The Effect of the Statewide Sharing Variance on Geographic Disparity in Kidney Transplantation in the United States

Background and objectives

The Statewide Sharing variance to the national kidney allocation policy allocates kidneys not used within the procuring donor service area (DSA), first within the state, before the kidneys are offered regionally and nationally. Tennessee and Florida implemented this variance. Known geographic differences exist between the 58 DSAs, in direct violation of the Final Rule stipulated by the US Department of Health and Human Services. This study examined the effect of Statewide Sharing on geographic allocation disparity over time between DSAs within Tennessee and Florida and compared them with geographic disparity between the DSAs within a state for all states with more than one DSA (California, New York, North Carolina, Ohio, Pennsylvania, Texas, and Wisconsin).

Design, setting, participants, & measurements

A retrospective analysis from 1987 to 2009 was conducted using Organ Procurement and Transplant Network data. Five previously used indicators for geographic allocation disparity were applied: deceased-donor kidney transplant rates, waiting time to transplantation, cumulative dialysis time at transplantation, 5-year graft survival, and cold ischemic time.

Results

Transplant rates, waiting time, dialysis time, and graft survival varied greatly between deceased-donor kidney recipients in DSAs in all states in 1987. After implementation of Statewide Sharing in 1992, disparity indicators decreased by 41%, 36%, 31%, and 9%, respectively, in Tennessee and by 28%, 62%, 34%, and 19%, respectively in Florida, such that the geographic allocation disparity in Tennessee and Florida almost completely disappeared. Statewide kidney allocations incurred 7.5 and 5 fewer hours of cold ischemic time in Tennessee and Florida, respectively. Geographic disparity between DSAs in all the other states worsened or improved to a lesser degree.

Conclusions

As sweeping changes to the kidney allocation system are being discussed to alleviate geographic disparity—changes that are untested run the risk of unintended consequences—more limited changes, such as Statewide Sharing, should be further studied and considered.     

The ErbB4 Ligand Neuregulin-4 Protects against Experimental Necrotizing Enterocolitis

Necrotizing enterocolitis (NEC) affects up to 10% of premature infants, has a mortality of 30%, and can leave surviving patients with significant morbidity. Neuregulin-4 (NRG4) is an ErbB4-specific ligand that promotes epithelial cell survival. Thus, this pathway could be protective in diseases such as NEC, in which epithelial cell death is a major pathologic feature. We sought to determine whether NRG4-ErbB4 signaling is protective in experimental NEC. NRG4 was used i) in the newborn rat formula feeding/hypoxia model; ii) in a recently developed model in which 14- to 16-day-old mice are injected with dithizone to induce Paneth cell loss, followed by Klebsiella pneumoniae infection to induce intestinal injury; and iii) in bacterially infected IEC-6 cells in vitro. NRG4 reduced NEC incidence and severity in the formula feed/hypoxia rat model. It also reduced Paneth cell ablation–induced NEC and prevented dithizone-induced Paneth cell loss in mice. In vitro, cultured ErbB4^−/− ileal epithelial enteroids had reduced Paneth cell markers and were highly sensitive to inflammatory cytokines. Furthermore, NRG4 blocked, through a Src-dependent pathway, Cronobacter muytjensii–induced IEC-6 cell apoptosis. The potential clinical relevance of these findings was demonstrated by the observation that NRG4 and its receptor ErbB4 are present in human breast milk and developing human intestine, respectively. Thus, NRG4-ErbB4 signaling may be a novel pathway for therapeutic intervention or prevention in NEC.Necrotizing enterocolitis (NEC) is a devastating intestinal disease primarily affecting premature infants. In the United States, NEC afflicts 7% of infants weighing <1500 g.¹ In addition to prematurity, risk factors include hypoxia, bacterial colonization of the intestine, and formula feeding.² The development of NEC seems to be multifactorial, and patients may have any combination of risk factors at the time of presentation. The current disease model is that the immature gut barrier, along with defects in endogenous antimicrobial activity,³ allows bacterial translocation across the epithelium, triggering an inflammatory response that further worsens gut barrier function. Pathogenic bacteria,^{4, 5} inflammatory cytokines such as tumor necrosis factor (TNF),^{6, 7, 8} and Paneth cell dropout³ have all been associated with human NEC and contribute to NEC-like injury in animal models.Available therapy for either prevention or treatment of NEC is limited, and patients currently face a mortality rate of approximately 30%.^{9, 10, 11} Breast-fed infants have a lower risk of NEC than their formula-fed peers,^{12, 13} and a variety of studies have attempted to identify and characterize factors in human milk that confer this protection. Candidate protective molecules to date include immunoglobulins, oligosaccharides, lactoferrin, and soluble growth factors, such as epidermal growth factor (EGF)¹⁴ and heparin-binding EGF-like growth factor (HB-EGF).¹⁵ In rat and mouse models, enteral administration of either EGF^{16, 17} or HB-EGF¹⁸ decreases the incidence and severity of NEC. The primary receptor for both EGF and HB-EGF is EGF receptor (EGFR), the prototypic member of the ErbB receptor tyrosine kinase family. However, HB-EGF also activates ErbB4, a member of the ErbB family whose potential role in the developing gut and NEC is not known.ErbB4 has unique biochemical properties distinguishing it from other ErbB family members. Compared with EGFR, ErbB2, or ErbB3, it recognizes a broader collection of ligands, including the EGF-like growth factors HB-EGF and betacellulin as well as the heregulin/neuregulin molecules.¹⁹ At the same time, the ErbB4 c-terminus contains a distinct and somewhat restricted set of functional docking sites for downstream effectors²⁰ and is thus predicted to elicit divergent cellular effects on activation versus other family members. In fact, we recently demonstrated that neuregulin-4 (NRG4), an ErbB4-specific ligand that does not bind or activate other family members, including EGFR,²¹ specifically promotes survival but not migration or proliferation of mouse colon epithelial cells.²² Thus, ErbB4 is a potentially unique and selective target for therapeutic protection in diseases in which intestinal epithelial cell death is a major pathologic feature.We previously reported that ErbB4 is up-regulated in adult human and murine colon inflammation in vivo²³ and that ErbB4 overexpression protects cultured colonocytes from cytokine-induced apoptosis in a ligand-dependent manner.²⁴ Furthermore, i.p. NRG4 administration reduces the severity of acute murine dextran sulfate sodium colitis.²² Thus, it seems that ErbB4 induction is a natural compensatory response meant to preserve the epithelium rather than part of disease pathology and that ErbB4 activation with exogenous ligand is protective against induced inflammation. However, the role of this signaling pathway in the small intestine, or during development, has not been described. We hypothesized that ErbB4 and its ligands have a protective role in the small bowel during postnatal development, particularly in the setting of NEC-associated acute injury and inflammation. To advance our understanding of ErbB4 biology in intestinal homeostasis and disease, we tested the hypothesis that NRG4-ErbB4 signaling is protective in experimental NEC.     

Proposed guidelines for the management of nodding syndrome

Nodding Syndrome is a poorly understood neurologic disorder of unknown aetiology that affects children and adolescents in Africa. Recent studies have suggested that the head nods are due to atonic seizures and Nodding Syndrome may be classified as probably symptomatic generalised epilepsy. As part of the Ugandan Ministry of Health clinical management response, a multidisciplinary team developed a manual to guide the training of health workers with knowledge and skills to manage the patients. In the absence of a known cause, it was decided to offer symptomatic care. The objective is to relieve symptoms, offer primary and secondary prevention for disability and rehabilitation to improve function. Initial management focuses on the most urgent needs of the patient and the immediate family until ‘stability’ is achieved. The most important needs were considered as seizure control, management of behavioural and psychiatric difficulties, nursing care, nutritional and subsequently, physical and cognitive rehabilitation. This paper summarises the processes by which the proposed guidelines were developed and provides an outline of the specific treatments currently being provided for the patients.     

Comparison of periodontal open flap debridement versus closed debridement with Er,Cr:YSGG laser

Background

Traditional periodontal open flap debridement (OFD) results in reduced pocket depth (PD), clinical attachment loss (CAL), gingival recession (GR) and postoperative pain and discomfort. The quest to overcome these shortcomings has led to research into Er,Cr:YSGG laser assisted pocket therapy (ELAPT). This study was designed to compare the clinical outcomes of ELAPT versus OFD.

Methods

Fifteen patients with a PD of ≥5 mm and ≤8 mm at two sites were selected. Test sites (Group 1) were treated by ELAPT and the control (Group 2) by OFD. Clinical parameters were recorded at baseline, 3 and 6 months and included Plaque Index (PI), Gingival Index (GI), modified Sulcular Bleeding Index (mSBI), PD, CAL and GR.

Results

Both treatments produced a reduction in PI, GI, mSBI and PD, an increase in GR, and a gain in CAL at 3 and 6 months. The mean gain of CAL in Group 1 at 3 and 6 months (1.60 ± 0.78 and 1.80 ± 0.63) was similar (p > 0.05) to the value of Group 2 (1.93 ± 0.88 and 2.00 ± 0.54). GR increased significantly (p < 0.05) only in Group 2 at 3 and 6 months (1.80 ± 0.56 and 1.87 ± 0.64) compared to Group 1 (0.50 ± 0.68 and 0.60 ± 0.74).

Conclusions

ELAPT compared with OFD results in similar CAL gains with less GR and significant reductions in PD, GI and mSBI, and may be considered as an alternative to surgical therapy.     

Thoracic surgical management of colorectal lung metastases: a questionnaire survey of members of the Society for Cardiothoracic Surgery in great Britain and Ireland

Introduction

Distant metastases to liver and lung are not uncommon in colorectal cancer. Resection of metastases is accepted widely as the standard of care. However, there is no firm evidence base for this. This questionnaire survey was carried out to assess the current practice preferences of cardiothoracic surgeons in Great Britain and Ireland.

Methods

An online questionnaire survey was emailed to cardiothoracic surgeons in Great Britain and Ireland. The survey was live for 12 weeks. Responses were collated with SurveyMonkey^®.

Results

Overall, there were 75 respondents. The majority (83%) indicated thoracic surgery as a specialist interest. Almost all (99%) used thoracic computed tomography (CT) for staging; 70% added liver CT and 51% added pelvic CT. Fluorodeoxyglucose positron emission tomography was used by 86%. The most frequent indication for pulmonary resection (97%) was solitary lung metastasis without extrathoracic disease. Video assisted thoracoscopic surgery (VATS) was used by 85%. In addition, thoracotomy was used by 96%. A third (33%) used radiofrequency ablation. Synchronous liver and lung resection was contraindicated for 83% of respondents. Over three-quarters (77%) thought that scientific equipoise exists presently for lung resection for colorectal lung metastases but only 21% supported a moratorium on this type of surgery until further evidence becomes available.

Conclusions

The results confirm that the majority of respondents use conventional cross-sectional imaging and either VATS or formal thoracotomy for resection. The results emphasise the continuing need for formal randomised trials to provide evidence of any survival benefit from pulmonary metastasectomy for colorectal lung metastases.     

More stressors prior to and during the course of bipolar illness in patients from the United States compared with the Netherlands and Germany

Considerable data suggest that compared to some European countries, in the U.S. there are more childhood onset bipolar disorders, more adverse courses of illness, and greater treatment resistance. Psychosocial variables related to these findings have not been adequately explored. Therefore we analyzed psychosocial stressors in three time domains: childhood; the year prior to illness Onset; and the Last Episode from questionnaires in 968 outpatients (mean age 41) with bipolar I or II disorder; 676 from four sites in the U.S. and 292 from three in the Netherlands and Germany (abbreviated here as Europe). Compared to the Europeans, those from the U.S. had significantly more stressors in childhood and prior to the last episode. Stressors prior to the last episode were related to: childhood stressors; an earlier age at illness onset; anxiety and substance abuse comorbidity; lower income; both parents having an affective illness; and feeling more stigma. These data suggest a greater prevalence of adverse life events in childhood and over the course of bipolar illness in the U.S. compared to the Netherlands and Germany. Clinical, therapeutic, and public health approaches to these illness-relevant stressors require further exploration.