Statistical Considerations in Identifying Mechanisms of Change

The statistical search for mechanisms of change involves multiple inferential tests, ones that generally follow a fixed sequence designed to demonstrate mediation. While there are several popular approaches to conducting such tests, e.g., SEM and MRA, the inflated Type I error rate problem associated with conducting these tests has received little, if any, attention. This paper offers 2 solutions to avoid committing Type I errors associated with mediational tests. Most straightforward, investigators may choose to use a Bonferroni adjustment. In contrast, a design-based approach can be used that tests rival explanations for the observed effects. Examples drawn from addiction research are provided.     

Psychological morbidity after myocardial infarction in an area of deprivation in the UK: evaluation of a self-help package.

BACKGROUND: Psychological morbidity after an acute myocardial infarction (AMI) is known to be common, but can be addressed by appropriate rehabilitation. The area in which this research was conducted experiences high rates of deprivation and of coronary heart disease and limited access to hospital-based rehabilitation. Responding to concern about psychological needs of AMI patients, a self-help package was introduced and evaluated alongside standard hospital-based cardiac rehabilitation. AIMS: To evaluate the impact of a home-based self-help package (the Heart Manual), alongside existing cardiac rehabilitation provision, on psychological morbidity and health status after AMI. A secondary aim was to assess the suitability of the Heart Manual for older patients aged over 80 years. METHODS: A controlled observational study, comparing two cohorts of patients discharged from hospital after AMI. The intervention group was given the self-help package in addition to standard care. The control group received standard care alone. Outcome measures used were the Hospital Anxiety and Depression Scale and the EuroQol. RESULTS: The intervention group showed significant improvement in anxiety and depression scores after 3 months and nonsignificant improvement in general health status. Patients who attended hospital-based rehabilitation classes, and those aged over 80 years, also benefited from the intervention. CONCLUSION: A home-based self-help rehabilitation package is an effective tool alongside hospital-based rehabilitation classes and can be given to all age groups.     

Interferon-gamma knockout fails to confer protection against obliteration in heterotopic murine tracheal allografts.

BACKGROUND: Interferon-gamma, produced by T-helper cells, activates macrophages and increases expression of major histocompatibility complex (MHC) products in acute and chronic rejection. We investigated the role of interferon-gamma in murine heterotopic tracheal allografts. METHODS: Tracheas from BALB/c mice were heterotopically transplanted to BALB/c (12 isografts: 2 weeks [n = 6] and 4 weeks [n = 6], C57BL/6 (12 allografts: 2 weeks [n = 6] and 4 weeks [n = 6]) and C57BL/6 interferon-gamma knockout mice (12 interferon-gamma knockout allografts: 2 weeks [n = 4] and 4 weeks [n = 8]). BALB/c interferon-gamma knockout tracheas were transplanted to C57BL/6 mice (reverse knockout: 4 weeks [n = 6]) and BALB/c interferon-gamma knockout mice (4 weeks [n = 2]). C57BL/6 tracheas were transplanted to Bm12 mice (MHC Class II mismatch allografts: 4 weeks [n = 6]). Conventional histology and immunohistochemistry for CD4, CD8 and CD11b were performed. RESULTS: Minimal (<20%) obliteration was seen at 2 weeks in the allograft groups. No obliteration was seen in the isograft groups. However, all allografts were completely obliterated at 4 weeks. Interferon-gamma knockout allograft combinations displayed severe rejection characterized by intense intra- and extraluminal infiltration by CD4-, CD8- and CD11b-labeled cells. The MHC Class II mismatch allograft group showed normal epithelium and mild sub-epithelial infiltration by CD4+ cells at 4 weeks (CD8-, CD11b-). CONCLUSIONS: Absence of interferon-gamma does not protect the allograft from obliteration. Epithelial destruction by cytotoxic T cells appears to be an important mechanism in the development of obliteration in murine heterotopic tracheal allografts.     

TGF-beta promotes the establishment of renal cell carcinoma bone metastasis.

Bone metastases develop in approximately 30% of patients with RCC, and the mechanisms responsible for this phenomenon are unknown. We found that TGF-beta1 stimulation of RCC bone metastasis cells promotes tumor growth and bone destruction possibly by stimulating paracrine interactions between tumor cells and the bone. INTRODUCTION: Bone metastasis is a frequent complication and causes marked morbidity in patients with renal cell carcinoma (RCC). Surprisingly, the specific mechanisms of RCC interaction with bone have been scarcely studied despite the inability to prevent or effectively treat bone metastasis. Bone is a reservoir for various growth factors including the pleiotropic cytokine TGF-beta1. TGF-beta1 has been shown to have tumor-supportive effects on advanced cancers and evidence suggests its involvement in promoting the development of breast cancer bone metastasis. Here, we studied the potential role of TGF-beta1 in the growth of RCC bone metastasis (RBM). MATERIALS AND METHODS: To inhibit TGF-beta1 signaling, RBM cells stably expressing a dominant-negative (DN) TGF-betaRII cDNA were generated. The in vivo effect of TGF-beta1 on RBM tumor growth and osteolysis was determined by histological and radiographic analysis, respectively, of athymic nude mice after intratibial injection of parental, empty vector, or DN RBM cells. The in vitro effect of TGF-beta1 on RBM cell growth was determined after TGF-beta1 treatment by MTT assay. RESULTS: TGF-beta1 and the TGF-beta receptors I and II (TGF-betaRI/II) were consistently expressed in both RBM tissues and cell lines. Inhibition of TGF-beta1 signaling in RBM cells significantly reduced tumor establishment and osteolysis observed in vivo after injection into the murine tibia, although no effect on tumor establishment was observed after injection of RBM cells subcutaneously or into the renal subcapsule. Treatment of five RBM cell lines with TGF-beta1 in vitro either had no effect (2/5) or resulted in a significant inhibition (3/5) of cell growth, suggesting that TGF-beta1 may promote RBM tumor growth indirectly in vivo. CONCLUSIONS: TGF-beta1 stimulation of RBM cells plays a role in promoting tumor growth and subsequent osteolysis in vivo, likely through the initiation of tumor-promoting paracrine interactions between tumor cells and the bone microenvironment. These data suggest that inhibition of TGF-beta1 signaling may be useful in the treatment of RBM.     

Enteric hyperoxaluria, nephrolithiasis, and oxalate nephropathy: potentially serious and unappreciated complications of Roux-en-Y gastric bypass.

BACKGROUND: Neither the presence nor prevalence of enteric hyperoxaluria has been recognized after Roux-en-Y gastric bypass (RYGBP). We have noted a high rate of oxalate nephrolithiasis and even 2 patients with oxalate nephropathy in this patient population postoperatively. Our aim was to determine the frequency of the occurrence and effects of enteric hyperoxaluria after RYGBP. METHODS: Retrospective review of all patients at our institution diagnosed with calcium oxalate nephrolithiasis or oxalate nephropathy after standard (n = 14) or distal (n = 9) RYGBP. The mean postoperative follow-up was 55 months. RESULTS: A total of 23 patients (14 men and 9 women; mean age 45 years; mean preoperative body mass index 55 kg/m(2)) developed enteric hyperoxaluria after RYGBP, defined by the presence of oxalate nephropathy (n = 2) or calcium oxalate nephrolithiasis (n = 21) and increased 24-hour excretion of urinary oxalate and/or calcium oxalate supersaturation. Enteric hyperoxaluria was recognized after a mean weight loss of 46 kg at 29 months (range 2-85) after RYGBP. Two patients developed renal failure and required chronic hemodialysis. Of the 21 patients with nephrolithiasis, 14 had no history of nephrolithiasis preoperatively, and 19 of 21 required lithotripsy or other intervention. Of the 23 patients, 20 tested had increased oxalate excretion, and 14 of 15 tested had high urine calcium oxalate supersaturation. CONCLUSION: Enteric hyperoxaluria, nephrolithiasis, and oxalate nephropathy must be considered with the other risks of RYGBP. Efforts should be made to identify factors that predispose patients to developing hyperoxaluria.     

Integrating disability management into strategic plans: creating healthy organizations.

The integration of disability management into the strategic planning of a corporation ensures a work environment is created that motivates employees to consistently meet customer expectations. Disability management strategies can achieve significant decreases to the human and financial cost of workers' compensation, sick leave or short term disability, and long-term disability. The business case for disability management including effective return to work programs clearly supports program implementation to enhance employee engagement, delivery of corporate priorities, and improvement to the company's bottom line.     

Routine postoperative chest x-ray following laparoscopic nephrectomy.

PURPOSE: To determine whether a routine postoperative chest x-ray is required following uneventful laparoscopic nephrectomy to rule out pneumothorax. METHODS: From June 1999 to May 2003, 308 laparoscopic nephrectomy cases were performed by 5 different surgeons. This consisted of 121 radical nephrectomies, 106 donor nephrectomies, 29 simple nephrectomies, 29 partial nephrectomies, and 23 nephroureterectomies. Of the 308 procedures, 186 postoperative chest x-ray s were obtained in the recovery room: 183 routinely and 3 for known intraoperative diaphragmatic injuries. Routine chest x-rays were not obtained in 122 cases due to the individual surgeon's preference. Of these 122 patients, 15 underwent chest x-ray performed while hospitalized secondary to pulmonary issues or fever. RESULTS: Of the 308 cases, 4 pneumothoraces were identified on chest x-ray. Three were identified in the patients who had intraoperative identification of diaphragmatic injury. The fourth pneumothorax was identified in a patient who did not have a routine postoperative chest x-ray but did have a chest x-ray obtained due to postoperative shoulder pain. The pneumothorax in this patient resolved spontaneously. No incidental findings existed of pneumothorax in any patient who underwent routine postoperative chest x-ray. CONCLUSION: In our series, a pneumothorax was identified either intraoperatively or based on postoperative clinical findings. None of the 183 routine postoperative chest x-rays changed patient management. Routine postoperative chest x-ray is not necessary in uncomplicated laparoscopic nephrectomy.     

Performance measures for evaluating services for people with a first episode of psychosis

Aim: The purpose of this project was to operationalize and apply a previously identified set of performance measures designed to evaluate services for those experiencing a first episode of a schizophrenia spectrum disorder. Methods: Operational definitions were developed for previously identified measures through an iterative process of discussions between clinical experts and health‐care evaluators. Data were collected from existing sources including corporate databases, clinical databases and chart review. Results: Definitions were developed for 44 measures covering seven of eight domains recommended for service level evaluation by the Canadian Institute for Health Information domains. Forty measures could be calculated. Conclusions: The measures represent a comprehensive set of performance measures suitable for the evaluation of services for people with a first‐episode psychosis. The measures could be used by other services in order to establish standards and norms for routine clinical practice.