Emergence of anomalous dynamics in soft matter probed at the European XFEL.

Dynamics and kinetics in soft matter physics, biology, and nanoscience frequently occur on fast (sub)microsecond but not ultrafast timescales which are difficult to probe experimentally. The European X-ray Free-Electron Laser (European XFEL), a megahertz hard X-ray Free-Electron Laser source, enables such experiments via taking series of diffraction patterns at repetition rates of up to 4.5 MHz. Here, we demonstrate X-ray photon correlation spectroscopy (XPCS) with submicrosecond time resolution of soft matter samples at the European XFEL. We show that the XFEL driven by a superconducting accelerator provides unprecedented beam stability within a pulse train. We performed microsecond sequential XPCS experiments probing equilibrium and nonequilibrium diffusion dynamics in water. We find nonlinear heating on microsecond timescales with dynamics beyond hot Brownian motion and superheated water states persisting up to 100 µs at high fluences. At short times up to 20 µs we observe that the dynamics do not obey the Stokes-Einstein predictions.

Demonstration of 3D photon correlation spectroscopy in the hard X-ray regime.

Three-dimensional photon correlation spectroscopy (3D PCS) is a well-known technique developed to suppress multiple scattering contributions in correlation functions, which are inevitably involved when an optical laser is employed to investigate dynamics in a turbid system. Here, we demonstrate a proof-of-principle study of 3D PCS in the hard X-ray regime. We employ an X-ray optical cross-correlator to measure the dynamics of silica colloidal nanoparticles dispersed in polypropylene glycol. The obtained cross correlation functions show very good agreement with auto-correlation measurements. This demonstration provides the foundation for X-ray speckle-based studies of very densely packed soft matter systems.

Core Motivations of Childhood Obsessive-Compulsive Disorder: The Role of Harm Avoidance and Incompleteness.

In an effort to improve patient conceptualization and targeted treatment, researchers have sought to accurately classify OCD subtypes. To date, the most common form of OCD classification has used the content of symptom topography as opposed to functional links between symptoms to categorize OCD. The aim of the current study was to explore the associations between these two forms of OCD classification. Participant topographical symptoms were self-reported using the Obsessive-Compulsive Inventory-Child Version (OCI-CV). Clinicians assessed whether participant symptoms were motivated by harm avoidance and/or incompleteness. Structural equation modeling was employed to explore the associations between harm avoidance and incompleteness and symptom dimensions in youth with OCD. Results showed that harm avoidance was significantly associated with doubting/checking, obsessing, and neutralizing symptoms, whereas incompleteness was associated with doubting/checking, ordering, and neutralizing symptoms. Findings are consistent with child and adult literature and highlight the importance of assessing the underlying function of OC behaviors.

The impact of delayed treatment of uncomplicated P. falciparum malaria on progression to severe malaria: A systematic review and a pooled multicentre individual-patient meta-analysis.

BACKGROUND: Delay in receiving treatment for uncomplicated malaria (UM) is often reported to increase the risk of developing severe malaria (SM), but access to treatment remains low in most high-burden areas. Understanding the contribution of treatment delay on progression to severe disease is critical to determine how quickly patients need to receive treatment and to quantify the impact of widely implemented treatment interventions, such as 'test-and-treat' policies administered by community health workers (CHWs). We conducted a pooled individual-participant meta-analysis to estimate the association between treatment delay and presenting with SM. METHODS AND FINDINGS: A search using Ovid MEDLINE and Embase was initially conducted to identify studies on severe Plasmodium falciparum malaria that included information on treatment delay, such as fever duration (inception to 22nd September 2017). Studies identified included 5 case-control and 8 other observational clinical studies of SM and UM cases. Risk of bias was assessed using the Newcastle-Ottawa scale, and all studies were ranked as 'Good', scoring ≥7/10. Individual-patient data (IPD) were pooled from 13 studies of 3,989 (94.1% aged <15 years) SM patients and 5,780 (79.6% aged <15 years) UM cases in Benin, Malaysia, Mozambique, Tanzania, The Gambia, Uganda, Yemen, and Zambia. Definitions of SM were standardised across studies to compare treatment delay in patients with UM and different SM phenotypes using age-adjusted mixed-effects regression. The odds of any SM phenotype were significantly higher in children with longer delays between initial symptoms and arrival at the health facility (odds ratio [OR] = 1.33, 95% CI: 1.07-1.64 for a delay of >24 hours versus ≤24 hours; p = 0.009). Reported illness duration was a strong predictor of presenting with severe malarial anaemia (SMA) in children, with an OR of 2.79 (95% CI:1.92-4.06; p < 0.001) for a delay of 2-3 days and 5.46 (95% CI: 3.49-8.53; p < 0.001) for a delay of >7 days, compared with receiving treatment within 24 hours from symptom onset. We estimate that 42.8% of childhood SMA cases and 48.5% of adult SMA cases in the study areas would have been averted if all individuals were able to access treatment within the first day of symptom onset, if the association is fully causal. In studies specifically recording onset of nonsevere symptoms, long treatment delay was moderately associated with other SM phenotypes (OR [95% CI] >3 to ≤4 days versus ≤24 hours: cerebral malaria [CM] = 2.42 [1.24-4.72], p = 0.01; respiratory distress syndrome [RDS] = 4.09 [1.70-9.82], p = 0.002). In addition to unmeasured confounding, which is commonly present in observational studies, a key limitation is that many severe cases and deaths occur outside healthcare facilities in endemic countries, where the effect of delayed or no treatment is difficult to quantify. CONCLUSIONS: Our results quantify the relationship between rapid access to treatment and reduced risk of severe disease, which was particularly strong for SMA. There was some evidence to suggest that progression to other severe phenotypes may also be prevented by prompt treatment, though the association was not as strong, which may be explained by potential selection bias, sample size issues, or a difference in underlying pathology. These findings may help assess the impact of interventions that improve access to treatment.

Monitoring Nanocrystal Self-Assembly in Real Time Using In Situ Small-Angle X-Ray Scattering.

Self-assembled nanocrystal superlattices have attracted large scientific attention due to their potential technological applications. However, the nucleation and growth mechanisms of superlattice assemblies remain largely unresolved due to experimental difficulties to monitor intermediate states. Here, the self-assembly of colloidal PbS nanocrystals is studied in real time by a combination of controlled solvent evaporation from the bulk solution and in situ small-angle X-ray scattering (SAXS) in transmission geometry. For the first time for the investigated system a hexagonal closed-packed (hcp) superlattice formed in a solvent vapor saturated atmosphere is observed during slow solvent evaporation from a colloidal suspension. The highly ordered hcp superlattice is followed by a transition into the final body-centered cubic superlattice upon complete drying. Additionally, X-ray cross-correlation analysis of Bragg reflections is applied to access information on precursor structures in the assembly process, which is not evident from conventional SAXS analysis. The detailed evolution of the crystal structure with time provides key results for understanding the assembly mechanism and the role of ligand-solvent interactions, which is important both for fundamental research and for fabrication of superlattices with desired properties.

Compact hard X-ray split-and-delay line for studying ultrafast dynamics at free-electron laser sources.

A compact hard X-ray split-and-delay line for studying ultrafast dynamics at free-electron laser sources is presented. The device is capable of splitting a single X-ray pulse into two fractions to introduce time delays from -5 to 815 ps with femtosecond resolution. The split-and-delay line can operate in a wide and continuous energy range between 7 and 16 keV. Compact dimensions of 60 × 60 × 30 cm with a total weight of about 60 kg make it portable and suitable for direct installation in an experimental hutch. The concept of the device is based on crystal diffraction. The piezo-driven stages utilized in the device give nanometre positioning accuracy. On-line monitoring systems based on X-ray cameras and intensity monitors are implemented to provide active alignment feedback. Performance estimates of the system are also presented.

A latent profile analysis of age of onset in trichotillomania.

BACKGROUND: Trichotillomania (TTM) onset may occur across the lifespan; however, adolescent onset is most frequently reported. Several studies have explored clinical differences between TTM age-of-onset groups with mixed results. We investigated empirically defined age-of-onset groups in adults with TTM, and clinical differences between groups. METHODS: Participants included 1,604 adult respondents to an internet survey who endorsed DSM-IV-TR TTM criteria. Latent profile analysis was performed to identify TTM age-of-onset subgroups, which were then compared on demographic and clinical features. RESULTS: The most optimal model was a 2-class solution comprised of a large group with average TTM onset during adolescence (n = 1,539; 95.9% of the sample; mean age of onset = 12.4) and a small group with average onset in middle adulthood (n = 65; 4.1% of the sample; mean age of onset = 35.6). The late-onset group differed from the early-onset group on several clinical variables (eg, less likely to report co-occurring bodyfocused repetitive behaviors). CONCLUSIONS: Findings suggest the presence of at least 2 distinct TTM age-of-onset subgroups: an early-onset group with onset during adolescence, and a late-onset group with onset in middle adulthood. Future research is needed to further validate these subgroups and explore their clinical utility.

Evidence Base Update of Psychosocial Treatments for Pediatric Obsessive-Compulsive Disorder: Evaluating, Improving, and Transporting What Works.

Pediatric obsessive-compulsive disorder is a chronic and impairing condition that often persists into adulthood. This review refreshes the state of support for psychosocial treatments and the predictors or moderators that relate to their efficacy and evaluates how the literature has improved since the last update in 2014. A secondary goal is to propose an additional framework for the categorization of studies based on central research questions rather than treatment format. Psychosocial treatment studies conducted since the last review are described and evaluated according to methodological rigor and evidence-based classification using the Journal of Clinical Child and Adolescent Psychology evidence-based treatment evaluation criteria. Findings again converge in support of cognitive-behavioral therapy (CBT) as an effective and appropriate first-line treatment for youth with obsessive-compulsive disorder. Family-focused CBT is now well-established. A number of other treatments including CBT+ D-Cycloserine, CBT+ Sertraline, CBT+ positive family interaction therapy, and technology-based CBT are now probably efficacious. Demographic, clinical, and family factors are consistent predictors of CBT outcome with conflicting findings for neurocognitive predictors. The field has advanced significantly since the last review, but there is still room for improvement. Some of the conclusions that can be drawn may be limited by our evaluation criteria. Future directions are proposed to advance treatment outcome research beyond a focus on which treatments work to exploring factors that account for how and why they work.

Plasmodium Infection Is Associated with Impaired Hepatic Dimethylarginine Dimethylaminohydrolase Activity and Disruption of Nitric Oxide Synthase Inhibitor/Substrate Homeostasis.

Inhibition of nitric oxide (NO) signaling may contribute to pathological activation of the vascular endothelium during severe malaria infection. Dimethylarginine dimethylaminohydrolase (DDAH) regulates endothelial NO synthesis by maintaining homeostasis between asymmetric dimethylarginine (ADMA), an endogenous NO synthase (NOS) inhibitor, and arginine, the NOS substrate. We carried out a community-based case-control study of Gambian children to determine whether ADMA and arginine homeostasis is disrupted during severe or uncomplicated malaria infections. Circulating plasma levels of ADMA and arginine were determined at initial presentation and 28 days later. Plasma ADMA/arginine ratios were elevated in children with acute severe malaria compared to 28-day follow-up values and compared to children with uncomplicated malaria or healthy children (p<0.0001 for each comparison). To test the hypothesis that DDAH1 is inactivated during Plasmodium infection, we examined DDAH1 in a mouse model of severe malaria. Plasmodium berghei ANKA infection inactivated hepatic DDAH1 via a post-transcriptional mechanism as evidenced by stable mRNA transcript number, decreased DDAH1 protein concentration, decreased enzyme activity, elevated tissue ADMA, elevated ADMA/arginine ratio in plasma, and decreased whole blood nitrite concentration. Loss of hepatic DDAH1 activity and disruption of ADMA/arginine homeostasis may contribute to severe malaria pathogenesis by inhibiting NO synthesis.

Treating Trichotillomania (Hair-Pulling Disorder) in a Child.

Although cognitive behavioral treatments (CBTs) have been recommended as first-line interventions for trichotillomania (hair-pulling disorder [HPD]), research on CBT for young children with HPD is limited. We illustrate the use of family-based CBT for HPD in an 8-year-old boy. The client had a 5-year history of chronic HPD and several large bald spots on the crown of his head. Treatment primarily comprised habit reversal training (HRT) and function-based interventions. The child showed significant improvement in HPD severity and impairment after 8 weekly sessions, although complete abstinence was not achieved. The findings underscore the importance of parental involvement in the treatment and show that children as young as 8 years of age can successfully use strategies taught in HRT.

HMOX1 gene promoter alleles and high HO-1 levels are associated with severe malaria in Gambian children.

Heme oxygenase 1 (HO-1) is an essential enzyme induced by heme and multiple stimuli associated with critical illness. In humans, polymorphisms in the HMOX1 gene promoter may influence the magnitude of HO-1 expression. In many diseases including murine malaria, HO-1 induction produces protective anti-inflammatory effects, but observations from patients suggest these may be limited to a narrow range of HO-1 induction, prompting us to investigate the role of HO-1 in malaria infection. In 307 Gambian children with either severe or uncomplicated P. falciparum malaria, we characterized the associations of HMOX1 promoter polymorphisms, HMOX1 mRNA inducibility, HO-1 protein levels in leucocytes (flow cytometry), and plasma (ELISA) with disease severity. The (GT)(n) repeat polymorphism in the HMOX1 promoter was associated with HMOX1 mRNA expression in white blood cells in vitro, and with severe disease and death, while high HO-1 levels were associated with severe disease. Neutrophils were the main HO-1-expressing cells in peripheral blood, and HMOX1 mRNA expression was upregulated by heme-moieties of lysed erythrocytes. We provide mechanistic evidence that induction of HMOX1 expression in neutrophils potentiates the respiratory burst, and propose this may be part of the causal pathway explaining the association between short (GT)(n) repeats and increased disease severity in malaria and other critical illnesses. Our findings suggest a genetic predisposition to higher levels of HO-1 is associated with severe illness, and enhances the neutrophil burst leading to oxidative damage of endothelial cells. These add important information to the discussion about possible therapeutic manipulation of HO-1 in critically ill patients.

Induction of strain-transcending antibodies against Group A PfEMP1 surface antigens from virulent malaria parasites.

Sequence diversity in pathogen antigens is an obstacle to the development of interventions against many infectious diseases. In malaria caused by Plasmodium falciparum, the PfEMP1 family of variant surface antigens encoded by var genes are adhesion molecules that play a pivotal role in malaria pathogenesis and clinical disease. PfEMP1 is a major target of protective immunity, however, development of drugs or vaccines based on PfEMP1 is problematic due to extensive sequence diversity within the PfEMP1 family. Here we identified the PfEMP1 variants transcribed by P. falciparum strains selected for a virulence-associated adhesion phenotype (IgM-positive rosetting). The parasites transcribed a subset of Group A PfEMP1 variants characterised by an unusual PfEMP1 architecture and a distinct N-terminal domain (either DBLα1.5 or DBLα1.8 type). Antibodies raised in rabbits against the N-terminal domains showed functional activity (surface reactivity with live infected erythrocytes (IEs), rosette inhibition and induction of phagocytosis of IEs) down to low concentrations (<10 µg/ml of total IgG) against homologous parasites. Furthermore, the antibodies showed broad cross-reactivity against heterologous parasite strains with the same rosetting phenotype, including clinical isolates from four sub-Saharan African countries that showed surface reactivity with either DBLα1.5 antibodies (variant HB3var6) or DBLα1.8 antibodies (variant TM284var1). These data show that parasites with a virulence-associated adhesion phenotype share IE surface epitopes that can be targeted by strain-transcending antibodies to PfEMP1. The existence of shared surface epitopes amongst functionally similar disease-associated P. falciparum parasite isolates suggests that development of therapeutic interventions to prevent severe malaria is a realistic goal.

Prolonged neutrophil dysfunction after Plasmodium falciparum malaria is related to hemolysis and heme oxygenase-1 induction.

It is not known why people are more susceptible to bacterial infections such as nontyphoid Salmonella during and after a malaria infection, but in mice, malarial hemolysis impairs resistance to nontyphoid Salmonella by impairing the neutrophil oxidative burst. This acquired neutrophil dysfunction is a consequence of induction of the cytoprotective, heme-degrading enzyme heme oxygenase-1 (HO-1) in neutrophil progenitors in bone marrow. In this study, we assessed whether neutrophil dysfunction occurs in humans with malaria and how this relates to hemolysis. We evaluated neutrophil function in 58 Gambian children with Plasmodium falciparum malaria [55 (95%) with uncomplicated disease] and examined associations with erythrocyte count, haptoglobin, hemopexin, plasma heme, expression of receptors for heme uptake, and HO-1 induction. Malaria caused the appearance of a dominant population of neutrophils with reduced oxidative burst activity, which gradually normalized over 8 wk of follow-up. The degree of neutrophil impairment correlated significantly with markers of hemolysis and HO-1 induction. HO-1 expression was increased in blood during acute malaria, but at a cellular level HO-1 expression was modulated by changes in surface expression of the haptoglobin receptor (CD163). These findings demonstrate that neutrophil dysfunction occurs in P. falciparum malaria and support the relevance of the mechanistic studies in mice. Furthermore, they suggest the presence of a regulatory pathway to limit HO-1 induction by hemolysis in the context of infection and indicate new targets for therapeutic intervention to abrogate the susceptibility to bacterial infection in the context of hemolysis in humans.

Evidence base update for psychosocial treatments for pediatric obsessive-compulsive disorder.

Pediatric obsessive-compulsive disorder (OCD) is a chronic and impairing condition that often persists into adulthood. Barrett, Farrell, Pina, Peris, and Piacentini (2008), in this journal, provided a detailed review of evidence-based psychosocial treatments for youth with OCD. The current review provides an evidence base update of the pediatric OCD psychosocial treatment literature with particular attention to advances in the field as well as to the methodological challenges inherent in evaluating such findings. Psychosocial treatment studies conducted since the last review are described and evaluated according to methodological rigor and evidence-based classification using the JCCAP evidence-based treatment evaluation criteria (Southam-Gerow & Prinstein, this issue). Findings from this review clearly converge in support of cognitive-behavioral therapy as an effective and appropriate first line treatment for youth with OCD (either alone or in combination with medication). Although no treatment for pediatric OCD has yet to be designated as "well-established," both individual and individual family-based treatments have been shown to be "probably efficacious." Moderators and predictors of treatment outcome are discussed as are the areas where we have advanced the field and the areas where we have room to grow. The methodological and clinical challenges inherent in a review of the evidence base are reviewed. Finally, future research directions are outlined.

The trichotillomania impact project in young children (TIP-YC): clinical characteristics, comorbidity, functional impairment and treatment utilization.

The aim was to investigate clinical characteristics of young children with a hair pulling problem. Parents/caregivers of young children (0-10 years old) with a hair pulling problem (N = 110) completed an online survey. The majority reported that their child experienced mild to moderate impairment/distress due to hair pulling, and overall clinical characteristics were similar to adult samples, although some differences were noted (e.g., less awareness of pulling). We also compared preschool-aged and school-aged children within the sample. Symptom severity, pleasure during pulling and gender ratio remained stable across the age groups. The preschool-aged children demonstrated less impairment/distress, comorbidity, and treatment seeking; pulled from fewer body areas; and were less likely to be aware of the act or experience tension prior to pulling. In conclusion, clinical characteristics of childhood hair pulling are largely similar to adult/adolescent hair pulling problems, but there are some notable differences, particularly among pre-school aged children.

Comparison of modeling methods to determine liver-to-blood inocula and parasite multiplication rates during controlled human malaria infection.

Controlled human malaria infection is used to measure efficacy of candidate malaria vaccines before field studies are undertaken. Mathematical modeling using data from quantitative polymerase chain reaction (qPCR) parasitemia monitoring can discriminate between vaccine effects on the parasite's liver and blood stages. Uncertainty regarding the most appropriate modeling method hinders interpretation of such trials. We used qPCR data from 267 Plasmodium falciparum infections to compare linear, sine-wave, and normal-cumulative-density-function models. We find that the parameters estimated by these models are closely correlated, and their predictive accuracy for omitted data points was similar. We propose that future studies include the linear model.

Hard X-ray Fourier transform holography at free electron lasers source.

We report on the feasibility of Fourier transform holography in the hard X-ray regime using a Free Electron Laser source. Our study shows successful single and multi-pulse holographic reconstructions of the nanostructures. We observe beam-induced heating of the sample exposed to the intense X-ray pulses leading to reduced visibility of the holographic reconstructions. Furthermore, we extended our study exploring the feasibility of recording holographic reconstructions with hard X-ray split-and-delay optics. Our study paves the way towards studying dynamics at sub-nanosecond timescales and atomic lengthscales.

PfHPRT: a new biomarker candidate of acute Plasmodium falciparum infection.

Plasmodium falciparum is a protozoan parasite that causes human malaria. This parasitic infection accounts for approximately 655,000 deaths each year worldwide. Most deaths could be prevented by diagnosing and treating malaria promptly. To date, few parasite proteins have been developed into rapid diagnostic tools. We have combined a shotgun and a targeted proteomic strategy to characterize the plasma proteome of Gambian children with severe malaria (SM), mild malaria, and convalescent controls in search of new candidate biomarkers. Here we report four P. falciparum proteins with a high level of confidence in SM patients, namely, PF10_0121 (hypoxanthine phosphoribosyltransferase, pHPRT), PF11_0208 (phosphoglycerate mutase, pPGM), PF13_0141 (lactate dehydrogenase, pLDH), and PF14_0425 (fructose bisphosphate aldolase, pFBPA). We have optimized selected reaction monitoring (SRM) assays to quantify these proteins in individual patients. All P. falciparum proteins were higher in SM compared with mild cases or control subjects. SRM-based measurements correlated markedly with clinical anemia (low blood hemoglobin concentration), and pLDH and pFBPA were significantly correlated with higher P. falciparum parasitemia. These findings suggest that pHPRT is a promising biomarker to diagnose P. falciparum malaria infection. The diagnostic performance of this marker should be validated prospectively.

Freeze-thaw lysates of Plasmodium falciparum-infected red blood cells induce differentiation of functionally competent regulatory T cells from memory T cells.

In addition to naturally occurring regulatory T (nTreg) cells derived from the thymus, functionally competent Treg cells can be induced in vitro from peripheral blood lymphocytes in response to TCR stimulation with cytokine costimulation. Using these artificial stimulation conditions, both naïve as well as memory CD4(+) T cells can be converted into induced Treg (iTreg) cells, but the cellular origin of such iTreg cells in vivo or in response to more physiologic stimulation with pathogen-derived antigens is less clear. Here, we demonstrate that a freeze/thaw lysate of Plasmodium falciparum schizont extract (PfSE) can induce functionally competent Treg cells from peripheral lymphocytes in a time- and dose-dependent manner without the addition of exogenous costimulatory factors. The PfSE-mediated induction of Treg cells required the presence of nTreg cells in the starting culture. Further experiments mixing either memory or naïve T cells with antigen presenting cells and CFSE-labeled Treg cells identified CD4(+) CD45RO(+) CD25(-) memory T cells rather than Treg cells as the primary source of PfSE-induced Treg cells. Taken together, these data suggest that in the presence of nTreg cells, PfSE induces memory T cells to convert into iTreg cells that subsequently expand alongside PfSE-induced effector T cells.

Regulatory T cells in malaria--friend or foe?

T cell-mediated inflammatory immune responses contribute to both the clearance and pathology of malaria infections; the host's ability to down-regulate inflammation once parasitemia is controlled is crucial to avoid immune-mediated pathology but remains poorly understood. Various regulatory populations of T lymphocytes can modulate inflammatory immune responses and there has been considerable recent interest in the potential for regulatory T cells to modify the outcome of both murine and human malaria infections. Here, we review these studies, focussing in particular on recent studies in humans, propose a model by which different regulatory T cell populations might contribute to the control of inflammation at different stages of infection and discuss the implications for the design of safe and effective malaria vaccines.