2008 Feb 13. . In the view of most authors, routine preoperative screening in patients with no symptoms of metal hypersensitivity is not usually indicated prior to implant placement. [QxMD MEDLINE Link]. Schalock PC, Thyssen JP. Local inflammatory symptoms similar to the symptoms of infection are also possible, including warmth, erythema, and swelling over the implant, though systemic complaints (eg, fever) are unlikely. Surgeons should be asking about allergies in this era of more and more people allergic to foods/environmental substances. Regen Biomater. Available at https://www.sciencedaily.com/releases/2014/10/141009153817.htm. 2021 Dec. 24 (8):1307-1316. [63] There is no agreement on which specific patients require testing. San Francisco CA 94123. [23] Hence, the lymphokine MIF may bethe most useful clinical test for diagnosis of hypersensitivity reaction to orthopedic implants. Correlation of MARS MRI findings with cup position, metal ion levels and function in metal-on-metal total hip arthroplasty. Santavirta S, Konttinen YT, Bergroth V, Grnblad M. Lack of immune response to methyl methacrylate in lymphocyte cultures. Hydrophilic materials are protein-resistant [4] Analgesic pain medicines may control symptoms but do not alter the underlying pathology. [QxMD MEDLINE Link]. The lymphocytes are then mixed with solutions of specific metal ions, such as nickel, chromium, cobalt, or titanium. They use this type of metal because it is the least [QxMD MEDLINE Link]. How do you know if your spouse is not happy? An allergic reaction could occur at a most inopportune time. [QxMD MEDLINE Link]. Immune Response to Implants and Biomaterials, encoded search term (Immune Response to Implants and Biomaterials) and Immune Response to Implants and Biomaterials, Conduits for Vascular Reconstruction in the Pediatric Patient. Metal artifact reduction sequence (MARS) magnetic resonance imaging (MRI) can be used to visualize local soft-tissue reactions; serum tests are used for screening. 148 (6):687-93. Fraker A, Griffin C, eds. The septic joint near the implanted hardware. Intraoperative cultures were obtained that all proved negative for an infectious cause. [QxMD MEDLINE Link]. At day 6, 3H-thymidine uptake is measured by using liquid scintillation. 2015 Dec. 98 (6):953-62. [43]. Swelling, pain, draining sinuses, and inflammation at the implant site may mimic infection. [45, 15] but, paradoxically, can also provoke an immune response to the coating substances themselves. The discrimination between nickel-sensitive and non-nickel-sensitive subjects by an in vitro lymphocyte transformation test. [15] Activated lymphocytes release cytokines (eg, interferon [IFN] gamma Prospective studies of patients who had positive skin patch test results showed no difference in reoperation rates as compared with patients who had negative skin patch test results. These include: FootEducation LLC Studies reveal that positive MIF test results to metals implanted in an orthopedic patient are well correlated with pain, swelling, and dermatologic reactions over that area. Donati ME, Savarino L, Granchi D, Ciapetti G, Cervellati M, Rotini R, et al. [QxMD MEDLINE Link]. This example presents a strong possibility of a true metal hypersensitivity reaction. Contact Dermatitis. [Full Text]. [QxMD MEDLINE Link]. However, if this is not satisfactory, patients may benefit from painful hardware removal once the fracture, fusion, or bone cut has fully healed. Ultrasonography (US) can also detect fluid around the implant [2], Bone marrow provides the same microenvironment for both bone and immune cells, where they share cellular signaling pathways to cooperate tightly in bone metabolism. The patient's symptoms resolved shortly thereafter. The fate of the implant depends on the immunomodulatory properties of the implant, [46] Antimicrobial peptide coatings, besides their direct action against microorganisms, may also exert an immune-regulatory effect by decreasing the immune response to the implant, resulting in osteointegration/bone formation around the implant. Carando S, Cannas M, Rossi P, Portigliatti-Barbos M. The lymphocytic transformation test (L.T.T.) Immune response to synthetic materials. Considerations of allergy and mechanics in the selection of orthopaedic implant materials [proceedings]. Materials (Basel). 2014 Aug 11. What are the side effects of having titanium in your body? [QxMD MEDLINE Link]. Biomaterials. Some research suggests that metal medical and dental implants may cause an autoimmune reaction in people with metal allergies and other genetic predispositions. [49, 50, 3] Initially, osteoclast activation is important for removal of necrotic tissue and as the first step for bone remodeling around the implant. J Arthroplasty. Some of the diseases researched in connection to metal devices include: Multiple sclerosis. (326):71-9. When they do occur, titanium allergy symptoms can range from mild to severe and can include: However, some people with metallosis also report experiencing the following symptoms: How to choose nickel free hypoallergenic jewelry? Incidence of metal sensitivity in patients with total joint replacements. Hi there! Rejection to the hardware is uncommon and generally would not just present with swelling alone. Likely possibilities that may need to be J Bone Joint Surg Br. The film has a strong inhibitory effect on the production of inflammatory cytokines released by macrophages 2020 Sep. 8:100080. A review of the literature and report of three cases. Can metal implants cause autoimmune disease? Carl N Graf, MD is a member of the following medical societies: American Medical AssociationDisclosure: Nothing to disclose. The consequences can be simple annoyances to life-threatening systemic illness. Hip pain, groin pain, or thigh pain are all signs that your hip replacement could have an issue, although other referred pains can cause these symptoms too. 20 (2):89-94. Antibacterial surface treatment for orthopaedic implants. zelik H, Vrana NE, Gudima A, Riabov V, Gratchev A, Haikel Y, et al. Both involve a robust intra-articular immune response; however, metal reaction shows predominance of perivascular lymphocytes, plasma cells, and macrophages, whereas infection is characterized by an abundance of neutrophils on biopsy. 2007 Dec. 28 (34):5044-8. Although the focus of this review is on orthopedic implants, the immune pathologic response is also relevant for cardiac, vascular, gastric, and other surgical implants. Waterman AH, Schrik JJ. Int J Dermatol. Expert Rev Med Devices. Vol 1: 565-74. Teo Wendy ZW, Schalock PC. Many of the same peri-operative risks apply for hardware removal, as for any surgical procedure. At the time of the operation, a collection of serous fluid was noted around the implanted hardware, but no other clinical evidence of infection was observed. However, with some individuals and with some types of surgeries, symptoms may arise. [3] These two groups of cells communicate via cytokines, signaling molecules, transcription factors, and receptors. 2012 Mar. [2, 3] Future implant design may depend on the relatively new specialty of osteoimmunology, with a shift in emphasis from immune "evasion" to immune "reprogramming." Svejgaard E, Thomsen M, Morling N, Hein Christiansen AH. Limited reactions can appear as a contact dermatitis on the skin that has been exposed to the metal. Blood levels of cobalt and chromium are typically 30 and 45 nmol/L, respectively, in unilateral well-functioning hip prostheses but increase to 6550 and 3400 nmol/L in failed prostheses. Case example. 2014 Jul 2. Goodman SB. [QxMD MEDLINE Link]. After skin patch testing, in-vitro lymphocyte proliferation testing is perhaps the most prevalent method of assessing hypersensitivities. [QxMD MEDLINE Link]. 2019 Aug. 21 (4):786-795. 1994. WebVery rarely patients develop an allergic reaction to donor bone. Corrosion and Degradation of Implanted Materials: Second Symposium. Developing immune-regulatory materials using immobilized monosaccharides with immune-instructive properties. Titanium has the ability to affect lung function causing lung diseases such as pleural disease, it can cause chest pain with tightness, breathing difficulties, coughing, irritation of the skin or eyes. The symptoms or signs of a rejected implant can be: systemic, meaning symptoms affecting the whole body; or; localized, meaning the affected area is limited to the area where the hernia mesh surgery was conducted (or the incision site). [88] The presence of known prior metal hypersensitivity was predictive of a good result with the use of an allergen-free implant for the revision surgery. Practitioners should have a low threshold for ordering advanced imaging, in that many of these patients are asymptomatic, and even low metal ion levels have been associated with local tissue reaction. [61] as compared with other modes of failure. Contact Dermatitis. Thomas P, von der Helm C, Schopf C, Mazoochian F, Frommelt L, Gollwitzer H, et al. Adult reconstructive surgery. Acta Biomater. It's free to sign up and bid on jobs. [2]. 3:6. When a hydrophilic surface is combined with a rough surface topography, there is a synergistic effect that yields even greater release of anti-inflammatory cytokines. WebYou may have a small amount of movement (rubbing) between the implants and the skin. Total arthroplasty of the left hip was recommended, but after consideration of her past orthopedic history, the patient was first referred to an allergist for metal allergy patch testing. Br J Dermatol. [4] Workup may be indicated before surgery for joint replacement patients with a history of skin reactions to metal jewelry, jean snaps, watch bands, metal glass frames, artificial nails, or skin glue. Medscape Education. [62] , but this is not yet commonly available. [63], Additionally, systemic contact dermatitis has been described when a patient becomes sensitized via the cutaneous route and cross-reacts systemically. In most instances, these screws and plates do not create symptomsand remain permanently in the foot. Immunomodulation with Self-Crosslinked Polyelectrolyte Multilayer-Based Coatings. [4] Bone cement hypersensitivity can be challenging, and revision using cementless procedures does not guarantee relief of presenting symptoms. ASTM STP 1144. EMMY NOMINATIONS 2022: Outstanding Limited Or Anthology Series, EMMY NOMINATIONS 2022: Outstanding Lead Actress In A Comedy Series, EMMY NOMINATIONS 2022: Outstanding Supporting Actor In A Comedy Series, EMMY NOMINATIONS 2022: Outstanding Lead Actress In A Limited Or Anthology Series Or Movie, EMMY NOMINATIONS 2022: Outstanding Lead Actor In A Limited Or Anthology Series Or Movie. 2014 Nov. 124 (11):5037-41. WebSearch for jobs related to Symptoms of body rejecting surgical hardware or hire on the world's largest freelancing marketplace with 22m+ jobs. [QxMD MEDLINE Link]. [QxMD MEDLINE Link]. Acta Orthop Scand. J Am Acad Orthop Surg. Initially, this may be treated with shoe modifications, padding over the area, and simple measures to reduce the local swelling and inflammation. Is it unhealthy to sit on the toilet too long? Baltazar Remigio R Espiritu, MD is a member of the following medical societies: American Academy of Allergy, Asthma and ImmunologyDisclosure: Nothing to disclose. For example, instead of the standard stainless steel fracture fixation devices, the surgeon can substitue titanium plates and screws in patients with known nickel allergy. Your skin has a natural barrier thats disrupted when it reacts to nickel and other allergens. [4] High chromium ion concentrations may be carcinogenic, and high cobalt ion concentrations may be both cardiotoxic and neurotoxic. 2021 Oct. 11:20-24. 2011 Apr. Nickel-associated delayed multiple white matter lesions after stent-assisted coil embolization of intracranial unruptured aneurysm. [63]. [23] The systemic response to deep implants can occur acutely or many years later. ScienceDaily. Patients with hardware for fractures have symptoms of nonunion, including pain and motion at the fracture site. [50], The switch from M1 to M2 is regulated by immune cells, including T cells of various subsets, cytokines, and microRNAs (miRNAs). 15 (3):173-90. 2017 Jun. Patients with joint replacement may present with loss of motion. Diagnostic dilemmas of Titanium Hypersensitivity in patients with medical implants: a case series. If your stitches have become infected, you may notice the following symptoms: redness or swelling around the stitches. [1], Biopsy of the synovial membrane at the time of revision surgery is one method for differentiating between infection and hypersensitivity reaction to the implant. 2019 Jul 21. Traditionally, skin patch testing has been the standard screening test for metal hypersensitivity; it is cost-effective and technically simple. However, because such a reaction is a diagnosis of exclusion, definitive proof is difficult to achieve. [60]. [53] Mitochondrial stress and cytokine secretion by synovial fibroblasts can be induced by cobalt ions released by failing hip implants. [QxMD MEDLINE Link]. Roughened, grit-blasted, or grooved surfaces increase the surface area available for ion release from the implant and thereby increase the local levels of dissolved metal. Trans Soc Biomaterials. Huber M, Reinisch G, Trettenhahn G, Zweymller K, Lintner F. Presence of corrosion products and hypersensitivity-associated reactions in periprosthetic tissue after aseptic loosening of total hip replacements with metal bearing surfaces. [1] with a foreign body reaction. Int Orthop. [3] M1 proinflammatory macrophages arrive as part of the initial inflammatory response Acta Pathol Microbiol Scand C. 1976 Dec. 84C (6):511-23. Websymptoms of body rejecting surgical hardware. Titanium allergy in dental implant patients: a clinical study on 1500 consecutive patients. Eur Ann Allergy Clin Immunol. Adkinson NF Jr, Bochner BS, Burks AW, Busse WW, Holgate ST, Lemanske RF JR, et al, eds. I also with a bad episode experience a temp and chronic fatigue. Philadelphia: American Society for Testing and Materials; 1992. Philadelphia: Elsevier Saunders; 2014. fever. The test result is considered negative if the lymphocytes migrate away from the particular metal ion solution, indicating that they are not reacting to the dissolved metal. After an implant is placed, a complex immune cascade follows that can lead to the following two possible outcomes, depending on the design of the implant The increasing frequency of metal allergies in the general population implies the potential need for prescreening of surgical patients to prevent possible allergic reactions to implants. Everness KM, Gawkrodger DJ, Botham PA, Hunter JA. Metal allergy was found with severe types of alopecia areata (AA) at the rate of 69.9% and the elimination of metal allergens from dental metals, cooking instruments lead to satisfactory hair regrowth and prevention of severe relapse of AA for the period of in average four years and four months at the rate of 75.5%. Ann Clin Biochem. If this is not acceptable for symptom relief, then consideration should be given to removing the hardware after the fracture or fusion has fully healed. [QxMD MEDLINE Link]. [QxMD MEDLINE Link]. J Bone Joint Surg Am. 2020 Jun. [QxMD MEDLINE Link]. If a hip replacement rejection is suspected, medical attention should be sought immediately so that the problem can be properly diagnosed and treated. The barometric pressure drops when storms are rolling in, and somehow, the body detects this change, causing swelling of soft tissue or expanding of joint fluid. WebCan surgical hardware rejection symptoms? [QxMD MEDLINE Link]. X-rays will reveal the hardware if it is metal (most screws are T and B lymphocytes in contact and atopic dermatitis. Hypersensitivity reactions to metal implants: laboratory options. The patient had positive nickel sensitivity, as shown on both skin patch testing and lymphokine MIF testing, and negative culture results with no clinical evidence of infection. 48 (3):245-9. Recognition of the potentially disastrous consequences of implant-associated infection [6, 83], The usual course of events in patients demonstrating true postimplantation metal hypersensitivity is such that symptoms develop over months to years; this may be long after the device has accomplished the goal of fracture stability. Metal sensitivity in patients treated for tibial fractures with plates of stainless steel. 1977 Oct. 38 (2):67-8. What are the Materials Metal Implants? The most common sign of hip replacement rejection is pain in the hip joint, although other symptoms, such as swelling and warmth around the joint, may also occur. William J Hopkinson, MD, FACS, FAAOS is a member of the following medical societies: American Academy of Orthopaedic Surgeons, American College of Surgeons, American Orthopaedic Association, American Orthopaedic Society for Sports Medicine, Illinois Association of Orthopaedic Surgeons, Illinois State Medical SocietyDisclosure: Nothing to disclose. Do Men Still Wear Button Holes At Weddings? [74, 76, 77] Such reports seem to indicate that the LTT, compared with dermal patch testing, may be equally well or better suited for the testing of implant-related sensitivity. [1]. [2] For example, osteoblast migration and proliferation are promoted by transforming growth factors (eg, TGF-) and interleukins (eg, IL-4) but inhibited by tumor necrosis factors (eg, TNF-) and other interleukins (eg, IL-1). What is the difference between aphasia and frontotemporal dementia? This patient received three different stainless steel devices at two different sites. Repeated or prolonged exposure to metals or other substances from jewelry, clothing, or implanted devices sensitizes T cells, which respond to an implanted device [QxMD MEDLINE Link]. In some cases, you may be able to feel a plate or screw if there is very little muscle or soft tissue covering them for instance, along the outside of your ankle or the top of your hand. [52]. 2015:910156. Nickel is one of the most frequent allergens, causing significant local contact dermatitis (skin reddening and itching). Cha c sn phm trong gi hng. [39] Although Carossino et al recommended routine skin patch testing with confirmatory LTT as a standard procedure for decreasing the potential for allergy-related complications in patients undergoing arthroplasty, Evaluation and management of metal hypersensitivity in total joint arthroplasty: a systematic review. [63]. These peptides are biocompatible with macrophages and neutrophils. [23] Gradual development of skin changes, pain, tenderness, and swelling over the area of the implanted hardware may be coupled with evidence of loosening of a previously stable implant. Nadim James Hallab, PhD is a member of the following medical societies: American Association of Immunologists, Orthopaedic Research Society, Sigma Xi, The Scientific Research Honor Society, Society for Leukocyte BiologyDisclosure: Received ownership interest from Orthopedic Analysis Inc for management position; Received ownership interest from Bioengineering Solutions Inc for management position. [4, 63, 39] most likely secondary to corrosion or bearing wear of the implant. In addition to the percentage of a particular metal contained within an alloy, the nature of the alloy and the local exposure of the implant are important. Evaluation of several immunological parameters in patients with aseptic loosening of hip arthroplasty. [3] Hydrophobic materials have an intrinsic immunogenicity with increased monocyte adhesion. [2, 49]. They can range from mild to severe and develop shortly after contact with gold or a long-time wearing. Demoly P, Michel F, Bousquet J. Applying diagnostic criteria may be useful in guiding the decision making process when faced with symptomatic or failing devices. This test selectively detects lymphokine MIF, which, when present, does indicate an active immune response and metal sensitivity. 1977 Oct. 59 (7):862-5. Pacheco KA. Many patients with implanted metal hardware have positive skin test results for those metals but nevertheless are completely asymptomatic. Plasma-spray coatings and grouting agents limit exposure and decrease ion release from the implant. Sensitization of patients receiving orthopaedic implants. At the second (left hip), complete healing again occurred, and the patient remained asymptomatic after a titanium device was implanted. [QxMD MEDLINE Link]. Alobaid MA, Richards SJ, Alexander MR, Gibson MI, Ghaemmaghami AM. Tests that may be more specific include the lymphocyte transformation test (LTT) and the lymphokine MIF test (see below), which have been used to help diagnose metal hypersensitivity. Hardware placed in the midfoot and forefoot may be prominent and may need to be replaced. [QxMD MEDLINE Link]. Eltit F, Noble J, Sharma M, Benam N, Haegert A, Bell RH, et al. [QxMD MEDLINE Link]. The patient underwent a left THA with the use of a cementless titanium implant with a ceramic head (see the first image below). 1991 Feb. 62 (1):29-32. Adv Healthc Mater. Rosemont, IL: American Academy of Orthopaedic Surgeons; 2001. J Neurointerv Surg. 2016 Nov 23. In the Chicago area, these tests are available at both Loyola University Medical Center and Rush Presbyterian Mecdical Center. Contact Dermatitis. These coating substances can encourage attachment of host cells and a local immune response against the infectious organism The presenting signs and symptoms of a nickel or other metal hypersensitivity to an implanted orthopedic device are variable but usually consist of the expected complaints of a patient with hardware failure. Contact Dermatitis. Acta Orthop Scand. The hardware was not loose, and the fracture was stable and clinically healed. [1, 3] Cardiac stents and patches are made of nitinol (an alloy of titanium and nickel). They can include itching, redness, tenderness, swelling, and warmth to the exposed area. 1989. How can I test myself for nickel allergy? [QxMD MEDLINE Link]. The rash generally appears on the area of the skin that comes into contact with the metal. [49, 50, 2, 3] ; these macrophages release proinflammatory mediators such as interleukin (IL)-1, IL-6, IL-16, and tumor necrosis factor (TNF)- [51], The clinical presentation of patients with metal implant reactions is often nonspecific. While the potential for a reaction exists, its thought to be extremely rare. Caicedo MS, Solver E, Coleman L, Hallab NJ. [3] Larger pores decrease inflammation. The symptoms can often be reproduced with motion of the joint or movement of nearby tendons. Int J Nanomedicine. Br J Dermatol. 58 (3):245-50. I had spinal fusion 7/30. My incision burst open, was on a wound vac for 8 weeks but wouldn't heal, had second surgery to clean and close the wound [QxMD MEDLINE Link]. Metal sensitivities among TJA patients with post-operative pain: indications for multi-metal LTT testing. [39] After placement of metal implants, sensitization (ie, a change from a negative result to a positive one) occurs in 2.7% of cases for chromium, 3.8% for nickel, and 3.8% for cobalt. However, patients with known symptomatic metal allergies do have poorer results. X-rays will reveal the hardware if it is metal (most screws are stainless steel or titanium). X-rays may also identify the area of the hardware which is likely to be causing the symptoms. Skin-patch testing or lymphocyte transformation testing (LTT), when the patch test result is questionable, prior to revision knee or hip replacement has been recommended, despite the limitations 469 (4):1127-33. Generalized sensitivity from an implanted orthopaedic antibiotic minichain containing nickel. [QxMD MEDLINE Link]. Swiontkowski MF, Agel J, Schwappach J, McNair P, Welch M. Cutaneous metal sensitivity in patients with orthopaedic injuries. [20, 30] Some 25% of patients with well-functioning prostheses have metal sensitivity. The results demonstrated increased uptake and lucency around the lag screw, indicative of hardware loosening. Kie-Swierczynska M. Allergy to chromate, cobalt and nickel in Ld 1977-1988. Metal screws and plates are often used in surgery to fix fractures, fuse joints, or stabilize bones that have been cut (osteotomies) in the foot and ankle. Metal Hypersensitivity and Total Knee Arthroplasty. Rostoker G, Robin J, Binet O, Blamoutier J, Paupe J, Lessana-Leibowitch M, et al. Contact Dermatitis. Cobalt, copper, and chromium are also common culprits. [84], No medical treatment is available, How do you know if your body is rejecting screws? The key to success is to design implants with biomaterials that modulate the local immune environment from proinflammatory to healing. Sci Adv. [20, 30, 32, 33] Demehri et al reported the rare occurrence of squamous cell skin cancer (specifically, Marjolin ulcer) associated with a contact allergic reaction to superficial metal implants, most likely secondary to chronic inflammation. Lymphocyte transformation in vitro in dermatophytosis. Biological effects of corrosion products from metals. Polyelectrolye multilayer films from hyaluronic acid have been developed, with good early experimental results. The results were positive for an allergy to nickel sulfate (with >20 mm of erythema noted) but negative for chromium and cobalt. [5, 6, 17, 18, 19] It is thought that the immune system may become sensitized to the presence of a metal implant with a resultant increase the incidence of positive skin testing, though it is unclear how often this response is pathologic. Physical signs Carbohydrates attached to tumor cells modulate dendritic cell function, switching them from inflammatory to tolerogenic; this hides the tumor from the host immune response. Patients that have previously had surgery to fix a fracture or to fuse a bone of the foot and ankle may have retained hardware that can become prominent and/or creates discomfort. When an implant is rejected by the body, the device fails. 2008 Dec. 23 (8):1212-8. Antibacterial infection and immune-evasive coating for orthopedic implants. Markel et al reported the use of a dual-mobility cobalt-chromium hip replacement prosthesis with which metal ion levels were undetectable or minimal after 1-2 years; in addition, percentages of B cells and T cells were normal, with no increase in CD16 inflammatory monocytes, indicating the absence of an immune response to the implant. Metal sensitivity is the most common type of immune response to implants. Case example. However, some metals (including cobalt) can cause soft-tissue inflammation via direct toxicity of the metal ions without the hypersensitivity response. The white blood cell (WBC) count and other assessments of inflammatory mediators (eg, platelet count, C-reactive protein [CRP] level, and erythrocyte sedimentation rate [ESR]) are not elevated or only minimally elevated, and they are not specific or reliable enough to aid in diagnosis. The typical symptoms of a gold allergy are swelling, rash, redness, itching, peeling, dark spots and blistering when in contact with gold jewellery. Elves MW, Wilson JN, Scales JT, Kemp HB. Radiolucencies around the hardware, screw migration, and changedposition of the implant imply loosening that could be due to hypersensitivity to the metal or could be the catalyst that induces a robust immune response. Another disappointment as now the hardware is coming loose from the bones and is unstable/more painful. [48] , leading to inflammation that activates macrophages as part of the inflammatory cascade. The presentation may include dermatitis and skin reactions, joint pain, joint effusions, and decreased wound healing. Metal sensitivity reactions to orthopedic implants. Like Helpful Hug 5 Reactions 1994 Mar. Kimber I, Bentley AN, Hilton J. [4], In light of these contradicting studies, it is difficult for the orthopedic surgeon to make the diagnosis of symptomatic metal allergy with confidence. Pahlavan S, Hegde V, Bracey DN, Jennings JM, Dennis DA.