planning Tools Project , and other perennial bunchgrasses. We considered Sandberg bluegrass separately from other perennial bunchgrasses because it is smaller and matures earlier than other grasses, and thus may be relevant to sage‐grouse during times of the year when other grasses are not available  until we found at least three seedlings. We then counted the total number of sagebrush seedlings and remnants in that plot. We calculated density as the total number of individuals divided by the area searched, then scaled to ha. We then binned sagebrush density into the following four categories for analysis: (1) 0 plants/ha, (2) 1–100 plants/ha, (3) 101–1000 plants/ha, and (4) >1000 plants/ha.We created interpolated vegetation cover and sagebrush density maps of the Soda Wildfire via a two‐step process. First, we ran a random forest analysis  and sagebrush , was applied in winter 2016 over 61,450 ha and in winter 2017 over 6855 ha. Aerial sagebrush/grass seeding, which consisted of Sandberg bluegrass and big sagebrush, was applied in winter 2018 over 9575 ha. Aerial forb seeding, which consisted of a species‐rich mix of forbs known to be preferred by sage‐grouse, was applied in winter 2016 over 2885 ha and in winter 2017 over 2420 ha. Drill seeding, which consisted of a mix of native and introduced grass species, was applied in fall 2015 over 7230 ha, in fall 2016 over 4620 ha, and in fall 2017 over 860 ha. Finally, pre‐emergent herbicide (imazapic) was applied in fall 2015/winter 2016  over 10,940 ha and in fall 2016 over 25,350 ha. In many cases, treatment coverages overlapped.The third type of environmental data were spatially explicit information on post‐fire restoration treatments applied within the study area. The U.S. Department of Interior implements an Emergency Stabilization and Rehabilitation (ESR) program to restore areas damaged by wildfire. The Soda Wildfire ESR included restoration treatments for the three years post‐fire, although treatments were applied at different times and over different extents of the burned area. Aerial sagebrush/forb seeding, which consisted of seed mixes of three naturalized forbs  around each sage‐grouse telemetry location, removing any part of the buffer that extended outside of the modeled sage‐grouse habitat within the Soda Wildfire perimeter. For each use buffer, we determined (1) the mean percent cover of each of the four post‐fire vegetation cover types, and the proportion of the buffer (2) composed of each sagebrush density bin, (3) composed of each pre‐fire land cover type, and (4) to which each post‐fire restoration treatment was applied. We also determined these characteristics for 500‐m buffers around random points available to sage‐grouse (“available buffers”). To do this, we first created, for each bird in each year and each season, a polygon with a 5‐km radius around all telemetry points, excluding area outside the modeled sage‐grouse habitat within the Soda Wildfire perimeter. Within each polygon, we then generated a set of random points that equaled the number of sage‐grouse telemetry points.2.5We built resource selection functions with generalized linear mixed‐effects models  or low sagebrush (second submodel). We chose this approach because cover of big sagebrush was negatively correlated with that of low sagebrush; thus, both could not be included in the same model. We then identified, for each year, the submodel with the lower Akaike's Information Criterion corrected for small sample size (AICc) value, and we carried only that model forward for subsequent analysis.To evaluate sage‐grouse response to post‐fire vegetation, our three models, one for each year, also included four fixed effects. These described four interactions, one each between season and cover of exotic annual grasses, forbs, perennial bunchgrasses, and Sandberg bluegrass. We excluded sagebrush density from these models because three of the density bins were correlated with perennial bunchgrass cover  and an additional 10 models with correlated variables Appendix  to evalu3x¯ ± SD = 581 ± 671 locations per bird; range = 35–2905 locations) collected from April 2016 to November 2018  from 28 sage‐grouse. This included 4333 locations from 10 birds in 2016, 6886 locations from 16 birds in 2017, and 5054 locations from 10 birds in 2018.We collected 39,813 telemetry locations from 41 sage‐grouse over the 3‐year study period. After removing sparse data, nighttime locations, and telemetry locations outside the study area, we used 16,273 locations . In general, the other vegetation cover types at sage‐grouse locations remained relatively constant across study years, with the average percent cover ranging from 10% to 14% for exotic annual grasses, from 1% to 2.5% for forbs, and from 13% to 16% for Sandberg bluegrass over the three years. In 2016, over 93% of sage‐grouse locations were in areas with no sagebrush and only 3.6% were in areas with sagebrush density >100 plants/ha. However, by 2018, only 33% were in areas with no sagebrush and almost 64% were in areas with sagebrush density >100 plants/ha.3.1In nearly all cases, for analyses of sage‐grouse response to pre‐fire land cover, post‐fire vegetation, and post‐fire treatments, the full  model had the majority of model weights . However, by the third post‐fire year (2018), sage‐grouse began to shift their landscape use towards areas that historically were comprised of big sagebrush, perhaps responding to growth of this species.Dietary preferences and forage quality of big and low sagebrush may partially explain these habitat selection patterns. Sage‐grouse are known to select low sagebrush plants because the leaves have more favorable secondary metabolites and fewer unfavorable metabolites and toxins than big sagebrush plants , most areas occupied by sage‐grouse did not have any sagebrush plants. In later years, when some areas had higher densities of sagebrush plants, the birds disproportionately used these areas. By 2018, selection of high‐density sagebrush was particularly strong in winter, when sage‐grouse rely on sagebrush for food and cover. Sage‐grouse also did not respond positively to the sagebrush/forb seeding treatments until the second year (2017), but this also may have been because of the slow growth of sagebrush plants. In contrast, use of forb cover and forb seeding treatment areas was high in 2016, especially in summer, when little other food was available. However, this use generally decreased in later years. Further, across all years, sage‐grouse more strongly selected for the forb treatment conducted in winter 2016 than they did for the forb treatment conducted in the following year. The decreasing use of forbs in summer was surprising because sage‐grouse rely on summer habitats that provide succulent forbs for forage . Similar to our study, the presence of scat was positively associated with sagebrush and negatively associated with exotic annual grass cover. However, post‐fire restoration treatments did not have any clear effects on the presence of scat. Thus, choice of monitoring approach, i.e. either capturing and tracking a limited number of animals for an extended time period or collecting scat from a greater number of animals at specific points in time, can affect inferences related to habitat selection.Our findings differ from a study analyzing the probability of the presence of sage‐grouse scat relative to post‐fire vegetation and treatments in our study area ; Data curation ; Formal analysis (lead); Methodology ; Visualization ; Writing – original draft (lead); Writing – review & editing . David M. Barnard: Data curation ; Investigation ; Methodology ; Writing – review & editing . Cara Applestein: Data curation ; Investigation ; Methodology ; Writing – review & editing . Matthew J. Germino: Conceptualization ; Data curation ; Funding acquisition ; Investigation ; Methodology ; Supervision ; Writing – review & editing . Ethan A. Ellsworth: Conceptualization ; Data curation ; Funding acquisition ; Investigation ; Methodology ; Resources ; Writing – review & editing . Don Major: Conceptualization ; Data curation ; Investigation ; Methodology ; Resources ; Writing – review & editing . Ann Moser: Data curation ; Investigation ; Methodology ; Resources ; Writing – review & editing . Todd E. Katzner: Conceptualization ; Data curation ; Methodology ; Supervision ; Visualization ; Writing – original draft (supporting); Writing – review & editing .Appendix S1Click here for additional data file.


Hospital report cards (HRCs) are usually presented in a textual and factual format, likely hampering information processing.This study aimed to investigate the effects of audiovisual and narrative information in HRCs on user responses, and to test differences between older and younger women.A 2  × 3  online experiment was conducted. Information about breast cancer care was used as a case example. Age (younger [<65] vs. older [≥65]) was included as a potential effect modifier.Mage = 56.06) completed an online survey. The outcomes were perceived cognitive load, satisfaction, comprehension, information recall and decisional conflict. Data were analysed using AN(C)OVAs.A total of 631 disease‐naïve women  information resulted in higher information satisfaction across age groups, but was associated with lower comprehension in older women. An experience narrative  increased satisfaction with attractiveness and emotional support of the information only in older women. A three‐way interaction effect was found, suggesting that older women were most satisfied with the comprehensibility of audiovisual factual or textual process narrative information. Younger women were most satisfied with the comprehensibility of audiovisual process narrative or textual factual information.Audiovisual and narrative information in an HRC showed beneficial effects on satisfaction measures. In particular, audiovisual information could be incorporated into HRCs to increase satisfaction with information.Lay persons helped in optimizing the visuals used in the stimulus materials by checking for clarity. One is that the content of HRCs is abstract and difficult to use when having to make multiattribute decisions, easily leading to cognitive overload.Being provided with audiovisual information in a hospital report card, compared to textual information, will have a positive effect on satisfaction with information, information comprehension and information recall, and a negative effect on perceived cognitive load and decisional conflict.To enhance information processing when provided with HRCs, one potentially fruitful strategy is to present information in an audiovisual modality (such as animated videos) instead of text. The assumed beneficial effect of audiovisual information is related to its ability to attract attention and foster interest in information.Being provided with narrative information in a hospital report card, compared to factual information, will have a positive effect on satisfaction with information, information comprehension and information recall, and a negative effect on perceived cognitive load and decisional conflict.Another interesting presentation format is a narrative narration style instead of a factual narration style.Outcome narratives contain information about the physical and psychological outcomes of decisions ,Process narratives focus on the cognitive axis of decisions ,Experience narratives focus on the experiential axis of decisions ,Being provided with audiovisual narrative information in a hospital report card, compared to other combinations of modality and narration style, will have a positive effect on satisfaction with information, information comprehension and information recall, and a negative effect on perceived cognitive load and decisional conflict.However, the effectiveness of incorporating narratives into decision support tools generally remains unclear.Testing the effects of modality and narration style is especially crucial in older adults such as older cancer patients, which is an ever‐growing group of patients worldwide.22.1This study contained a between‐subjects factorial 2  × 3  experimental design in which the manipulations were performed in the descriptions of quality indicators  in an HRC. We chose to manipulate specifically this information because the indicators in fact form the basis of the hospital comparison and are used to choose a hospital.https://osf.io/j5sp3?view_only=9a6f6f06d4024e498ce9c7d940ecc193). Written consent was obtained from the participants.Age  was included as a potential effect modifier. Participants were stratified by age and randomly assigned to one of the six experimental conditions via automatic randomisation . The Medical Ethics Committee of Amsterdam UMC, location VUmc, approved the study (2016.587). The study was also preregistered (see 2.2https://borstkanker.nl/nl/monitor-borstkankerzorg-0) about four hospitals  and six quality indicators . For the audiovisual conditions, the three textual scripts were recorded as voice‐overs  and used in animated videos .2.3f) and a two‐sided significance level of .05 showed that at least 619 participants needed to be included for sound power (0.95). Ultimately, 631 participants were included.Participants were women aged 18 years and older who had no breast cancer or a history of having it . We chose to recruit so‐called analogue patients to avoid participants having prior knowledge about the quality indicators. Using analogue patients has been shown to be a valid approach in experimental communication research.2.4Flycatcher sent participants a link to the online survey. Participants were first informed about the aim and content of the study, the confidentiality of data and voluntary participation. Next, participants provided informed consent. Participants were randomly assigned to one of the six conditions. After reading/watching the information provided, participants were directed to the survey. Participants had to fill in all questions on a page before they could move on to the next page. This ensured that only completed surveys were submitted and no data were missing. For examining the data quality, Flycatcher checked completed surveys on answers to open questions , consistency in answers, straight lining and time spent on completing the survey.2.5How would you rate your overall health during the past week? and How would you rate your overall quality of life during the past week?).I wanted to know how the story from the texts/videos ended; α = .73).In my imagination, it was like I was [character in stimulus material]; α = .95).1 = totally disagree to 7 = totally agree).The survey covered our dependent variables (see below). Moreover, sociodemographic and medical background variables , and control variables  were included. Comorbidity was defined as having two or more health problems, and quality of life was measured by two items  developed by Eveland and Dunwoodyα = .82).Four items measured on a 7‐point Likert scale  from the Website Satisfaction Scale were used to measure satisfaction with information (α = .94).α = .89), five items related to the subscale ‘Satisfaction with comprehensibility’ (α = .92) and four items related to the subscale ‘Satisfaction with emotional support’ (α = .95).Twelve items measured on a 7‐point Likert scale  MC Oost, (b) St Nathaniel, (c) Noordhaven Ziekenhuis, (d) IJssel MC, (e) It does not matter and (f) I don't know. For each question, one or two response options could be correct. Participants were enabled to revisit the stimulus materials while filling in comprehension questions. The final score was the sum of correct answers, and ranged from 0 to 15.Information comprehension was measured by fifteen multiple‐choice questions.2.9Fourteen open‐ended questions based on the Netherlands Patient Information Recall Questionnaire were used to measure information recall.2.10α = .94). Both a total scale score and scores for five subscales were calculated. Three items related to ‘Informed’ (α = .86), three items related to ‘Values clarity’ (α = .87), three items related to ‘Support’ (α = .74), three items related to ‘Uncertainty’ (α = .87) and four items related to ‘Effective decision’ (α = .91).Sixteen items measured on a 5‐point Likert scale from the Decisional Conflict Scale2.11Mage = 60.95). These women were recruited through PanelCom (http://www.panelcom.nl), and were randomly assigned to the factual (n = 14), process narrative (n = 14) or experience narrative (n = 14) textual script. The two narrative texts were perceived as more narrative compared to the factual text (p < .001). Using factor analysis, three subscales were constructed for use as a manipulation check in the survey, with three items belonging to the subscale ‘Factual’ (α = .84), three items belonging to ‘Process narrative’ (α = .93) and three items belonging to ‘Experience narrative’ (α = .92). All items were measured on a 7‐point Likert scale .Before data collection, a pilot test of the stimulus materials and survey was conducted. For the textual conditions, the scripts were pretested among 42 women  than process narrative information , t(404) = 6.12, p < .001, 95% confidence interval (CI): . Process narrative information was perceived as more narrative  than factual information , t(404) = −12.90, p < .001, 95% CI: . Hence, it can be concluded that the manipulation ‘factual vs. process narrative’ was successful. Factual information was also perceived as more factual  than experience narrative information , t(423) = 8.19, p < .001, 95% CI: . Furthermore, experience narrative information was perceived as more narrative  than factual information , t(423) = −13.74, p < .001, 95% CI: . Hence, it can be concluded that the manipulation ‘factual vs. experience narrative’ was successful. Process narrative information was perceived as less narrative  than experience narrative information , t(429) = −2.79, p = .005, 95% CI: . Additionally, experience narrative information was perceived as more narrative  than process narrative information , t(429) = −4.73, p < .001, 95% CI: . Hence, it can be concluded that the manipulation ‘process narrative vs. experience narrative’ was successful.Factual information was perceived as more factual  and the background variables  were tested using one‐way analysis of variances (ANOVAs). The effects of modality, modality*age, narration style, narration style*age, modality*narration style and modality*narration style*age on the dependent variables were tested using two‐way ANOVAs. Post‐hoc analyses were performed to analyse the differences between the conditions. We adopted a cut‐off age of 65 years to categorize participants into ‘younger’ (18–64 years old) and ‘older’ (65 years or older) participants, which is generally accepted in studies that investigate the effects of ageing on health‐related outcomes. To adjust for the effects of multiple‐hypothesis testing, a Bonferroni correction was applied.p ≤ .05 were considered significant.Descriptive statistics showed that younger women had a higher level of eduaction, and had higher health literacy and numeracy than older women . The majority of all participants showed an adequate level of health literacy (81.3%), but less than half of them (37.3%) answered the numeracy question correctly. Transportation into the story was moderate , while identification with the character from the narratives was quite low . There were no differences between older and younger participants in transportation and identification.Table F‐test statistics per research question can be found in Appendix Table 3.2Mdif = 3.39, p = .001, 95% CI: ), and particularly with the attractiveness of information  and emotional support from information  than women receiving textual information. We observed the reverse effect for comprehension, with women receiving audiovisual information comprehending information less .We found a significant main effect of modality on four out of the 13 outcome measures. Women receiving audiovisual information were more satisfied with information in general . Among younger women, no interaction effects were found. After adjusting for educational level or health literacy in ANCOVAs, there was no longer any interaction between modality and age for comprehension. In contrast, after adjusting for numeracy, the interaction effect remained intact.A significant interaction between modality and age was found, showing that older women receiving textual information, compared to older women receiving audiovisual information, had significantly higher comprehension , and specifically higher satisfaction with emotional support from information . In contrast, among younger women, no significant differences were found. Furthermore, older women receiving experience narrative information, compared to younger women receiving experience narrative information, were significantly more satisfied with emotional support from information . After adjusting for educational level or health literacy in two additional ANCOVAs, interaction effects remained intact. After adjusting for numeracy, the interaction effect between narration style and age on satisfaction with emotional support from information remained intact, but the effect on overall satisfaction with information was no longer significant.No significant main effects of narration style were found on any of our 13 outcome measures. However, significant interaction effects were found between narration style and age. In older women, experience narrative information, compared to factual information, was associated with higher overall satisfaction with information . The same was found for older women receiving textual process narrative information compared to textual factual information . These effects were not found for younger women. Younger women receiving audiovisual process narrative information  or textual factual information , compared to older women receiving the same information, were more satisfied with the comprehensibility of information. After adjusting for educational level, health literacy or numeracy in an additional ANCOVA in three separate models, the interaction effect on satisfaction with comprehensibility remained intact. After adjusting for numeracy, the interaction effect on overall satisfaction with information and on making informed choices  became significant.No significant two‐way interactions between modality and narration style were demonstrated. We did find a significant three‐way interaction for satisfaction with comprehensibility of information  contained more information than the factual condition. We intentionally chose to keep the basic information identical in our experimental conditions and to add contextual information to the narrative conditions. A limitation is, however, that the difference in length might partly explain why narratives did not produce enhanced cognitive outcomes. It has been shown before that providing more information can lead to less recall.5Our study mainly yielded beneficial effects of audiovisual and narrative information on satisfaction measures, which did not translate into differences in information processing . We can recommend incorporating audiovisual information in HRCs. An audiovisual format seems to increase satisfaction with the information. Higher satisfaction with the information, in turn, might lead to a higher uptake of HRCs, ultimately contributing to better informed hospital choices. However, given the limited effects on the other study outcomes, it should be investigated whether and when adding audiovisual information to HRCs is of real added value in practice. Narrative information cannot necessarily be recommended for broad groups of patients, but the effects of narratives in older women suggest that this strategy might have potential. We recommend elaborating on the effects of experience narratives in different groups of older patients in future research.The authors declare that there are no conflict of interests.Nida Gizem Yılmaz contributed to the design of the work, analysis and interpretation of data, and writing of the manuscript. Danielle R. M. Timmermans contributed to the acquisition, design of the work, interpretation of data and giving feedback on the manuscript. Julia C. M. Van Weert contributed to the acquisition, design of the work, interpretation of data and giving feedback on the manuscript. Johanneke Portielje contributed to the interpretation of data and giving feedback on the manuscript. Olga C. Damman contributed to the acquisition, design of the work, analysis and interpretation of data, and giving feedback on the manuscript.Supplementary information.Click here for additional data file.Supplementary information.Click here for additional data file.Supplementary information.Click here for additional data file.Supplementary information.Click here for additional data file.


Angioimmunoblastic T‐cell lymphoma (AITL) is the subtype of mature T‐cell non‐Hodgkin lymphoma. Compared with diffuse large B‐cell lymphoma (DLBCL), AITL patients are frequently accompanied with Epstein–Barr virus (EBV) infection. To date, there is no report on the subsequent development of AITL in patients with EBV‐positive DLBCL. We performed a rare case of EBV‐positive AITL developing one year after initial diagnosis of EBV‐positive DLBCL. The patient showed poor response to the chemotherapy regimen, and poor survival. The left inguinal lymph node biopsy of initial diagnosis shows morphological  and IHC staining with positive for CD20 , PAX‐5 , and Ki‐67 . We presented a rare case of EBV‐positive AITL developing one  year after initial diagnosis of EBV‐positive DLBCL. The patient showed poor response to the chemotherapy regimen and poor survival.Angioimmunoblastic T‐cell lymphoma (AITL) is a subtype of mature T‐cell non‐Hodgkin lymphoma. Compared with diffuse large B‐cell lymphoma (DLBCL), AITL patients are frequently accompanied with Epstein–Barr virus (EBV) infection. To date, there is no report on the subsequent development of AITL in patients with EBV‐positive DLBCL. Here we described a rare case of EBV‐positive AITL developing one year after initial diagnosis of EBV‐positive DLBCL.22‐microglobulin, and alanine aminotransferase (ALT) were all within the normal range. The laboratory of EBV viral IgM‐capsid antigen (VCA) and EBV‐DNA was positive. The titer of EBV VCA was 1:80, and the copy number of EBV‐DNA was 1.06 × 106/mL. Then, the patient underwent biopsy of left inguinal lymph node; a large number of diffuse large‐sized proliferation atypical lymphoid cells can be seen under microscope. Immunohistochemically (IHC), the atypical cells were positive for CD20, CD19, PAX‐5, and MUM‐1, but negative for CD3, CD5, CD10, Bcl‐6, CyclinD1, CD138, and TdT  scan disclosed generalized lymphadenopathy in the mediastinum, hilum, bilateral inguinal region, right lung, and right kidney. However, the complete blood count, coagulation markers, albumin, lactate dehydrogenase (LDH), creatinine, βIn March 2020, 1 year after initial diagnosis of EBV‐positive DLBCL, the patient was readmitted to our hospital because of nasopharyngeal discomfort. CT scan revealed multiple enlargements of mediastinum, hilum, bilateral inguinal lymph nodes, right lung, right kidney lymph nodes, and thickened nasopharyngeal wall. Bone marrow aspiration was normal. A left inguinal lymph node biopsy was performed, and to our surprise, it revealed angioimmunoblastic T‐cell lymphoma (AITL). Immunohistochemically, the cancer cells were positive for most pan‐T‐cell antigens such as CD3, CD4, CD5, CD7, and T follicular helper (TFH) biomarkers including CD10, Bcl‐6, and CXCL13, but negative for CD20, ALK, PD‐1, EMA, and Perforin (Figure 3DLBCL is the most common type of malignant hematological diseases and also the most common type of B‐cell non‐Hodgkin lymphoma.EBV‐positive DLBCL patients following AITL have been reported in some case reports.Only one case of AITL development after treatment of EBV‐negative DLBCL was reported.To our knowledge, there is no report on the subsequent development of AITL in patients with EBV‐positive DLBCL. Now, we presented a rare case of EBV‐positive AITL developing one year after initial diagnosis of EBV‐positive DLBCL. The patient showed poor response to the previous R‐miniCHOP chemotherapy regimen and then treated with chidamide and prednisolone. Unfortunately, similar to the above case, the patient finally died three months after diagnosis secondary EBV‐positive AITL. We hypothesized that EBV plays an important role in the development of DLBCL transform to AITL. In conclusion, this is a rare disease with a generally poor prognosis. However, the specific mechanism of this phenomenon is still unknown.Written informed consent was obtained from all participants. Ethical approval was obtained from the Ethics Committee of the Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, China, in accordance with the ethical guidelines of the 1975 Declaration of Helsinki. Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor‐in‐Chief of this journal.Written informed consent for publication was obtained from all participants.None declared.Chaoyu Wang, Yi Gong, Qingming Jiang, Xiping Liang, and Rui Chen conceptualized and designed the study. Chaoyu Wang and Yi Gong drafted the article. All the authors approved the final version.