The role of endocrine therapy in the treatment of patients in a postmenopausal hormonal state and with estrogen receptor (ER)‐positive, human epidermal growth factor receptor 2 (HER2)‐positive advanced or metastatic breast cancer (AMBC) is unclear.We analyzed the data from 94 patients with ER‐positive HER2‐positive AMBC enrolled in the Safari study (UMIN000015168), a retrospective cohort study of 1072 ER‐positive AMBC patients in a postmenopausal hormonal state who received fulvestrant 500 mg (F500): (1) to compare time to treatment failure (TTF) and overall survival (OS) by treatment group, and TTF by treatment line; (2) in patients who received endocrine therapy (including F500) or anti‐HER2 therapy as initial systemic therapy before chemotherapy, to investigate relations between TTF for the first‐line therapy or time to chemotherapy (TTC) and OS; (3) to investigate factors associated with OS.n = 20) than in those who received later‐line F500 therapy (n = 74) . In the 59 patients who received endocrine therapy or anti‐HER2 therapy as initial systemic therapy before chemotherapy, those with TTC ≥3 years had longer median OS than those with TTC <3 years . Longer TTC was associated with prolonged OS.The TTF was longer in the patients treated with F500 as first‐ or second‐line therapy . Time to treatment failure (TTF) was longer in patients who received F500 as first‐ or second‐line therapy, suggesting that those for whom advanced treatment lines are needed have disease resistance to both endocrine and anti‐HER2 therapies. In the 59 patients who received endocrine therapy (including F500) or anti‐HER2 therapy as initial systemic therapy before being switched to chemotherapy, median overall survival was longer in those with time to chemotherapy (TTC) ≥3 years, suggesting that this may be a helpful cut‐off value for indicating clinical outcomes.A subgroup analysis of the Safari study was carried out to investigate clinical outcomes in patients in a postmenopausal hormonal state and with estrogen receptor‐positive, human epidermal growth factor receptor 2 (HER2)‐positive advanced or metastatic breast cancer who received fulvestrant 500 mg (F500) with or without anti‐HER2 therapy ( Fulvestrant 500 mg (F500) has been shown to be more efficacious than the aromatase inhibitor (AI) anastrozole 1 mg as first‐line endocrine therapy for postmenopausal women with ER‐positive advanced or metastatic breast cancer (AMBC).The Safari study  was a large‐scale multicenter retrospective cohort study carried out to investigate clinical outcomes in patients in a postmenopausal state and with ER‐positive AMBC who received treatment with F500 in Japan. The results have been reported previously.Few clinical trials have focused on the subgroup of postmenopausal patients with ER‐positive HER2‐positive AMBC; therefore, limited data are available on the efficacy of endocrine therapy in this population. Owing to the higher biological grade of HER2‐positive breast cancer and with the treatment goal of OS prolongation, the standard therapy for ER‐positive HER2‐positive AMBC is widely recognized as the combination of chemotherapy and anti‐HER2 therapy.22.1The Safari study (UMIN000015168) was a retrospective multicenter cohort study using data from >1000 ER‐positive AMBC patients in a postmenopausal hormonal state , who received treatment with F500 at 16 sites in Japan between November 25, 2011 (the date on which F500 was approved in Japan), and December 31, 2014. Patients who received F500 plus anti‐HER2 therapy , denosumab, and zoledronic acid were included in the Safari study, whereas patients were excluded if they received F500 in combination with other endocrine therapies and/or chemotherapies and/or nontrastuzumab targeted therapies. Further details of the study design, and a description of the patient cohort, are available in a previous publication.2.2AMBC was defined as locally advanced unresectable, de novo metastatic, or recurrent metastatic breast cancer . Tumors were considered ER‐positive if ≥10% (before the 2010 introduction of the ASCO/CAP Guideline RecommendationsA membrane‐staining score of 3+ was recorded as an HER2‐positive result and a score of 1+ or 0 as HER2‐negative. Fluorescence in situ hybridization (FISH) was carried out if the immunohistochemical HER2 score was equivocal . A HER2‐positive FISH result was regarded as confirmatory even if the ISH score was 1+.2.3Patients were followed up according to the National Comprehensive Cancer Network Guidelines for Invasive Breast Cancer (Version 4.2018),2.4We report the results of subgroup analyses of data from the Safari study. Three analyses were carried out to investigate clinical outcomes in the subgroup of patients with ER‐positive HER2‐positive AMBC who received F500 with or without anti‐HER2 therapy.Data for TTF and OS were analyzed and the results were compared across subgroups. TTF was defined as the time from the start of F500 treatment to its discontinuation. Details of the definitions of treatment failure are available in the main Safari study report  were analyzed to compare TTF (time from the start of F500 treatment to its discontinuation) and OS by treatment group , and TTF by treatment line (first‐ or second‐line vs. third‐ or later‐line).Data from all the ER‐positive HER2‐positive AMBC patients (2.4.2n = 59) were analyzed to investigate relations between TTC and OS. A cut‐off value of 3 years for TTC was used.Data from the ER‐positive HER2‐positive AMBC patients who received endocrine therapy (including F500) or anti‐HER2 therapy as initial systemic therapy for AMBC before being switched to chemotherapy due to disease progression (2.4.3n = 59). Additionally, after excluding data from 8 patients with de novo stage IV cancer, data from the remaining 51 patients were analyzed because the biological characteristics of recurrent cancer differ from those of stage IV disease. For reference, factors associated with OS were investigated in all the ER‐positive HER2‐positive AMBC patients who received F500 with or without anti‐HER2 therapy (n = 94).Factors associated with OS were investigated in the ER‐positive HER2‐positive AMBC patients who received endocrine therapy (including F500) or anti‐HER2 therapy as initial systemic therapy for AMBC before being switched to chemotherapy  or anti‐HER2 therapy as initial systemic therapy for AMBC before being switched to chemotherapy  and those treated with F500 plus anti‐HER2 therapy  , median TTF in all the ER‐positive HER2‐positive AMBC patients who received F500 with or without anti‐HER2 therapy was 4.4 months   than in those treated with F500 as third‐ or later‐line therapy (n = 74), the results being 6.6 months  and 3.7 months , respectively   from the start of AMBC treatment Figure .3.2.2Of the 59 patients with ER‐positive HER2‐positive AMBC who received endocrine therapy (including F500) or anti‐HER2 therapy as initial systemic therapy before being switched to chemotherapy, 47 (80%) received this treatment as endocrine therapy alone; 4 (7%), as anti‐HER2 therapy alone; and 8 (14%), as endocrine plus anti‐HER2 therapy Table .p = 0.001) . Patients with TTC ≥3 years had significantly longer median OS than those with TTC <3 years: 10.5 years  vs. 5.9 years   , although patients with longer TTF tended to have longer OS Figure a. By con) Figure b.3.2.3n = 59), the results of the univariate analysis showed longer TTC and TTF to be significantly associated with prolonged OS, whereas the results of the multivariate analysis showed only TTC as a factor significantly associated with prolonged OS  (Table In the patients who received endocrine therapy (including F500) or anti‐HER2 therapy as initial systemic therapy for AMBC before being switched to chemotherapy (p = 0.006). Factors shown by the results of multivariate analysis to be significantly associated with prolonged OS were younger age at AMBC diagnosis  and strong HER2 expression   Table .n = 94), the results of both univariate and multivariate analysis showed younger age at diagnosis of AMBC to be a factor significantly associated with prolonged OS  and HER2‐negative subgroup (n = 828) was 5.4 monthsIn this subgroup analysis using data from ER‐positive HER2‐positive AMBC patients enrolled in the large‐scale, retrospective cohort Safari study, the median TTF was 4.4 months . For comparison, TTF in the overall Safari study population . This suggests that the necessity for the use of advanced treatment lines indicates resistance to both endocrine and anti‐HER2 therapies.4.2Few data are available regarding the efficacy of fulvestrant in patients with ER‐positive HER2‐positive AMBC, and therefore, its role in the treatment of this population is unclear. Although differences between previous studies  preclude their direct comparison, we here present the following data for reference.In a pooled analysis of data from 102 postmenopausal women with ER‐positive HER2‐positive AMBC treated with fulvestrant , the median duration of fulvestrant treatment was 8.1 months.In the retrospective HERMIONE 9 study, in which real‐world data from 87 patients  with ER‐positive HER2‐positive advanced breast cancer treated with F500 plus trastuzumab were analyzed, progression‐free survival (PFS) was 12.9 months and 77% of patients had been treated using three or more previous therapies (both chemotherapy and endocrine therapy with or without anti‐HER2 therapy).4.3The standard first‐line treatment for HER2‐positive AMBC is anti‐HER2 therapy plus chemotherapy.According to the Japanese Breast Cancer Society Clinical Practice Guidelines for systemic treatment of breast cancer, endocrine therapy combined with anti‐HER2 therapy may be considered for patients with ER‐positive HER2‐positive metastatic breast cancer and for whom chemotherapy is contraindicated.The efficacy of sequential use of endocrine therapy with or without anti‐HER2 therapy for the treatment of AMBC remains uncertain. Because nonsteroidal AIs are widely used in the adjuvant setting for postmenopausal patients with ER‐positive disease, F500 may be an option for first‐line endocrine therapy in cases of recurrence or progression despite adjuvant AI therapy.In the Safari study, 59 (63%) of 94 ER‐positive HER2‐positive patients received endocrine therapy (including F500) or anti‐HER2 therapy as initial systemic therapy for AMBC before being switched to chemotherapy. In this population, the median TTF and median TTC were 8.1 months and 22.7 months, respectively. Longer TTC (≥3 years) was found to be significantly associated with prolonged OS, suggesting that this cut‐off value may be a useful indicator of clinical outcomes. Such cut‐off values are useful when physicians discuss treatment options with patients. Because of the current scarcity of evidence in this population, these findings from real‐world data may be useful and contribute to the literature on the potential use of initially chemotherapy‐free regimens.In the present study, some patients did not receive anti‐HER2 therapy as a first‐line treatment, presumably because of concomitant or underlying disease or conditions. However, detailed reasons were not collected in the Safari study. It should be noted that when the Safari study was conducted, physicians generally followed the concept of the Hortobagyi algorithm4.4Multivariate analysis identified longer TTC as a factor predicting prolonged OS. Thus, our results confirm that longer TTC is a good predictor of survival. Additionally, our results showed younger age to be significantly associated with prolonged OS. This finding is consistent with those reported for the overall Safari study population, in which age < 60 years correlated positively with prolonged OS (median 7.0 years).4.5At the time of the Safari study, cyclin‐dependent kinase 4 and 6 (CDK4/6) inhibitors were unavailable. However, one finding of the present subgroup analysis, namely that patients with HER2‐positive breast cancer that is sensitive to endocrine therapy (as shown by their longer TTF) generally have longer OS, suggests that the addition of a CDK 4/6 inhibitor to endocrine therapy may benefit postmenopausal patients with ER‐positive HER2‐positive AMBC and who are not candidates for chemotherapy; the combination of a CDK 4/6 inhibitor plus endocrine therapy would avoid the risk of adverse effects associated with chemotherapy. Other nonchemotherapeutic options for treatment of ER‐positive HER2‐positive advanced breast cancer include the combination of endocrine therapy plus anti‐HER2 therapy .In patients with hormone receptor‐positive HER2‐negative advanced breast cancer, addition of CDK4/6 inhibitors  to endocrine therapy has been shown to improve PFS, enabling a prolonged endocrine therapy‐based period and resulting in favorable OS .Against this background, we believe that the findings of our subgroup analysis, in which data from the retrospective cohort Safari study were used to investigate the effectiveness of F500 in a real‐world clinical setting, may provide useful information for clinicians treating patients with ER‐positive HER2‐positive AMBC. We found that patients in a postmenopausal hormonal state and with ER‐positive HER2‐positive AMBC, who received F500 with or without anti‐HER2 therapy, TTF was longer in the patients treated with F500 as first‐ or second‐line therapy than in those who received later‐line F500 therapy. We also found that in the patients who received endocrine therapy or anti‐HER2 therapy as initial systemic therapy before chemotherapy, those with TTC ≥3 years had longer median OS than those with TTC <3 years. These findings suggest that if their disease condition permits, endocrine therapy plus anti‐HER2 therapy may be considered a useful treatment option, providing better quality of life, for patients with ER‐positive HER‐positive AMBC.4.6The present study provides original data on the use of targeted agents early in the care of Japanese patients with ER‐positive HER2‐positive AMBC, in terms of the clinical outcomes achieved using this treatment approach. The improvements in both TTF and OS found in the patients who received targeted therapy (endocrine therapy or anti‐HER2 therapy) before chemotherapy support further research on the efficacy and safety of upfront targeted agents , or the earlier integration of such agents, used before chemotherapy.4.7As with the original Safari study, there are several limitations because of the retrospective nature of the study, including the absence of a comparative treatment group and use of TTF instead of PFS. As explained previously,The present subgroup analysis is limited by the small sample size, which is attributable to the small number of ER‐positive HER2‐positive AMBC patients included in the Safari study. Some of the patients had undergone surgery for primary tumors before anti‐HER2 therapy became available and, therefore, could not receive anti‐HER2 therapy during the perioperative period.Furthermore, because in the present study enrollment of patients started shortly after the approval of F500, physicians may have selected F500 for patients who had developed resistance to an AI‐based regimen, even when endocrine therapy may have been an option. Whether AI or F500 is preferable as a first‐line treatment is an important clinical question that needs further investigation.Performance status (PS) could have been a confounding factor in the present study because it potentially affects the prognosis and treatment outcome of patients with AMBC. However, we were unable to adjust for the influence of PS because our retrospective analysis relied on real‐world data with incomplete PS information; in daily clinical practice, PS data are rarely documented in the medical record.5In this subgroup analysis of the Safari study of patients in a postmenopausal state and with ER‐positive HER2‐positive AMBC, TTF was longer in patients who received F500 as first‐ or second‐line therapy. In the patients who received endocrine therapy (including F500) or anti‐HER2 therapy as initial systemic therapy before being switched to chemotherapy, the prolonged OS was observed in patients with TTC ≥3 years suggesting that this may be a helpful cut‐off value for indicating clinical outcomes.Misato Masuyama: Conceptualization (lead); data curation ; formal analysis ; investigation ; methodology ; writing – original draft (lead); writing – review and editing (lead). Norikazu Masuda: Conceptualization ; data curation ; funding acquisition ; investigation ; methodology ; project administration ; resources ; supervision (lead); writing – original draft ; writing – review and editing . Hidetoshi Kawaguchi: Conceptualization ; data curation ; investigation ; methodology ; project administration ; writing – original draft ; writing – review and editing . Yutaka Yamamoto: Conceptualization ; data curation ; investigation ; methodology ; writing – review and editing . Shigehira Saji: Data curation ; investigation ; writing – review and editing . Takahiro Nakayama: Conceptualization ; data curation ; investigation ; methodology ; writing – review and editing . Kenjiro Aogi: Data curation ; investigation ; writing – review and editing . Keisei Anan: Data curation ; investigation ; writing – review and editing . Shoichiro Ohtani: Data curation ; investigation ; writing – review and editing . Nobuaki Sato: Data curation ; investigation ; writing – review and editing . Toshimi Takano: Data curation ; investigation ; writing – review and editing . Eriko Tokunaga: Data curation ; investigation ; writing – review and editing . Seigo Nakamura: Data curation ; investigation ; writing – review and editing . Yoshie Hasegawa: Data curation ; investigation ; writing – review and editing . Masaya Hattori: Data curation ; investigation ; writing – review and editing . Tomomi Fujisawa: Data curation ; investigation ; writing – review and editing . Satoshi Morita: Conceptualization ; data curation ; formal analysis ; methodology ; writing – review and editing . Miki Yamaguchi: Data curation ; investigation ; writing – review and editing . Toshinari Yamashita: Data curation ; investigation ; writing – review and editing . Daisuke Yotsumoto: Data curation ; investigation ; writing – review and editing . Masakazu Toi: Conceptualization ; data curation ; investigation ; methodology ; writing – review and editing . Shinji Ohno: Data curation ; investigation ; writing – review and editing .Funding for this study was provided by the JBCRG and AstraZeneca.Masuda N received grants to his institution from Chugai Pharmaceutical, Eli Lilly, AstraZeneca, Pfizer, Daiichi Sankyo, MSD, Eisai, Novartis Pharma, Sanofi, Kyowa Kirin, Nippon Kayaku; received personal fees including honoraria from Chugai Pharmaceutical, Pfizer, AstraZeneca, Eli Lilly, and Eisai; is a member of the board of directors (unpaid) for Japan Breast Cancer Research Group (JBCRG) and Japanese Breast Cancer Society (JBCS). Kawaguchi H received support including funding from AstraZeneca and JBCRG; received consulting fees from AstraZeneca, Chugai Pharmaceutical, Eisai, and Pfizer; received personal fees (honoraria for lectures) from Pfizer, Chugai Pharmaceutical, AstraZeneca, Eisai, Kyowa Kirin, Novartis Pharma, Maruho, Eli Lilly, Taiho Pharmaceutical, Daiichi Sankyo and Nippon Kayaku. Yamamoto Y received grants to his institution from Chugai Pharmaceutical, Kyowa Kirin, Eisai, Daiichi Sankyo, Nippon Kayaku, Taiho Pharmaceutical, Takeda Pharmaceutical, Eli Lilly, Pfizer, and Novartis Pharma; received personal fees (honoraria for lectures) from AstraZeneca, Chugai Pharmaceutical, Kyowa Kirin, Novartis Pharma, Eli Lilly, Pfizer, Daiichi Sankyo, Nippon Kayaku, Taiho Pharmaceutical, Eisai and Takeda Pharmaceutical; is a member of the advisory board for AstraZeneca, Chugai Pharmaceutical, Novartis Pharma, Eli Lilly, Pfizer, Daiichi Sankyo and a member of the board of directors for JBCRG and JBCS. Saji S received grants to his institution from Taiho Pharmaceutical, Eisai, Chugai Pharmaceutical, Takeda Pharmaceutical, MSD, AstraZeneca, Daiichi Sankyo, and Eli Lilly; received personal fees including honoraria from Chugai Pharmaceutical, Kyowa Kirin, MSD, Novartis Pharma, Eisai, Takeda Pharmaceutical, Daiichi Sankyo, Eli Lilly, AstraZeneca, Pfizer, Taiho Pharmaceutical, Ono Pharmaceutical, and Nippon Kayaku; is a member of the data safety monitoring board / advisory board for Chugai Pharmaceutical, AstraZeneca, Eli Lilly, Pfizer, Kyowa Kirin, and Daiichi Sankyo; is an executive board member for JBCRG, JBCS, Japanese Society of Medical Oncology (JSMO) and Breast International Group (BIG). Nakayama T received personal fees (honoraria for lectures) from Chugai Pharmaceutical, Eli Lilly, Novartis Pharma, AstraZeneca, Pfizer, Taiho Pharmaceutical, Daiichi Sankyo, and Eisai. Aogi K received grants to his institution from Chugai Pharmaceutical, Eisai, and Takeda Pharmaceutical; received personal fees including honoraria from AstraZeneca, Taiho Pharmaceutical, Novartis Pharma, Chugai Pharmaceutical, Daiichi Sankyo, Pfizer, and Eli Lilly. Anan K received personal fees including honoraria from Pfizer, Chugai Pharmaceutical, AstraZeneca, Eisai, and Eli Lilly. Ohtani S received personal fees including honoraria from Pfizer, Eli Lilly, Chugai Pharmaceutical, and Daiichi Sankyo. Sato N received personal fees (honoraria for lectures) from Chugai Pharmaceutical, Kyowa Kirin, Taiho Pharmaceutical, Eli Lilly, Nippon Kayaku, Daiichi Sankyo, and Celltrion Healthcare Japan. Takano T received grants to his institution from Chugai Pharmaceutical, Daiichi Sankyo, Ono Pharmaceutical, MSD, and Eisai; received personal fees (honoraria for lectures) from Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Eli Lilly, and Celltrion Healthcare Japan. Tokunaga E received personal fees including honoraria from Eli Lilly, AstraZeneca, and Daiichi Sankyo. Nakamura S received grants to his institution from Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Konica Minolta, and Taiho Pharmaceutical; received personal fees including honoraria from AstraZeneca, Chugai Pharmaceutical, and Eisai. Hattori M received personal fees including honoraria from Eli Lilly and Daiichi Sankyo. Morita S received grants to his institution from Eisai; received personal fees including honoraria from AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Eisai, Eli Lilly, MSD, Pfizer, Taiho Pharmaceutical, and Novartis Pharma. Yamaguchi M received personal fees (honoraria for lectures) from Pfizer, Chugai Pharmaceutical, Novartis Pharma, Eli Lilly, Daiichi Sankyo, and Taiho Pharmaceutical. Yamashita T received grants to his institution from Nippon Kayaku, Chugai Pharmaceutical, Taiho Pharmaceutical, and Kyowa Kirin; received personal fees (honoraria for lectures) from Nippon Kayaku, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Eli Lilly, Novartis Pharma, Taiho Pharmaceutical, AstraZeneca, Pfizer, and Kyowa Kirin. Toi M received grants to his institution from Chugai Pharmaceutical, Takeda Pharmaceutical, Pfizer, Kyowa Kirin, Taiho Pharmaceutical, JBCRG, Eisai, Daiichi Sankyo, AstraZeneca, Astellas, Shimadzu, Yakult, Nippon Kayaku, AFI technology, Luxonus, and Shionogi; received personal fees (honoraria for lecture/lecture chair) from Chugai Pharmaceutical, Takeda Pharmaceutical, Pfizer, Kyowa Kirin, Taiho Pharmaceutical, Eisai, Daiichi Sankyo, AstraZeneca, Eli Lilly, MSD, Exact Science, Novartis Pharma, Konica Minolta, Shimadzu, Yakult, and Nippon Kayaku; is a member of the advisory board for Kyowa Kirin, Daiichi Sankyo, Eli Lilly, Konica Minolta, Bristol Myers Squibb, and Athenex Oncology; is a member of the board of directors (unpaid) for JBCRG, Kyoto Breast Cancer Research Network (KBCRN) and Organization for Oncology and Translational Research (OOTR). Ohno S received a grant to his institution from Eisai; received personal fees including honoraria from Chugai Pharmaceutical, AstraZeneca, Eisai, Pfizer, and Eli Lilly. Masuyama M, Hasegawa Y, Fujisawa T, and Yotsumoto D have no conflict of interest to declare regarding the present study.The study was conducted in compliance with the Declaration of Helsinki, “Guidelines for Clinical Evaluation Methods of Anti‐Cancer Drugs,” and “Ethical Guidelines for Epidemiology Research .” The protocol was approved by the Institutional Ethics Committee at each study site. The requirement for informed consent was waived because of the retrospective, anonymous nature of the data collection.http://www.umin.ac.jp/ctr/index‐j.htm), under the unique ID UMIN000015168.The study is registered with the UMIN Clinical Trials Registry (Figure S1.Click here for additional data file.Figure S2.Click here for additional data file.Table S1–S3.Click here for additional data file.


To estimate the proportions of specific hypometabolic patterns and their association with neuropsychiatric symptoms (NPS) in patients with cognitive impairment (CI).18F‐FDG PET and clinical/demographic information, NPS assessments were recorded and analyzed to explore the associations between hypometabolic patterns and clinical features by correlation analysis and multivariable logistic regression models.This multicenter study with 1037 consecutive patients was conducted from December 2012 to December 2019. R = 0.171, p = 0.04), anxiety , and appetite and eating abnormalities  in AD.Patients with clinical Alzheimer's disease  and dementia with Lewy bodies  mostly had AD‐pattern hypometabolism, and 76/137 (55.5%) of patients with frontotemporal lobar degeneration showed frontal and anterior temporal pattern (FT‐P) hypometabolism. Besides corticobasal degeneration, patients with behavioral variant frontotemporal dementia (36/58), semantic dementia (7/10), progressive non‐fluent aphasia (6/9), frontotemporal lobar degeneration and amyotrophic lateral sclerosis (3/5), and progressive supranuclear palsy (21/37) also mostly showed FT‐P hypometabolism. The proportion of FT‐P hypometabolism was associated with the presence of hallucinations  hypometabolism was common in FTLD, especially in patients with bvFTD, SD, PNFA, FTLD/ALS, and PSP. The proportion of FT‐P hypometabolism was associated with the presence of hallucinations, anxiety, and appetite and eating abnormalities in AD. Hypometabolic patterns can help to early identify and manage neuropsychiatric symptoms in cognitive impairment. Dementia is broadly characterized by cognitive and psychological dysfunction that significantly impairs daily and social functioning. Overall, approximately more than half of dementia cases are attributable to Alzheimer's disease (AD), followed by vascular dementia (VaD), dementia with Lewy bodies (DLB), and frontotemporal lobar degeneration (FTLD). Currently, early identification, differential diagnosis, and improved therapy have become an important part of CI management.[18F]‐Fluorodeoxyglucose positron emission tomography (18F‐FDG‐PET) is a biomarker for neuronal degeneration with good diagnostic accuracy, thus it is widely used in current clinical research and has now been recommended as a reliable tool for diagnosis in patients with CI.Therefore, we performed a multicenter study to estimate the proportion of the primary hypometabolic pattern in a large sample of patients with a variety of MCI and dementia syndromes, evaluate the associations between AD‐pattern (AD‐P) and frontotemporal lobe‐pattern (FT‐P) hypometabolism and NPS, and examine the apolipoprotein E (APOE) ε4 allele, amyloid‐β (Aβ), or Tau deposition on PET scans in this cohort of patients.2The Ethics Committees of Tianjin Huanhu Hospital, Beijing Tiantan Hospital, Shanghai Huashan Hospital, Peking Union Medical College Hospital, and Tianjin Medical University General Hospital approved all research activities in this cohort study and waived informed consent because the data were pseudonymized from registers. The study followed the Strengthening the Reporting of Observational Studies in Epidemiology reporting guideline.2.118F‐FDG PET, with or without Aβ‐PET (11C‐PIB PET or 18F‐AV45 PET), or Tau‐PET ([18F]PM‐PBB3) within 3 months of the initial clinical diagnosis.A total of 1037 consecutive patients with CI were recruited at the PET/CT Center of Beijing Tiantan Hospital, Shanghai Huashan Hospital, the Cognitive Clinic of Tianjin Huanhu Hospital, Peking Union Medical College Hospital, and Tianjin Medical University General Hospital between December 2012 and December 2019. All participants were 40–92 years of age. The inclusion criteria were as follows: a clinical diagnosis of MCI, dementia of any type or other unclassifiable dementia (ODs), and imaging with For the present analyses, 382 patients whose clinical data were not recorded in detail by their clinicians were excluded; 975 patients had Aβ‐PET and 540 patients had Tau‐PET done, and 220 patients had APOE genotype detection. NPSs were provided by 325 participants across the 12‐item Neuropsychiatric Inventory (NPI) data.2.2The clinical assessment was performed by neurologists specialized in dementia care and included a detailed history taken from the primary caregivers of the patient, a physical examination, cognitive assessments, laboratory tests , and neuroimaging (brain MRI/CT and PET‐CT).Neuropsychological assessments were assessed during the 2 weeks before PET imaging. The Mini‐Mental State Examination‐Chinese version (MMSE), the Montreal Cognitive Assessment (MoCA), and the Clinical Dementia Rating (CDR) scale were used to evaluate global cognitive function and the severity of CI among all of the participants. Scores on the MMSE and MoCA range from 0 (severe impairment) to 30 (no impairment). CDR range from 0.0 (no dementia), 0.5 (MCI), 1.0 (mild), 2.0 (moderate) to 3.0 (severe). NPS were assessed with the 12‐item NPI using the information provided by their caregivers. The composite score of each subscale ranges between 0 (no NPS) and 12 and the total composite score between 0 (no NPS) and 144.2.318F‐FDG, and a 10‐min static PET scan was obtained 40 min after injection of 18F‐FDG. The 3D Aβ PET images were acquired by a Discovery Elite scanner  at Beijing Tiantan Hospital or a Siemens Biograph 64 PET/CT scanner at PET center of Huashan Hospital. We analyzed data acquired 40–60 minutes post‐injection for 11C‐PIB  and 50 min post‐injection for [18F] AV45 . Patients were diagnosed as PIB‐positive or AV45‐positive on the basis of both visual interpretations of elevated binding in the neocortex and semiquantitative assessment with standardized uptake value ratio (SUVR) > 1.40 or SUVR >1.11, respectively.Acquisition procedures for FDG‐PET and Aβ‐PET have been fully described in a previous study.18F]PM‐PBB3 ([18F]‐APN‐1607) PET scans were obtained on a Siemens Biograph 64 PET/computed tomography (CT) system  in three‐dimensional (3D) mode at Huashan Hospital. A low‐dose CT transmission scan was performed for attenuation correction. Ninety minutes after intravenous injection of 370 MBq [18F]‐APN‐1607, PET imaging was performed with a 20‐min acquisition. Image reconstruction was obtained by a 3‐D ordered‐subset expectation maximization algorithm . SUVRs were calculated using cerebellar gray matter as reference with SPM12 (http://www.fil.ion.ucl.ac.uk/spm) and cat12 (http://www.neuro.uni‐jena.de/cat/) software implemented in MATLAB 2018b . All PET images were coregistered with T1 images, spatially normalized in the Montreal Neurological Institute template, and then smoothed. The regional SUVR z score was defined as: /SD of SUVR value observed in healthy controls. A regional z score ≥ 2 was considered to define positive findings for semiquantitative interpretation at the regional level.18F‐APN‐1607 tau PET imaging (2‐region positivity approach) were diagnosed as [18F]‐APN‐1607‐positive.PM‐PBB3 ([18F]‐APN‐1607) PET, 95.0% (513/540) of patients were Tau‐positive, and over 90.0% of patients with VaD , FTLD , clinical AD , or DLB  were Tau‐positive, respectively. Clinical AD patients comprised 49.5% (54/109) of APOE ε4 carriers. The NPS of all participants are displayed in Table In total, 1037 patients with CI  were recruited, of whom 80 had MCI, 741 had clinical AD, 137 had FTLD, 28 had DLB, 5 had VaD, and 46 had other diagnoses (Table 66.8% (693/1037) of patients showed AD‐P hypometabolism predominantly in the posterior regions, including the posterior temporoparietal association cortex and posterior cingulate cortex, with or without frontal lobe involvement, and 20.2% (209/1037) of patients showed FT‐P hypometabolism predominantly in the anterior regions, including the frontal and anterior temporal areas, anterior cingulate gyrus, and insula  but not the course of the disease.Figure R = 0.171, p = 0.04), anxiety , and appetite and eating abnormalities  in AD  PET could detect the discriminatory performance of AD [the max AUCs = 0.806 (95%CI: 0.754–0.857)], FTLD [the max AUCs = 0.841 (95%CI: 0.794–0.889)] from other subtypes of CI.The ROC curves in Figure 4In this multicenter neuroimaging cohort study among patients with CI, the majority of AD, DLB, and CBD patients demonstrated AD‐P hypometabolism, while FTLD and its main subtypes, including bvFTD, SD, PNFA, FTLD/ALS, and PSP, showed predominantly FT‐P hypometabolism, whereas no specific hypometabolic patterns were found in MCI. The combination of metabolic pattern and biomarkers can effectively distinguish AD/FTLD from other types of dementia. In addition, the higher proportion of AD‐P hypometabolism was associated with old age, Aβ deposition, Tau aggregation, and worse cognition, although not with APOE ε4 allele or the course of disease. Furthermore, a higher proportion of FT‐P hypometabolism was related to the presence of hallucinations, anxiety, and appetite and eating abnormalities in AD.4.1In the present study, over half of patients with clinical AD and DLB showed AD‐P hypometabolism, which was consistent with previous neuroimaging research.Patients with FTLD predominantly demonstrated extensive cortical hypometabolism in the frontal and anterior temporal areas, cingulate gyri, uncus, insula, and subcortical areas, including the basal ganglia  and medial thalamic regions. Our results found that 55.5% FTLD patients performed FT‐P hypometabolism, and 32.8% showed AD‐P hypometabolism. The proportion of frontal hypometabolism was lower than literatureRegional glucose metabolism in FDG‐PET is reported in association with NPS. For instance, frontal region hypometabolism is observed in preclinical AD, MCI, and AD patients with depression.These findings have potential clinical and programmatic relevance for standardizing early diagnosis of dementia, and improving the accuracy of differential diagnosis. The significant differences in hypometabolic patterns across CI types makes FDG‐PET a helpful parameter in the differential diagnosis of CI, while the independent application of AD‐P and FT‐P hypometabolism plays a minor role in the diagnosis of MCI and DLB.4.2We present a multicenter cohort study with comprehensive neurological assessment and molecular imaging biomarkers in a large group of CI patients. First, a little part of the target participants had “clinical diagnosis” due to the absence of blood and CSF biomarkers, it might weaken the strength of our finding. Moreover, the main limitation in this study is the qualitative interpretation of the FDG‐PET images with AD‐P or FT‐P and the lack of amyloid and Tau deposition pattern. The lack of detailed descriptions of brain regions limited us from doing more analysis, likely a detailed evaluation of the relationship among NPS, hypometabolic areas, Aβ, and Tau deposition patterns.5These results suggest that brain hypometabolic patterns are (i) significantly different across CI types, (ii) associated with old age, Aβ deposition, Tau aggregation, and worse cognition, and (iii) related to the presence of hallucination, anxiety, and appetite and eating abnormalities in AD. In addition, the combined application of AD‐P or FT‐P hypometabolism and biomarkers can effectively distinguish AD/FTLD from other types of dementia. Furthermore, specific hypometabolic patterns are associated with NPS and beneficial for the early identification and management of NPS in patients with CI.Dr. YJ had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: YJ and YG. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: JG. Critical revision of the manuscript for important intellectual content: ZS, LA, and NZ. Statistical analysis: YC, JG, and SL. Obtained funding: YJ and ZS. Administrative, technical, or material support: CZ, XZ, LC, and RC.The authors declare that they have no competing interests.Appendix S1Click here for additional data file.


Daptomycin causes serious side effects like rhabdomyolysis at high doses. At lower doses it can cause isolated hyperkalemia without frank rhabdomyolysis. Checking BMP along with CK helps taking timely measures to prevent adverse consequences.Hyperkalemia is a common yet challenging clinical condition faced daily by physicians worldwide. Accurate etiology and timely management are paramount in correcting this preventable yet life‐threatening electrolyte imbalance. Very seldom has Daptomycin been implicated as a culprit for hyperkalemia. We present one such unique case where a low dose of Daptomycin led to hyperkalemia, and timely identification improved patient outcomes. We present a 69‐year‐old woman with multiple comorbidities admitted to the intensive care unit to manage diabetic ketoacidosis and sepsis. She developed acute kidney injury due to intravenous contrast, volume depletion, and obstructive uropathy. Interestingly although initially normokalemic, as her renal function started improving with sound urine output, she developed recurrent hyperkalemia, which required medical management. The etiology of hyperkalemia was initially unclear, but on closer review, it was discovered that Daptomycin was the potential culprit. Although case studies with high‐dose Daptomycin causing rhabdomyolysis and hyperkalemia have been reported, low‐dose Daptomycin causing hyperkalemia without rhabdomyolysis has never been reported, bringing forth the uniqueness of our article. It is typically dosed at 4–6 mg/kg body weight/day. Common side effects include anemia, diarrhea, nausea, vomiting, and rarely rhabdomyolysis; hyperkalemia as a side effect is extremely rare.22 body surface area.A 69‐year‐old Caucasian heavy‐set woman presented to the emergency room with complaints of extreme fatigue, generalized weakness, nausea, dysuria, left flank discomfort, reduced output from the nephrostomy tubes for 3–4 days, fever with chills for 24 h, and a wound with discharge on the right leg stump for 2 days prior to presentation. Her past medical history included diabetes mellitus type 2, hypertension, peripheral vascular disease status post bilateral below‐knee amputations, history of right ovarian cancer with diffuse metastasis status post total abdominal hysterectomy with bilateral salpingo‐oophorectomy and chemotherapy (in remission), bilateral hydronephrosis secondary to extrinsic ureteral compression from ovarian metastatic lesions status post bilateral nephrostomy tubes, chronic kidney disease (CKD) stage 3 with a baseline creatinine around 1.4 mg/deciliter (mg/dL), and an estimated glomerular filtration rate (eGFR) around 40 mL/min/1.73 m2 along with elevated serum blood glucose level of 757 mg/dL. Computed tomography (CT) of abdomen‐pelvis with intravenous (IV) contrast revealed the presence of bilateral nephrostomy tubes without hydronephrosis or pyelonephritis and a thick bladder wall suspicious of cystitis.Upon admission, her vitals revealed an elevated blood pressure of 170/70 mmHg, normal oxygen saturation on room air, heart rate of 112 beats per minute, and she was afebrile. Complete blood count (CBC) results showed a hemoglobin level of 9.9 gram (gm)/deciliter (dL), thrombocytosis with a platelet count of 385 × 10 × 9/Liter(L), and a white blood cell count of 12.1 × 10 × 9/L. Basic metabolic panel (BMP) results revealed sodium levels of 140 millimole/ Liter (mmoL/L) (after correction for hyperglycemia), potassium levels of 4.6 mmoL/L, serum bicarbonate levels of 18 mmoL/L, an anion gap of 21, blood urea nitrogen (BUN) levels of 21 mg/dL, creatinine levels of 1.4 mg/dL, and eGFR of 40 mL/min/1.73 mKlebsiella, Citrobacter, Staph aureus, Enterococcus, Candida albicans, and Acinetobacter. Peripheral blood cultures were negative. Cultures from the stump discharge grew Candida albicans, Staph epidermidis, and Enterococcus faecalis. An MRI of the right leg revealed soft tissue edema, fluid collection, and possible signs of early osteomyelitis. Surgical debridement showed necrotic tissue and abscess, after which stump revision was performed. The antibiotic regimen was changed to vancomycin and cefepime based on the cultures from the right leg wound discharge and nephrostomy tube urine. At this point, infectious disease was consulted to assist with antibiotic management, who recommended discontinuing vancomycin and cefepime, switching to Daptomycin at 4 mg/kg every 48 h for 5 days, and IV fluconazole.She was admitted to the intensive care unit (ICU) for diabetic ketoacidosis with suspected sepsis and started on an insulin drip and antibiotics, IV vancomycin and Zosyn. Urgent bilateral nephrostomy tube exchange was performed on Day 2 as the tubes were not draining correctly. Cultures from the nephrostomy tubes grew She developed acute renal failure during the hospital course due to IV contrast exposure, severe volume depletion, and obstructive uropathy. Creatinine has worsened from 1.5 mg/dL on admission to 2.6 mg/dL on day 5. Following nephrostomy tube exchange, correction of diabetic ketoacidosis, and volume replacement, her renal function returned to baseline within 4–5 days. She had sound urine output and stable hemodynamics. Her potassium levels, within the standard limit so far, went from 4.8 mEq/L to 5.7 mEq/L within 24 h without any identifiable cause. Throughout this time, she was not on potassium supplements, ACE inhibitors, or angiotensin receptor blockers, nor she consumed a high‐potassium diet. Her potassium levels continued to rise slowly, reaching 5.9 mEq/L. Hyperkalemia was managed with IV Lasix, Veltassa (patiromer), calcium gluconate, and additional insulin doses. On closer observation, it was noticed that her potassium appeared to worsen after she started receiving Daptomycin. Her potassium levels began to improve 48 h after stopping Daptomycin. Creatinine kinase (CK) levels were checked, as rhabdomyolysis can occur with Daptomycin use. However, our patient did not have rhabdomyolysis . No further elevation in serum potassium levels was observed during the rest of her hospitalization, suggesting that her hyperkalemia was precipitated by Daptomycin. The correlation of creatinine, potassium level and others are depicted in Table 3Daptomycin, a lipopeptide antibacterial agent, is used in treating complicated skin and soft tissue infections and Staphylococcus aureus‐mediated bloodstream infections.Daptomycin being bactericidal, acts by forming complexes with cell membrane calcium and phosphatidylglycerol (PG), creating selective pore‐channels in the membrane for cations such as Na+, K+, and other alkali metal ions.Commonly reported side effects of Daptomycin include anemia, diarrhea, nausea, vomiting, local injection site reactions, and headache. Although infrequent, Daptomycin can induce myotoxicity, characterized by elevated creatinine kinase levels, myalgias, myositis, weakness, and occasionally rhabdomyolysis.Two case reports were found, which were published by Budovich et al., where they described a case of Daptomycin‐induced hyperkalemia in a patient with normal renal function,Myotoxic effects are more likely at higher doses, such as 8 mg/kg/day, than at lower doses.In our case, she had multiple conditions that could have caused hyperkalemia, such as insulin deficiency (DKA), obstruction of the nephrostomy tubes, tissue breakdown from the stump, thrombocytosis, and acute kidney injury (AKI). Nevertheless, she did not have hyperkalemia due to any of these conditions. All these conditions have been resolved by the time hyperkalemia manifested. The only factor significantly correlated with the onset of hyperkalemia was the timing of Daptomycin administration.She did not have hyperkalemia when her serum creatinine was as high as 2.6 mg/dL but when her creatinine improved to 1.8 mg/dL and further to 1.5 mg/dL, she had persistenlty elevated serum potassium. This development of sudden hyperkalemia coincided with the introduction of IV Daptomycin rather than her AKI and resolved after discontinuing the drug.She has CKD 3 at baseline with baseline creatinine around 1.4 mg/dL and Egfr around 40 mL/min to 45 mL/min. She did not have hyperkalemia on admission and at discharge. She did not have hyperkalemia even at post hospitalization follow‐up few months later. This proves that her hyperkalemia is not from her CKD.Usually hyperkalemia becomes an issue at advanced CKD (that is when Egfr is below 20 mL/min). But our patient's CKD was not at such an advanced stage where she would be at risk for hyperkalemia. Moreover CKD alone does not lead to hyperkalemia unless there is a precipitating event/cause. In our patient's case, Daptomycin was that trigger.Our patient was on fluconazole which can cause hyperkalemia through adrenal insufficiency. However, she had no signs or symptoms to suspect adrenal insufficiency as her BP was stable, and she had no hyponatremia. There was no evidence of cell lysis based on the patient's average phosphorus level of 4.5 mg/dL and creatine kinase level of 20 units/L. Studies tell us that when used in low doses, Daptomycin can cause potassium to shift from the intracellular space by creating pores in the cell membrane without resulting in complete cell lysis. This mechanism may explain the hyperkalemia observed in our patient without evidence of cell lysis. It is important to note that the patient did not have constipation; instead, she had multiple bowel movements daily, likely because of antibiotics. When the patient developed hyperkalemia, urine sodium, and chloride levels were 69 mEq/L and 61 mEq/L, respectively. These levels were measured while the patient was receiving IVfluids . Unfortunately, we did not measure urine potassium levels in our patient.In our patient, hyperkalemia developed after initiating Daptomycin, and each dose of Daptomycin resulted in a spike in serum potassium levels. Discontinuing Daptomycin led to an improvement in serum potassium levels without any other intervention. This could be attributed to the low dose (4 mg/kg) she was receiving. Daptomycin can induce pore formation in rhabdomyocytes at such low doses, causing intracellular potassium leakage into the serum without triggering frank rhabdomyolysis.The dosing frequency directly impacts skeletal muscle more than peak plasma concentrations of Daptomycin. Administering the drug less frequently gives time for the repair of damaged myocytes. The current recommendation is to monitor serum CPK concentration at least weekly and more frequently if clinically indicated.4Our case demonstrates that low doses of Daptomycin can induce hyperkalemia without causing rhabdomyolysis. Our patient received a dose every 48 h. We recommend that in patients with CKD or AKI, the dosing of Daptomycin should be even less frequent due to its renal elimination, all potential hyperkalemia‐causing drugs should be avoided, and close monitoring of serum potassium and CPK should be practiced. More reports must be published to inform clinicians of this rare association between Daptomycin and hyperkalemia.Praveen Errabelli: Conceptualization; writing – original draft. Maulik Lathiya: Data curation; writing – review and editing. Sasmit Roy: Writing – review and editing.The authors declare no funding for the article.The authors declare no conflicts of interests.Written informed consent was obtained from the patient to publish this report in accordance with the journal's patient consent policy.


The significance of T helper 17 (Th17) cells in the pathogenesis of rheumatoid arthritis (RA) has recently been demonstrated in many studies. Retinoic acid receptor‐related orphan receptor γt (RORγt) is a transcription factor that is specifically involved in the generation of Th17 cells. Besides, the chemokine receptor CCR6, the receptor for CCL20, is characteristically expressed by these cells. Considering the pivotal roles of Th17 cells in RA pathogenesis, in this study, we assessed the gene expression of CCR6 and RORγt in the peripheral blood leukocytes of new case RA patients. Also, we evaluated their association with anticyclic citrullinated peptide (anti‐CCP) antibodies and disease activity.Forty‐five new case RA patients and 45 healthy persons have been recruited in this investigation. The gene expression of CCR6 and RORγt was evaluated by quantitative real‐time PCR (qRT‐PCR), and anti‐CCP antibodies plasma levels were measured using the enzyme‐linked immunosorbent assay (ELISA) technique. Disease activity was measured according to the disease activity score‐28 (DAS‐28) formula.p < .05 and p < .01, respectively). Moreover, there was a positive correlation between RORγt gene expression and parameters, including gene expression of CCR6 , plasma levels of CCL20 , ESR , DAS‐28 , anti‐CCP , and RF . Also, CCR6 gene expression was positively associated with the DAS‐28 , plasma levels of anti‐CCP , and ESR .The gene expression of CCR6 and RORγt increased remarkably in new case RA patients compared to healthy controls (Increased gene expression of CCR6 and RORγt in peripheral blood leukocytes of new case RA patients may contribute to the exacerbation and pathogenesis of RA. The gene expression of CCR6 and RORγt increased remarkably in new case RA patients compared to healthy controls. Moreover, there was a positive correlation between RORγt gene expression and parameters, including gene expression of CCR6, plasma levels of CCL20, ESR, DAS‐28, anti‐CCP, and RF. Also, CCR6 gene expression was positively associated with the DAS‐28, plasma levels of anti‐CCP, and ESR. Increased gene expression of CCR6 and RORγt in peripheral blood leukocytes of new case RA patients may contribute to the exacerbation and pathogenesis of RA Besides, 45 age‐ and gender‐matched healthy subjects lacking any background of autoimmune diseases were chosen as the control group. The study was per the Declaration of Helsinki and was performed with approval from the Ethics Committee of the KUMS . All the patients and control population signed informed consent. Meanwhile, all the patients were diagnosed according to the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) 2010 classification criteria for RA2.2Total RNA was extracted from whole blood specimens according to the manufacturer's instructions . The concentration and purity of the extracted RNA were measured using a NanoDrop 2000 UV–Vis Spectrophotometer (Thermo Scientific), and further, its purity was evaluated by 1% agarose gel electrophoresis. The extracted RNA was aliquoted and stored at −70°C until use. Complementary DNA (cDNA) synthesis was conducted using the Easy cDNA Synthesis Kit (Parstous Biotechnology) according to the manufacturer's guidelines.2.3http://www.ncbi.nlm.nih.gov/tools/primer-blast/). Real‐time PCR analysis was accomplished in a final volume of 15 µL containing 1 μL of cDNA, 0.5 mM of each forward and reverse primer, 7.5 μL of PCR Master Mix (Parstous Biotechnology), and 5.5 μL of ddH2O. The PCR reactions were carried out on the Light cycler 96 (Roche) using the thermal cycling parameters . All samples were run in duplicates to diminish the risk of false‐positive or false‐negative results owing to technical errors. The relative quantity of target mRNA in samples was computed and normalized to the corresponding GAPDH mRNA transcript level as a housekeeping gene. The relative gene expression for each sample was determined using the following formula (ratio = (Etarget)ΔCt target (control‐sample)/(ERef)ΔCt Ref (control‐sample)), as formerly described by Pfaffl.Primer designing for genes of CCR6, RORγt, and GAPDH, as an internal control for normalization, was accomplished using online software, including Oligocalc and Oligoanalyzer. The oligonucleotide sequences of the designed primers and their PCR product length are represented in Table ratio = EtargetΔCt2.4The plasma levels of anti‐CCP and CCL20 have been measured using the enzyme‐linked immunosorbent assay  based on the manufacturer's recommendations.2.5½ + 0.28 (SJ)½ + 0.70 ln (ESR) + 0.014 GH , as described previously by Inoue et al.The disease activity score was evaluated by an expert rheumatologist according to the formula DAS28 = 0.56 (TJ)2.6p value is based on the independent t‐test or Mann–Whitney nonparametric test for statistical comparisons between both RA and control groups. The correlation between the two variables was determined by the Spearman rank correlation analysis. The p value is considered statistically significant at the level of <.05.Statistical analysis was performed with SPSS software  and the software GraphPad Prisms® 6.0 (GraphPad Software). The 1‐sample Kolmogorov–Smirnov test (1‐sample K–S test) determined the distribution normality in the groups. The 33.1p > .05). Moreover, the mean BMI was significantly greater in the new case RA patients when compared to the controls (p < .05). The demographic information and clinical properties of participants are shown in Table The current study investigated 45 new case RA patients and 45 healthy persons. In terms of age and sex, there was no significant difference between new case RA patients and controls   , CCL20 plasma levels , ESR , DAS‐28 , anti‐CCP plasma levels , and rheumatoid factor (RF) , in the newly diagnosed RA patients , plasma levels of anti‐CCP , and ESR  RORγt, a ligand‐dependent transcription factor belonging to the superfamily of the nuclear hormone receptor (NHR), is the Th17 cell‐specific transcription factor regulating the transcription of IL‐17, an inflammatory cytokine.The current study has some limitations: First, the sample size examined in this study, especially the sample size of the new case RA patients, was small and may not be indicative of all patients with RA in Kermanshah province. Second, we could not access the synovial fluid specimens of the new case RA patients owing to ethical considerations. Also, investigating the protein expression levels of CCR6 and RORγt, as well as characteristic cytokines secreted from Th17 cells, might be fruitful for better interpreting our results.5In summation, increased expression of CCR6 and RORγt genes may contribute to the attraction and migration of Th17 cells to the sites of inflammation occurring in RA, including the inflamed joints, and also may be associated with RA pathogenesis. Furthermore, considering that all RA patients in our study were newly diagnosed, it can be concluded that CCR6 and RORγt have a key role in early pathological events in RA and may contribute to RA progression and exacerbation. Nonetheless, to confirm our findings, further detailed studies, including assessing the protein expression levels of CCR6 and RORγt, as well as cytokines secreted from Th17 cells, are warranted in the synovial tissues and the inflamed joints of RA patients.Seyed Askar Roghani, Ramin Lotfi, and Mahdi Taghadosi contributed to the idea design, checked the final results, and performed the final revision of the manuscript. Seyed Askar Roghani, Ramin Lotfi, Masood Ghasemzade Soroush, Ali Khorasanizadeh, Parisa Feizollahi, and Zahra Mohammadi Kish performed experiments, calculations, and manuscript writing. Shirin Assar, Parviz Soufivand, and Mehran Pournazari as the specialist physicians referred the RA patients for sampling. All authors reviewed and approved the final manuscript for publication.The authors declare no conflict of interest.This study was done in concord with the principles of the Helsinki Declaration. Approval was granted by the Ethics Committee of the Kermanshah University of Medical Sciences , Kermanshah, Iran. Written informed consent was taken from all individual participants included in the study.


The maternal dietary pattern has a significant association with birthweight. The focus should be given to maternal dietary patterns to prevent suboptimal and high birthweight.Birthweight is a useful public health measure of maternal health, nutrition, healthcare delivery, and child morbidity and mortality. Previous research did not focus on dietary patterns but rather on a single or a few foods or nutrients. This study aimed to assess the maternal dietary pattern and its association with birthweight in northern Ethiopia. A hospital‐based cross‐sectional study was conducted among 373 pregnant mothers in their third trimester of pregnancy who came to attend their routine antenatal care service. The food frequency questionnaire was collected from the previous week, and the birthweight data were collected from the medical records after delivery. Three maternal dietary patterns were identified; dietary pattern includes eggs, milk, milk products, and certain fruits and roots. Dietary pattern 2 includes certain vegetables, green leafy vegetables, vitamin A‐rich vegetables, pulses such as beans, peas, and chickpeas, and drinks like coffee, tea, and soda. Dietary pattern 3 includes meat, nuts, and grains such as teff, corn, wheat, and white flour. Dietary pattern 1 ( Complex interactions between nutrients are not taken into account by the single‐nutrient analysis, and it is challenging to analyze nutrient impacts separately. According to our research, the food patterns of pregnant women in their third trimester of pregnancy can be best explained by three unique dietary patterns. A higher birthweight result was observed in women who ingested more eggs, milk and milk products, pulses, vegetables and roots, fruits, beverages, and sweets. For the majority of the time, food habits usually remain steady during pregnancy, and there is a strong correlation between the maternal dietary pattern and birthweight. Specifically, in Ethiopia, 1 in every 35 neonates dies within the first month  effects of nutrients  visit, 1188 on their fourth ANC visit, and a total of 2852 deliveries. The study was conducted from March 1 to May 29, 2020.2.2A hospital‐based cross‐sectional study was conducted among pregnant women who were in their third trimester of pregnancy (>37 weeks of gestation) coming to attend their routine antenatal care service and their respective live‐born baby medical records in Adigrat general hospital, Tigray, Ethiopia. Mothers with ultrasound‐confirmed multiple pregnancies, who were mentally unstable and critically ill, mothers with pregnancy‐induced hypertension, and gestational diabetes mellitus were excluded from the study since they need special dietary intake.2.3p = 28.3%, was taken  and Food Frequency Questioner (FFQ). WDDs were collected using 24‐h dietary recall intake history taken from the Food and Agricultural Organization (FAO) guideline. The FAO guideline was translated to the local language, Tigrigna, and then translated back to English to maintain its consistency, and no frequent food types were removed.The dietary history was taken from the previous day of the data collection day. The dietary pattern was assessed using the modified Hellen FFQ containing 43 food types  and one supervisor collected the data. The birthweight of the newborn was the main outcome variable, the independent variables were the sociodemographic characteristics, reproductive characteristics, medical and risky behavior characters, and nutritional factors.2.5The collected data were coded and checked for consistency and completeness up to the end of each data collection period. The data were entered using Epidata Manager version 4.6.0.2 and exported to the Statistical Package for Social Sciences (SPSS) software version 25 for Windows. The descriptive statistics of numeric variables were presented using median and interquartile range (IQR), and frequency and percentages were used for categorical variables.Principal component analysis (PCA) was used to generate dietary patterns with varimax rotation. The 43 food types that were collected using FFQ of 1‐week duration were grouped into 10 food groups before doing PCA. To maximize each variable's loading on one of the extracted components while minimizing its loading on all other factors, the variance was based on rotated sums of squared loading, and the varimax with Keiser normalization was employed as the orthogonal rotation approach.p‐value <.2 in the bivariate linear regression model were entered into the multiple linear regression model. An adjusted β with its 95% CI was presented, and a p < .05 and was used to declare the statistical significance. An adjusted R2 was taken to determine the proportion of variation that was explained by the regression model.Strong associations were defined as factor loadings with a magnitude >0.3  of THE College of Health Sciences, Mekelle University (ERC 1553/2020). The data collected from the medical records were handled with strict confidentiality; neither the case records nor the data extracted were used for any other purpose, and all information collected from pregnant mothers was stored anonymously. This research was carried out following the Helsinki Declaration of 1964.33.1Of the 373 study participants, 354 pregnant mothers completed the study yielding a response rate of 94.91%. Nineteen (5.09%) mothers were excluded from the study because sixteen mothers were lost before delivery and three mothers had a stillbirth. The median age of the study participants was 26 years with an IQR (23–31) years. Two hundred ninety‐nine (84.46%) pregnant mothers were urban residents and 327 (92.37%) pregnant mothers were married (Table 3.2The mean birthweight of the newborn was 3125 g with a standard deviation of (±460) g. Three hundred thirteen (88.42%) mothers were multigravida while 198 (84.26%) of the mothers were multiparous, with a median birth interval of 24 months IQR 17.5–36 months. Almost all (98.31%) of the pregnant mothers were not ever cigarette smokers. Concerning the pregnant mother's serostatus, 27 (7.63%) of them were human immunodeficiency virus positive. Thirteen (3.67%) and four (1.13%) mothers were diagnosed with sexually transmitted diseases (STDs) and malaria during their current pregnancy, respectively. Concerning the mode of delivery of the pregnant mothers, 54 (15.25%) gave birth by cesarean section, while the rest gave birth by spontaneous vaginal delivery  of the pregnant mothers were eating fast foods. One hundred eighty‐eight (55.46%) of the pregnant mothers reported having received nutritional counseling from a health professional during the current pregnancy. Regarding the feeding frequency, 285 (80.51%) of the mothers ate greater than three times a day, and concerning the anemia status of the mothers, 341 (96.33%) had a hemoglobin level of ≥11 g/dL. In addition, 234 (88.64%) of the mothers were provided with iron–folic acid supplementations. The median gestational weight gain during the current pregnancy was 10.5 kg with IQR  on dietary pattern 1 included eggs, milk, and milk products, certain fruits , and roots (potato and carrot).Dietary pattern 2 was characterized by high factor loadings for certain vegetables (green leafy vegetables and vitamin A‐rich vegetables), pulses , and drinks like coffee, tea, and soda. Dietary pattern 3 had higher loading factors for nuts, grains , and meat. Dietary pattern 3 also had very low (negative) factor loadings for eggs, milk, and milk products, and pulses Table .3.5F = 22.61, p ≤ .001. Similarly, there is a statistically significant difference in the newborn birthweight among pregnant mothers with different household monthly income categories, F = 2.77, p = .04. Moreover, there is a statistically significant difference in the newborn birthweight among pregnant mothers with different mid‐upper‐arm circumference measurements, F = 9.52, p = .001 , mean difference of − 358.8 . Similarly, there is a statistically significant difference in the newborn birthweight between pregnant mothers with MUAC <21 and 21–23 cm; mothers with MUAC <21 cm had low‐birthweight babies than those with MUAC 21–23 cm (p = .04), mean difference of − 191.56 .According to the Tukey post hoc test analysis, there is a statistically significant difference in the newborn birthweight between pregnant mothers with a household monthly income of ≥$ 324.79 and those with $ 156.45–232.4, and mothers with a household monthly income of $ 156.45–232.4 had low‐birthweight babies than those with ≥$ 324.79 . In addition, there is a statistically significant difference in the newborn birthweight between pregnant mothers with MUAC >23 cm and those with 21–23 cm, and mothers with MUAC 21–23 cm had low‐birthweight babies than those with MUAC >23 cm (p = .04), mean difference of 125.95  . Similarly, a 1 unit increase in the loadings of dietary pattern 2 was associated with a 66.76 g increase in birthweight, β = 66.76   pattern score and higher birthweight in a study conducted in China  loading factor for grains and sweetened beverages and alcohol, which is associated with higher birth and weight outcomes.High adherence to dietary patterns 1 and 2 was found to significantly increase the likelihood of having an infant with a higher birthweight. A 1 unit increase in the loadings of dietary pattern 1 was linked to an increase in birthweight of 52.45 g, while a 1 unit increase in the loadings of dietary pattern 2 was linked to an increase in birthweight of 66.76 g. Similar results were found in earlier investigations, which indicated that residence also appeared to be significantly related to birthweight  and do not require particular dietary regimens. Dietary intake was evaluated before the outcomes were known, which is another significant strength.The limitation of this study is predominantly that the FFQ used to collect data was not an FFQ specifically prepared for this study population. Each population has its dietary habits. Age, socioeconomic standing, racial or ethnic origin, cultural practices, and access to food can all affect them ; funding acquisition ; methodology ; project administration ; supervision ; writing – original draft ; writing – review and editing . selamawit Asfaw Beyene: Conceptualization ; supervision ; writing – review and editing . Freweini Gebrearegay Tela: Conceptualization ; supervision ; writing – review and editing . Zenawi Hagos Gufue: Software ; supervision ; writing – original draft ; writing – review and editing . Helen Teweldebirhan Hailu: Software ; supervision ; writing – original draft ; writing – review and editing .


GBA gene mutations (GBA‐PD) develop nonmotor complications more frequently than noncarriers. However, an objective characterization of both cardiovascular and sudomotor autonomic dysfunction using extensive clinical and instrumental measures has never been provided so far. Survival is reduced in GBA‐PD regardless of age and dementia, suggesting that other hitherto unrecognized factors are involved.Patients with Parkinson's disease (PD) and To provide instrumental measures of pattern and severity of autonomic dysfunction in GBA‐PD and explore their correlation with other non‐motor symptoms and implications for clinical practice.In this cross‐sectional study, 21 GBA‐PD and 24 matched PD noncarriers underwent extensive assessment of motor and non‐motor features, including neuropsychological testing. Cardiovascular autonomic function was explored through a comprehensive battery of indexes, including power spectral analysis of the R‐R intervals and blood pressure short‐term variability during resting state and active maneuvers. Dynamic Sweat Test was used to assess post‐ganglionic sudomotor dysfunction.Despite minimal or absent clinical correlates, cardiovagal and sympathetic indexes, heart rate variability parameters and sudomotor postganglionic function were more severely impaired in GBA‐PD than noncarriers , suggesting more prominent cardiac sympatho‐vagal demodulation, efferent baroreflex failure and peripheral sympathetic dysfunction in GBA‐PD. Cardiovascular dysautonomia showed marginal correlations with cognitive impairment.Compared to PD noncarriers, GBA‐PD display more severe instrumental autonomic abnormalities, which may be underestimated by purely clinical measures, despite their relevance on morbidity and mortality. This supports the necessity of implementing instrumental autonomic assessment in all GBA‐PD, regardless of clinically overt symptoms. GBA gene, encoding for the lysosomal enzyme Glucocerebrosidase (GCase), are the most frequent genetic risk factor for Parkinson's disease (PD).GBA mutations (GBA‐PD) is partially independent from aging and dementia,Heterozygous variants in the Despite clinical evidence of greater dysautonomia in GBA‐PD is well‐established,To date, only a study provided initial evidence of impaired heart‐rate variability and lower vagal modulation in GBA‐PD compared to PD noncarriers, but instrumental assessment was limited to rest and active standing, and sudomotor dysfunction was not explored.In this scenario, this study aimed to provide an extensive clinical and instrumental characterization of both cardiovascular and sudomotor autonomic dysfunction through standardized broadly available autonomic testing protocols in a cohort of well‐characterized GBA‐PD versus matched PD noncarriers. In addition, we explored whether greater dysautonomia proceeds in parallel with more severe cognitive impairment in GBA‐PD. We expected (1) to confirm GBA‐PD patients have more frequent and severe autonomic dysfunction than PD noncarriersLRRK2, parkin, PINK1, SNCA); (5) inability to attend at our Institute due to restrictions . Out of 716 patients with parkinsonism screened for GBA mutations from September 1, 2008 to September 30, 2020, we found 80 GBA‐PD individuals. Out of this cohort, 25 GBA‐PD were recruited between July 15 to October 20, 2020. Study flow chart is shown in Fig. This cross‐sectional study included patients with clinical diagnosis of PDDetails of the genetic analysis are available in the All the subjects were evaluated at the Movement Disorder Unit of the Neurologic Institute Carlo Besta  by Neurologists experienced in movement disorders. Data were collected on main demographical and clinical information, family history, ongoing drugs and device‐aided therapies for PD. Clinical work‐up, performed for all patients in morning hours and ON‐medication, included assessment of motor and non‐motor symptoms, quality of life and functional impairment through the Italian version of the following internationally‐validated scales: Movement Disorder Society‐Unified Parkinson's Disease Rating Scale (MDS‐UPDRS),Patients had clinical, neuropsychological, and autonomic testing on the same day. Patients were instructed to take the usual first Levodopa dose in the morning (8.00 am), then the neurologist performed the clinical scales (9.00 am) followed by the neuropsychological assessment (10.30–12.30 am); finally, patients underwent autonomic testing (1.00–2.00 pm).Autonomic function testing was performed for all patients in controlled conditions of temperature and humidity according to standard operating procedures. Before testing, all patients were instructed to stop any coffee, tea or taurine‐containing beverages, and all potential confounding medications for at least five half‐lives, except for dopaminergic therapy .Heart rate (HR) and beat‐to‐beat systolic blood pressure (sBP) and diastolic blood pressure (dBP) were recorded continuously using the Task Force® Monitor device . Thereafter, a standard Ewing's test batterySpectral analysis in the frequency domain of HR and BP beat‐to‐beat variability based on current HR variability (HRV) Guidelines were used to derive the high  and low frequency  powers of RR variability, as well as their ratio (LF/HF).We used the handgrip test (HT) to assess the non‐baroreflex mediated α‐adrenergic response. The HT was performed by asking patients to firmly squeeze a blood pressure monitor applying an isometric force at the 30% of maximal effort for 3 min.http://imagej.nih.gov/ij].2/min.Sudomotor function was investigated using the Dynamic Sweat Test (DST), which measures post‐ganglionic sudomotor function by stimulating the skin via iontophoresis at 2 mA for 5′ using pilocarpine.P value < 0.05 indicated statistical significance. The comparison of variables between PD noncarriers and different mutations sub‐groups was addressed as secondary aim. Details about descriptive statistics, regression and correlations analyses are provided in the All the analyses were performed with the software STATA 16 . The primary aim was to compare PD carriers of GBA mutations to PD noncarriers. Therefore, the sample size was calculated on the primary outcome measure (SDNN index), which is the only index of long‐term time‐domain analysis  that significantly differentiated PD patients and healthy control individuals.This study was performed in agreement with the principles of the Declaration of Helsinki and approved by the local Ethics Committee (CE n.85/2021). All patients signed written informed consent.Among GBA‐PD, 14  underwent sequencing of exons 8, 9, 10 and 11 of GBA gene, while sequencing of the entire gene was performed sequenced in the remaining 7 patients (33.3%). Eleven patients (52%) carried severe GBA mutations , while 10 patients (47.6%) carried mild GBA mutations or risk variants .Demographic, clinical and motor features are reported in Table GBA‐PD, mainly GBA‐SM, displayed a greater burden of nonmotor symptoms than PD noncarriers according to the NMSS total score, particularly involving sleep , and pain in GBA‐SM.Clinical scales and questionnaires did not reveal major differences on items related to autonomic dysfunction between GBA‐PD and noncarriers  obtained by regression analysis Table , Fig. 1.Concerning frequency‐domain analysis, groups did not differ for LF/HF ratio in basal resting conditions and during DB. During HUTT, the upward trend of LH/HF ratio was less evident for GBA‐PD than noncarriers Fig. . Compare2/min in GBA‐PD than noncarriers in the most affected body side  while in only 4.2% (n = 1/24) of noncarriers, due to greater impairment in attentive/executive functions , verbal memory  and visuo‐spatial abilities  and Benson Figure Copy  and greater functional impairment at PD‐CFRS , while VR correlated with Benson figure copy  and RAVL recognition task . In PD noncarriers, E:I ratio positively correlated with Benson figure Copy scores , but no associations emerged between E:I ratio and FAB and between VR and all cognitive tests. Compensatory rise of HR at 3 min of HUTT was negatively associated with FAB scores in GBA‐PD  and not in PD noncarriers. Similar results were obtained after stratifying both groups according to median scores of cognitive tests and to diagnosis of PD‐MCI  proved so robust to even differentiate GBA‐PD according to mutation type (PD noncarriers < GBA‐MM < GBA‐SM). Normal HRV in long‐term (at least 24‐h) recordings is an index of good cardiovascular health and overall autonomic integrity.Our data suggest a similar cardiac sympathetic function in GBA‐PD and PD noncarriers during active maneuvers, along with a relative preservation of baroreflex‐mediated vasoconstrictive α‐adrenergic responses (SI‐2 index) in GBA‐PD.Post‐ganglionic sweat output was significantly more impaired in GBA‐PD than PD noncarriers, with a seemingly selective involvement of the most affected body side. In PD, sweating dysfunction displays a length‐dependent progression, resulting in hypo‐anhidrotic areas at distal sites and compensatory axial sweating.We found a positive association between worse cognitive performances and parasympathetic dysfunction, particularly the E:I ratio. However, this was not specific to GBA‐PD, because the E:I ratio was positively associated to visuo‐spatial abilities in both carriers and noncarriers.Nevertheless, only GBA‐PD displayed a significant association between the E:I ratio and FAB scores as well as concomitant MCI. This is consistent with previous studies showing an association between reduced parasympathetic measures  and greater risk for MCI in PD.We acknowledge that our study has limitations, the most relevant being the small sample size.Therefore, further study in larger cohorts of GBA‐PD versus PD noncarriers, additionally including patients with dementia with Lewy bodies and non‐PD healthy control groups, is needed to replicate the present findings. Moreover, autonomic testing had been performed without stopping DA agonists and Levodopa for at least five half‐lives as we did for other concomitant medications potentially impacting autonomic testing but limited to 24 h after the last DA agonists intake and at least 5 h away from the last levodopa intake. Levodopa was not stopped because its pharmacodynamic effects (long‐duration response) last much longer than five half‐lives.P < 0.001) were obtained for all time‐domain spectral data analyses, even when limiting analysis to severe versus mild GBA mutations, emphasizing the strong effect of GBA mutations on cardiovascular autonomic function, particularly on HRV.Despite such limitations, there are strengths worth emphasizing. First, this is the first study providing a comprehensive instrumental assessment of both cardiovascular and sudomotor autonomic function in a well‐characterized cohort of GBA‐PD, studied with standardized operative protocols and in reproducible conditions and compared to carefully matched PD controls. In confirmation, despite small sample size, highly significant differences  should be included as outcome measures in disease‐modifying clinical trials and in future prospective studies investigating survival in GBA‐PD.The present study demonstrates that GBA‐PD display more severe cardiovascular autonomic impairment, mainly due to greater cardiac sympathetic and parasympathetic demodulation and impaired efferent baroreflex, along with a more pronounced sudomotor dysfunction. Critically, clinical correlates of these autonomic abnormalities could be minimal or absent, despite their potential impact on morbidity  and mortality. Translated into clinical practice, we suggest assessing cardiovascular autonomic reflexes instrumentally in all GBA‐PD patients , even in the absence of clinical complaints and particularly in younger individuals, whose compensatory mechanisms could mask or delay any symptom. We also encourage to use standardized autonomic protocols to promote comparability of data among centers. Finally, in a “(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.G.D.: 1A, 1C, 2A, 2C, 3A, 3BG.S.: 1A, 1C, 2A, 2C, 3A, 3BE.C.: 1A, 2A, 2B, 3BB.G.: 1C, 3AA.F.: 1CA.E.E.: 3BS.H.M.J.P.: 1B, 3BS.P.: 1B, 3BP.A.: 3BF.I.: 1CN.G.A.: 3BL.M.R.: 3BR.E.: 1B, 3BR.C.: 1A, 1B, 1C, 2A, 2C, 3A, 3BEthical 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 Committee of the Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano (reference number: CE n.85/2021). The study was conducted in accordance with the declaration of Helsinki and written informed consent was obtained by study participants.Funding Sources and Conflicts of Interest: All the authors report no conflict of interest related to this manuscript.Financial Disclosures for Previous 12 Months: RC has received speaking honoraria from Zambon Italia; Zambon SAU; Bial Italia Srl; Advisory board fees from Bial; Research support from the Italian Ministry of Health; Editor‐in‐Chief of the neuromuscular and movement disorders section of Brain Sciences; Associate Editor of Parkinsonism and Related Disorders, Frontiers in Neurology and Frontiers in Ageing Neuroscience. EC has received speaking honoraria from Zambon Italia. All other authors report no financial disclosures.Data S1. Supplementary material.Click here for additional data file.Data S2. Supplementary material.Click here for additional data file.Figure S1. Flow‐chart of the study.Click here for additional data file.Figure S2. Scatter plots for E:I ratio, RRI variation during DB and VR ratio values for PD noncarriers (PD) and GBA‐PD  and for PD noncarriers, GBA‐SM, and GBA‐MM , showing 25th and 75th percentile , the median (middle line) and the minimum to the maximum values (lines extending from box ranges).Click here for additional data file.Figure S3. Scatter plots of LF/HF ratio at 1, 3, 5 and 7 min at HUTT for PD noncarriers (PD) and GBA‐carriers (A) and for PD, GBA‐SM, and GBA‐MM (B), showing 25th and 75th percentile , the median (middle line) and the minimum to the maximum values (lines extending from box ranges), excluding outliers.Click here for additional data file.TABLE S1. Instrumental cardiovascular and sudomotor autonomic assessment in GBA‐L444P (GBA‐SM) and GBA‐N370S (GBA‐MM).Click here for additional data file.


The most common indications for anticoagulation were arterial/venous thrombus (n = 45), Fontan physiology (n = 32), and mechanical valve thrombus prophylaxis (n = 27). The anticoagulation medications used were warfarin (n = 57), heparin (n = 52), enoxaparin (n = 25), fondaparinux (n = 5), rivaroxaban (n = 2), and both heparin and warfarin (n = 3). Interventions were performed in 96 cases (67%). The median length of the procedure was 122.5 [15–760] minutes, and the median time to achieve hemostasis was 18.0  minutes. Adverse events were present in 11 cases (7.6%), and of those only 2 cases (1.4%) were bleeding-related complications. Our single-center data suggest that performing cardiac catheterization on pediatric patients while on uninterrupted anticoagulation is safe and does not substantially increase the risk of bleeding complications based on a cohort of patients that varied in age, size, diagnosis, medical complexity, and type of intervention performed. Patients on warfarin therapy for a mechanical valve are most likely to benefit from this practice, as the ability to continue warfarin therapy avoids the need for bridging and other interruption-related complications.This is the first report specifically describing outcomes of pediatric patients who underwent cardiac catheterization while on uninterrupted anticoagulation. One hundred forty-four cardiac catheterizations were identified that met inclusion criteria at our institution from 11/2014 to 10/2019. The median age and weight of the patients were 6.3 [0.01–20.9] years and 19.3 [2.1–172.5] kg, respectively. Seventy-eight (54%) catheterizations involved inpatients. The most common cardiac diagnoses among the cohort were single ventricle ( Anticoagulation is often held in pediatric patients undergoing cardiac catheterization based on adult guidelines and practices. In adults, oral anticoagulation agents are held (with or without heparin bridging) prior to cardiac catheterization due to concerns for potential bleeding complications , 2. For In children undergoing cardiac catheterization, the incidence of bleeding or hematoma has been shown to be low at 0.6–0.8% , 11. HowThis was a retrospective study performed with Institutional Review Board approval (protocol number CHLA-19-00456). Patients who were treated with systemic anticoagulation and underwent cardiac catheterization from 11/2014 to 10/2019 at our institution were identified using institutional databases and retrospectively reviewed. Exclusion criteria included interruption of systemic anticoagulation prior to cardiac catheterization and individuals on aspirin monotherapy.Data collected included patient demographics, cardiac diagnosis, date of last cardiac surgery, indication for anticoagulation, type of anticoagulation used, whether arterial or venous access was utilized, largest sheath size, use of ultrasound for vascular access, interventions performed, preoperative and intraoperative labs, hemostasis method and time, and adverse events. For patients that received manual pressure for hemostasis, times were estimated by time stamps for sheath removal and dressing placement in the electronic medical record. Adverse events were classified as minor, moderate, major, or catastrophic according to previously published and tested definitions .Continuous variables are presented as median [range] as they were not normally distributed. The statistical analysis was done with JMP Pro 15.1  and Microsoft Excel 16.16.10.n = 41), conotruncal defects (n = 37), and structurally normal heart (n = 16) , Fontan physiology including primary prophylaxis, fenestration, or thrombus (n = 32), mechanical valve , extracorporeal membrane oxygenation , heart failure (n = 9), and coronary artery aneurysm (n = 8) (Table n = 57), heparin (n = 52), enoxaparin (n = 25), fondaparinux (n = 5), rivaroxaban (n = 2), and both heparin and warfarin (n = 3). Fifty-three patients were on antiplatelet agents in addition to systemic anticoagulation . Additional anticoagulation was administered during catheterization in 92 cases, including heparin in 87 cases and bivalirudin in 5 cases. The median bolus doses of heparin and bivalirudin given were 72 units/kg [17.5–101.9 units/kg] and 0.5 mg/kg [0.45–0.50 mg/kg)], respectively.Ultrasound was utilized for vascular access in 78 cases (54%) Table . Both arn = 159) were common and performed in 96 cases (67%) (Table n = 67), stent implantation (n = 31), vascular embolization (n = 18), transeptal puncture (n = 10), transjugular liver biopsy (n = 10), thrombectomy (n = 11), Fontan fenestration occlusion (n = 6), endomyocardial biopsy (n = 3), valvuloplasty (n = 2), and balloon atrial septostomy (n = 1). The median length of the procedure was 122.5 [15–760] minutes, and the median time to achieve hemostasis for cases that received manual pressure was 18.0  minutes.Interventions or special diagnostic procedures  (%) Table . They inAdverse events were present in 11 cases (7.6%). There were six minor (4.2%) events . There was one moderate (0.7%) event . There were four major (2.8%) events . Bleeding complications were present in two cases (1.4%), both of which were classified as minor. Both patients were on warfarin as the anticoagulation agent with INRs of 2.8 and 3.1.This is the first report specifically describing outcomes of pediatric patients who underwent cardiac catheterization while on uninterrupted anticoagulation. Our single-center data suggest that this practice is safe and does not substantially increase the risk of bleeding complications in a cohort of patients that varied in age, size, diagnosis, and type of intervention performed. The most common indications for anticoagulation were venous or arterial thrombosis, Fontan physiology, and mechanical valve thrombus prophylaxis. Patients were most likely to be on warfarin (39.6%) or heparin (36.1%) for anticoagulation.Patients on warfarin therapy for a mechanical valve are most likely to benefit from this practice, as interruption of warfarin therapy is not ideal. The ability to continue warfarin therapy avoids the need for bridging, a period without anticoagulation therapy, as well as the need to transition the patient back to warfarin therapy. This practice can help to minimize the number of lab draws and length of hospital stay, particularly in young infants where management of warfarin can be challenging. In adults this has been shown to be a safer practice in patients undergoing pacemaker or defibrillator implantation with lower rates of device-pocket hematoma in the group that did not have interruption of warfarin therapy . FurtherOne of the outcome measures of this study was time to hemostasis. The median time to hemostasis in all catheterizations using manual pressure was 18.0  minutes, with 62% requiring more than 15 min of compression. Waragai et al. published a study assessing hemostasis times in pediatric patients, which demonstrated a mean time to hemostasis of 16.1 min, with 36% requiring more than 15 min of compression [Overall complication rates (7.6%) seen in this study are consistent with previously published rates which have ranged from 7.3 to 15% , 11, 17.While we were able to show the complications are relatively minor and rare while performing a variety of transcatheter interventions, it is important to tailor the anticoagulation plan to the patient. The diagnosis, indication for anticoagulation, bleeding risk of the planned intervention, access site, and anticipate sheath sizes should all be considered. Additionally, it is important to assess the activated clotting time and modify the intraprocedural anticoagulation dose if necessary . In our There were several limitations to our study. This is a retrospective study with data from a single center with a relatively small sample size. The patient cohort is heterogenous with a variety of diagnoses, indications for anticoagulation, anticoagulation therapies, and therapeutic goals. Additionally, there was no control group to compare the cohort’s outcomes to. Despite these limitations, there are several important observations that can be made from this study.This study demonstrates cardiac catheterization with a variety of interventions and utilizing a range of arterial and venous sheaths may be performed safely in pediatric patients on uninterrupted anticoagulation. Bleeding-related complications were similar to previously reported rates in patients not on anticoagulation, and observed complications were all mild in nature. Further studies in a larger cohort of patients are needed to better characterize the effects of uninterrupted vs interrupted anticoagulation in pediatric patients undergoing cardiac catheterization.