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Mental disorders present challenges in diagnosis and treatment due to their complex and heterogeneous nature. Electroencephalogram (EEG) has shown promise as a source of potential biomarkers for these disorders. However, existing methods for analyzing EEG signals have limitations in addressing heterogeneity and capturing complex brain activity patterns between regions. This paper proposes a novel random effects state-space model (RESSM) for analyzing large-scale multi-channel resting-state EEG signals, accounting for the heterogeneity of brain connectivities between groups and individual subjects. We incorporate multi-level random effects for temporal dynamical and spatial mapping matrices and address non-stationarity so that the brain connectivity patterns can vary over time. The model is fitted under a Bayesian hierarchical model framework coupled with a Gibbs sampler. Compared to previous mixed-effects state-space models, we directly model high-dimensional random effects matrices of interest without structural constraints and tackle the challenge of identifiability. Through extensive simulation studies, we demonstrate that our approach yields valid estimation and inference. We apply RESSM to a multi-site clinical trial of major depressive disorder (MDD). Our analysis uncovers significant differences in resting-state brain temporal dynamics among MDD patients compared to healthy individuals. In addition, we show the subject-level EEG features derived from RESSM exhibit a superior predictive value for the heterogeneous treatment effect compared to the EEG frequency band power, suggesting the potential of EEG as a valuable biomarker for MDD., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Biometric Society.)

Electroencephalogram (EEG) provides noninvasive measures of brain activity and is found to be valuable for the diagnosis of some chronic disorders. Specifically, pre-treatment EEG signals in the alpha and theta frequency bands have demonstrated some association with antidepressant response, which is well-known to have a low response rate. We aim to design an integrated pipeline that improves the response rate of patients with major depressive disorder by developing a treatment policy guided by the resting state pre-treatment EEG recordings and other treatment effects modifiers. First, we design an innovative automatic site-specific EEG preprocessing pipeline to extract features with stronger signals than raw data. We then estimate the conditional average treatment effect (CATE) using causal forests and use a doubly robust technique to improve efficiency in the estimation of the average treatment effect. We present evidence of heterogeneity in the treatment effect and the modifying power of the EEG features, as well as a significant average treatment effect, a result that cannot be obtained with conventional methods. Finally, we employ an efficient policy learning algorithm to learn an optimal depth-2 treatment assignment decision tree and compare its performance with Q-Learning and outcome-weighted learning via simulation studies and an application to a large multi-site, double-blind, randomized controlled clinical trial, EMBARC., (© 2024 John Wiley & Sons Ltd.)

The Gram-positive human pathogen Group A Streptococcus (GAS, Streptococcus pyogenes ) employs an arsenal of virulence factors that contribute to its pathogenesis. The pilus is an important factor that enables the pathogen to adhere to and colonize host tissues. Emerging research in pilus function shows that pili's involvement in establishing infection extends beyond host adhesion. The diversity of GAS pilus types reflect the varying characteristics identified in different pili. With the development of new experimental systems and animal models, a wider range of biological functions have been explored. This brief review summarizes recent reports of new functions in different GAS pilus types and the methodologies that contributed to the findings. The established importance of the pilus in GAS pathogenesis makes this surface structure a promising vaccine target. This article also reviews recent advancements in pilus-based vaccine strategies and discusses certain aspects that should be considered in vaccine development according to the newly defined properties of pili.

The human complement system is an important part of the innate immune response in the fight against invasive bacteria. Complement responses can be activated independently by the classical pathway, the lectin pathway, or the alternative pathway, each resulting in the formation of a C3 convertase that produces the anaphylatoxin C3a and the opsonin C3b by specifically cutting C3. Other important features of complement are the production of the chemotactic C5a peptide and the generation of the membrane attack complex to lyse intruding pathogens. Invasive pathogens like Staphylococcus aureus and several species of the genus Streptococcus have developed a variety of complement evasion strategies to resist complement activity thereby increasing their virulence and potential to cause disease. In this review, we focus on secreted complement evasion factors that assist the bacteria to avoid opsonization and terminal pathway lysis. We also briefly discuss the potential role of complement evasion factors for the development of vaccines and therapeutic interventions., (Copyright © 2023 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Microneedles (MNs) is an emerging technology that employs needles ranging from 10 to 1000 μm in height, as a minimally invasive technique for various procedures such as therapeutics, disease monitoring and diagnostics. The commonly used method of fabrication, micromolding, has the advantage of scalability, however, micromolding is unable to achieve rapid customizability in dimensions, geometries and architectures, which are the pivotal factors determining the functionality and efficacy of the MNs. 3D printing offers a promising alternative by enabling MN fabrication with high dimensional accuracy required for precise applications, leading to improved performance. Furthermore, enabled by its customizability and one-step process, there is propitious potential for growth for 3D-printed MNs especially in the field of personalized and on-demand medical devices. This review provides an overview of considerations for the key parameters in designing MNs, an introduction on the various 3D-printing techniques for fabricating this new generation of MNs, as well as highlighting the advancements in biomedical applications facilitated by 3D-printed MNs. Lastly, we offer some insights into the future prospects of 3D-printed MNs, specifically its progress towards translation and entry into market., Competing Interests: The authors declare no conflicts of interest., (© 2023 The Authors.)

Modern neuroimaging technologies have substantially advanced the measurement of brain activity. Electroencephalogram (EEG) as a noninvasive neuroimaging technique measures changes in electrical voltage on the scalp induced by brain cortical activity. With its high temporal resolution, EEG has emerged as an increasingly useful tool to study brain connectivity. Challenges with modeling EEG signals of complex brain activity include interactions among unknown sources, low signal-to-noise ratio, and substantial between-subject heterogeneity. In this work, we propose a state space model that jointly analyzes multichannel EEG signals and learns dynamics of different sources corresponding to brain cortical activity. Our model borrows strength from spatially correlated measurements and uses low-dimensional latent states to explain all observed channels. The model can account for patient heterogeneity and quantify the effect of a subject's covariates on the latent space. The EM algorithm, Kalman filtering, and bootstrap resampling are used to fit the state space model and provide comparisons between patient diagnostic groups. We apply the developed approach to a case-control study of alcoholism and reveal significant attenuation of brain activity in response to visual stimuli in alcoholic subjects compared to healthy controls., (© 2022 The International Biometric Society.)

Skin microbiome sampling is currently performed with tools such as swabs and tape strips to collect microbes from the skin surface. However, these conventional approaches may be unable to detect microbes deeper in the epidermis or in epidermal invaginations. We describe a sampling tool with a depth component, a transepidermal microprojection array (MPA), which captures microbial biomass from both the epidermal surface and deeper skin layers. We leveraged the rapid customizability of 3D printing to enable systematic optimization of MPA for human skin sampling. Evaluation of sampling efficacy on human scalp revealed the optimized MPA was comparable in sensitivity to swab and superior to tape strip, especially for nonstandard skin surfaces. We observed differences in species diversity, with the MPA detecting clinically relevant fungi more often than other approaches. This work delivers a tool in the complex field of skin microbiome sampling to potentially address gaps in our understanding of its role in health and disease.

Falls in the aging population are a major public health concern. Outdoor falls in community-dwelling older adults are often triggered by uneven pedestrian walkways. Our understanding of the motor control adaptations to walk over an uneven surface, and the effects of aging on these adaptations is sparse. Here, we study changes in muscle co-contraction, a clinically accepted measure of motor control, due to changes in walking surfaces typically encountered in the outdoor built environment. We address the following research questions: 1) are there walking surface and sex-based differences in muscle co-contractions between young and older adults? and 2) is muscle co-contraction associated with age? We calculated muscle co-contractions from 13 young and 17 older adults during walking at self-selected speeds over even and uneven brick walkways. Muscle co-contraction at the ankle joint was determined from the tibialis anterior and lateral gastrocnemius muscle pair, and at the knee joint from the rectus femoris and semitendinosus muscle pair. Older adults displayed 8-13% greater ankle muscle co-contractions during walking over uneven compared to even surfaces. We found 55-61% (entire gait) and 73-75% (stance phase) greater ankle muscle co-contractions in older females compared to older males during walking over even and uneven surfaces. We found 31-43% greater knee muscle co-contractions in older females compared to older males during the swing phase of walking over even and uneven surfaces. This study underscores the need for determining muscle co-contractions from even and uneven surfaces for quantifying motor control deficits due to aging or neuromuscular disorders., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Mycobacterium tuberculosis (Mtb) remains a global epidemic despite the widespread use of Bacillus Calmette-Guérin (BCG). Consequently, novel vaccines are required to facilitate a reduction in Mtb morbidity and mortality. PilVax is a peptide delivery strategy for the generation of highly specific mucosal immune responses and is based on the food-grade bacterium Lactococcus lactis that is used to express selected peptides engineered within the Streptococcus pyogenes M1T1 pilus, allowing for peptide amplification, stabilization and enhanced immunogenicity. In the present study, the dominant T-cell epitope from the Mtb protein Ag85B was genetically engineered into the pilus backbone subunit and expressed on the surface of L. lactis. Western blot and flow cytometry confirmed formation of pilus containing the peptide DNA sequence. B-cell responses in intranasally vaccinated mice were analyzed by ELISA while T-cell responses were analyzed by flow cytometry. Serum titers of peptide-specific immunoglobulin (Ig) G and IgA were detected, confirming that vaccination produced antibodies against the cognate peptide. Peptide-specific IgA was also detected across several mucosal sites sampled. Peptide-specific CD4 + T cells were detected at levels similar to those of mice immunized with BCG. PilVax immunization resulted in an unexpected increase in the numbers of CD3 + CD4 - CD8 - [double negative (DN)] T cells in the lungs of vaccinated mice. Analysis of cytokine production following stimulation with the cognate peptide showed the major cytokine producing cells to be CD4 + T cells and DN T cells. This study provides insight into the antibody and peptide-specific cellular immune responses generated by PilVax vaccination and demonstrates the suitability of this vaccine for conducting a protection study., (© 2021 Australian and New Zealand Society for Immunology, Inc.)

Group A Streptococcus (GAS) ( Streptococcus pyogenes ) is an important human pathogen associated with significant global morbidity and mortality for which there is no safe and efficacious vaccine. The T antigen, a protein that polymerizes to form the backbone of the GAS pilus structure, is a potential vaccine candidate. Previous surveys of the tee gene, which encodes the T antigen, have identified 21 different tee types and subtypes such that any T antigen-based vaccine must be multivalent and carefully designed to provide broad strain coverage. In this study, the crystal structures of three two-domain T antigens (T3.2, T13, and T18.1) were determined and found to have remarkable structural similarity to the previously reported T1 antigen, despite moderate overall sequence similarity. This has enabled reliable modeling of all major two-domain T antigens to reveal that T antigen sequence variation is distributed along the full length of the protein and shields a highly conserved core. Immunoassays performed with sera from immunized animals and commercial T-typing sera identified a significant cross-reactive antibody response between T18.1, T18.2, T3.2, and T13. The existence of shared epitopes between T antigens, combined with the remarkably conserved structure and high level of surface sequence divergence, has important implications for the design of multivalent T antigen-based vaccines., (Copyright © 2019 American Society for Microbiology.)

The present study aimed to describe and analyze the losses and gains experienced by battered Filipino women as a result of their decision to stay in or leave an abusive relationship. In-depth, semistructured interviews were conducted with 60 battered women, 30 of the women were still living with their abusive husbands/partners and 30 have left their abusive husbands/partners. Results from the phenomenological data analysis of the qualitative data revealed that the women who stayed in and left their abusive partners experienced both losses and gains. For the women who stayed in an abusive relationship, they lost a sense of self, the opportunity for a better life, peace of mind, psychological well-being, and love for their partners. However, these women had the benefits of having a complete family and a partner to help raise their children. In contrast, despite not having a complete family or a partner to help them raise their children, women who left an abusive relationship gained back their sense of self, peace of mind, freedom, inner strength, and hope. Implications for counseling practice were discussed.

Background: Mixed models are a useful tool for evaluating the association between an outcome variable and genetic variables from a family-based genetic study, taking into account the kinship coefficients. When there are ultrahigh dimensional genetic variables (ie, p  ≫  n ), it is challenging to fit any mixed effect model., Methods: We propose a two-stage strategy, screening genetic variables in the first stage and then fitting the mixed effect model in the second stage to those variables that survive the screening. For the screening stage, we can use the sure independence screening (SIS) procedure, which fits the mixed effect model to one genetic variable at a time. Because the SIS procedure may fail to identify those marginally unimportant but jointly important genetic variables, we propose a joint screening (JS) procedure that screens all the genetic variables simultaneously. We evaluate the performance of the proposed JS procedure via a simulation study and an application to the GAW20 data., Results: We perform the proposed JS procedure on the GAW20 representative simulated data set ( n  = 680 participant(s) and p  = 463,995 CpG cytosine-phosphate-guanine [CpG] sites) and select the top d  = ⌊ n / log( n )⌋ variables. Then we fit the mixed model using these top variables. Under significance level, 5%, 43 CpG sites are found to be significant. Some diagnostic analyses based on the residuals show the fitted mixed model is appropriate., Conclusions: Although the GAW20 data set is ultrahigh dimensional and family-based having within group variances, we were successful in performing subset selection using a two-step strategy that is computationally simple and easy to understand., Competing Interests: Not applicable.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Background: Trovafloxacin is a broad-spectrum antibiotic, recently identified as an inhibitor of pannexin-1 (Panx1) channels. Panx1 channels are important conduits for the adenosine triphosphate (ATP) release from live and dying cells that enhances the inflammatory response of immune cells. Elevated extracellular levels ATP released upon injury activate purinergic pathways in inflammatory cells that promote migration, proliferation, phagocytosis, and apoptotic signals. Here, we tested whether trovafloxacin administration attenuates the neuroinflammatory response and improves outcomes after brain trauma., Methods: The murine controlled cortical impact (CCI) model was used to determine whether in vivo delivery of trovafloxacin has anti-inflammatory and neuroprotective actions after brain trauma. Locomotor deficit was assessed using the rotarod test. Levels of tissue damage markers and inflammation were measured using western blot, qPCR, and immunofluorescence. In vitro assays were used to evaluate whether trovafloxacin blocks ATP release and cell migration in a chemotactic-stimulated microglia cell line., Results: Trovafloxacin treatment of CCI-injured mice significantly reduced tissue damage markers and improved locomotor deficits. In addition, trovafloxacin treatment significantly reduced mRNA levels of several pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), which correlates with an overall reduction in the accumulation of inflammatory cell types (neutrophils, microglia/macrophages, and astroglia) at the injury zone. To determine whether trovafloxacin exerted these effects by direct action on immune cells, we evaluated its effect on ATP release and cell migration using a chemotactic-stimulated microglial cell line. We found that trovafloxacin significantly inhibited both ATP release and migration of these cells., Conclusion: Our results show that trovafloxacin administration has pronounced anti-inflammatory and neuroprotective effects following brain injury. These findings lay the foundation for future studies to directly test a role for Panx1 channels in pathological inflammation following brain trauma.

The use of Bisphenol A (BPA) has widely been replaced in consumer products by analogs BPB, BPE, BPF, BPS, and BPAF. Recent studies have linked these substitutes to similar adverse health outcomes as BPA, including disruption of endocrine pathways in animal and human studies. We designed a novel MS method, developed specifically for this study, to capture the most relevant BPA alternatives, BPB, BPE, BPF, BPS, BPAF and 4-NP in human blood and urine to quantify potential in utero exposures. To our knowledge, this is the first study to explore in utero exposure to these BPA analogs and the first U.S. study to test for BPA in maternal/fetal pairs. The method was run on 30 paired maternal urine and fetal cord blood samples from mothers undergoing elective Caesarean sections. 90% of mothers and 77% of babies tested positive for at least one BP analog. 83% of mothers tested positive for BPAF, 60% for BPS, 57% for BPB, 17% for BPF and 7% for BPA. 57% of babies tested positive for BPAF and 50% for BPF. BPA and BPB were detected in one cord blood sample each. BPS was not detected in cord blood. BPE was not detected in any fetal cord blood or maternal urine samples. These findings demonstrate the pervasiveness of some BP analogs in pregnant women and their babies at birth., Competing Interests: Competing interests: The authors declare that they have no competing interests.

Background: Cisplatin eligibility for clinical trials has been defined as glomerular filtration rate (GFR) ≥ 60 mL/min due to the risk of nephrotoxicity in patients with renal impairment. For urothelial cancer, substitution of carboplatin instead of cisplatin compromises outcomes. We evaluated change in GFR in patients treated with cisplatin despite baseline GFR < 60 mL/min to determine risk of nephrotoxicity., Patients and Methods: Patients treated between 2009 and 2014 at our institution were identified by the institutional review board-approved cystectomy database. GFR percentage change was compared by age (< 75 vs. ≥ 75 years), pretreatment GFR (< 60 vs. ≥ 60 mL/min), therapy setting (neoadjuvant, adjuvant, or metastatic), primary disease site, and comorbidities (diabetes, hypertension, and hyperlipidemia). The associations between overall survival and age or GFR were also assessed., Results: There were 81 patients who received cisplatin-based therapy and whose pre- and posttreatment GFR were available. Median GFR change was -1.6% for patients with pretreatment GFR < 60 mL/min compared to -10.9% for patients with pretreatment GFR ≥ 60 mL/min (P = .17). Therapy setting was the only factor in our study to be significantly associated with GFR change (P = .027). No association was found between overall survival and pre- or posttreatment GFR, GFR percentage change, or age., Conclusion: Our data support the hypothesis that urothelial cancer patients with GFR < 60 mL/min do not experience a greater decline in renal function after cisplatin compared to patients with GFR ≥ 60 mL/min. If validated, this may extend the option of cisplatin-based therapy to previously ineligible patients., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The lack of standardised protocols for the assessment of functional antibodies has hindered Streptococcus pyogenes research and the development of vaccines. A robust, high throughput opsonophagocytic bactericidal assay to determine protective antibodies in human and rabbit serum has been developed that utilises bioluminescence as a rapid read out., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Group A Streptococcus (GAS), or Streptococcus pyogenes, is a human pathogen that causes diseases ranging from skin and soft tissue infections to severe invasive diseases, such as toxic shock syndrome. Each GAS strain carries a particular pilus type encoded in the variable fibronectin-binding, collagen-binding, T antigen (FCT) genomic region. Here, we describe the functional analysis of the serotype M2 pilus encoded in the FCT-6 region. We found that, in contrast to other investigated GAS pili, the ancillary pilin 1 lacks adhesive properties. Instead, the backbone pilin is important for host cell adhesion and binds several host factors, including fibronectin and fibrinogen. Using a panel of recombinant pilus proteins, GAS gene deletion mutants and Lactococcus lactis gain-of-function mutants we show that, unlike other GAS pili, the FCT-6 pilus also contributes to immune evasion. This was demonstrated by a delay in blood clotting, increased intracellular survival of the bacteria in macrophages, higher bacterial survival rates in human whole blood and greater virulence in a Galleria mellonella infection model in the presence of fully assembled FCT-6 pili., (© 2016 John Wiley & Sons Ltd.)

Acute rheumatic fever (ARF) is an autoimmune response to Group A Streptococcus (GAS) infection. Repeated GAS exposures are proposed to 'prime' the immune system for autoimmunity. This notion of immune-priming by multiple GAS infections was first postulated in the 1960s, but direct experimental evidence to support the hypothesis has been lacking. Here, we present novel methodology, based on antibody responses to GAS T-antigens, that enables previous GAS exposures to be mapped in patient sera. T-antigens are surface expressed, type specific antigens and GAS strains fall into 18 major clades or T-types. A panel of recombinant T-antigens was generated and immunoassays were performed in parallel with serum depletion experiments allowing type-specific T-antigen antibodies to be distinguished from cross-reactive antibodies. At least two distinct GAS exposures were detected in each of the ARF sera tested. Furthermore, no two sera had the same T-antigen reactivity profile suggesting that each patient was exposed to a unique series of GAS T-types prior to developing ARF. The methods have provided much-needed experimental evidence to substantiate the immune-priming hypothesis, and will facilitate further serological profiling studies that explore the multifaceted interactions between GAS and the host.

Galleria mellonella (greater wax moth or honeycomb moth) has been introduced as an alternative model to study microbial infections. G. mellonella larvae can be easily and inexpensively obtained in large numbers and are simple to use as they don't require special lab equipment. There are no ethical constraints and their short life cycle makes them ideal for large-scale studies. Although insects lack an adaptive immune response, their innate immune response shows remarkable similarities with the immune response in vertebrates. This review gives a current update of what is known about the immune system of G. mellonella and provides an extensive overview of how G. mellonella is used to study the virulence of Gram-positive and Gram-negative bacteria. In addition, the use of G. mellonella to evaluate the efficacy of antimicrobial agents and experimental phage therapy are also discussed. The review concludes with a critical assessment of the current limitatons of G. mellonella infection models.

Objective: To determine if multiple streptococcal species can be easily labeled for biophotonic imaging using a toxin-antitoxin stabilized reporter plasmid containing the native firefly luciferase gene, originally developed for use in Group A Streptococcus., Results: A number of streptococcal species including Group B Streptococcus, Group C Streptococcus, Group G Streptococcus, S. iniae, S. vestibularis, and S. salivarius were successfully transformed with the reporter plasmid. In absence of antibiotic selection, the plasmid had variable stability amongst the six strains. The expression of firefly luciferase was highest in Group B Streptococcus and S. iniae, as observed by the brightest signal and lowest detection limits in vitro., Conclusion: Multiple streptococcal species can be easily transformed with our toxin-antitoxin stabilized bioluminescent reporter plasmid. However, this plasmid shows variable stability and signal in different species, restricting its use for certain applications.

Streptococcus pyogenes is an important human pathogen that causes a wide range of diseases. Using bioinformatics analysis of the complete S. pyogenes strain SF370 genome, we have identified a novel S. pyogenes virulence factor, which we termed streptococcal 5'-nucleotidase A (S5nA). A recombinant form of S5nA hydrolyzed AMP and ADP, but not ATP, to generate the immunomodulatory molecule adenosine. Michaelis-Menten kinetics revealed a Km of 169 μm and a Vmax of 7550 nmol/mg/min for the substrate AMP. Furthermore, recombinant S5nA acted synergistically with S. pyogenes nuclease A to generate macrophage-toxic deoxyadenosine from DNA. The enzyme showed optimal activity between pH 5 and pH 6.5 and between 37 and 47 °C. Like other 5'-nucleotidases, S5nA requires divalent cations and was active in the presence of Mg(2+), Ca(2+), or Mn(2+). However, Zn(2+) inhibited the enzymatic activity. Structural modeling combined with mutational analysis revealed a highly conserved catalytic dyad as well as conserved substrate and cation-binding sites. Recombinant S5nA significantly increased the survival of the non-pathogenic bacterium Lactococcus lactis during a human whole blood killing assay in a dose-dependent manner, suggesting a role as an S. pyogenes virulence factor. In conclusion, we have identified a novel S. pyogenes enzyme with 5'-nucleotidase activity and immune evasion properties., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

Background: The prevalence of pediatric hormonal disorders and hormonally-sensitive cancers are rising. Chemicals including bisphenol A (BPA), phthalates, parabens, 4-nonylphenol (4NP) and triclosan have been linked to disruption of endocrine pathways and altered hormonal status in both animal and human studies. Additionally, changes in estrogen metabolism have been associated with pediatric endocrine disorders and linked to estrogen-dependent cancers. The main objective of the study was to measure the presence of these environmental chemicals in prepubescent children and assess the relationship between chemical metabolites and estrogen metabolism., Methods: 50 subjects (25 male, 25 female) were recruited from the principal investigator's existing patient population at his pediatric primary care office. The first 5 boys and 5 girls in each age group (4 through 8 years old inclusive) who presented for annual examinations were included, as long as they were Tanner Stage I (prepubertal) on physical exam, without diagnosis of hormonally-related condition and/or cancer and able to give a urine sample. Urine samples were collected in glass containers for analysis of chemical and estrogen metabolites. Study kits and lab analysis were provided by Genova Diagnostics (Duluth, GA). Summary statistics for the concentrations of each chemical metabolite as well as estrogen metabolites were computed (minimum, maximum, median and inter-quartile range) for males only, for females only and for all subjects. Comparisons between groups (e.g. males v. females) were assessed using the nonparametric Wilcoxon test, since the data was skewed. The correlation between concentrations of chemical metabolites and estrogen metabolites in prepubescent children were examined by the Spearman's correlation coefficient (ρ)., Results: 100 % of subjects had detectable levels of at least five chemicals [corrected] in their urine, and 74 % had detectable levels of eight or more chemicals. 28 % of subjects had measurable levels of 4NP. No associations were found between the urine levels of chemicals and estrogen metabolites., Conclusions: Endocrine disrupting environmental chemicals were detected in all children in the study, with measurable levels of 4NP in nearly 1/3 of subjects. This is the first known published study of 4NP levels in American children. No associations were found between the urine levels of chemicals tested and estrogen metabolites. The presence of multiple chemicals in a majority of children's urine coupled with increasing prevalence of pediatric hormonal disorders warrants further research to elucidate potential causal mechanisms in pre- and post-pubertal children.

Background: Head lice most commonly affect children, ages 3 to 11. Concerns exist about the safety and efficacy of pesticide-based treatments. Published studies suggest dimethicone is a potentially safe and effective non-toxic treatment, but have not evaluated 100% dimethicone in a pediatric population. The objectives were to evaluate the efficacy and safety of 100% dimethicone for the treatment of head lice in children, monitored by school nurses., Methods: This was a multi-site, open-label study of a 100% dimethicone gel for the treatment of head lice in a pediatric population. Children (ages 3-12) suspected of infestation with head lice were evaluated by school nurses at six schools and daycare programs in New York and New Jersey. Inclusion criteria were presence of at least three live lice, or one live louse and 10 viable eggs (eggs found within 1.27 cm of the scalp) and no use of any head lice treatment within four weeks of enrollment. Counts of live lice and viable eggs found in 58 subjects were tracked at baseline (Day 0) and on Day 1, Day 7, and Day 14 after treatment., Results: After 1 day of treatment with 100% dimethicone, 98.30% of subjects were free of live lice and 55.20% were free of viable eggs. On day 14, 96.50% were still free of live lice, and 80.70% were free of viable eggs. All subjects were monitored by the school nurse at baseline and throughout the study period for adverse effects, including scalp erythema, excoriation, flaking and edema. There was one adverse event of skin irritation lasting 10 min, and no serious adverse events reported. Overall, scalp conditions improved from the baseline: 10 subjects (17.5%) reported mild to moderate scalp erythema on day 1, compared with only one subject (1.7%) on day 14; 8 subjects (14.3%) reported mild scalp excoriation on day 1, with none reporting on day 14., Conclusions: 100% dimethicone was found to be a safe and highly effective treatment for pediatric head lice. Because dimethicone avoids pesticide exposure and resistance issues, dimethicone should be considered as a first-line treatment for head lice., Trial Registration: NCT02213055 Date of registration: August 8, 2014. STANDARDS OF REPORTING: The CONSORT 2010 Checklist was consulted during the review of this manuscript. Please note that sections pertaining specifically to randomized controlled trials (RCT's) were not applicable.

We present a case report of a 41-year-old woman of Malay ethnicity who presented with an 11-day history of fever and left-sided lymphadenopathy after consuming 'Miracle Mineral Solution' (sodium chlorite solution) for the first time. A diagnosis of Kikuchi-Fujimoto disease was established via lymph node biopsy after other differentials were excluded. The aetiology of Kikuchi-Fujimoto disease remains controversial, but viral, autoimmune and physicochemical causes have been suggested as possibilities. In this case, we hypothesise that oxidative injury from sodium chlorite initiated an inflammatory response, which triggered the onset of Kikuchi-Fujimoto disease., (2014 BMJ Publishing Group Ltd.)

Group A streptococcus (GAS; Streptococcus pyogenes) is a Gram-positive human pathogen that causes a broad range of diseases ranging from acute pharyngitis to the poststreptococcal sequelae of acute rheumatic fever. GAS pili are highly diverse, long protein polymers that extend from the cell surface. They have multiple roles in infection and are promising candidates for vaccine development. This study describes the structure of the T6 backbone pilin (BP; Lancefield T-antigen) from the important M6 serotype. The structure reveals a modular arrangement of three tandem immunoglobulin-like domains, two with internal isopeptide bonds. The T6 pilin lysine, essential for polymerization, is located in a novel VAKS motif that is structurally homologous to the canonical YPKN pilin lysine in other three- and four-domain Gram-positive pilins. The T6 structure also highlights a conserved pilin core whose surface is decorated with highly variable loops and extensions. Comparison to other Gram-positive BPs shows that many of the largest variable extensions are found in conserved locations. Studies with sera from patients diagnosed with GAS-associated acute rheumatic fever showed that each of the three T6 domains, and the largest of the variable extensions (V8), are targeted by IgG during infection in vivo. Although the GAS BP show large variations in size and sequence, the modular nature of the pilus proteins revealed by the T6 structure may aid the future design of a pilus-based vaccine., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

NanoLuc luciferase (Nluc) is an engineered enzyme that catalyses the substrate, furimazine, to produce light. Nluc has higher sensitivity than the commonly used bioluminescent reporter, firefly luciferase (FFluc). We have introduced Nluc into a toxin-antitoxin stabilised plasmid for the efficient labeling of group A Streptococcus. Comparison of signal strength and kinetic properties between Nluc-labeled bacteria and similarly previously-labeled FFluc bacteria, showed that the bioluminescent signal produced by Nluc-labeled bacteria is up to 15-times higher than FFluc-labeled bacteria during the logarithmic phase. However, with Nluc we were unable to differentiate between bacteria that are metabolically active and inactive because of its ATP-independence. Nluc therefore offers a more sensitive reporter but, perhaps, one more restricted for downstream applications.

There is a dearth of research on battered Filipino women's stay or leave decision-making process. The present study interviewed 40 battered women in the Philippines to explore factors associated with their decisions to stay or leave their husbands or partners. Results revealed that (a) battered women's decision to stay was associated with intrapersonal and interpersonal factors such as personality characteristics, lack of personal resources, absence of social support, presence of children, length of relationship, and sociocultural factors and (b) battered women's decision to leave their abusive partners was associated with factors such as personality characteristics, personal resources, social support, nature of abuse, and spousal factors. Implications for research and practice were discussed.

The SVZ (subventricular zone) contains neural stem cells and progenitors of various potentialities. Although initially parsed into A, B, and C cells, this germinal zone is comprised of a significantly more diverse population of cells. Here, we characterized a subset of postnatal PRPs (PDGF-AA-responsive precursors) that express functional PDGFα and β receptors from birth to adulthood. When grown in PDGF-AA, dissociated neonatal rat SVZ cells divided to produce non-adherent clusters of progeny. Unlike the self-renewing EGF/FGF-2-responsive precursors that produce neurospheres, these PRPs failed to self-renew after three passages; therefore, we refer to the colonies they produce as spheroids. Upon differentiation these spheroids could produce neurons, type 1 astrocytes and oligodendrocytes. When maintained in medium supplemented with BMP-4 they also produced type 2 astrocytes. Using lineage tracing methods, it became evident that there were multiple types of PRPs, including a subset that could produce neurons, oligodendrocytes, and type 1 and type 2 astrocytes; thus some of these PRPs represent a unique population of precursors that are quatropotential. Spheroids also could be generated from the newborn neocortex and they had the same potentiality as those from the SVZ. By contrast, the adult neocortex produced less than 20% of the numbers of spheroids than the adult SVZ and spheroids from the adult neocortex only differentiated into glial cells. Interestingly, SVZ spheroid producing capacity diminished only slightly from birth to adulthood. Altogether these data demonstrate that there are PRPs that persist in the SVZ that includes a unique population of quatropotential PRPs.

Bioluminescence is a rapid and cost-efficient optical imaging technology that allows the detection of bacteria in real-time during disease development. Here, we report a novel strategy to generate a wide range of bioluminescent group A streptococcus (GAS) strains by using a toxin-antitoxin-stabilized plasmid. The bacterial luciferin-luciferase operon (lux) or the firefly luciferase gene (ffluc) was introduced into GAS via a stabilized plasmid. The FFluc reporter gave significantly stronger bioluminescent signals than the Lux reporter, and was generally more stable. Plasmid-based luciferase reporters could easily be introduced into a variety of GAS strains and the signals correlated linearly with viable cell counts. Co-expression of the streptococcal ω-ε-ζ toxin-antitoxin operon provided segregational stability in the absence of antibiotics for at least 17 passages in vitro and up to 7 days in a mouse infection model. In addition, genome-integrated reporter constructs were also generated by site-specific recombination, but were found to be technically more challenging. The quick and efficient generation of various M-type GAS strains expressing plasmid-based luciferase reporters with comparable and quantifiable bioluminescence signals allows for comparative analysis of different GAS strains in vitro and in vivo.

Racial residential segregation is associated with health inequalities in the USA, and one of the primary mechanisms is through influencing features of the neighborhood physical environment. To better understand how Black residential segregation might contribute to health risk, we examined retail redlining; the inequitable distribution of retail resources across racially distinct areas. A combination of visual and analytic methods was used to investigate whether predominantly Black census block groups in New York City had poor access to retail stores important for health. After controlling for retail demand, median household income, population density, and subway ridership, percent Black was associated with longer travel distances to various retail industries. Our findings suggest that Black neighborhoods in New York City face retail redlining. Future research is needed to determine how retail redlining may perpetuate health disparities and socioeconomic disadvantage.

Group A streptococcus is a strict human pathogen that can cause a wide range of diseases, such as tonsillitis, impetigo, necrotizing fasciitis, toxic shock, and acute rheumatic fever. Modeling human diseases in animals is complicated, and rapid, simple, and cost-effective in vivo models of GAS infection are clearly lacking. Recently, the use of non-mammalian models to model human disease is starting to re-attract attention. Galleria mellonella larvae, also known as wax worms, have been investigated for modeling a number of bacterial pathogens, and have been shown to be a useful model to study pathogenesis of the M3 serotype of GAS. In this study we provide further evidence of the validity of the wax worm model by testing different GAS M-types, as well as investigating the effect of bacterial growth phase and incubation temperature on GAS virulence in this model. In contrast to previous studies, we show that the M-protein, among others, is an important virulence factor that can be effectively modeled in the wax worm. We also highlight the need for a more in-depth investigation of the effects of experimental design and wax worm supply before we can properly vindicate the wax worm model for studying GAS pathogenesis.

The feasibility of cancer immunotherapy mediated by T lymphocytes is now a clinical reality. Indeed, many tumour associated antigens have been identified for cytotoxic CD8 T cells, which are believed to be key mediators of tumour rejection. However, for aggressive malignancies in specialised anatomic sites such as the brain, a limiting factor is suboptimal tumour infiltration by CD8 T cells. Here we take advantage of recent advances in T cell biology to differentially polarise CD4 T cells in order to explore their capacity to enhance immunotherapy. We used an adoptive cell therapy approach to work with clonal T cell populations of defined specificity. Th1 CD4 T cells preferentially homed to and accumulated within intracranial tumours compared with Th2 CD4 T cells. Moreover, tumour-antigen specific Th1 CD4 T cells enhanced CD8 T cell recruitment and function within the brain tumour bed. Survival of mice bearing intracranial tumours was significantly prolonged when CD4 and CD8 T cells were co-transferred. These results should encourage further definition of tumour antigens recognised by CD4 T cells, and exploitation of both CD4 and CD8 T cell subsets to optimise T cell therapy of cancer.

In the elderly, immunosenescence and malnourishment can contribute to increased risk and severity of upper respiratory tract infections (URTI). Gold kiwifruit (Actinidia chinensis 'Hort16A') contains nutrients important for immune function and mitigation of symptoms of infection, including vitamins C and E, folate, polyphenols and carotenoids. The objective of the present study was to evaluate whether regular consumption of gold kiwifruit reduces symptoms of URTI in older people, and determine the effect it has on plasma antioxidants, and markers of oxidative stress, inflammation and immune function. A total of thirty-two community-dwelling people (≥65 years) participated in a randomised crossover study, consuming the equivalent of four kiwifruit or two bananas daily for 4 weeks, with treatments separated by a 4-week washout period. Participants completed the Wisconsin Upper Respiratory Symptom Survey-21 daily, and blood samples were collected at baseline and at the end of each treatment and washout period. Gold kiwifruit did not significantly reduce the overall incidence of URTI compared with banana, but significantly reduced the severity and duration of head congestion, and the duration of sore throat. Gold kiwifruit significantly increased plasma vitamin C, α-tocopherol and lutein/zeaxanthin concentrations, and erythrocyte folate concentrations, and significantly reduced plasma lipid peroxidation. No changes to innate immune function (natural killer cell activity, phagocytosis) or inflammation markers (high-sensitivity C-reactive protein, homocysteine) were detected. Consumption of gold kiwifruit enhanced the concentrations of several dietary plasma analytes, which may contribute to reduced duration and severity of selected URTI symptoms, offering a novel tool for reducing the burden of URTI in older individuals.

Streptococcal mitogenic exotoxin Z-2 (SMEZ-2) is a streptococcal superantigen that primarily stimulates human T cells bearing Vβ8 and mouse T cells bearing Vβ11. Mutagenesis of T cell receptor (TCR)-binding residues (W75L, K182Q, D42C) produced a mutant called M1 that was >10(5)-fold less active toward human peripheral blood lymphocytes and splenocytes from transgenic mice that express human CD4 and either human HLA-DR3-DQ2 or HLA-DR4-DQ8. Similarly, cytokine production in response to M1 in lymphocyte culture was rendered undetectable, and no change in the frequency of Vβ11-bearing T cells in mice receiving M1 was observed. M1 toxoid was tested as a potential vaccine conjugate. Vaccination with 1 to 10 μg M1 conjugated to ovalbumin (M1-ovalbumin) resulted in more rapid and quantitatively higher levels of anti-ovalbumin IgG, with endpoint titers being 1,000- to 10,000-fold greater than those in animals immunized with unconjugated ovalbumin. Substantially higher levels of anti-ovalbumin IgG were observed in mice transgenic for human major histocompatibility complex (MHC) class II. Substitution of M1 with an MHC class II binding mutant (DM) eliminated enhanced immunity, suggesting that M1 enhanced the delivery of antigen via MHC class II-positive antigen-presenting cells that predominate within lymphoid tissue. Immunization of animals with a conjugate consisting of M1 and ovalbumin peptide from positions 323 to 339 generated levels of anti-peptide IgG 100-fold higher than those in animals immunized with peptide alone. Coupling of a TCR-defective superantigen toxoid presents a new strategy for conjugate vaccines with the additional benefit of targeted delivery to MHC class II-bearing cells.

In this work we propose a fully Bayesian semiparametric method to estimate the intensity of an inhomogeneous spatial point process. The basic idea is to first convert intensity estimation into a Poisson regression setting via binning data points on a regular grid, and then model the log intensity semiparametrically using an adaptive version of Gaussian Markov random fields to smooth the corresponding counts. The inference is carried by an efficient Markov chain Monte Carlo simulation algorithm. Compared to existing methods for intensity estimation, for example, parametric modeling and kernel smoothing, the proposed estimator not only provides inference regarding the dependence of the intensity function on possible covariates, but also uses information from the data to adaptively determine the amount of smoothing at the local level. The effectiveness of using our method is demonstrated through simulation studies and an application to a rainforest dataset., (© 2010, The International Biometric Society.)

This article investigated opinions on what constitute parental abuse with interviews of 30 high school students, 30 parents, and 28 counselors. Despite increased reported cases of emotional abuses and child maltreatments in the Philippines, few empirical studies have explored the exact nature of parental verbal abuses in this country. This study is designed to address this gap in the literature. The results revealed nine categories of parental verbal abuses namely: (a) Put downs and shaming, (b) Rejection, (c) Blaming, (d) Fault Exaggerating, (e) Threat, (f) Invoking harm, (g) Regrets, (h) Unfair comparison, and (i) Negative prediction. Implications for research and practice were discussed.

Kiwifruit is a good source of several vitamins and minerals and dietary fibre, and contains a number of phytochemicals; so kiwifruit potentially provides health benefits beyond basic nutrition. Consumption of green kiwifruit can have positive effects on cardiovascular health through antioxidant activity, inhibition of platelet aggregation and lowered TAG levels, and gut health through improving laxation, aiding digestion and promoting a healthy gut microflora. The importance of nutrition on immune function is well recognised, with deficiencies in vitamins A, C, E, B6 and B12, folic acid, Zn, Cu, Fe and Se being associated with impaired immune function and increased susceptibility to diseases. Evidence is growing that kiwifruit enhances immunity, with several small murine studies showing enhancement of innate and adaptive immune function. Few studies have examined the effect of kiwifruit on immune function in human subjects, but a recent study has revealed that kiwifruit up-regulates several 'immune' and 'DNA and repair'-related gene sets, and down-regulates one gene set related to Ig secretion. Taken together, the evidence from the literature provides supporting data for designing a human intervention trial to validate the ability of kiwifruit to support immune function in healthy and immunocompromised populations.

Background: Perceived stress has been associated with fewer health-promoting behaviors in new primiparous mothers, but less is known about the mechanisms responsible for such effects., Objective: The objective of this study was to examine the hypothesis that the relationship between perceived stress and health-promoting behaviors is mediated partially by a primiparous mother's sense of optimism. The transactional model of stress and coping and the model of behavioral self-regulation were used as the theoretical framework for the study., Methods: An ex post facto cross-sectional design was used for this study. Participants consisted of 174 primiparous mothers who had given birth within the previous 12 months. Participants completed a self-reported online questionnaire consisting of the Perceived Stress Scale, the Health-Promoting Lifestyle Profile II, and the revised Life Orientation Test., Results: Results indicated that perceived stress predicted less health-promoting behaviors in new primiparous mothers (p < .001). Importantly, this relationship was mediated partially by the optimism displayed by the mother (p < .001)., Conclusions: The findings indicated that optimism partially mediated the relationship between perceived stress and health-promoting behaviors in new primiparous mothers. The implications for psychological practice are discussed.

Objective: Social science and health literature have identified residential segregation as a critical factor in exposure to health-related resources, including food environments. Differential spatial patterning of food environments surrounding schools has significant import for youth. We examined whether fast food restaurants clustered around schools in New York City, and whether any observed clustering varied as a function of school type, school racial demographics, and area racial and socioeconomic demographics., Method: We geocoded fast food locations from 2006 (n=817) and schools from 2004-2005 (n=2096; public and private, elementary and secondary) in the five boroughs of New York City. A point process model (inhomogeneous cross-K function) examined spatial clustering., Results: A minimum of 25% of schools had a fast food restaurant within 400 m. High schools had higher fast food clustering than elementary schools. Public elementary and high schools with large proportions of Black students or in block groups with large proportions of Black residents had higher clustering than White counterparts. Finally, public high schools had higher clustering than private counterparts, with 1.25 to 2 times as many restaurants than expected by chance., Conclusion: The results suggest that the geography of opportunity as it relates to school food environments is unequal in New York City., (Copyright 2010 Elsevier Inc. All rights reserved.)

The high prevalence of obesity in African American populations may be due to the food environment in residential communities, and the density of fast food restaurants is an important aspect of the restaurant landscape in US cities. This study investigated racial and socioeconomic correlates of fast food density in New York City. We found that predominantly Black areas had higher densities of fast food than predominantly White areas; high-income Black areas had similar exposure as low-income Black areas; and national chains were most dense in commercial areas. The results highlight the importance of policy level interventions to address disparities in food environments as a key goal in obesity prevention efforts.

T cell mediated immunotherapies are proposed for many cancers including malignant astrocytoma. As such therapies become more potent, but not necessarily more tumor-specific, the risk of collateral autoimmune damage to normal tissue increases. Tumors of the brain present significant challenges in this respect, as autoimmune destruction of brain tissue could have severe consequences. To investigate local immune reactivity toward a tumor-associated antigen in the brain, transgenic mice were generated that express a defined antigen (CW3 170-179) in astroglial cells. The resulting six transgenic mouse lines expressed the transgenic self-antigen in cells of the gastrointestinal tract and CNS compartments, or in the CNS alone. By challenging transgenic mice with tumor cells that express CW3, self/tumor-specific immune responses were visualized within a normal polyclonal T cell repertoire. A large expansion of the endogenous CW3 170-179-specific CD8 T cell population was observed in nontransgenic mice after both subcutaneous and intracerebral implantation of tumor cells. In contrast, CW3 170-179-specific immune responses were not observed in transgenic mice that exhibited extracerebral transgene expression. Importantly, in certain groups of mice in which transgene expression was restricted to the CNS, antigen-specific immune responses occurred when tumor was implanted subcutaneously, but not intracerebrally. This local immune tolerance in the brain was induced via peripheral (extrathymic) rather than central (thymic) tolerance mechanisms. Thus, this study highlights the role of regional immune regulation in the prevention of autoimmunity in the brain, and the potential impact of these mechanisms for brain tumor immunotherapy., ((c) 2008 Wiley-Liss, Inc.)

We analyzed a very large set of molecular interactions that had been derived automatically from biological texts. We found that published statements, regardless of their verity, tend to interfere with interpretation of the subsequent experiments and, therefore, can act as scientific "microparadigms," similar to dominant scientific theories [Kuhn, T. S. (1996) The Structure of Scientific Revolutions (Univ. Chicago Press, Chicago)]. Using statistical tools, we measured the strength of the influence of a single published statement on subsequent interpretations. We call these measured values the momentums of the published statements and treat separately the majority and minority of conflicting statements about the same molecular event. Our results indicate that, when building biological models based on published experimental data, we may have to treat the data as highly dependent-ordered sequences of statements (i.e., chains of collective reasoning) rather than unordered and independent experimental observations. Furthermore, our computations indicate that our data set can be interpreted in two very different ways (two "alternative universes"): one is an "optimists' universe" with a very low incidence of false results (<5%), and another is a "pessimists' universe" with an extraordinarily high rate of false results (>90%). Our computations deem highly unlikely any milder intermediate explanation between these two extremes.