To investigate the arterial stiffness (AS) risk within urinary albumin‐to‐creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) categories and the joint effect between kidney disease parameters and metabolic goal achievement on AS risk in adult people with type 2 diabetes (T2D).2 and brachial‐ankle pulse wave velocity value >the 75th percentile (1770.0 cm/s). Three metabolic goals were defined as glycated hemoglobin <7%, BP <130/80 mmHg, andlow‐density lipoprotein cholesterol <2.6 mmol/L.A total of 27 439 Chinese participants with T2D from 10 National Metabolic Management Centers (MMC) were categorized into four albuminuria/decreased eGFR groups. The criteria for decreased eGFR and AS were eGFR <90 ml/min/1.73 mp = .311). When the metabolic goals added up to ≥2 for patients with decreased eGFR, they showed significantly lower AS risk .After full adjustment, odds ratios (ORs) for AS were highest for albuminuria and decreased eGFR (2.23 [1.98–2.52]) and were higher for albuminuria and normal eGFR (1.52 [1.39–1.67]) than for those with nonalbuminuria and decreased eGFR (1.17 [1.04–1.32]). Both UACR and eGFR in the subgroup or overall population independently correlated with AS risk. The achievement of ≥2 metabolic goals counteracted the association between albuminuria and AS risk (OR: 0.93; 95% CI: 0.80–1.07; Both higher UACR and lower eGFR are determinants of AS risk, with UACR more strongly related to AS than eGFR in adults with T2D. The correlation between albuminuria/decreased eGFR and AS was modified by the achievement of multiple metabolic elements. HighlightsProvide key information on the correlation between kidney disease measures and arterial stiffness by evaluating urine albumin‐creatinine ratio and estimated glomerular filtration rate simultaneously in a large sample with type 2 diabetes.Improving management of arterial stiffness, before reaching the chronic kidney disease stage, should also be emphasized in clinical practice.The correlation between albuminuria/decreased estimated glomerular filtration rate and arterial stiffness was modified by the achievement of multiple metabolic elements, underlining the importance of targeting multiple metabolic risk factors in the management of arterial health. Chronic kidney disease (CKD), defined by abnormal renal function .Varying criteria with respect to eGFR and albuminuria levels could influence the findings of analyzing AS. Besides, the two risk factors might confound each other. Diabetic patients may present albuminuria without abnormal eGFR, abnormal eGFR without albuminuria, or both albuminuria and abnormal eGFR. Therefore, it is necessary to take eGFR and albuminuria levels into consideration simultaneously. In addition, we defined eGFR <90 ml/min/1.73 m22.1n = 2482), or with missing brachial‐ankle pulse wave velocity (baPWV) data (n = 1755), a history of major CVD , incomplete data on related medical record (n = 199), or ankle‐brachial index (ABI) <0.9 (n = 1185), 27 439 eligible participants were finally available for this analysis.We enrolled participants from 10 MMCs, which are in Shanghai (two sites), Beijing (one site), Zhejiang (two sites), Henan (two sites), Guizhou (one stie), Yunnan (one site), and Jiangsu (one site) province. The details of this MMC project have been presented previously.The Ethical Review Committees of Ruijin Hospital and other centers  have approved the study protocol. The study was conducted following the Declaration of Helsinki and each patient signed an informed consent form.2.2Trained interviewers collected all the data in local MMCs complying with a standard protocol.Blood glucose, serum C peptide, HbA1c, biochemical test items, and the UACR were examined in local MMCs. Homeostasis model assessment of insulin resistance (HOMA2‐IR) are calculated on the basis of fasting blood glucose (FBG) and fasting C peptide concentrations by the HOMA calculator v2.2.3.2.32, decreased eGFR is established; otherwise, normal eGFR is present. For those with albuminuria, UACR >33.9 mg/mmol was used to define macroalbuminuria.Diabetes was diagnosed according to the 1999 World Health Organization criteria.2.4The SPSS software (Version 22.0) was employed for the current analysis. The characteristics of the participants were described according to eGFR and albuminuria status. Continuous variables were presented as means ± SD, or median (interquartile range). Categorical variables were expressed as the count (percentage). Skewered data was converted logarithmically before statistical analysis. One‐way analysis of variance (ANOVA) and the chi‐square test were used to compare differences among groups for continuous and categorical variables, respectively.2 decrease in eGFR) and as a categorical variable: <60, 60–74, 75–89 (reference category in the subgroup of patients with decreased eGFR). UACR was examined continuously after logarithmic transformation and also classified as microalbuminuria and macroalbuminuria. The independent association of eGFR, UACR, or eGFR and UACR categories with AS was explored by multivariable logistic regression. Three models were used to adjusting for potential confounding factors. Model 1 included age, sex, body mass index (BMI), diabetes duration, systolic blood pressure (SBP), triglycerides (TG), high‐density lipoprotein cholesterol (HDL‐C), FBG, HbA1c, and HOMA2‐IR were added to Model 2. Medication usage , lifestyle factors (both smoking and drinking status), education level, and family history of diabetes were further added to Model 3. UACR and eGFR were mutually adjusted.eGFR was analyzed as a continuous measure  and the presence of albuminuria/decreased eGFR (no or yes), with adjustments for age, sex, BMI, diabetes duration, TG, HOMA2‐IR, medication usage, lifestyle factors, education level, family history of diabetes, and other metabolic goal achievement (yes or no). We also conducted interaction analysis between individual metabolic goal achievement and albuminuria/decreased eGFR. Combined effect of the overall achievement of ABCs  and albuminuria/decreased eGFR on AS risk, as compared with participants without albuminuria/decreased eGFR, was also analyzed. A 33.1p < .05, Table p < .05). In addition, participants with albuminuria and decreased eGFR had longer diabetes duration, lower eGFR, and higher SBP, fasting serum C peptide, HOMA2‐IR, UACR, and baPWV levels in comparison with all other groups  and 17%  higher AS risk compared with the nonalbuminuria and normal eGFR group, as shown in Table p < .001; Model 3). Similar findings were obtained when Cockcroft‐Gault formula was used for eGFR estimation . After full adjustment, the albuminuria only and decreased eGFR only groups were associated with 52% . The significant association of eGFR (per 15 ml/min/1.73 m2 decrease in eGFR) with AS risk was also detected in the decreased eGFR subgroup  and per 15 ml/min/1.73 m2 decrease in eGFR  correlated significantly with AS risk.When continuous UACR was logarithmically converted in the subgroup of patients with albuminuria, it was significantly correlated with higher AS risk after full adjustment .We analyzed the joint effect of the presence of albuminuria and individual metabolic goal achievement on AS risk based on classification of participants into four subgroups. The same categorization was also performed for patients with decreased eGFR. Compared with the nonalbuminuria participants with HbA1c <7.0%, other subgroups had significantly higher AS risk after adjusting for multiple confounders. The risks for AS increased by 70% , 37% , and 164%  in participants with albuminuria (+) & HbA1c <7%, albuminuria (−) & HbA1c ≥7%, and albuminuria (+) & HbA1c ≥7% . The risks of AS and decreased eGFR were also further evaluated in participants with 0, 1, or≥2 achieved metabolic goals. Compared with participants with normal eGFR, those with <2 achieved metabolic goals exhibited higher AS risk (p < .05). When the target metabolic goals added up to ≥2 for patients with decreased eGFR, they showed significantly lower risk for AS compared with the reference group  study.Our research extends previous knowledge by reporting the strong association between UACR  and AS risk in a large sample of adult patients with T2D. Either albuminuria2) with AS risk suggests that even if kidney function decreased slightly, it may also affect subclinical atherosclerosis. This observation suggests that future endeavors toward vascular destiffening should also pay attention to individuals with modestly decreased renal function. Adjusting for potential confounders, the association between eGFR  and AS risk persisted in the overall population or subgroups with decreased eGFR. Our results are in line with the prior findings involving elderly community/population‐based cohort2 and those with higher eGFR.The association of nonalbuminuria and decreased eGFR (eGFR <90 ml/min/1.73 mp = .079) or decreased eGFR (p = .733), which may suggest that albuminuria or decreased eGFR outweighed the effect of LDL‐C level on AS risk in these patients. It is noteworthy that the AS risk increased by more than 5 times in the patients with poorly controlled BP and albuminuria in comparison with the reference group, which supports improved BP control as an important intervention to prevent arterial disease. Consistent with our finding, a follow‐up study in an early CKD population identified BP as the most important determinant of PWV change.Furthermore, we reported a combined effect between albuminuria/decreased eGFR and metabolic goal achievement on AS risk. For each metabolic element, participants with albuminuria/decreased eGFR and poorly controlled metabolic elements had significantly higher AS risk than having neither. However, there was no statistically significant difference between participants with and without well‐controlled LDL‐C level in those having albuminuria , albeit as the most important modifiable determinant of AS, does not always witness improvement in AS.2. Therefore, our findings cannot be directly extrapolated to other population with higher percentage of renal insufficiency. Finally, the cross‐sectional nature of the current study could not establish the causal association of decreased eGFR or albuminuria with AS.The advantages of this study included a large sample size from 10 centers, exclusion of baseline major CVD, the standardized questionnaire to collect baseline data, evaluation of eGFR and UACR levels simultaneously, the wide coverage of eGFR and UACR levels, the definition of a slight reduction in eGFR, and analysis for the combined effect of kidney disease measures and metabolic goal achievement. There are also some limitations. The UACR levels were examined once at the first visit, which may lead to bias to a certain degree. However, the bias could be kept minimal by means of a large sample. In addition, in the decreased eGFR group, there was a limited number of patients with eGFR <60 ml/min/1.73 m2) without the occurrence of CKD can herald patients′ higher risk for AS. Both continuous or categorized UACR and eGFR in the subgroup or overall population independently and positively correlated with the AS risk after multiple adjustment. More important, the significant and positive association between albuminuria or decreased eGFR and AS was counteracted or reversed by ≥2 metabolic goal achievement. Our findings put an emphasis on the importance of stringent metabolic management for the improvement of CVD.In conclusion, patients with albuminuria and normal eGFR or nonalbuminuria and decreased eGFR were at higher AS risk independent of potential confounders, with the former higher than the latter. Even a modest reduction in eGFR Click here for additional data file.


We aimed to develop models to predict new‐onset overactive bladder in 5 years using a large prospective cohort of the general population.This is a secondary analysis of a longitudinal cohort study in Japan. The baseline characteristics were measured between 2008 and 2010, with follow‐ups every 5 years. We included subjects without overactive bladder at baseline and with follow‐up data 5 years later. Overactive bladder was assessed using the overactive bladder symptom score. Baseline characteristics  and blood test data were included as predictors. We developed two competing prediction models for each sex based on logistic regression with penalized likelihood (LASSO). We chose the best model separately for men and women after evaluating models' performance in terms of discrimination and calibration using an internal validation via 200 bootstrap resamples and a temporal validation.C‐statistic, calibration intercept, and slope for the best performing models were 0.77 , 0.28 and 1.15 for males, and 0.77 , 0.20 and 1.08 for females. Internal and temporal validation gave broadly similar estimates of performance, indicating low optimism.We analyzed 7218 participants . The median age was 60 and 55 years, and the number of new‐onset overactive bladder was 223 (10.0%) and 288 (5.8%) per 5 years in males and females, respectively. The in‐sample estimates for We developed risk prediction models for new‐onset overactive bladder among men and women with good predictive ability. AUCarea under the curveBMIbody mass indexBNPB‐type natriuretic peptideCIconfidence intervalDCAdecision curve analysiseGFRestimated glomerular filtration rateHbA1chemoglobin A1cHRQOLhealth‐related quality of lifeIQRinterquartile rangeOABoveractive bladderOABSSoveractive bladder symptom scoreOSAobstructive sleep apneaPSAprostate‐specific antigenROCreceiver operating characteristicTRIPODTransparent Reporting of a Multivariable Prediction Model for Individual Prognosis or DiagnosisOAB is defined as “a symptom characterized by urinary urgency, with or without urgency incontinence, usually with urinary frequency and nocturia in the absence of infection or other obvious pathology.”Population‐based prediction models are expected to support population health planning and policy decision‐making.However, to the best of our knowledge, no such model has been reported to predict new‐onset of OAB. This may be due to the lack of sufficient data to develop a predictive model. This would require a large dataset, collected using a prospective design. We have recently reported a longitudinal analysis of voiding dysfunction using a large prospective cohort data from the general population.In this study, we aim to develop and validate models to predict incident OAB in 5 years using a large prospective cohort from the general population in Japan. In addition, as the mechanism of OAB onset is different between male and female due to factors such as the prostate, menopause, and delivery, we a priori had decided to develop a different model for each sex. To make the model easier to use, we aimed to build a web‐based application to visualize the predicted results interactively.This study followed the TRIPOD statement Fig. .8 The This is a secondary analysis of the Nagahama study, a prospective population‐based cohort study in Japan. This cohort project is conducted by the Kyoto University, the Nagahama City Office, and the non‐profit organization Zeroji Club, and the details of the Nagahama study are reported elsewhere.Participants were recruited from the general community residents of Nagahama city in central Japan. Inclusion criteria were as follows: age 30 to 74 years, ability to independently participate in health examinations, no difficulties in communicating in Japanese, no serious diseases or other health issues, and voluntary participation. From all participants, we excluded those who have been diagnosed with OAB at baseline, based on the definition of the OABSS.The outcome was new‐onset OAB at the 5‐year follow‐up assessment. We used OABSS, a self‐report measure assessing urinary urgency during the past week Appendix . The queBased on the literature, expert opinions, and the permissible number of variables estimated from sample size calculation Appendix , we pre‐λ) required for LASSO, we followed a 10‐fold cross‐validation. We evaluated models' performance in both discrimination and calibration.C‐statistic). Model calibration, which measures the agreement between the predictions and the observed outcomes, was evaluated with calibration intercepts and slopes and was visualized with calibration plots. Good calibration is indicated by a calibration intercept near 0 and a calibration slope near 1.C‐statistics, calibration intercept, and slope. In addition to that, we also performed a temporal validation by splitting the sample into 3 sets according to the year of baseline assessment . We used the first 2 sets (2008 and 2009) as the training set, and the 2010 set as the testing set, to evaluate discrimination and calibration. We selected the final model after comparing cross‐validation performance. If performance was deemed to be similar across the models, we adopted the simpler one. We used the “glmnet” package in R (version 4.1.2) for our analyses.https://github.com/SatoshiFunada/2021OAB_prediction_model. After deciding on the final model, we programmed a Shiny application in R to present the prediction results interactively.Models 1 and 2 were developed separately for men and women using the logistic regression model, with penalized likelihood using the LASSO penalty to avoid “overfitting” of data and reduce the predictors.Figure We did not detect problematic multicollinearity between predictor valuables by checking scatter plot matrix and calculating variance inflation factor Table . Table 2C‐statistic, i.e., the C‐statistic calculated using the whole dataset for both training and testing using the LASSO models. Models 1 and 2 demonstrated similarly good discrimination for males and females, with an apparent C‐statistic ranging from 0.76 to 0.78 in all instances. Figure vs 0.06 and slopes were 1.08 vs 1.03, for Model 1 vs 2 respectively). Figure Figure C‐statistic ranged from 0.75 to 0.76 in males and females, only slightly worse than the apparent C‐statistic in most cases. In males, Models 1 and 2 showed equal performance in the optimism‐corrected calibration . On the other hand, Model 2 showed better calibration than Model 1 in females . Next, we performed a temporal validation of Models 1 and 2 in both male and female . In females, Models 1 and 2 showed similar calibration . Based on results after the internal and temporal validation, we selected Model 2 as our final model for males. For females, Model 2 performed slightly better than Model 1. However, given that differences were small, and also given that Model 1 was a simpler model, we selected Model 1 as our final model for females. We created an interactive web‐based application, in which baseline characteristics can be selected as the input, and the corresponding predicted probability of new‐onset OAB 5 years later can be generated .We performed an internal validation using 200 bootstrap resamples Table . Models ale Fig. ; Table 3We developed risk prediction models of new‐onset OAB for male and female in 5 years and performed internal and temporal validation using a large prospective cohort of the general population in Japan. The selected best performing prediction model for male included questionnaire assessment and blood test results as predictors, accounting for the anatomical complexity of male compared to female. On the other hand, only questionnaire assessment but no blood tests were included for female, which makes it easier to use in daily practice. Based on internally and temporally validated estimates of model performance, we deemed that both models, for men and women, had good predictive abilities.In the model development stage, we included age, OABSS questionnaires, HbA1c, eGFR, and BNP for both males and females; however, other predictors were totally different. This is probably because the etiology of OAB is different between males and females;We found that for males, the prediction model including results from blood tests in the predictor list  was better than that with only the questionnaire data. In general, among models with equal performance, the simpler the prediction model, the better they were (“Occam's razor”). Considering the ease of use, the model not including blood tests (Model 1) would perhaps be instead recommended for males. However, in a clinical setting, serum PSA is often tested to screen for prostate cancer and is useful to predict prostate volume and lower urinary symptoms in male.Our prediction models have some implications for clinicians and policy makers. Our models can help identify high‐risk populations of incident OAB in 5 years. This may help clinicians and policy makers deliver early interventions to such people to prevent new‐onset OAB, including encouraging them to keep healthy eating habits and maintain a healthy weight, and to performing pelvic floor muscle exercise.This study has several strengths. First, to the best of our knowledge, these are the first published prediction models for incident OAB. Second, we used a large prospective cohort data with high follow‐up rate (85%) and few missing data (2.1%) compared with previous follow‐up studies about urinary symptoms.There were several limitations in our study. First, as the study participants were healthy volunteers instead of a random sample, there may be some concerns about lack of representativeness. Second, our models did not include several possible predictors, such as prostate volume, use of some drugs such as anticholinergics, frailty, neurological disorders, and pelvic organ prolapse, which could have an influence on OAB symptoms. However, it is not pragmatic to measure all these clinical/biological markers in a large epidemiological study. Moreover, had we measured them, it would not serve the purpose of prediction in the general population either: widely informative and applicable prediction models should use easily measurable characteristics. Third, we defined new‐onset OAB only according to the criteria by OABSS at follow‐up assessment without frequency‐volume chart. As OAB symptoms may be influenced by the treatment and fluctuate over time, we may have misclassified some new‐onset OAB patients during the 5 years. Information about treatment and further follow‐up study is expected to strengthen the model accuracy. Fourth, our data were not enough to evaluate possible interactions and non‐linear relationships to improve the model performance. Fifth, the participants were between the ages of 35 and 70, and our models may not be extrapolated to other age groups. Sixth, although we examined temporal validity, the Nagahama cohort is a single cohort, and we did not perform neither geographic validation in Japan nor global external validation with a fully independent external cohort outside Japan. To evaluate the general applicability of the models, future studies are needed to demonstrate the external validity of the models with other cohort data.In conclusion, we have developed risk prediction models for new‐onset OAB in the general population with good performance. Future studies are necessary to evaluate the generalizability of the models and develop new models with better performance, possibly including some additional strong predictors. We expect that our models will help identify high‐risk populations for incident OAB, so that we could start prevention earlier.Satoshi Funada: Conceptualization; data curation; formal analysis; funding acquisition; methodology; software; visualization; writing – original draft. Yan Luo: Conceptualization; methodology; software; validation; visualization; writing – review and editing. Takashi Yoshioka: Conceptualization; methodology; writing – review and editing. Kazuya Setoh: Data curation; investigation; resources; writing – review and editing. Yasuharu Tabara: Data curation; funding acquisition; investigation; resources; supervision; writing – review and editing. Hiromitsu Negoro: Conceptualization; methodology; writing – review and editing. Koji Yoshimura: Conceptualization; methodology; writing – review and editing. Fumihiko Matsuda: Data curation; investigation; resources; writing – review and editing. Orestis Efthimiou: Conceptualization; formal analysis; methodology; software; supervision; validation; writing – review and editing. Osamu Ogawa: Conceptualization; supervision; writing – review and editing. Toshi A Furukawa: Conceptualization; methodology; supervision; writing – review and editing. Takashi Kobayashi: Conceptualization; project administration; supervision; writing – review and editing. Shusuke Akamatsu: Conceptualization; methodology; supervision; writing – review and editing.SF has a research grant from the Ministry of Education, Culture, Sports, Science and Technology of Japan, JSPS KAKENHI Grant Number JP 20 K18964 and a research grant from the KDDI Foundation. YL is receiving a Grant‐in‐Aid for JSPS Fellow (KAKENHI Grant Number 21 J15050). TY has research grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan, JSPS KAKENHI Grant Number JP 21 K17228 for other works not related to this study. SA has a research grant from Astellas, grants from Astra Zeneca, grants from Tosoh. SA receives honoraria from Janssen, Astra Zeneca, Astellas, and Sanofi outside of the submitted work. TAF reports grants and personal fees from Mitsubishi‐Tanabe, personal fees from MSD, personal fees from Shionogi, personal fees from Sony, outside the submitted work. In addition, TAF has a patent 2018–177 688 concerning smartphone CBT apps pending, and intellectual properties for Kokoro‐app licensed to Mitsubishi‐Tanabe. OE was supported by the Swiss National Science Foundation (Ambizione grant number 180083). None of the contributing authors have any conflict of interest, including specific financial interests or relationships and affiliations relevant to the subject matter or materials discussed in the manuscript.Approval of the research protocol by an Institutional Reviewer Board: G278.Informed consent was obtained from all participants.Not applicable.Not applicable.Figure S1. TRIPOD checklist.Figure S2. ROC curve. (a) Model 1 in male; (b) Model 2 in male; (c) Model 1 in female; and (d) Model 2 in female.Figure S3. Calibration plot. (a) Model 1 in male; (b) Model 2 in male; (c) Model 1 in female; and (d) Model 2 in female.Figure S4. DCA. (a) male and (b) female.Figure S5. ROC curve and calibration plot in internal validity. ROC curve: (a) Model 1 in male, (b) Model 2 in male, (c) Model 1 in female, and (d) Model 2 in female. Calibration plot: (e) Model 1 in male, (f) Model 2 in male, (g) Model 1 in female, and (h) Model 2 in female.Click here for additional data file.Table S1. Clinical characteristics of the participants at baseline.Table S2. OABSS at baseline and follow‐up.Table S3. Clinical characteristics of the participants excluding OAB at baseline.Table S4. VIF of predictor valuables.Click here for additional data file.Appendix S1. Overactive bladder symptom score.Appendix S2. Sample size calculation.Appendix S3. Candidate predictor variables.Click here for additional data file.


The characteristics of heart failure (HF) with mildly reduced ejection fraction (EF) (HFmrEF) overlap with those of HF with reduced EF (HFrEF) and HF with preserved EF (HFpEF) and need to be further explored. This study aimed to evaluate left ventricular (LV) function and coronary microcirculation in patients with mildly reduced ejection fraction after acute ST-segment elevation myocardial infarction (STEMI).We enrolled 119 patients with STEMI who had undergone speckle tracking imaging and myocardial contrast echocardiography during hospitalization from June 2016 to June 2021. They were classified into normal, HFmrEF, and HFrEF groups according to their left ventricular EF (LVEF): ≥ 50%, 40–50%, and ≤ 40%, respectively. The data of the HFmrEF group were analyzed and compared with those of the normal and HFrEF groups.P = 0.052), but they were both lower than that of the normal group . The HFmrEF group exhibited significantly poorer myocardial perfusion index (1.24 ± 0.33) than the normal group  but displayed no significant difference from the HFrEF group . Moreover, a significant difference in the incidence of regional wall motion (WM) abnormalities in the three groups was observed (P = 0.009), and the WM score index of patients with HFmrEF was 1.76 ± 0.30, similar to that of patients with HFrEF , but poorer than that in the normal group .HFmrEF was observed in 32 patients (26.9%), HFrEF in 17 (14.3%), and normal LVEF in 70 patients (58.8%). The mean global longitudinal strain (GLS) of all patients was − 11.9 ± 3.8%. The GLS of HFmrEF patients was not significantly different from that of the HFrEF group (− 9.9 ± 2.5% and − 8.0 ± 2.3%, respectively, GLS is a more sensitive tool than LVEF for detecting LV systolic dysfunction. The LV systolic function, coronary microcirculation, and WM in patients with HFmrEF was poorer than that of patients with normal LVEF, but comparable to that in patients with HFrEF. Patients with HFmrEF after STEMI require more attention and appropriate management. Heart failure (HF) has been classified into HF with reduced ejection fraction (EF) (HFrEF) and HF with preserved EF (HFpEF) according to left ventricular EF (LVEF) –3. HowevSpeckle tracking imaging (STI)-derived global longitudinal strain (GLS) is a reproducible and feasible parameter in clinical use, that offers incremental prognostic data over LVEF in a variety of cardiac conditions . MyocardAll consecutive patients with STEMI who had completed STI and MCE during hospitalization at Peking University People’s Hospital from June 2016 to June 2021 were enrolled in the study. Patients were diagnosed with STEMI after an expert physician review based on the 2018 Joint ESC/American College of Cardiology/American Heart Association/World Heart Federation fourth universal definition of myocardial infarction . PatientAll patients underwent echocardiography, STI, and MCE during hospitalization. Echocardiograms were performed using a Vivid E95 Console Ultrasound Machine . We used an M5Sc transducer with a 2.5–3.5 MHz imaging frequency for each study. At least three consecutive cardiac cycles were performed. According to the 2015 American Society of Echocardiography (ASE) and European Association of Cardiovascular Imaging (EACI) echocardiography guidelines , the int2 test. Statistical significance was set at P < 0.05.All statistical analyses were performed using the SPSS software . Continuous variables are described as means ± standard deviations (SD) for normally distributed variables and as medians (interquartile ranges) for non-normally distributed variables. Categorical variables are described as numbers (percentages). Associations among variables were evaluated using analysis of variance (ANOVA) with LSD test, Kruskal–Wallis H test, and χOverall, 119 patients with STEMI were enrolled. In these patients, 32 patients (26.9%) had HFmrEF, 70 patients (58.8%) had normal LVEF (≥ 50%), and 17 patients (14.3%) had HFrEF. There were no differences in sex, age, BMI, smoking, clinical history, laboratory tests, and medicine treatment except for plasma B-type natriuretic peptide (BNP) levels (Table Percutaneous coronary intervention (PCI) was performed in 110 patients 92.4%). Twenty-eight patients (23.5%) had received intravenous thrombolysis, and they subsequently underwent selected PCI. Nine patients did not receive any kind of revascularization (thrombolysis or PCI). The median time of pain to flow restored  was 5.3 (3.0–18.9) h. There were statistical differences in Killip grade, time of symptom to flow restored, culprit vessel, ST-segment elevation level, and time of ST-segment recovery > 50% of symptoms among the three groups. No statistical differences were observed in peak troponin I, thrombolysis percentage, PCI percentage, TIMI flow in the culprit vessel pre-PCI, and slow flow/no-reflow during PCI (Table .4%. TwenAll the patients had completed echocardiogram and MCE within 7 days after STEMI. One hundred and ten 92.4%) patients had completed PCI before MCE. The rates of PCI before MCE of the 3 groups were showed in Table .4% patieP = 0.052), but they were both lower than that of the normal group (P < 0.001). The WMSI in the HFmrEF group was 1.76 ± 0.30, which was comparable to that in the HFrEF , but poorer than that in the normal group  . Patients with HFmrEF displayed a mean MPI of 1.24 ± 0.33, which was not significantly different from that in the HFrEF group , but was significantly poorer than that in the normal group  .All the above parameters were significantly different among the three groups Table . The GLSCurrently, the therapeutically relevant classification of HF remains based on LVEF. All guidelines use the terminology of HFpEF and HFrEF, but differ in the terminology used in patients with EFs between 40 and 49% . HFpEF iP = 0.052), but significantly lower than that in the normal group . Additionally, WMSI in the HFmrEF group also resembled that in the HFrEF group  and was significantly poorer than that in the normal group . These results reveal significant adverse remodeling beyond systolic functional impairment and WM in patients with HFmrEF, comparable to the changes seen in patients with HFrEF, but different from those in patients with LVEF > 50%. And these distinctions were not affected by the medicine treatment. Therefore, patients with HFmrEF after STEMI require greater attention.A total of 119 patients with STEMI were enrolled in this study, 26.9% with HFmrEF and 14.3% with HFrEF. The median BNP levels in the HFmrEF and HFrEF groups were 290 (170–901) pg/mL and 625 (167–1534) pg/mL, respectively. A total of 58.8% of the patients had an LVEF ≥ 50%. The normal value for GLS depends on the definition of the measurement position in the myocardium, vendor, and version of the analysis software, resulting in considerable heterogeneity in the published literature. The 2015 ASE guidelines recommend that a peak GLS in the range of -20% can be expected in a healthy person . By meanP = 0.486), which were both poorer than that in normal group . This result reveals that the coronary microcirculation status in patients with HFmrEF is comparable to that in patients with HFrEF, but poorer than that in patients with LVEF > 50%. The presence of CMD after STEMI predicts adverse prognoses such as rehospitalization, HF, and mortality  was significantly longer than that in the normal group [4.9 (2.5–10.8) h] and HFmrEF group [5.0 (3.0–24.4) h]. Indeed, patients with HFrEF had worse clinical symptoms, critical conditions, and delayed PCI combined to develop worse cardiac function in this group. Therefore, delayed PCI resulted in patients with HFrEF experiencing even worse LV systolic dysfunction and CMD. Nevertheless, patients with HFmrEF showed similar LV systolic function and coronary microcirculation perfusion to those with HFrEF, and these results further confirmed that patients with HFmrEF might have a poor prognosis. However, our study only involved patients with STEMI who underwent either emergency PCI, selective PCI (including post-thrombolysis), or patients who did not receive any revascularization (thrombolysis or PCI). Meanwhile, the study is relatively small and includes only 119 patients. It’s the limit of this study. However, we demonstrated the difference among the groups in spite of the small size. In the future, further studies with larger sample sizes are required. Meanwhile the lack of clinical outcome and follow-up data is the limitation of our article. Whether echocardiographic parameters will recover during follow-up and whether GLS will improve earlier than LVEF? More study about the prognosis and echocardiographic parameters outcome need to be done in the future.GLS derived from STI can detect LV systolic dysfunction earlier than LVEF. LV systolic function, coronary microcirculation perfusion, and WM abnormalities associated with HFmrEF after STEMI are all different from those in normal LVEF (≥ 50%), but comparable to those associated with HFrEF. Therefore, patients with HFmrEF after STEMI require urgent attention and more appropriate management.


Anti‐IgLON5 disease is an autoimmune encephalopathy with sleep disturbances as a hallmark in the majority of reported cases. Additional clinical symptoms are heterogenous and include movement disorders, bulbar dysfunction, autonomic disorders, and neurocognitive impairment.Here, we report the case of an 87‐year‐old woman presenting with isolated progressive hemichorea. An extensive diagnostic work‐up revealed antibodies against IgLON5 in the serum. Neither history nor polysomnography (PSG) unveiled signs and features of sleep dysfunction typically reported in anti‐IgLON5 disease.In an extensive literature review we identified twelve other studies reporting about patients with confirmed anti‐IgLON5 disease and chorea as extrapyramidal movement disorder in their clinical phenotype. Subsequently, clinical characteristics of these patients were carefully evaluated.Our results support the diversity of clinical phenotypes in anti‐IgLON5 disease, adding isolated hemichorea to the spectrum of presenting symptoms. As sleep‐related disorders are often not the leading reason for consultation and only revealed by PSG examination, we suggest that screening for antibodies against IgLON5 should be considered in patients presenting with unexplained movement disorders, including isolated hemichorea. IgLON5‐associated autoimmunity was first described as a central nervous system disorder with typical sleep disturbances.Here, we describe a case of anti‐IgLON5 disease manifesting with isolated progressive hemichorea lacking sleep‐related symptoms typically observed in anti‐IgLON5 disease in PSG. Furthermore, an extensive literature search was conducted to compare the clinical phenotypes of reported cases of anti‐IgLON5 disease presenting with chorea as extrapyramidal movement disorder.An 87‐year‐old right‐handed woman of Caucasian descent presented in our outpatient department with slowly progressive hemichorea of the right side of the body that had started 2 years earlier . Family,Neuropsychological testing revealed normal cognitive functioning, and continuous blood pressure measurement in supine and standing position did not reveal any orthostatic dysregulation.Cerebral magnetic resonance imaging (cMRI) did not show any structural abnormalities of the basal ganglia. Molecular‐genetic testing for Huntington's disease was negative.Extensive peripheral blood tests including electrolytes, glucose, homocysteine, holotranscobalamine, vitamins B1, B3, and B12, folic acid, HbA1c, neuroakanthocythes, antinuclear, anticardiolipin, and antiphospholipid antibodies, antimyeloperoxidase, antithyroid peroxidase, antithyroglobulin antibodies and serum onconeural antibodies panel  were unremarkable. However, testing of antibodies directed toward neuronal surface antigens revealed positive anti‐IgLON5 serum antibodies. The patient declined lumbar puncture.Polysomnographic examination was performed and revealed normal sleep architecture without the typical pattern of IgLON5‐associated sleep abnormalities. Repeated electroencephalographic examinations displayed no abnormalities. A whole body FDG‐PET‐CT scan did not show malignant lesions or inflammatory processes.HLA‐class II typing was negative for the HLA‐DRB1*10:01 allele but revealed the HLA‐DQB1*05:03 allele.Symptomatic treatment with tiapride was started showing a good therapeutic effect but was stopped by the patient due to the undesirable side effect of hair loss, resulting again in a worsening of chorea. Immunotherapy with corticosteroids as well as immunomodulating treatment with intravenous immunoglobulins was declined by the patient. A second therapeutic attempt with tiapride was started after some weeks, showing again a good therapeutic effect and was well tolerated by the patient this time. Hemichorea improved subjectively by 50%  as it did 21 months after diagnosis, when the patient presented to the traumatology department due to a fracture of her right ankle. The patient declined further follow‐up visits because of her advanced age.We identified 12 case reports and case seriesHere, we report a case of anti‐IgLON5 disease presenting with progressive hemichorea, lacking the characteristic sleep pattern often associated with antibodies against IgLON5. To the best of our knowledge this is the first report of anti‐IgLON5 disease in a patient presenting with isolated hemichorea, and in which neither history nor PSG examination yielded sleep abnormalities that are usually associated with this disease. Typically, patients with anti‐IgLON5 disease and chorea suffer from additional clinical symptoms Table . TherefoTypical sleep disturbances during NREM and REM sleep, including stridor and obstructive sleep apnea, snoring, insomnia and limb movements during sleep, associated with antibodies targeting the extracellular domain of the IgLON5 immunoglobulin‐like cell adhesion molecule, were described as the first hallmark of anti‐IgLON5 disease.In a clinical follow‐up 21 months after diagnosis, our patient still had isolated hemichorea. The onset of sleep‐related disorders only months or years after initial symptoms is also a possible clinical course in anti‐IgLON5 disease.Concerning diagnostic features in anti‐IgLON5 disease, there is indeed a significant association between anti‐IgLON5 disease and the HLA‐DRB1*10:01‐DQB1*05:01 haplotype.Reports of anti‐IgLON5 disease questioned the relevance of immunotherapy, and most patients of the two earliest case series showed disease progression leading to death irrespective of immunotherapy.This case report suggests that anti‐IgLON5 disease should be considered in patients presenting with adult onset hemichorea, even in the absence of typical sleep disorders associated with anti‐IgLON5 disease. In clinical routine, isolated hemichorea is usually associated with structural abnormalities in the basal ganglia. Therefore, an unremarkable cMRI in a patient with isolated hemichorea should be regarded as a red flag for a probable autoimmune etiology, including anti‐IgLON5 disease. As there is already some evidence for response to early immunotherapy,(1) Research project: A. Conception, B. Organization, C. Execution.(2) Manuscript preparation: A. Writing of the first draft, B. Review and Critique.A.G.: 1A, 1C, 2A.A.H.: 2B.P.M.: 2B.M.P.: 2B.A.HE.: 2B.F.D.: 2B.A.D.: 2B.K.S.: 1A, 1B, 1C, 2B.B.H.: 1A, 1B, 1C, 2A, 2B.Ethical Compliance Statement: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Ethics approval of this manuscript was obtained by the ethics committee of the Medical University of Innsbruck (No. 1010/2022). Patient informed consent for video recording and publication was obtained as well.Funding Sources and Conflicts of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work.Financial Disclosures for the Previous 12 Months: Anna Hussl, Philipp Mahlknecht, and Marina Peball declare that there are no additional disclosures to report. Anna Grossauer received travel grants from the Austrian Parkinson Society. Anna Heidbreder received honoraria for lectures or advisory board from Jazz Pharmaceuticals, UCB, Desitin, and travel support from Jazz Pharmaceuticals. Florian Deisenhammer has participated in meetings sponsored by or received honoraria for acting as an advisor/speaker for Almirall, Alexion, Biogen, Celgene, Genzyme‐Sanofi, Janssen, Merck, Novartis Pharma, and Roche. His institution has received research grants from Biogen and Genzyme Sanofi. He is section editor of the MSARD Journal (Multiple Sclerosis and Related Disorders). Atbin Djamshidian received honoraria from Novo Nordisk, Roche, Biogen und Abbvie. Klaus Seppi reports personal fees from Teva, UCB, Lundbeck, AOP Orphan Pharmaceuticals AG, Roche, Gruenenthal, Stada, Lucher Pharma, Biogen, BIAL, and AbbVie, honoraria from the International Parkinson and Movement Disorders Society, and research grants from FWF Austrian Science fund, Michael J. Fox Foundation and AOP Orphan Pharmaceuticals AG. Beatrice Heim reports honoraria from AOP orphan Pharmaceuticals AG.


Burkitt lymphoma (BL) is an aggressive B‐cell lymphoma that, in some instances, may show a granulomatous reaction associated with a favourable prognosis and occasional spontaneous regression. In the present study, we aimed to define the tumour microenvironment (TME) in four such cases, two of which regressed spontaneously.All cases showed aggregates of tumour cells with the typical morphology, molecular cytogenetics and immunophenotype of BL surrounded by a florid epithelioid granulomatous reaction. All four cases were Epstein–Barr virus (EBV)‐positive with type I latency. Investigation of the TME showed similar features in all four cases. The analysis revealed a proinflammatory response triggered by Th1 lymphocytes and M1 polarised macrophages encircling the neoplastic cells with a peculiar topographic distribution.in‐vivo picture of the role that specific immune cell subsets might play during the early phase of BL, which may be capable of maintaining the tumour in a self‐limited state or inducing its regression. These novel results may provide insights into new potential therapeutic avenues in EBV‐positive BL patients in the era of cellular immunotherapy.Our data provide an   Burkitt lymphoma (BL) is an aggressive B‐cell lymphoma characterised by diffuse proliferation of medium‐sized monomorphic lymphoid cells with basophilic cytoplasm and cohesive growth. A so‐called starry sky pattern is usually present, owing to the presence of numerous macrophages with tangible apoptotic bodies. However, some cases show a florid granulomatous reaction and are characterised by a favourable outcome and, in rare instances, spontaneous regression.Only in the last decade has the cellular background in which lymphoma cells thrive become an important target of inquiry. The functions of what used to be considered passive bystanders are quickly becoming elucidated, in order to provide potential targets for immunotherapy. In recent years, a model has been developed to describe the complex mechanism of macrophage activation as polarisation towards two opposite states, namely M1 and M2, with proinflammatory and protumoral properties respectively. The M1/M2 nomenclature has been inspired by the Th1 versus Th2 concept.Th1 lymphocytes and M1 macrophages are the primary sources of proinflammatory cytokines, which also promote cancer immunosurveillance and cytotoxicity. On the other hand, these effects are counterbalanced by M2 macrophages, Th2 lymphocytes and regulatory T cells (Tregs) having anti‐inflammatory and protumoral effects.Differentiation of CD4+ T cells into Th1 and Th2 effector cells is controlled by the transcription factors T‐box protein expressed in T cells  and GATA‐binding protein 3 (GATA3), respectively. T‐bet overexpression causes differentiation into the Th1 lineage, whereas loss of T‐bet expression induces default commitment to the Th2 and Th17 lineages.Th1 lymphocytes are well‐known IFN‐γ secretors, being involved in the regulation of macrophage polarisation, promoting and maintaining the formation of granulomas.However, the immunophenotypic features that distinguish M1 and M2 macrophages are still not standardised.Epstein–Barr virus (EBV)‐specific T‐cell responses in BL have not been fully elucidated. Indeed, Epstein–Barr nuclear antigen (EBNA) 1, which is usually the only latent protein expressed in EBV+ BL, has the ability to inhibit proteasomal processing through its Gly‐Ala repeat domain.Therefore, the aim of this study was to investigate the immune landscape in four cases of EBV+ BL with a granulomatous reaction, focusing on the quantitative and topographic distribution of the innate immunity  and adaptive immunity (Th1/Th2 lymphocytes and Tregs) cell subsets.A formalin‐fixed paraffin‐embedded (FFPE) BL case was retrieved from the Department of Medical Biotechnologies, University of Siena, Siena, Italy (case 1), and two cases (case 2 and case 3) were retrieved from the LYWS of the 18th EAHP meeting, in Basel, Switzerland, 2016, and were included in the workshop report.In‐situ hybridisation for EBV‐encoded small RNAs (EBERs) was performed on deparaffinised 4‐mm‐thick FFPE tissue sections with a Dako Detection Kit for EBER . The slides were counterstained with haematoxylin and fixed in Faramount (DakoCytomation).The diagnosis of BL was issued by expert haematopathologists following the criteria described in the 2017 World Health Organization classification of tumours of haematopoietic and lymphoid tissue.in‐situ hybridisation for MYC rearrangement was performed for each case, with a break‐apart probe (BAP)  and a dual fusion probe , according to the manufacturer’s instructions. For each specimen, a 4‐µm‐thick tissue section embedded in paraffin was cut. Briefly, the slides were incubated in heat pretreatment solution, washed, digested, dehydrated, and hybridised with probes. At least 100 intact non‐overlapping nuclei were analysed manually on a Leica DM 600B  fluorescence microscope equipped with 4′,6‐diamidino‐2‐phenylindole, Spectrum Green and Spectrum Orange filters.Fluorescence The antibody panels used for multiplex immunohistochemistry (mIHC) consisted of eight different triple and double stains: (i) CD68, CD163, and c‐Maf; (ii) programmed death‐ligand 1 (PD‐L1), CD163, and c‐Maf; (iii) CD4, CD25, and forkhead box P3 (FOXP3); (iv) CD8, programmed cell death protein 1 (PD‐1), and lymphocyte‐activation gene 3 (LAG3); (v) pSTAT1, CD68, and CD123; (vi) CD4 and T‐bet; (vii) CD4 and GATA3; and (viii) CD20 and T‐bet (see Table S1 for antibody characteristics). CD56 and CD57 were included as single stains. Double staining and triple staining were performed with an automated staining system  for open procedures, according to the manufacturer’s protocols.Tissue sections from the same set of cases and without antibody/chromogens were used as negative controls. Three tonsils, three reactive lymph nodes and three cases of conventional BL with the typical starry sky pattern were used as positive controls.Case 1 was a 65‐year‐old female with an isolated right axillary lymphadenopathy and no signs of systemic infection. She underwent excision of the enlarged lymph node, and a diagnosis of focal involvement by EBV‐positive B cells with features of BL was made, associated with reactive lymphadenitis, and a granulomatous reaction. The computed tomography–positron emission tomography (CT‐PET) scan showed no evidence of other hypermetabolic lymph nodes. Bone marrow biopsy showed normal haematopoiesis, and flow cytometry analysis showed a normal phenotype. Therefore, the patient was followed closely, and a ‘watch and wait’ strategy was used, without any chemotherapy. The patient was well and in good condition 30 months after the initial diagnosis.Case 2 was a 16‐year‐old male who presented with recurrent swelling on the left side of the neck. First, he was treated with antibiotic therapy for an upper respiratory tract infection. After 7 months, a diagnosis of viral infection was made, without specific treatment. Because of persistent lymph node enlargement, an excisional lymph node biopsy was performed. The lymph node was 60 mm in diameter, and a diagnosis of BL with a granulomatous reaction was made. The patient had no signs of other lymphadenopathies, splenomegaly, or hepatomegaly. The levels of lactate dehydrogenase (LDH) and β2‐microglobulin were normal. A CT‐PET scan showed no evidence of disease, and the bone marrow biopsy was also negative. The patient refused multi‐agent chemotherapy. After 4 years, he was in complete remission without any treatment.Case 3 was a 47‐year‐old female who presented with cervical swelling for 1 month without B symptoms. A computed tomography (CT) scan showed a 33 × 24‐mm lymphadenopathy next to the left parotid. Peripheral blood and biochemical parameters were normal, except for LDH: 512 U/l . The left submandibular lymph node was excised for further investigation, and a diagnosis of BL with granulomatous reaction was proposed. Multi‐agent chemotherapy was initiated. After three cycles of chemotherapy, the patient was in complete remission, and after 2 years of follow‐up he showed no evidence of disease.Case 4 was a 12‐year‐old male from Kigoma, Tanzania. He was admitted to the local hospital for a swelling in the right lower jaw region that had persisted for >2 months. Prior to the swelling, there was a history of trauma followed by mobility of the lower jaw and regional pain. After tooth extraction, there was no reduction in the symptoms and there was a further increase in the swelling. The patient was sent to a reference centre for further management. The CT scan of the head showed features suggestive of BL in the right lower jaw region, mild right maxillary sinusitis, no evidence of cervical or mediastinal lymphadenopathy, and no evidence of brain involvement. Surgical enucleation and curettage of the tumour was performed. After six cycles of chemotherapy with rituximab, cyclophosphamide, oncovin (vincristine), doxorubicin, and methotrexate, the patient showed no residual disease and was discharged. After 16 months of follow‐up, the patient was asymptomatic.The morphological and immunophenotypic features of all four cases are summarised in Table MYC translocation as shown with both dual fusion and a BAP; Figure in‐situ hybridisation , and prominent perisinusoidal and perifollicular clear areas composed of monocytoid B‐lymphoid cells. Exclusively within the monocytoid B‐lymphoid cell areas, nests of dark‐appearing, atypical cells were occasionally present Figure . Some nen Figure . ImmunohCases 2, 3 and 4  were scarce (5–20%) Figure ; Table 2et al.The pSTAT1/CD68/CD123 triple staining highlighted that macrophages (CD68+) express nuclear pSTAT1, indicating IFN‐γ priming and confirming an M1 phenotype of the macrophages Figure ; Table 2In this article, we report four cases of localised (stage I) EBV‐positive BL with a prominent granulomatous reaction and a similar TME consisting of Th1 lymphocytes and M1 macrophages. The TME described above is quite different from that of conventional BL with the typical starry sky pattern, in which the most prominent component of TME is represented by M2 macrophages.in‐vivo picture of a T‐bet‐mediated immune response fostered by IFN‐γ and subsequent granuloma formation comprising M1 polarised macrophages with an activated STAT1 signalling pathway.Another important observation in this study was the peculiar topographic distribution of the reactive inflammatory cells. In fact, Th1 lymphocytes, pDCs and M1 macrophages were detected in the immediate proximity of the BL cells. Intriguingly, we also observed numerous CD20+/T‐bet+ cells, which more probably represented monocytoid B cells, around the clusters of BL cells.We believe that the fractions of cells that we scored in our IHC experiments reflect specific Th states according to the expression of selected Th proteins. However, we need to consider a variety of states and transitions that may form part of the highly dynamic tumour‐infiltrating T‐cell landscape and that we are not taking into account. Besides Th1 and Th2, in addition Th0, Th17, Th9 and Th22 cells and other potentially relevant Th phenotypes could contribute to the overall Th infiltration of BL, such as bcl‐6+ and/or c‐Maf+ T follicular helper cells, which are variably represented among CD4+ T cells in lymphomas of the GC phenotype, or variants in regulatory subsets that may be aberrantly expanded in tumours, such as eomesodermin+/granzyme K+/type 1 regulatory‐like CD4+ effectors.Therefore, our findings need to be confirmed in further studies using different methods that allow more comprehensive characterisation of the TME .The interplay with the TME may be a crucial event for the outcome of EBV‐related diseases, and the viral interaction with host immune surveillance requires further investigation in correlation with the EBV latency programme. It has been shown that the pattern of viral protein expression determines the immunogenicity of the infected cells.A further observation of this study concerned the distinctive morphological features of case 1. In fact, in this case the nests of BL cells were found exclusively within prominent areas of clear cells identified as monocytoid B cells, which might represent a possible niche from which BL cells originate and spread, as has been previously reported for Hodgkin’s lymphoma.in‐vivo picture of the immune surveillance of BL with a granulomatous reaction that might explain why an aggressive lymphoma is kept in check and behaves in such a self‐limiting way. In contrast to conventional BL, the important role of Th1 and M1 macrophages in the TME is highlighted. In addition, the recognition of TME features of BL may be helpful for identifying a subset of BL patients with a better prognosis, and who are thus suitable for less burdensome therapy. Further studies are warranted to investigate the reason why similar tumour cells trigger different immune responses.BL in the setting of a granulomatous reaction and conspicuous monocytoid B‐cell hyperplasia might be easily overlooked, and making the correct diagnosis may be challenging.In addition, our data may provide the rationale for new potential therapeutic avenues to explore in EBV‐positive BL patients in the era of immunotherapy, and in particular adoptive T‐cell therapy with EBNA1‐specific Th1 cells.The authors declare that they have no conflicts of interest.All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This was a non‐interventional study on archived tissue samples.R. Santi, F. Vergoni, D. Di Stefano, B. Puccini, E. Sabattini, C. Agostinelli, N. Bassüllü, T. Tecimer, A. S. Demiroz, L. Mnango, and S. Dirnhofer: provided tumour samples and clinical data. A. Akarca, E. Sorrentino, R. Guazzo, and L. Mundo: performed IHC and cytogenetic analysis. M. Granai, S. Lazzi, V. Mancini, R. Santi, F. Vergoni, G. Cevenini, C. Tripodo, G. Di Stefano, M. Ponzoni, E. Sabattini, C. Agostinelli, S. Dirnhofer, T. Marafioti, L. Quintanilla‐Martinez, F. Fend, and L. Leoncini: analysed and interpreted the data. M. Granai, S. Lazzi, T. Marafioti, L. Quintanilla‐Martinez, F. Fend, and L. Leoncini: designed and coordinated the study. M. Granai, S. Lazzi, L. Quintanilla‐Martinez, F. Fend, and L. Leoncini: interpreted the data and wrote the manuscript.Data S1. Supplementary materials and methods.Click here for additional data file.Figure S1. High number of M2 macrophages in a reactive lymph node.Click here for additional data file.Figure S2. Dichotomous role of IFN‐γ.Click here for additional data file.Figure S3. Th1 and Th2 expression in the controls.Click here for additional data file.Figure S4. Expression of T‐bet in B cells.Click here for additional data file.Figure S5. Partial lymph node involvement by BL in an HIV‐positive patient.Click here for additional data file.Table S1. Antibody characteristics.Click here for additional data file.Table S2. The individual scores of the observers and the agreement for all separate cell types.Click here for additional data file.


To date, allogenic stem cell transplant (ASCT) remains the only potential curative option for patients with primary myelofibrosis (PMF). However, relapse rates and associated mortality remain a concern. A second ASCT may not be feasible due to advancing age, declined functional status, donor unavailability, toxicities associated with a second ASCT. Herein, we report the first case of utilizing initially azacitidine and subsequently oral decitabine + cedazuridine (decitabine), in the context of relapsed PMF post‐ASCT. Utilizing both hypomethylating agents provided disease control and improved donor/myeloid lineage chimerism levels, and the patient also remained transfusion independent, with preserved functional status and quality of life. DespiteStudies have demonstrated an association between decrease donor chimerism (DC)/myeloid lineage chimerism (MLC) and relapse , 5, 6, 7Here we report, to our knowledge, the first case of a patient with high‐risk PMF relapsed post‐ASCT using a haploidentical‐donor, who achieved disease control with improved MLC, using initially azacitidine and subsequently oral decitabine + cedazuridine (decitabine), remains alive after 30 months since DR.Patient has a 72F JAK2+ PMF relapsed post‐ASCT after 3 years. On initial presentation, she was 66, JAK2+ PMF with anemia, blast, and splenomegaly. In September 2017, she underwent ASCT with a haploidentical‐donor. On day 60 post‐ASCT, DC was 100%. The marrow reported cellularity 60% with MF2–3 of 3, JAK2 undetectable.In April 2020, DC dropped to 79.6% in bone marrow biopsy (BMB). In May 2020, it revealed hypercellular marrow with MF2, with blast 7%, with JAK2+, indicating DR with progression. A second transplant was considered highly risky given her advanced age and no alternative donor. DLI was also considered highly risky. Therefore, azacitidine was initiated to provide disease control , 9.After three cycles of azacitidine, BMB showed normocellular marrow with MF1–2, with <5% blast and T‐cell lineage chimerism (TLC) at 100% and MLC at 89.3%. After seven cycles of azacitidine, the patient began to experience leukopenia and neutropenia, with TLC at 100%, but MLC declined to 76%. Repeat BMB showed a chronic phase of MF with no blast. But given persistent neutropenia azacitidine was held.By September 2021, BMB demonstrated PMF with a blast nearing 10%, indicating MPN accelerated‐phase. TLC was 99.1%, MLC dropped to 2.8%. Therefore, decitabine was initiated as a second line HA. After four cycles of decitabine, BMB showed chronic phase PMF with MF3, and blast 1%. Unfractionated chimerism was 44.8%. The patient remained well, transfusion independent, and cycle 5 restarted after a delay of 12 weeks due to cytopenia, with a reduced dose (Table Despite advances in novel treatments for MPNs, ASCT remains the only curative option; however, retrospective studies have suggested relapse rate range from 18.3% to 25% at 5‐year post‐ASCT, with morality related to DR up to 41% . A seconAzacitidine has been shown to provide improved DC , 8 and aA pilot study administered low‐dose decitabine to 14 patients who have undergone ASCT for either high‐risk MDS or AML . These pThis is the first case demonstrating response and improving MLC to oral decitabine after progression on azacitidine for relapsed PMF post‐ASCT. Although during the time that azacitidine was held due to cytopenia, the patient did progress to accelerated phase MPN with 10% blast, disease control and improved MLC were re‐achieved through decitabine. Furthermore, the patient remained transfusion independent, with preserved performance and functional status. Although our findings are limited to this case report, such positive patient outcomes do warrant the further investigation of the potential use of HAs as ST relapsed post‐ASCT, as it potentially allows for a possible prolongation of survival with preserved quality of life.The authors have no conflicts of interest to disclose.The authors received no specific funding for this work.Consent obtained from patient for this case report.Consent was obtained from the patient.


Necrotizing fasciitis is a rare complication of varicella‐zoster viral infection in adults, occurring due to a secondary bacterial infection. A 35‐year‐old female healthy patient had post‐varicella zoster infection with NSAID use as a possible risk factor. She was diagnosed early by clinical and laboratory parameters. Chickenpox can cause life‐threatening infections, including meningitis and soft tissue infection. NSAIDs increase the risk of soft tissue infection. Early diagnosis and aggressive resuscitation with supportive organ care and antibiotic therapy are key to survival. Around 47% of chicken pox infection occurs in the adult population, with male predominance.23/μl), hyperglycemia (RBS 16.2 mmol/L), impaired renal function (BUN 14.5 mg/dl and serum creatinine 124 μmol/L), and anemia (Hb 7.2 g/dl) with high C‐reactive protein (324 mg/L). She was diagnosed as a case of NF by severe pain in thigh, high index of suspicion and use of abnormal basic laboratory parameters, LRINF scoreStreptococcus pyrogens and Pseudomonas aeruginosa, both were sensitive to Tazocin®. By day 4, she was on enteral feeds, off vasopressors, and her trachea was extubated by day 5. The patient remained stable, all invasive lines were removed, and an oral diet was initiated. She was transferred to the surgical ward on day 7 and from there discharged home to be followed in outpatient clinics.A 35‐year‐old female presented to the emergency department with severe pain and yellowish discharge in the left thigh for 2 days. She had a history of chickenpox for 2 weeks, diagnosed by typical skin rash, itchy, and progressively started from the abdomenand spread all over body associated with high‐grade fever and myalgia. Thigh rashes became painful, and she was taking regular ibuprofen, nonsteroidal anti‐inflammatory drug (NSAID), for a week. She was awake, dehydrated, tachycardiac (110–120 beats/min), tachypneic (24–29 breath/min), and febrile (39°C), with borderline blood pressure (90/50 mm Hg). On local examination, there were blackish lesions involving the posterior aspect of the left thigh, : UA, MIH, SM, AIE, MAM, AJN. All authors read and approved the final manuscript.This study was not funded.The authors declare that they have no competing interests.The article describes a case report. Therefore, no additional permission from our Ethics Committee was required (MRC‐04‐20‐1018).Written informed consent was obtained from the patients to publish this report in accordance with the journal's patient consent policy.


In contrast, regional‐scale species distributions and species diversity were largely stable. Surprisingly, the effect size of ecological response did not increase with study duration, and shifts in responses did not occur at the same time as shifts in temperature. This may be as the long‐term studies include both periods of warming and temperature stability, and that ecological responses lag behind warming. Our findings demonstrate a regional climate fingerprint across a long timescale. We contend that natural history collections provide a unique window on a broad spectrum of ecological responses at timescales beyond most ecological monitoring programs. Natural history collections are thus an essential source for long‐term ecological research.Climate change has dramatic impacts on ecological systems, affecting a range of ecological factors including phenology, species abundance, diversity, and distribution. The breadth of climate change impacts on ecological systems leads to the occurrence of fingerprints of climate change. However, climate fingerprints are usually identified across broad geographical scales and are potentially influenced by publication biases. In this study, we used natural history collections spanning over 250 years, to quantify a range of ecological responses to climate change, including phenology, abundance, diversity, and distributions, across a range of taxa, including vertebrates, invertebrates, plants, and fungi, within a single region, Central Norway. We tested the hypotheses that ecological responses to climate change are apparent and coherent at a regional scale, that longer time series show stronger trends over time and in relation to temperature, and that ecological responses change in trajectory at the same time as shifts in temperature. We identified a clear regional coherence in climate signal, with decreasing abundances of limnic zooplankton (on average by 7691 individuals m In this study we used natural history collections spanning over 250 years, to quantify a range of ecological responses to climate change, including phenology, abundance, diversity, and distributions, across a range of taxa, including vertebrates, invertebrates, plants and fungi, within a single region; Central Norway. Our findings demonstrate a regional climate fingerprint across a long timescale, demonstrating the value of natural history collections to ecological research. ImpactsSynthesizing ecological fingerprints of climate change may be challenging. For example, Brown et al.  found thNatural history collections are an underexploited resource for long‐term ecological research. Natural history collections can be used to quantify a range of ecological responses including distributions, phenology, and species interactions, to multiple drivers of change, including climate change, non‐native species, and pollution, across a large range of taxa and at decadal to centurial scales , ecosystems , and ecological variables including distributions, diversity, and phenology. We investigate whether ecological responses across a range of taxa, ecosystems, and ecological variables within a single region vary over time and in association with changing temperature. We use natural history collections spanning over 250 years from Central Norway. We test the hypotheses that 1. Ecological variables derived from natural history collections show similar trends over time and with temperature. 2. Longer natural history collection time series show stronger temporal trends and responses to temperature and 3. Breakpoints in the temporal trends in the ecological state  occur at similar times as breakpoints in the temperature trends.22.1https://www.ntnu.edu/museum/natural‐history‐collections. These collections contain around 1.4 million specimens from many parts of the world, but the majority (ca. 65%) are from Central Norway. Our study region was defined broadly as Central Norway, of which the county of Trøndelag forms the greater part . We downloaded the whole dataset . The transect is located in subalpine birch (Betula pubescens) woodland at 800–880 m.a.s.l. in Endalen  and suitability for repeated territory counts . The transect was surveyed annually around 10 times per year mainly during morning hours, spread over 3–4 periods when breeding birds in the area are most active , following a standard procedure described in  was used as a response variable.Abundance data of boreal forest breeding birds were acquired from surveying a 0.24 km2.2.3−3) was used as a response variable.To assess the abundance of limnic zooplankton, we used a dataset  and temperature  we first estimated linear regression slopes and standard errors for each species (or sampling station) within each ecological response Table . We thenTo ensure that the effect sizes are interpretable in ecological terms, we used unscaled (raw) response variables to present each ecological effect size in isolation. However, to synthesize the effect sizes across ecological responses, allowing us to address hypothesis 2, we used the absolute effect size estimated using centered and scaled ecological response variables. Centering (on the mean) and scaling (by standard deviation) allow each effect size to be interpreted as standard deviation units from the mean. We used the absolute value to account for the expected differences in direction of ecological responses to climate .To test whether there were shifts in the slope of the relationship between ecological responses and time, and whether these corresponded with changes in the temporal trends in temperature data, we again used segmented regression. Within each ecological response that spanned 80 years or greater, we tested for one or two significant breakpoints . If one or two significant breakpoints existed, the years of these were extracted. We used Kolmogorov–Smirnov test to test whether the distribution significantly differed from a simulated uniform and normal distribution, and a bimodal distribution with peaks at the same years as breakpoints in the temperature data.33.1n = 100, p < .001). During the first phase, there was an increase in mean annual temperature between 1900 and 1946 of an average of 0.05°C (±0.008 standard error) per year. From 1946 to 1979, the temperature showed a slight decrease (−0.02°C year−1 ± 0.010 standard error) while between 1980 and 2020, the mean annual temperature again increased by 0.06°C year−1 .Across 22 species, plant flowering phenology showed an average advance of 9 days per century  or temperature . However, animal distributions decreased in latitude over time  while plant distributions decreased in latitude with temperature . Due to the low overlap between marine invertebrate distribution data, and marine temperature data, it was not possible to investigate how marine invertebrate distributions varied with temperature. Effect sizes for individual species are shown in Table Species distributions on average did not change over time  and within the two ecological response types with high variation in response duration . The effect size between ecological response and temperature also decreased with dataset duration , and was not present within either distribution data  or phenology data .The log‐transformed absolute scaled effect size of relationships between ecological responses and time, decreased with the duration of the dataset . It also significantly differed from a uniform distribution  and a simulated bimodal distribution . Cumulative distribution functions of these are shown in Figure In total there were 131 breakpoints across the (nonmarine) distribution data and plant phenology data Figure . There w4By quantifying a range of ecological responses across taxa within a single region, our study documents a regionally coherent fingerprint of climate change on Central Norwegian nature; a fingerprint with higher spatial specificity than at global scales  are similar in direction but generally weaker than observed in studies across Europe , this species grows in spring‐influenced snow beds along an altitudinal gradient from subalpine to mid‐alpine vegetation. One possible explanation for the delayed flowering might be that the early flowering subalpine populations have gradually been lost and we only have high‐altitude populations left. The species with the greatest advance in flowering, albeit with large variation, was Arabidopsis suecica. This is a postglacial allopolyploid species formed via hybridization of A. thaliana and A. arenosa  is consistent with elevational advances in the distribution of low‐elevation stoneflies in the Appalachians, with increases in elevation of up to 250 m for 0.7°C warming Sheldon, .4.3−1), centroid (2.41 ± 2.45 km year−1), or leading edge (0.81 ± 0.65 km year−1). The only terrestrial taxonomic groups with significant range shift in their meta‐analysis were reptiles , arachnids (poleward moving leading edge), and insects (poleward moving trailing edge and centroid). Their suggested mechanisms for distribution stability are antagonistic effects between climatic effects and human‐related drivers, such as habitat loss and fragmentation. It may also be the case, that for our regional‐scale study, latitudinal distributions do not occur at a suitable scale for testing climate signals, potentially underestimating the effect of warming  over time, or in relation to temperature. This is in contrast to multiple studies both marine  a normal distribution than a bimodal distribution with peaks in the years with breakpoints in the temperature trends. This may be as ecological responses are lagged responses to temperature , pollution, and the spread of non‐native species ; formal analysis (lead); investigation (lead); visualization (lead); writing – original draft (lead). Ann Evankow: Formal analysis (supporting); investigation (supporting); writing – review and editing (supporting). Tanja Kofod Petersen: Conceptualization (supporting); formal analysis (supporting); investigation (supporting); writing – review and editing . Peter Ranke: Investigation ; writing – review and editing . Nellie Nilsen: Investigation ; writing – review and editing . Grace Turner: Investigation ; writing – review and editing . Kaare Aagaard: Investigation ; writing – review and editing . Torkild Bakken: Conceptualization ; methodology ; writing – review and editing . Jan G. Davidsen: Conceptualization ; investigation ; writing – review and editing . Glenn Dunshea: Conceptualization ; investigation ; writing – review and editing . Anders G. Finstad: Conceptualization ; investigation ; writing – review and editing . Kristian Hassel: Conceptualization ; investigation ; writing – review and editing . Magne Husby: Conceptualization ; investigation ; writing – review and editing . Karstein Hårsaker: Conceptualization ; investigation ; writing – review and editing . Jan Ivar Koksvik: Investigation ; writing – review and editing . Tommy Prestø: Conceptualization ; investigation ; writing – review and editing . Vibekke Vange: Conceptualization ; investigation ; writing – review and editing .Figure S1 & S2Click here for additional data file.Table S1Click here for additional data file.Table S2Click here for additional data file.


Comorbid anxiety disorders and anxious distress are highly prevalent in major depressive disorder (MDD). The presence of the DSM‐5 anxious distress specifier (ADS) has been associated with worse treatment outcomes and chronic disease course. However, little is known about the neurobiological correlates of anxious distress in MDD.N = 24) and without ADS  and healthy controls . Both categorical and dimensional measures of ADS were investigated.We probed the relation between the DSM‐5 ADS and task‐related reactivity to emotional faces, as well as resting‐state functional connectivity patterns of intrinsic salience and basal ganglia networks in unmedicated MDD patients with —part of a larger striato‐limbic cluster. MDD/ADS+ did not differ from MDD/ADS− or controls in resting‐state functional connectivity of the salience or basal ganglia networks.MDD/ADS+ patients had higher left amygdala responses to emotional faces compared to MDD/ADS− patients (Current findings suggest that amygdala and striato‐limbic hyperactivity to emotional faces may be a neurobiological hallmark specific to MDD with anxious distress, relative to MDD without anxious distress. This may provide preliminary indications of the underlying mechanisms of anxious distress in depression, and underline the importance to account for heterogeneity in depression research. Imaging sessions were performed at the university medical centers in Amsterdam, Leiden, and Groningen. This study was approved by the Ethical Review Boards of each participating center. After receiving written information, each participant gave written informed consent.Participants were recruited from the Netherlands Study of Depression and Anxiety (NESDA), a longitudinal observational cohort study  in these measures, independent sample 2.3.1‐defined simple contrasts were performed in FSL FEAT, using FLAME 1 mixed‐effects modeling  relative to controls in separate ANCOVA's.For the emotional faces task, each participant's imaging data were analyzed in the context of the General Linear Model, using delta functions to model responses to stimuli . First‐level contrast images for emotional faces  versus scrambled faces were produced. Group analyses were performed using the FEAT toolbox of FSL. First‐level contrasts were entered into second‐level analyses of covariance (ANCOVA) for group comparisons, including group as a three‐level factor . As we were primary interested in group differences between MDD/ADS+ and MDD/ADS−, a prioriWe had a primary focus on amygdala responsiveness, employing region of interest (ROI) analyses based on Harvard‐Oxford anatomical templates for the left and right amygdala in one bilateral amygdala mask . For sake of completeness, we additionally ran all group analyses at whole‐brain level. To illustrate significant associations and post hoc sensitivity analyses, mean percent signal change values were extracted from a 5 mm sphere around the peak‐voxels using FEATquery.2.3.2For the resting‐state scan, we investigated large‐scale intrinsic functional connectivity networks. Standard group independent component analyses (ICA) were carried out using probabilistic ICA in FSL MELODIC , performed with Randomise. To correct for multiple comparisons across voxels, test statistics were corrected using family‐wise error and threshold‐free cluster enhancement implemented in Randomise. Significant group differences were followed up with additional comparisons between MDD/ADS+versus controls, and MDD/ADS− versus controls to test deviations from the control reference group. Additionally, second‐level regression analyses were run, investigating associations between the dimensional ADS score and functional connectivity patterns in all participants. Furthermore, as secondary analyses, to assess specificity of the neural correlates of the ADS relative to traditional DSM‐based diagnoses, we additionally compared MDD/ANX+, MDD/ANX−, and controls; and all MDD participants were taken together irrespective of anxiety  relative to controls.Next, the subject‐specific component maps were identified with dual regression in FSL  method. To illustrate significant associations and to run post hoc sensitivity analyses, mean percent signal change values were extracted from a 5‐mm sphere around the peak voxels.As two networks of interest were tested , 33.1n = 136 . In total, 36.4% of MDD participants (n = 28) scored positive on the ADS. Average scores on the ADS dimensional measure were significantly higher in MDD patients  compared to healthy controls , and in MDD/ADS+ patients  compared to MDD/ADS− patients , and a higher average number of anxiety disorders (p = .019). Particularly the presence of SAD was higher in MDD/ADS+ relative to MDD/ADS− (p = .038), whereas GAD (p = .299) and PD and/or agoraphobia (p = .141) did not show significant differences in prevalence. Compared to controls, MDD participants  were significantly younger and less educated  = −5.735, p < .001), and BAI total scores, t(75) = −5.796, p < .001). MDD/ADS+ participants further displayed significantly higher scores relative to MDD/ADS− on fear and worry symptoms , leaving an overall imaging sample of 3.2Complete emotional faces task data were available for 83 unmedicated MDD participants and 59 controls. After preprocessing, eight participants were excluded due to excessive movement (>|2/5|mm or >|0.4|rad) and six to insufficient data quality . A final sample of 128 participants was available, including 24 MDD/ADS+ participants, 48 MDD/ADS− participants, and 55 controls. The main task effect  yielded significant BOLD responses in the bilateral amygdala, hippocampus, fusiform gyrus, right inferior frontal gyrus, and other regions Table , compara3.2.1xyz −14, −2, −14, Z = 4.02, k = 167, p = .015) and nonsignificantly in the right amygdala compared to controls . There were no differences in amygdala reactivity in MDD/ADS− relative to controls. Whole‐brain analyses suggested this amygdala effect was part of a larger cluster spanning the left putamen, amygdala, and hippocampus, in which MDD/ADS+ displayed stronger responses relative to MDD/ADS− , though this did not reach significance at the whole ‐brain level. MDD/ADS+ nor MDD/ADS− showed significant differences compared to controls in this cluster.In the primary comparisons within the bilateral amygdala ROI, MDD/ADS+ participants displayed stronger left amygdala responses towards emotional faces compared to MDD/ADS− , particularly in the left amygdala .In secondary analyses, to assess DSM‐diagnosis‐based group differences in emotional faces reactivity, we further compared MDD/ANX+, MDD/ANX−, and controls, and MDD3.3r = .31, BG: r = .50).Complete resting state data were available for 79 unmedicated MDD participants and 58 controls. After preprocessing, nine participants were excluded due to excessive movement (>|2/5|mm or >|0.4|rad in any direction) and three to insufficient data quality . A final sample of 125 participants was available, including 27 MDD/ADS+ participants, 41 MDD/ADS− participants, and 57 controls. From ICA at the whole‐ group level the SN and BGN were identified Figure ; The SN 3.3.1n = 125), ADS dimensional scores were positively associated with SN‐thalamus functional connectivity, though this did not hold after FDR correction for the multiple networks of interest . Also, post hoc sensitivity analyses showed this association was no longer significant when correcting for depression severity or depression status, nor when including only MDD patients (n = 68). ADS dimensional scores were not significantly associated with BGN FC.In our primary ADS‐based group comparisons, no significant differences were observed between MDD/ADS+, MDD/ADS−, and controls, in functional connectivity of the SN or BGN. Across all participants n = 15, ADS di3.3.2all with controls. No significant functional connectivity differences were observed between MDD/ANX+, MDD/ANX−, and controls in SN FC. Nonsignificant increased BGN‐middle frontal gyrus connectivity was observed in MDD/ANX+ relative to MDD/ANX− . MDDall was associated with increased SN‐putamen FC relative to controls though this was no longer significant after FDR correction for including two networks of interest . There was no indication of differences in amygdala reactivity in MDD/ADS− relative to controls.In the current study, we investigated if the presence of the DSM‐5 ADS in a sample of unmedicated MDD participants was associated with specific neural reactivity to emotional faces, and functional connectivity patterns during rest. We observed increased amygdala reactivity—part of a larger striato‐limbic cluster—to emotional faces in MDD with ADS (MDD/ADS+), relative to MDD without ADS (MDD/ADS−). There was also a suggestion of higher amygdala reactivity in MDD/ADS+ relative to controls, but this did not reach statistical significance  to controls, suggesting SN hyperconnectivity may not be specific to ADS but rather related to depression in general.The MDD‐ADS groups did not differ significantly in resting‐state functional connectivity of the salience (SN) or BGN. ADS dimensional scores were subthreshold positively associated with SN‐right thalamus functional connectivity, warranting further investigation. However, subthreshold higher SN‐right putamen connectivity was also observed when comparing all MDD patients  present across the different anxiety disorders included in this study. Dimensional anxiety levels have previously shown stronger associations with functional neuroimaging measures in MDD than discrete (comorbid) anxiety disorders  and without (MDD/ANX−) comorbid anxiety disorders, nor when comparing MDDp = .072), although the difference in amygdala reactivity between MDD/ADS+ and healthy controls was in the same direction as the difference between MDD/ADS+ and MDD/ADS−. Alternatively, if the amygdala hyperreactivity observed in MDD/ADS+ is only present relative to MDD/ADS− but not healthy controls, this may imply that MDD/ADS− display amygdala hypo‐reactivity relative to controls, thereby indicating opposing amygdala responses in anxious and non‐anxious MDD as has been suggested by, for example, Oathes et al.  rather than anxious distress.We observed no differences between ADS groups in functional connectivity of the SN or BGN. ADS dimensional scores were positively associated with SN–thalamus connectivity. However, the association was no longer significant after correction for multiple testing, nor when correcting for depression severity or depression status. Fitting with this notion, MDDAlterations in SN connectivity have previously been reported in MDD (meta‐analysis/reviews by Dutta et al., 4.3To our knowledge, this is one of the first studies investigating functional neuroimaging correlates of the DSM‐5 ADS in MDD. We included a medication‐free, and clinically well‐phenotyped group of MDD participants. This allowed us to not only compare MDD with and without anxious distress, but to also run sensitivity analyses investigating MDD with and without comorbid anxiety. The relatively small sample size however, and the smaller proportion of MDD participants with ADS compared to previous studies (36% vs. 54%–75%; Gaspersz et al., 4.4The current study further builds on the work suggesting the DSM‐5 ADS is a clinically relevant aspect of depression. With a simple 5‐item questionnaire, it is relatively easy to administer in the clinic. A better understanding of the neurobiological underpinnings of anxious depression is highly relevant, especially considering worse treatment and trajectory predictions observed in anxious depression. Neuro‐informed interventions based on biotypes or specifically targeting affected neural circuitry may improve future treatment options for mood and anxiety patients (Williams, 5Current findings suggest that amygdala and striato‐limbic hyperactivity to emotional faces may be a neurobiological hallmark specific to MDD with ADS, relative to MDD without anxious distress. The ADS was not convincingly associated with resting‐state functional connectivity patterns in salience and basal ganglia networks, and the subthreshold observed SN hyperconnectivity may have been related to depression diagnosis rather than anxious distress. The DSM‐5 ADS is a clinically relevant, easy to administer concept, and the current findings shed a light on the possible neurobiological mechanisms underlying anxious distress in MDD and its clinical presentation. This furthermore underlines the importance to account for heterogeneity in depression research and treatment. Though replication studies are necessary, this study provides a better understanding of the neurobiology of anxious distress, and may in the future help to improve and personalize treatment options for individuals with anxious depression.The authors declare no conflicts of interest.Supporting information.Click here for additional data file.