Effect of Ligand Modification on the Mechanism of Electrocatalytic Hydrogen Production by Ni(pyridinethiolate)3- Derivatives.

The effects of ligand modification on the catalytic mechanism of hydrogen production by Ni(PyS)3- derivatives, made with electron-withdrawing and -donating substitutions to the pyridinethiolate (PyS)- ligands, are studied experimentally and computationally using density functional theory. Thermodynamic data, spin density maps, and frontier molecular orbital diagrams were generated for reaction intermediates. Comparison of computed values for E0 and p Ka with experimental values supports the proposed mechanisms. The rate of electrochemical hydrogen production is correlated with the effect of ligand modification. Notably, the presence of an electron-donating substituent favors an alternative mechanism for hydrogen production. Computationally it was determined that the electron-donating substituent causes deviation from the original chemical-electrochemical-chemical-electrochemical (CECE) mechanism of Ni(PyS)3- to a CCEE mechanism, while the CECE mechanism is maintained for all catalysts substituted with electron-withdrawing groups.

Mass cytometry identifies a distinct monocyte cytokine signature shared by clinically heterogeneous pediatric SLE patients.

Systemic Lupus Erythematosus (SLE) is a heterogeneous autoimmune disease with heightened disease severity in children. The incomplete understanding of the precise cellular and molecular events that drive disease activity pose a significant hurdle to the development of targeted therapeutic agents. Here, we performed single-cell phenotypic and functional characterization of pediatric SLE patients and healthy controls blood via mass cytometry. We identified a distinct CD14hi monocyte cytokine signature, with increased levels of monocyte chemoattractant protein-1 (MCP1), macrophage inflammatory protein-1ß (Mip1ß), and interleukin-1 receptor antagonist (IL-1RA). This signature was shared by every clinically heterogeneous patient, and reproduced in healthy donors' blood upon ex-vivo exposure to plasma from clinically active patients only. This SLE-plasma induced signature was abrogated by JAK1/JAK2 selective inhibition. This study demonstrates the utility of mass cytometry to evaluate immune dysregulation in pediatric autoimmunity, by identification of a multi-parametric immune signature that can be further dissected to delineate the events that drive disease pathogenesis.

Curing the historically incurable: treatment success with ledipasvir/sofosbuvir for chronic hepatitis C virus in a heavily treatment-experienced individual.

WHAT IS KNOWN AND OBJECTIVE: Significant progression in the treatment of chronic hepatitis C virus has been made with the introduction of direct-acting antivirals (DAAs). However, limited data are available for the retreatment of individuals who have failed multiple prior DAAs. CASE DESCRIPTION: We report a single case of an individual who was unsuccessfully treated with five prior hepatitis C virus treatment regimens including simeprevir plus sofosbuvir who was successfully cured after treatment with ledipasvir/sofosbuvir. WHAT IS NEW AND CONCLUSION: Ledipasvir/sofosbuvir may be an option for treating patients who have failed multiple prior DAA regimens; however, further research is warranted.

CD161(int)CD8+ T cells: a novel population of highly functional, memory CD8+ T cells enriched within the gut.

The C-type lectin-like receptor CD161 is expressed by lymphocytes found in human gut and liver, as well as blood, especially natural killer (NK) cells, T helper 17 (Th17) cells, and a population of unconventional T cells known as mucosal-associated invariant T (MAIT) cells. The association of high CD161 expression with innate T-cell populations including MAIT cells is established. Here we show that CD161 is also expressed, at intermediate levels, on a prominent subset of polyclonal CD8+ T cells, including antiviral populations that display a memory phenotype. These memory CD161(int)CD8+ T cells are enriched within the colon and express both CD103 and CD69, markers associated with tissue residence. Furthermore, this population was characterized by enhanced polyfunctionality, increased levels of cytotoxic mediators, and high expression of the transcription factors T-bet and eomesodermin (EOMES). Such populations were induced by novel vaccine strategies based on adenoviral vectors, currently in trial against hepatitis C virus. Thus, intermediate CD161 expression marks potent polyclonal, polyfunctional tissue-homing CD8+ T-cell populations in humans. As induction of such responses represents a major aim of T-cell prophylactic and therapeutic vaccines in viral disease and cancer, analysis of these populations could be of value in the future.

High-dimensional immune profiling of total and rotavirus VP6-specific intestinal and circulating B cells by mass cytometry.

In-depth phenotyping of human intestinal antibody secreting cells (ASCs) and their precursors is important for developing improved mucosal vaccines. We used single-cell mass cytometry to simultaneously analyze 34 differentiation and trafficking markers on intestinal and circulating B cells. In addition, we labeled rotavirus (RV) double-layered particles with a metal isotope and characterized B cells specific to the RV VP6 major structural protein. We describe the heterogeneity of the intestinal B-cell compartment, dominated by ASCs with some phenotypic and transcriptional characteristics of long-lived plasma cells. Using principal component analysis, we visualized the phenotypic relationships between major B-cell subsets in the intestine and blood, and revealed that IgM(+) memory B cells (MBCs) and naive B cells were phenotypically related as were CD27(-) MBCs and switched MBCs. ASCs in the intestine and blood were highly clonally related, but associated with distinct trajectories of phenotypic development. VP6-specific B cells were present among diverse B-cell subsets in immune donors, including naive B cells, with phenotypes representative of the overall B-cell pool. These data provide a high dimensional view of intestinal B cells and the determinants regulating humoral memory to a ubiquitous, mucosal pathogen at steady-state.

Increasing incidence and geographic distribution of neonatal abstinence syndrome: United States 2009 to 2012.

OBJECTIVE: Neonatal abstinence syndrome (NAS), a postnatal opioid withdrawal syndrome, increased threefold from 2000 to 2009. Since 2009, opioid pain reliever prescriptions and complications increased markedly throughout the United States. Understanding recent changes in NAS and its geographic variability would inform state and local governments in targeting public health responses. STUDY DESIGN: We utilized diagnostic and demographic data for hospital discharges from 2009 to 2012 from the Kids' Inpatient Database and the Nationwide Inpatient Sample. NAS-associated diagnoses were identified utilizing International Classification of Diseases, Ninth Revision, Clinical Modification codes. All analyses were conducted with nationally weighted data. Expenditure data were adjusted to 2012 US dollars. Between-year differences were determined utilizing least squares regression. RESULTS: From 2009 to 2012, NAS incidence increased nationally from 3.4 (95% confidence interval (CI): 3.2 to 3.6) to 5.8 (95% CI 5.5 to 6.1) per 1000 hospital births, reaching a total of 21,732 infants with the diagnosis. Aggregate hospital charges for NAS increased from $732 million to $1.5 billion (P<0.001), with 81% attributed to state Medicaid programs in 2012. NAS incidence varied by geographic census division, with the highest incidence rate (per 1000 hospital births) of 16.2 (95% CI 12.4 to 18.9) in the East South Central Division (Kentucky, Tennessee, Mississippi and Alabama) and the lowest in West South Central Division Oklahoma, Texas, Arkansas and Louisiana 2.6 (95% CI 2.3 to 2.9). CONCLUSION: NAS incidence and hospital charges grew substantially during our study period. This costly public health problem merits a public health approach to alleviate harm to women and children. States, particularly, in areas of the country most affected by the syndrome must continue to pursue primary prevention strategies to limit the effects of opioid pain reliever misuse.

Variation in treatment of neonatal abstinence syndrome in US children's hospitals, 2004-2011.

OBJECTIVE: Neonatal abstinence syndrome (NAS) is a drug withdrawal syndrome experienced by opioid-exposed infants. There is no standard treatment for NAS and surveys suggest wide variation in pharmacotherapy for NAS. Our objective was to determine whether different pharmacotherapies for NAS are associated with differences in outcomes and to determine whether pharmacotherapy and outcome vary by hospital. STUDY DESIGN: We used the Pediatric Health Information System Database from 2004 to 2011 to identify a cohort of infants with NAS requiring pharmacotherapy. Mixed effects hierarchical negative binomial models evaluated the association between pharmacotherapy and hospital with length of stay (LOS), length of treatment (LOT) and hospital charges, after adjusting for socioeconomic variables and comorbid clinical conditions. RESULT: Our cohort included 1424 infants with NAS from 14 children's hospitals. Among hospitals in our sample, six used morphine, six used methadone and two used phenobarbital as primary initial treatment for NAS. In multivariate analysis, when compared with NAS patients initially treated with morphine, infants treated with methadone had shorter LOT (incidence rate ratio (IRR) = 0.55; P < 0.0001) and LOS (IRR = 0.60; P < 0.0001). Phenobarbital as a second-line agent was associated with increased LOT (IRR = 2.09; P<0.0001), LOS (IRR = 1.78; P < 0.0001) and higher hospital charges (IRR = 1.84; P < 0.0001). After controlling for case-mix, hospitals varied in LOT, LOS and hospital charges. CONCLUSION: We found variation in hospital in treatment for NAS among major US children's hospitals. In analyses controlling for possible confounders, methadone as initial treatment was associated with reduced LOT and hospital stay.

Primary care for adults with Down syndrome: adherence to preventive healthcare recommendations.

BACKGROUND: Due to significant medical improvements, persons with Down syndrome now live well into adulthood. Consequently, primary care for adults with Down syndrome needs to incorporate routine care with screening for condition-specific comorbidities. This study seeks to evaluate the adherence of primary care physicians to age- and condition-specific preventive care in a cohort of adults with Down syndrome. METHODS: In this retrospective observational cohort study, preventive screening was evaluated in patients with Down syndrome aged 18-45 years who received primary care in an academic medical centre from 2000 to 2008. Comparisons were made based on the field of patients' primary care providers (Family or Internal Medicine). RESULTS: This cohort included 62 patients, median index age = 33 years. Forty per cent of patients received primary care by Family Physicians, with 60% seen by Internal Medicine practices. Patient demographics, comorbidities and overall screening patterns were similar between provider groups. Despite near universal screening for obesity and hypothyroidism, adherence to preventive care recommendations was otherwise inconsistent. Screening was 'moderate' (50-80%) for cardiac anomalies, reproductive health, dentition, and the combined measure of behaviour, psychological, or memory abnormalities. Less than 50% of patients were evaluated for obstructive sleep apnea, atlanto-axial instability, hearing loss or vision loss. CONCLUSIONS: We observed inconsistent preventive care in adults with Down syndrome over this 8.5-year study. This is concerning, given that the adverse effects of many of these conditions can be ameliorated if discovered in a timely fashion. Further studies must evaluate the implications of screening practices and more timely identification of comorbidities on clinical outcomes.

Health care in adults with Down syndrome: a longitudinal cohort study.

BACKGROUND: Individuals with Down syndrome increasingly survive into adulthood, yet little is known about their healthcare patterns as adults. Our study sought to characterise patterns of health care among adults with Down syndrome based on whether they had fully transitioned to adult-oriented providers by their inception in this cohort. METHODS: In this retrospective observational cohort study, healthcare utilisation and annualised patient charges were evaluated in patients with Down syndrome aged 18-45 years who received care in a single academic health centre from 2000 to 2008. Comparisons were made based on patients' provider mix (only adult-focused or 'mixed' child- and adult-focused providers). RESULTS: The cohort included 205 patients with median index age = 28 years; 52% of these adult patients had incompletely transitioned to adult providers and received components of their care from child-focused providers. A higher proportion of these 'mixed' patients were seen exclusively by subspecialty providers (mixed = 81%, adult = 46%, P < 0.001), suggesting a need for higher intensity specialised services. Patients in the mixed provider group incurred higher annualised charges in analyses adjusted for age, mortality, total annualised encounters, and number of subspecialty disciplines accessed. These differences were most pronounced when stratified by whether patients were hospitalised during the study period (e.g., difference in adjusted means between mixed versus adult provider groups: $571 without hospitalisation, $19,061 with hospitalisation). CONCLUSIONS: In this unique longitudinal cohort of over 200 adults aged 18-45 years with Down syndrome, over half demonstrated incomplete transition to adult care. Persistent use of child-focused care, often with a subspecialty emphasis, has implications for healthcare charges. Future studies must identify reasons for distinct care patterns, examine their relationship with clinical outcomes, and evaluate which provider types deliver the highest quality care for adults with Down syndrome and a wide variety of comorbidities.

Minimal information about T cell assays: the process of reaching the community of T cell immunologists in cancer and beyond.

Many assays to evaluate the nature, breadth, and quality of antigen-specific T cell responses are currently applied in human medicine. In most cases, assay-related protocols are developed on an individual laboratory basis, resulting in a large number of different protocols being applied worldwide. Together with the inherent complexity of cellular assays, this leads to unnecessary limitations in the ability to compare results generated across institutions. Over the past few years a number of critical assay parameters have been identified which influence test performance irrespective of protocol, material, and reagents used. Describing these critical factors as an integral part of any published report will both facilitate the comparison of data generated across institutions and lead to improvements in the assays themselves. To this end, the Minimal Information About T Cell Assays (MIATA) project was initiated. The objective of MIATA is to achieve a broad consensus on which T cell assay parameters should be reported in scientific publications and to propose a mechanism for reporting these in a systematic manner. To add maximum value for the scientific community, a step-wise, open, and field-spanning approach has been taken to achieve technical precision, user-friendliness, adequate incorporation of concerns, and high acceptance among peers. Here, we describe the past, present, and future perspectives of the MIATA project. We suggest that the approach taken can be generically applied to projects in which a broad consensus has to be reached among scientists working in fragmented fields, such as immunology. An additional objective of this undertaking is to engage the broader scientific community to comment on MIATA and to become an active participant in the project.

Getting heavier, younger: trajectories of obesity over the life course.

CONTEXT: Although recent trends in obesity have been well documented, generational patterns of obesity from early childhood through adulthood across birth cohorts, which account for the recent epidemic of childhood obesity, have not been well described. Such trends may have implications for the prevalence of obesity-associated conditions among population subgroups, including type 2 diabetes. OBJECTIVE: Our objective was to evaluate trajectories of obesity over the life course for the US population, overall and by gender and race. DESIGN, SETTING AND PARTICIPANTS: We conducted an age, period and birth cohort analysis of obesity for US individuals who participated in the National Health and Nutrition Examination Surveys (NHANES) (1971-2006). MAIN OUTCOME MEASURES: Obesity was defined as a body mass index >or=95th percentile for individuals aged 2-16 years or >or=30 kg m(-2) among individuals older than 16 years. Age was represented by the age of the individual at each NHANES, period was defined by the year midpoint of each survey, and cohort was calculated by subtracting age from period. RESULTS: Recent birth cohorts are becoming obese in greater proportions for a given age, and are experiencing a greater duration of obesity over their lifetime. For example, although the 1966-1975 and 1976-1985 birth cohorts had reached an estimated obesity prevalence of at least 20% by 20-29 years of age, this level was only reached by 30-39 years for the 1946-1955 and 1956-1965 birth cohorts, by 40-49 years for the 1936-1945 birth cohort and by 50-59 years of age for the 1926-1935 birth cohort. Trends are particularly pronounced for female compared with male, and black compared with white cohorts. CONCLUSIONS: The increasing cumulative exposure to excess weight over the lifetime of recent birth cohorts will likely have profound implications for future rates of type 2 diabetes, and mortality within the US population.

Not without my permission: parents' willingness to permit use of newborn screening samples for research.

BACKGROUND: State newborn screening (NBS) programs are considering the storage and use of NBS blood samples for research. However, no systematic assessment of parents' attitudes exists. METHODS: We conducted an Internet-based survey of a nationally representative parent sample. We examined parents' willingness (1) to permit use of their children's NBS samples for research with/without their permission and (2) to allow NBS sample storage. Using bivariate and multinomial logistic regression, we examined the association of parent and child characteristics with parents' willingness to permit NBS sample storage and use for research, respectively. RESULTS: The response rate was 49.5%. If permission is obtained, 76.2% of parents were 'very or somewhat willing' to permit use of the NBS sample for research. If permission is not obtained, only 28.2% of parents were 'very or somewhat willing'. Of parents surveyed, 78% would permit storage of their children's NBS sample. Parents who refused NBS sample storage were also less willing to permit use of the NBS sample for research. CONCLUSIONS: Three-quarters of parents would permit use of their children's NBS samples for research - if their permission is obtained. Parents not in favor of storing NBS samples often opposed the use of NBS samples for research.

Differences associated with age, transfer status, and insurance coverage in end-of-life hospital care for children.

BACKGROUND: More than 40% of childhood mortality occurs while children are hospitalized. End-of-life health care utilization patterns for children have not been well characterized at the national level. OBJECTIVE: To describe patterns of length of stay, total charges, and principal diagnoses for children who die while admitted to a hospital, versus those who survive to discharge. METHODS: We conducted a cross-sectional analysis of 3 years spanning a decade of the Nationwide Inpatient Sample (NIS), a nationally representative dataset of hospital discharges, to analyze sociodemographic characteristics and patterns of hospital resource use associated with in-hospital mortality. RESULTS: Inpatient mortality rate was significantly higher for non-newborn infants (<1 year old) than for all other age groups, and the overall number of deaths was greatest for newborns. Patients transferred between hospitals had significantly greater mortality rate, compared with patients admitted not on transfer. Insured children had lower mortality rates compared to uninsured, and decedents had significantly longer length of stay and higher charges compared with survivors. Uninsured decedents did not have longer lengths of stay than survivors, and hospital charges were significantly lower for uninsured children compared with insured children. CONCLUSION: As hospital staff strive to meet the needs of ill children and their families, they must be cognizant of the high burden of mortality among the youngest children and those transferred between hospitals, and the potential for less resource use and higher mortality risk for children without insurance, because these patients may require expanded services not readily available in most hospital settings.

Blimp-1; immunoglobulin secretion and the switch to plasma cells.

The transcription factor Blimp-1 governs the generation of plasma cells and immunoglobulin secretion. Recent microarray experiments indicate that Blimp-1 regulates a large set of genes that constitute a significant part of the plasma cell expression signature. The variety of differentially expressed genes indicates that Blimp-1 affects numerous aspects of plasma cell maturation, ranging from migration, adhesion, and homeostasis, to antibody secretion. In addition, Blimp-1 regulates immunoglobulin secretion by affecting the nuclear processing of the mRNA transcript and by affecting protein trafficking by regulating genes that impact on the activity of the endoplasmic reticulum. Interestingly, the differentiation events that Blimp-1 regulates appear to be modulated depending on the activation state of the B cell. This modulation may be due at least in part to distinct regions of Blimp-1 that regulate unique sets of genes independently of each other. These data hint at the complexity of Blimp-1 and the genetic program that it initiates to produce a pool of plasma cells necessary for specific immunity.

Adrenal ganglioneuroma in a patient presenting with severe hypertension and diarrhea.

Ganglioneuromas (GNs) are neural crest cell-derived tumors and rarely occur in the adrenal gland. There are presently no markers that can reliably distinguish benign and malignant neuroendocrine tumors. Here we describe a 63-year-old woman who developed sudden chest pain and hypertension combined with increased stool frequency. An incidental adrenal mass 5 cm in size with a bright signal on T2-weighted magnetic resonance imaging was discovered. Biochemical evaluation and (131)I-metaiodobenzylguanidine (MIBG) scintigraphy were negative. Histopathological examination revealed a mature adrenal GN. Neuroblastoma, the immature form of a GN, is known for deletions on chromosomal locus 1p36, and adrenal tumors frequently show allele loss on 17p. To further elucidate the histo- and pathogenesis of adrenal GN, we performed loss of heterozygosity studies on chromosomal loci 1p34-36 and 17p13 (the p53 gene locus) after careful microdissection of tumor and normal tissue. We did not detect allelic losses at these loci with the informative polymorphic markers used, suggesting that these loci are not involved in tumorigenesis. In addition, immunohistochemical investigation of the GN was positive for vasoactive intestinal peptide, a hormone commonly expressed in ganglion cells. We suggest that in our patient with an adrenal GN, the combination of biochemical, scintigraphic, molecular, immunohistochemical, and histopathological findings are all consistent with the benign morphology of this tumor.

Is use of antiretroviral therapy among homosexual men associated with increased risk of transmission of HIV infection?

BACKGROUND/OBJECTIVE: There is concern that use of highly active antiretroviral therapy (HAART) may be linked to increased sexual risk behaviour among homosexual men. We investigated sexual risk behaviour in HIV positive homosexual men and the relation between use of HAART and risk of HIV transmission. METHODS: A cross sectional study of 420 HIV positive homosexual men attending a London outpatient clinic. Individual data were collected from computer assisted self interview, STI screening, and clinical and laboratory databases. RESULTS: Among all men, sexual behaviour associated with a high risk of HIV transmission was commonly reported. The most frequently reported type of partnership was casual partners only, and 22% reported unprotected anal intercourse with one or more new partners in the past month. Analysis of crude data showed that men on HAART had fewer sexual partners (median 9 versus 20, p=0.28), less unprotected anal intercourse (for example, 36% versus 27% had insertive unprotected anal intercourse with a new partner in the past year, p=0.03) and fewer acute sexually transmitted infections (33% versus 19%, p=0.004 in the past 12 months) than men not on HAART. Self assessed health status was similar between the two groups: 72% on HAART and 75% not on HAART rated their health as very or fairly good, (p=0.55). In multivariate analysis, differences in sexual risk behaviour between men on HAART and men not on HAART were attenuated by adjustment for age, time since HIV infection. CD4 count and self assessed health status. CONCLUSION: HIV positive homosexual men attending a London outpatient clinic commonly reported sexual behaviour with a high risk of HIV transmission. However, behavioural and clinical risk factors for HIV transmission were consistently lower in men on HAART than men not on HAART. Although use of HAART by homosexual men with generally good health is not associated with higher risk behaviours, effective risk reduction interventions targeting known HIV positive homosexual men are still urgently needed.

Therapeutic considerations in the treatment of obesity hypertension.

Obesity, now recognized as an independent risk factor for cardiovascular disease, is closely associated with hypertension. Complex mechanisms link increasing body weight with increasing blood pressure. Treatment of the obese patient with hypertension requires consideration of physiologic changes related to obesity hypertension. Lifestyle modification, including weight reduction and increased physical activity, can directly influence blood pressure levels and improve blood pressure control in obese, hypertensive patients. Clinical trials are needed to determine the most effective antihypertensive drugs for the obese, hypertensive patient. Antiobesity drugs offer viable adjunctive pharmacotherapy for obesity hypertension, but additional long-term studies are needed to support their safety and efficacy.