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1.
Scott Med J ; 69(1): 10-17, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38050379

ABSTRACT

BACKGROUND: Poor mental health in medical students is a global concern. Effective interventions are required, which are tailored towards the training-related stressors medical students experience. The Reboot coaching programme is an online, tailored intervention based on cognitive-behavioural principles. AIMS: To evaluate whether the Reboot coaching programme tailored for medical students was feasible and associated with improvements in mental health outcome indicators. METHODS: Medical students participated in two group online workshops and a one-to-one coaching call with a Reboot-trained licensed psychological therapist. Participants provided data at: baseline (T1), post-workshops (T2), post-coaching call (T3) and 4-month follow-up (T4). Outcome measures included resilience, confidence, burnout and depression. Feedback was provided regarding the workshops at T2. RESULTS: 115 participants (93/80.9% women; mage = 23.9; SD = 2.8) were recruited, 83 (72.2%) completed all intervention elements and 82 (71.3%) provided T4 data, surpassing recruitment and retention targets. There were significant improvements following baseline in resilience (ps < .001), confidence (ps < .001), burnout (ps < .001) and depression (ps ≤ .001). Most participants agreed the workshops imparted useful skills (n = 92; 99%) and would recommend Reboot to others (n = 89; 95.6%). CONCLUSIONS: Existing interventions have produced mixed results regarding their effectiveness in improving medical students' mental health. Reboot is a feasible intervention in this group which is associated with improvements in resilience, confidence, burnout and depression. Further controlled studies of Reboot are now needed.


Subject(s)
Mentoring , Resilience, Psychological , Students, Medical , Humans , Female , Male , Students, Medical/psychology , Depression , Burnout, Psychological
2.
J Patient Saf ; 19(8): 553-563, 2023 Dec 01.
Article in English | MEDLINE | ID: mdl-37712844

ABSTRACT

BACKGROUND: Incident investigation remains a cornerstone of patient safety management and improvement, with recommendations meant to drive action and improvement. There is little empirical evidence about how-in real-world hospital settings-recommendations are generated or judged for effectiveness. OBJECTIVES: Our research questions, concerning internal hospital investigations, were as follows: (1) What approaches to incident investigation are used before the generation of recommendations? (2) What are the processes for generating recommendations after a patient safety incident investigation? (3) What are the number and types of recommendations proposed? (4) What criteria are used, by hospitals or study authors, to assess the quality or strength of recommendations made? METHODS: Following PRISMA-ScR guidelines, we conducted a scoping review. Studies were included if they reported data from investigations undertaken and recommendations generated within hospitals. Review questions were answered with content analysis, and extracted recommendations were categorized and counted. RESULTS: Eleven studies met the inclusion criteria. Root cause analysis was the dominant investigation approach, but methods for recommendation generation were unclear. A total of 4579 recommendations were extracted, largely focusing on individuals' behavior rather than addressing deficiencies in systems (<7% classified as strong). Included studies reported recommendation effectiveness as judged against predefined "action" hierarchies or by incident recurrence, which was not comprehensively reported. CONCLUSIONS: Despite the ubiquity of incident investigation, there is a surprising lack of evidence concerning how recommendation generation is or should be undertaken. Little evidence is presented to show that investigations or recommendations result in improved care quality or safety. We contend that, although incident investigations remain foundational to patient safety, more enquiry is needed about how this important work is actually achieved and whether it can contribute to improving quality of care.


Subject(s)
Delivery of Health Care , Quality of Health Care , Humans , Patient Safety , Health Facilities , Safety Management
3.
J Bone Joint Surg Am ; 103(13): 1184-1192, 2021 07 07.
Article in English | MEDLINE | ID: mdl-34038393

ABSTRACT

BACKGROUND: Metastatic bone disease in the periacetabular region represents a potentially devastating problem for patients. Surgical treatment can offer pain relief and restore function. We describe a series of patients treated with minimally invasive osteoplasty and screw fixation with or without ablation. METHODS: Thirty-eight patients with 16 different metastatic tumor subtypes were managed with osteoplasty and screw fixation with or without ablation at a single institution. A retrospective review was performed to determine functional outcomes with use of the 1993 Musculoskeletal Tumor Society (MSTS) score as well as changes in narcotic usage. RESULTS: MSTS scores improved for all patients following surgery. Narcotic usage decreased in >80% of patients. Approximately half of the operations were outpatient procedures. Complications were minimal, there were no delays in chemotherapy or radiation due to surgical wound concerns, and there were no surgery-related deaths. The mean duration of follow-up was 9 months, with a 39% survival rate at the time of writing. Six of the 12 patients who survived for >1 year required additional procedures at a mean of 12 months (range, 4 to 23 months). CONCLUSIONS: Treatment of periacetabular metastatic disease with minimally invasive stabilization with or without ablation provides pain relief and functional improvement with lower complication rates than previously reported open reconstruction techniques. The minimally invasive approach allows for rapid initiation of chemotherapy and radiation. Patients with particularly aggressive cancers that are poorly responsive to systemic therapies and radiation may have progression of disease and may require additional procedures. Conversion to total hip arthroplasty was uncomplicated, and the cement and screw constructs were retained, providing a stable base for the arthroplasty reconstruction. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.


Subject(s)
Acetabulum , Bone Neoplasms/surgery , Plastic Surgery Procedures , Aged , Analgesics, Opioid/therapeutic use , Antineoplastic Agents/therapeutic use , Arthroplasty, Replacement, Hip , Bone Cements/therapeutic use , Bone Neoplasms/mortality , Bone Neoplasms/secondary , Bone Screws , Female , Follow-Up Studies , Humans , Male , Middle Aged , Minimally Invasive Surgical Procedures/adverse effects , Minimally Invasive Surgical Procedures/mortality , Physical Functional Performance , Postoperative Complications , Radiotherapy , Plastic Surgery Procedures/adverse effects , Plastic Surgery Procedures/mortality , Reoperation , Retrospective Studies , Survival Rate , Time Factors , Treatment Outcome
4.
Instr Course Lect ; 70: 475-492, 2021.
Article in English | MEDLINE | ID: mdl-33438929

ABSTRACT

Metastatic bone disease to the pelvis can lead to lower quality of life and function secondary to pain. Historically, treatment was palliative with radiation therapy and chemotherapy used to reduce pain. The Harrington procedure and subsequent modifications improved pain and function. In the subset of patients with complications, this would delay potential life-prolonging interventions such as chemotherapy and radiation therapy. Percutaneous palliative pain procedures including ablation and cementoplasty have been developed by interventional radiology for pelvic lesions and have been shown to be safe and efficacious. Additionally, percutaneous methods of pelvic fracture fixation have been developed. Modern image guidance technologies have allowed an expanded multidisciplinary approach to pelvic metastatic disease in a minimally invasive fashion with combinations of ablation, internal fixation, and cementation to improve patient quality of life and outcomes with decreased morbidity and rapid return to radiation and systemic therapies.


Subject(s)
Bone Neoplasms , Cementoplasty , Bone Neoplasms/therapy , Fracture Fixation, Internal , Humans , Quality of Life , Treatment Outcome
5.
J Orthop Res ; 39(10): 2124-2129, 2021 10.
Article in English | MEDLINE | ID: mdl-33300165

ABSTRACT

Periacetabular metastatic lesions cause debilitating weight-bearing pain and pose a risk of pelvic pathologic fracture. Minimally invasive percutaneous stabilization is an alternative palliative therapy over extensive open reconstructive surgeries. This study aimed to investigate the biomechanical behaviors of three distinct techniques of percutaneous periacetabular stabilization. A total of 20 composite hemipelves custom-made to contain Harrington type III periacetabular lesion based on a patient's computed tomograpy scans were assigned to treatment groups of cementoplasty alone using polymethyl methacrylate (Cement), screw fixation alone using ischial and posterior-to-anterior screws (Screws), cement-augmented screws (Screws&Cement), and a control group (Untreated). All hemipelves were loaded in a mechanical test configuration mimicking a single-legged stance, and failure load, failure deformation, and construct stiffness were determined. In the experiments, Screws&Cement demonstrated the highest yield strength (4711 ± 362 N) and was 12% higher than Cement (4005 ± 304 N, p = 0.019), 125% higher than Screws (2097 ± 359 N, p < 0.0001), and 184% higher than Untreated (1658 ± 254 N, p < 0.0001). No significant difference in yield strength was found between Screws and Untreated. Screws&Cement also demonstrated the highest stiffness (1013 ± 92 N/mm), followed by Cement (893 ± 49 N/mm), and both groups were significantly stiffer than Screws (543 ± 114 N/mm, p < 0.0001) and Untreated (580 ± 91 N/mm, p < 0.0001 for Screws&Cement, and p = 0.0003 for Cement). This study demonstrated that a cement-augmented periacetabular reconstruction is an effective option for percutaneous treatment of Harrington III periacetabular metastatic lesion. The addition of pelvic screws over cementoplasty significantly improved the pelvis load-bearing strength. When large periacetabular lesions are present, augmented screw fixation appears to be the superior choice of treatment.


Subject(s)
Bone Screws , Fractures, Bone , Biomechanical Phenomena , Bone Cements , Fractures, Bone/surgery , Humans , Pelvis/surgery , Weight-Bearing
7.
Semin Intervent Radiol ; 36(3): 221-228, 2019 Aug.
Article in English | MEDLINE | ID: mdl-31435130

ABSTRACT

In addition to being a major source of cancer-related pain, metastatic osseous lesions are frequently at risk for pathologic fracture and its accompanying morbidity. While bony metastases are commonly thought of as occurring within the vertebral column, over 80% are found outside the spine. Percutaneous interventional treatment options for nonspinal metastases offer a broad array of minimally invasive, image-guided procedures that are rapidly effective, reduce the need for opioids, and often work in complementary fashion with adjunct treatments in radiation oncology, orthopaedic surgery, and/or medical oncology. This article presents an approach to assess extraspinal metastases, reviews available interventional techniques in use today, and offers example cases as an introductory primer to the thought process used for selecting the appropriate interventional treatment.

8.
Semin Intervent Radiol ; 36(3): 229-240, 2019 Aug.
Article in English | MEDLINE | ID: mdl-31435131

ABSTRACT

Metastatic disease involving the pelvis is common, often resulting in significant pain and disability. Several percutaneous interventions for unstable pelvic metastatic disease have been described, including osteoplasty, ablation, and screw fixation, that when used alone or in combination can significantly reduce pain and disability from metastatic bone disease. While it is possible to make a significant impact in patient care with basic principles and techniques, certain advanced techniques can extend the application of percutaneous interventions while minimizing morbidity.

9.
J Surg Oncol ; 120(3): 366-375, 2019 Sep.
Article in English | MEDLINE | ID: mdl-31236956

ABSTRACT

BACKGROUND: Desmoid tumors are rare locally invasive, benign neoplasms that develop along aponeurotic structures. Current treatment is complicated by associated morbidity and high recurrence rates. METHODS: A retrospective, single-institution review identified 23 patients (age: 16-77) with extra-abdominal desmoid tumors who received CT-guided percutaneous cryoablation as either a first-line (61%) or salvage (39%) treatment in 30 sessions between 2014 and 2018. Median maximal lesion diameter was 69 mm (range: 11-209). Intent was curative in 52% and palliative in 48%. Contrast-enhanced cross-sectional imaging was obtained before and after treatment in addition to routine clinical follow-up. RESULTS: Technical success was achieved in all patients. The median follow-up was 15.4 months (3.5-43.4). Symptomatic improvement was demonstrated in 89% of patients. At 12 months, the average change in viable volume was -80% (range -100% to + 10%) and response by modified response evaluation criteria in solid tumors (mRECIST) was CR 36%, PR 36%, and SD 28% No rapid postablation growth or track seeding was observed. Four patients underwent repeat cryoablation for either residual or recurrent disease. Two patients sustained a major procedural complication consisting of significant neuropraxia. CONCLUSION: Cryoablation for desmoid tumors demonstrates a high degree of symptom improvement and local tumor control on early follow-up imaging with relatively low morbidity.


Subject(s)
Cryosurgery/methods , Fibromatosis, Aggressive/surgery , Abdominal Wall/diagnostic imaging , Abdominal Wall/pathology , Abdominal Wall/surgery , Adolescent , Adult , Aged , Extremities/diagnostic imaging , Extremities/pathology , Extremities/surgery , Female , Fibromatosis, Aggressive/diagnostic imaging , Fibromatosis, Aggressive/pathology , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Retrospective Studies , Thoracic Wall/diagnostic imaging , Thoracic Wall/pathology , Thoracic Wall/surgery , Tomography, X-Ray Computed , Young Adult
10.
Ultrasound Q ; 35(4): 346-354, 2019 Dec.
Article in English | MEDLINE | ID: mdl-30807547

ABSTRACT

Magnetic resonance-guided focused ultrasound (MRgFUS) utilizes high-intensity focused ultrasound to noninvasively, thermally ablate lesions within the body while sparing the intervening tissues. Magnetic resonance imaging provides treatment planning and guidance, and real-time magnetic resonance thermometry provides continuous monitoring during therapy. Magnetic resonance-guided focused ultrasound is ideally suited for the treatment of extra-abdominal desmoid fibromatosis due to its noninvasiveness, lack of ionizing radiation, low morbidity, and good safety profile. Conventional treatments for these benign tumors, including surgery, radiation, and chemotherapy, can carry significant morbidity. Magnetic resonance-guided focused ultrasound provides a safe and effective alternative treatment in this often-young and otherwise healthy patient population. While there is considerable experience with MRgFUS for treatment of uterine fibroids, painful bone lesions, and essential tremor, there are few reports in the literature of its use for treatment of benign or malignant soft tissue tumors. This article reviews the principles and biologic effects of high-intensity focused ultrasound, provides an overview of the MRgFUS treatment system and use of magnetic resonance thermometry, discusses the use of MRgFUS for the treatment of extra-abdominal desmoid tumors, and provides several case examples.


Subject(s)
Fibromatosis, Aggressive/therapy , High-Intensity Focused Ultrasound Ablation/methods , Magnetic Resonance Imaging/methods , Therapy, Computer-Assisted/methods , Fibromatosis, Aggressive/diagnosis , Humans
11.
Nurs Older People ; 30(7): 18-27, 2018 11 29.
Article in English | MEDLINE | ID: mdl-30426731

ABSTRACT

Delirium is a common neuropsychiatric disorder that all those working with older people will have encountered at some stage. Delirium is often poorly identified in hospital settings and therefore not optimally managed. After data collection on the acute medical unit in an acute hospital trust in the UK it was evident that patients with signs of delirium were not being formally assessed and therefore not appropriately managed in many cases. A quality improvement project introduced the 4AT delirium assessment tool to try to ensure that patients with delirium were being identified. The project team carried out several plan-do-studyact cycles to bring about our changes, which included a 4AT assessment sticker for nursing staff to complete and teaching for all healthcare staff. Through involvement of all members of the multidisciplinary team and ongoing feedback and changes we were able to increase assessment of delirium from 0% to 64%. There is ongoing work to be done to continue to improve delirium management, but by initially improving the assessment and identification of delirium we will make a difference to these patients' outcomes.


Subject(s)
Delirium/diagnosis , Nursing Diagnosis , Surveys and Questionnaires , Aged , Decision Trees , Delirium/nursing , Female , Geriatric Nursing , Health Services for the Aged , Humans , Male , Quality Improvement
12.
Radiol Case Rep ; 12(3): 467-471, 2017 Sep.
Article in English | MEDLINE | ID: mdl-28828103

ABSTRACT

Pulmonary artery pseudoaneurysm is a very rare complication of penetrating thoracic trauma. We present a case of a 27-year-old woman who developed a 6.5-cm traumatic pulmonary artery pseudoaneurysm after suffering multiple stab wounds to the chest and the abdomen. The pseudoaneurysm was successfully treated endovascularly with vascular plug occlusion and coil embolization.

13.
Semin Intervent Radiol ; 34(2): 121-131, 2017 Jun.
Article in English | MEDLINE | ID: mdl-28579680

ABSTRACT

Metastatic disease involving the spine and pelvis is common, often resulting in significant pain and disability. Several percutaneous interventions have been described, including osteoplasty, ablation, and screw fixation, that when used alone or in combination can significantly reduce pain and disability from metastatic bone disease. Although it is possible to make a significant impact in patient care with basic principles and techniques, certain advanced techniques can extend the application of percutaneous interventions while minimizing morbidity.

14.
J Vasc Interv Radiol ; 25(10): 1595-603, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25156647

ABSTRACT

PURPOSE: To characterize the distribution of absorbed radiation dose after glass microsphere radioembolization for hepatocellular carcinoma (HCC) using yttrium-90 ((90)Y) positron emission tomography/computed tomography (PET/CT). MATERIALS AND METHODS: In this retrospective study, 64 (90)Y PET/CT scans performed after treatment were evaluated following (90)Y glass-bead radioembolization in patients with advanced HCC. The intended dose to the target volume ranged from 83-129 Gy. Three-dimensional "dose maps" were created from reconstructed PET images using a voxel-based S-value transformation. Liver parenchyma and liver tumors were contoured on cross-sectional imaging and aligned with the created dose maps. RESULTS: There were 113 tumors examined as part of 64 lobar treatments. The average tumor size was 4.8 cm ± 4.0 with an average tumor dose of 173 Gy ± 109. The average dose to the nontumor parenchyma within the target volume was 93.4 Gy ± 32.6, with on average 50% of the parenchymal voxels receiving > 79 Gy ± 23 and 10% receiving > 173 Gy ± 55. The average and median tumor-to-parenchymal weighted dose ratios were 2.2 and 1.9, respectively. CONCLUSIONS: Using recommended dosimetry and administration techniques for lobar glass microsphere radioembolization, high doses to target tumors as well as background parenchyma were achieved on average with modest preferential uptake within tumors. There was wide variation in measured tumor and parenchymal doses after hepatic radioembolization for HCC, suggesting the need for continued development of patient-specific dosimetry.


Subject(s)
Carcinoma, Hepatocellular/radiotherapy , Embolization, Therapeutic/methods , Hepatic Artery , Liver Neoplasms/radiotherapy , Multimodal Imaging/methods , Positron-Emission Tomography , Radiopharmaceuticals/administration & dosage , Radiotherapy Dosage , Tomography, X-Ray Computed , Yttrium Radioisotopes/administration & dosage , Aged , Carcinoma, Hepatocellular/diagnostic imaging , Carcinoma, Hepatocellular/pathology , Embolization, Therapeutic/adverse effects , Female , Glass , Humans , Injections, Intra-Arterial , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/pathology , Male , Microspheres , Middle Aged , Predictive Value of Tests , Radiopharmaceuticals/adverse effects , Retrospective Studies , Treatment Outcome , Tumor Burden , Yttrium Radioisotopes/adverse effects
15.
J Nucl Med ; 55(9): 1452-8, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24982437

ABSTRACT

UNLABELLED: PET/CT imaging after radioembolization is a viable method for determining the posttreatment (90)Y distribution in the liver. Low true-to-random coincidence ratios in (90)Y PET studies limit the quantitative accuracy of these studies when reconstruction algorithms optimized for traditional PET imaging are used. This study examined these quantitative limitations and assessed the feasibility of generating radiation dosimetry maps in liver regions with high and low (90)Y concentrations. METHODS: (90)Y PET images were collected on a PET/CT scanner and iteratively reconstructed with the vendor-supplied reconstruction algorithm. PET studies on a Jaszczak cylindric phantom were performed to determine quantitative accuracy and minimum detectable concentration (MDC). (90)Y and (18)F point-source studies were used to investigate the possible increase in detected random coincidence events due to bremsstrahlung photons. Retrospective quantitative analyses were performed on (90)Y PET/CT images obtained after 65 right or left hepatic artery radioembolizations in 59 patients. Quantitative image errors were determined by comparing the measured image activity with the assayed (90)Y activity. PET images were converted to dose maps through convolution with voxel S values generated using MCNPX, a Monte Carlo N-particle transport code system for multiparticle and high-energy applications. Tumor and parenchyma doses and potential bias based on measurements found below the MDC were recorded. RESULTS: Random coincidences were found to increase in (90)Y acquisitions, compared with (18)F acquisitions, at similar positron emission rates because of bremsstrahlung photons. Positive bias was observed in all images. Quantitative accuracy was achieved for phantom inserts above the MDC of 1 MBq/mL. The mean dose to viable tumors was 183.6 ± 156.5 Gy, with an average potential bias of 3.3 ± 6.4 Gy. The mean dose to the parenchyma was 97.1 ± 22.1 Gy, with an average potential bias of 8.9 ± 4.9 Gy. CONCLUSION: The low signal-to-noise ratio caused by low positron emission rates and high bremsstrahlung photon production resulted in a positive bias on (90)Y PET images reconstructed with conventional iterative algorithms. However, quantitative accuracy was good at high activity concentrations, such as those found in tumor volumes, allowing for adequate tumor (90)Y PET/CT dosimetry after radioembolization.


Subject(s)
Embolization, Therapeutic , Image Processing, Computer-Assisted , Yttrium Radioisotopes , Humans , Phantoms, Imaging , Positron-Emission Tomography , Radiometry , Tomography, X-Ray Computed
16.
Kidney Int ; 75(9): 936-44, 2009 May.
Article in English | MEDLINE | ID: mdl-19225557

ABSTRACT

In the setting of high salt intake, aldosterone stimulates fibrosis in the heart, great vessels, and kidney of rats. We used uninephrectomized rats treated with angiotensin II and placed on a high salt diet to exaggerate renal fibrosis. We then tested whether mineralocorticoid receptor blockade by spironolactone or aldosterone synthase inhibition by FAD286 have similar effects on end-organ damage and gene expression. Individually, both drugs prevented the hypertensive response to uninephrectomy and high salt intake but not when angiotensin II was administered. Following 4 weeks of treatment with FAD286, plasma aldosterone was reduced, whereas spironolactone increased aldosterone at 8 weeks of treatment. Angiotensin II and high salt treatment caused albuminuria, azotemia, renovascular hypertrophy, glomerular injury, increased plasminogen activator inhibitor-1 (PAI-1), and osteopontin mRNA expression, as well as tubulointerstitial fibrosis in the kidney. Both drugs prevented these renal effects and attenuated cardiac and aortic medial hypertrophy while reducing osteopontin and transforming growth factor-beta mRNA expression in the aorta. The two drugs also reduced cardiac interstitial fibrosis but had no effect on that of the perivascular region. Although spironolactone enhanced angiotensin II and salt-stimulated PAI-1 mRNA expression in aorta and heart, spironolactone and FAD286 prevented renal PAI-1 mRNA protein expression. Our study shows that mineralocorticoid receptor antagonism and aldosterone synthase inhibition similarly decrease hypertrophy and interstitial fibrosis of the kidney and heart caused by angiotensin II and high salt.


Subject(s)
Angiotensin II/adverse effects , Cytochrome P-450 CYP11B2/antagonists & inhibitors , Heart Diseases/drug therapy , Kidney Diseases/drug therapy , Mineralocorticoid Receptor Antagonists/pharmacology , Sodium Chloride, Dietary/adverse effects , Animals , Enzyme Inhibitors/pharmacology , Fibrosis/drug therapy , Heart Diseases/chemically induced , Heart Diseases/pathology , Kidney Diseases/chemically induced , Kidney Diseases/pathology , Rats , Spironolactone/pharmacology
17.
Xenotransplantation ; 12(3): 197-208, 2005 May.
Article in English | MEDLINE | ID: mdl-15807770

ABSTRACT

BACKGROUND: The induced antibodies against Galalpha1,3Gal (Gal) and non-Gal epitopes may contribute to delayed xenograft rejection (DXR). We asked whether blockade of the CD40/CD154 and CD28/B7 co-stimulatory pathways modulates the baboon elicited antibody response to pig Gal and non-Gal antigens. METHODS: Eighteen baboons received heterotopic heart transplants from pigs transgenic for human decay-accelerating factor (n = 13) or membrane cofactor protein (n = 5). Ten reference ''conventional therapy'' animals received cyclosporin A, cyclophosphamide and mycophenolate mofetil, with (n = 4) or without (n = 6) anti-CD20. Eight ''co-stimulation blockade'' animals received anti-CD154 mAb (IDEC-131) and anti-thymocyte globulin, with (n = 4) or without (n = 4) anti-CD20; two of these animals also received CTLA4-Fc. Anti-alphaGal IgG and IgM, anti-non-Gal antibodies and graft histology were assessed serially. RESULTS: Excluding two early graft failures, median graft survival with conventional therapy was 15 days (range 6 to 36 days, n = 8). Anti-Gal IgG antibody remained low through day 6 to 10, only one graft failure was accompanied by significant rise in anti-Gal IgG, and the anti-non-Gal response was weak (n = 2) or absent (n = 7). However many recipients succumbed with infection (n = 4) or coagulopathy (n = 2); DXR and ICOS+ T cells were prevalent in long-surviving grafts. With co-stimulation blockade, excluding three early graft failures, median graft survival was 7 days (range 6 to 11 days, n = 5). This regimen was very well tolerated, but increased anti-Gal antibody titer within 14 days was associated with graft failure in four of six animals. Although an anti-non-Gal response was present in three of six animals during IDEC-131 monotherapy (one strong, two weak), it was absent in both cases with additional CTLA4-Fc treatment. CONCLUSIONS: As used here, CD154 blockade alone does not completely prevent induction of Gal and non-Gal anti-pig antibodies. Our preliminary data suggest that other co-stimulation pathways, including CD28/B7 and ICOS, are sufficient to mediate high-titer anti-non-Gal antibody to porcine antigens in baboons, and contribute significantly to the pathogenesis of DXR.


Subject(s)
Antibodies/pharmacology , B7-1 Antigen/immunology , CD28 Antigens/immunology , CD40 Ligand/immunology , Heart Transplantation/immunology , Papio , Swine , Transplantation, Heterologous/immunology , Anemia/etiology , Animals , Animals, Genetically Modified , Antibodies/blood , Antibody Formation , Disaccharides/immunology , Female , Graft Rejection/pathology , Graft Survival , Heart Transplantation/adverse effects , Immunohistochemistry , Leukopenia/etiology , Male , Myocardium/metabolism , Myocardium/pathology , Thrombocytopenia/etiology , Transplantation, Heterologous/adverse effects
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