Changes in brain activity with tominersen in early-manifest Huntington's disease.

It is unknown whether alterations in EEG brain activity caused by Huntington's disease may be responsive to huntingtin-lowering treatment. We analysed EEG recordings of 46 patients (mean age = 47.02 years; standard deviation = 10.19 years; 18 female) with early-manifest Stage 1 Huntington's disease receiving the huntingtin-lowering antisense oligonucleotide tominersen for 4 months or receiving placebo as well as 39 healthy volunteers (mean age = 44.48 years; standard deviation = 12.94; 22 female) not receiving treatment. Patients on tominersen showed increased resting-state activity within a 4-8 Hz frequency range compared with patients receiving placebo (cluster-based permutation test, P < 0.05). The responsive frequency range overlapped with EEG activity that was strongly reduced in Huntington's disease compared with healthy controls (cluster-based permutation test, P < 0.05). The underlying mechanisms of the observed treatment-related increase are unknown and may reflect neural plasticity as a consequence of the molecular pathways impacted by tominersen treatment. Hawellek et al. report that patients with Huntington's disease treated with the huntingtin-lowering antisense oligonucleotide tominersen exhibited increased EEG power in the theta/alpha frequency range. The underlying mechanisms of the observed changes are unknown and may reflect neural plasticity as a consequence of the molecular pathways impacted by tominersen treatment.

Demonstration of a compact plasma accelerator powered by laser-accelerated electron beams.

Plasma wakefield accelerators are capable of sustaining gigavolt-per-centimeter accelerating fields, surpassing the electric breakdown threshold in state-of-the-art accelerator modules by 3-4 orders of magnitude. Beam-driven wakefields offer particularly attractive conditions for the generation and acceleration of high-quality beams. However, this scheme relies on kilometer-scale accelerators. Here, we report on the demonstration of a millimeter-scale plasma accelerator powered by laser-accelerated electron beams. We showcase the acceleration of electron beams to 128 MeV, consistent with simulations exhibiting accelerating gradients exceeding 100 GV m-1. This miniaturized accelerator is further explored by employing a controlled pair of drive and witness electron bunches, where a fraction of the driver energy is transferred to the accelerated witness through the plasma. Such a hybrid approach allows fundamental studies of beam-driven plasma accelerator concepts at widely accessible high-power laser facilities. It is anticipated to provide compact sources of energetic high-brightness electron beams for quality-demanding applications such as free-electron lasers.

Prediction of venous thromboembolism using clinical and serum biomarker data from a military cohort of trauma patients.

INTRODUCTION: Venous thromboembolism (VTE) is a frequent complication of trauma associated with high mortality and morbidity. Clinicians lack appropriate tools for stratifying trauma patients for VTE, thus have yet to be able to predict when to intervene. We aimed to compare random forest (RF) and logistic regression (LR) predictive modelling for VTE using (1) clinical measures alone, (2) serum biomarkers alone and (3) clinical measures plus serum biomarkers. METHODS: Data were collected from 73 military casualties with at least one extremity wound and prospectively enrolled in an observational study between 2007 and 2012. Clinical and serum cytokine data were collected. Modelling was performed with RF and LR based on the presence or absence of deep vein thrombosis (DVT) and/or pulmonary embolism (PE). For comparison, LR was also performed on the final variables from the RF model. Sensitivity/specificity and area under the curve (AUC) were reported. RESULTS: Of the 73 patients (median Injury Severity Score=16), nine (12.3%) developed VTE, four (5.5%) with DVT, four (5.5%) with PE, and one (1.4%) with both DVT and PE. In all sets of predictive models, RF outperformed LR. The best RF model generated with clinical and serum biomarkers included five variables (interleukin-15, monokine induced by gamma, vascular endothelial growth factor, total blood products at resuscitation and presence of soft tissue injury) and had an AUC of 0.946, sensitivity of 0.992 and specificity of 0.838. CONCLUSIONS: VTE may be predicted by clinical and molecular biomarkers in trauma patients. This will allow the development of clinical decision support tools which can help inform the management of high-risk patients for VTE.

Hybrid LWFA-PWFA staging as a beam energy and brightness transformer: conceptual design and simulations.

We present a conceptual design for a hybrid laser-driven plasma wakefield accelerator (LWFA) to beam-driven plasma wakefield accelerator (PWFA). In this set-up, the output beams from an LWFA stage are used as input beams of a new PWFA stage. In the PWFA stage, a new witness beam of largely increased quality can be produced and accelerated to higher energies. The feasibility and the potential of this concept is shown through exemplary particle-in-cell simulations. In addition, preliminary simulation results for a proof-of-concept experiment in Helmholtz-Zentrum Dresden-Rossendorf (Germany) are shown. This article is part of the Theo Murphy meeting issue 'Directions in particle beam-driven plasma wakefield acceleration'.

Hippocampal dysfunction in the pathophysiology of schizophrenia: a selective review and hypothesis for early detection and intervention.

Scientists have long sought to characterize the pathophysiologic basis of schizophrenia and develop biomarkers that could identify the illness. Extensive postmortem and in vivo neuroimaging research has described the early involvement of the hippocampus in the pathophysiology of schizophrenia. In this context, we have developed a hypothesis that describes the evolution of schizophrenia-from the premorbid through the prodromal stages to syndromal psychosis-and posits dysregulation of glutamate neurotransmission beginning in the CA1 region of the hippocampus as inducing attenuated psychotic symptoms and initiating the transition to syndromal psychosis. As the illness progresses, this pathological process expands to other regions of the hippocampal circuit and projection fields in other anatomic areas including the frontal cortex, and induces an atrophic process in which hippocampal neuropil is reduced and interneurons are lost. This paper will describe the studies of our group and other investigators supporting this pathophysiological hypothesis, as well as its implications for early detection and therapeutic intervention.

Baseline demographics, clinical features and predictors of conversion among 200 individuals in a longitudinal prospective psychosis-risk cohort.

BACKGROUND: DSM-5 proposes an Attenuated Psychosis Syndrome (APS) for further investigation, based upon the Attenuated Positive Symptom Syndrome (APSS) in the Structured Interview for Psychosis-Risk Syndromes (SIPS). SIPS Unusual Thought Content, Disorganized Communication and Total Disorganization scores predicted progression to psychosis in a 2015 NAPLS-2 Consortium report. We sought to independently replicate this in a large single-site high-risk cohort, and identify baseline demographic and clinical predictors beyond current APS/APSS criteria. METHOD: We prospectively studied 200 participants meeting criteria for both the SIPS APSS and DSM-5 APS. SIPS scores, demographics, family history of psychosis, DSM Axis-I diagnoses, schizotypy, and social and role functioning were assessed at baseline, with follow-up every 3 months for 2 years. RESULTS: The conversion rate was 30% (n = 60), or 37.7% excluding participants who were followed under 2 years. This rate was stable across time. Conversion time averaged 7.97 months for 60% who developed schizophrenia and 15.68 for other psychoses. Mean conversion age was 20.3 for males and 23.5 for females. Attenuated odd ideas and thought disorder appear to be the positive symptoms which best predict psychosis in a logistic regression. Total negative symptom score, Asian/Pacific Islander and Black/African-American race were also predictive. As no Axis-I diagnosis or schizotypy predicted conversion, the APS is supported as a distinct syndrome. In addition, cannabis use disorder did not increase risk of conversion to psychosis. CONCLUSIONS: NAPLS SIPS findings were replicated while controlling for clinical and demographic factors, strongly supporting the validity of the SIPS APSS and DSM-5 APS diagnosis.

Haemagglutinin mutations and glycosylation changes shaped the 2012/13 influenza A(H3N2) epidemic, Houston, Texas.

While the early start and higher intensity of the 2012/13 influenza A virus (IAV) epidemic was not unprecedented, it was the first IAV epidemic season since the 2009 H1N1 influenza pandemic where the H3N2 subtype predominated. We directly sequenced the genomes of 154 H3N2 clinical specimens collected throughout the epidemic to better understand the evolution of H3N2 strains and to inform the H3N2 vaccine selection process. Phylogenetic analyses indicated that multiple co-circulating clades and continual antigenic drift in the haemagglutinin (HA) of clades 5, 3A, and 3C, with the evolution of a new 3C subgroup (3C-2012/13), were the driving causes of the epidemic. Drift variants contained HA substitutions and alterations in the potential N-linked glycosylation sites of HA. Antigenic analysis demonstrated that viruses in the emerging subclade 3C.3 and subgroup 3C-2012/13 were not well inhibited by antisera generated against the 3C.1 vaccine strains used for the 2012/13 (A/Victoria/361/2011) or 2013/14 (A/Texas/50/2012) seasons. Our data support updating the H3N2 vaccine strain to a clade 3C.2 or 3C.3-like strain or a subclade that has drifted further. They also underscore the challenges in vaccine strain selection, particularly regarding HA and neuraminidase substitutions derived during laboratory passage that may alter antigenic testing accuracy.

Temporal association of stress sensitivity and symptoms in individuals at clinical high risk for psychosis.

BACKGROUND: Increased sensitivity and exposure to stress are associated with psychotic symptoms in schizophrenia and its risk states, but little is known about the co-evolution of stress sensitivity and exposure with positive and other symptoms in a clinical high-risk (CHR) cohort. METHOD: A combined cross-sectional and longitudinal design was used to examine the associations over time of stress sensitivity and exposure (i.e. life events) with 'prodromal' symptoms in a cohort of 65 CHR patients assessed quarterly for up to 4 years, and at baseline in 24 healthy controls similar in age and gender. RESULTS: Impaired stress tolerance was greater in patients, in whom it was associated over time with positive and negative symptoms, in addition to depression, anxiety and poor function. By contrast, life events were comparable in patients and controls, and bore no association with symptoms. In this treated cohort, there was a trajectory of improvement in stress tolerance, symptoms and function over time. CONCLUSIONS: Impaired stress tolerance was associated with a wide range of 'prodromal' symptoms, consistent with it being a core feature of the psychosis risk state. Self-reported life events were not relevant as a correlate of clinical status. As in other treated CHR cohorts, most patients improved over time across symptom domains.

The relationship of social function to depressive and negative symptoms in individuals at clinical high risk for psychosis.

BACKGROUND: Social dysfunction is a hallmark symptom of schizophrenia which commonly precedes the onset of psychosis. It is unclear if social symptoms in clinical high-risk patients reflect depressive symptoms or are a manifestation of negative symptoms. METHOD: We compared social function scores on the Social Adjustment Scale-Self Report between 56 young people (aged 13-27 years) at clinical high risk for psychosis and 22 healthy controls. The cases were also assessed for depressive and 'prodromal' symptoms (subthreshold positive, negative, disorganized and general symptoms). RESULTS: Poor social function was related to both depressive and negative symptoms, as well as to disorganized and general symptoms. The symptoms were highly intercorrelated but linear regression analysis demonstrated that poor social function was primarily explained by negative symptoms within this cohort, particularly in ethnic minority patients. CONCLUSIONS: Although this study demonstrated a relationship between social dysfunction and depressive symptoms in clinical high-risk cases, this association was primarily explained by the relationship of each of these to negative symptoms. In individuals at heightened risk for psychosis, affective changes may be related to a progressive decrease in social interaction and loss of reinforcement of social behaviors. These findings have relevance for potential treatment strategies for social dysfunction in schizophrenia and its risk states and predict that antidepressant drugs, cognitive behavioral therapy and/or social skills training may be effective.

Factors affecting the variation in the adult temporomandibular joint of archaeological human populations.

To elucidate factors that may affect the variation in the bony components of temporomandibular joint (TMJ), a preliminary study was conducted on the temporal articular surface of the TMJ of 30 skulls from Iron Age and medieval populations from Lithuania and a mixed Neolithic and Bronze Age population from the Central Elbe-Saale region (CESR). Using three-dimensional (3D) photos of the skulls, length and width measurements of the TMJ were obtained and compared with external skull measurements. Distinct, random variation between the TMJ values from opposite sides of the cranium were identified as fluctuating asymmetry. ANOVA results suggest significant differences in the length of the TMJ between the population of the CESR and the two Lithuanian populations, but not between the two Lithuanian populations. Environmental factors, including geography, may be responsible for the variation in the TMJ form.

A new approach for evaluating circadian blood pressure levels and variability from 24 h ambulatory blood pressure profiles.

In 24 h blood pressure monitoring the severity of arterial hypertension is generally classified on the basis of the arithmetic mean of the diastolic blood pressure between 6 AM and 10 PM. In the present study Fourier analysis was used for evaluation of circadian blood pressure level and variability. A common reference profile was calculated on the basis of a group of 50 normotensive profiles. This reference profile is characterized by the fact that the sum of the squares of the distances between the individual profiles and the reference profile is a minimum. The individual 24 h profiles of 103 patients with untreated arterial hypertension were also each described by a Fourier series and were then compared with the normotensive reference profile. The comparison was made not only with respect to the absolute pressure over 24 h but also with respect to the circadian fluctuations in blood pressure. Our results show that the Fourier analysis of 24 h blood pressure profiles presented here can be used for more precise evaluation of 24 h blood pressure profiles.

[Analysis of circadian blood pressure profiles using Fourier analysis]. / Analyse von zirkadianen Blutdruckprofilen mit Hilfe der Fourieranalyse.

Blood pressure is subject to considerable circadian and situational fluctuation. In 24-h blood-pressure monitoring the severity of arterial hypertension is generally classified on the basis of the arithmetic mean of the diastolic blood pressure between 07.00 and 22.00 hours. In the present study Fourier analysis was used to generate continuous functions from the discrete blood-pressure values measured during 24-h blood-pressure monitoring in a sample of 50 normotensive persons aged from 25 to 80 years. A common reference profile was then constructed from these 50 profiles. This reference profile is characterized by the fact that the sum of the integrals over the squares of the distances between the individual profiles and the reference profile is the smallest possible. The reference profile is thus the best approximation of all normotensive profiles and practically ignores individual blood pressure fluctuations. The individual 24-h profiles of 80 patients with untreated arterial hypertension were classified on the basis of the daytime mean as mild, moderate or severe arterial hypertension and also each is described by a Fourier series. The pathological profiles were then compared with the normotensive reference profile. The comparison was made, not only with respect to the absolute pressure over 24 h, but also with respect to the circadian fluctuations in blood pressure. Comparison of the profiles shows that the Fourier analysis of 24-h blood-pressure profiles presented here permits reliable analysis and classification of arterial hypertension and can thus be used for more precise evaluation of the influence of antihypertensives on 24-h blood-pressure profiles.

Determination of S-phenylmercapturic acid in the urine--an improvement in the biological monitoring of benzene exposure.

In an inhalation study rats were exposed to different doses of benzene, ranging from 1 to 500 p.p.m. The urine was sampled during the inhalation period of 8 h and for 24 h after exposure. S-Phenylmercapturic acid (S-PMA) in the urine was determined by amino acid analysis. Phenol was measured by gas chromatography/mass spectrometry. In both cases the correlation between benzene uptake and the excretion of the urinary metabolites was significant at the level of P = 0.01. The same significant correlation (P = 0.01) was demonstrable after i.p. administration of benzene at doses between 0.7 and 140.0 microliters/kg body weight. In the case of two collectives of workers who were exposed to air concentrations of up to 0.15 p.p.m. for 8 h and of up to 1.13 p.p.m. for 12 h respectively, the amount of S-PMA in the first urine samples after the shift was significantly higher than in samples collected at the beginning of the shift (P = 0.01). In the first collective the mean values and the standard deviations of the S-PMA concentrations in the samples at the beginning of the shift were 12.0 +/- 16.7 compared with 48.5 +/- 64.5 micrograms/g creatinine at shift end. In the second collective they were 25.1 +/- 25.1 compared with 70.9 +/- 109.2 micrograms/g creatinine. The level of significance of the difference between the concentration values of S-PMA at the beginning and end of the shift was P = 0.01. The phenol concentration did not differ significantly. These results suggest that S-PMA can be regarded as a useful indicator for monitoring individuals and collectives exposed to benzene at levels even less than 1 p.p.m.