Changes in Lean Tissue Mass, Fat Mass, Biological Parameters and Resting Energy Expenditure over 24 Months Following Sleeve Gastrectomy

Laurent Maïmoun, Safa Aouinti, Marion Puech, Patrick Lefebvre, Melanie Deloze, Pascal de Santa Barbara, Eric Renard, Jean-Paul Christol, Justine Myzia, Marie-Christine Picot, Denis Mariano-Goulart, David Nocca, Laurent Maïmoun, Safa Aouinti, Marion Puech, Patrick Lefebvre, Melanie Deloze, Pascal de Santa Barbara, Eric Renard, Jean-Paul Christol, Justine Myzia, Marie-Christine Picot, Denis Mariano-Goulart, David Nocca

Abstract

Sleeve gastrectomy (SG) induces weight loss but its effects on body composition (BC) are less well known. The aims of this longitudinal study were to analyse the BC changes from the acute phase up to weight stabilization following SG. Variations in the biological parameters related to glucose, lipids, inflammation, and resting energy expenditure (REE) were concomitantly analysed. Fat mass (FM), lean tissue mass (LTM), and visceral adipose tissue (VAT) were determined by dual-energy X-ray absorptiometry in 83 obese patients (75.9% women) before SG and 1, 12 and 24 months later. After 1 month, LTM and FM losses were comparable, whereas at 12 months the loss of FM exceeded that of LTM. Over this period, VAT also decreased significantly, biological parameters became normalized, and REE was reduced. For most of the BC, biological and metabolic parameters, no substantial variation was demonstrated beyond 12 months. In summary, SG induced a modification in BC changes during the first 12 months following SG. Although the significant LTM loss was not associated with an increase in sarcopenia prevalence, the preservation of LTM might have limited the reduction in REE, which is a longer-term weight-regain criterion.

Keywords: HOMA; Hba1c; IGF-1; IGFBP-3; c-reactive protein; fat mass; lean tissue mass; resting energy expenditure; sleeve gastrectomy; visceral adipose tissue.

Conflict of interest statement

I certify that neither I nor my co-authors have a conflict of interest as described above that is relevant to the subject matter or materials included in this work.

Figures

Figure 1
Figure 1
Variation in anthopometric and body composition parameters at different times. BMI: body mass index (A); FM: fat mass (B); LTM: lean tissue mass (C); LTM/FM ratio (D); ALM: appendicular lean mass (E); ALMI(h2): appendicular lean mass index (height2) (F); ALM/height2, ALMI(BMI) (G): appendicular lean mass index (BMI); TAT: total adipose tissue (H); VAT: visceral adipose tissue (I); SAT: subcutaneous adipose tissue (J). Lower whisker represents the smallest observation greater than or equal to lower hinge −1.5 × IQR. Upper whisker represents the largest observation less than or equal to upper hinge +1.5 × IQR. Lower and upper hinges represent, respectively, the 25 and the 75% quartile values. The open circles represent the mean value in each time. Data beyond the end of the whiskers are called outliers points and are plotted individually. IQR, interquartile range.
Figure 2
Figure 2
Variation in biological parameters at different times. BMI: body mass index (A); FM: fat mass (B); LTM: lean tissue mass (C); LTM/FM ratio (D); ALM: appendicular lean mass (E); ALMI(h2): appendicular lean mass index (height2) (F); ALM/height2, ALMI(BMI) (G): appendicular lean mass index (BMI); TAT: total adipose tissue (H); VAT: visceral adipose tissue (I); SAT: subcutaneous adipose tissue (J). Lower whisker represents the smallest observation greater than or equal to lower hinge −1.5 × IQR. Upper whisker represents the largest observation less than or equal to upper hinge + 1.5 × IQR. Lower and upper hinges represent, respectively, the 25 and the 75% quartile values. The open circles represent the mean value in each time. Data beyond the end of the whiskers are called outlier points and are plotted individually. IQR, interquartile range.

References

    1. Jensen M.D., Ryan D.H., Apovian C.M., Ard J.D., Comuzzie A.G., Donato K.A., Hu F.B., Hubbard V.S., Jakicic J.M., Kushner R.F., et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Obesity Society. J. Am. Coll. Cardiol. 2013;63:2985–3023. doi: 10.1016/j.jacc.2013.11.004.
    1. Albanopoulos K., Tsamis D., Natoudi M., Alevizos L., Zografos G., Leandros E. The impact of laparoscopic sleeve gastrectomy on weight loss and obesity-associated comorbidities: The results of 3 years of follow-up. Surg. Endosc. 2016;30:699–705. doi: 10.1007/s00464-015-4262-2.
    1. Beamish A.J., Olbers T., Kelly A.S., Inge T.H. Cardiovascular effects of bariatric surgery. Nat. Rev. Cardiol. 2016;13:730–743. doi: 10.1038/nrcardio.2016.162.
    1. Kennedy-Dalby A., Adam S., Ammori B.J., Syed A.A. Weight loss and metabolic outcomes of bariatric surgery in men versus women—A matched comparative observational cohort study. Eur. J. Intern. Med. 2014;25:922–925. doi: 10.1016/j.ejim.2014.10.020.
    1. Voorwinde V., Steenhuis I.H.M., Janssen I.M.C., Monpellier V.M., van Stralen M.M. Definitions of Long-Term Weight Regain and Their Associations with Clinical Outcomes. Obes. Surg. 2020;30:527–536. doi: 10.1007/s11695-019-04210-x.
    1. Frisard M.I., Greenway F.L., Delany J.P. Comparison of methods to assess body composition changes during a period of weight loss. Obes. Res. 2005;13:845–854. doi: 10.1038/oby.2005.97.
    1. Schiavo L., Pilone V., Tramontano S., Rossetti G., Iannelli A. May Bioelectrical Impedance Analysis Method Be Used in Alternative to the Dual-Energy X-Ray Absorptiometry in the Assessment of Fat Mass and Fat-Free Mass in Patients with Obesity? Pros, Cons, and Perspectives. Obes. Surg. 2020;30:3212–3215. doi: 10.1007/s11695-020-04614-0.
    1. Johnson Stoklossa C.A., Forhan M., Padwal R.S., Gonzalez M.C., Prado C.M. Practical Considerations for Body Composition Assessment of Adults with Class II/III Obesity Using Bioelectrical Impedance Analysis or Dual-Energy X-Ray Absorptiometry. Curr. Obes. Rep. 2016;5:389–396. doi: 10.1007/s13679-016-0228-5.
    1. Shepherd J.A., Baim S., Bilezikian J.P., Schousboe J.T. Executive summary of the 2013 International Society for Clinical Densitometry Position Development Conference on Body Composition. J. Clin. Densitom. 2013;16:489–495. doi: 10.1016/j.jocd.2013.08.005.
    1. Maimoun L., Lefebvre P., Aouinti S., Picot M.C., Mariano-Goulart D., Nocca D., Montpellier Study Group of Bariatric S. Acute and longer-term body composition changes after bariatric surgery. Surg. Obes. Relat. Dis. 2019;15:1965–1973. doi: 10.1016/j.soard.2019.07.006.
    1. Maimoun L., Lefebvre P., Jaussent A., Fouillade C., Mariano-Goulart D., Nocca D. Body composition changes in the first month after sleeve gastrectomy based on gender and anatomic site. Surg. Obes. Relat. Dis. 2017;13:780–787. doi: 10.1016/j.soard.2017.01.017.
    1. Sivakumar J., Chen Q., Sutherland T.R., Read M., Ward S., Chong L., Hii M.W. Body Composition Differences Between Excess Weight Loss ≥ 50% and < 50% at 12 Months Following Bariatric Surgery. Obes. Surg. 2022;32:2556–2566. doi: 10.1007/s11695-022-06128-3.
    1. Haghighat N., Ashtary-Larky D., Bagheri R., Aghakhani L., Asbaghi O., Amini M., Moeinvaziri N., Hosseini B., Wong A., Shamekhi Z., et al. Preservation of fat-free mass in the first year after bariatric surgery: A systematic review and meta-analysis of 122 studies and 10,758 participants. Surg. Obes. Relat. Dis. 2022;18:964–982. doi: 10.1016/j.soard.2022.02.022.
    1. Barzin M., Heidari Almasi M., Mahdavi M., Khalaj A., Valizadeh M., Hosseinpanah F. Body Composition Changes Following Sleeve Gastrectomy Vs. One-Anastomosis Gastric Bypass: Tehran Obesity Treatment Study (TOTS) Obes. Surg. 2021;31:5286–5294. doi: 10.1007/s11695-021-05722-1.
    1. Sherf-Dagan S., Zelber-Sagi S., Buch A., Bar N., Webb M., Sakran N., Raziel A., Goitein D., Keidar A., Shibolet O. Prospective Longitudinal Trends in Body Composition and Clinical Outcomes 3 Years Following Sleeve Gastrectomy. Obes. Surg. 2019;29:3833–3841. doi: 10.1007/s11695-019-04057-2.
    1. Gomez-Ambrosi J., Andrada P., Valenti V., Rotellar F., Silva C., Catalan V., Rodriguez A., Ramirez B., Moncada R., Escalada J., et al. Dissociation of body mass index, excess weight loss and body fat percentage trajectories after 3 years of gastric bypass: Relationship with metabolic outcomes. Int. J. Obes. 2017;41:1379–1387. doi: 10.1038/ijo.2017.134.
    1. Angrisani L., Santonicola A., Iovino P., Formisano G., Buchwald H., Scopinaro N. Bariatric Surgery Worldwide 2013. Obes. Surg. 2015;25:1822–1832. doi: 10.1007/s11695-015-1657-z.
    1. Shantavasinkul P.C., Omotosho P., Muehlbauer M.J., Natoli M., Corsino L., Tong J., Portenier D., Torquati A. Metabolic profiles, energy expenditures, and body compositions of the weight regain versus sustained weight loss patients who underwent Roux-en-Y gastric bypass. Surg. Obes. Relat. Dis. 2021;17:2015–2025. doi: 10.1016/j.soard.2021.09.007.
    1. Marks B.L., Rippe J.M. The importance of fat free mass maintenance in weight loss programmes. Sport. Med. 1996;22:273–281. doi: 10.2165/00007256-199622050-00001.
    1. Montague C.T., O’Rahilly S. The perils of portliness: Causes and consequences of visceral adiposity. Diabetes. 2000;49:883–888. doi: 10.2337/diabetes.49.6.883.
    1. Despres J.P., Lemieux I. Abdominal obesity and metabolic syndrome. Nature. 2006;444:881–887. doi: 10.1038/nature05488.
    1. Rao V.N., Fudim M., Mentz R.J., Michos E.D., Felker G.M. Regional adiposity and heart failure with preserved ejection fraction. Eur. J. Heart Fail. 2020;22:1540–1550. doi: 10.1002/ejhf.1956.
    1. Fontana L., Eagon J.C., Trujillo M.E., Scherer P.E., Klein S. Visceral fat adipokine secretion is associated with systemic inflammation in obese humans. Diabetes. 2007;56:1010–1013. doi: 10.2337/db06-1656.
    1. Favre L., Marino L., Roth A., Acierno J., Jr., Hans D., Demartines N., Pitteloud N., Suter M., Collet T.H. The Reduction of Visceral Adipose Tissue after Roux-en-Y Gastric Bypass Is more Pronounced in Patients with Impaired Glucose Metabolism. Obes. Surg. 2018;28:4006–4013. doi: 10.1007/s11695-018-3455-x.
    1. Santini S., Vionnet N., Pasquier J., Suter M., Hans D., Gonzalez-Rodriguez E., Pitteloud N., Favre L. Long-term body composition improvement in post-menopausal women following bariatric surgery: A cross-sectional and case-control study. Eur. J. Endocrinol. 2022;186:255–263. doi: 10.1530/EJE-21-0895.
    1. Ray K.K., Colhoun H.M., Szarek M., Baccara-Dinet M., Bhatt D.L., Bittner V.A., Budaj A.J., Diaz R., Goodman S.G., Hanotin C., et al. Effects of alirocumab on cardiovascular and metabolic outcomes after acute coronary syndrome in patients with or without diabetes: A prespecified analysis of the ODYSSEY OUTCOMES randomised controlled trial. Lancet Diabetes Endocrinol. 2019;7:618–628. doi: 10.1016/S2213-8587(19)30158-5.
    1. Geldsetzer P., Manne-Goehler J., Marcus M.E., Ebert C., Zhumadilov Z., Wesseh C.S., Tsabedze L., Supiyev A., Sturua L., Bahendeka S.K., et al. The state of hypertension care in 44 low-income and middle-income countries: A cross-sectional study of nationally representative individual-level data from 1.1 million adults. Lancet. 2019;394:652–662. doi: 10.1016/S0140-6736(19)30955-9.
    1. Katzmarzyk P.T., Greenway F.L., Heymsfield S.B., Bouchard C. Clinical utility and reproducibility of visceral adipose tissue measurements derived from dual-energy X-ray absorptiometry in White and African American adults. Obesity. 2013;21:2221–2224. doi: 10.1002/oby.20519.
    1. Cruz-Jentoft A.J., Bahat G., Bauer J., Boirie Y., Bruyere O., Cederholm T., Cooper C., Landi F., Rolland Y., Sayer A.A., et al. Sarcopenia: Revised European consensus on definition and diagnosis. Age Ageing. 2019;48:601. doi: 10.1093/ageing/afz046.
    1. McLean R.R., Shardell M.D., Alley D.E., Cawthon P.M., Fragala M.S., Harris T.B., Kenny A.M., Peters K.W., Ferrucci L., Guralnik J.M., et al. Criteria for clinically relevant weakness and low lean mass and their longitudinal association with incident mobility impairment and mortality: The foundation for the National Institutes of Health (FNIH) sarcopenia project. J. Gerontol. A Biol. Sci. Med. Sci. 2014;69:576–583. doi: 10.1093/gerona/glu012.
    1. Fielding R.A., Vellas B., Evans W.J., Bhasin S., Morley J.E., Newman A.B., Abellan van Kan G., Andrieu S., Bauer J., Breuille D., et al. Sarcopenia: An undiagnosed condition in older adults. Current consensus definition: Prevalence, etiology, and consequences. International working group on sarcopenia. J. Am. Med. Dir. Assoc. 2011;12:249–256. doi: 10.1016/j.jamda.2011.01.003.
    1. Roza A.M., Shizgal H.M. The Harris Benedict equation reevaluated: Resting energy requirements and the body cell mass. Am. J. Clin. Nutr. 1984;40:168–182. doi: 10.1093/ajcn/40.1.168.
    1. Buhler J., Rast S., Beglinger C., Peterli R., Peters T., Gebhart M., Meyer-Gerspach A.C., Wolnerhanssen B.K. Long-Term Effects of Laparoscopic Sleeve Gastrectomy and Roux-en-Y Gastric Bypass on Body Composition and Bone Mass Density. Obes. Facts. 2021;14:131–140. doi: 10.1159/000512450.
    1. Martinez M.C., Meli E.F., Candia F.P., Filippi F., Vilallonga R., Cordero E., Hernandez I., Eguinoa A.Z., Burgos R., Vila A., et al. The Impact of Bariatric Surgery on the Muscle Mass in Patients with Obesity: 2-Year Follow-up. Obes. Surg. 2022;32:625–633. doi: 10.1007/s11695-021-05815-x.
    1. Golzarand M., Toolabi K., Djafarian K. Changes in Body Composition, Dietary Intake, and Substrate Oxidation in Patients Underwent Laparoscopic Roux-en-Y Gastric Bypass and Laparoscopic Sleeve Gastrectomy: A Comparative Prospective Study. Obes. Surg. 2019;29:406–413. doi: 10.1007/s11695-018-3528-x.
    1. Coluzzi I., Raparelli L., Guarnacci L., Paone E., Del Genio G., le Roux C.W., Silecchia G. Food Intake and Changes in Eating Behavior After Laparoscopic Sleeve Gastrectomy. Obes. Surg. 2016;26:2059–2067. doi: 10.1007/s11695-015-2043-6.
    1. Harvie M.N., Pegington M., Mattson M.P., Frystyk J., Dillon B., Evans G., Cuzick J., Jebb S.A., Martin B., Cutler R.G., et al. The effects of intermittent or continuous energy restriction on weight loss and metabolic disease risk markers: A randomized trial in young overweight women. Int. J. Obes. 2011;35:714–727. doi: 10.1038/ijo.2010.171.
    1. Tam C.S., Frost E.A., Xie W., Rood J., Ravussin E., Redman L.M., Pennington C.T. No effect of caloric restriction on salivary cortisol levels in overweight men and women. Metabolism. 2014;63:194–198. doi: 10.1016/j.metabol.2013.10.007.
    1. Juiz-Valina P., Pena-Bello L., Cordido M., Outeirino-Blanco E., Pertega S., Varela-Rodriguez B., Garcia-Brao M.J., Mena E., Sangiao-Alvarellos S., Cordido F. Altered GH-IGF-1 Axis in Severe Obese Subjects is Reversed after Bariatric Surgery-Induced Weight Loss and Related with Low-Grade Chronic Inflammation. J. Clin. Med. 2020;9:2614. doi: 10.3390/jcm9082614.
    1. Kojta I., Chacinska M., Blachnio-Zabielska A. Obesity, Bioactive Lipids, and Adipose Tissue Inflammation in Insulin Resistance. Nutrients. 2020;12:1305. doi: 10.3390/nu12051305.
    1. Pellitero S., Granada M.L., Martinez E., Balibrea J.M., Guanyabens E., Serra A., Moreno P., Navarro M., Romero R., Alastrue A., et al. IGF1 modifications after bariatric surgery in morbidly obese patients: Potential implications of nutritional status according to specific surgical technique. Eur. J. Endocrinol. 2013;169:695–703. doi: 10.1530/EJE-13-0209.
    1. Ohira M., Watanabe Y., Yamaguchi T., Onda H., Yamaoka S., Abe K., Nakamura S., Tanaka S., Kawagoe N., Nabekura T., et al. The Relationship between Serum Insulin-Like Growth Factor-1 Levels and Body Composition Changes after Sleeve Gastrectomy. Obes. Facts. 2021;14:641–649. doi: 10.1159/000519610.
    1. De Marinis L., Bianchi A., Mancini A., Gentilella R., Perrelli M., Giampietro A., Porcelli T., Tilaro L., Fusco A., Valle D., et al. Growth hormone secretion and leptin in morbid obesity before and after biliopancreatic diversion: Relationships with insulin and body composition. J. Clin. Endocrinol. Metab. 2004;89:174–180. doi: 10.1210/jc.2002-021308.
    1. Maimoun L., Serrand C., Mura T., Renard E., Nocca D., Lefebvre P., Boudousq V., Avignon A., Mariano-Goulart D., Sultan A. Definition of an adapted cut-off for determining low lean tissue mass in older women with obesity: A comparison to current cut-offs. Sci. Rep. 2022;12:16905. doi: 10.1038/s41598-022-21258-5.
    1. Ruthes E.M.P., Lenardt B.C.C., Lass A.D., Petroski C.A., de Mello M.F., de Andrade Junior A.B., Souza C.J.F., de Matos O., Castelo-Branco C. Lean mass and strength profile of women submitted to bariatric surgery: Comparison of the EWGSOP2 and FNIH classification for sarcopenia—ASBS program phase II. Gynecol. Endocrinol. 2022;38:868–873. doi: 10.1080/09513590.2022.2119956.
    1. Vassilev G., Galata C., Finze A., Weiss C., Otto M., Reissfelder C., Blank S. Sarcopenia after Roux-en-Y Gastric Bypass: Detection by Skeletal Muscle Mass Index vs. Bioelectrical Impedance Analysis. J. Clin. Med. 2022;11:1468. doi: 10.3390/jcm11061468.
    1. Voican C.S., Lebrun A., Maitre S., Lainas P., Lamouri K., Njike-Nakseu M., Gaillard M., Tranchart H., Balian A., Dagher I., et al. Predictive score of sarcopenia occurrence one year after bariatric surgery in severely obese patients. PLoS ONE. 2018;13:e0197248. doi: 10.1371/journal.pone.0197248.
    1. Johnstone A.M., Murison S.D., Duncan J.S., Rance K.A., Speakman J.R. Factors influencing variation in basal metabolic rate include fat-free mass, fat mass, age, and circulating thyroxine but not sex, circulating leptin, or triiodothyronine. Am. J. Clin. Nutr. 2005;82:941–948. doi: 10.1093/ajcn/82.5.941.
    1. Fidilio E., Comas M., Giribes M., Cardenas G., Vilallonga R., Palma F., Pelaez R.B., Simo R., Ciudin A. Evaluation of Resting Energy Expenditure in Subjects with Severe Obesity and Its Evolution after Bariatric Surgery. Obes. Surg. 2021;31:4347–4355. doi: 10.1007/s11695-021-05578-5.
    1. Moize V., Andreu A., Rodriguez L., Flores L., Ibarzabal A., Lacy A., Jimenez A., Vidal J. Protein intake and lean tissue mass retention following bariatric surgery. Clin Nutr. 2013;32:550–555. doi: 10.1016/j.clnu.2012.11.007.
    1. Hassannejad A., Khalaj A., Mansournia M.A., Rajabian Tabesh M., Alizadeh Z. The Effect of Aerobic or Aerobic-Strength Exercise on Body Composition and Functional Capacity in Patients with BMI ≥35 after Bariatric Surgery: A Randomized Control Trial. Obes. Surg. 2017;27:2792–2801. doi: 10.1007/s11695-017-2717-3.
    1. Siervo M., Faber P., Lara J., Gibney E.R., Milne E., Ritz P., Lobley G.E., Elia M., Stubbs R.J., Johnstone A.M. Imposed rate and extent of weight loss in obese men and adaptive changes in resting and total energy expenditure. Metabolism. 2015;64:896–904. doi: 10.1016/j.metabol.2015.03.011.
    1. Faria S.L., Kelly E., Faria O.P. Energy expenditure and weight regain in patients submitted to Roux-en-Y gastric bypass. Obes. Surg. 2009;19:856–859. doi: 10.1007/s11695-009-9842-6.
    1. Faria S.L., Faria O.P., Buffington C., de Almeida Cardeal M., Rodrigues de Gouvea H. Energy expenditure before and after Roux-en-Y gastric bypass. Obes. Surg. 2012;22:1450–1455. doi: 10.1007/s11695-012-0672-6.
    1. Bazzocchi A., Ponti F., Cariani S., Diano D., Leuratti L., Albisinni U., Marchesini G., Battista G. Visceral Fat and Body Composition Changes in a Female Population After RYGBP: A Two-Year Follow-Up by DXA. Obes. Surg. 2015;25:443–451. doi: 10.1007/s11695-014-1422-8.
    1. Heath M.L., Kow L., Slavotinek J.P., Valentine R., Toouli J., Thomson C.H. Abdominal adiposity and liver fat content 3 and 12 months after gastric banding surgery. Metabolism. 2009;58:753–758. doi: 10.1016/j.metabol.2008.05.021.
    1. Zang Y., Zhu C., Wen X., Wang X., Li L., Rampersad S., Lu L., Zhou D., Qian C., Cui R., et al. Laparoscopic sleeve gastrectomy improves body composition and alleviates insulin resistance in obesity related acanthosis nigricans. Lipids Health Dis. 2017;16:209. doi: 10.1186/s12944-017-0598-z.
    1. Gletsu-Miller N., Hansen J.M., Jones D.P., Go Y.M., Torres W.E., Ziegler T.R., Lin E. Loss of total and visceral adipose tissue mass predicts decreases in oxidative stress after weight-loss surgery. Obesity. 2009;17:439–446. doi: 10.1038/oby.2008.542.
    1. Sun J., Lv H., Li M., Zhao L., Liu Y., Zeng N., Wei X., Chen Q., Ren P., Liu Y., et al. How much abdominal fat do obese patients lose short term after laparoscopic sleeve gastrectomy? A quantitative study evaluated with MRI. Quant. Imaging Med. Surg. 2021;11:4569–4582. doi: 10.21037/qims-20-1380.
    1. Guida B., Cartaldi M., Busetto M., Aiello M.L., Musella M., Capone D., Parolisi S., Policastro V., Ragozini G., Belfiore A. Predictors of fat-free mass loss 1 years after laparoscopic sleeve gastrectomy. J. Endocrinol. Investig. 2018;41:1307–1315. doi: 10.1007/s40618-018-0868-2.
    1. Nuijten M.A.H., Monpellier V.M., Eijsvogels T.M.H., Janssen I.M.C., Hazebroek E.J., Hopman M.T.E. Rate and Determinants of Excessive Fat-Free Mass Loss after Bariatric Surgery. Obes. Surg. 2020;30:3119–3126. doi: 10.1007/s11695-020-04654-6.

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