Letters
Further prospective studies from a variety of practice settings that include comprehensive longitudinal follow-up are needed to clarify the age-related risk of CRC among elderly patients after surveillance colonoscopy. However, an equally important task is to better characterize the spectrum of agerelated risks as well as impact of surveillance on overall survival in the elderly population. We are grateful to Pinsky and Schoen for contributing their findings to the discussion. We hope that additional work will continue to provide much needed insight into this issue so that patients as well as clinicians can make more informed decisions regarding the risks and benefits of ongoing surveillance. Bechien U. Wu, MD, MPH Author Affiliation: Center for Digestive Health Research, Division of Gastroenterology, Kaiser Permanente Los Angeles Medical Center, Los Angeles, California. Corresponding Author: Bechien U. Wu, MD, MPH, Center for Digestive Health Research, Division of Gastroenterology, Kaiser Permanente Los Angeles Medical Center, 1526 N. Edgemont Ave, Los Angeles, CA 90027 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Pinsky PF, Schoen RE. Colorectal cancer incidence by age among patients undergoing surveillance colonoscopy [published online March 30, 2015]. JAMA Intern Med. doi:10.1001/jamainternmed.2015.0344. 2. Tran AH, Man Ngor EW, Wu BU. Surveillance colonoscopy in elderly patients: a retrospective cohort study. JAMA Intern Med. 2014;174(10):1675-1682.
LESS IS MORE
Insertion Site for Central Venous Catheters To the Editor I applaud the new series “Less Is More,” which highlights the concept of cost-conscious care in a concise, reader-friendly format. In their article demonstrating the costs associated with central venous catheters (CVCs), Patel et al1 suggest that an internal jugular vein site decreases the risk of infection compared with a subclavian vein site. Recognizably, the data on catheterrelated complications is plentiful but mostly not conclusive.2,3 Several confounders exist that confuse the picture and require that recommendations be made for specific scenarios (eg, medical vs surgical or trauma intensive care vs other hospitalized patients vs ambulatory patients; cancer vs noncancer patients; hemodialysis vs nonhemodialysis patients; implantable vs tunneled vs peripherally inserted catheters). In addition, the results might vary on the basis of different outcomes, ie, bloodstream infection, thrombosis, and venous stenosis. A meta-analysis using more recent data found that there was no appreciable difference in rates of infection with subclavian, internal jugular, or femoral site.2 A separate Cochrane Database Systematic Review also concluded that both subclavian and internal jugular vein sites were considered comparable in regard to the risk of infectious and mechanical or thrombotic complications.3 In view of these reviews, it might be appropriate to reconsider the risk of infection attributed to the insertion site. As recently shown, on average, 20% of physicians are unaware of their patients CVCs4; thus, it is important for clinicians to keep in mind the recommendation to use central cathjamainternalmedicine.com
eters only when absolutely necessary and for as short a period as required. In all, I agree with the authors that further research is needed in this area. Kleper N. F. de Almeida, MD Author Affiliation: Comprehensive Infectious Diseases, Wellington, Florida. Corresponding Author: Kleper N. F. de Almeida, MD, Comprehensive Infectious Diseases, 10115 Forest Hill Blvd, Ste102, Wellington, FL 33414 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Patel P, Aung H, Post J. Does my patient still need this central venous catheter? a teachable moment. JAMA Intern Med. 2014;174(11):1725-1726. 2. Marik PE, Flemmer M, Harrison W. The risk of catheter-related bloodstream infection with femoral venous catheters as compared to subclavian and internal jugular venous catheters: a systematic review of the literature and meta-analysis. Crit Care Med. 2012;40(8):2479-2485. 3. Ge X, Cavallazzi R, Li C, Pan SM, Wang YW, Wang FL. Central venous access sites for the prevention of venous thrombosis, stenosis and infection. Cochrane Database Syst Rev. 2012;3:CD004084. 4. Chopra V, Govindan S, Kuhn L, et al. Do clinicians know which of their patients have central venous catheters? a multicenter observational study. Ann Intern Med. 2014;161(8):562-567.
To the Editor Patel and colleagues1(p1726) wrote that central venous catheters should be placed in the internal jugular vein “which carries a lower risk of infection than the subclavian route.” This statement is unsubstantiated from studies published to date, and this is not the recommendation in recent guidelines.2,3 For shortterm, nontunneled central venous catheters inserted in the intensive care unit, our meta-analysis suggested that subclavian insertion is associated with a lower risk of infection.4 In addition, the anatomic site used to insert a port for administration of chemotherapy had no effect on infectious and noninfectious complications.5 Ultimately, decisions regarding which anatomic site to insert a central venous catheter depend on patient-specific risk factors (eg, obesity, bleeding diathesis, hyperinflation of the lungs), availability of ultrasound guidance, and experience of the inserter. Leonard A. Mermel, DO, ScM Jean-Jacques Parienti, MD, PhD Author Affiliations: Department of Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island (Mermel); Division of Infectious Diseases, Department of Epidemiology & Infection Control, Rhode Island Hospital, Providence (Mermel); Department of Biostatistics & Clinical Research, Côte de Nacre University Hospital Center, Caen, France (Parienti); Risques Microbiens, Faculté de Médecine, Université de Caen Basse-Normandie, Caen, France (Parienti). Corresponding Author: Leonard A. Mermel, DO, ScM, Division of Infectious Diseases, Department of Epidemiology & Infection Control, Rhode Island Hospital, 593 Eddy St, Providence, RI 02903 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Patel P, Aung H, Post J. Does my patient still need this central venous catheter? a teachable moment. JAMA Intern Med. 2014;174(11):1725-1726. 2. O’Grady NP, Alexander M, Burns LA, et al; Healthcare Infection Control Practices Advisory Committee. Guidelines for the prevention of intravascular catheter-related infections. Am J Infect Control. 2011;39(4)(suppl 1):S1-S34. 3. Marschall J, Mermel LA, Fakih M, et al; Society for Healthcare Epidemiology of America. Strategies to prevent central line–associated bloodstream infections in acute care hospitals: 2014 update. Infect Control Hosp Epidemiol. 2014;35(7): 753-771.
(Reprinted) JAMA Internal Medicine May 2015 Volume 175, Number 5
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a Florida International University Medical Library User on 05/13/2015
861
Letters
4. Parienti JJ, du Cheyron D, Timsit J-F, et al. Meta-analysis of subclavian insertion and nontunneled central venous catheter–associated infection risk reduction in critically ill adults. Crit Care Med. 2012;40(5):1627-1634. 5. Biffi R, Orsi F, Pozzi S, et al. Best choice of central venous insertion site for the prevention of catheter-related complications in adult patients who need cancer therapy: a randomized trial. Ann Oncol. 2009;20(5):935-940.
Further Insight Into the Cardiovascular Risk Calculator: Time to Rethink the Strategy? To the Editor The Original Investigation by Cook et al1 and the accompanying Invited Commentary2 in JAMA Internal Medicine outline problems with the process of developing the American College of Cardiology (ACC) and American Heart Association (AHA) Prevention Guidelines and with the associated cardiovascular disease (CVD) risk calculator. Overprediction of CVD risk by the ACC/AHA risk calculator has been demonstrated in the 3 validation cohorts used by guideline developers and in more contemporary data from the derivation cohorts.3 Now, using data from the Women’s Health Study, Cook et al1 have found that statin use, revascularization procedures, and underascertainment of events do not explain the discrepancies. While there may be problems with the way the US guidelines were developed, a more fundamental problem is the lack of a large, contemporary longitudinal data set representative of the US population. This would obviate the need to combine data from studies of varying age. In the United Kingdom (UK) there is now a CVD risk score, QRISK2, which has been derived from such a data set4 and has been approved as a “gold standard” by the National Institute for Health and Care Excellence. QRISK2 was derived from a nationally representative cohort of 2.3 million patients aged 35 to 74 years (>16 million person-years) with 140 000 CVD events and was extracted from the routine clinical data in electronic health records (EHRs) of UK general practice populations at minimal cost. QRISK2 can be updated rapidly as new risk factors emerge or others change, and risk scores are being produced for other diseases. Risk scores can be externally validated very rapidly using other research databases.5 Rather than devising ever more complex methods of combining data from expensive cohort studies, the US health care system should focus on (1) developing highquality EHRs from at least a representative sample of patient-centered medical homes as soon as possible and (2) using data from these EHRs to develop risk prediction tools as has been done in the UK.
3. Ridker PM, Cook NR. Statins: new American guidelines for prevention of cardiovascular disease. Lancet. 2013;382(9907):1762-1765. 4. Hippisley-Cox J, Coupland C, Vinogradova Y, et al. Predicting cardiovascular risk in England and Wales: prospective derivation and validation of QRISK2. BMJ. 2008;336(7659):1475-1482. 5. Collins GS, Altman DG. Predicting the 10 year risk of cardiovascular disease in the United Kingdom: independent and external validation of an updated version of QRISK2. BMJ. 2012;344:e4181.
Should the Term Coagulopathy in Cirrhosis Be Abandoned?
Michael Soljak, PhD Azeem Majeed, PhD
To the Editor The case reported by Roberts and Bambha1 regarding a 61-year-old woman with cirrhosis is of particular interest because it reflects the difficulty to face an old concept, which still continues to influence the clinical practice. This cirrhotic patient was planned for a surgical intervention and treated with a freshfrozen plasma because of a prolonged prothrombin time and a putative risk of bleeding. Such an approach was based on the common belief that cirrhosis is complicated by the so-called coagulopathy, which theoretically should increase the risk of bleeding. The term coagulopathy has been coined because of impaired clotting activation detected by laboratory tests in association with deterioration of liver function; the frequent coexistence of hyperfibrinolysis, low platelet count, and platelet dysfunction reinforced the concept that coagulopathy is associated with cirrhosis.2 This concept has been recently challenged for several reasons. The prolongation of global tests of clotting activation does not actually reflect hemostatic changes in vivo and may be a laboratory artifact.3 Also, cirrhotic patients actually disclose a tendency to a hypercoagulation state, which is related to endotoxemia and may be detected in both peripheral and portal circulation, and to an increased platelet activation.4,5 It is difficult to believe that under these circumstances patients with cirrhosis are at high risk of bleeding; thus, apart from gastrointestinal tract bleeding, which is independent from changes of clotting system, spontaneous bleeding in cirrhosis is rare.2 Conversely, in vivo data reporting the existence of platelet and clotting activation may explain the increased risk for thrombosis overall in portal circulation. This opens a new and challenging scenario as portal vein thrombosis, which may occur in approximately 20% of cirrhotic patients,2 should be treated with antithrombotic drugs. However, planning trials with anticoagulants in cirrhosis will be very difficult because the persistent concept of “coagulopathy in cirrhosis” is likely to be a barrier against the use of anticoagulants. For this reason, a consensus should be reached that cirrhosis is characterized by a tendency to thrombosis more than to bleeding and that the term coagulopathy is inadequate to depict the clinical picture of this setting.
Author Affiliations: Department of Primary Care & Public Health, Imperial College London, London, England.
Francesco Violi, MD
Corresponding Author: Michael Soljak, PhD, Department of Primary Care & Public Health, Imperial College London, St Dunstans Rd, Reynolds Building, Third Floor, London W6 8RP, England ([email protected]).
Author Affiliation: Department of Internal Medicine, Sapienza University, Rome, Italy.
Conflict of Interest Disclosures: None reported. 1. Cook NR, Ridker PM. Further insight into the cardiovascular risk calculator: the roles of statins, revascularizations, and underascertainment in the Women’s Health Study. JAMA Intern Med. 2014;174(12):1964-1971. 862
2. Nissen SE. Prevention guidelines: bad process, bad outcome. JAMA Intern Med. 2014;174(12):1972-1973.
Corresponding Author: Francesco Violi, MD, Department of Internal Medicine, Sapienza University, Viale del Policlinico, 155, 00161 Rome, Italy 00161 ([email protected]). Conflict of Interest Disclosures: None reported.
JAMA Internal Medicine May 2015 Volume 175, Number 5 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a Florida International University Medical Library User on 05/13/2015
jamainternalmedicine.com
Further prospective studies from a variety of practice settings that include comprehensive longitudinal follow-up are needed to clarify the age-related risk of CRC among elderly patients after surveillance colonoscopy. However, an equally important task is to better characterize the spectrum of agerelated risks as well as impact of surveillance on overall survival in the elderly population. We are grateful to Pinsky and Schoen for contributing their findings to the discussion. We hope that additional work will continue to provide much needed insight into this issue so that patients as well as clinicians can make more informed decisions regarding the risks and benefits of ongoing surveillance. Bechien U. Wu, MD, MPH Author Affiliation: Center for Digestive Health Research, Division of Gastroenterology, Kaiser Permanente Los Angeles Medical Center, Los Angeles, California. Corresponding Author: Bechien U. Wu, MD, MPH, Center for Digestive Health Research, Division of Gastroenterology, Kaiser Permanente Los Angeles Medical Center, 1526 N. Edgemont Ave, Los Angeles, CA 90027 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Pinsky PF, Schoen RE. Colorectal cancer incidence by age among patients undergoing surveillance colonoscopy [published online March 30, 2015]. JAMA Intern Med. doi:10.1001/jamainternmed.2015.0344. 2. Tran AH, Man Ngor EW, Wu BU. Surveillance colonoscopy in elderly patients: a retrospective cohort study. JAMA Intern Med. 2014;174(10):1675-1682.
LESS IS MORE
Insertion Site for Central Venous Catheters To the Editor I applaud the new series “Less Is More,” which highlights the concept of cost-conscious care in a concise, reader-friendly format. In their article demonstrating the costs associated with central venous catheters (CVCs), Patel et al1 suggest that an internal jugular vein site decreases the risk of infection compared with a subclavian vein site. Recognizably, the data on catheterrelated complications is plentiful but mostly not conclusive.2,3 Several confounders exist that confuse the picture and require that recommendations be made for specific scenarios (eg, medical vs surgical or trauma intensive care vs other hospitalized patients vs ambulatory patients; cancer vs noncancer patients; hemodialysis vs nonhemodialysis patients; implantable vs tunneled vs peripherally inserted catheters). In addition, the results might vary on the basis of different outcomes, ie, bloodstream infection, thrombosis, and venous stenosis. A meta-analysis using more recent data found that there was no appreciable difference in rates of infection with subclavian, internal jugular, or femoral site.2 A separate Cochrane Database Systematic Review also concluded that both subclavian and internal jugular vein sites were considered comparable in regard to the risk of infectious and mechanical or thrombotic complications.3 In view of these reviews, it might be appropriate to reconsider the risk of infection attributed to the insertion site. As recently shown, on average, 20% of physicians are unaware of their patients CVCs4; thus, it is important for clinicians to keep in mind the recommendation to use central cathjamainternalmedicine.com
eters only when absolutely necessary and for as short a period as required. In all, I agree with the authors that further research is needed in this area. Kleper N. F. de Almeida, MD Author Affiliation: Comprehensive Infectious Diseases, Wellington, Florida. Corresponding Author: Kleper N. F. de Almeida, MD, Comprehensive Infectious Diseases, 10115 Forest Hill Blvd, Ste102, Wellington, FL 33414 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Patel P, Aung H, Post J. Does my patient still need this central venous catheter? a teachable moment. JAMA Intern Med. 2014;174(11):1725-1726. 2. Marik PE, Flemmer M, Harrison W. The risk of catheter-related bloodstream infection with femoral venous catheters as compared to subclavian and internal jugular venous catheters: a systematic review of the literature and meta-analysis. Crit Care Med. 2012;40(8):2479-2485. 3. Ge X, Cavallazzi R, Li C, Pan SM, Wang YW, Wang FL. Central venous access sites for the prevention of venous thrombosis, stenosis and infection. Cochrane Database Syst Rev. 2012;3:CD004084. 4. Chopra V, Govindan S, Kuhn L, et al. Do clinicians know which of their patients have central venous catheters? a multicenter observational study. Ann Intern Med. 2014;161(8):562-567.
To the Editor Patel and colleagues1(p1726) wrote that central venous catheters should be placed in the internal jugular vein “which carries a lower risk of infection than the subclavian route.” This statement is unsubstantiated from studies published to date, and this is not the recommendation in recent guidelines.2,3 For shortterm, nontunneled central venous catheters inserted in the intensive care unit, our meta-analysis suggested that subclavian insertion is associated with a lower risk of infection.4 In addition, the anatomic site used to insert a port for administration of chemotherapy had no effect on infectious and noninfectious complications.5 Ultimately, decisions regarding which anatomic site to insert a central venous catheter depend on patient-specific risk factors (eg, obesity, bleeding diathesis, hyperinflation of the lungs), availability of ultrasound guidance, and experience of the inserter. Leonard A. Mermel, DO, ScM Jean-Jacques Parienti, MD, PhD Author Affiliations: Department of Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island (Mermel); Division of Infectious Diseases, Department of Epidemiology & Infection Control, Rhode Island Hospital, Providence (Mermel); Department of Biostatistics & Clinical Research, Côte de Nacre University Hospital Center, Caen, France (Parienti); Risques Microbiens, Faculté de Médecine, Université de Caen Basse-Normandie, Caen, France (Parienti). Corresponding Author: Leonard A. Mermel, DO, ScM, Division of Infectious Diseases, Department of Epidemiology & Infection Control, Rhode Island Hospital, 593 Eddy St, Providence, RI 02903 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Patel P, Aung H, Post J. Does my patient still need this central venous catheter? a teachable moment. JAMA Intern Med. 2014;174(11):1725-1726. 2. O’Grady NP, Alexander M, Burns LA, et al; Healthcare Infection Control Practices Advisory Committee. Guidelines for the prevention of intravascular catheter-related infections. Am J Infect Control. 2011;39(4)(suppl 1):S1-S34. 3. Marschall J, Mermel LA, Fakih M, et al; Society for Healthcare Epidemiology of America. Strategies to prevent central line–associated bloodstream infections in acute care hospitals: 2014 update. Infect Control Hosp Epidemiol. 2014;35(7): 753-771.
(Reprinted) JAMA Internal Medicine May 2015 Volume 175, Number 5
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a Florida International University Medical Library User on 05/13/2015
861
Letters
4. Parienti JJ, du Cheyron D, Timsit J-F, et al. Meta-analysis of subclavian insertion and nontunneled central venous catheter–associated infection risk reduction in critically ill adults. Crit Care Med. 2012;40(5):1627-1634. 5. Biffi R, Orsi F, Pozzi S, et al. Best choice of central venous insertion site for the prevention of catheter-related complications in adult patients who need cancer therapy: a randomized trial. Ann Oncol. 2009;20(5):935-940.
Further Insight Into the Cardiovascular Risk Calculator: Time to Rethink the Strategy? To the Editor The Original Investigation by Cook et al1 and the accompanying Invited Commentary2 in JAMA Internal Medicine outline problems with the process of developing the American College of Cardiology (ACC) and American Heart Association (AHA) Prevention Guidelines and with the associated cardiovascular disease (CVD) risk calculator. Overprediction of CVD risk by the ACC/AHA risk calculator has been demonstrated in the 3 validation cohorts used by guideline developers and in more contemporary data from the derivation cohorts.3 Now, using data from the Women’s Health Study, Cook et al1 have found that statin use, revascularization procedures, and underascertainment of events do not explain the discrepancies. While there may be problems with the way the US guidelines were developed, a more fundamental problem is the lack of a large, contemporary longitudinal data set representative of the US population. This would obviate the need to combine data from studies of varying age. In the United Kingdom (UK) there is now a CVD risk score, QRISK2, which has been derived from such a data set4 and has been approved as a “gold standard” by the National Institute for Health and Care Excellence. QRISK2 was derived from a nationally representative cohort of 2.3 million patients aged 35 to 74 years (>16 million person-years) with 140 000 CVD events and was extracted from the routine clinical data in electronic health records (EHRs) of UK general practice populations at minimal cost. QRISK2 can be updated rapidly as new risk factors emerge or others change, and risk scores are being produced for other diseases. Risk scores can be externally validated very rapidly using other research databases.5 Rather than devising ever more complex methods of combining data from expensive cohort studies, the US health care system should focus on (1) developing highquality EHRs from at least a representative sample of patient-centered medical homes as soon as possible and (2) using data from these EHRs to develop risk prediction tools as has been done in the UK.
3. Ridker PM, Cook NR. Statins: new American guidelines for prevention of cardiovascular disease. Lancet. 2013;382(9907):1762-1765. 4. Hippisley-Cox J, Coupland C, Vinogradova Y, et al. Predicting cardiovascular risk in England and Wales: prospective derivation and validation of QRISK2. BMJ. 2008;336(7659):1475-1482. 5. Collins GS, Altman DG. Predicting the 10 year risk of cardiovascular disease in the United Kingdom: independent and external validation of an updated version of QRISK2. BMJ. 2012;344:e4181.
Should the Term Coagulopathy in Cirrhosis Be Abandoned?
Michael Soljak, PhD Azeem Majeed, PhD
To the Editor The case reported by Roberts and Bambha1 regarding a 61-year-old woman with cirrhosis is of particular interest because it reflects the difficulty to face an old concept, which still continues to influence the clinical practice. This cirrhotic patient was planned for a surgical intervention and treated with a freshfrozen plasma because of a prolonged prothrombin time and a putative risk of bleeding. Such an approach was based on the common belief that cirrhosis is complicated by the so-called coagulopathy, which theoretically should increase the risk of bleeding. The term coagulopathy has been coined because of impaired clotting activation detected by laboratory tests in association with deterioration of liver function; the frequent coexistence of hyperfibrinolysis, low platelet count, and platelet dysfunction reinforced the concept that coagulopathy is associated with cirrhosis.2 This concept has been recently challenged for several reasons. The prolongation of global tests of clotting activation does not actually reflect hemostatic changes in vivo and may be a laboratory artifact.3 Also, cirrhotic patients actually disclose a tendency to a hypercoagulation state, which is related to endotoxemia and may be detected in both peripheral and portal circulation, and to an increased platelet activation.4,5 It is difficult to believe that under these circumstances patients with cirrhosis are at high risk of bleeding; thus, apart from gastrointestinal tract bleeding, which is independent from changes of clotting system, spontaneous bleeding in cirrhosis is rare.2 Conversely, in vivo data reporting the existence of platelet and clotting activation may explain the increased risk for thrombosis overall in portal circulation. This opens a new and challenging scenario as portal vein thrombosis, which may occur in approximately 20% of cirrhotic patients,2 should be treated with antithrombotic drugs. However, planning trials with anticoagulants in cirrhosis will be very difficult because the persistent concept of “coagulopathy in cirrhosis” is likely to be a barrier against the use of anticoagulants. For this reason, a consensus should be reached that cirrhosis is characterized by a tendency to thrombosis more than to bleeding and that the term coagulopathy is inadequate to depict the clinical picture of this setting.
Author Affiliations: Department of Primary Care & Public Health, Imperial College London, London, England.
Francesco Violi, MD
Corresponding Author: Michael Soljak, PhD, Department of Primary Care & Public Health, Imperial College London, St Dunstans Rd, Reynolds Building, Third Floor, London W6 8RP, England ([email protected]).
Author Affiliation: Department of Internal Medicine, Sapienza University, Rome, Italy.
Conflict of Interest Disclosures: None reported. 1. Cook NR, Ridker PM. Further insight into the cardiovascular risk calculator: the roles of statins, revascularizations, and underascertainment in the Women’s Health Study. JAMA Intern Med. 2014;174(12):1964-1971. 862
2. Nissen SE. Prevention guidelines: bad process, bad outcome. JAMA Intern Med. 2014;174(12):1972-1973.
Corresponding Author: Francesco Violi, MD, Department of Internal Medicine, Sapienza University, Viale del Policlinico, 155, 00161 Rome, Italy 00161 ([email protected]). Conflict of Interest Disclosures: None reported.
JAMA Internal Medicine May 2015 Volume 175, Number 5 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a Florida International University Medical Library User on 05/13/2015
jamainternalmedicine.com
