Boltzmann's equation at 150: Traditional and modern solution techniques for charged particles in neutral gases.

Seminal gas discharge experiments of the late 19th and early 20th centuries laid the foundations of modern physics, and the influence of this "golden era" continues to resonate well into the 21st century through modern technologies, medical applications, and fundamental scientific investigations. Key to this continuing success story has been the kinetic equation formulated by Ludwig Boltzmann in 1872, which provides the theoretical foundations necessary for analyzing such highly non-equilibrium situations. However, as discussed here, the full potential of Boltzmann's equation has been realized only in the past 50 years or so, with modern computing power and analytical techniques facilitating accurate solutions for various types of charged particles (ions, electrons, positrons, and muons) in gases. Our example of thermalization of electrons in xenon gas highlights the need for such accurate methods-the traditional Lorentz approximation is shown to be hopelessly inadequate. We then discuss the emerging role of Boltzmann's equation in determining cross sections by inverting measured swarm experiment transport coefficient data using machine learning with artificial neural networks.

Biologic treatment for severe chronic rhinosinusitis with nasal polyps: a systematic review and meta-analysis.

BACKGROUND: Chronic rhinosinusitis with nasal polyps is often severe, debilitating and difficult to treat. Biologics that target key inflammatory pathways have the potential to treat this disease; this study aimed to evaluate their effectiveness. METHODOLOGY: Systematic review and meta-analysis of randomised controlled trials of biologics in chronic rhinosinusitis with nasal polyps. Primary outcomes were extent of disease, objective disease severity and disease-specific quality of life, with outcomes measured at different end-of-treatment timepoints in different studies (range 16-52 weeks). RESULTS: Eleven trials were identified with 2035 participants. Ten studies reported change in polyp size, estimating a reduction of -1.25 in the treatment group. Six studies reported reduction in Lund-Mackay score where the pooled mean difference was -4.90. Five studies included peak nasal inspiratory flow with a pooled mean difference of 33.54, indicating improved nasal airflow. Seven studies reported change in olfactory score with an overall pooled effect of 6.56 suggesting improved olfaction. The SNOT-22 score in nine studies gave an overall pooled effect of -14.53, indicating improved quality of life. CONCLUSIONS: Biologics can be effective in treating nasal polyps, with reduction in polyp size and extent of disease, and improved sense of smell and quality of life. There is significant heterogeneity in the outcomes for individual biologics, highlighting the need for further studies.

High-resolution entry and exit surface dosimetry in a 1.5 T MR-linac.

The magnetic field of a transverse MR-linac alters electron trajectories as the photon beam transits through materials, causing lower doses at flat entry surfaces and increased doses at flat beam-exiting surfaces. This study investigated the response of a MOSFET detector, known as the MOSkin™, for high-resolution surface and near-surface percentage depth dose measurements on an Elekta Unity. Simulations with Geant4 and the Monaco treatment planning system (TPS), and EBT-3 film measurements, were also performed for comparison. Measured MOSkin™ entry surface doses, relative to Dmax, were (9.9 ± 0.2)%, (10.1 ± 0.3)%, (11.3 ± 0.6)%, (12.9 ± 1.0)%, and (13.4 ± 1.0)% for 1 × 1 cm2, 3 × 3 cm2, 5 × 5 cm2, 10 × 10 cm2, and 22 × 22 cm2 fields, respectively. For the investigated fields, the maximum percent differences of Geant4, TPS, and film doses extrapolated and interpolated to a depth suitable for skin dose assessment at the beam entry, relative to MOSkin™ measurements at an equivalent depth were 1.0%, 2.8%, and 14.3%, respectively, and at a WED of 199.67 mm at the beam exit, 3.2%, 3.7% and 5.7%, respectively. The largest measured increase in exit dose, due to the electron return effect, was 15.4% for the 10 × 10 cm2 field size using the MOSkin™ and 17.9% for the 22 × 22 cm2 field size, using Geant4 calculations. The results presented in the study validate the suitability of the MOSkin™ detector for transverse MR-linac surface dosimetry.

Toward a complete and comprehensive cross section database for electron scattering from NO using machine learning.

We review experimental and theoretical cross sections for electron scattering in nitric oxide (NO) and form a comprehensive set of plausible cross sections. To assess the accuracy and self-consistency of our set, we also review electron swarm transport coefficients in pure NO and admixtures of NO in Ar, for which we perform a multi-term Boltzmann equation analysis. We address observed discrepancies with these experimental measurements by training an artificial neural network to solve the inverse problem of unfolding the underlying electron-NO cross sections while using our initial cross section set as a base for this refinement. In this way, we refine a suitable quasielastic momentum transfer cross section, a dissociative electron attachment cross section, and a neutral dissociation cross section. We confirm that the resulting refined cross section set has an improved agreement with the experimental swarm data over that achieved with our initial set. We also use our refined database to calculate electron transport coefficients in NO, across a large range of density-reduced electric fields from 0.003 to 10 000 Td.

An improved set of electron-THFA cross sections refined through a neural network-based analysis of swarm data.

We review experimental and theoretical cross sections for electron transport in α-tetrahydrofurfuryl alcohol (THFA) and, in doing so, propose a plausible complete set. To assess the accuracy and self-consistency of our proposed set, we use the pulsed-Townsend technique to measure drift velocities, longitudinal diffusion coefficients, and effective Townsend first ionization coefficients for electron swarms in admixtures of THFA in argon, across a range of density-reduced electric fields from 1 to 450 Td. These measurements are then compared to simulated values derived from our proposed set using a multi-term solution of Boltzmann's equation. We observe discrepancies between the simulation and experiment, which we attempt to address by employing a neural network model that is trained to solve the inverse swarm problem of unfolding the cross sections underpinning our experimental swarm measurements. What results from our neural network-based analysis is a refined set of electron-THFA cross sections, which we confirm is of higher consistency with our swarm measurements than that which we initially proposed. We also use our database to calculate electron transport coefficients in pure THFA across a range of reduced electric fields from 0.001 to 10 000 Td.

Third-order transport coefficient tensor of charged-particle swarms in electric and magnetic fields.

Third-order transport coefficient tensor of charged-particle swarms in neutral gases in the presence of spatially uniform electric and magnetic fields is considered using a multiterm solution of Boltzmann's equation and Monte Carlo simulation technique. The structure of the third-order transport coefficient tensor and symmetries along its individual components in varying configurations of electric and magnetic fields are addressed using a group projector technique and through symmetry considerations of the Boltzmann equation. In addition, we focus upon the physical interpretation of the third-order transport coefficient tensor by considering the extended diffusion equation which incorporates the contribution of the third-order transport coefficients to the density profile of charged particles. Numerical calculations are carried out for electron and ion swarms for a range of model gases with the aim of establishing accurate benchmarks for third-order transport coefficients. The effects of ion to neutral-particle mass ratio are also examined. The errors of the two-term approximation for solving the Boltzmann equation and limitations of previous treatments of the high-order charged-particle transport properties are also highlighted.

Multiple-therapy-resistant major depressive disorder: a clinically important concept.

Many novel therapeutic options for depression exist that are either not mentioned in clinical guidelines or recommended only for use in highly specialist services. The challenge faced by clinicians is when it might be appropriate to consider such 'non-standard' interventions. This analysis proposes a framework to aid this decision.Declaration of interestIn the past 3 years R.H.M.W. has received support for research, expenses to attend conferences and fees for lecturing and consultancy work (including attending advisory boards) from various pharmaceutical companies including Astra Zeneca, Cyberonics, Eli Lilly, Janssen, LivaNova, Lundbeck, MyTomorrows, Otsuka, Pfizer, Roche, Servier, SPIMACO and Sunovion. D.M.B.C. has received fees from LivaNova for attending an advisory board. In the past 3 years A.J.C. has received fees for lecturing from Astra Zeneca and Lundbeck; fees for consulting from LivaNova, Janssen and Allergan; and research grant support from Lundbeck.In the past 3 years A.C. has received fees for lecturing from pharmaceutical companies namely Lundbeck and Sunovion. In the past 3 years A.L.M. has received support for attending seminars and fees for consultancy work (including advisory board) from Medtronic Inc and LivaNova. R.M. holds joint research grants with a number of digital companies that investigate devices for depression including Alpha-stim, Big White Wall, P1vital, Intel, Johnson and Johnson and Lundbeck through his mindTech and CLAHRC EM roles. M.S. is an associate at Blueriver Consulting providing intelligence to NHS organisations, pharmaceutical and devices companies. He has received honoraria for presentations and advisory boards with Lundbeck, Eli Lilly, URGO, AstraZeneca, Phillips and Sanofi and holds shares in Johnson and Johnson. In the past 3 years P.R.A.S. has received support for research, expenses to attend conferences and fees for lecturing and consultancy work (including attending an advisory board) from life sciences companies including Corcept Therapeutics, Indivior and LivaNova. In the past 3 years P.S.T. has received consultancy fees as an advisory board member from the following companies: Galen Limited, Sunovion Pharmaceuticals Europe Ltd, myTomorrows and LivaNova. A.H.Y. has undertaken paid lectures and advisory boards for all major pharmaceutical companies with drugs used in affective and related disorders and LivaNova. He has received funding for investigator initiated studies from AstraZeneca, Eli Lilly, Lundbeck and Wyeth.

Fitness variation among host species and the paradox of ineffective rhizobia.

Legumes can preferentially select beneficial rhizobial symbionts and sanction ineffective strains that fail to fix nitrogen. Yet paradoxically, rhizobial populations vary from highly beneficial to ineffective in natural and agricultural soils. Classic models of symbiosis focus on the single dimension of symbiont cost-benefit to sympatric hosts, but fail to explain the widespread persistence of ineffective rhizobia. Here, we test a novel framework predicting that spatio-temporal and community dynamics can maintain ineffective strains in rhizobial populations. We used clonal and multistrain inoculations and quantitative culturing to investigate the relative fitness of four focal Bradyrhizobium strains varying from effective to ineffective on Acmispon strigosus. We found that an ineffective Bradyrhizobium strain can be sanctioned by its native A. strigosus host across the host's range, forming fewer and smaller nodules compared to beneficial strains. But the same ineffective Bradyrhizobium strain exhibits a nearly opposite pattern on the broadly sympatric host Acmispon wrangelianus, forming large nodules in both clonal and multistrain inoculations. These data suggest that community-level effects could favour the persistence of ineffective rhizobia and contribute to variation in symbiotic nitrogen fixation.

Intranasal bevacizumab in the treatment of HHT -related epistaxis: a systematic review.

BACKGROUND: Hereditary haemorrhagic telangiectasia (HHT) remains a difficult disease for the ENT specialist to manage. Affected patients often report recurrent epistaxis as the most debilitating symptom. The pathogenesis of the disease is due to genetic mutations affecting angiogenesis. For this reason, the anti-angiogenic therapy bevacizumab has gained popularity in the local treatment of epistaxis in patients with HHT. OBJECTIVE: A systematic review of the efficacy of bevacizumab in local treatment of epistaxis in patients with HHT based on epistaxis duration, frequency, severity and impact on quality of life. METHODS: A systematic search was performed using the PubMed, MEDLINE and EMBASE databases. The Preferred Items for Systematic Reviews and Meta-Analyses guidelines were followed. Studies that measured the efficacy of intranasal bevacizumab treatment of epistaxis in patients with HHT were included for qualitative analysis. RESULTS: Thirteen studies (four randomised controlled trials, three prospective studies, three retrospective studies, one case series and two case reports) with a total of 357 patients were included. Local administration (either by submucosal injection or topically) did not have a significant impact on epistaxis duration, frequency, severity or quality of life compared to placebo or other local treatments. CONCLUSIONS: The available evidence suggests that intranasal bevacizumab treatment does not have a significant effect on epistaxis in patients with HHT. There are several limitations that require further investigation to confidently rule out local bevacizumab as an effective therapy in HHT related epistaxis.

Differential effects on gene transcription and hematopoietic differentiation correlate with GATA2 mutant disease phenotypes.

Heterozygous GATA2 mutations underlie an array of complex hematopoietic and lymphatic diseases. Analysis of the literature reporting three recurrent GATA2 germline (g) mutations (gT354M, gR396Q and gR398W) revealed different phenotype tendencies. Although all three mutants differentially predispose to myeloid malignancies, there was no difference in leukemia-free survival for GATA2 patients. Despite intense interest, the molecular pathogenesis of GATA2 mutation is poorly understood. We functionally characterized a GATA2 mutant allelic series representing major disease phenotypes caused by germline and somatic (s) mutations in zinc finger 2 (ZF2). All GATA2 mutants, except for sL359V, displayed reduced DNA-binding affinity and transactivation compared with wild type (WT), which could be attributed to mutations of arginines critical for DNA binding or amino acids required for ZF2 domain structural integrity. Two GATA2 mutants (gT354M and gC373R) bound the key hematopoietic differentiation factor PU.1 more strongly than WT potentially perturbing differentiation via sequestration of PU.1. Unlike WT, all mutants failed to suppress colony formation and some mutants skewed cell fate to granulocytes, consistent with the monocytopenia phenotype seen in GATA2-related immunodeficiency disorders. These findings implicate perturbations of GATA2 function shaping the course of development of myeloid malignancy subtypes and strengthen complete or nearly complete haploinsufficiency for predisposition to lymphedema.

Neural substrates of cue reactivity and craving in gambling disorder.

Cue reactivity is an established procedure in addictions research for examining the subjective experience and neural basis of craving. This experiment sought to quantify cue-related brain responses in gambling disorder using personally tailored cues in conjunction with subjective craving, as well as a comparison with appetitive non-gambling stimuli. Participants with gambling disorder (n=19) attending treatment and 19 controls viewed personally tailored blocks of gambling-related cues, as well as neutral cues and highly appetitive (food) images during a functional magnetic resonance imaging (fMRI) scan performed ~2-3 h after a usual meal. fMRI analysis examined cue-related brain activity, cue-related changes in connectivity and associations with block-by-block craving ratings. Craving ratings in the participants with gambling disorder increased following gambling cues compared with non-gambling cues. fMRI analysis revealed group differences in left insula and anterior cingulate cortex, with the gambling disorder group showing greater reactivity to the gambling cues, but no differences to the food cues. In participants with gambling disorder, craving to gamble correlated positively with gambling cue-related activity in the bilateral insula and ventral striatum, and negatively with functional connectivity between the ventral striatum and the medial prefrontal cortex. Gambling cues, but not food cues, elicit increased brain responses in reward-related circuitry in individuals with gambling disorder (compared with controls), providing support for the incentive sensitization theory of addiction. Activity in the insula co-varied with craving intensity, and may be a target for interventions.

Structural basis of the interaction of the breast cancer oncogene LMO4 with the tumour suppressor CtIP/RBBP8.

LIM-only protein 4 (LMO4) is strongly linked to the progression of breast cancer. Although the mechanisms underlying this phenomenon are not well understood, a role is emerging for LMO4 in regulation of the cell cycle. We determined the solution structure of LMO4 in complex with CtIP (C-terminal binding protein interacting protein)/RBBP8, a tumour suppressor protein that is involved in cell cycle progression, DNA repair and transcriptional regulation. Our data reveal that CtIP and the essential LMO cofactor LDB1 (LIM-domain binding protein 1) bind to the same face on LMO4 and cannot simultaneously bind to LMO4. We hypothesise that overexpression of LMO4 may disrupt some of the normal tumour suppressor activities of CtIP, thereby contributing to breast cancer progression.

Striatal dopamine synthesis capacity in twins discordant for schizophrenia.

BACKGROUND: Elevated striatal dopamine synthesis capacity is thought to be fundamental to the pathophysiology of schizophrenia and has also been reported in people at risk of psychosis. It is therefore unclear if striatal hyperdopaminergia is a vulnerability marker for schizophrenia, or a state feature related to the psychosis itself. Relatives of patients with schizophrenia are themselves at increased risk of developing the condition. In this study we examined striatal dopamine synthesis capacity in both members of twin pairs discordant for schizophrenia. METHOD: In vivo striatal dopamine synthesis capacity was examined using fluorine-18-l-dihydroxyphenylalanine (18F-DOPA) positron emission tomography (PET) scans in seven twin pairs discordant for schizophrenia and in a control sample of 10 healthy control twin pairs. RESULTS: Striatal 18F-DOPA uptake was not elevated in the unaffected co-twins of patients with schizophrenia (p=0.65) or indeed in the twins with schizophrenia (p=0.89) compared to the control group. Levels of psychotic symptoms were low in the patients with schizophrenia who were in general stable [mean (s.d.) Positive and Negative Syndrome Scale (PANSS) total=56.8 (25.5)] whereas the unaffected co-twins were largely asymptomatic. CONCLUSIONS: Striatal dopamine synthesis capacity is not elevated in symptom-free individuals at genetic risk of schizophrenia, or in well-treated stable patients with chronic schizophrenia. These findings suggest that striatal hyperdopaminergia is not a vulnerability marker for schizophrenia.

The effect of electrospray solvent composition on desorption electrospray ionisation (DESI) efficiency and spatial resolution.

In desorption electrospray ionisation (DESI) the interaction between the electrospray and the surface is key to two important analytical parameters, the spatial resolution and the sensitivity. We evaluate the effect of the electrospray solvent type, organic solvent fraction with water, analyte solubility and substrate wettability on DESI erosion diameter and material transferral into useful ion signal. To do this five amino acids, glycine, alanine, valine, leucine and phenylalanine are prepared as thin films on three substrates, UV/ozone treated glass, glass and polytetrafluoroethylene (PTFE). Four different solvents, acetonitrile (ACN), methanol (MeOH), ethanol (EtOH) and propan-2-ol (IPA), are used with organic solvent fractions with water varying from 0.1 to 1. These model systems allow the solubility or wettability to be kept constant as other parameters are varied. Additionally, comparison with electrospray ionisation (ESI) allows effects of ionisation efficiency to be determined. It is shown that the DESI efficiency is linearly dependent on the solubility (for these materials at least) and for analytes with solubilities below 1.5 g kg(-1), additional strategies may be required for DESI to be effective. We show that the DESI erosion diameter improves linearly with organic solvent fraction, with an organic solvent fraction of 0.9 instead of 0.5 leading to a 2 fold improvement. Furthermore, this leads to a 35 fold increase in DESI efficiency, defined as the molecular ion yield per unit area. It is shown that these improvements correlate with smaller droplet sizes rather than surface wetting or ionisation.

Mechanisms underlying psychosis and antipsychotic treatment response in schizophrenia: insights from PET and SPECT imaging.

Molecular imaging studies have generated important in vivo insights into the etiology of schizophrenia and treatment response. This article first reviews the PET and SPECT evidence implicating dopaminergic dysfunction, especially presynaptic dysregulation, as a mechanism for psychosis. Second, it summarises the neurochemical imaging studies of antipsychotic action, focussing on D2/3 receptors. These studies show that all currently licensed antipsychotic drugs block striatal D2/3 receptors in vivo- a site downstream of the likely principal dopaminergic pathophysiology in schizophrenia- and that D2/3 occupancy above a threshold is required for antipsychotic treatment response. However, adverse events, such as extra-pyramidal side-effects or hyperprolactinemia, become much more likely at higher occupancy levels, which indicates there is an optimal 'therapeutic window' for D2/3 occupancy, and questions the use of high doses of antipsychotic treatment in clinical practice and trials. Adequate D2/3 blockade by antipsychotic drugs is necessary but not always sufficient for antipsychotic response. Molecular imaging studies of clozapine, the one antipsychotic licensed for treatment resistant schizophrenia, have provided insights into the mechanisms underlying its unique efficacy. To link this pharmacology to the phenomenology of the illness, we discuss the role of dopamine in motivational salience and show how i) psychosis could be viewed as a process of aberrant salience, and ii) antipsychotics might provide symptomatic relief by blocking this aberrant salience. Finally, we discuss the implications of these PET and SPECT findings for new avenues of drug development.

Developing repeatable measurements for reliable analysis of molecules at surfaces using desorption electrospray ionization.

Desorption electrospray ionization (DESI) is a powerful ambient ionization technique that can provide high-sensitivity mass spectrometry information directly from surfaces at ambient pressure. Although a growing amount of research has been devoted to exploring different applications, there are few studies investigating the basic parameters and underpinning metrology. An understanding of these is crucial to develop DESI as the robust and reliable technique required for significant uptake by industry. In this work, we begin with a systematic study of the parameters affecting the repeatability, sensitivity, and rate of consumption of material with DESI. To do this we have developed a model sample consisting of a thin uniform film of controlled thickness of Rhodamine B on glass. This model sample allowed assessment of optimal sensitivity and spot shape under different conditions. In addition, it allowed us to study the surface in more detail to understand why and how each parameter affects these. Using the model sample to optimize the instrument parameters for DESI led to an absolute intensity repeatability of better than 15%, achieved over a period of 1 day. This model sample provides valuable insight into the electrospray-sample interaction and the desorption mechanism. Confocal microscopy of areas analyzed by DESI allow droplet distribution, material utilization, and spot size to be determined. Studying surface erosion also gives the erosion rate of material, analogous to the sputtering yield in secondary ion mass spectrometry. The results of the study provide a clear description that explains the differences observed with changing electrospray parameters allowing optimization of the technique, for both spatial resolution and sensitivity.

Elements in rice on the Swedish market: part 2. Chromium, copper, iron, manganese, platinum, rubidium, selenium and zinc.

A survey of the levels of some essential and non-essential trace elements in different types of rice available on the Swedish retail market was carried out in 2001-03. The types of rice included long and short grain, brown, white, and parboiled white. The mean levels found were: chromium (Cr) = 0.008 mg kg(-1), copper (Cu) = 1.9 mg kg(-1), iron (Fe) = 4.7 mg kg(-1), manganese (Mn) = 16 mg kg(-1), platinum (Pt) < 0.0003 mg kg(-1), rubidium (Rb) = 3.3 mg kg(-1), selenium (Se) =0.1 mg kg(-1); and zinc (Zn) = 15 mg kg(-1). Inductively coupled plasma-mass spectrometry (ICP-MS) was used for the determination of Pt, Rb, and Se, after acid digestion. All other elements were determined using atomic absorption spectrometry (AAS) after dry ashing. Intake calculations were performed and it was concluded that rice may contribute considerably to the daily requirements of the essential elements Cu, Fe, Mn, Se, and Zn if rice consumption is high. The levels of some elements, e.g. Fe and Mn, were significantly higher in brown compared with white rice.

Elements in rice from the Swedish market: 1. Cadmium, lead and arsenic (total and inorganic).

A survey of the levels of cadmium, lead and arsenic in different types of rice available on the Swedish retail market was carried out in 2001--03. The types of rice included long and short grain, brown, white, and parboiled white rice. The mean levels found were as follows: total As: 0.20 mg kg(-1), inorganic As: 0.11 mg kg(-1); Cd: 0.024 mg kg(-1); and Pb: 0.004 mg kg(-1). ICP-MS was used for the determination of As (total and inorganic) after acid digestion. Lead and cadmium were determined using graphite furnace atomic absorption spectrometry (GFAAS) after dry ashing. In countries where rice is a staple food, it may represent a significant contribution in relation to the provisional tolerable weekly intake for Cd and inorganic As.

Clinical assessment and core outcome variables are poor predictors of hip arthritis diagnosed by MRI in juvenile idiopathic arthritis.

OBJECTIVES: To compare the diagnostic performance of clinical assessment against magnetic resonance imaging (MRI) diagnosed hip arthritis in a juvenile idiopathic arthritis (JIA) population. To determine the clinical and serological predictors of MRI diagnosed hip arthritis. METHODS: A total of 34 JIA patients with established disease (mean disease duration 6.3 yrs) had their hip MRIs scored for features of active hip arthritis and hip damage. Results were compared with clinical variables (disease subtype, history of hip pain, core outcome variables (COV)) and the clinician's assessment of active hip arthritis. RESULTS: MRI features of active hip arthritis were found in 45 hips (70%) and hip damage in 36 hips (56%). Clinical assessment had fair agreement with MRI scoring of active arthritis in patients with disease duration <4 yrs (kappa score 0.38, P = 0.045). Clinical assessment had a sensitivity of 25.7% and specificity of 91% for detecting MRI diagnosed arthritis. Of the core outcome variables only erythrocyte sedimentation rate predicted inflammation detected on MRI (r = 0.44, P = 0.014). CONCLUSIONS: The association between the clinician's assessment, core outcome variables and MRI findings in this study was limited. This indicates that clinical and laboratory findings are inadequate diagnostic tools for the assessment of hip arthritis when compared with MRI as the gold standard.