Spectral Bayesian network theory.

A Bayesian Network (BN) is a probabilistic model that represents a set of variables using a directed acyclic graph (DAG). Current algorithms for learning BN structures from data focus on estimating the edges of a specific DAG, and often lead to many 'likely' network structures. In this paper, we lay the groundwork for an approach that focuses on learning global properties of the DAG rather than exact edges. This is done by defining the structural hypergraph of a BN, which is shown to be related to the inverse-covariance matrix of the network. Spectral bounds are derived for the normalized inverse-covariance matrix, which are shown to be closely related to the maximum indegree of the associated BN.

SIRT3 promotes auditory function in young adult FVB/nJ mice but is dispensable for hearing recovery after noise exposure.

Noise-induced hearing loss (NIHL) affects millions of people worldwide and presents a large social and personal burden. Pharmacological activation of SIRT3, a regulator of the mitochondrial oxidative stress response, has a protective effect on hearing thresholds after traumatic noise damage in mice. In contrast, the role of endogenously activated SIRT3 in hearing recovery has not been established. Here we tested the hypothesis that SIRT3 is required in mice for recovery of auditory thresholds after a noise exposure that confers a temporary threshold shift (TTS). SIRT3-specific immunoreactivity is present in outer hair cells, around the post-synaptic regions of inner hair cells, and faintly within inner hair cells. Prior to noise exposure, homozygous Sirt3-KO mice have slightly but significantly higher thresholds than their wild-type littermates measured by the auditory brainstem response (ABR), but not by distortion product otoacoustic emissions (DPOAE). Moreover, homozygous Sirt3-KO mice display a significant reduction in the progression of their peak 1 amplitude at higher frequencies prior to noise exposure. After exposure to a single sub-traumatic noise dose that does not permanently reduce cochlear function, compromise cell survival, or damage synaptic structures in wild-type mice, there was no difference in hearing function between the two genotypes, measured by ABR and DPOAE. The numbers of hair cells and auditory synapses were similar in both genotypes before and after noise exposure. These loss-of-function studies complement previously published gain-of-function studies and help refine our understanding of SIRT3's role in cochlear homeostasis under different damage paradigms. They suggest that SIRT3 may promote spiral ganglion neuron function. They imply that cellular mechanisms of homeostasis, in addition to the mitochondrial oxidative stress response, act to restore hearing after TTS. Finally, we present a novel application of a biomedical statistical analysis for identifying changes between peak 1 amplitude progressions in ABR waveforms after damage.

Statistical projection of post-vaccination antibody kinetics between dosing schedules.

Determining a recommended dosage schedule is a crucial component of vaccine administration, and is often subject to reassessment. Ideally, recommendations will be supported by multiple arm clinical trials. However, the considerable cost in both resources and time means that a method of predicting post-vaccine humoral antibody levels associated with a hypothetical schedule using data collected from a currently implemented schedule would be of significant benefit to vaccination practice. In this paper we propose such a methodology, which permits statistical estimation of the population mean and standard deviation of log transformed antibody titers of various post-vaccination time points of a hypothetical schedule, using a longitudinal sample of antibody titers from an observed schedule. The method is based on the decomposition of humoral antibody kinetic history into distinct phases, for example, peak phase, decay phase and post-booster phase. The method is feasible because each phase has its own discernable kinetic laws. Of particular interest will be estimation of antibody levels immediately preceding a booster dose (typically the lowest level attained during the schedule), and the antibody levels following a booster dose.

Serum antibody response to Moraxella catarrhalis proteins in stringently defined otitis prone children.

BACKGROUND: Moraxella catarrhalis (Mcat) is a frequent pathogen of acute otitis media (AOM) in young children. Here we prospectively assessed naturally-induced serum antibodies to four Mcat vaccine candidate proteins in stringently defined otitis prone (sOP) and non-otitis prone (NOP) children age 6-36months old following nasopharyngeal (NP) colonization, at onset of AOM and convalescence from AOM. METHODS: Serum IgG and IgM antibody against recombinant Mcat proteins, oligopeptide permease A (OppA), outer membrane protein (OMP) CD, hemagglutinin (Hag), and PilA clade 2 (PilA2), were quantitated by ELISA. RESULTS: During NP colonization by Mcat all four antigens were immunogenic in both sOP and NOP children. However, sOP children had lower antibody responses than NOP children across age 6-36months, similar to our findings for protein vaccine candidates of Streptococcus pneumoniae (Spn) and Nontypeable Haemophilus influenzae (NTHi). sOP children displayed a later and lower peak of antibody rise than NOP children for all four antigens during NP colonization of Mcat. The age-dependent increase of antibody ranked as OppA>Hag5-9>OMP CD>PilA2 in both sOP and NOP children. Lower serum antibody levels to the Mcat antigens were measured in sOP compared to NOP children at the onset of AOM. We did not find a consistent significant increase of antibody at the convalescence phase after an AOM event. CONCLUSIONS: sOP children is a highly vulnerable population that mount lower serum antibody responses to Mcat candidate vaccine proteins compared to NOP children during asymptomatic NP carriage and at onset of AOM.

Impaired Proinflammatory Response in Stringently Defined Otitis-prone Children During Viral Upper Respiratory Infections.

BACKGROUND: Viral upper respiratory infections (URIs) are common and often precipitate acute otitis media (AOM), caused by bacterial otopathogens, in young children. Acute inflammatory responses initiated in the early phase of viral URI contribute to preventing the development of AOM. Stringently-defined otitis-prone (sOP) children are susceptible to recurrent AOM. METHODS: We assessed proinflammatory cytokine and chemokine levels in the nasopharynxes during viral URIs, and examined the different nasopharyngeal responses between viral URI events and the following AOM episodes in both sOP and non-otitis-prone (NOP) children. RESULTS: The sOP children exhibited significantly more AOM episodes per child (8.86-fold higher), viral URIs (P < .0001), and viral URIs followed by AOMs (P < .0001) than the NOP children. The sOP children had lower nasal proinflammatory levels of interleukin (IL)-6 (P = .05), IL-10 (P = .001), tumor necrosis factor (TNF)-α (P = .004), and regulated on activation, normal T-cell-expressed and -secreted (RANTES; P = .002) than NOP children during viral URIs. NOP children had higher levels of IL-6 (P = .02), IL-10 (P = .02), interferon-γ (P = .003), TNF-α (P = .006), IL-1ß (P = .022), monocyte chemoattractant protein 1 (P = .028), RANTES (P = .005), IL-2 (P = .002), and IL-17 (P = .007) during viral URIs versus AOMs following the URIs, when compared to sOP children. CONCLUSIONS: We conclude that sOP children have more frequent viral URIs than NOP children, due to deficient antiviral nasopharyngeal proinflammatory cytokine and chemokine responses.

Effectiveness of 13-valent pneumococcal conjugate vaccination for protection against acute otitis media caused by Streptococcus pneumoniae in healthy young children: a prospective observational study.

BACKGROUND: With wide use of the seven-valent pneumococcal conjugate vaccine (PCV7) for protection against acute otitis media caused by Streptococcus pneumoniae serotypes included in the vaccine, efficacy testing for the 13-valent vaccine (PCV13) was not feasible. We aimed to assess the effectiveness of PCV13 in preventing acute otitis media caused by the six serotypes in PCV13 that were not in PCV7. METHODS: We did a longitudinal observational study in healthy children seen as outpatients in a private paediatric practice in Rochester, NY, USA. Children aged up to 30 months who had received the full primary series of PCV13 with other recommended vaccines were eligible to participate and were followed up to age 30-36 months to identify episodes of acute otitis media, during which we collected middle-ear fluid (MEF) by tympanocentesis. We assessed MEF for the serotypes common to PCV7 and PCV13 (4, 6B, 9V, 14, 18C, 19F, and 23F) and the six additional serotypes specific to PCV13 (1, 3, 5, 6A, 7F, and 19A). As controls, we included children enrolled in a longitudinal study in the study centre from Oct 1, 2007, to Sept 30, 2009, who had been vaccinated with PCV7, had MEF prospectively collected at the onset of acute otitis media, and been followed up until age 30 months. The primary outcome was the effectiveness of PCV13 to prevent acute otitis media caused by pneumococci expressing the six capsular serotypes not included in PCV7 (1, 3, 5, 6A, 7F, and 19A). This study is registered with ClinicalTrials.gov, number NCT01199016. FINDINGS: From Sept 28, 2010, to Sept 30, 2013, we enrolled 239 children (123 [51%] boys and 116 [49%] girls; median age 6·3 months [IQR 6·1-8·6]) in the PCV13 cohort, and 162 completed the study. Of 348 children (184 [53%] boys and 164 [47%] girls; 6·5 months [6·1-9·1]) included in the PCV7 cohort, 248 completed follow-up. 223 MEF samples were obtained at onset of acute otitis media from 90 children in the PCV13 cohort. 53 (24%) of 223 samples were culture positive for S pneumoniae, compared with 89 (31%) of 284 samples in the PCV7 cohort (p=0·06). Four (8%) of 53 samples in the PCV13 cohort contained pneumococci expressing one of the additional PCV13 capsular serotypes, compared with 46 (52%) of 89 samples in the PCV7 cohort, giving a relative reduction of 86% (95% CI 61-94, p=0·0010). The greatest reduction in MEF samples was in serotype 19A (two [4%] in the PCV13 cohort vs 46 [52%] in the PCV7 cohort; relative reduction 91% [58-97, p=0·0010]). INTERPRETATION: PCV13 prevents acute otitis media caused by S pneumoniae expressing serotypes included in the vaccine. FUNDING: Pfizer.

Haemophilus influenzae-protein D specific antibody correlate with protection against acute otitis media in young children.

BACKGROUND: Haemophilus influenzae (Hi) causes respiratory infections and pathogenesis of this microbe begins in the human nasopharynx (NP). The objective of this study was to assess the correlation of NP colonization-induced serum antibody levels to Hi protein D with risk of acute otitis media (AOM) in children <2 yr. METHODS: 455 sera from 213 children (age 6-24 months old) were collected when they were colonized with Hi and when the children developed AOM. Presence of Hi during AOM was confirmed by culture of middle ear fluid. Quantitative ELISA was used to determine serum IgG against protein D antigen. RESULTS: Asymptomatic Hi NP colonization reduced the risk of future AOM infections. Higher serum IgG titers against Hi protein D were correlated with reduced future AOM risk. CONCLUSION: Colonization by Hi reduces future AOM risk. Higher antibody levels against protein D correlates with lower risk of AOM caused by Hi.

Three Innate Cytokine Biomarkers Predict Presence of Acute Otitis Media and Relevant Otopathogens.

BACKGROUND: 1.1Diagnosis of Acute Otitis Media (AOM) is challenging, resulting in frequent over diagnosis and improper prescription of antibiotics. A serum biomarker of AOM would significantly improve pediatric care for this common illness. METHODS: 1.2Serum samples were studied from 197 children 6-36 months old during health, during viral Upper Respiratory Infection (URI) without middle ear involvement, and at the onset of AOM (confirmed by tympanocentesis). Serum concentrations of S100A12, IL-10, and ICAM-1 were measured by ELISA. Otopathogens were identified by culture of middle ear fluid. A predictive model for infection and causative otopathogen was developed based on density distributions of the measured cytokines. RESULTS: 1.3A biomarker score derived from subject age and serum concentrations of S100A12, IL-10, and ICAM-1 was significantly able to distinguish both between health and disease and between upper respiratory infections with and without middle ear involvement (AOM vs URI), and further predicted the specific causative bacterial pathogen. This biomarker could also identify recurrent OM-prone children. CONCLUSIONS: 1.4For the first time we show that a biomarker risk score derived from serum cytokine levels can predict the presence of bacterial AOM, the likely Otopathogen, and the recurrent OM-prone child. CLINICAL SIGNIFICANCE: 1.5(1) AOM is a widespread pediatric infection with a substantial economic burden. (2) Three serum cytokines can discriminate between URI and AOM, reducing over diagnosis. (3) Prediction of responsible pathogen enables targeted antibiotic prescription.

Effects of the New York State Workers Compensation Board Medical Treatment Guidelines on Return to Work.

OBJECTIVE: Examine the association between New York State Workers' Compensation Medical Treatment Guidelines (Guidelines) adherence and return-to-work after occupational low back injuries. Assess adherence to Guidelines by examining diagnostic and treatment utilization. METHOD: Retrospective chart review of cases. Outcomes of interest were lost time duration and diagnostic/treatment utilization rates. Time to event analyses performed using Kaplan-Meier plots and Cox proportional hazard model. RESULTS: Care received after implementation of Guidelines resulted in decreased lost time. Treatment rates were consistent, while diagnostic imaging use was inconsistent with Guidelines recommendations. CONCLUSIONS: Guidelines use positively influenced return-to-work after acute occupational low back injuries. Inconsistencies in following Guidelines were observed for diagnostic tests, having a potential paradoxical effect on lost time. Further studies are necessary to test for additional hypotheses.

Modeling specific antibody responses to natural immunization to predict a correlate of protection against infection before commencing a clinical vaccine trial.

BACKGROUND: Clinical trials of vaccines for children to prevent acute otitis media (AOM) infections caused by the bacteria Streptococcus pneumonia (Spn) are in Phase I. The objective of this study was to use serum antibody measurements to pneumococcal purified protein candidate antigens that occurred after natural "immunization" to predict a correlate of protection response needed following an injectable vaccine against AOM in children. METHODS: 590 nasal and serum samples were collected from 129 healthy children at 6, 9, 12, 15, 18, 24 and 30-36 months of age and when the child developed AOM. Middle ear fluid to detect Spn was collected at every episode of AOM. Quantitative ELISA was used to determine serum IgG against 7 Spn vaccine antigens: PspA clade 3, PspA clade 5, PhtD, PhtE, LytB, PcpA and Ply. A correlate of protection (COP) was estimated by regressing AOM events against age adjusted antibody levels induced by nasopharyngeal colonization and AOM infections, using logistic regression and generalized estimating equation methods. RESULTS: A significant COP was found for Spn PhtD (p = 0.0015), PhtE (p = 0.00034), LytB (p = 0.004), PcpA (p = 0.002), and Ply (p = 0.007) between higher antibody levels and reduced frequency of AOM. We estimated that a 2-fold higher antibody level in a child than the mean antibody level induced by NP colonization (after adjusting for subject age) to PhtD, LytB, PcpA, PhtE or Ply reduced the risk of AOM by 14-21%, a 4-fold higher level reduced it by 25-38% and a 10-fold higher level reduced it by 39-54%. CONCLUSION: We developed a model to predict the necessary level of serum antibody and fold higher above a threshold to PhtD, PhtE, LytB, PcpA and Ply that would correlate with a reduced likelihood of AOM in children age 6-24 months old if enrolled in a Phase III clinical efficacy trial.

A model for the regulation of follicular dendritic cells predicts invariant reciprocal-time decay of post-vaccine antibody response.

Follicular dendritic cells (FDC) play a crucial role in the regulation of humoral immunity. They are believed to be responsible for long-term persistence of antibody, due to their role in antibody response induction and their ability to retain antigen in immunogenic form for long periods. In this article, a regulatory control model is proposed which links persistence of humoral immunity with cellular processes associated with FDCs. The argument comprises three elements. The first is a literature review of population-level studies of post-vaccination antibody persistence. It is found that reciprocal-time (∝1/t) decay of antibody levels is widely reported, over a range of ages, observation times and vaccine types. The second element is a mathematical control model for cell population decay for which reciprocal-time decay is a stable attractor. Additionally, control effectors are easily identified, leading to models of homeostatic control of the reciprocal-time decay rate. The final element is a literature review of FDC functionality. This reveals a striking concordance between cell properties required by the model and those widely observed of FDCs, some of which are unique to this cell type. The proposed model is able to unify a wide range of disparate observations of FDC function under one regulatory principle, and to characterize precisely forms of FDC regulation and dysregulation. Many infectious and immunological diseases are increasingly being linked to FDC regulation, therefore a precise understanding of the underlying mechanisms would be of significant benefit for the development of new therapies.

Effect of oral sodium bicarbonate on fibroblast growth factor-23 in patients with chronic kidney disease: a pilot study.

BACKGROUND: The regulation of fibroblast growth factor-23 (FGF23) secretion in patients with chronic kidney disease (CKD) is incompletely understood. An in vitro study showed that metabolic acidosis increased FGF23 in mouse bone. The objective of this study is to evaluate the effect of oral sodium bicarbonate on circulating FGF23 levels in patients with CKD. METHODS: This was a single-blind pilot study. Twenty adults with estimated glomerular filtration rate between 15-45 mL/min/1.73 m(2) and serum bicarbonate between 20-24 mEq/L were treated with placebo for 2 weeks, followed by increasing doses of oral sodium bicarbonate (0.3, 0.6 and 1.0 mEq/kg/day) in 2 week intervals for a total of 6 weeks. C-terminal FGF23 levels were measured at the initial visit, after 2 weeks of placebo and after 6 weeks of bicarbonate therapy. Wilcoxon matched-pairs signed-rank test was used to compare FGF23 before and after sodium bicarbonate. RESULTS: After 6 weeks of oral sodium bicarbonate, the median FGF23 increased significantly from 150.9 RU/mL (IQR 107.7-267.43) to 191.4 RU/mL (IQR 132.6-316.9) (p = 0.048) and this persisted after excluding participants who received activated vitamin D. CONCLUSIONS: FGF23 increased after short-term oral sodium bicarbonate therapy in patients with CKD and mild metabolic acidosis. It is unclear whether this was due to the alkalinizing effect of sodium bicarbonate or other factors. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov ( NCT00888290 ) on April 23, 2009.

Inflammation-associated cytokine analysis identifies presence of respiratory bacterial pathogens in the nasopharynx.

We sought to determine if inflammatory cytokines are induced during asymptomatic nasopharyngeal (NP) colonization by the common respiratory bacteria Streptococcus pneumoniae (Spn), non-typeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis (Mcat). 85 serum samples were studied from 85 children 6-36 months of age when children were healthy and potentially NP colonized with Spn, NTHi or Mcat. Immunoassays were used to quantitate serum sICAM-1, IL-10 and S100A12 levels. Logistic regression was used to develop a predictive model for NP colonization probability for causative bacterial pathogen presence. Serum levels of sICAM-1, IL-10 and S100A12 increased during asymptomatic NP colonization by Spn, NTHi and Mcat. In a statistical model using risk scoring, we found high positive predictive and negative value, sensitivity and specificity when using these three cytokines to identify the presence of Spn, NTHi and Mcat in the NP. For the first time, we show that inflammatory cytokines are induced in serum during asymptomatic NP colonization by Spn, NTHi and Mcat.

A microRNA biomarker of hepatocellular carcinoma recurrence following liver transplantation accounting for within-patient heterogeneity.

BACKGROUND: Liver cancer, of which hepatocellular carcinoma (HCC) is by far the most common type, is the second most deadly cancer (746,000 deaths in 2012). Currently, the only curative treatment for HCC is surgery to remove the malignancy (resection) or to remove the entire diseased liver followed by transplantation of healthy liver tissue. Given the shortage of healthy livers, it is crucial to provide transplants to patients that have the best chance of long-term survival. Currently, transplantation is determined via the Milan criteria-patients within Milan (single tumor < 5 cm or 2-3 tumors < 3 cm with no extrahepatic spread nor intrahepatic vascular invasion) are typically eligible for transplantation. However, combining microRNA expression profiling with the Milan criteria can improve prediction of recurrence. HCC often presents with multiple distinct tumor foci arising from local spread of a primary tumor or from the oncogenic predisposition of the diseased liver. Substantial genomic heterogeneity between tumor foci within a single patient has been reported; therefore, biomarker development must account for the possibility of highly heterogeneous genomic profiles from the same individual. METHODS: MicroRNA profiling was performed on 180 HCC tumor samples from 89 patients who underwent liver transplantation at the University of Rochester Medical Center. The primary outcome was recurrence-free survival time, and patients were observed for 3 years post-transplantation. RESULTS: MicroRNA expression profiles were used to develop a biomarker that distinguishes HCC patients at greater risk of recurrence post-transplantation. Unsupervised clustering uncovered two distinct subgroups with vast differences in standard transplantation selection criteria and recurrence-free survival times. These subgroups were subsequently used to identify microRNAs strongly associated with HCC recurrence. Our results show that reduced expression of five specific microRNAs is significantly associated with HCC recurrence post-transplantation. CONCLUSIONS: MicroRNA profiling of distinct tumor foci, coupled with methods that address within-subject tumor heterogeneity, has the potential to significantly improve prediction of HCC recurrence post-transplantation. The development of a clinically applicable HCC biomarker would inform treatment options for patients and contribute to liver transplant selection criteria for practitioners.

Serum cytokine biomarkers accurately predict presence of acute otitis media infection and recovery caused by Haemophilus influenzae.

OBJECTIVE: We sought to develop an optimal model using a combination of serum biomarker pro-inflammatory and dampening inflammatory cytokine proteins to predict the presence of acute otitis media (AOM) infection and recovery caused by Nontypeable Haemophilus influenzae (NTHi). METHODS: 88 serum samples were studied from 34 children 6-36 months of age at healthy visits, at onset of AOM diagnosed by qualified pediatricians and confirmed by tympanocentesis to be caused by NTHi and follow up 3 weeks to 4 months later. Immunoassays were used to quantitate serum S100A12, IL-10 and sICAM-1 cytokine levels. Middle ear fluids permitted identification of otopathogens. Logistic regression was used to develop a predictive model for infection probability and recovery. RESULTS: A significant association between serum S100A12 and IL-10 cytokine levels as biomarkers of AOM infection was found for NTHi. Almost all NTHi positive AOMs could be predicted by calculations using serum S100A12 and IL-10 levels in a statistical model we derived. Including measurements of sICAM-1 did not improve predictability of NTHi AOM or recovery beyond that achieved using S100A12 and IL-10. The model showed clearly the ability of low biomarker scores to predict cure at follow-up once biomarker lag was correctly modeled. CONCLUSION: We developed a serum molecular biomarker risk score that can predict the presence and recovery from AOM caused by the common respiratory bacteria NTHi that causes the infection in the clinical context of possible AOM.

Functional Immune Cell Differences Associated With Low Vaccine Responses in Infants.

BACKGROUND: We sought to understand why some children respond poorly to vaccinations in the first year of life. METHODS: A total of 499 children (6-36 months old) provided serum and peripheral blood mononuclear cell samples after their primary and booster vaccination. Vaccine antigen-specific antibody levels were analyzed with enzyme-linked immunosorbent assay, and frequency of memory B cells, functional T-cell responses, and antigen-presenting cell responses were assessed in peripheral blood mononuclear cell samples with flow cytometric analysis. RESULTS: Eleven percent of children were low vaccine responders, defined a priori as those with subprotective immunoglobulin G antibody levels to ≥66% of vaccines tested. Low vaccine responders generated fewer memory B cells, had reduced activation by CD4(+) and CD8(+) T cells on polyclonal stimulation, and displayed lower major histocompatibility complex II expression by antigen-presenting cells. CONCLUSIONS: We conclude that subprotective vaccine responses in infants are associated with a distinct immunologic profile.

An information theoretic approach to pedigree reconstruction.

Network structure is a dominant feature of many biological systems, both at the cellular level and within natural populations. Advances in genotype and gene expression screening made over the last few decades have permitted the reconstruction of these networks. However, resolution to a single model estimate will generally not be possible, leaving open the question of the appropriate method of formal statistical inference. The nonstandard structure of the problem precludes most traditional statistical methodologies. Alternatively, a Bayesian approach provides a natural methodology for formal inference. Construction of a posterior density on the space of network structures allows formal inference regarding features of network structure using specific marginal posterior distributions. An information theoretic approach to this problem will be described, based on the Minimum Description Length principle. This leads to a Bayesian inference model based on the information content of data rather than on more commonly used probabilistic models. The approach is applied to the problem of pedigree reconstruction based on genotypic data. Using this application, it is shown how the MDL approach is able to provide a truly objective control for model complexity. A two-cohort model is used for a simulation study. The MDL approach is compared to COLONY-2, a well known pedigree reconstruction application. The study highlights the problem of genotyping error modeling. COLONY-2 requires prior error rate estimates, and its accuracy proves to be highly sensitive to these estimates. In contrast, the MDL approach does not require prior error rate estimates, and is able to accurately adjust for genotyping error across the range of models considered.

Familial and microbiological contribution to the otitis-prone condition.

OBJECTIVE: Our group has an ongoing clinical research project investigating the immunology of the otitis-prone (OP) phenotype. In light of evidence that this condition arises from underlying immunological defects, we examined our sample population of stringently defined OP (sOP) children suffering 3 episodes of acute otitis media within 6 months or 4 within a year for a familial association with the sOP phenotype. METHODS: We analyzed the frequency of sOP within and between families and the nasopharyngeal (NP) otopathogen colonization patterns within and between families. RESULTS: The presence of sOP siblings significantly predicted that additional children in the same family would likewise become sOP, with an odds ratio of 3.7 (95% CI 0.77-15.2, 95% lower bound 0.95). We further present evidence for an environmental contribution to this effect by means of prolonged exposure to otopathogens within family units. CONCLUSION: sOP children have a significant familial association. The tendency of siblings to share similar patterns of microbial NP colonization contributes to this association. Further research is necessary to determine whether and to what extent genetics are involved.

Serum antibody response to Moraxella catarrhalis proteins OMP CD, OppA, Msp22, Hag, and PilA2 after nasopharyngeal colonization and acute otitis media in children.

BACKGROUND: There is no licensed vaccine for Moraxella catarrhalis (Mcat), which is a prominent bacterium causing acute otitis media (AOM) in children and lower respiratory tract infections in adults. Nasopharyngeal (NP) colonization caused by respiratory bacteria results in natural immunization of the host. To identify Mcat antigens as vaccine candidates, we evaluated the development of naturally induced antibodies to 5 Mcat surface proteins in children 6-30 months of age during Mcat NP colonization and AOM. METHODS: Human serum IgG against the recombinant Mcat proteins, outer membrane protein (OMP) CD, oligopeptide permease (Opp)A, hemagglutinin (Hag), Moraxella surface protein (Msp)22, and PilA clade 2 (PilA2) was quantitated by using an ELISA assay. RESULTS: There were 223 Mcat NP colonization episodes documented in 111 (60%) of 184 children in the study. Thirty five Mcat AOM episodes occurred in 30 (16%) of 184 children. All 5 Mcat candidate vaccine antigens evaluated stimulated a significant rise in serum IgG levles over time from 6 to 36 months of age (P<0.001), with a rank order as follows: Msp22=OppA>OMP CD=Hag=PilA2. Children with no detectable Mcat NP colonization showed a higher serum IgG level against OppA, Hag, and Msp22 compared to those with Mcat NP colonization (P<0.05). Individual data showed that some children responded to AOM with an antibody increase to one or more of the studied Mcat proteins but some children failed to respond. CONCLUSIONS: Serum antibody to Mcat candidate vaccine proteins OMP CD, OppA, Msp22, Hag, and PilA2 increased with age in naturally immunized children age 6-30 months following Mcat NP colonization and AOM. High antibody levels against OppA, Msp22, and Hag correlated with reduced carriage. The results support further investigation of these vaccine candidates in protecting against Mcat colonization and infection.

Comparing 10-yr renal outcomes in deceased donor and living donor liver transplants.

Few studies have explored whether the type of LT, deceased donor LT (DDLT) or living donor LT (LDLT), impacts long-term renal outcomes. We performed a retrospective analysis of 220 LT recipients at our institution to study their renal outcomes at 10 yr. Exclusion criteria were age ≤ 18 yr, graft survival ≤ 6 months, and multiorgan transplants; 108 DDLTs and 62 LDLTs were eligible. At baseline, DDLTs had a lower eGFR than LDLTs and 10.2% of DDLTs were on dialysis as compared to 0% of LDLTs. At 10 yr, seven DDLT and three LDLT recipients required dialysis or renal transplant (p = 0.75). In recipients with graft survival >6 months, DDLTs had a slower decline in eGFR as compared to LDLTs (p < 0.01). Among LDLTs, the decline in eGFR continued over the entire 10-yr period, whereas among DDLTs, the decline in eGFR slowed significantly after six months (p = 0.01). This difference between the two groups was not seen among patients in the highest quartile of baseline eGFR. Patient survival and graft survival were similar. In conclusion, the incidence of end-stage renal disease was similar in both DDLT and LDLT patients, but LDLT recipients seem to have a more sustained decline in eGFR when compared with DDLT recipients.