Validation of healthcare professional proxy-reported children's International Mucositis Evaluation Scale.

OBJECTIVE: The objective was to describe the reliability and validity of the healthcare professional proxy-report version of the Children's International Mucositis Evaluation Scale (ChIMES). METHODS: We included pediatric patients who were between 4 and 21 years of age and scheduled to undergo hematopoietic cell transplantation. Mucositis was evaluated by trained healthcare professionals who scored ChIMES, the World Health Organization oral toxicity scale, mouth, and throat pain visual analogue scale, National Cancer Institute-Common Terminology Criteria and the Oral Mucositis Daily Questionnaire. Measures were completed daily and evaluated on days 7-17 post-stem cell infusion for this analysis. Psychometric properties examined were internal consistency, test-retest reliability (days 13 and 14), and convergent construct validity. RESULTS: There were 192 participants included. Cronbach's alpha was 0.90 for ChIMES Total Score and 0.93 for ChIMES Percentage Score. Test-retest reliability were as follows: intraclass correlation coefficient (ICC) 0.82 (95% confidence interval (CI) 0.77-0.85) for ChIMES Total Score and ICC 0.82 (95% CI 0.77-0.86) for ChIMES Percentage Score. In terms of construct validation, all correlations between measures met or exceeded those hypothesized (all p < 0.05). CONCLUSIONS: The healthcare professional proxy-report version of ChIMES is reliable and valid for children and adolescents undergoing hematopoietic cell transplantation.

Decision making in frail patients at risk of postoperative delirium: A case study and literature review.

Preoperative frailty is strongly associated with risks of postoperative delirium. However, gaps exist in targeted recommendations for clinical decision making related to surgical interventions in frail older patients. A case study is presented involving a frail 74-year-old referred to the palliative care team for assistance with clinical decision making and in weighing risks and benefits of a surgical intervention. A literature review on the quantification of postoperative delirium risk and how this information might inform medical decision making in frail surgical patients did not identify clear clinical guidelines. In the absence of practice guidelines, the Patient Priorities Care model is proposed as a framework to help providers working with patients and caregivers facing complex medical decisions to better align interventions with patient values.

Development of a modified lymphocyte transformation test for diagnosing drug-induced liver injury associated with an adaptive immune response.

Drug-induced liver injury (DILI) is a growing problem. Diagnostic methods to differentiate DILI caused by an adaptive immune response from liver injury of other causes or to identify the responsible drug in patients receiving multiple drugs, herbals and/or dietary supplements (polypharmacy) have not yet been established. The lymphocyte transformation test (LTT) has been proposed as a diagnostic method to determine if a subject with an apparent hypersensitivity reaction has become sensitized to a specific drug. In this test, peripheral blood mononuclear cells (PBMC) collected from a subject are incubated with drug(s) suspected of causing the reaction. Cell proliferation, measured by the incorporation of [3H]-thymidine into new DNA, is considered evidence of a drug-specific immune response. The objectives of the current studies were to: (1) develop and optimize a modified version of the LTT (mLTT) and (2) investigate the feasibility of using the mLTT for diagnosing DILI associated with an adaptive immune response and identifying the responsible drug. PBMC collected from donors with a history of drug hypersensitivity reactions to specific drugs (manifested as skin rash) were used as positive controls for assay optimization. Following optimization, samples collected from 24 subjects enrolled in the U.S. Drug-Induced Liver Injury Network (DILIN) were tested in the mLTT. Using cytokine and granzyme B production as the primary endpoints to demonstrate lymphocyte sensitization to a specific drug, most samples from the DILIN subjects failed to respond. However, robust positive mLTT responses were observed for two of four samples from three DILIN subjects with hepatitis due to isoniazid (INH). We conclude that the mLTT, as performed here on frozen and thawed PBMC, is not a reliable test for diagnosing DILI caused by all drugs, but that it may be useful for confirming the role of the adaptive immune response in DILI ascribed to INH.

Caphosol for prevention of oral mucositis in pediatric myeloablative haematopoietic cell transplantation.

BACKGROUND: The primary objective was to determine whether topically administered Caphosol, rinsed orally four times daily at the initiation of conditioning, reduces the duration of severe oral mucositis (OM) compared with placebo among children and adolescents undergoing haematopoietic cell transplantation (HCT). METHODS: This was a Children's Oncology Group multicentre randomised double-blinded placebo-controlled clinical trial. Patients between the ages of 4 and 21 years who were scheduled to undergo myeloablative HCT for any indication were randomised to Caphosol or placebo saline rinses four times daily from initiation of conditioning through day +20. Subjects were assessed daily for OM using the World Health Organisation (WHO) Oral Toxicity Scale, Mouth Pain Categorical Scale (0-10) and the Oral Mucositis Daily Questionnaire (OMDQ). The primary end point was duration of severe OM (WHO ⩾3). RESULTS: The study enrolled 220 participants with a median age of 13.7 years (range 4.0-21.9); 163 (74%) received allogeneic HCT. The mean (±s.d.) duration of severe OM was not reduced among Caphosol (4.5±5.0 days) vs placebo (4.5±4.8; P=0.99) recipients. The incidence of severe OM in the Caphosol and placebo arms was 63% (57 out of 91) and 68% (62 out of 91), respectively (P=0.44). There were no significant differences in any of the secondary end points between the groups. CONCLUSIONS: Caphosol did not reduce severe OM when compared with placebo among children and adolescents undergoing myeloablative HCT. Studies to identify effective interventions for OM are needed in this population.

Fat malabsorption and increased intestinal oxalate absorption are common after Roux-en-Y gastric bypass surgery.

BACKGROUND: Hyperoxaluria and increased calcium oxalate stone formation occur after Roux-en-Y gastric bypass (RYGB) surgery for morbid obesity. The etiology of this hyperoxaluria is unknown. We hypothesized that after bariatric surgery, intestinal hyperabsorption of oxalate contributes to increases in plasma oxalate and urinary calcium oxalate supersaturation. METHODS: We prospectively examined oxalate metabolism in 11 morbidly obese subjects before and 6 and 12 months after RYGB (n = 9) and biliopancreatic diversion-duodenal switch (BPD-DS) (n = 2). We measured 24-hour urinary supersaturations for calcium oxalate, apatite, brushite, uric acid, and sodium urate; fasting plasma oxalate; 72-hour fecal fat; and increases in urine oxalate following an oral oxalate load. RESULTS: Six and 12 months after RYGB, plasma oxalate and urine calcium oxalate supersaturation increased significantly compared with similar measurements obtained before surgery (all P ≤ .02). Fecal fat excretion at 6 and 12 months was increased (P = .026 and .055, 0 vs 6 and 12 months). An increase in urine oxalate excretion after an oral dose of oxalate was observed at 6 and 12 months (all P ≤ .02). Therefore, after bariatric surgery, increases in fecal fat excretion, urinary oxalate excretion after an oral oxalate load, plasma oxalate, and urinary calcium oxalate supersaturation values were observed. CONCLUSION: Enteric hyperoxaluria is often present in patients after the operations of RYGB and BPD-DS that utilize an element of intestinal malabsorption as a mechanism for weight loss.

Age-related changes in marmoset trabecular and cortical bone and response to alendronate therapy resemble human bone physiology and architecture.

In older humans, bone elongation ceases, periosteal expansion continues, and bone remodeling remains a dominant metabolic process. An appropriate animal model of type I and type II osteoporosis would be a species with sealed growth plates and persistence of bone remodeling. The rat is commonly used as a primary model, but due to delayed epiphyseal closure with continuous modeling and lack of Haversian remodeling, Food and Drug Administration guidelines recommend assessment of bone quality in an additional, non rodent, remodeling species. This study investigated the skeletal characteristics of senescent marmosets to evaluate their suitability as an osteoporosis model. Animals were randomized across three experimental groups; controls for both sexes and marmosets receiving alendronate for either 30 or 60 days (28 microg/kg, sc, twice per week). Outcome measures included serum chemistry and bone biomarkers, DEXA, histomorphometry, micro-computed tomography, and histopathology. Results showed that the adult marmoset skeleton has similar anatomical characteristics to the adult human, including the absence of growth plates, presence of Haversian system, and true remodeling of cancellous and cortical bone. Structural analyses of senescent marmoset cancellous bone demonstrated loss of trabecular mass and architecture similar to skeletal changes described for elderly men and women. Treatment with alendronate improved trabecular volume and number by reducing bone resorption, although bone formation was also reduced through coupling of bone remodeling. The common marmoset may provide a valuable model for research paradigms targeting human bone pathology and osteoporosis due to skeletal features that are similar to age-related changes and response to bisphosphonate therapy reported for humans.

Clinical outcomes and graft characteristics in pediatric matched sibling donor transplants using granulocyte colony-stimulating factor-primed bone marrow and steady-state bone marrow.

Matched sibling donor (MSD) transplant is a life-saving procedure for children with various hematological malignancies and non-malignancies. Traditionally, steady-state bone marrow (S-BM) has been used as the source of stem cells. More recently, peripheral blood stem cell (PBSC) after granulocyte-colony stimulating factor (G-CSF) mobilization has gained popularity. Adult studies of G-CSF-primed BM (G-BM) have shown that it produces rapid white blood cell engraftment like PBSC, but with less chronic graft-vs.-host disease. No such study has been published in pediatric patients. We conducted a pilot clinical trial of G-BM for pediatric patients. Ten patients were enrolled and were compared to a contemporaneous group of 12 patients who received S-BM. Patients in the G-BM group received a higher dose of total nucleated cells/kg (7.01 vs. 3.76 x 10(8), p = 0.0009), higher granulocyte-macrophage colony-forming units (CFU-GM)/kg (7.19 vs. 3.53 x 10(5), p = 0.01) and had shorter inpatient length of stay (28 vs. 40 days, p = 0.04). The engraftment, transfusion requirement and disease-free survival between the two groups were similar. We concluded that G-BM should be considered as an alternative graft source to S-BM, with the benefits of larger graft cell dose, higher CFU-GM dose and shorter length of stay.

The role of rehabilitation medicine and palliative care in the treatment of patients with end-stage disease.

Rehabilitation medicine and palliative care share many common goals. They strive to maximize physical function and emotional well-being to the highest extent possible given the nature of the underlying disease process. Many patients with end-stage disease experience symptoms and functional losses that diminish their quality of life. This article outlines the benefits that active rehabilitation therapy can provide to patients in the terminal stages of their disease and some of the ethical and practical issues faced in the planning and provision of this care.

PAR-1 deficiency protects against neuronal damage and neurologic deficits after unilateral cerebral hypoxia/ischemia.

Cardiovascular and neurologic surgeries often involve a temporary reduction in cerebral blood flow. In these conditions, as well as during cerebral ischemia and traumatic brain injury, the temporary loss of oxygen and glucose initiates a cascade of cellular events that culminate in neuronal death and damage. Understanding the mechanisms that contribute to neuronal death after hypoxia/ischemia is critically important for treatment of such brain injury. Here, we use a model of combined cerebral hypoxia/ischemia (H/I) to examine the role of protease-activated receptor-1 (PAR-1) in hypoxic/ischemic neuronal damage. Our data show that PAR-1-deficient mice have smaller lesion volumes than wild-type controls after 45 minutes of H/I. The results of the genetic block of PAR-1 were corroborated using a PAR-1 antagonist, which decreased infarct volume in wild-type C57Bl6 mice. Examination of cellular responses to H/I reveals that PAR-1 -/- animals have less cellular death and diminished glial fibrillary acidic protein expression. Additionally, PAR-1 -/- mice exhibit less motor behavior impairment in rotorod and inverted wire-hang tests. These data suggest that PAR-1 contributes to hypoxic/ischemic brain injury and are consistent with other studies that implicate serine proteases and their receptors in neuropathology after cerebral insults.

Types and rate of implementation of palliative care team recommendations for care of hospitalized veterans.

BACKGROUND: Hospital-based interdisciplinary palliative care teams (PCTs) are increasingly being established to meet the growing demand for high quality care for patients with life-limiting illnesses in which the goal is comfort rather than cure. Two recent studies suggest that PCTs teams are highly effective in influencing care of patients within large academic medical centers. The current study examines whether the previously demonstrated success of palliative care teams within subspecialty academic health centers could be replicated in an urban Veterans Affairs medical center (VAMC). OBJECTIVE: To describe the characteristics of patients referred to, recommendations made by, and implementation rate of an interdisciplinary PCT in an urban VAMC. DESIGN: Retrospective, observational study. SETTING/SUBJECTS: One hundred patients referred by inpatient doctor to the PCT between October 1999 and March 2002 in a 214-bed VA hospital in the New York City area. MEASUREMENTS: Patient demographics, prevalence of five types of recommendations by the PCT and implementation rate by primary physician: (1) advance directives; (2) discharge planning; (3) pain management; (4) symptom management of dyspnea, delirium, constipation, nausea, anxiety, and depression; and (5) consultation orders for other services. RESULTS: The average number of recommendations per patient was 2.84 and 84.2% were implemented. The most frequent recommendations concerned discharge plans. The reasons recommendations were not implemented included: (1) patient or family refusal noted in the medical record, (2) the patient's clinical status changed, including patient death, and (3) the attending physician chose a different dose, medication, or route of administration than was recommended. CONCLUSIONS: Overall, most recommendations were implemented by the referring physicians. This finding is consistent with several prior studies demonstrating that PCTs in acute care can and do influence processes of care for hospitalized patients. Well-designed observational studies and randomized controlled trials of specific palliative care interventions and their effect on patient, family, and health care system outcomes are needed.

Diffuse alveolar hemorrhage in pediatric hematopoietic cell transplant patients.

OBJECTIVE: Diffuse alveolar hemorrhage (DAH) is defined as a syndrome of hypoxia, dyspnea, infiltrates on chest radiograph, and bloody fluid on successive bronchoalveolar lavages without apparent infection. Minimal experience has been reported with DAH after hematopoietic cell transplant (HCT) in children. We reviewed the incidence, management and outcome of DAH in a pediatric HCT population. METHODS: Retrospective review of 138 patients undergoing allogeneic (n = 89) or autologous (n = 49) HCT at a referral children's medical center between January 1996 and April 2000. RESULTS: Seven (5.1%) of 138 patients met criteria for DAH; all were allogeneic recipients. Mean age of DAH patients was 11 years (range: 1.4-15.2). Median onset of DAH following HCT was day 24 (range: 10-50), median day of engraftment day 20 and white blood cell count 0.54 x 10(9)/L (range: < 0.1-7.03), with no difference between survivors and nonsurvivors. All patients developed clinical respiratory failure and 6 required intubation, with PaO(2)/fraction of inspired oxygen <200. Patients were intubated a median of 12 days (range: 1-75). All patients experienced >1 episode of bleeding and 3 patients required reintubation after successful extubation resulting from recurrent DAH. Bronchoalveolar lavage fluid cultures were negative for viruses, bacteria and fungi. All DAH patients received steroids. Three patients died with progressive pulmonary failure and other organ system involvement. Four of 7 DAH patients (57%) survived to discharge, but 3 died from disease relapse at days 116, 138, and 273 post-HCT. CONCLUSION: DAH occurred more frequently in allogeneic HCT recipients compared with autologous recipients. Onset of DAH coincided closely with white blood cell engraftment. Although associated with significant respiratory failure and need for mechanical ventilation, HCT patients can survive DAH.