Do non-rearfoot runners experience greater second metatarsal stresses than rearfoot runners?

Stress fracture of the second metatarsal is a common and problematic injury for runners. The choice of foot strike pattern is known to affect external kinetics and kinematics but its effect on internal loading of the metatarsals is not well understood. Models of various complexities can be used to investigate the effects of running characteristics on metatarsal stresses. This study aimed to compare second metatarsal stress between habitual rearfoot and non-rearfoot strikers during barefoot running, using a novel participant-specific finite element model, including accurate metatarsal and soft tissue geometry. Synchronised force and kinematic data were collected during barefoot overground running from 20 participants (12 rearfoot strikers). Stresses were calculated using a previously evaluated and published 3D finite element model. Non-rearfoot strikers demonstrated greater external loading and joint contact forces than rearfoot runners, but there were no differences in stresses between groups. Additionally, the study allowed for a qualitative assessment of bone geometries and stresses. No correlation was found between bone volume and stresses, however, there was found to be a large variation in metatarsal shapes, possibly accounting for the lack of difference in stresses. This emphasises the importance of bone geometry when estimating bone stress and supports the suggestion that external forces should not be assumed to be representative of internal loading.

Three dimensional finite element modelling of metatarsal stresses during running.

Second metatarsal stress fractures are a problematic injury for runners and are formed when the rate of repair of bone is outpaced by the damage accumulated during loading. Measuring the peak stresses on the bone during running gives an indication of damage accumulation but direct measurement is invasive. Finite element modelling is a viable alternative method of accurately estimating bone stresses but tends to be too computationally expensive for use in applied research. This study presents a novel and simple finite element model which can estimate bone stresses on the second metatarsal during the stance phase of walking and running, accounting for joint reaction forces and soft tissue effects. The influence of the forces and kinematic inputs to the model and the presence of the soft tissues was quantified using a sensitivity analysis. The magnitudes of maximum stress from the model are similar to existing finite element models and bone staple strain gauge values collected during walking and running. The model was found to be most sensitive to the pitch angle of the metatarsal and the joint reaction forces and was less sensitive to the ground reaction forces under the metatarsal head, suggesting that direct measurement of external forces should not be assumed to represent internal stresses.

Incorporating subject-specific geometry to compare metatarsal stress during running with different foot strike patterns.

Stress fracture of the second metatarsal is a common and problematic injury for runners. The choice of foot strike pattern is known to affect external kinetics and kinematics but its effect on internal loading of the metatarsals is not well understood. Subject-specific models of the second metatarsal can be used to investigate internal loading in a non-invasive manner. This study aimed to compare second metatarsal stress between habitual rearfoot and non-rearfoot strikers during barefoot running, using a novel subject-specific mathematical model, including accurate metatarsal geometry. Synchronised force and kinematic data were collected during barefoot overground running from 20 participants (12 rearfoot strikers). Stresses were calculated at the plantar and dorsal periphery of the midshaft of the metatarsal using a subject-specific beam theory model. Non-rearfoot strikers demonstrated greater external loading, bending moments and compressive forces than rearfoot strikers, but there were no differences in peak stresses between groups. Statistical parametric analysis revealed that non-rearfoot strikers had greater second metatarsal stresses during early stance but that there was no difference in peak stresses. This emphasises the importance of bone geometry when estimating bone stress and supports the suggestion that external forces should not be assumed to be representative of internal loading.

Altered forefoot function following a military training activity.

BACKGROUND: Injury rates are high in populations that regularly undertake weight-bearing physical activity, particularly military populations. Military training activities, that often include load carriage, have been associated with lower limb injury occurrence, specifically stress fractures. RESEARCH QUESTION: Recent work identified plantar loading variables as risk factors for lower limb stress fractures in Royal Marines recruits that were assessed during barefoot running. This study aimed to quantify how those plantar loading variables changed in Royal Marines recruits following a prolonged military load carriage activity, to further understand potential mechanisms for lower limb stress fractures. METHODS: Bilateral, synchronised plantar pressure and lower limb kinematic data were recorded during barefoot running at 3.6 m s-1 (±5%) pre- and post- a 12.8-km training activity (∼150 min). The training activity was completed with an average speed typical of walking (1.4 m.s-1), and 35.5 kg of additional load was carried throughout. Data were collected from 32 male Royal Marines recruits who completed the training activity in week-21 of the 32-week training programme. Plantar pressure variables and ankle dorsiflexion were compared between pre- and post-activity. RESULTS: Post-activity there was reduced loading under the forefoot and increased loading under the rearfoot and midfoot. There was no change in dorsiflexion touchdown angle, but an increase in peak dorsiflexion and range of motion post-activity. SIGNIFICANCE: The increased rearfoot loading, reduced forefoot loading and increased ankle dorsiflexion following a prolonged military load carriage activity suggest a reduced transfer of loading from the rearfoot to the forefoot during stance, which may have implications for the development of stress fractures, particularly of the metatarsals.

Immune expression in children with Wilms tumor: a pilot study.

BACKGROUND: Given improvements in multimodality therapy, survival among children with Wilms tumor (WT) exceeds 90%. However, 15% of children with favorable histology and 50% of children with anaplastic WT experience recurrence or progression. Of patients with advanced disease, only 50% survive to adulthood. In adult malignancies (including renal tumors), patient survival has improved with the advent of immunotherapy. However, little is known about the immune microenvironment of WT, making the potential role of immunotherapy unclear. OBJECTIVE: The objective of the study is to perform an exploratory, descriptive analysis of the immune milieu in WT. STUDY DESIGN: Between 2016 and 2017, all pediatric patients with WT, some of whom received neoadjuvant chemotherapy, underwent ex vivo wedge biopsy at the time of nephrectomy. The fresh tumor tissue and peripheral blood samples were analyzed for infiltrating immune infiltrate and effector cells using flow cytometry. Immunohistochemistry was performed for CD4, CD8, and PD-L1 expression. Matched blood samples were obtained for each patient, and circulating immune cells were analyzed by flow cytometry. RESULTS: A total of six patients were enrolled. One patient with neuroblastoma was excluded. The remaining five patients included the following: two with unilateral WT (resected before chemotherapy), two with bilateral WT (resected after neoadjuvant chemotherapy), and one with Denys-Drash syndrome, end-stage renal disease, and history of WT in the contralateral kidney. Immune analysis showed that WT were infiltrated by immune cells regardless of chemotherapy status. CD8 and CD4 T cells were present in the tumor tissue and exhibited an activated phenotype. Elevated levels of natural killer (NK) cells were observed in the tumors (Figure). Immune checkpoint PD-L1 was also found expressed in one of the tumors stained. DISCUSSION: In this pilot study, it was found that WTs were infiltrated by immune cells (CD45+) both before and after chemotherapy. Elevated levels of NK cells infiltrating the tumor specimens, which were quantitatively increased compared with levels of NK cells circulating in the blood, were noted. T cells, particularly CD4+ and CD8+ T cells, were present in tumor specimens. Tumor-infiltrating CD4 and CD8 T cells displayed an activated phenotype as defined by increased expression of human leukocyte antigen-DR isotype (HLA-DR), programmed cell death protein 1 (PD1), and CD57. Together, these findings suggest that WT microenvironment is immune engaged and may be susceptible to immunotherapy similar to other malignancies. CONCLUSIONS: These pilot data suggest an immune-engaged tumor microenvironment is present within WT. This implies that WT may be susceptible to immunotherapy similar to adult renal tumors and other adult malignancies. Follow-up studies are currently underway.

Professional caregivers' knowledge, beliefs and attitudes about awareness in advanced dementia: a systematic review of qualitative studies.

OBJECTIVES: Awareness can be defined as a response to, or evaluation of, an aspect of one's situation or internal state. Awareness becomes impaired as dementia progresses; however, the exact nature and degree of impairment in advanced dementia remains unclear. The extent to which caregivers understand or make assumptions about the level and nature of awareness in advanced dementia may have a significant impact on their ability to appropriately respond to and care for the person with dementia. This systematic review examines the literature regarding professional caregiver perceptions about awareness in advanced dementia. DESIGN: A systematic search of online literature databases (PsychInfo, Medline, Embase, CINAHL) was conducted up to January 15, 2018, using a range of search terms related to dementia, awareness and caregiver attitudes. RESULTS: The systematic review included a total of 10 qualitative studies that were heterogeneous in aspects of design, including analyses. Narrative synthesis was used to integrate results. Four major themes were identified from review of the papers: how professional caregivers defined awareness; professional caregiver beliefs about what influences the expression of awareness; professional caregiver beliefs around how to assess awareness in advanced dementia; and the perceived impact of episodes of increased awareness on the person with dementia and caregiver. Sub-themes were identified within each of these areas. CONCLUSION: This review highlights the importance of professional caregiver perceptions of awareness in advanced dementia. Supporting professional caregivers to assess and understand the nature of awareness in advanced dementia would improve their approach to care and outcomes for people with dementia.

The efficacy of HI-6 DMS in a sustained infusion against percutaneous VX poisoning in the guinea-pig.

Post-exposure nerve agent treatment usually includes administration of an oxime, which acts to restore function of the enzyme acetylcholinesterase (AChE). For immediate treatment of military personnel, this is usually administered with an autoinjector device, or devices containing the oxime such as pralidoxime, atropine and diazepam. In addition to the autoinjector, it is likely that personnel exposed to nerve agents, particularly by the percutaneous route, will require further treatment at medical facilities. As such, there is a need to understand the relationship between dose rate, plasma concentration, reactivation of AChE activity and efficacy, to provide supporting evidence for oxime infusions in nerve agent poisoning. Here, it has been demonstrated that intravenous infusion of HI-6, in combination with atropine, is efficacious against a percutaneous VX challenge in the conscious male Dunkin-Hartley guinea-pig. Inclusion of HI-6, in addition to atropine in the treatment, improved survival when compared to atropine alone. Additionally, erythrocyte AChE activity following poisoning was found to be dose dependent, with an increased dose rate of HI-6 (0.48mg/kg/min) resulting in increased AChE activity. As far as we are aware, this is the first study to correlate the pharmacokinetic profile of HI-6 with both its pharmacodynamic action of reactivating nerve agent inhibited AChE and with its efficacy against a persistent nerve agent exposure challenge in the same conscious animal.

Efficacy of the antinicotinic compound MB327 against soman poisoning - Importance of experimental end point.

Medical countermeasures for acute poisoning by organophosphorus nerve agents are generally assessed over 24h following poisoning and a single administration of treatment. At 24h, the antinicotinic bispyridinium compound MB327 (1,10-(propane-1,3-diyl)bis(4-tert-butylpyridinium)) dimethanesulfonate is as effective as the oxime HI-6 against poisoning by soman, when used as part of a treatment containing atropine and avizafone. In this study, we hypothesised that an earlier endpoint, at 6h, would be more appropriate for the pharmacokinetics and mechanism of action of MB327 and would therefore result in improved protection. MB327 diiodide (33.8mg/kg) or the oxime HI-6 DMS (30mg/kg), in combination with atropine and avizafone (each at 3mg/kg) was administered intramuscularly to guinea pigs 1min following subcutaneous soman and the LD50 of the nerve agent was determined at 6h after poisoning for each treatment. The treatment containing HI-6 gave a similar level of protection at 6h as previously determined at 24h (protection ratios 3.9 and 2.9, respectively). In contrast, the protection achieved by treatment containing MB327 showed a striking increase at 6h (protection ratio >15.4) compared to the 24h end point (protection ratio 2.8). The treatment gave full protection for at least 5h against doses of soman up to 525µg/kg; in contrast, mortality began in animals treated with HI-6 after 1h. This study demonstrates the importance of using an appropriate end point and has shown that treatment including MB327 was far superior to oxime-based treatment for poisoning by soman, when assessed over a pharmacologically-relevant duration. The improved outcome was seen following a single dose of treatment: it is possible that additional doses to maintain therapeutic plasma concentrations would further increase survival time. Antinicotinic compounds therefore offer a promising addition to treatment, particularly for rapidly aging or oxime-insensitive nerve agents.

Bioscavenger is effective as a delayed therapeutic intervention following percutaneous VX poisoning in the guinea-pig.

The prolonged systemic exposure that follows skin contamination with low volatility nerve agents, such as VX, requires treatment to be given over a long time due to the relatively short half-lives of the therapeutic compounds used. Bioscavengers, such as butyrylcholinesterase (BChE), have been shown to provide effective post-exposure protection against percutaneous nerve agent when given immediately on signs of poisoning and to reduce reliance on additional treatments. In order to assess the benefits of administration of bioscavenger at later times, its effectiveness was assessed when administration was delayed for 2h after the appearance of signs of poisoning in guinea-pigs challenged with VX (4×LD50). VX-challenged animals received atropine, HI-6 and avizafone on signs of poisoning and 2h later the same combination with or without bioscavenger. Five out of 6 animals which received BChE 2h after the appearance of signs of poisoning survived to the end of the study at 48h, compared with 6 out of 6 which received BChE immediately on signs. All the animals (n=6+6) that received only MedCM, without the addition of BChE, died within 10h of poisoning. The toxicokinetics of a sub-lethal challenge of percutaneous VX were determined in untreated animals. Blood VX concentration peaked at approximately 4h after percutaneous dosing with 0.4×LD50; VX was still detectable at 36h and had declined to levels below the lower limit of quantification (10pg/mL) by 48h in 7 of 8 animals, with the remaining animal having a concentration of 12pg/mL. These studies confirm the persistent systemic exposure to nerve agent following percutaneous poisoning and demonstrate that bioscavenger can be an effective component of treatment even if its administration is delayed.

Nutrient reference value: non-communicable disease endpoints--a conference report.

Nutrition is complex-and seemingly getting more complicated. Most consumers are familiar with "essential nutrients," e.g., vitamins and minerals, and more recently protein and important amino acids. These essential nutrients have nutrient reference values, referred to as dietary reference intakes (DRIs) developed by consensus committees of scientific experts convened by the Institute of Medicine of the National Academy of Sciences, Engineering, and Medicine and carried out by the Food and Nutrition Board. The DRIs comprise a set of four nutrient-based reverence values, the estimated average requirements, the recommended dietary allowances (RDAs), the adequate intakes and the tolerable upper intake levels for micronutrient intakes and an acceptable macronutrient distribution range for macronutrient intakes. From the RDA, the US Food and Drug Administration (FDA) derives a labeling value called the daily value (DV), which appears on the nutrition label of all foods for sale in the US. The DRI reports do not make recommendations about whether the DV labeling values can be set only for what have been defined to date as "essential nutrients." For example, the FDA set a labeling value for "dietary fiber" without having the DV. Nutrient reference values-requirements are set by Codex Alimentarius for essential nutrients, and regulatory bodies in many countries use these Codex values in setting national policy for recommended dietary intakes. However, the focus of this conference is not on essential nutrients, but on the "nonessential nutrients," also termed dietary bioactive components. They can be defined as "Constituents in foods or dietary supplements, other than those needed to meet basic human nutritional needs, which are responsible for changes in health status (Office of Disease Prevention and Health Promotion, Office of Public Health and Science, Department of Health and Human Services in Fed Regist 69:55821-55822, 2004)." Substantial and often persuasive scientific evidence does exist to confirm a relationship between the intake of a specific bioactive constituent and enhanced health conditions or reduced risk of a chronic disease. Further, research on the putative mechanisms of action of various classes of bioactives is supported by national and pan-national government agencies, and academic institutions, as well as functional food and dietary supplement manufacturers. Consumers are becoming educated and are seeking to purchase products containing bioactives, yet there is no evaluative process in place to let the public know how strong the science is behind the benefits or the quantitative amounts needed to achieve these beneficial health effects or to avoid exceeding the upper level (UL). When one lacks an essential nutrient, overt deficiency with concomitant physiological determents and eventually death are expected. The absence of bioactive substances from the diet results in suboptimal health, e.g., poor cellular and/or physiological function, which is relative and not absolute. Regrettably at this time, there is no DRI process to evaluate bioactives, although a recent workshop convened by the National Institutes of Health (Options for Consideration of Chronic Disease Endpoints for Dietary Reference Intakes (DRIs); March 10-11, 2015; http://health.gov/dietaryguidelines/dri/ ) did explore the process to develop DVs for nutrients, the lack of which result in increased risk of chronic disease (non-communicable disease) endpoints. A final report is expected soon. This conference (CRN-International Scientific Symposium; "Nutrient Reference Value-Non-Communicable Disease (NRV-NCD) Endpoints," 20 November in Kronberg, Germany; http://www.crn-i.ch/2015symposium/ ) explores concepts related to the Codex NRV process, the public health opportunities in setting NRVs for bioactive constituents, and further research and details on the specific class of bioactives, n-3 long-chain polyunsaturated fatty acids (also termed omega-3 fatty acids) and their constituents, specifically docosahexaenoic acid and eicosapentaenoic acid.

Long-Term Follow-Up Results following Elective Treatment of Unruptured Intracranial Aneurysms with the Pipeline Embolization Device.

BACKGROUND AND PURPOSE: Numerous reports of treatment of wide-neck aneurysms by flow diverters have been published; however, long-term outcomes remain uncertain. This article reports the imaging results of unruptured aneurysms treated electively with the Pipeline Embolization Device for up to 56 months and clinical results for up to 61 months. MATERIALS AND METHODS: One hundred nineteen aneurysms in 98 patients from 3 centers admitted between August 2009 and June 2011 were followed at 6-month, 1-year, and 2+-year postprocedural timeframes. Analyses on the effects of incorporated vessels, previous stent placement, aneurysm size, and morphology on aneurysm occlusion were performed. RESULTS: The 1- and 2+-year imaging follow-ups were performed, on average, 13 and 28 months postprocedure. At 2+-year follow-up, clinical data were 100% complete and imaging data were complete for 103/116 aneurysms (88.8%) with a 93.2% occlusion rate. From 0 to 6 months, TIA, minor stroke, and major stroke rates were 4.2%, 3.4%, and 0.8% respectively. After 6 months, 1 patient had a TIA of uncertain cause, with an overall Pipeline Embolization Device-related mortality rate of 0.8%. An incorporated vessel was significant for a delay in occlusion (P = .009) and nonocclusion at 6 months and 1 year, with a delayed mean time of occlusion from 9.1 months (95% CI, 7.1-11.1 months) to 16.7 months (95% CI, 11.4-22.0 months). Other factors were nonsignificant. CONCLUSIONS: The Pipeline Embolization Device demonstrates continued very high closure rates at 2+ years, with few delayed clinical adverse sequelae. The presence of an incorporated vessel in the wall of the aneurysm causes a delay in occlusion that approaches sidewall closure rates by 2 years.

Safety of the pipeline embolization device in treatment of posterior circulation aneurysms.

BACKGROUND AND PURPOSE: The published results of treating internal carotid artery aneurysms with the PED do not necessarily apply to its use in the posterior circulation because disabling brain stem infarcts can be caused by occlusion of a single perforator. In this multicenter study, we assessed the safety of PED placement in the posterior circulation. MATERIALS AND METHODS: A prospective case registry was maintained of all posterior circulation aneurysms treated with PEDs at 3 Australian neurointerventional centers during a 27-month period. The objective was to assess the complications and aneurysm occlusion rates associated with posterior circulation PEDs. RESULTS: Thirty-two posterior circulation aneurysms were treated in 32 patients. No deaths or poor neurologic outcomes occurred. Perforator territory infarctions occurred in 3 (14%) of the 21 patients with basilar artery aneurysms, and in all 3, a single PED was used. Two asymptomatic intracranial hematomas were recorded. No aneurysm rupture or PED thrombosis was encountered. The overall rate of permanent neurologic complications was 9.4% (3/32); all 3 patients had very mild residual symptoms and a good clinical outcome. Aneurysm occlusion was demonstrated in 85% of patients with >6 months of follow-up and 96% of patients with >1 year of follow-up. CONCLUSIONS: The PED is effective in the treatment of posterior circulation aneurysms that are otherwise difficult or impossible to treat with standard endovascular or surgical techniques, and its safety is similar to that of stent-assisted coiling techniques. A higher clinical perforator infarction rate may be associated with basilar artery PEDs relative to the internal carotid artery.

Immediate and midterm results following treatment of unruptured intracranial aneurysms with the pipeline embolization device.

BACKGROUND AND PURPOSE: A number of flow-diverting devices have become available for endovascular occlusion of cerebral aneurysms. This article reports immediate and midterm results in treating unruptured aneurysms with the PED. MATERIALS AND METHODS: A prospective registry was established at 3 Australian neurointerventional units. Aneurysms were treated on the basis of unfavorable anatomy or recurrence following previous treatment. Aneurysms were treated with PED or PED and coils. Data including antiplatelet therapy, technical issues, complications, and imaging findings were recorded during at least a 6-month period. RESULTS: A total of 57 aneurysms in 54 patients were treated by 5 neurointerventional radiologists. Forty-one aneurysms were asymptomatic, and 16 patients had mass-induced neurological deficit. Clinical follow-up was available in 57 aneurysms with imaging follow-up at 6 months in 56. Permanent morbidity and mortality in the series was 0% at 6 months. Four TIAs and 1 small retinal branch occlusion occurred, but no stroke. The demonstrated aneurysm occlusion rate at 1 month was 61.9%, and the overall occlusion rate at 6 months was 85.7%. In cases previously untreated, the 6-month occlusion was 92.5%. Three of 6 aneurysms with a previous stent in situ were occluded. Two patients (3.5%) had asymptomatic in-construct stenosis of >50%. Acute aneurysm-provoked mass effect resolved or improved significantly in all cases. CONCLUSIONS: Use of the PED is safe and efficacious in difficult aneurysms with a high occlusion rate at 6 months, but lower occlusion rates were seen in a small population with previous stents in situ.

Implementation of the EU environmental noise directive: lessons from the first phase of strategic noise mapping and action planning in Ireland.

The first phase of noise mapping and action planning in Ireland, in accordance with EU Directive 2002/49/EC, is now complete. In total this included one agglomeration, one airport and approximately 600 km of major roads outside the agglomeration. These noise maps describe the level of noise exposure of approximately 1.25 million people. The first phase of noise mapping was dealt with by five noise mapping bodies while 26 action planning authorities were involved in the development of the associated action plans. The second phase of noise mapping, due to be completed in 2012, sees a reduction in the defined thresholds describing the required agglomerations, roads and railways that have to be mapped. This will have a significant impact on the extent of mapping required. In Ireland this will result in an increased number of local authorities being required to develop strategic noise maps for their area along with the further development of associated action plans. It is appropriate at this point to review the work process and results from the first phase of noise mapping in Ireland in order to establish areas that could be improved, throughout the noise mapping project. In this paper a review of the implementation procedures focussing on (dominant) road traffic noise is presented. It is identified that more standardisation is needed and this could be achieved by the establishment of a national expert steering group.

Estimating human exposure to transport noise in central Dublin, Ireland.

This paper reports on research conducted to determine estimates of the extent of environmental noise exposure from road transport on residents and workers in central Dublin, Ireland. The Harmonoise calculation method is used to calculate noise values for the study area while a Geographical Information System (GIS) is utilised as a platform upon which levels of noise exposure are estimated. Residential exposure is determined for L(den) and L(night) while worker exposure is determined for L(den). In order to analyse the potential of traffic management as a noise abatement measure, traffic was redirected from the main residential areas to alternative road links and the revised exposure levels were determined. The results show that the extent of noise exposure in Dublin is considerable, and in relative terms, it is worse for the night-time period. In addition, the results suggest also that traffic management measures have the potential to lead to significant reductions in the level of noise exposure provided that careful consideration is given to the impact of traffic flows on residential populations.

Congenital diaphragmatic hernia: a systematic review and summary of best-evidence practice strategies.

OBJECTIVES: Recent reports suggest that specific care strategies improve survival of infants with congenital diaphragmatic hernia (CDH). This review presents details of care from centers reporting high rates of survival among CDH infants. STUDY DESIGN: We conducted a MEDLINE search (1995 to 2006) and searched all citations in the Cochrane Central Register of Controlled Trials. Studies were included if they contained reports of >20 infants with symptomatic CDH, and >75% survival of isolated CDH. RESULT: Thirteen reports from 11 centers met inclusion criteria. Overall survival, including infants with multiple anomalies, was 603/763 (79%; range: 69 to 93%). Survival for isolated CDH was 560/661 (85%; range: 78 to 96%). The frequency of extracorporeal membrane oxygenation (ECMO) use for isolated CDH varied widely among reporting centers 251/622 (40%; range: 11 to 61%), as did survival for infants with isolated CDH placed on ECMO: 149/206 (73%; range: 33 to 86%). There was no suggestion of benefit from use of antenatal glucocorticoids given after 34 weeks gestation or use of postnatal surfactant. Low mortality was frequently attributed to minimizing lung injury and adhering to center-specific criteria for ECMO. CONCLUSION: Use of strategies aimed at minimizing lung injury, tolerance of postductal acidosis and hypoxemia, and adhering to center-specific criteria for ECMO were strategies most consistently reported by successful centers. The literature lacks randomized clinical trials of these or other care strategies in this complex patient population; prospective studies of safety and long-term outcome are needed.