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• W4240195825 abstract "The Review Section of JHS will contain at least 3 clinically relevant articles selected by the editor to be offered for CME in each issue. For CME credit, the participant must read the articles in print or online and correctly answer all related questions through an online examination. The questions on the test are designed to make the reader think and will occasionally require the reader to go back and scrutinize the article for details. The JHS CME Activity fee of $20.00 includes the exam questions/answers only and does not include access to the JHS articles referenced. Statement of Need: This CME activity was developed by the JHS review section editors and review article authors as a convenient education tool to help increase or affirm reader's knowledge. The overall goal of the activity is for participants to evaluate the appropriateness of clinical data and apply it to their practice and the provision of patient care. Accreditation: The ASSH is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. AMA PRA Credit Designation: The American Society for Surgery of the Hand designates this Journal-Based CME activity for a maximum of 2.00 “AMA PRA Category 1 Credits™”. Physicians should claim only the credit commensurate with the extent of their participation in the activity. ASSH Disclaimer: The material presented in this CME activity is made available by the ASSH for educational purposes only. This material is not intended to represent the only methods or the best procedures appropriate for the medical situation(s) discussed, but rather it is intended to present an approach, view, statement, or opinion of the authors that may be helpful, or of interest, to other practitioners. Examinees agree to participate in this medical education activity, sponsored by the ASSH, with full knowledge and awareness that they waive any claim they may have against the ASSH for reliance on any information presented. The approval of the US Food and Drug Administration is required for procedures and drugs that are considered experimental. Instrumentation systems discussed or reviewed during this educational activity may not yet have received FDA approval. Provider Information can be found at http://www.assh.org/Pages/ContactUs.aspx. Technical Requirements for the Online Examination can be found at http://jhandsurg.org/cme/home. Privacy Policy can be found at http://www.assh.org/pages/ASSHPrivacyPolicy.aspx. ASSH Disclosure Policy: As a provider accredited by the ACCME, the ASSH must ensure balance, independence, objectivity, and scientific rigor in all its activities. David Ring, MD, PhD, has no relevant conflicts of interest to disclose. All authors of this journal-based CME activity have no relevant conflicts of interest to disclose. In the printed or PDF version of this article, author affiliations can be found at the bottom of the first page. Ghazi M. Rayan, MD, has no relevant conflicts of interest to disclose. The editorial and education staff involved with this journal-based CME activity has no relevant conflicts of interest to disclose. •Describe the clinical manifestations of Raynaud disease.•Distinguish between Raynaud disease and Raynaud phenomenon.•Review the nonsurgical treatment of Raynaud disease.•Discuss the current opinion of Raynaud disease surgical treatment.•Assess the literature, gaps, and shortcomings of Raynaud disease management. Deadline: Each examination purchased in 2014 must be completed by January 31, 2015, to be eligible for CME. A certificate will be issued upon completion of the activity. Estimated time to complete each month's JHS CME activity is up to 2 hours. Copyright © 2014 by the American Society for Surgery of the Hand. All rights reserved. A healthy 22-year-old woman presents after experiencing several episodes of sudden onset color change in both hands after cold exposure. The color changes are described as sharply demarcated paleness of the bilateral index, long, ring, and little fingers accompanied by a tingling sensation in the digits. Episodes resolve after warming the hands. She has no other concerns. Physical examination and laboratory studies reveal a normal Allen test, symmetrical findings, absence of digital trophic changes, normal nailfold capillary examination, normal erythrocyte sedimentation rate, and negative antinuclear antibodies. The episodes are uncomfortable and she asks what can be done to prevent future episodes or lessen the severity of the symptoms. What is the best treatment for Raynaud disease (RD)? Raynaud disease is characterized by cold hypersensitivity and profound episodic digital color changes thought to occur as the result of an exaggerated vasoconstrictive response of the digital arteries to cold temperatures, blunt trauma, or emotional stress. By definition, patients with RD do not have an underlying associated cause for vasospastic events and irreversible tissue injury does not occur from the condition.1LeRoy E.C. Medsger Jr., T.A. Raynaud's phenomenon: a proposal for classification.Clin Exp Rheumatol. 1992; 10: 485-488PubMed Google Scholar, 2Block J.A. Sequeira W. Raynaud's phenomenon.Lancet. 2001; 357: 2042-2048Abstract Full Text Full Text PDF PubMed Scopus (310) Google Scholar, 3Wigley F.M. Clinical practice: Raynaud's phenomenon.N Engl J Med. 2002; 347: 1001-1008Crossref PubMed Scopus (347) Google Scholar In contrast, Raynaud phenomenon occurs in patients with a diagnosis of collagen vascular disease, scleroderma in particular, and is a progressive condition characterized by digital trophic changes, an abnormal Allen test, asymmetric findings, and abnormal angiography.4Porter S.B. Murray P.M. Raynaud phenomenon.J Hand Surg Am. 2013; 38: 375-378Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar Treatment is supportive and includes avoiding cold exposure, wearing gloves, and ceasing smoking. However, RD is not to be confused with Buerger disease. If nondrug measures have failed, calcium channel blockers are typically first-line drug therapy,5Thompson A.E. Pope J.E. Calcium channel blockers for primary Raynaud's phenomenon: a meta-analysis.Rheumatology. 2005; 44: 145-150Crossref PubMed Scopus (177) Google Scholar whereas other oral medications with vasodilatory properties,6Stewart M. Morling J.R. Oral vasodilators for primary Raynaud's phenomenon.Cochrane Database Syst Rev. 2012; 7: CD006687PubMed Google Scholar digital botulinum toxin injections,7Neumeister M.W. Botulinum toxin type A in the treatment of Raynaud's phenomenon.J Hand Surg Am. 2010; 35: 2085-2092Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar and biofeedback techniques8Karavidas M.K. Tsai P.S. Yucha C. McGrady A. Lehrer P.M. Thermal biofeedback for primary Raynaud's phenomenon: a review of the literature.Appl Psychophysiol Biofeedback. 2006; 31: 203-216Crossref PubMed Scopus (27) Google Scholar have also been used. Patients with RD tend to be otherwise healthy women in whom symptoms begin before the age of 30. Although the incidence of RD varies among studies, a Framingham cohort analysis yielded a prevalence of symptoms consistent with RD in approximately 11% of women and 8% of men.9Suter L.G. Murabito J.M. Felson D.T. Fraenkel L. The incidence and natural history of Raynaud's phenomenon in the community.Arthritis Rheum. 2005; 52: 1259-1263Crossref PubMed Scopus (94) Google Scholar The prevalence of RD is lower in warmer climates.10Maricq H.R. Carpentier P.H. Weinrich M.C. et al.Geographic variation in the prevalence of Raynaud's phenomenon: a 5 region comparison.J Rheumatol. 1997; 24: 879-889PubMed Google Scholar The pathogenesis of RD is not fully understood, and proposed mechanisms are largely based on investigation in patients with Raynaud phenomenon associated with scleroderma. However, evidence suggests reduced endothelin-dependent vasodilation activity as an etiologic factor.11Herrick A.L. Pathogenesis of Raynaud's phenomenon.Rheumatology (Oxford). 2005; 44: 587-596Crossref PubMed Scopus (319) Google Scholar, 12Zamora M.R. O'Brien R.F. Rutherford R.B. Weil J.V. Serum endothelin-1 concentrations and cold provocation in primary Raynaud's phenomenon.Lancet. 1990; 336: 1144-1147Abstract PubMed Scopus (210) Google Scholar, 13Cardelli M.B. Kleinsmith D.M. Raynaud's phenomenon and disease.Med Clin North Am. 1989; 73: 1127-1141PubMed Google Scholar In addition, reduction of the immunoreactivity of calcitonin gene-related peptide,14Bunker C.B. Terenghi G. Springall D.R. Polak J.M. Dowd P.M. Deficiency of calcitonin gene-related peptide in Raynaud's phenomenon.Lancet. 1990; 336: 1530-1533Abstract PubMed Scopus (110) Google Scholar increased vasoconstriction in peripheral vessels via overproduction of endothelin-1,12Zamora M.R. O'Brien R.F. Rutherford R.B. Weil J.V. Serum endothelin-1 concentrations and cold provocation in primary Raynaud's phenomenon.Lancet. 1990; 336: 1144-1147Abstract PubMed Scopus (210) Google Scholar, 15Fagius J. Blumberg H. Sympathetic outflow to the hand in patients with Raynaud's phenomenon.Cardiovasc Res. 1985; 19: 249-253Crossref PubMed Scopus (48) Google Scholar or vasoconstriction in peripheral vessels mediated predominantly by sympathetic postjunctional α2 receptors in response to the cold have also been implicated in the pathogenesis.16Coffman J.D. Cohen R.A. Role of alpha-adrenoceptor subtypes mediating sympathetic vasoconstriction in human digits.Eur J Clin Invest. 1988; 18: 309-313Crossref PubMed Scopus (55) Google Scholar, 17Flavahan N.A. Cooke J.P. Shepherd J.T. Vanhoutte P.M. Human postjunctional alpha-1 and alpha-2 adrenoceptors: differential distribution in arteries of the limbs.J Pharmacol Exp Ther. 1987; 241: 361-365PubMed Google Scholar, 18Chotani M.A. Flavahan S. Mitra S. Daunt D. Flavahan N.A. Silent alpha(2C)-adrenergic receptors enable cold-induced vasoconstriction in cutaneous arteries.Am J Physiol Heart Circ Physiol. 2000; 278: H1075-H1083PubMed Google Scholar Enhanced platelet aggregation19Cuenca R. Fernández-Cortijo J. Lima J. et al.[Platelet function study in primary Raynaud's phenomenon and Raynaud's phenomenon associated with scleroderma].Med Clin (Barc). 1990; 95: 761-763PubMed Google Scholar has also been reported in RD. Twelve prospective, randomized, double-blind, placebo-controlled trials of calcium channel blockers with treatment periods ranging from 1 to 10 weeks showed that nifedipine, at doses of 10 to 20 mg 3 times daily, significantly reduced the frequency and severity of symptoms of RD.20Nilsson H. Jonason T. Leppert J. Ringqvist I. The effect of the calcium-entry blocker nifedipine on cold-induced digital vasospasm: a double-blind crossover study versus placebo.Acta Med Scand. 1987; 221: 53-60Crossref PubMed Scopus (31) Google Scholar, 21Sarkozi J. Bookman A.A. Mahon W. Ramsay C. Detsky A.S. Keystone E.C. Nifedipine in the treatment of idiopathic Raynaud's syndrome.J Rheumatol. 1986; 13: 331-336PubMed Google Scholar, 22Corbin D.O. Wood D.A. Macintyre C.C. Housley E. A randomized double blind cross-over trial of nifedipine in the treatment of primary Raynaud's phenomenon.Eur Heart J. 1986; 7: 165-170PubMed Google Scholar, 23Gjorup T. Kelbaek H. Hartling O.J. Nielsen S.L. Controlled double-blind trial of the clinical effect of nifedipine in the treatment of idiopathic Raynaud's phenomenon.Am Heart J. 1986; 111: 742-745Abstract Full Text PDF PubMed Scopus (32) Google Scholar, 24Waller D.G. Challenor V.F. Francis D.A. Roath O.S. Clinical and rheological effects of nifedipine in Raynaud's phenomenon.Br J Clin Pharmacol. 1986; 22: 449-454Crossref PubMed Scopus (25) Google Scholar, 25Rodeheffer R.J. Rommer J.A. Wigley F. Smith C.R. Controlled double-blind trial of nifedipine in the treatment of Raynaud's phenomenon.N Engl J Med. 1983; 308: 880-883Crossref PubMed Scopus (195) Google Scholar, 26Comparison of sustained-release nifedipine and temperature biofeedback for treatment of primary Raynaud phenomenon: results from a randomized clinical trial with 1-year follow-up.Arch Intern Med. 2000; 160: 1101-1108Crossref PubMed Scopus (94) Google Scholar, 27Challenor V.F. Waller D.G. Hayward R.A. Griffin M.J. Roath O.S. Vibrotactile sensation and response to nifedipine dose titration in primary Raynaud's phenomenon.Angiology. 1989; 40: 122-128Crossref PubMed Scopus (10) Google Scholar, 28Kahan A. Weber S. Amor B. et al.Calcium entry blocking agents in digital vasospasm (Raynaud's phenomenon).Eur Heart J. 1983; 4: 123-129Crossref PubMed Google Scholar, 29Redondo F.R. Noguerado A. Asensio J.P. Bote L. Alvaro-Gracia J.M. Castellano O. Tratamiento del fenomeno de Raynaud con nifedipina: un studio controlado a doble ciego.Rev Esp Reumatol. 1986; 13: 121-123Google Scholar, 30Ettinger W.H. Wise R.A. Schaffhauser D. Wigley F.M. Controlled double-blind trial of dazoxiben and nifedipine in the treatment of Raynaud's phenomenon.Am J Med. 1984; 77: 451-456Abstract Full Text PDF PubMed Scopus (44) Google Scholar, 31Kahan A. Foult J.M. Weber S. Amor B. Menkes C.J. Degeorges M. Nifedipine and alpha 1-adrenergic blockade in Raynaud's phenomenon.Eur Heart J. 1985; 6: 702-705PubMed Google Scholar In 2 trials of 2 weeks' duration each, nicardipine at doses of 20 mg 3 times daily and 50 mg extended release daily did not significantly reduce the severity or frequency of RD symptoms.32Kahan A. Amor B. Menkes C.J. Weber S. Guerin F. Degeorges M. Nicardipine in the treatment of Raynaud's phenomenon: a randomized double-blind trial.Angiology. 1987; 38: 333-337Crossref PubMed Scopus (22) Google Scholar, 33Controlled multicenter double-blind trial of nicardipine in the treatment of primary Raynaud phenomenon: French Cooperative Multicenter Group for Raynaud Phenomenon, Paris, France.Am Heart J. 1991; 122: 352-355PubMed Google Scholar Two trials involving nisoldipine versus placebo at doses of 10 and 20 mg daily for 2- and 4-week durations showed no statistically significant differences.34Challenor V.F. Waller D.G. Francis D.A. Francis J.L. Mani R. Roath S. Nisoldipine in primary Raynaud's phenomenon.Eur J Clin Pharmacol. 1987; 33: 27-30Crossref PubMed Scopus (12) Google Scholar, 35Gjorup T. Hartling O.J. Kelbaek H. Nielsen S.L. Controlled double blind trial of nisoldipine in the treatment of idiopathic Raynaud's phenomenon.Eur J Clin Pharmacol. 1986; 31: 387-389Crossref PubMed Scopus (21) Google Scholar Diltiazem 120 mg 3 times daily significantly reduced both the frequency and severity of RD symptoms over a 2-week treatment duration in 1 trial.36Kahan A. Amor B. Menkes C.J. A randomised double-blind trial of diltiazem in the treatment of Raynaud's phenomenon.Ann Rheum Dis. 1985; 44: 30-33Crossref PubMed Scopus (61) Google Scholar A meta-analysis reviewed the above 17 trials containing a total of 348 patients and concluded that calcium channel blockers demonstrated a statistically significant benefit in reducing the frequency and severity of symptoms in patients with RD. Overall, a 33% reduction in the severity of symptoms and an average decrease of 2.8 to 5.0 episodes over a 1-week period were demonstrated.5Thompson A.E. Pope J.E. Calcium channel blockers for primary Raynaud's phenomenon: a meta-analysis.Rheumatology. 2005; 44: 145-150Crossref PubMed Scopus (177) Google Scholar With regard to oral vasodilators other than calcium channel blockers, 2 crossover trials noted that captopril 25 mg 3 times daily over 2 periods of 6 weeks each did not reduce severity or frequency of symptoms.37Rustin M.H. Almond N.E. Beacham J.A. et al.The effect of captopril on cutaneous blood flow in patients with primary Raynaud's phenomenon.Br J Dermatol. 1987; 117: 751-758Crossref PubMed Scopus (32) Google Scholar, 38Madsen J.L. Hvidt S. [Raynaud's disease treated with captopril (Capoten): a randomized double-blind cross-over study].Ugeskr Laeger. 1984; 146: 2695-2697PubMed Google Scholar A trial of buflomedil 300 mg twice daily over 6 months showed significant reduction in the frequency but not the severity of episodes.39Le Quentrec P. Lefebvre M.L. Double-blind placebo-controlled trial of buflomedil in the treatment of Raynaud's phenomenon: six-month follow-up.Angiology. 1991; 42: 289-295Crossref PubMed Scopus (16) Google Scholar Beraprost 40 μg 3 times daily over 3 weeks showed no benefit in severity or frequency of symptoms, but significantly more adverse events.40Vayssairat M. Controlled multicenter double blind trial of an oral analog of prostacyclin in the treatment of primary Raynaud's phenomenon: French Microcirculation Society Multicentre Group for the Study of Vascular Acrosyndromes.J Rheumatol. 1996; 23: 1917-1920PubMed Google Scholar A crossover trial of dazoxiben 100 mg 4 times daily demonstrated no reduction in frequency of symptoms.30Ettinger W.H. Wise R.A. Schaffhauser D. Wigley F.M. Controlled double-blind trial of dazoxiben and nifedipine in the treatment of Raynaud's phenomenon.Am J Med. 1984; 77: 451-456Abstract Full Text PDF PubMed Scopus (44) Google Scholar A crossover trial of ketanserin 40 mg twice daily over 6 weeks showed a significant decrease in the severity but not frequency of symptoms.41van de Wal H.J. Wijn P.F. van Lier H.J. Skotnicki S.H. The effectiveness of ketanserin in patients with primary Raynaud's phenomenon: a randomized, double blind, placebo controlled study.Int Angiol. 1987; 6: 313-322PubMed Google Scholar A crossover trial of moxisylyte (thymoxamine) 40 mg 4 times daily over 2 periods of 2 weeks each noted significant reduction in frequency of symptoms, but significantly increased the number of adverse events.42Jaffe G.V. Grimshaw J.J. Thymoxamine for Raynaud's disease and chilblains.Br J Clin Pract. 1980; 34: 343-346PubMed Google Scholar The Cochrane Peripheral Vascular Diseases Group published its own systemic review of studies involving the use of oral vasodilators other than calcium channel blockers for the treatment of RD, which included the above 8 studies involving a total of 290 participants, and concluded that there was no evidence for the use of oral vasodilatory agents other than calcium channel blockers for the treatment of RD.6Stewart M. Morling J.R. Oral vasodilators for primary Raynaud's phenomenon.Cochrane Database Syst Rev. 2012; 7: CD006687PubMed Google Scholar Neumeister7Neumeister M.W. Botulinum toxin type A in the treatment of Raynaud's phenomenon.J Hand Surg Am. 2010; 35: 2085-2092Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar published results of a retrospective study in which 33 patients underwent digital injections of botulinum toxin type A for ischemic pain related to either RD or Raynaud phenomenon; a reduction in resting pain was reported in 28 patients. The 5 patients who did not respond to injection therapy carried a diagnosis of either end-stage scleroderma, mixed connective tissue disease, or lupus. Two randomized, placebo-controlled trials reported that temperature biofeedback (TBF) resulted in a significant decrease in symptom frequency from RD for up to 3 years compared with either autogenic training or electromyograph biofeedback.43Freedman R.R. Ianni P. Role of cold and emotional stress in Raynaud's disease and scleroderma.Br Med J (Clin Res Ed). 1983; 287: 1499-1502Crossref PubMed Scopus (54) Google Scholar, 44Freedman R.R. Sabharwal S.C. Ianni P. Desai N. Wenig P. Mayes M. Nonneural beta-adrenergic vasodilating mechanism in temperature biofeedback.Psychosom Med. 1988; 50: 394-401PubMed Google Scholar However, 3 other randomized, placebo-controlled trials and 1 nonrandomized trial found no significant difference between TBF and various relaxation techniques.45Surwit R.S. Pilon R.N. Fenton C.H. Behavioral treatment of Raynaud's disease.J Behav Med. 1978; 1: 323-335Crossref PubMed Scopus (56) Google Scholar, 46Keefe F.J. Surwit R.S. Pilon R.N. Biofeedback, autogenic training, and progressive relaxation in the treatment of Raynaud's disease: a comparative study.J Appl Behav Anal. 1980; 13: 3-11Crossref PubMed Scopus (49) Google Scholar, 47Jobe J.B. Sampson J.B. Roberts D.E. Kelly J.A. Comparison of behavioral treatments for Raynaud's disease.J Behav Med. 1986; 9: 89-96Crossref PubMed Scopus (11) Google Scholar, 48Jacobson A.M. Manschreck T.C. Silverberg E. Behavioral treatment for Raynaud's disease: a comparative study with long-term follow-up.Am J Psychiatry. 1979; 136: 844-846PubMed Google Scholar In the Raynaud's Treatment Study,26Comparison of sustained-release nifedipine and temperature biofeedback for treatment of primary Raynaud phenomenon: results from a randomized clinical trial with 1-year follow-up.Arch Intern Med. 2000; 160: 1101-1108Crossref PubMed Scopus (94) Google Scholar patients with RD who were given nifedipine had better outcomes than those treated with TBF. The Raynaud's Treatment Study and the study by Guglielmi et al49Guglielmi R.S. Roberts A.H. Patterson R. Skin temperature biofeedback for Raynaud's disease: a double-blind study.Biofeedback Self Regul. 1982; 7: 99-120Crossref PubMed Scopus (28) Google Scholar found no significant difference when comparing patients who received TBF with those in the control groups. Investigation of interventions for RD is hindered by the absence of objectively measurable pathophysiology, unclear definitions and diagnostic criteria for pathophysiologic peripheral vasoconstriction, arbitrary and subjective definitions of benefit, substantial placebo response, natural fluctuation of symptoms (regression to the mean), and no validated scales to measure these entirely subjective outcomes. The vast majority of studies to date are small. Most were crossover designs without washout periods. There was also variability in study objectives for different trials. Safety and efficacy data for long-term use are lacking for medications. Finally, there was no standardization in training of biofeedback techniques, which had high rates of training failure, short treatment duration, and in several cases mixed patients with Raynaud phenomenon and RD. To improve future studies, we need a consensus definition and objective measure that can differentiate normal peripheral vasoconstriction from RD. Multicenter, adequately powered, long-term, randomized, placebo-controlled, prospective clinical trials separating patients with RD from those with Raynaud phenomenon are needed to clarify the role of medications in the treatment of RD. Consistent use of a validated scale to measure outcomes would help with comparison of future studies. Further studies of biofeedback and stress management merit additional exploration with improved study methodology. This patient's clinical history and physical examination is classic for RD. However, evaluation should rule out mechanical injury, drug exposure, connective tissue diseases (especially scleroderma), proximal vascular abnormalities such as mural thrombi and proximal aneurysms, extrinsic vascular obstruction, hyperviscosity states, and malignancy.2Block J.A. Sequeira W. Raynaud's phenomenon.Lancet. 2001; 357: 2042-2048Abstract Full Text Full Text PDF PubMed Scopus (310) Google Scholar We initially recommend avoidance of cold stimuli, keeping the extremities warm with additional clothing such as gloves, and the use of insulated drinking containers for cold beverages. For patients who are unsatisfied with this approach, we prescribe a low-dose, extended-release calcium channel blocker such as nifedipine 30 mg daily. Nifedipine can be titrated up to 90 mg daily for symptom reduction if tolerated and there are no contraindications such as hypotension or the concomitant use of hypertensive medications. We do not consider peripheral digital sympathectomy, arterial bypass, or temperature biofeedback treatment alternatives in patients with RD. Journal CME QuestionsJournal of Hand SurgeryVol. 39Issue 1Preview Full-Text PDF" @default.
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