Meeting the Demand for Results and Accountability: A Call for Action on Health Data from Eight Global Health Agencies

Margaret Chan, Director-General of the WHO, and the heads of seven other global health agencies, call for a concerted global effort to collect better health data

Spectral decomposition of EEG microstates in post-traumatic stress disorder

Microstates offer a promising framework to study fast-scale brain dynamics in the resting-state electroencephalogram (EEG). However, microstate dynamics have yet to be investigated in post-traumatic stress disorder (PTSD), despite research demonstrating resting-state alterations in PTSD. We performed microstate-based segmentation of resting-state EEG in a clinical population of participants with PTSD (N = 61) and a non-traumatized, healthy control group (N = 61). Microstate-based measures (i.e., occurrence, mean duration, time coverage) were compared group-wise using broadband (1–30 Hz) and frequency-specific (i.e., delta, theta, alpha, beta bands) decompositions. In the broadband comparisons, the centro-posterior maximum microstate (map E) occurred significantly less frequently (d = -0.64, pFWE = 0.03) and had a significantly shorter mean duration in participants with PTSD as compared to controls (d = -0.71, pFWE \u3c 0.01). These differences were reflected in the narrow frequency bands as well, with lower frequency bands like delta (d = -0.78, pFWE \u3c 0.01), theta (d = -0.74, pFWE = 0.01), and alpha (d = -0.65, pFWE = 0.02) repeating these group-level trends, only with larger effect sizes. Interestingly, a support vector machine classification analysis comparing broadband and frequency-specific measures revealed that models containing only alpha band features significantly out-perform broadband models. When classifying PTSD, the classification accuracy was 76 % and 65 % for the alpha band and the broadband model, respectively (p = 0.03). Taken together, we provide original evidence supporting the clinical utility of microstates as diagnostic markers of PTSD and demonstrate that filtering EEG into distinct frequency bands significantly improves microstate-based classification of a psychiatric disorder

Short Children with CHARGE Syndrome: Do They Benefit from Growth Hormone Therapy?

AIM: The aim of this study was to evaluate the response to recombinant growth hormone (GH) treatment in short children with CHARGE syndrome. PATIENTS: We identified 51 children (28 boys and 23 girls) in KIGS (Pfizer International Growth Database). The median chronological age was 7.6 years at the start of GH therapy and 13.2 years at the latest visit. Evaluation for GH deficiency (n = 33) was based on the following: peak GH level 7.3 μg/l and IGF-I level -2.01 standard deviation score (SDS). Sixteen subjects (9 boys) were followed longitudinally for 2 years. RESULTS: Birth length (median SDS, -0.47) and weight (-0.97) were slightly reduced. At the start of GH therapy, height was -3.6 SDS, BMI -0.7 SDS, and the GH dose was 0.26 mg/kg/week. At the latest visit after 2.7 years of GH therapy, height had increased to -2.2 SDS and BMI to -0.5 SDS. In the longitudinal group, height increased from -3.72 SDS at the start of GH therapy to -2.92 SDS after 1 year to -2.37 SDS after 2 years of therapy (start - 2 years: p < 0.05), height velocity increased from -1.69 to 2.98 to 0.95 SDS, and BMI and GH dose (mg/kg/week) remained almost unchanged. CONCLUSIONS: Our data show a positive effect of conventional doses of GH on short-term growth velocity for the longitudinal as well as for the total group, without any safety issues.This study was sponsored by Pfizer Inc.This is the author accepted manuscript. The final version is available from Karger via http://dx.doi.org/10.1159/00038201

Impression Evolution During Ad Exposure: Typicality Effects From 100 Ms Onwards

Although print ads display all information simultaneously, people are unable to process this all at once. This research investigates how people rapidly try to identify what ads are for over the course of a single ad exposure, and how this influences subsequent attention, impression formation, and memory. Three studies show that typical ads--which can be rapidly identified accurately--are liked even after 100ms, and retain this high liking. We find that evaluations for atypical ads, however, improve or deteriorate within a single exposure depending on the specific identification process engendered, and that memory effects critically depend on exposure duration

A Combination of Two Human Monoclonal Antibodies Limits Fetal Damage by Zika Virus in Macaques

Human infection by Zika virus (ZIKV) during pregnancy can lead to vertical transmission and fetal aberrations, including microcephaly. Prophylactic administration of antibodies can diminish or prevent ZIKV infection in animal models, but whether passive immunization can protect nonhuman primates and their fetuses during pregnancy has not been determined. Z004 and Z021 are neutralizing monoclonal antibodies to domain III of the envelope (EDIII) of ZIKV. Together the two antibodies protect nonpregnant macaques against infection even after Fc modifications to prevent antibody-dependent enhancement in vitro (ADE) and extend their half-lives. Here we report on prophylactic co-administration of the Fc-modified antibodies to pregnant rhesus macaques challenged 3 times with ZIKV during first and second trimester. The two antibodies did not entirely eliminate maternal viremia but limited vertical transmission protecting the fetus from neurologic damage. Thus, maternal passive immunization with two antibodies to EDIII can shield primate fetuses from the harmful effects of ZIKV

The IpaC carboxyterminal effector domain mediates Src-dependent actin polymerization during Shigella invasion of epithelial cells

Shigella, the causative agent of bacillary dysentery, invades epithelial cells by locally reorganizing the actin cytoskeleton. Shigella invasion requires actin polymerization dependent on the Src tyrosine kinase and a functional bacterial type III secretion (T3S) apparatus. Using dynamic as well as immunofluorescence microscopy, we show that the T3S translocon component IpaC allows the recruitment of the Src kinase required for actin polymerization at bacterial entry sites during the initial stages of Shigella entry. Src recruitment occurred at bacterial-cell contact sites independent of actin polymerization at the onset of the invasive process and was still observed in Shigella strains mutated for translocated T3S effectors of invasion. A Shigella strain with a polar mutation that expressed low levels of the translocator components IpaB and IpaC was fully proficient for Src recruitment and bacterial invasion. In contrast, a Shigella strain mutated in the IpaC carboxyterminal effector domain that was proficient for T3S effector translocation did not induce Src recruitment. Consistent with a direct role for IpaC in Src activation, cell incubation with the IpaC last 72 carboxyterminal residues fused to the Iota toxin Ia (IaC) component that translocates into the cell cytosol upon binding to the Ib component led to Src-dependent ruffle formation. Strikingly, IaC also induced actin structures resembling bacterial entry foci that were enriched in activated Src and were inhibited by the Src inhibitor PP2. These results indicate that the IpaC effector domain determines Src-dependent actin polymerization and ruffle formation during bacterial invasion

Regulatory objectivity in action: Mild cognitive impairment and the collective production of uncertainty

In this paper, we investigate recent changes in the definition and approach to Alzheimer’s disease brought about by growing clinical, therapeutic and regulatory interest in the prodromal or preclinical aspects of this condition. In the last decade, there has been an increased interest in the biomolecular and epidemiological characterization of pre-clinical dementia. It is argued that early diagnosis of dementia, and particularly of Alzheimer‘s disease, will facilitate the prevention of dementing processes and lower the prevalence of the condition in the general population. The search for a diagnostic category or biomarker that would serve this purpose is an ongoing but problematic endeavour for research and clinical communities in this area. In this paper, we explore how clinical and research actors, in collaboration with regulatory institutions and pharmaceutical companies, come to frame these domains as uncertainties and how they re-deploy uncertainty in the ‘collective production’ of new diagnostic conventions and bioclinical standards. While drawing as background on ethnographic, documentary and interview data, the paper proposes an in-depth, contextual analysis of the proceedings of an international meeting organized by the Peripheral and Central Nervous System Drug Advisory Committee of the US Food and Drug Administration to discuss whether or not a particular diagnostic convention — mild cognitive impairment — exists and how best it ought to be studied. Based on this analysis we argue that the deployment of uncertainty is reflexively implicated in bioclinical collectives’ search for rules and conventions, and furthermore that the collective production of uncertainty is central to the ‘knowledge machinery’ of regulatory objectivity

Structural basis for Zika envelope domain III recognition by a germline version of a recurrent neutralizing antibody

Recent epidemics demonstrate the global threat of Zika virus (ZIKV), a flavivirus transmitted by mosquitoes. Although infection is usually asymptomatic or mild, newborns of infected mothers can display severe symptoms, including neurodevelopmental abnormalities and microcephaly. Given the large-scale spread, symptom severity, and lack of treatment or prophylaxis, a safe and effective ZIKV vaccine is urgently needed. However, vaccine design is complicated by concern that elicited antibodies (Abs) may cross-react with other flaviviruses that share a similar envelope protein, such as dengue virus, West Nile virus, and yellow fever virus. This cross-reactivity may worsen symptoms of a subsequent infection through Ab-dependent enhancement. To better understand the neutralizing Ab response and risk of Ab-dependent enhancement, further information on germline Ab binding to ZIKV and the maturation process that gives rise to potently neutralizing Abs is needed. Here we use binding and structural studies to compare mature and inferred-germline Ab binding to envelope protein domain III of ZIKV and other flaviviruses. We show that affinity maturation of the light-chain variable domain is important for strong binding of the recurrent VH3-23/VK1-5 neutralizing Abs to ZIKV envelope protein domain III, and identify interacting residues that contribute to weak, cross-reactive binding to West Nile virus. These findings provide insight into the affinity maturation process and potential cross-reactivity of VH3-23/VK1-5 neutralizing Abs, informing precautions for protein-based vaccines designed to elicit germline versions of neutralizing Abs

Transportation Noise and Blood Pressure in a Population-Based Sample of Adults

Background: There is some evidence for an association between traffic noise and ischemic heart disease; however, associations with blood pressure have been inconsistent, and little is known about health effects of railway noise