ADHD and overweight in boys: cross-sectional study with birth weight as a controlled factor

Population studies indicate a strong relationship between birth weight (BW) and body size in later life. However, BW as a variable was never accounted for in studies on the relationship between attention-deficit/hyperactivity disorder (ADHD) and overweight. This study aims to assess the relationship between ADHD and overweight with control of birth weight and other confounding factors. Prevalence of overweight was compared in clinical sample of 219 boys with ADHD and 396 boys without ADHD, aged 6–18 years. The following factors were controlled: BW, parents income and education level, place of residence, ADHD type, selected comorbid disorders and stimulant treatment. Overweight and obesity were diagnosed according to the criteria proposed by the International Obesity Task Force. Logistic regression analysis was used to estimate the association between ADHD and the prevalence of overweight and obesity. Boys with ADHD differed significantly from the control group in distribution of low BW (8.2 vs. 3.0 %, χ ² = 8.23, p = 0.02). Low BW was associated with a lower prevalence of overweight than normal and high BW (0 vs. 12.14 %, χ ² = 4.12, p = 0.04). Overweight was observed significantly more often in boys with ADHD (17.3 vs. 8.3 %, χ ² = 11.23, p < 0.001) even after adjustment for BW and other variables (OR = 2.44, 95 % CI 1.38–4.29, p = 0.002) and after controlling for ADHD type, stimulant treatment and selected comorbid disorders. Independently to applied analysis, obesity was not associated with ADHD. Lower birth weight is over twice more often observed in boys with ADHD than in control group. Although this phenomenon may reduce the rate of overweight in the studied group, ADHD remains strongly associated with increased prevalence of overweight.     

Case series of rash associated with influenza B in school children

This case series describes morbilliform and other rash presentations among schoolchildren during a March 2014 outbreak of influenza‐like illness (ILI) in British Columbia, Canada. Multiplex nucleic acid testing of nasopharyngeal specimens and paired serologic investigations identified that influenza B, characterized as B/Massachusetts/02/2012‐like (Yamagata‐lineage), was the only viral aetiology and most likely cause of ILI and rash. An association between influenza B and rash has been described infrequently elsewhere, and not previously in North America. Influenza B should be considered in the differential diagnosis of febrile exanthem. Evaluation of the nature, incidence and contributing agent–host–environment interactions, and immunologic mechanisms to possibly explain influenza‐associated rash is warranted.     

Aggregatibacter actinomycetemcomitans Cytolethal Distending Toxin Activates the NLRP3 Inflammasome in Human Macrophages,Leading to the Release of Proinflammatory Cytokines

The cytolethal distending toxin (Cdt) is produced from a number of bacteria capable of causing infection and inflammatory disease. Our previous studies with Actinobacillus actinomycetemcomitans Cdt demonstrate not only that the active toxin subunit functions as a phosphatidylinositol-3,4,5-triphosphate (PIP3) phosphatase but also that macrophages exposed to the toxin were stimulated to produce proinflammatory cytokines. We now demonstrate that the Cdt-induced proinflammatory response involves the activation of the NLRP3 inflammasome. Specific inhibitors and short hairpin RNA (shRNA) were employed to demonstrate requirements for NLRP3 and ASC as well as caspase-1. Furthermore, Cdt-mediated inflammasome activation is dependent upon upstream signals, including reactive oxygen species (ROS) generation and Cdt-induced increases in extracellular ATP levels. Increases in extracellular ATP levels contribute to the activation of the P2X₇ purinergic receptor, leading to K⁺ efflux. The relationship between the abilities of the active toxin subunit CdtB to function as a lipid phosphatase, activate the NLRP3 inflammasome, and induce a proinflammatory cytokine response is discussed. These studies provide new insight into the virulence potential of Cdt in mediating the pathogenesis of disease caused by Cdt-producing organisms such as Aggregatibacter actinomycetemcomitans.     

Discharge diagnoses versus medical record review in the identification of community-acquired sepsis

IntroductionWe evaluated the accuracy of hospital discharge diagnoses in the identification of community-acquired sepsis and severe sepsis.MethodsWe reviewed 379 serious infection hospitalizations from 2003 to 2012 from the national population-based reasons for geographic and racial differences in stroke (REGARDS) cohort. Through manual review of medical records, we defined criterion-standard community-acquired sepsis events as the presence of a serious infection on hospital presentation with ≥2 systemic inflammatory response syndrome criteria. We also defined criterion-standard community-acquired severe sepsis events as sepsis with >1 sequential organ failure assessment organ dysfunction. For the same hospitalizations, we identified sepsis and severe sepsis events indicated by Martin et al. and Angus et al. International Classifications of Diseases 9th edition discharge diagnoses. We evaluated the diagnostic accuracy of the Martin and Angus criteria for detecting criterion-standard community-acquired sepsis and severe sepsis events.ResultsAmong the 379 hospitalizations, there were 156 community-acquired sepsis and 122 community-acquired severe sepsis events. Discharge diagnoses identified 55 Martin-sepsis and 89 Angus-severe sepsis events. The accuracy of Martin-sepsis criteria for detecting community-acquired sepsis were: sensitivity 27.6%; specificity 94.6%; positive predictive value (PPV) 78.2%; negative predictive value (NPV) 65.1%. The accuracy of the Angus-severe sepsis criteria for detecting community-acquired severe sepsis were: sensitivity 42.6%; specificity 86.0%; PPV 58.4%; NPV 75.9%. Mortality was higher for Martin-sepsis than community-acquired sepsis (25.5% versus 10.3%, P = 0.006), as well as for Angus-severe sepsis than community-acquired severe sepsis (25.5 versus 11.5%, P = 0.002). Other baseline characteristics were similar between sepsis groups.ConclusionsHospital discharge diagnoses show good specificity but poor sensitivity for detecting community-acquired sepsis and severe sepsis. While sharing similar baseline subject characteristics as cases identified by hospital record review, discharge diagnoses selected for higher mortality sepsis and severe sepsis cohorts. The epidemiology of a sepsis population may vary with the methods used for sepsis event identification.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-015-0771-6) contains supplementary material, which is available to authorized users.     

Black-white racial disparities in sepsis: a prospective analysis of the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort

IntroductionSepsis is a major public health problem. Prior studies using hospital-based data describe higher rates of sepsis among black than whites participants. We sought to characterize racial differences in incident sepsis in a large cohort of adult community-dwelling adults.MethodsWe analyzed data on 29,690 participants from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. We determined the associations between race and first-infection and first-sepsis events, adjusted for participant sociodemographics, health behaviors, chronic medical conditions and biomarkers. We also determined the association between race and first-sepsis events limited to first-infection events. We contrasted participant characteristics and hospital course between black and white sepsis hospitalizations.ResultsAmong eligible REGARDS participants there were 12,216 (41.1 %) black and 17,474 (58.9 %) white participants. There were 2,600 first-infection events; the incidence of first-infection events was lower for black participants than for white participants (12.10 vs. 15.76 per 1,000 person-years; adjusted HR 0.65; 95 % CI, 0.59-0.71). There were 1,526 first-sepsis events; the incidence of first-sepsis events was lower for black participants than for white participants (6.93 vs. 9.10 per 1,000 person-years, adjusted HR 0.64; 95 % CI, 0.57-0.72). When limited to first-infection events, the odds of sepsis were similar between black and white participants (adjusted OR 1.01; 95 % CI, 0.84-1.21). Among first-sepsis events, black participants were more likely to be diagnosed with severe sepsis (76.9 % vs. 71.5 %).ConclusionIn the REGARDS cohort, black participants were less likely than white participants to experience infection and sepsis events. Further efforts should focus on elucidating the underlying reasons for these observations, which are in contrast to existing literature.     

Metallic lead nanospheres discovered in ancient zircons

Zircon (ZrSiO₄) is the most commonly used geochronometer, preserving age and geochemical information through a wide range of geological processes. However, zircon U–Pb geochronology can be affected by redistribution of radiogenic Pb, which is incompatible in the crystal structure. This phenomenon is particularly common in zircon that has experienced ultra-high temperature metamorphism, where ion imaging has revealed submicrometer domains that are sufficiently heterogeneously distributed to severely perturb ages, in some cases yielding apparent Hadean (>4 Ga) ages from younger zircons. Documenting the composition and mineralogy of these Pb-enriched domains is essential for understanding the processes of Pb redistribution in zircon and its effects on geochronology. Using high-resolution scanning transmission electron microscopy, we show that Pb-rich domains previously identified in zircons from East Antarctic granulites are 5–30 nm nanospheres of metallic Pb. They are randomly distributed with respect to zircon crystallinity, and their association with a Ti- and Al-rich silica melt suggests that they represent melt inclusions generated during ultra-high temperature metamorphism. Metallic Pb is exceedingly rare in nature and previously has not been reported in association with high-grade metamorphism. Formation of these metallic nanospheres within annealed zircon effectively halts the loss of radiogenic Pb from zircon. Both the redistribution and phase separation of radiogenic Pb in this manner can compromise the precision and accuracy of U–Pb ages obtained by high spatial resolution methods.Zircon is the mineral of choice for precisely determining the timing of both magmatism and metamorphism in a wide range of geological samples as well as providing constraints on the source and time of deposition of clastic sedimentary rocks. Accurate zircon geochronometry is facilitated by zircon having a lattice structure that is stable over a wide range of temperatures and pressures (1), together with the fact that whatever Pb is present derives almost entirely from radioactive decay of U and Th. During its growth, zircon incorporates small amounts of nonformula elements, including Hf, Ti, and Y, and rare earth elements, U and Th, but generally excludes Pb. This incompatibility of Pb raises questions about how radiogenic Pb is retained in zircon, especially through geological events where elevated temperature, fluid activity, and deformation can enhance element mobility. Furthermore it has been established that an irregular redistribution of lead in metamorphic zircon can degrade the precision and accuracy of U–Pb isotopic data, in extreme cases leading to spurious ages (2, 3).Experimental and natural studies have revealed that element mobility in zircon is strongly dependent on the accumulation of α-recoil damage (4, 5). Multiple α-decay events along the U and Th decay chains leading to stable daughter Pb isotopes destroy the crystal lattice, creating amorphous domains tens of nanometers in size (6, 7). As the number of these domains increases over time, they begin to overlap until the so-called first percolation point is reached at 2.2 × 10¹⁸ α-decay events per gram (8). At this point, the zircon is considered “metamict,” and the diffusivity of Pb and other elements is enhanced compared with diffusion in crystalline zircon. Therefore, loss of Pb from metamict zircon is highly likely and is further enhanced by the chemical instability of amorphous materials (9). Although healing of radiation damage occurs during metamorphism, its degree and nature is dependent on the U content, the density of radiation damage, and the temperatures involved. Zircon with concentrations of U and Th typical of those found in common rocks (less than 0.5%) will not accumulate significant radiation damage above ca. 350–400 °C (5, 10). However, in zircon that is already metamict, complete recovery through thermal annealing will not occur at these temperatures (5). During high-temperature metamorphism (>600 °C), there is a complex interplay of factors at work on zircon that can act both for and against preservation of initial U–Th–Pb isotopic signatures and thus its ability to preserve accurate age information.Migration of radiogenic Pb in zircon has been established by several studies that reveal heterogeneous distribution of Pb on various length scales. These include transmission electron microscopy (TEM) studies (11), ion microprobe imaging (2) and tomography (12), and atom probe tomography (13), the latter study suggesting that migration occurs by diffusion of Pb through crystalline zircon into noncrystalline domains produced by α-recoil damage.In the Napier Complex of Enderby Land, East Antarctica, metasedimentary and metaigneous gneisses preserve zircon ages greater than 3.8 Ga (14, 15). The central–western part of the Napier Complex experienced an early metamorphic event at ∼2.8 Ga (16) and then underwent ultra-high temperature (UHT) metamorphism at ca. 2,550–2,480 Ma (17), with peak temperatures of ∼1,050–1,120 °C and pressures of 7–11 kbar (16). The isotopic complexity of zircon grains from Enderby Land was recognized in the earliest studies that used secondary ion mass spectrometry (SIMS) for U–Pb dating (18, 19). The reliability of the oldest zircon ages, which include some reversely discordant analyses (i.e., with U–Pb ages older than ²⁰⁷Pb/²⁰⁶Pb ages), has been questioned based on evidence from ion imaging for disturbance of the U–Pb system (2). This is important because ²⁰⁷Pb/²⁰⁶Pb ages are generally considered to be more robust than U–Pb ages for older zircons. However, if radiogenic Pb has been decoupled from its parent U and not locally incorporated into the crystal lattice during an ancient geological event, when radiogenic ²⁰⁷Pb/²⁰⁶Pb values are significantly higher than at present, reverse discordance and spuriously old ²⁰⁷Pb/²⁰⁶Pb age estimates may result (2, 3, 18).     

Editor's choice: Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma

Background

Immune checkpoint inhibitors targeting programmed cell death 1 (PD1) or its ligand (PD-L1) showed activity in several cancer types.

Methods

We performed immunohistochemistry for CD3, CD8, CD20, HLA-DR, phosphatase and tensin homolog (PTEN), PD-1, and PD-L1 and pyrosequencing for assessment of the O6-methylguanine-methyltransferase (MGMT) promoter methylation status in 135 glioblastoma specimens (117 initial resection, 18 first local recurrence). PD-L1 gene expression was analyzed in 446 cases from The Cancer Genome Atlas.

Results

Diffuse/fibrillary PD-L1 expression of variable extent, with or without interspersed epithelioid tumor cells with membranous PD-L1 expression, was observed in 103 of 117 (88.0%) newly diagnosed and 13 of 18 (72.2%) recurrent glioblastoma specimens. Sparse-to-moderate density of tumor-infiltrating lymphocytes (TILs) was found in 85 of 117 (72.6%) specimens (CD3+ 78/117, 66.7%; CD8+ 52/117, 44.4%; CD20+ 27/117, 23.1%; PD1+ 34/117, 29.1%). PD1+ TIL density correlated positively with CD3+ (P < .001), CD8+ (P < .001), CD20+ TIL density (P < .001), and PTEN expression (P = .035). Enrichment of specimens with low PD-L1 gene expression levels was observed in the proneural and G-CIMP glioblastoma subtypes and in specimens with high PD-L1 gene expression in the mesenchymal subtype (P = 5.966e-10). No significant differences in PD-L1 expression or TIL density between initial and recurrent glioblastoma specimens or correlation of PD-L1 expression or TIL density with patient age or outcome were evident.

Conclusion

TILs and PD-L1 expression are detectable in the majority of glioblastoma samples but are not related to outcome. Because the target is present, a clinical study with specific immune checkpoint inhibitors seems to be warranted in glioblastoma.