Kidney transplant utilising donors after circulatory death: The first report from the African continent.

BACKGROUND: At Groote Schuur Hospital in Cape Town, South Africa, the number of deceased organ donors has declined over the past 2 decades, necessitating a more liberal approach to donor selection. In 2007, measures to expand the deceased kidney donor pool were implemented, including an HIV positive-to-positive transplant programme and the utilisation of extended-criteria donors as well as donors after circulatory death (DCDs). OBJECTIVES: To report on our institutional experience with DCD kidney transplants and to encourage this approach among other African centres to improve access to transplantation. METHODS: An observational cohort study of consecutive DCD kidney transplants at Groote Schuur Hospital over a 17-year period was performed. Primary endpoints were 1-, 2- and 5-year graft and patient survival. Secondary endpoints included the incidence of delayed graft function (DGF), 30-day morbidity, length of stay, and donor and recipient clinical characteristics. RESULTS: Fifteen DCD procurements were performed, with no kidneys discarded. Thirty kidney transplants were performed, with a median (interquartile range) cold ischaemic time of 11.5 (8 - 14) hours. The incidence of DGF was 60.0%, and 30-day morbidity (other than DGF) was 20.0%. Graft survival at 1, 2 and 5 years was 100%, 96.0% and 73.7%, respectively. Patient survival at 1, 2 and 5 years was 93.3%, 93.3% and 88.4%, respectively. CONCLUSION: Long-term graft and patient survival was comparable with the international literature. DCD may present a unique opportunity to expand deceased donation throughout Africa, particularly in areas affected by a lack of brain death legislation and religious or cultural objections to donation after brain death.

Does anesthesia duration or number of cases per patient predict safety events?

BACKGROUND: The need for dental rehabilitation under general anesthesia is increasing, with varying needs between patients. Mortality has been found to be a rare event in these patients; however other perioperative events can and do occur. Previous studies have established increased incidence of perioperative events with younger, sicker children, and longer anesthetics, however, no studies to date have evaluated if the incidence of perioperative events is more closely associated with one long anesthetic or multiple anesthetics per patient. AIMS: To evaluate the association of perioperative events related to single anesthetic duration or number of anesthetics per patient for dental rehabilitation. METHODS: After Children's Wisconsin Human Research Protection Program determined this quality activity did not meet the definition of human subjects research, we performed an epidemiologic observational evaluation by extracting all dental related cases (dental alone or with oral surgeon vs. dental with other specialties) with an associated general anesthesia encounter from Children's Wisconsin electronic data warehouse from June 1, 2015 to December 31, 2021. These cases occurred at a free-standing children's hospital or associated pediatric-only ambulatory surgery center. The risk of perioperative safety events was analyzed for previously identified risk groups such as American Society of Anesthesiologists Physical Status (ASA-PS), patient age, anesthesia case time with the addition of number of dental cases per patient. RESULTS: In this study, 8468 procedures were performed on 8082 patients. Of this cohort, 7765 patients underwent one procedure for dental care while 317 patients underwent a total of 703 dental-related procedures, ranging from two to five procedures per patient. Multivariable logistic regression identified increased risk of perioperative events in patients with ASA-PS 3 (n = 1459, rate 1.78%, p value .001, OR 5.7, CI 2.1-15.5) and ASA-PS 4 (n = 86, rate 5.8%, p < .001, OR 17.2, CI 4.4-67.3), anesthesia duration (p < .001, OR 1.46, CI 1.21-1.76), but no increased risk with number of anesthetics per patient (p value .54, OR 0.81, CI 0.4-1.61). CONCLUSIONS: Limiting dental care under general anesthesia to multiple short cases may decrease the risk of perioperative events when compared to completing all treatment in one long operative session.

Geographic remoteness from a multidisciplinary team is associated with an increased clinical staging of head and neck cancer: a Newcastle (Australia) study.

The purpose of this study was to investigate the relationship between a patient's residential distance from a tertiary referral regional multidisciplinary team (MDT) and the clinical staging of their head and neck cancer (HNC) at presentation. A retrospective cohort study was performed of all attendees with HNC who had undergone an MDT assessment. The period of study was January 2016 to January 2017. The primary predictor variable was the patient's residential distance from the MDT. Demographic and clinicopathological factors were recorded. The primary outcome variable was the clinical staging conferred by the MDT. Descriptive and ordinal logistical regression analyses were conducted to examine the data. There were 286 observations; 230 patients were male and 56 were female. The mean age of the cohort was 66.52 years. The average residential distance from the MDT was 68.16 km. Regression analysis, while not statistically significant, indicated that those living more than 100 km (range 102-592 km) from the MDT had a 1.49 times increased risk of being diagnosed with an advanced stage of cancer when compared to those living less than 100 km away. This study provides insights into the potential adverse effect geographic remoteness has on initial staging of HNC and the need for further strategies to serve this at-risk population.

COVID-19 social-distancing measures altered the epidemiology of facial injury: a United Kingdom-Australia comparative study.

The purpose of this study was to undertake a retrospective cross-sectional analysis to compare the frequency and characteristics of facial injury presentations at a UK and an Australian tertiary referral hospital during the implementation of COVID-19 social-distancing measures. The primary predictor variables were a heterogeneous set of factors grouped into logical categories: demographics, injury mechanisms and site, and management. The primary outcome variable was the presentation of a hard or soft tissue facial injury. A descriptive statistical analysis was undertaken on the assembled data. The study found a clinical and statistically significant reduction in the frequency (absolute number) of facial injuries at each study site. In addition, a striking similarity common in both countries was an increase in the number of facial injuries due to falls and a reduction in facial injuries due to interpersonal violence. Conservative (non-operative) management of facial injury increased at both sites. The implementation of COVID-19 social-distancing public health measures, which aimed to limit community transmission of the coronavirus, had a secondary serendipitous effect of reducing the frequency of facial injury presentations and altering their epidemiological characteristics at both a UK and Australian tertiary referral hospital.

Crop production in the USA is frequently limited by a lack of pollinators.

Most of the world's crops depend on pollinators, so declines in both managed and wild bees raise concerns about food security. However, the degree to which insect pollination is actually limiting current crop production is poorly understood, as is the role of wild species (as opposed to managed honeybees) in pollinating crops, particularly in intensive production areas. We established a nationwide study to assess the extent of pollinator limitation in seven crops at 131 locations situated across major crop-producing areas of the USA. We found that five out of seven crops showed evidence of pollinator limitation. Wild bees and honeybees provided comparable amounts of pollination for most crops, even in agriculturally intensive regions. We estimated the nationwide annual production value of wild pollinators to the seven crops we studied at over $1.5 billion; the value of wild bee pollination of all pollinator-dependent crops would be much greater. Our findings show that pollinator declines could translate directly into decreased yields or production for most of the crops studied, and that wild species contribute substantially to pollination of most study crops in major crop-producing regions.

Complaints of neuropathic pain, noxious cervical plexus neuropathy and neck tightness are reported by patients who undergo neck dissection: an institutional study and narrative review.

There exists a subgroup of patients who undergo neck dissection (ND) who postoperatively complain of either neuropathic pain, dysaesthesia and/or discomfort that is located within the dermatomal distribution of the cervical plexus. The purpose of our study was to determine the prevalence, characteristic, and demographics of these symptoms in our patient cohort. We undertook a retrospective randomised observational cohort study of 105 patients who had undergone ND. The primary predictor variable was the undertaking of a ND. The secondary outcome variable was the complaint of either neuropathic pain or a noxious neuropathy, at a minimum of twelve months after surgery. A recognised symptom questionnaire and a visual analogue score was employed for the purpose of the study. A descriptive and statistical analysis was applied to the assembled data. Twenty patients (19%) complained of either spontaneous (n=9) or evoked (n=11) neuropathic pain that occurred within the surgical site. In addition, 71 patients (68%) described an altered sensation in the dermatomal distribution of the great auricular or tranverse cervical nerves while 70 patients (67%) described the feeling of 'neck tightness'. There were no characteristics of the study cohort that underpinned these results. Neuropathic pain can occur following ND. This can cause distress to a small but defined group of patients. Despite its importance, we found a paucity of studies in the literature that have investigated neuropathic pain following ND. We believe this condition requires more research attention and clinical awareness.

ORE identifies extreme expression effects enriched for rare variants.

MOTIVATION: Non-coding rare variants (RVs) may contribute to Mendelian disorders but have been challenging to study due to small sample sizes, genetic heterogeneity and uncertainty about relevant non-coding features. Previous studies identified RVs associated with expression outliers, but varying outlier definitions were employed and no comprehensive open-source software was developed. RESULTS: We developed Outlier-RV Enrichment (ORE) to identify biologically-meaningful non-coding RVs. We implemented ORE combining whole-genome sequencing and cardiac RNAseq from congenital heart defect patients from the Pediatric Cardiac Genomics Consortium and deceased adults from Genotype-Tissue Expression. Use of rank-based outliers maximized sensitivity while a most extreme outlier approach maximized specificity. Rarer variants had stronger associations, suggesting they are under negative selective pressure and providing a basis for investigating their contribution to Mendelian disorders. AVAILABILITY AND IMPLEMENTATION: ORE, source code, and documentation are available at https://pypi.python.org/pypi/ore under the MIT license. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Transabdominal Intrapericardial Approach in Liver Transplantation for Unresectable Primary Hepatic Functioning Paraganglioma With Invasion Into Hepatic Veins and Suprahepatic Vena Cava: A Surgical and Anesthesia Management Challenge.

Primary hepatic functional paraganglioma is a rare form of extra-adrenal catecholamine-secreting tumor. Definitive treatment of functioning paraganglioma is challenging because of the critical location of the tumor frequently in close proximity to vital structures and risk of excessive catecholamine release during operative manipulation. We report the multidisciplinary management approach for a case of unresectable primary hepatic functional paraganglioma with invasion into the hepatic veins and suprahepatic vena cava. To our knowledge, this is the first report showing that orthotopic liver transplantation is curative for patients with unresectable primary hepatic paraganglioma. For locally advanced unresectable hepatic paraganglioma that involves the intrapericardial vena cava, a meticulous pre- and intraoperative medical management and transabdominal intrapericardial vascular control of the suprahepatic vena cava during orthotopic liver transplantation allows for complete extirpation of the tumor and achieves optimal outcome.

Integrative transcriptomic analysis reveals key drivers of acute peanut allergic reactions.

Mechanisms driving acute food allergic reactions have not been fully characterized. We profile the dynamic transcriptome of acute peanut allergic reactions using serial peripheral blood samples obtained from 19 children before, during, and after randomized, double-blind, placebo-controlled oral challenges to peanut. We identify genes with changes in expression triggered by peanut, but not placebo, during acute peanut allergic reactions. Network analysis reveals that these genes comprise coexpression networks for acute-phase response and pro-inflammatory processes. Key driver analysis identifies six genes (LTB4R, PADI4, IL1R2, PPP1R3D, KLHL2, and ECHDC3) predicted to causally modulate the state of coregulated networks in response to peanut. Leukocyte deconvolution analysis identifies changes in neutrophil, naive CD4+ T cell, and macrophage populations during peanut challenge. Analyses in 21 additional peanut allergic subjects replicate major findings. These results highlight key genes, biological processes, and cell types that can be targeted for mechanistic study and therapeutic targeting of peanut allergy.

Liquor legislation, last drinks, and lockouts: the Newcastle (Australia) solution.

The aim of this study was to determine whether the regional implementation of prohibitive liquor legislation, introduced in order to limit the sale of and access to alcohol, can lead to a sustained reduction in the incidence of assault occasioning facial injury, as seen in patients presenting to a level 1 trauma hospital. A retrospective observational cohort study was conducted to document patients who were identified as an acute hospital presentation of assault occasioning facial injury. The period of study was 2003-2015; this ensured a similar period of time before and after the implementation of the legislation in 2008. A statistical analysis was undertaken to assess the rates of change in oral and maxillofacial (OMF) assault admissions pre and post legislation. The study found that pre-legislation numbers of OMF assaults increased at a rate of 14% per annum and then decreased at a rate of 21% per annum post legislation (31% relative rate ratio reduction). Similar trends were seen for all males, males aged 18-35 years, and males where alcohol was recorded at clinical presentation. The introduction of 'last drinks' and 'lock out' legislation has led to a significant and sustained reduction in assaultive alcohol-related facial injury in Newcastle.

Immunoglobulin (Ig)M antibodies to proteinase 3 in granulomatosis with polyangiitis and microscopic polyangiitis.

Anti-neutrophil cytoplasmic antibodies (ANCA) appear to play an important role in the pathogenesis of ANCA-associated vasculitis (AAV). However, ANCA alone are not sufficient to generate disease, and some evidence suggests that infectious triggers may serve as inciting events for AAV disease activity. Antibodies of the immunoglobulin (Ig)M isotype often serve as markers of recent infection, and IgM ANCA have been identified previously in patients with AAV, although the frequency and clinical relevance of IgM ANCA is not well established. We sought to characterize IgM ANCA more clearly by creating a novel enzyme-linked immunosorbent assay (ELISA) for IgM antibodies to proteinase 3 [IgM proteinase 3 (PR3)-ANCA], which we applied to two large, clinically well-characterized trial cohorts of patients with granulomatosis with polyangiitis and microscopic polyangiitis. In the first cohort, IgM PR3-ANCA occurred with a frequency of 15·0%, and were associated with a higher degree of disease severity and a trend towards a higher rate of alveolar haemorrhage (29·6 versus 15·7%, P = 0·10). Analysis of follow-up samples in this cohort showed that the presence of IgM PR3-ANCA was transient, but could recur. In the second cohort, IgM PR3-ANCA occurred with a frequency of 41·1%, and were also associated with a higher degree of disease severity. A higher rate of alveolar haemorrhage was observed among those with IgM PR3-ANCA (45·3 versus 15·8%; P < 0·001). The association of transient IgM PR3-ANCA with an acute respiratory manifestation of AAV suggests a possible link between an infectious trigger and AAV disease activity.

Complementary activities of DOT1L and Menin inhibitors in MLL-rearranged leukemia.

Chromosomal rearrangements of the mixed lineage leukemia (MLL/KMT2A) gene leading to oncogenic MLL-fusion proteins occur in ~10% of acute leukemias and are associated with poor clinical outcomes, emphasizing the need for new treatment modalities. Inhibition of the DOT1-like histone H3K79 methyltransferase (DOT1L) is a specific therapeutic approach for such leukemias that is currently being tested in clinical trials. However, in most MLL-rearranged leukemia models responses to DOT1L inhibitors are limited. Here, we performed deep-coverage short hairpin RNA sensitizer screens in DOT1L inhibitor-treated MLL-rearranged leukemia cell lines and discovered that targeting additional nodes of MLL complexes concomitantly with DOT1L inhibition bears great potential for superior therapeutic results. Most notably, combination of a DOT1L inhibitor with an inhibitor of the MLL-Menin interaction markedly enhanced induction of differentiation and cell killing in various MLL disease models including primary leukemia cells, while sparing normal hematopoiesis and leukemias without MLL rearrangements. Gene expression analysis on human and murine leukemic cells revealed that target genes of MLL-fusion proteins and MYC were suppressed more profoundly upon combination treatment. Our findings provide a strong rationale for a novel targeted combination therapy that is expected to improve therapeutic outcomes in patients with MLL-rearranged leukemia.

Development and Characterization of Novel Rat Anti-mERß Sera.

Estrogens regulate normal sexual and reproductive development in females. Their actions are mediated mainly by estrogen receptor (ER)α and ERß. Understanding the function of ERs necessitates knowing their cellular location and protein partners, which, in turn, requires reliable and specific antibodies. Several antibodies are available for ERα; however, discrepancies in immunoreactivity have been reported for ERß. Here, we have developed antisera for mouse ERß (mERß) using a specific C-terminal 18-amino acid peptide conjugated to mariculture keyhole limpet hemocyanin. Sprague Dawley rats were immunized, and the resulting antisera were characterized by Western blot analysis of nuclear extracts from tissues of wild-type (WT) mice, and mice genetically modified to lack either ERα (CERαKO) or ERß (CERßKO). An approximately 56-kDa protein was detected in the hypothalamus, uterus, ovary, mammary gland, testes, and epididymis of WT mice, consistent with the predicted molecular size of ERß. In addition, the same protein band was identified in in vitro synthesized mERß protein and in the mammary glands of CERαKO mice. The approximately 56-kDa protein was not observed in in vitro synthesized mERα protein or in any tissue examined in the CERßKO mice. Immunohistochemistry using the antisera revealed ERß staining in the granulosa cells of WT ovaries and in the mediobasal hypothalamus, paraventricular nucleus, and cerebral cortex in the WT adult mouse brain. These data suggest that the novel rat anti-mERß sera are specific to ERß to allow investigators to explore to cellular and physiological role of ERß in the brain and other mouse tissues.

Establishing the Feasibility of Face Transplantation in Granulomatosis With Polyangiitis.

Granulomatosis with polyangiitis (GPA; formerly Wegener's granulomatosis) is a rare vasculitis that commonly starts in the craniofacial region. We report a case that was masked by prior facial trauma and associated with pyoderma gangrenosum (PG). Disease progression and aggressive debridements led to severe facial tissue loss. The decision to perform a face transplant was controversial because of the risk of disease relapse on the facial allograft. We reviewed renal transplant outcomes in GPA for possible relevance. A PubMed search retrieved 29 studies. Patient and graft survival, relapse, morbidity, mortality, rejection and immunosuppression were assessed. Ten-year patient survival and graft survival were 84.4% and 72.6%, respectively. GPA relapse occurred in 31.5%, and upper airway/ocular relapse occurred in 17.8% (resolved in 76.9%). Mortality was 12.3%. Acute and chronic rejection rates were 14.9% and 6.8%, respectively. Traditional posttransplant immunosuppression was effective. Our review suggests that GPA renal transplant outcomes are comparable to general renal transplant cohorts. Furthermore, transplanted GPA patients exhibit lower disease relapse secondary to lifelong immunosuppression. This supported our decision to perform a face transplant in this patient, which has been successful up to the present time (1-year posttransplantation). Untreated GPA and PG are potential causes of worse surgical outcomes in the craniofacial region.

Comparability of patients with ANCA-associated vasculitis enrolled in clinical trials or in observational cohorts.

OBJECTIVES: To analyse the differences between patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) entered into randomised clinical trials (RCTs) and those followed in large observational cohorts. METHODS: The main characteristics and outcomes of patients with generalised and/or severe GPA or MPA with a five-factor score ≥ 1 enrolled in the French Vasculitis Study Group (FVSG) or the US-Canadian-based Vasculitis Clinical Research Consortium cohorts were compared to those enrolled in one of 2 FVSG clinical RCTs (WEG91, WEGENT) or 3 European Vasculitis Society clinical trials (CYCLOPS, CYCAZAREM, IMPROVE). RESULTS: 657 patients (65.3% with GPA) in RCTs were compared to 437 in cohorts (90.6% with GPA). RCT patients were older at diagnosis than the cohort patients (56.6 ± 13.9 vs. 46.8 ± 17.3 years), had higher Birmingham vasculitis activity score (19.5 ± 9.1 vs. 16.9 ± 7.4), and more frequent kidney disease (84.0% vs. 54.9%) but fewer ear, nose, and throat symptoms (56.8% vs. 72.2%). At 56 months post-diagnosis, mortality and relapse rates, adjusted for age and renal function, were higher for patients with GPA in RCTs vs. cohorts (10.7% vs. 2.5% [p=0.001] and 22.5% vs. 15.6% [p=0.03], respectively) but similar for patients with MPA (6.2% vs. 6.6% [p=0.92] and 16.6% vs. 10.1% [p=0.39], respectively). CONCLUSIONS: Patients with GPA or MPA in RCTs and those in observational cohorts show important differences that should be remembered when interpreting results based on these study populations.

Outcomes of nonsevere relapses in antineutrophil cytoplasmic antibody-associated vasculitis treated with glucocorticoids.

OBJECTIVE: Nonsevere relapses are more common than severe relapses in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), but their clinical course and treatment outcomes remain largely unexamined. We undertook this study to analyze the outcomes of patients with nonsevere relapses in the Rituximab in ANCA-Associated Vasculitis (RAVE) trial who were treated with prednisone according to a prespecified protocol. METHODS: RAVE was a randomized, double-blind, placebo-controlled trial comparing rituximab (RTX) to cyclophosphamide (CYC) followed by azathioprine (AZA) for induction of remission. Patients who experienced nonsevere relapses between months 1 and 18 were treated with a prednisone increase without a concomitant change in their nonglucocorticoid immunosuppressants, followed by a taper. RESULTS: Forty-four patients with a first nonsevere relapse were analyzed. In comparison to the 71 patients who maintained relapse-free remission over 18 months, these patients were more likely to have proteinase 3-ANCAs, diagnoses of granulomatosis with polyangiitis (Wegener's), and a history of relapsing disease at baseline. A prednisone increase led to remission in 35 patients (80%). However, only 13 patients (30%) were able to maintain second remissions through the followup period (mean 12.5 months); 31 patients (70%) had a second disease relapse, 14 of them with severe disease. The mean time to second relapse was 9.4 months (4.7 months in the group treated with RTX versus 13.7 months in the group treated with CYC/AZA; P < 0.01). Patients who experienced nonsevere relapses received more glucocorticoids than those who maintained remission (6.7 grams versus 3.8 grams; P < 0.01). CONCLUSION: Treatment of nonsevere relapses in AAV with an increase in glucocorticoids is effective in restoring temporary remission in the majority of patients, but recurrent relapses within a relatively short interval remain common. Alternative treatment approaches are needed for this important subset of patients.

Intra-operative monitoring of the spinal accessory nerve: a systematic review.

OBJECTIVE: To investigate evidence that intra-operative nerve monitoring of the spinal accessory nerve affects the prevalence of post-operative shoulder morbidity and predicts functional outcome. METHODS: A search of the Medline, Scopus and Cochrane databases from 1995 to October 2012 was undertaken, using the search terms 'monitoring, intra-operative' and 'accessory nerve'. Articles were included if they pertained to intra-operative accessory nerve monitoring undertaken during neck dissection surgery and included a functional shoulder outcome measure. Further relevant articles were obtained by screening the reference lists of retrieved articles. RESULTS: Only three articles met the inclusion criteria of the review. Two of these included studies suggesting that intra-operative nerve monitoring shows greater specificity than sensitivity in predicting post-operative shoulder dysfunction. Only one study, with a small sample size, assessed intra-operative nerve monitoring in neck dissection patients. CONCLUSION: It is unclear whether intra-operative nerve monitoring is a useful tool for reducing the prevalence of accessory nerve injury and predicting post-operative functional shoulder outcome in patients undergoing neck dissection. Larger, randomised studies are required to determine whether such monitoring is a valuable surgical adjunct.

Rituximab for the treatment of relapses in antineutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVE: Disease relapses are frequent in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). This study was undertaken to evaluate outcomes in patients with AAV who are re-treated with rituximab (RTX) and prednisone for severe disease relapses. METHODS: The Rituximab in AAV trial was a randomized, double-blind, placebo-controlled trial comparing the rates of remission induction among patients treated with RTX (n = 99) and patients treated with cyclophosphamide (CYC) followed by azathioprine (AZA) (n = 98). Prednisone was tapered to discontinuation after 5.5 months. After remission was achieved, patients who experienced a severe disease relapse between months 6 and 18 were eligible to receive RTX and prednisone on an open-label basis according to a prespecified protocol. Investigators remained blinded with regard to the original treatment assignment. RESULTS: Twenty-six patients received RTX for disease relapse after remission had initially been achieved with their originally assigned treatment. Fifteen of these patients were initially randomized to receive RTX and 11 to receive CYC/AZA. Thirteen (87%) of the patients originally assigned to receive RTX and 10 (91%) originally assigned to receive CYC/AZA achieved remission again with open-label RTX (an overall percentage of 88%). In half of the patients treated with open-label RTX, prednisone could be discontinued entirely. Patients in this cohort experienced fewer adverse events compared to the overall study population (4.7 adverse events per patient-year versus 11.8 adverse events per patient-year). CONCLUSION: Re-treatment of AAV relapses with RTX and glucocorticoids appears to be a safe and effective strategy, regardless of previous treatment.

Health assessment of gasoline and fuel oxygenate vapors: developmental toxicity in mice.

CD-1 mice were exposed to baseline gasoline vapor condensate (BGVC) alone or to vapors of gasoline blended with methyl tertiary butyl ether (G/MTBE). Inhalation exposures were 6h/d on GD 5-17 at levels of 0, 2000, 10,000, and 20,000mg/m(3). Dams were evaluated for evidence of maternal toxicity, and fetuses were weighed, sexed, and evaluated for external, visceral, and skeletal anomalies. Exposure to 20,000mg/m(3) of BGVC produced slight reductions in maternal body weight/gain and decreased fetal body weight. G/MTBE exposure did not produce statistically significant maternal or developmental effects; however, two uncommon ventral wall closure defects occurred: gastroschisis (1 fetus at 10,000mg/m(3)) and ectopia cordis (1 fetus at 2000mg/m(3); 2 fetuses/1 litter at 10,000mg/m(3)). A second study (G/MTBE-2) evaluated similar exposure levels on GD 5-16 and an additional group exposed to 30,000mg/m(3) from GD 5-10. An increased incidence of cleft palate was observed at 30,000mg/m(3) G/MTBE. No ectopia cordis occurred in the replicate study, but a single observation of gastroschisis was observed at 30,000mg/m(3). The no observed adverse effect levels for maternal/developmental toxicity in the BGVC study were 10,000/2000mg/m(3), 20,000/20,000 for the G/MTBE study, and 10,000/20,000 for the G/MTBE-2 study.