Prevalence and Distribution of Potential Vascularized Composite Allotransplant Donors, Implications for Optimizing the Donor-recipient Match.

BACKGROUND: Vascularized composite allotransplantation (VCA) is an emerging and growing field. Little is known about the prevalence and distribution of the adult potential donor population in the United States now that it falls under the oversight of the United Network for Organ Sharing (UNOS). METHODS: We assessed the UNOS database from 2008 to 2015 to estimate the prevalence and distribution of adult potential vascularized composite allograft donors. Donor inclusion and exclusion criteria were developed in a way to minimize risk to recipients and were applied to the dataset. Donors were categorized by factors that influence vascularized composite allograft matching including ABO blood type, cytomegalovirus status, and ethnicity (correlate for skin color) and sorted by UNOS region. RESULTS: Just under half of all brain dead donors met the inclusion/exclusion criteria. Blood type O, cytomegalovirus+, White donors represented the most frequent donor profile while blood type AB, cytomegalovirus-, Asian donors were the least common. UNOS region 3 had the most and region 1 had the least potential VCA donors per year. Nearly all potential VCA donors were solid organ donors with the liver being the most commonly donated solid organ in this population. CONCLUSIONS: A large portion of the solid organ donor pool would qualify as adult vascularized composite allograft donors in the current UNOS system. These data will assist transplant teams in determining the prevalence and distribution of vascularized composite allograft donors for their individual patients awaiting composite allografts based on relevant matching characteristics in addition to standard transplant criteria.

d-Methionine reduces tobramycin-induced ototoxicity without antimicrobial interference in animal models.

BACKGROUND: Tobramycin is a critical cystic fibrosis treatment however it causes ototoxicity. This study tested d-methionine protection from tobramycin-induced ototoxicity and potential antimicrobial interference. METHODS: Auditory brainstem responses (ABRs) and outer hair cell (OHC) quantifications measured protection in guinea pigs treated with tobramycin and a range of d-methionine doses. In vitro antimicrobial interference studies tested inhibition and post antibiotic effect assays. In vivo antimicrobial interference studies tested normal and neutropenic Escherichia coli murine survival and intraperitoneal lavage bacterial counts. RESULTS: d-Methionine conferred significant ABR threshold shift reductions. OHC protection was less robust but significant at 20kHz in the 420mg/kg/day group. In vitro studies did not detect d-methionine-induced antimicrobial interference. In vivo studies did not detect d-methionine-induced interference in normal or neutropenic mice. CONCLUSIONS: d-Methionine protects from tobramycin-induced ototoxicity without antimicrobial interference. The study results suggest d-met as a potential otoprotectant from clinical tobramycin use in cystic fibrosis patients.

CSF neurofilament light chain is elevated in OMS (decreasing with immunotherapy) and other pediatric neuroinflammatory disorders.

Using a panel of seven brain cell-specific biomarkers in cerebrospinal fluid (CSF), pediatric opsoclonus-myoclonus syndrome (OMS) (n=234) was compared to pediatric non-inflammatory neurological controls (n=84) and other inflammatory neurological disorders (OIND) (n=44). Only CSF NFL was elevated in untreated OMS versus controls (+83%). It was 87% higher in OIND than in OMS. On combination treatment with front-loaded ACTH, IVIg, rituximab, median CSF NFL decreased by 60% to control levels. These biochemical data suggest neuronal/axonal injury in some children with OMS without indicators of astrogliosis, and reduction on sufficient immunotherapy.

Active comparator-controlled, rater-blinded study of corticotropin-based immunotherapies for opsoclonus-myoclonus syndrome.

To test the efficacy and safety of corticotropin-based immunotherapies in pediatric opsoclonus-myoclonus syndrome, 74 children received corticotropin alone or with intravenous immunoglobulin (groups 1 and 2, active controls); or both with rituximab (group 3) or cyclophosphamide (group 4); or with rituximab plus chemotherapy (group 5) or steroid sparers (group 6). There was 65% improvement in motor severity score across groups (P < .0001), but treatment combinations were more effective than corticotropin alone (P = .0009). Groups 3, 4, and 5 responded better than group 1; groups 3 and 5 responded better than group 2. The response frequency to corticotropin was higher than to prior corticosteroids (P < .0001). Fifty-five percent had adverse events (corticosteroid excess), more so with multiagents (P = .03); and 10% had serious adverse events. This study demonstrates greater efficacy of corticotropin-based multimodal therapy compared with conventional therapy, greater response to corticotropin than corticosteroid-based therapy, and overall tolerability.

Chemokine/cytokine profiling after rituximab: reciprocal expression of BCA-1/CXCL13 and BAFF in childhood OMS.

The aim of the study was to test the hypothesis that B-cell repopulation following rituximab (anti-CD20) therapy is orchestrated by chemokines and non-chemokine cytokines. Twenty-five children with opsoclonus-myoclonus syndrome (OMS) received rituximab with or without conventional agents. A comprehensive panel of 40 chemokines and other cytokines were measured in serum by ELISA and multiplexed fluorescent bead-based immunoassay. Serum BAFF concentration changed dramatically (even after first infusion) and inversely with B-cell depletion/repopulation and CXCL13 concentration at 1, 3, and 6 months. Negative correlations were found for BAFF concentration vs blood B cell percentage and serum CXCL13 concentration; positive correlations with serum rituximab concentrations. Six months after initiation of therapy, no significant difference in the levels of APRIL, CXCL10, IL-6, or 17 other cytokines/chemokines were detected. These data reveal a major role for BAFF in peripheral B cell repopulation following rituximab-induced B-cell depletion, and novel changes in CXCL13. ClinicalTrials.gov NCT0024436.

A validity study of the Working Group's Autobiographical Memory Test for individuals with moderate to severe intellectual disability.

The purpose of the present study was to investigate the validity of the Working Group's Autobiographical Memory Test as a dementia screening tool for individuals with moderate to severe intellectual disabilities (ID). Twenty-one participants with Dementia of Alzheimer's Type (DAT) and moderate to severe ID and 42 controls with similar levels of ID were tested. The majority were re-tested one year after the initial evaluation. The DAT group scored considerably lower than the control group on the initial evaluation. The controls with DS exhibited a considerable decline on the follow-up evaluation whereas other participants exhibited little changes. This demonstrates an insignificant overall difference between the DAT group and the control group on the follow-up evaluation. Virtually all participants exhibited the same scores on 3 out of 6 test items and the percentage of participants who correctly answered the remaining three test items were not significantly different from the DAT or control groups. In conclusion, the Working Group's Autobiographical Memory Test may be useful as a dementia screening tool for individuals with moderate to severe ID from DS when validated with a large sample size study. However, it is questionable whether this test is a reliable dementia screening tool for individuals with moderate to severe ID from non-DS etiologies. This test has a significant psychometric weakness because of the restricted score variability among the participants.

Pediatric dosing of rituximab revisited: serum concentrations in opsoclonus-myoclonus syndrome.

To longitudinally assess serum concentrations of rituximab, it was administered intravenously to 25 children with opsoclonus-myoclonus syndrome at 375 mg/m2 on each of 4 consecutive weeks with (Group I and II) or without (Group III) conventional immunotherapy. Serum rituximab levels, drawn before and after each infusion and at later intervals, were analyzed by enzyme-linked immunosorbent assay. Rituximab concentration increased stepwise with each infusion, dropping by the next infusion, thereby forming 4 discrete peaks (Cmax) and troughs (Cmin). It then fell precipitously to trace levels at 4 months. However, Cmax and Cmin curves differed significantly between groups. Compared with the youngest children (Group I), the oldest (Group III) had a 34% lower rituximab concentration at the fourth infusion, 45% less IgM depletion 1 month later, and received 20% less rituximab when the dose was recalculated as mg/kg. Serum IgM and rituximab levels were negatively correlated. Peak rituximab concentration did not correlate with adrenocorticotropic hormone dose. These results indicate that the degree of serum IgM depletion is a useful indicator for rituximab dose equivalency in children of different ages. They also suggest that pediatric rituximab dosing should be based on body weight, not surface area. (ClinicalTrials.gov NCT00244361).

B cell depletion therapy for new-onset opsoclonus-myoclonus.

Twelve immunotherapy-naïve children with opsoclonus-myoclonus syndrome and CSF B cell expansion received rituximab, adrenocorticotropic hormone (ACTH), and IVIg. Motor severity lessened 73% by 6 mo and 81% at 1 yr (P < 0.0001). Opsoclonus and action myoclonus disappeared rapidly, whereas gait ataxia and some other motor components improved more slowly. ACTH dose was tapered by 87%. Reduction in total CSF B cells was profound at 6 mo (-93%). By study end, peripheral B cells returned to 53% of baseline and serum IgM levels to 63%. Overall clinical response trailed peripheral B cell and IgM depletion, but improvement continued after their levels recovered. All but one non-ambulatory subject became ambulatory without additional chemotherapy; two relapsed and remitted; four had rituximab-related or possibly related adverse events; and two had low-titer human anti-chimeric antibody. Combination of rituximab with conventional agents as initial therapy was effective and safe. A controlled trial with long-term safety monitoring is indicated.

Correlates of physical activity self-efficacy among breast cancer survivors.

OBJECTIVE: To determine physical activity (PA) self-efficacy correlates in breast cancer survivors. METHODS: Mail survey of 192 breast cancer survivors. RESULTS: Structural equation analyses demonstrated significant and direct associations for perceived PA barriers (beta=-.29), fatigue (beta=-.24), social support (beta=.12), enjoyment (beta=.12), and prediagnosis PA (beta=.11) with barriers self-efficacy. Prediagnosis PA (beta=.51), social support (beta=.26), and barriers self-efficacy (beta=.13) demonstrated direct associations with current leisure PA. Task self-efficacy analysis results were similar except perceived barriers and prediagnosis PA were not associated with task self-efficacy. CONCLUSIONS: Multiple potential efficacy correlates exist and may vary based on the aspect of self-efficacy examined.

Comparison of caretaker report and hands-on neurodevelopmental screening in high-risk infants.

Caretaker report in developmental screening of high-risk infants has not been investigated adequately. We compare a caretaker-completed neurodevelopmental prescreening questionnaire (NPQ) to a hands-on screener (Bayley Infant Neurodevelopmental Screener; BINS) and attempt to identify factors that influence agreement in a high-risk sample. From 1,436 infants drawn from 5 centers, 471 were prospectively evaluated at 6-months corrected age, 376 at 12-months, and 244 at 24-months. Fifty-five percent were male; 28% African American, 70% Caucasian, 3% other; M gestational age = 31.2 weeks, M birth weight = 1568 g. Caretakers completed the NPQ (based on the BINS) while watching a video depicting infants engaged in items. The BINS was subsequently administered. Sensitivity ranged from 80%-91%, specificity 57%-82%, and overall agreement 70%-83%, depending on age. Mean NPQ summary scores were lower than the BINS. Agreement varied depending on BINS risk status, being best in the high-risk group, and worst in the moderate risk group. Background variables had minimal impact at 6 and 12 months with BINS risk status being the primary influence; at 24-months, race, intraventricular hemorrhage, and respiratory distress syndrome were influential. Caretaker report is useful in a high-risk population, although the infant's neurodevelopmental status influences such early on; ethnic background and biomedical variables become more important at 2 years.

Characteristics of smokers calling a national reactive telephone helpline.

PURPOSE: Although reactive telephone helplines for quitting smoking are increasingly popular in the United States, the characteristics of callers using this resource have not been adequately studied. The objective of this study was to describe the characteristics of the current smokers calling a national reactive telephone helpline (i.e., study population). DESIGN AND SETTING: In this cross-sectional study, information was obtained from eligible participants telephonically. SUBJECTS: The study included 890 adult current smokers who were new callers to a national reactive helpline. MEASURES: The information collected included selected demographic and smoking-related characteristics. ANALYSIS: The proportions of the above characteristics were analyzed. RESULTS: There was a significant overepresentation of blacks, non-Hispanics, women, and urban residents, as well as poorer, older, less educated, and heavier smokers in the study population (p < .01 for all comparisons). CONCLUSIONS: Reactive telephone helplines may be preferentially used by population segments who are disadvantaged or smoke heavily and thus are in greatest need for assistance. These helplines may therefore fill a much-needed niche in the marketplace of smoking cessation strategies.

Neuroepidemiologic trends in 105 US cases of pediatric opsoclonus-myoclonus syndrome.

Opsoclonus-myoclonus syndrome (OMS) is a rare, autoimmune neurological disorder that is poorly recognized and undertreated. Neuroblastoma is found in one half of the cases. Because of the high incidence of spontaneous regression of neuroblastoma, it is unknown whether not finding a tumor means there was none. To define demographic trends and the standard of care in the first large series of OMS, 105 children were recruited over a 13-year period in a retrospective questionnaire survey. Children with and without a tumor differed little in viral-like prodrome and neurological symptoms. Earliest neurological symptoms were staggering and falling, leading to a misdiagnosis of acute cerebellitis. Later symptoms included body jerks, drooling, refusal to walk or sit, speech problems, decreased muscle tone, opsoclonus, and inability to sleep. Tumor resection alone did not provide adequate therapy for most. Adrenocorticotropic hormone (ACTH), prednisone, and intravenous immunoglobulin were used with equal frequency, but ACTH was associated with the best early response. More than one half of the children had relapses. Residual behavioral, language, and cognitive problems occurred in the majority. The delay in diagnosis (11 weeks) and initiation of treatment (17 weeks) is unacceptably long.

CSF B-cell expansion in opsoclonus-myoclonus syndrome: a biomarker of disease activity.

Lack of a biomarker of disease activity has hindered the therapy of childhood opsoclonus-myoclonus syndrome (OMS), which is purported to be mediated humorally. To determine if the cerebrospinal fluid (CSF) B lymphocyte, which may traffic into the central nervous system (CNS) to produce antibody locally, is one such biomarker, B lymphocytes were immunophenotyped in the CSF and blood of 56 children with OMS and 26 pediatric controls by dual-laser flow cytometry. Neurological severity was rated blindly from videotapes using a validated 12-item motor evaluation scale. Children with OMS manifested a 4- to 7-fold higher percentage of total B-cells in CSF (P < 0.0001), including CD5(+) (P = 0.001) and CD5(-) (P = 0.0004) B-cell subsets, compared with controls, in whom the percentages were negligible and unchanging with age. CSF expansion of both B-cell subsets increased with disease severity and decreased with disease duration (P

Improved outcomes associated with limiting identification of Candida spp. in respiratory secretions.

Pneumonia due to infection with Candida spp. is extremely rare even though these yeasts are commonly cultured from respiratory secretions. The diagnosis of pneumonia due to Candida spp. should be made only by demonstrating tissue invasion of a biopsy specimen. Physicians might misinterpret the presence of Candida spp. in respiratory secretions as being the etiological agent of pneumonia. This study describes the practice of limiting identification (ID) of rapidly growing yeasts (i.e., Candida spp.) in respiratory secretions and its impact on patients. Before November 2001, rapidly growing yeasts found in respiratory secretions were identified to the species level. After November, rapidly growing yeasts were reported as "yeasts, not Cryptococcus." The group of patients with respiratory secretions processed before November 2001 is called the full ID group (n = 267); the group with samples processed after that date is called the limited ID group (n = 77). Full ID patients had an average length of hospital stay of 12.1 days/patient; that of limited ID patients was 10.1 days/patient, a decrease of 2 days/patient (P = 0.02). The full ID patients had an average cost of 9,407 dollars/patient; that of limited ID patients was 6,973 dollars/patient, a decrease of 2,434 dollars/patient (P = 0.03). Antifungal medications were used in 103 of 267 (39%) full ID patients and in 16 of 77 (21%) limited ID patients, a decrease of 18% (P = 0.004). Limited ID patients had a mortality rate of 14.3%; that of full ID patients was 18.7%, a decrease of 4.4% (P = 0.37). This policy of limiting yeast ID did not impair the diagnosis of pneumonia. Rather, decreases in lengths of stay, costs, and administration of unnecessary antifungal therapy were observed after instituting this policy.

Small group learning in medical education: a second look at the Springer, Stanne, and Donovan meta-analysis.

All in all, the evidence is not convincing. Only four of the nine randomized studies used the conventional small-group learning paradigm and qualify as studies of small-group learning, which are relevant to medical education. The results of one of the four are impossible to interpret because of the involvement of the investigator in teaching and test construction. The three remaining studies showed no effect, a negative effect, and a positive effect, respectively. The nonrandomized studies failed to establish the comparability of the groups. The evidence does not support the authors' call for "more widespread implementation of small-group learning in undergraduate SMET". Small-group learning has not been shown to support the acquisition of content any better [or worse] than large-group learning. In medical education, small-groups are employed in large part to develop team work skills, communication skills, and peer- and self-assessment skills. But these outcomes are not addressed in this meta-analysis. More seriously, our rereading of these studies raises general concerns about meta-analysis in education, which have important implications for evidence-based medical education. The meta-analysis under discussion at first appeared to be just the kind needed to guide an evidence-based educational enterprise. However, a closer look revealed both what is lacking in the meta-analysis and some of the ways educational research and reporting need to be changed if anything like evidence-based education is ever to become a reality. At the least, study design must be clearly described. In addition, if the design is nonrandomized, the groups should be described in sufficient detail to allow a meaningful interpretation of the role of preexisting differences on the outcome measures. (This is why we limited our discussion here to the randomized studies.) Also, effect-size measures should be reported for all comparisons that bear on the impact of the intervention, including preexisting differences. Reporting significance is not enough. This shows only whether sampling error can be ruled out (with a low probability of error, p < .05) as a possible explanation of the connection between the intervention and the outcome. The effect can still be trivial and the comparisons confounded. In addition, descriptions of the actual educational interventions employed need to be more comprehensive and precise. For the most part, the papers would have been strengthened by providing more information for replicating the studies and for deciding which should be included in a given meta-analysis. Perhaps most seriously, our rereading of these studies makes us wonder about the possibility of meaningfully synthesizing the results of educational studies, given their idiosyncrasies and their many extraneous, uncontrolled factors. The conclusions from most educational studies, then--whether randomized or not--must be highly qualified, with explicit warnings about preexisting differences and other confounding factors that plausibly account for the study results. However, these narrative qualifications do nothing to adjust the effect-size measures, which are typically pooled or synthesized across studies--confounds and all. The idiosyncrasies of the studies seem to preclude a blanket qualification that can be applied conceptually across the collection of studies to arrive at a sound conclusion from the synthesis. In brief, the meta-analysis considered here does not support the application of small-group learning in medical education and it raises questions about meta-analysis in education with implications for evidence-based education.

The prediction of breast reduction weight.

Reimbursement for reduction mammaplasty has become more stringent because many insurers require specific documentation of patient symptoms and estimated weight of planned breast resection. The purpose of this study was to develop a simple, clinically useful method for predicting weight of breast tissue to be removed, using routine, easily obtained predictors (i.e., height, weight, age, measurements from sternal notch to nipple, and measurements from sternal notch to inframammary crease). Data were available from a retrospective review of 263 women undergoing reduction mammaplasty. Analyses were performed to predict resected weights obtained both in the operating room and by a pathologist for left and right breasts separately. Regression analyses showed that the sternal notch-to-nipple measurement accounted for nearly all of the explained variance in the resected weights, with correlations around 0.80 between sternal notch to nipple and resected weight. For sternal notch-to-nipple measurements > or 28.5 cm, predicted resected weights were approximately 600 g or more, and in general, 80 percent or more patients had specimen weights >500 grams. From 25.5 to 28 cm, the predicted weights ranged from about 400 to 600 g and the prediction rate of weights >500 g was 50 percent. The senior author predicted the resected breast weight to be >500 g 94 percent of the time. The equation alone did not produce an accurate prediction in the critical range, 400 to 600 g. The experienced surgeon more accurately predicted resected weights with use of practiced spatial relationship skills.