著者

Takahiro Yamauchi Yasuo Okumura Koichi Nagashima Ryuta Watanabe Yuki Saito Katsuaki Yokoyama Naoya Matsumoto Katsumi Miyauchi Sakiko Miyazaki Hidemori Hayashi Yuya Matsue Yuji Nishizaki Shuko Nojiri Tohru Minamino Hiroyuki Daida

出版者

The Japanese Circulation Society

雑誌

Circulation Journal (ISSN:13469843)

巻号頁・発行日

pp.CJ-23-0318, (Released:2023-08-09)

参考文献数

30

被引用文献数

2

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Background: The HELT-E2S2score, which assigns 1 point to Hypertension, Elderly aged 75–84 years, Low body mass index <18.5 kg/m2, and Type of atrial fibrillation (AF: persistent/permanent), and 2 points to Extreme Elderly aged ≥85 years and previous Stroke, has been proposed as a new risk stratification for strokes in Japanese AF patients, but has not yet undergone external validation.Methods and Results: We evaluated the prognostic performance of the HELT-E2S2score for stroke risk stratification using 2 large-scale registries in Japanese AF patients (n=7,020). During 23,241 person-years of follow-up (mean follow-up 1,208±450 days), 287 ischemic stroke events occurred. The C-statistic using the HELT-E2S2score was 0.661 (95% confidence interval [CI], 0.629–0.692), which was numerically higher than with the CHADS2score (0.644, 95% CI 0.613–0.675; P=0.15 vs. HELT-E2S2) or CHA2DS2-VASc score (0.650, 95% CI, 0.619–0.680; P=0.37 vs. HELT-E2S2). In the SAKURA AF Registry, the C-statistic of the HELT-E2S2score was consistently higher than the CHADS2and CHA2DS2-VASc scores across all 3 types of facilities comprising university hospitals, general hospitals, and clinics. However, in the RAFFINE Study, its superiority was only observed in general hospitals.Conclusions: The HELT-E2S2score demonstrated potential value for risk stratification, particularly in a super-aged society such as Japan. However, its superiority over the CHADS2or CHA2DS2-VASc scores may vary across different hospital settings.

著者

Mariko Harada-Shiba Hidenori Arai Yasushi Ishigaki Shun Ishibashi Tomonori Okamura Masatsune Ogura Kazushige Dobashi Atsushi Nohara Hideaki Bujo Katsumi Miyauchi Shizuya Yamashita Koutaro Yokote Working Group by Japan Atherosclerosis Society for Making Guidance of Familial Hypercholesterolemia

出版者

Japan Atherosclerosis Society

雑誌

Journal of Atherosclerosis and Thrombosis (ISSN:13403478)

巻号頁・発行日

pp.CR003, (Released:2018-06-07)

参考文献数

74

被引用文献数

167

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Statement1. Familial hypercholesterolemia (FH) is an autosomal hereditary disease with the 3 major clinical features of hyper-LDL-cholesterolemia, premature coronary artery disease and tendon and skin xanthomas. As there is a considerably high risk of coronary artery disease, in addition to early diagnosis and intensive treatment, family screening (cascade screening) is required (Recommendation level A)2.For a diagnosis of FH, at least 2 of the following criteria should be satisfied:① LDL-C ≥180 mg/dL, ② Tendon/skin xanthomas, ③ History of FH or premature coronary artery disease (CAD) within 2nd degree blood relatives (Recommendation level A)3. Intensive lipid-lowering therapy is necessary for the treatment of FH. First-line drug should be statin. (Recommendation level A, evidence level 3)4.Screening for coronary artery disease as well as asymptomatic atherosclerosis should be conducted periodically in FH patients. (Recommendation level A)5. For homozygous FH, consider LDL apheresis and treatment with PCSK9 inhibitors or MTP inhibitors. (Recommendation level A)6.For severe forms of heterozygous FH who have resistant to drug therapy, consider PCSK9 inhibitors and LDL apheresis. (Recommendation level A)7.Refer FH homozygotes as well as heterozygotes who are resistant to drug therapy, who are children or are pregnant or have the desire to bear children to a specialist. (Recommendation level A)

著者

Masakazu Yamagishi Nagara Tamaki Takashi Akasaka Takanori Ikeda Kenji Ueshima Shiro Uemura Yutaka Otsuji Yasuki Kihara Kazuo Kimura Takeshi Kimura Yoshiki Kusama Shinichiro Kumita Hajime Sakuma Masahiro Jinzaki Hiroyuki Daida Yasuchika Takeishi Hiroshi Tada Taishiro Chikamori Kenichi Tsujita Kunihiko Teraoka Kenichi Nakajima Tomoaki Nakata Satoshi Nakatani Akihiko Nogami Koichi Node Atsushi Nohara Atsushi Hirayama Nobusada Funabashi Masaru Miura Teruhito Mochizuki Hiroyoshi Yokoi Kunihiro Yoshioka Masafumi Watanabe Toshihiko Asanuma Yuichi Ishikawa Takahiro Ohara Koichi Kaikita Tokuo Kasai Eri Kato Hiroshi Kamiyama Masaaki Kawashiri Keisuke Kiso Kakuya Kitagawa Teruhito Kido Toshio Kinoshita Tomonari Kiriyama Teruyoshi Kume Akira Kurata Satoshi Kurisu Masami Kosuge Eitaro Kodani Akira Sato Yasutsugu Shiono Hiroki Shiomi Junichi Taki Masaaki Takeuchi Atsushi Tanaka Nobuhiro Tanaka Ryoichi Tanaka Takuya Nakahashi Takehiro Nakahara Akihiro Nomura Akiyoshi Hashimoto Kenshi Hayashi Masahiro Higashi Takafumi Hiro Daisuke Fukamachi Hitoshi Matsuo Naoya Matsumoto Katsumi Miyauchi Masao Miyagawa Yoshitake Yamada Keiichiro Yoshinaga Hideki Wada Tetsu Watanabe Yukio Ozaki Shun Kohsaka Wataru Shimizu Satoshi Yasuda Hideaki Yoshino on behalf of the Japanese Circulation Society Working Group

出版者

The Japanese Circulation Society

雑誌

Circulation Journal (ISSN:13469843)

巻号頁・発行日

pp.CJ-19-1131, (Released:2021-02-16)

参考文献数

1401

被引用文献数

50

著者

Miho Nishitani-Yokoyama Katsumi Miyauchi Kazunori Shimada Takayuki Yokoyama Shohei Ouchi Tatsuro Aikawa Mitsuhiro Kunimoto Miki Yamada Akio Honzawa Shinya Okazaki Hiroyuki Daida

出版者

The Japanese Circulation Society

雑誌

Circulation Journal (ISSN:13469843)

巻号頁・発行日

vol.83, no.1, pp.101-109, 2018-12-25 (Released:2018-12-25)

参考文献数

23

被引用文献数

1 13

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Background:Cardiac rehabilitation (CR) is an established multidisciplinary secondary preventive program. We investigated the effects of CR involving intensive physical activity (PA) on coronary plaque volume and components in patients with acute coronary syndrome (ACS).Methods and Results:We enrolled 32 consecutive patients with ACS in early phase II CR and randomly assigned them to an intensive CR group (n=18; CR participation ≥twice/week, daily PA ≥9,000 steps) or a standard CR group (n=14; CR participation ≥once/2weeks, daily PA ≥6,000 steps). Serial integrated backscatter intravascular ultrasound was performed for non-culprit lesions at baseline and after 8 months. Baseline clinical data were identical between the 2 groups. Unexpectedly, CR participation and PA did not differ significantly between the 2 groups, and there was no significant difference in plaque volume (PV) or components between the 2 groups. Subsequently, we classified the patients into 2 groups according to median PA (7,000 steps). There were significant differences in percent change of PV and of lipid volume between these 2 groups. In addition, these changes were negatively and independently correlated with PA.Conclusions:No significant difference was observed in PV or components between the intensive CR and the standard CR groups. Intensive PA, however, may retard coronary PV and ameliorate lipid component in patients with ACS participating in late phase II CR.

著者

Kazuo Kimura Takeshi Kimura Masaharu Ishihara Yoshihisa Nakagawa Koichi Nakao Katsumi Miyauchi Tomohiro Sakamoto Kenichi Tsujita Nobuhisa Hagiwara Shunichi Miyazaki Junya Ako Hirokuni Arai Hideki Ishii Hideki Origuchi Wataru Shimizu Hirofumi Takemura Yoshio Tahara Yoshihiro Morino Kenji Iino Tomonori Itoh Yoshitaka Iwanaga Keiji Uchida Hirohisa Endo Ken Kongoji Kenji Sakamoto Hiroki Shiomi Takao Shimohama Atsushi Suzuki Jun Takahashi Ichiro Takeuchi Akihito Tanaka Toshihiro Tamura Takahiro Nakashima Teruo Noguchi Daisuke Fukamachi Tomohiro Mizuno Junichi Yamaguchi Kenji Yodogawa Masami Kosuge Shun Kohsaka Hideaki Yoshino Satoshi Yasuda Hiroaki Shimokawa Atsushi Hirayama Takashi Akasaka Kazuo Haze Hisao Ogawa Hiroyuki Tsutsui Tsutomu Yamazaki on behalf of the Japanese Circulation Society Joint Working Group

出版者

The Japanese Circulation Society

雑誌

Circulation Journal (ISSN:13469843)

巻号頁・発行日

pp.CJ-19-0133, (Released:2019-03-29)

参考文献数

1064

被引用文献数

31 316

著者

Junya Ako Kiyoshi Hibi Kenichi Tsujita Takafumi Hiro Yoshihiro Morino Ken Kozuma Toshiro Shinke Hiromasa Otake Kiyoko Uno Michael J Louie Yoshiharu Takagi Katsumi Miyauchi

出版者

The Japanese Circulation Society

雑誌

Circulation Journal (ISSN:13469843)

巻号頁・発行日

pp.CJ-19-0412, (Released:2019-08-20)

参考文献数

20

被引用文献数

34

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Background:In patients with acute coronary syndrome (ACS), alirocumab reduced the risk of recurring ischemic events. ODYSSEY J-IVUS assessed the effect of alirocumab on coronary atheroma volume in Japanese patients recently hospitalized with ACS and hypercholesterolemia, using intravascular ultrasound imaging analysis.Methods and Results:Patients (n=206) who at index ACS diagnosis either had low-density lipoprotein cholesterol (LDL-C) ≥2.59 mmol/L (≥100 mg/dL) despite stable statin therapy, or were not on statins with LDL-C levels above target after statin initiation, were randomized (1:1) to alirocumab (75 mg every 2 weeks [Q2 W]/up to 150 mg Q2 W), or standard of care (SoC; atorvastatin ≥10 mg/day or rosuvastatin ≥5 mg/day) for 36 weeks. The primary efficacy endpoint (week [W] 36 mean [standard error] percent change in normalized total atheroma volume [TAV] from baseline) was −3.1 (1.0)% with SoC vs. −4.8 (1.0)% with alirocumab (between-group difference: −1.6 [1.4]; P=0.23). W36 absolute change from baseline in percent atheroma volume was −1.3 (0.4)% (SoC) and −1.4 (0.4)% (alirocumab; nominal P=0.79). At W36, LDL-C was reduced from baseline by 13.4% (SoC) vs. 63.9% (alirocumab; nominal P<0.0001). In total, 61.8% (SoC) and 75.7% (alirocumab) of patients reported treatment-emergency adverse events.Conclusions:In Japanese patients with ACS and hypercholesterolemia inadequately controlled despite statin therapy, from baseline to W36, a numerically greater percent reduction in normalized TAV was observed with alirocumab vs. SoC, which did not reach statistical significance.

著者

Ryo Naito Katsumi Miyauchi Hirokazu Konishi Shuta Tsuboi Manabu Ogita Tomotaka Dohi Takatoshi Kasai Hiroshi Tamura Shinya Okazaki Kikuo Isoda Hiroyuki Daida

出版者

一般社団法人 日本動脈硬化学会

雑誌

Journal of Atherosclerosis and Thrombosis (ISSN:13403478)

巻号頁・発行日

pp.32284, (Released:2015-11-11)

参考文献数

16

被引用文献数

1 5

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Aim: Current Japanese guidelines state the target level of low-density lipoprotein cholesterol (LDL-C) of <100mg/dL for secondary prevention of coronary artery disease (CAD). However, this level was set considering the results of trials mainly conducted in Western countries. In addition, the effect of achieving target LDL-C on secondary prevention is unknown. Methods: We examined the effects of achieving target LDL-C on clinical outcomes. Patients who underwent percutaneous coronary intervention at Juntendo University Hospital (Tokyo, Japan) from 2004 to 2010 and received follow-up coronary angiography (CAG) were analyzed. The study population was divided into two groups based on the follow-up LDL-C. The incidence of major adverse cardiovascular events within 3 years after the follow-up CAG was examined. Results: A total of 1321 consecutive patients were enrolled. Sixty-three percent of the patients achieved the target LDL-C. The rate of 3-year events was lower in the group that achieved the target LDL-C (achieved group). The adjusted relative risk reduction in the achieved group was 26% (p=0.02). In the sub-analysis among the four groups stratified by baseline LDL-C of 140 and follow-up LDL-C of 100, the adjusted hazard ratio for 3-year events was 1.84 (95% confidence interval; 1.10-3.24)in Group 3 (baseline <140, follow-up ≥100) and 2.05 (1.18-3.74) Group 4 (baseline ≥140, follow-up ≥100) [Group 2 (baseline ≥140, follow-up <100) as reference]. Conclusions: Our data suggested that follow-up LDL-C <100mg/dL was appropriate for secondary prevention of CAD in Japanese population.

著者

Junnichi Ishii Kosuke Kashiwabara Yukio Ozaki Hiroshi Takahashi Fumihiko Kitagawa Hideto Nishimura Hideki Ishii Satoshi Iimuro Hideki Kawai Takashi Muramatsu Hiroyuki Naruse Hiroshi Iwata Sadako Tanizawa-Motoyama Hiroyasu Ito Eiichi Watanabe Yutaka Matsuyama Yoshihiro Fukumoto Ichiro Sakuma Yoshihisa Nakagawa Kiyoshi Hibi Takafumi Hiro Seiji Hokimoto Katsumi Miyauchi Hiroshi Ohtsu Hideo Izawa Hisao Ogawa Hiroyuki Daida Hiroaki Shimokawa Yasushi Saito Takeshi Kimura Masunori Matsuzaki Ryozo Nagai

出版者

Japan Atherosclerosis Society

雑誌

Journal of Atherosclerosis and Thrombosis (ISSN:13403478)

巻号頁・発行日

vol.29, no.10, pp.1458-1474, 2022-10-01 (Released:2022-10-01)

参考文献数

33

被引用文献数

1 11

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Aim: We investigated the relationship between small dense low-density cholesterol (sdLDL-C) and risk of major adverse cardiovascular events (MACE) in patients treated with high- or low-dose statin therapy.Methods: This was a prospective case-cohort study within the Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) study, a randomized trial of high- or low-dose (4 or 1 mg/d pitavastatin, respectively) statin therapy, in patients with stable coronary artery disease (CAD). Serum sdLDL-C was determined using an automated homogenous assay at baseline (randomization after a rule-in period, >1 month with 1 mg/d pitavastatin) and 6 months after randomization, in 497 MACE cases, and 1543 participants randomly selected from the REAL-CAD study population.Results: High-dose pitavastatin reduced sdLDL-C by 20% than low-dose pitavastatin (p for interaction <0.001). Among patients receiving low-dose pitavastatin, baseline sdLDL-C demonstrated higher MACE risk independent of LDL-C (hazard ratio [95% confidence interval], 4th versus 1st quartile, 1.67 [1.04–2.68]; p for trend=0.034). High-dose (versus low-dose) pitavastatin reduced MACE risk by 46% in patients in the highest baseline sdLDL-C quartile (>34.3 mg/dL; 0.54 [0.36–0.81]; p=0.003), but increased relative risk by 40% in patients with 1st quartile (≤ 19.5 mg/dL; 1.40 [0.94–2.09]; p=0.099) and did not alter risk in those in 2nd and 3rd quartiles (p for interaction=0.002).Conclusions: These findings associate sdLDL-C and cardiovascular risk, independent of LDL-C, in statin-treated CAD patients. Notably, high-dose statin therapy reduces this risk in those with the highest baseline sdLDL-C.

著者

Toshiaki Toyota Takeshi Morimoto Satoshi Iimuro Retsu Fujita Hiroshi Iwata Katsumi Miyauchi Teruo Inoue Yoshihisa Nakagawa Yosuke Nishihata Hiroyuki Daida Yukio Ozaki Satoru Suwa Ichiro Sakuma Yutaka Furukawa Hiroki Shiomi Hirotoshi Watanabe Kyohei Yamaji Naritatsu Saito Masahiro Natsuaki Yasuo Ohashi Masunori Matsuzaki Ryozo Nagai Takeshi Kimura

出版者

The Japanese Circulation Society

雑誌

Circulation Journal (ISSN:13469843)

巻号頁・発行日

pp.CJ-22-0168, (Released:2022-09-14)

参考文献数

20

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Background: The relationship between very low on-treatment low-density lipoprotein cholesterol (LDL-C) level and cardiovascular event risk is still unclear in patients receiving the same doses of statins.Methods and Results: From the REAL-CAD study comparing high-dose (4 mg/day) with low-dose (1 mg/day) pitavastatin therapy in patients with stable coronary artery disease, 11,105 patients with acceptable statin adherence were divided into 3 groups according to the on-treatment LDL-C level at 6 months (<70 mg/dL, 70–100 mg/dL, and ≥100 mg/dL). The primary outcome measure was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, or unstable angina requiring emergent admission. The adjusted risks of the LDL-C <70 mg/dL group relative to the LDL-C 70–100 mg/dL group (reference) was not significantly different for the primary outcome measure in both 1 mg/day and 4 mg/day strata (HR 0.84, 95% CI 0.58–1.18, P=0.32, and HR 1.25, 95% CI 0.88–1.79, P=0.22). The adjusted risk of the LDL-C ≥100 mg/dL group relative to the reference group was not significant for the primary outcome measure in the 1 mg/day stratum (HR 0.82, 95% CI 0.60–1.11, P=0.21), whereas it was highly significant in the 4 mg/day stratum (HR 3.32, 95% CI 2.08–5.17, P<0.001).Conclusions: A very low on-treatment LDL-C level (<70 mg/dL) was not associated with lower cardiovascular event risk compared with moderately low on-treatment LDL-C level (70–100 mg/dL) in patients receiving the same doses of statins.

著者

Mizuki Miura Masao Yamasaki Yukari Uemura Masatomo Yoshikawa Katsumi Miyauchi Hiroyuki Tanaka Hideki Miyachi Jun Yamashita Makoto Suzuki Takeshi Yamamoto Ken Nagao Issei Komuro Morimasa Takayama

出版者

The Japanese Circulation Society

雑誌

Circulation Journal (ISSN:13469843)

巻号頁・発行日

vol.80, no.2, pp.461-468, 2016-01-25 (Released:2016-01-25)

参考文献数

22

被引用文献数

14 18

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Background:Previous trials have found that low low-density lipoprotein-cholesterol (LDL-C) on admission was associated with increased mortality in patients with acute myocardial infarction (AMI). There are few reports, however, on the effect of low LDL-C with or without in-hospital statin treatment on short-term prognosis in AMI patients.Methods and Results:A total of 9,032 AMI patients underwent primary PCI in 68 centers in the Tokyo CCU Network Registry during 2009–2012, in whom LDL-C was measured in 6,486. We divided them into 4 groups: statin-treated/LDL-C <100 mg/dl (n=1,236), statin-treated/LDL-C ≥100 mg/dl (n=3,671), statin-naïve/LDL-C <100 mg/dl (n=662), and statin-naïve/LDL-C ≥100 mg/dl (n=917). We assessed hospital mortality within 30 days. In-hospital all-cause mortality was significantly lower in the statin-treated/LDL-C ≥100-mg/dl group (3.2%, P<0.001). On multivariate Cox regression analysis, adjusted for age, gender, hypertension, diabetes mellitus, dyslipidemia and other clinical factors, the combination of statin treatment and LDL-C ≥100 mg/dl was an independent predictor of lower in-hospital mortality (adjusted HR, 0.211; 95% CI: 0.096–0.462; P<0.001). In the LDL-C <100-mg/dl patients, statin treatment also independently reduced in-hospital mortality (adjusted HR, 0.467; 95% CI: 0.223–0.976; P=0.043). Spontaneously low LDL-C was associated with increased short-term mortality.Conclusions:Statin treatment was associated with better short-term outcome in patients with AMI, even in patients with low LDL-C. (Circ J 2016; 80: 461–468)

著者

Masaru Hiki Tetsuro Miyazaki Kazunori Shimada Yurina Sugita Megumi Shimizu Tatsuro Aikawa Shohei Ouchi Tomoyuki Shiozawa Kiyoshi Takasu Shuhei Takahashi Atsutoshi Takagi Katsumi Miyauchi Hiroyuki Daida

出版者

一般社団法人 日本動脈硬化学会

雑誌

Journal of Atherosclerosis and Thrombosis (ISSN:13403478)

巻号頁・発行日

pp.37424, (Released:2017-03-24)

参考文献数

27

被引用文献数

9

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Aim: Polyunsaturated fatty acids (PUFAs) take part in various biological events linked to the pathogenesis of venous thromboembolism (VTE), including inflammation, endothelial dysfunction, and hypercoagulability. Several studies have demonstrated the association between PUFAs and the occurrence of VTE. However, the role of PUFAs in the pathogenesis of VTE remains unclear.Methods: We enrolled 45 patients with acute VTE and 37 age-, gender-, and body mass index-matched healthy volunteers to examine their PUFA levels. Serum omega 3 (eicosapentaenoic acid: EPA and docosahexaenoic acid: DHA) and omega 6 (dihomogammalinolenic acid: DGLA and arachidonic acid: AA) fatty acids levels were measured within 24 h of admission.Results: Patients with VTE showed significantly higher AA and lower EPA levels, and lower EPA/AA ratios than the controls. Multivariate analysis revealed that AA was an independent marker for VTE. In addition, we divided the patients based on their median age (58 years old). The younger patients with VTE showed significantly lower EPA/AA levels than their age-matched controls, whereas older patients with VTE showed a significantly higher AA/DGLA levels than the older controls.Conclusions: High serum AA levels and low EPA levels are associated with the development of acute VTE, suggesting that the imbalance of PUFAs may be a potential therapeutic target for preventing acute VTE.

著者

Hiroaki Takashima Yukio Ozaki Takeshi Morimoto Takeshi Kimura Takafumi Hiro Katsumi Miyauchi Yoshihisa Nakagawa Masakazu Yamagishi Hiroyuki Daida Tomofumi Mizuno Kenji Asai Yasuo Kuroda Takashi Kosaka Yasushi Kuhara Akiyoshi Kurita Kazuyuki Maeda Tetsuya Amano Masunori Matsuzaki for the JAPAN-ACS Investigators

出版者

日本循環器学会

雑誌

Circulation Journal (ISSN:13469843)

巻号頁・発行日

vol.76, no.12, pp.2840-2847, 2012 (Released:2012-11-22)

参考文献数

32

被引用文献数

4 6

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Background: The JAPAN-ACS (Japan Assessment of Pitavastatin and Atorvastatin in Acute Coronary Syndrome) trial showed that intensive statin therapy could induce significant coronary plaque regression in acute coronary syndrome (ACS). We evaluated the impact of metabolic syndrome (MetS) and its components on coronary plaque regression in the JAPAN-ACS patients. Methods and Results: Serial intravascular ultrasound measurements over 8–12 months were performed in 242 ACS patients receiving pitavastatin or atorvastatin. Patients were divided into groups according to the presence of MetS or the number of MetS components. Although the percent change in plaque volume (%PV) was not significantly different between the MetS (n=119) and non-MetS (n=123) groups (P=0.50), it was significantly associated with an increasing number of MetS components (component 0: −24.0%, n=7; components 1: −20.8%, n=31; components 2: −16.1%, n=69; components 3: −18.7%, n=83; components 4: −13.5%, n=52; P=0.037 for trend). The percent change in body mass index (%BMI) significantly correlated with %PV (r=0.15, P=0.021), especially in the MetS components 4 group (r=0.35, P=0.017). In addition, %BMI was an independent predictor of plaque regression after adjustment for the changes of low- and high-density lipoprotein cholesterol, triglycerides and HbA1c. Conclusions: The clustering of MetS components, but not the presence of MetS itself, could attenuate coronary plaque regression during intensive statin therapy in ACS patients. Therefore, to achieve a greater degree of plaque regression, it is necessary to treat to each MetS component and use lifestyle modification.  (Circ J 2012; 76: 2840–2847)