Bone Marrow has long been a delicacy reserved for the wealthy of ancient times. Decadent dishes served to royalty with special spoons to scoop up the precious gem of the innermost hidden treasure of animals was the subject of artists and even poets as they “sucked the marrow out of life.” Was this just an exercise in poetic justice, or was there some true benefit of enjoying this carnivorous treat? We went to the Wooden Spoon Restaurant in Brighton, Michigan (675 West Grand River, Brighton, MI) to find out.
Here they serve a roasted, smoked canoe sliced appetizer of bone beef bone marrow. They have been serving this appetizer as part of their rotating appetizer menu for a few years with many of their long term patrons praising the benefits of this tasty, tantalizing treat.
We met first with the head chef and partner, Steve Pilon who came up with the concept and he had his right hand Sous Chef Mason prepare this for us as we filmed the entire event. Here is the simple recipe:
Ask your local butcher to give you a “canoe cut” version of the femur of any cow cut in 1/3rds or 1/4th.
Place this bone side down to keep the precious bone marrow cargo protected from leaking out in the smoker for 20 minutes at a temp of about 250 degrees fahrenheit.
You can remove from the smoker and wrap and freeze if you wish or proceed to cook this in a 400 degree convection oven for 8 minutes on a cooking sheet. Make sure that the marrow is facing upward and cradled nicely by the bone edges. You do not want the marrow to run out onto the sheet. The marrow is done when it is bubbly, but not runny. You want it to be firm like a foam, but not a liquid .
Transfer carefully with the bone marrow side up onto a plate and garnish with a nice contrasting salad of arugula, grapefruit and blue cheese as well as some pickled onion on the side.
From a scientific standpoint, bone marrow is one of the most perfect fats to eat. This is the only part of the cow which is an unsaturated fat making it special in taste and dietary value. There are 0% trans-fats in bone marrow and it is also a source of a complete dietary protein. Some other great benefits of bone marrow is the fact that it contains Adioponectin which is something that not only gives marrow its unique flavor, but it can also help protect chronic diseases such as diabetes and cardiovascular disease. Apiopenectin also helps to break down other fats in our body and places a role in preserving our body’s vital nutrition during starvation or fasting. The collagen content of bone marrow also helps your digestive tract as well as helps make your skin look healthy. Overall, eating bone marrow is a way to obtain the perfect fat and there is no bones about that!
If you would like to schedule a visit to the Wooden Spoon Restaurant at 675 West Grand River, Brighton, MI , please call 810-588-4386. Open for lunch and dinner Mondays thru Saturday (always closed on Sundays!) If you would like to schedule a face to face appointment with Dr. Loniewski, please call 810-299-8552.
What is the Real Cost of Knee Joint Replacement Vs. Stem Cell Therapy?
Have you ever wondered what the real cost to your personal bottom line would be if you were scheduled for a joint replacement? What if the same time you were given the option to consider a stem cell procedure for that same knee? Although the joint replacement is a covered benefit of many insurance plans, everyone knows that there are always some part of the procedure not covered and you have to plan for lost wages. Thus, we have developed a simple exercise below to help you work out that difference in cost between the two options. To complete this exercise, you will need a copy of your health insurance plan to find out your deductibles and it would be helpful to have your employer benefits so you can find out if you have paid time off and your current balance in your health spending account.
Are you ready to do some real Jethro Bodine ciphering? Get out a pencil and some of your health insurance information.
Circle the total number of joints you need replaced: 1234
We need to determine your potential lost wages since this is an actual cost of the procedure. Are you currently working?
If yes, What Category of Work are you employed ?
Sedentary - clerical
Moderate - lifting under 30 lbs. , occasional squat or kneel
High- walking 8 hrs a day, constant stairs, squatting, kneeling and lifting over 30 lbs.
Not working - 0 weeks off work
Sedentary - 6 weeks off work for joint replacement
Moderate - 8 weeks off work for joint replacement
High- 12 weeks off work for joint replacement
Subtract 1 week to reconcile to a stem cell procedure ( ie sedentary 6 weeks -1 week = 5 weeks off). It normally takes a patient upto one week to recover after a stem cell procedure, although most patients can return to work the next day.
Write that number here: ___________________________
Select your rough estimate of income per week:
$500 to $1000
$1000 to $3000
$3,000 to $5000
Multiply the income per week by the level of work number ( ie $1,000 x 5= $5,000)
This is the amount of wages lost if you had your joint replaced. If you need two or more joints replaced, multiply this number by the number of joints ( ie $5,000 x 2 = $10,000)
LINE A: TOTAL INCOME LOST ______________________
Note- the above line may be reduced if you have paid time off or if you have some income replacement insurance. Please contact your human resource office for details.
Now lets calculate the insurance cost of the joint replacement.
What is your total maximum out of pocket deductible per year on your health insurance?
$4,000- $5,000 (most common)
$7,500 to $12,500
$12,500 or over
I do not know my maximum.
Write the Maximum Out of Pocket amount here: _____________________
If you do not know the maximum, we can get an idea by answering the following questions:
What is your annual deductible on your health insurance?
If you have co-insurance what is percentage ratio? The cost of a total joint is approximately $35,000
I have no co-insurance
90/10 (meaning the insurance pays 90% and you pay 10%)
80/20 - (*most common )
What are the co-pays for each physical therapy or doctor visit?
Add up each above and write down the estimated maximum here: _________
LINE B: Total Costs Not Covered : __________________________
If you have Medicare without secondary insurance, place in $7,000 since this is 20% of $35,000 .
Now let's find out if you can get reimbursed for any of these costs.
What is the amount in your yearly Health Spending Account (HSA)? Maximum is $3450 for individuals and $6,900 for families. If over 55, add in another $1,000.
I do not have an HSA
$2,000- $3,000 (most common)
LINE C: Total reimbursable in your HSA: ______________________
Your Total Cost of a total joint is determined with the following formula: Line A + Line B - Line C = Total Cost of Joint Replacement
Example: Johnny Joint has two bad knees which need to be replaced. He works at the local city government in the maintenance department and his job is high demand. He earns $750 per week in gross wages and he has a total maximum out of pocket cost of $3,000 and has a health spending account of $2,500 but he already spent $500 on medications. What would Johnny’s cost be for replacing his joints this year :
Line A= $750 x 11= $9,000 lost wages
Line B= $3,000 max out of pocket costs
Line C = $2,000 HSA
Johnny Joint Cost for his single knee replacement this year = $9,000 + $3,000 - $2,000= $10,000
If Johnny has both knees replaced he might get lucky and have this done within the same year. Most patients have the other knee done after one year. But, even if he did have this done in the same year, the cost would be the following:
Line A = $9,000
Line B = $0
Line C = $0
The total cost would be : $9,000 +$0 - $0 = $9,000
Johnny’s total cost for both knee replacements would be $19,000
Compare this to the cost of a stem cell procedure which would be the following.
Stem Cell Procedure cost example :
The average cost for a stem cell procedure for both knees is $6,000
Most health spending accounts allow reimbursements for procedures deemed medically necessary and thus, Johnny could deduct $2,000 from this total to bring the cost down to $4,000
The net difference between Johnny having both knees replaced vs a stem cell procedure would be : $19,000 - $4,000 = $15,000! and “you can take that to the bank” as Jethro would say to Mr. Drysdale.
Do Some Cipering Yourself
Cost of Joint Replacement =
Line A _________+ Line B _________ - Line C ___________
Cost of Stem Cell Procedure (advanced level of cell therapy) =
$4,000 for one joint $6,000 for two joints - Line C________________
Write Total Joint Cost Here: ____________________________
Subtract Total Joint Cost from Stem Cell to find how much you may save and
write this amount Here: _____________________________________
This amount may change depending upon a few circumstances such as the choice of our ultimate plan; the need for an arthroscopic procedure; or the desire for a general anesthetic at a local surgical center.
If you would like a face to face conversation with Dr. Loniewski, call 810-299-8552 for an appointment.
Are Stem Cells Better Than Most Common Treatments for Knee Pain?
Some of the most convincing evidence for the use of stem cell therapy exists for arthritis of the knee. While we can’t comment much on the use of stem cells for arthritis in other joints, each joint manifests unique results in our clinical practice, with knees showing particularly beneficial outcomes.
What’s the Evidence Stem Cells work for knee arthritis?
First, let us look at literature which illustrates a series of cases as a “proof of concept” type of study. Dr. Chris Centeno developed a method of using bone marrow derived stem cells through his patented and marketed Regenexx™ stem cell clinics, which are based in Colorado. Dr. Centeno published his findings from his patient registry evaluations, wherein he looked at 373 patients who received this treatment in the form of an injection into the osteoarthritic knee. He examined these patients at one, three, and six month intervals, as well as once a year. Over this period of time, Dr. Centeno found that all his patients showed improvements in pain and function, and that the severity of the arthritis did not have an impact on the outcome.There is, however, a problem with such a study: it does not compare the treatment in question against another form of treatment, allowing us to determine which treatment may be a better choice.
Stem Cells Better than Hyaluronic Injections (Chicken Fat)
If we now compare the results of bone marrow derived stem cells to commonly accepted non-surgical treatments for osteoarthritis of the knee, we can start to evaluate which treatment is superior.
Spanish researchers performed such a study when they compared cultured bone marrow stem cells to a commonly treatment called Hyaluronic Acid (sometimes known in the United States as rooster injections or chicken fat injections to the knee). Hyaluronic injections are a very common form of treatment in the United States; over 4 million of these injections are given each year, and it is a commonly accepted and covered treatment by many health insurance carriers. These Spanish researchers compared a form of cultured bone marrow stem cells taken from a separate individual, and injected it into the knee of patients. Another group received the standard single injection of hyaluronic injection. Both sets of patients were followed for a year, being monitored with surveys and an MRI.
At the end of one year, the stem cell recipient patients showed significantly lower pain scores and higher functionality scores. In addition, the group that received the stem cell treatment had improved MRI findings.
Stem Cells Better than Arthroscopy and Micro-fracture.
If we compare bone marrow derived cells to commonly accepted surgical treatments for arthritis, we also find some interesting results. One common surgical treatment used to treat isolated areas of arthritis of the knee is to debride, scrape, or puncture holes in the areas where there is exposed bone. (This action can only be done in patients who have good cartilage surrounding the worn area.) These techniques were made very popular for professional athletes suffering from high impact trauma. The original form of this surgery was developed in Okemos, Michigan by Dr. Lanny Johnson, who invented most of our modern arthroscopic procedures.
The procedure was further promoted by Dr. Steadman at the famous Vail Clinic. This updated procedure poked or drilled small holes within the exposed bone in hopes that this would allow stem cells from the bone of the knee to fill in the space, stimulating healing. This method is currently known as a micro-fracture technique. However, this procedure involved a degree of pain, as the small breaks require the patient to maintain a very strict adherence to limited weight bearing.
Dr. Koh from South Korea’s Center for Stem Cell and Arthritis Research decided to compare the results of stem cells taken from fat and fixed with a special type of fibrin glue to a micro-fractured area of the knee, and compare this to a standard microfracture technique. He followed over 40 patients in each group for over two years. During this time, he not only compared their MRI’s, but also was able to perform a visual arthroscopic examination and biopsy of most of the participants in the study - 57 of the 80 patient, to be exact. Dr. Koh and his research group discovered that patients who received the stem cells and micro-fracture had statically significant improvement in their pain scores (36 vs. 30-point improvement), as well as improved MRI findings, with 65% of the patients in the stem cell group showing complete cartilage coverage vs. 45% in the non-stem cell group. Note that this study used cultured, fat-derived stem cells, and therefore results should be viewed with caution, particularly when being compared to bone marrow.
Dr. Lisa Fortier from Cornell, a veterinary physician, performed a series of studies evaluating the use of the same type of bone marrow we use for knees and its effect on horses. One interesting study of her’s evaluated using a simple injection of bone marrow concentrate versus performing the microfracture surgery in horses. Dr. Fortier and her team followed the horses with sequential MRI studies after one year, and discovered that the bone marrow group had improved findings in the area of the bone next to the injury, as well as the tissue textures.
Stem Cells Better than Most Surgeries for Knee Arthritis
Another commonly used treatment for arthritis is called a high tibial osteotomy, abbreviated HTO. This procedure corrects the bow of the knee joint and helps to restore it to natural alignment. During the procedure, the shin or femur bone is cut and moved over to correct the bow. Dr. Wong and his research team in Singapore evaluated the effects of cultured (grown) stem cells on improving the outcome of this surgery for osteoarthritic knees. Fifty-six patients were randomly assigned to receive stem cells and hyaluronic injection, while others were given the hyaluronic injection alone three weeks after their corrective bone procedure. Both groups were followed for over two years, with follow-up MRI’s performed at the one year mark. In the end, the patients who received the cultured stem cells had improved pain and function scores, as well as improved MRI findings. A follow up study conducted in Italy found similar positive results.
Researchers in Singapore performed another study evaluating if surgery is even necessary for cartilage defects of the knee. The very first cartilage cell procedure approved by the FDA was named Autologous Chondrocyte Implantation (ACI). Surgeons would harvest, or sample, some cartilage from a patient during the patient’s first surgery. This sample would then be sent to a company in Boston, where the team would culture and expand only the cartilage cells. Afterward, the cells would be shipped back to the surgeon; a second surgery would be performed upon which the patient’s knee is opened up and a pouch is made from the covering of the shin bone, then glued to create a small pouch where the cultured cells are injected.
This process would require two surgeries and prolonged sessions of physical therapy. Because of this, the researchers proposed they simply inject stem cells rather than requiring the patient to undergo two prolonged surgeries.
Seventy-two patients were placed into one of two test groups. The first group comprised of thirty-six patients, and all received the two stage ACI surgery. The second group consisted of thirty-six patients as well, and all received a single injection of bone marrow derived stem cells. Both groups of patients were then followed for two years. Both groups showed significant improvements in outcome; however, the two stage ACI surgery group did not show improvement if the patient was above the age of 45, while age made no difference for the stem cell injection group.
Researchers in Jabalpur, India were curious if they could improve the results of a very common surgery used to treat arthritic knees with mechanical symptoms such as meniscus tears (cartilage ring tears). Arthroscopy is a minimally invasive procedure using a mini fiber optic camera to look within the knee and treat common conditions such as a tear or loose pieces of cartilage. The researchers divided fifty patients into two groups. Group A received the standard arthroscopic procedure and group B received the arthroscopic procedure, but also received some bone marrow derived stem cells. The stem cell group B had improved quality of life as well as reduced pain.
What???? Stem Cells are Better than Knee Replacement!!!
Now, what about comparing stem cell therapy to one of our best-known treatments for arthritis of the knee - knee replacement surgery? Knee replacement surgery is a very reliable and durable method of relieving the pain and dysfunction of arthritis; in fact, the American Academy of Hip and Knee Surgeons (AAHKS) reports that over 90% of patients have relief of pain and over 80% of these patients have the same joint replacement in place over 20 years from the time of their surgery.
Although 90% of patients experience pain relief, this does not quantify the degree of the pain relief - for example, most patients may receive pain relief, but a portion of this 90% may only receive ten to twenty percent reduction of their pain, which is not satisfactory. Because of this, we must look at the whole group of joint replacement patients. When we look at this whole group, we find that twenty-seven to thirty percent of the patients are dissatisfied with this joint replacement. These findings were also discussed in a review article by researchers at Bristol University, UK.
Dr. Loniewski has personally replaced over 5,000 joints in his career, and can confirm that this is a good option for patients who have severe deformity of the knee. However, the knee replacement procedure does has some concerns. The first is the potential complication rates.
A review of over 160,000 patients through a national database by researchers from Rush University in Chicago found that the 30-day complication rate form both hip and knee replacement was 16%. Patients over the age of 70 or with histories of malnutrition, diabetes, cardiac disease, and smoking had higher risks.
Other than the higher complication rate, potential patients should consider the inconvenience of a joint replacement surgery. Although some joint replacements can be done in a minimally invasive manner and some patients can have this done as an outpatient, there is still the simple fact that the knee is maximally manipulated with the cutting of bone and the release of ligaments, as well as the implantation of foreign metal and plastic. For this reason, even with our modern minimally invasive techniques, patients still require 24/7 around-the-clock care for a minimum of two weeks; most require three weeks.
Following surgery, patients cannot drive their cars, shop, or enjoy a night out while the knee heals. They are recommended to attend physical therapy at least twice a week for a minimum of three weeks. You the patient cannot return to work (even sedentary types of work) for these same three weeks, and any moderate or high demand types of work (food service, factory) must be put on hold for up to three months. There is also the need for narcotic medications as well as medications to prevent blood clots.
Finally, these procedures normally only treat one knee at a time, meaning patients may have to repeat the treatment within the same year.
Phillipe Hernigou, MD from the University of Paris recognized the shortcomings of joint replacement as well as the benefits of bone marrow derived stem cell therapy and decided to compare the two treatments in some well-designed long term studies. He first looked at using this treatment for young patients who traditionally required joint replacement for a devastating type of arthritis of the knee called avascular necrosis - a condition where the blood supply to the bone around the knee is diminished, and the result is death of the bone and cartilage.
This condition normally occurs in younger patients during the third and fourth decades of life. The thought of replacing a knee in such a young group is concerning since most joint replacements have a limited life expectancy, while younger patients will likely have multiple joint surgeries in the future. His research team decided to evaluate the use of autologous bone marrow derived stem cell therapy injected into the diseased bone near the joint to treat this condition and compare it to traditional joint replacement in the same patient. Thirty patients with an average age of twenty-eight were randomized to receive a stem cell replacement to one knee and a joint replacement to the other knee.
The randomization process eliminated bias in selecting the less severe knee for one specific treatment. All the patients were followed for an amazing twelve years of average follow up. MRI’s were performed prior to the surgery and again at 24 months, five years, and at the last follow-up visit. X-rays were also reviewed and compared to the initial study. Samples of bone marrow were taken at specific sites in the arthritic knee as well as the pelvis where the bone marrow was harvested. The surgical procedure to replace the knee took an average 1.5 times longer than the entire stem cell procedure on the other knee.
After the surgery, patients reported a higher rate of blood clots on the side which received the knee replacement (15% vs. 0%). At the last follow up, six of the thirty knees (20%) with the knee replacement required another surgery, while only three of the stem cell knees (10%) required a knee replacement - but at longer periods out of six, eight and twelve years from the stem cell procedure. The patients recorded their satisfaction with each knee.
The knee replacement group showed eight of thirty (26%) reporting excellent pain relief, and the stem cell side reported four of thirty (13.3%); but there were a much higher number of patients in the poor pain relief after the knee replacement, with four out of thirty (13.3%) and only one out of thirty (3%) from the stem cell side. Most importantly, however, is that when patients were asked to point to the knee they preferred more, 70% of patients pointed to the stem cell side!
When Dr. Hernigou evaluated the sequential MRIs of the stem cell treated knee, he found that there was an increase in cartilage volume as well as a significant decrease in the size of the bone marrow lesion (BML), which is an area of inflamed bone and a cause of pain. Even when some of the stem cell knees required a joint replacement, sampling of the bone and cartilage revealed that the patients who had a poor response still had an average 45% increase in bone mass and required a less invasive type of knee replacement than the other side. In addition, none of the stem cell knees that required a knee replacement required further surgeries.
Dr. Hernigou’s team also looked at treating the very elderly with the same treatment. This study comprised of sixty elderly male patients all 85 years old or older. Group A was treated with the standard total knee replacement for both knees., while Group B was treated with the bone marrow stem cells to both knees injected directly into the bony part of the knee next to the joint. Group C had one knee injected with the stem cells, and the other knee replaced. After an average of six years (ranging from two to fifteen years), the patients in Group B (stem cell group) showed the following:
Improved knee function scores (Knee Society Scores).There was a 16.3-point improvement for the stem cell group versus only an 8.9-point improvement for total knee group.
Faster functional recovery- At 9 months, the stem cell group had faster recovery than the total knee group.
Lower complication rates. Blood clots occurred in only 2% of the stem cell group compared to 12% in the knee replacement group. None of the stem cell patients required a blood transfusion, and 29.3% of the total knee group required blood transfusions.
Higher use of analgesic medicationssuch as narcotics were used in the total knee group.
Lower re-operation rate. Only one of the stem cell patients required further surgery or conversion to a total knee. However, 5% of the total knee patients required further surgery.
Higher overall satisfaction. In Group C, when patients were asked to point to the knee which they preferred, 70% of the patients pointed to the stem cell therapy knee.
It is very interesting that Dr. Hernigou has been able to demonstrate that cell based treatments help the two most vulnerable populations affected by arthritis of the knee. Both the very young and the very old may benefit from this treatment with superior safety, efficiency and patient satisfaction.
Here is what we learned today: Stem Cell Therapy for Knees Have Proof that they have superior results to:
Not only is this therapy superior in results to the most commonly used treatments, it is safer and less expensive.
If you would like a face to face consultation with Dr. Loniewski to discuss your knee pain and the options available, please call 810-299-8552 for an appointment.
1 - Safety of Cell Therapy with Mesenchymal Stromal Cells (SafeCell): A Systematic Review and Meta-Analysis of Clinical Trials. Lalu MM, McIntyre L, Pugliese C, Fergusson D, Winston BW, Marshall JC, Granton J, Stewart DJ, Canadian Critical Care Trials Group. PLoS ONE. 2012 Oct 25; 7(10): e47559 PMC [article] PMCID: PMC3485008 PMID: 23133515 DOI: 10.1371/journal.pone.0047559
2 - Cancer risk is not increased in patients treated for orthopaedic diseases with autologous bone marrow cell concentrate. Hernigou P, Homma Y, Flouzat-Lachaniette CH, Poignard A, Chevallier N, Rouard H. J Bone Joint Surg Am. 2013 Dec 18;95(24):2215-21. doi: 10.2106/JBJS.M.00261. PubMed [citation] PMID:24352775
3 - A dose response analysis of a specific bone marrow concentrate treatment protocol for knee osteoarthritis. Centeno CJ, Al-Sayegh H, Bashir J, Goodyear S, Freeman MD. BMC Musculoskeletal Disorders. 2015 Sep 18; 16: 258 PMC [article]
4 - Treatment of Knee Osteoarthritis With Allogeneic Bone Marrow Mesenchymal Stem Cells: A Randomized Controlled Trial. Vega A, Martín-Ferrero MA, Del Canto F, Alberca M, García V, Munar A, Orozco L, Soler R, Fuertes JJ, Huguet M, Sánchez A, García-Sancho J.
Transplantation. 2015 Aug;99(8):1681-90. doi: 10.1097/TP.0000000000000678. PMID: 25822648
5 - Adipose-Derived Mesenchymal Stem Cells With Microfracture Versus Microfracture Alone: 2-Year Follow-up of a Prospective Randomized Trial. Koh YG, Kwon OR, Kim YS, Choi YJ, Tak DH. Arthroscopy. 2016 Jan;32(1):97-109. doi: 10.1016/j.arthro.2015.09.010. Epub 2015 Nov 14. PMID:26585585
6 - Minimally Manipulated Bone Marrow Concentrate Compared with Microfracture Treatment of Full-Thickness Chondral Defects: A One-Year Study in an Equine Model. Chu CR, Fortier LA, Williams A, Payne KA, McCarrel TM, Bowers ME, Jaramillo D. J Bone Joint Surg Am. 2018 Jan 17;100(2):138-146. doi: 10.2106/JBJS.17.00132. PMID: 29342064
7 - Injectable cultured bone marrow-derived mesenchymal stem cells in varus knees with cartilage defects undergoing high tibial osteotomy: a prospective, randomized controlled clinical trial with 2 years' follow-up. Wong KL, Lee KB, Tai BC, Law P, Lee EH, Hui JH. Arthroscopy. 2013 Dec;29(12):2020-8. doi: 10.1016/j.arthro.2013.09.074. PubMed [citation] PMID:24286801
8 - Combination of High Tibial Osteotomy and Autologous Bone Marrow Derived Cell Implantation in Early Osteoarthritis of Knee: A Preliminary Study. Cavallo M, Sayyed-Hosseinian SH, Parma A, Buda R, Mosca M, Giannini S. Archives of Bone and Joint Surgery. 2018 Mar; 6(2): 112-118 PMC [article]PMCID: PMC5867354 PMID:29600263
9 - Autologous bone marrow-derived mesenchymal stem cells versus autologous chondrocyte implantation: an observational cohort study. Nejadnik H, Hui JH, Feng Choong EP, Tai BC, Lee EH. Am J Sports Med. 2010 Jun;38(6):1110-6. doi: 10.1177/0363546509359067. Epub 2010 Apr 14. PubMed [citation] PMID: 20392971
10 - The new avenues in the management of osteo-arthritis of knee--stem cells. Varma HS, Dadarya B, Vidyarthi A. J Indian Med Assoc. 2010 Sep;108(9):583-5. PubMed [citation] PMID:21510531
11 - A review of the clinical approach to persistent pain following total hip replacement. Lam YF, Chan PK, Fu H, Yan CH, Chiu KY.
Hong Kong Med J. 2016 Dec;22(6):600-7. Epub 2016 Oct 31. Review. PubMed [citation]
12 - Total knee replacement: is it really an effective procedure for all?
Wylde V, Dieppe P, Hewlett S, Learmonth ID. Knee. 2007 Dec;14(6):417-23. Epub 2007 Jun 26. Review. PubMed [citation] PMID: 17596949
13 - Complications Following Outpatient Total Joint Arthroplasty: An Analysis of a National Database.
Courtney PM, Boniello AJ, Berger RA. J Arthroplasty. 2017 May;32(5):1426-1430. doi: 10.1016/j.arth.2016.11.055. Epub 2016 Dec 14. PubMed [citation] PMID: 28034481
14 - Subchondral stem cell therapy versus contralateral total knee arthroplasty for osteoarthritis following secondary osteonecrosis of the knee.
Hernigou P, Auregan JC, Dubory A, Flouzat-Lachaniette CH, Chevallier N, Rouard H.
Int Orthop. 2018 Mar 27. doi: 10.1007/s00264-018-3916-9. PubMed [citation] PMID: 29589086
15 - Benefits of small volume and small syringe for bone marrow aspirations of mesenchymal stem cells. Hernigou P, Homma Y, Flouzat Lachaniette CH, Poignard A, Allain J, Chevallier N, Rouard H. Int Orthop. 2013 Nov;37(11):2279-87. doi: 10.1007/s00264-013-2017-z. Epub 2013 Jul 24.PubMed [citation] PMID: 23881064 PMCID: PMC382489
16 - Autologous conditioned serum for the treatment of osteoarthritis and other possible applications in musculoskeletal disorders. Frizziero A, Giannotti E, Oliva F, Masiero S, Maffulli N. Br Med Bull. 2013;105:169-84. doi: 10.1093/bmb/lds016. Epub 2012 Jul 4. Review. PubMed [citation]PMID:22763153
17 - Subchondral stem cell therapy versus contralateral total knee arthroplasty for osteoarthritis following secondary osteonecrosis of the knee. Hernigou P, Auregan JC, Dubory A, Flouzat-Lachaniette CH, Chevallier N, Rouard H. Int Orthop. 2018 Mar 27. doi: 10.1007/s00264-018-3916-9. [Epub ahead of print] PubMed [citation] PMID: 29589086
Four Reasons to Use Board Certified Orthopedic Surgeons over Health Spas
Heath Spa - Where are the Doctors?
Board Certified Orthopedic Surgeons
By: Edward G. Loniewski, DO, FACOS, FAOAO
In our area which is around the Detroit, Michigan area of Southeastern Michigan there are health spas offering stem cell therapy. Many health spas are wonderful facilities for a massage, manicure, liposuction, hair plugs or even a facial. However, they may not be the best place for a stem cell therapy for arthritis. There are four major reasons.
#1 Proper Diagnosis - Physicians at health spas are more than likely wonderful and nice physicians who are the jack of all trades, yet the master of none!. They might be very experienced recognizing and treating common skin and hair conditions, but they are not board certified and fellowship trained specialists in arthritis. Thus, making the correct diagnosis of your joint as well as the joint above and below is critical to administering the correct treatments. If they miss commonly seen conditions such as pes anserinus bursitis of the knee or even a simple medial meniscus tear, your stem cell outcome will be compromised by this misdiagnosis. Board certified and fellowship trained orthopedic surgeons specializing in joint conditions have at least 6 to 10 years more experience than practitioners at a health spa. You have to make the right diagnosis first to recommend the right treatment.
#2 Proper Delivery and Customized Treatments - Injecting the cells into the correct area using the correct delivery system is critical to your outcome. Most health spa physicians have great experience injecting wrinkles or crows feet, but they have little experience injecting into and around major joints of the body such as your knee, shoulder and hip. Not only do they have limited experience injecting these joints, they have even less experience using the right type of needle, technique and imaging tools such as ultrasounds to ensure the therapy is injected into the correct area.
#3 Recognizing Complications - Although complications with cell based therapies are very rare, they can happen. If an infection does occur to a joint or tendon, many physicians in a medical spa will quickly refer you to an emergency room where they will call a board certified orthopedic surgeon to come in and treat this complication. Also, should you develop a meniscus tear or ligament tear, this is something a physician at a health spa can not and should not handle. Thus, we can recognize and treat any complications if they should arise.
#4 Customized Dosing - Many health spas use the same formula and dosing for a face lift as they do for arthritis of the knee. We know that the dosing of cell based therapies for rotator cuff problems of the shoulder is a totally different dosing than for arthritis of the knee. However, a medical spa will use the same dosing and technique they use for a facial treatment to your knee. Again, the jack of all trades and yet the master of none.
So, although health spas make us all feel and look good, they may not be the best place to go for treatment of your arthritis or joint ,ligament, muscle or tendon problems. At Advancedortho.net we are board certified and fellowship trained orthopedic surgeons specializing in proper diagnosis; delivery and continued treatment of orthopedic joint, tendon, ligament and bone problems. This is what we do all the time so let us do what we do the best. These are your cells for your healing delivered by a clinic who specializes in joint and tendon problems. Call 810-299-8550 for a proper evaluation and treatment plan now.
There are two major reasons to use bone marrow as the source of stem cells:
This is the only source of stem cells allowed by the FDA
This is the most comprehensive stem cell treatment
The FDA ruled on the use of cell based therapies in November of 2017 and autologous bone marrow-derived stem cells were determined to be both homologous and minimally manipulated and thus allowed for use in conditions such as arthritis. You can read the report here . What this means in plain English is that the cells taken from your own bone marrow are safe because they are not changed or manipulated in a dangerous manner, and they are placed back into an environment which is like the place they were taken (homologous). Only bone marrow cells can lay this claim. Cells taken from fat or from other humans or placental tissue are deemed to be in violation of the FDA regulations. This is because they are manipulated and changed as well as being placed in an area where they are not naturally found in the human body.
The other reason why we use bone marrow cells is because it provides the complete package for restoring the normal balance between damage and repair. This is not just stem cells. Bone marrow provides important plasma proteins and growth factors. One of the most important components of the cell based therapy are the proteins which help prep the area for cell health. Bone marrow or plasma contains these important proteins which help reduce harmful chemicals and encourage cell growth. Bone marrow also contains many of the growth factors found in platelet rich plasma but in higher concentrations. These growth factors help fertilize the field so the native stem cells can function properly. Thus, bone marrow or platelet rich plasma therapy is the only compressive and legal cell therapy providing all the right stuff.
Cost Effective Alternatives to Supartz or Chicken Fat Injections
As of April 1, 2018, Blue Cross and Blue Shield of Michigan will no longer cover any hyaluronic acid injections for arthritis. This includes injections better known as Supartz, Synvisc, Effflexa or sometimes referred to as roster comb and/or chicken fat injections. Medicare and Blue Cross products covering Medicare will still cover these injections. The rationale is not due to any adverse reactions or increasing cost of the injections, but rather due to a recommendation from the American Academy of Orthopedic Surgeons. Without insurance reimbursement, these treatments can cost up to $1600 which is a terrible burden for our patients. However, Advanced Orthopedic Specialists and Dr. Edward G. Loniewski have come up with some very cost effective treatment alternatives that are more effective, safer and less time consuming than the current hyaluronic injection series.
In summary, we have the following cost effective options:
• Platelet Rich Plasma (PRP) injections – This uses the healing growth factors of your own blood to relieve pain and restore function better than hyaluronic injections with just one treatment.
• Homeopathic Traumeel and Zeel Injections- Imported from Germany and clinically proven to reduce pain without any known side effects. Three injections given one week apart.
• Joint Builder Ultra- This special combination of oral hyaluronic acid, glucosamine, boswellia and MSM provide relief of pain.
• Multi-Waved Locked System (MLS) Laser- Medical grade dual laser therapy to reduce inflammation and pain without any injection or side effects.
Please contact our office at 810-299-8550 for the most current pricing.
This blog will focus on homeopathic injections as an alternative:
Homeopathic Injections- Samuel Hahnemann brought the idea that “like cures like” to the modern world in the early 1800’s and this was so popular by the late 1800’s that the University of Michigan opened its own homeopathic college in 1891. Homeopathy fell on hard times when many medical journals and standard medical organizations refused to recognize this form of medicine as legitimate theory.
However, this may change soon with the release of some recent studies by such institutions such as the Case Medical Center and the University of Miami. In addition, some basic science studies now show some significant positive biologic changes occurring with these preparations. The first study compared a homeopathic preparation called Zeel to two traditional arthritis medication called Celebrex (celcoxib) and Vioxx (refacoxib). Although there are some flaws in the design of the controls of this study and no use of a placebo, it did conclude that there was no statistical superiority of any of the medications in the treatment of mild to moderate arthritis of the knee. This meant that the homeopathic preparation performed just as effectively as two traditional medications The MOZArT study helped justify this concept by putting together a blinded and placebo controlled study conducted in the United States at Case Hospitals in Cleveland. Over 252 patients between the ages of 45-80 with moderate to severe osteoarthritis of their knee were enrolled to either receive 3 injections of Traumeel/ Zeel combination or a placebo of saline. They received one injection per week for 3 weeks. They completed pain and function scores as well as 50-foot walking test and a global physician assessment. Patients were accessed about every 2 weeks for 99 days. The homeopathic injection group with Traumeel and Zeel had statically significant improvements in all parameters.
Another interesting study evaluated the biochemical effect of Traumeel in vitro (in a test tube) on human T-Cells and gut epithelial cells. The researchers at The Center for Integrative Complementary Medicine in Jerusalem, Israel found that Traumeel had a profound effect on the pro-inflammatory production of Interleukin 1-beta (IL-1B), Tumor Necrosis Factor-alpha ( TNF-a) and Interleukin-8 ( IL-8). Traumeel reduced these toxic, inflammatory byproducts of cells by 50-70% in both active and resting cells and this effect had an inverse relationship to the concentration of the product thus proving the long-held concepts of homeopathy. In plain English this means that the homeopathic preparation dramatically reduced harmful biochemical markers which are important in the treatment of arthritis. These pro-inflammatory products especially Interleukin-1 beta are extremely important in joint homeostasis or the restoration of normal biochemical function of the knee. In addition, it appears that Traumeel has further effects on the activation of biochemical pathways which help with the repair of a damaged joint. Researchers at the University of Leipzig found that exposing chondrocytes (cartilage cells) to Traumeel caused an elevation of Transforming Growth Factor – Beta (TGF-B) as well as stimulating the basic function of cartilage cells while also reducing harmful chemicals called Matrix Metalleoproteinases (MMP-13). This study helped to solidify the previous study and it revealed that this homeopathic solution not only stimulated positive effects on cartilage cells, but also helped protect these cells.
Traumeel is a botanical mixture of approximately 14 biologic minerals and is designed for short term pain relief of inflammation caused by trauma, or arthritis. It can be used orally, topically or as an injection into a joint. Zeel is also a botanical mixture of 14 biologic minerals in differing dosing to provide longer term relief of pain caused by an arthritic joint and is proposed to slow down the degenerative process of arthritis. These preparations have been used by practitioners in Germany and Austria for over 30 years with excellent safety profiles.
A combination of just 2 cc of Traumeel and 2 cc of Zeel with 1-2 cc of standard local anesthetic can be injected into almost any arthritic joint with little need for any time off work or activities. Most patients notice changes beginning after the second injection and most notice relief for at least 3-6 months. The injections of Traumeel and Zeel do not interfere with other medications, nor cause any changes in blood sugars which is a problem with corticosteroid injections. The injections can be safely injected into tendons or ligaments without fear of rupture or destruction. The treatments can also be repeated without concerns about resistance or further damage to the joint surface.
Because these are botanical minerals and they are diluted beyond a traditional pharmaceutical product, the prices are naturally lower. This is much lower than platelet rich plasma or even hyaluronic injections. Because this natural botanical preparation does not produce harmful effects on cellular preparations, this can be safely used in patients receiving stem cell or PRP injections for faster pain relief while helping to restore the normal biochemical environment of an arthritic joint. Advanced Orthopedic Specialists is excited to offer this option to our patients as we continually strive to provide “state of the art care in a friendly environment.” If you are interested in scheduling an appointment with Dr. Edward Loniewski to discuss this natural and cost effective treatment, call 810-299-8550 as we are always happy to help.
Cost Effective Alternatives to Supartz or Chicken Fat Injections
As of April 1, 2018, Blue Cross and Blue Shield of Michigan will no longer cover any hyaluronic acid injections for arthritis. This includes injections better known as Supartz™, Synvisc™, Effflexa™ or sometimes referred to as roster comb and/or chicken fat injections. Medicare and Blue Cross products covering Medicare will still cover these injections. The rationale is not due to any adverse reactions or increasing cost of the injections, but rather due to a recommendation from the American Academy of Orthopedic Surgeons. Without insurance reimbursement, these treatments can cost up to $1600 which is a terrible burden for our patients. However, Advanced Orthopedic Specialists and Dr. Edward G. Loniewski have come up with some very cost effective treatment alternatives that are more effective, safer and less time consuming than the current hyaluronic injection series.
In summary, we have the following cost effective options:
Platelet Rich Plasma (PRP) injections – This uses the healing growth factors of your own blood to relieve pain and restore function better than hyaluronic injections with just one treatment
Homeopathic Traumeel™ and Zeel™ Injections- Imported from Germany and clinically proven to reduce pain without any known side effects. Three injections given one week apart
Joint Builder Ultra™- This special combination of oral hyaluronic acid, glucosamine, boswellia and MSM provide relief of pain
Multi-Waved Locked System (MLS) Laser™- Medical grade dual laser therapy to reduce inflammation and pain without any injection or side effects
This blog will focus on Platelet Rich Plasma as an alternative:
Platelet Rich Plasma (PRP) is a treatment we have used at Advanced Orthopedic Specialists since 2005. Dr. Loniewski has performed over 4,000 of these treatments with very good and safe results. This is the most natural injection you can receive since it comes from your own blood. Thus, there is no rejection or adverse reactions. One single blood poke is all it takes to obtain about 40 cc of your own blood. This is processed under sterile conditions and using good manufacturing processes to concentrate this down to about 5 cc of a concentrated platelet formulation. Platelets are the part of your blood which forms a scab when you bleed. These platelets contain many natural growth factors which help in the healing process to reduce pain and inflammation. We use a special process to double spin and concentrate only the good growth factors. One single injection given in a single office visit can provide pain relief that is superior to the results of hyaluronic acid injections and may last up to one year. Approximately 80% of patients receive pain relief starting around 2-6 weeks after the treatment and this normally lasts for approximately one year. A great review article entitled “The effects of platelet rich plasma in the treatment of large-joint osteoarthritis: a systemic review.” compared 13 studies of hyaluronic acid to PRP. Twelve of these were for knee arthritis. All the studies revealed that PRP had statistically significant benefit in knee osteoarthritis compared to hyaluronic acid. Many professional athletes use this treatment to help accelerate their healing process. For years, this was only available to the rich and famous or the elite athlete, but we have figured out a method to offer this to the general public. If you would like to learn more about the benefits of PRP, you can visit our web site here. Advanced Orthopedic Specialists and Dr. Edward Loniewski has found ways to offer you treatments proven to be more effective and lower in cost than hyaluronic injections. Call our office at 810-299-8550 to schedule an appointment and discuss these options. Future blogs will discuss the other options in detail.
 Teitze DC et al The effects of platelet rich plasma in the treatment of large-joint osteoarthritis: a systemic review. Physiology and Sports Medicine 2014, May; 42(2) 27-37.
Advanced Orthopedic Specialists is now offering one of the most comprehensive arthritis programs in the country. We now offer cutting edge therapies including surgical and non-surgical options to fit any lifestyle and severity of symptoms. Dr. Loniewski has had more experience developing these therapies than any other physician in the area. He has been continually improving these therapies since 1995 and acts as a consultant to many other practices across the country. He has completed well over 4,000 of these procedures and can provide a customized therapy program tailored to your specific symptoms and conditions as well as your active lifestyle. Just like no one drug is for every patient, no single cell based therapy is for every arthritic knee, hip, or shoulder. We offer a comprehensive program with multiple state of the art therapies to match each patient's condition as well as the specific lifestyle demands. Call 810-299-8550 for an appointment today.
Knee Arthroscopy Stem Cell Therapy by Laith Farjo, M.D.
Watch as Dr. Laith Farjo discusses what stem cell therapy is, and how it is incorporated into an actual knee arthroscopy surgery.
How Do Stem Cells Work?
By: Edward G. Loniewski, DO , FACOS, FAOAO- Advanced Orthopedic Specialists - Brighton, MI
This is a very common question asked not only by our patients, but also many educated physicians using this therapy. After years and years of trying to understand this process myself, I have attempted to simplify this very complex and complicated system down to 3 easy to remember mechanisms. The problem with simplifying a complex system is that it can leave out some other minor systems at work, but if we want to take a 10,000 foot look at this mountain of information, I believe that you can begin to make more sense of this process by boiling this down to a few basic mechanisms. The goal is not to make anyone an expert, but rather just an informed consumer so you can make an educated and knowledgeable decision if this therapy may be a viable treatment for either yourself or your loved ones. Many great philosophers in the past such as Camus, Kierkegaard and Aristotle have suggested we narrow down complex systems into three reasons, examples or theories because it allowed the student to understand the subject in a coherent manner. Thus, I am following their suggestion to narrow this down to 3 main mechanisms. But I think a more important reason is that I can’t remember more than three things at a time!
Before we talk about stem cells, we need to clarify that common stem cell therapies used in the United States contain a very small number of stem cells. Many treatment centers may only transfer a few thousand cells and thus, the mechanisms of action of these treatments are not due solely to the stem cells. Rather, they are due to the other nurturing biochemical compounds found around these cells. Therefore, bone marrow is very important in this process. Bone marrow is the natural home environment for stem cells in your body. This is where they are born, raised and utilized. Thus, we need to consider the contributions of the bone marrow products surrounding the stem cells such as Interleukin 1-B receptor antagonist (that was a mouthful) and Alpha 2 Macroglobulin as well as Transforming Growth Factor- Beta. These are important to help set the proper environment for stem cells to conduct their work. So, the title of this section is a bit misleading and should say “How does Cell Therapy Work?”
So, what are these three mechanisms of action? They are very easy to remember since they all start with R. This is what we call a pneumonic because they sound similar and are easier to remember. These mechanisms are:
We will take each one and explain how this mechanism relates to cell based therapies.
Reduce- Cell based therapies reduce the harmful biochemical storm in your joint. We normally have nice balance of specific biochemicals in our joints. They serve to help maintain the normal cell function of the joint. However, as we age, or with trauma or with specific inflammatory diseases of the joint, this chemical balance is upset and we have too many pro-inflammatory chemicals causing continued destruction. One of the most important biochemical families are the interleukins and especially interleukin-1-beta. This is normally used to help regulate our response to infection or inflammation. However, the production of this biochemical begins to rise and cause widespread inflammation and destruction of both cartilage and bone. Interleukin 1-B is the “Kingpin” or “Godfather” of these biochemicals and REDUCING IL-1 B will help restore this normal balance. Many biochemical pathways lead back to Interleukin-1 B and just like the Corleone family, when we start to investigate who is causing all this crime and destruction, many pathways lead back to the “Godfather” biochemical. Interleukin-1B controls the judges, the newspapers, and the police in New York City just like Don Corleone.
How is this done? Our own bone marrow contains a natural inhibitor of IL-1 B called Interleukin 1-B receptor antagonist. This is the antidote for the toxic effects of IL-1B and it is found intimately wrapped in the environment of your stem cells throughout your bone marrow. When we take your own bone marrow, there is a nice concentration of this natural inhibitor already present and connected to your stem cells. Race horses have used Interleukin 1-B Receptor Antagonist for the past 12 years to treat arthritis and improve their performance. In fact, this therapy is so effective and popular, one horses in the 2017 Kentucky Derby was named IRAP which stands for the IL-1 B receptor antagonist. As humans, you only require a small amount of interleukin-1 B receptor antagonist in a ratio of 100:1 for it to be effective in REDUCING its activity.
Thus, Bone Marrow Concentrate taken from your own pelvis can REDUCE the biochemical storm happening in your joint naturally and effectively. Without this reduction, there is little hope that any cartilage cells will survive and continued destruction will occur.
Our next mechanism involves Restoring the normal cell to cell communication of a joint.
Your joint is an organ just like a kidney, brain or heart. An organ is a group of specialized cells working together to perform a specific function. For example, your kidney cells function together to filter out toxins in your blood and help maintain healthy blood pressure. Your joint has specific cells designed to allow smooth and efficient movement of your body. To accomplish this goal, the specialized cells need to talk to one another through a special communication mechanism for one cell to talk to another local cell. This is called paracrine signaling. A diseased joint has a dysfunction of this signaling due to guess who….”The Godfather.” In a normal joint, cartilage cells need to talk to other cartilage cells to help with their normal function. Bone cells need to talk to other bone cells to do the same. When Interleukin 1-B is elevated, tunneling through the diseased bone next to your joint occurs and bone cells start to talk to cartilage cells rather than other bone cells through a mechanism called “cross talk”.
This cross talk is just like someone trying to give you directions to a restaurant when everyone else is talking very loudly in the background. Both parties on the line become frustrated and eventually hang up. Your bone and cartilage cells do the same and become dysfunctional unable to perform the specialized functions they were born to do because they cannot communicate effectively with each other. The bone marrow concentration helps RESTORE this normal cell to cell signaling by reducing the Interleukin-1 B and shutting down the tunnels between bone and cartilage. Over time, the small tunnels are shut down and cartilage cells now talk only to cartilage cells so they can function like a normal organ. Normal tissue function returns which in turn RESTORES the normal function of the joint as an organ.
Finally, we can discuss Regenerate as the third, but least important mechanism of cell therapy. Although many so called stem cell clinics claim the regenerative properties of their therapy is the most important mechanism, as we can see from the two previous mechanisms, unless you have a stable environment first, there is no reason to regenerate any tissue because it will be either destroyed by the biochemical storm caused by the Godfather or if by some miracle, there is tissue growth, the cells won’t be able to function as a normal organ because of the loss of paracrine signaling or cell to cell communication. So, cell based therapies REDUCE this biochemical imbalance and RESTORE normal cell to cell communication setting the stage for proper REGENERATION.
Think about this process compared to another very common disease in our country. Alcoholism is very prevalent in our society. I don’t really need to remind anyone of it’s prevalence. Ironically, just about the same number of people in the United States are affected by Arthritis as Alcoholism which is about 28 million. If we look at one of the most effective treatments for alcoholism, we can see a parallel to the three mechanisms of cell based therapies. Alcohol recovery programs normally begin with the removal of the harmful chemicals, or alcohol, causing the problem. In cell based therapies, we remove the harmful biochemical causing continued destruction. Without the removal of alcohol, the destructive process continues and this is the same for your joint. Next, critical relationships are restored through personal, family and marriage counseling. During counseling, broken lines of communication are restored.
In cell based therapy, broken and dysfunctional cell to cell communication is restored. Once the harmful chemical has been REDUCED and the communication RESTORED, now the family can thrive and function again and grow in a stable, non-toxic and loving environment. Your joint is the same with the REDUCED toxic chemicals and in a stable RESTORED environment promoting the REGENERATION of new tissue. The amount of new tissue may be very small in relation to the dramatic effects of reducing the toxins and restoring the normal function of the cells, but it is still a property of the mesenchymal stem cells delivered in the bone marrow concentrate. There is little relationship between the amount of tissue regenerated and the relief of your pain. However, there is a direct and linear relationship between levels of Interleukin-1 beta and the severity of your arthritic symptoms. Thus, reducing this harmful biochemical is paramount to the restoration and regeneration of your joint.
To prove this point, think of the last time you took a pill for your arthritis pain. Not everyone responds to these pills, but most people have some relief for a brief period of time after taking such a medication. Pills such as Aleve or Motrin have absolutely no effect on regenerating new cartilage tissue. Yet, you may have experienced some relief for about 4 to 6 hrs. Have you ever wondered how this happened? From a biochemical perspective, this medication reduced one of the biochemical pathways causing pain in your joint. Yet, this is pill in your stomach and not in your joint and it did not regenerate any new tissue and may have contributed to some further tissue destruction, but it provided some relief! Bone marrow concentrate stem cell therapy provides long term REDUCTION of the most important “Godfather” biochemical pathways for years and it RESTORES normal cell to cell communication leading to an optimal environment for the icing on the cake which is REGENERATION of some tissue.
I hope this simple explanation has accomplished its goal of making you a more informed and educated consumer and hopefully you can now understand if this therapy may be helpful for your our your loved one’s joint. The use of cell therapy can help your body naturally reduce a harmful chemical imbalance; restore cell to cell communication; and regenerate new tissue all adding up to a joint with lower pain and higher function without side effects or the inconvenience and risk of major surgery.