The Gender Euphoria Scale (GES): a protocol for developing and validating a tool to measure gender euphoria in transgender and gender diverse individuals.

Background: Gender euphoria (i.e., a positive feeling associated with one's gender identity, expression, or affirmation) is widely discussed among transgender and gender diverse (hereafter referred to as trans) individuals. However, as a construct, gender euphoria has never been formally measured and has rarely been empirically studied. Hence, this protocol paper illustrates our process for developing and validating a new tool to measure gender euphoria, known as the Gender Euphoria Scale (GES), for use with trans populations. Methods: Deductive methods including findings from previous research and a review of existing measures, together with inductive methods such as expert feedback and focus groups with trans individuals, were used to generate a preliminary item pool for the GES. Pilot testing with trans community members and mental health clinicians was then used to refine items and develop a preliminary scale. Trans participants involved in an ongoing longitudinal study (TRANSform) were invited to complete the scale alongside measures of personality and gender factors to assess validity. Participants were then invited to complete the scale two weeks after initial completion to assess the test-retest reliability of the scale. The next stage in the scale development process will be to examine the dimensionality of the GES using exploratory factor analytic techniques. The scale will then be assessed for internal consistency, temporal stability, discriminant validity, and convergent validity. Conclusion: This paper outlines the development and characterization of a novel tool to measure gender euphoria for the first time. The GES will facilitate research opportunities to better understand the nature of gender euphoria and its influences, and may be used clinically to examine relationships between gender euphoria and gender affirming interventions. Hence, we expect the GES to make a significant contribution to both research and clinical practice with trans communities.

A case of severe allergic eosinophilic asthma with nasal polyposis in a patient affected by Birt-Hogg-Dubé syndrome successfully treated with benralizumab.

SUMMARY: Birt-Hogg-Dubé (BHD) syndrome is a rare genetic pathology characterized by cutaneous fibrofolliculomas, pulmonary cysts and kidney tumours. Severe asthma is the most serious form of asthma that does not respond to standard treatments. We present the case of a 68 years-old male patient who had frequent respiratory tract infections, shortness of breath and decline in lung function, nasal polyposis and hypertrophy of the nasal turbinates, for this reason was treated as a severe asthmatic patient for several years with ICS + LABA and high doses of OCS. When we tried to reduce OCS the patient had worsening of the symptoms, we requested a HRTC scan that showed presence of several cysts spread ubiquitously. The patient had a family history of pneumothorax, for this reason we requested a genetic test that resulted in a heterozygous point mutation on exon 12 (c.1429 C > T) of FLCN gene. Despite the diagnosis of BHD syndrome, the patient's clinical condition kept on suggesting an underlying severe asthma and the blood tests we requested pointed out a high percentage of eosinophils, for this reason we opted for the administration of benralizumab that resulted in an excellent asthma control and increased quality of life.

End-to-end image analysis pipeline for liquid-phase electron microscopy.

Liquid phase transmission electron microscopy allows the imaging of materials in liquid environments. The sample is encapsulated within electron-beam transparent windows and hence protected by the ultrahigh vacuum necessary within the electron gun. Such an approach allows to study biological and soft materials in their natural environment and offers the possibility of accessing their dynamic nature. Yet, the electron beam scattering from the windows and solvent increases the image noise and blur. Herein, we propose a pipeline to both de-noise and sharpen images obtained by liquid transmission electron microscopy. We develop the workflow in a way that it does not require any human interference, nor introduce artefacts, but actually unveils features of the imaged samples covered by the noise and the blur. LAY DESCRIPTION: Transmission Electron Microscopy TEM is one of the most powerful techniques for structural determination at the nanoscale, with the ability to image matter down to the atomic level. TEM is only possible by keeping the electron beam under high vacuum in order to avoid undesired scattering events in the beam path. High vacuum means that the TEM samples must conventionally be in solid-state. Thus, samples in liquid form or containing liquids, like water, need special preparation techniques which tend to alter the structure and chemical nature of the sample. Such alterations are particularly critical for biological and soft organic materials where the structures are controlled by the presence of water and/or other liquids. The development of new cameras, materials and sample holders have made possible for TEM to be performed on liquid samples. Liquid Phase Transmission Electron Microscopy (LTEM) offers the possibility to investigate nanoscopic structures in liquid state and monitor dynamic processes. However important limitations come from the liquid nature of samples in the imaging process such as the low contrast afforded by organic and biological materials and additional noise and blur introduced by the liquid sample and its thickness. Existing image analysis algorithms for TEM result inadequate for LTEM. The end-to-end image analysis method herein has the ability to recover the original images together with their sharpness, without introducing any artefacts. The proposed algorithms offer the great advantage of unveiling image details which are not usually seen during imaging, thus allowing a better understanding of the nature, structure and ultimately the function of the investigated structures. The fully automatised analysis method allows to efficiently process dozens of images in few hours, improving dramatically the performance of LTEM imaging.

Onset of granulomatosis with polyangiitis obscured by heart disease in an elderly man.

We describe a case of 85-year-old man who presented to the Emergency Department with sudden dyspnea. He had a past medical history of cardiomyopathy and radiography and nonenhanced computed tomography (CT) of the chest showed pulmonary edema. Despite intravenous diuretic therapy, there was no clinical improvement. Cardiac CT was then performed showing a solid pulmonary nodular lesion with intralesional cavitations, ground-glass opacities, and peripheral vascularization. CT-guided needle lung biopsy yielded a diagnosis of granulomatosis with polyangiitis (Wegener granulomatosis). Medical treatment with cyclophosphamide and prednisone produced rapid symptomatic improvement and complete resolution of the radiological findings. This case demonstrates the challenges in making this diagnosis in an elderly patient with heart disease. We found very few documented cases where there was onset of granulomatosis with polyangiitis at this age.

Primary psychosis with comorbid drug abuse and drug-induced psychosis: Diagnostic and clinical evolution at follow up.

The study reports a follow-up assessment of 48 patients with concomitant drug abuse at the first admission for psychosis. We focused on the diagnostic distinction between primary psychosis with concomitant drug abuse and drug induced psychosis, to observe whether the diagnoses are stable over time and whether the clinical course significantly differs. The study examined 25 primary psychotic disorder with comorbid drug abuse and 23 drug-induced psychotic disorder patients. Diagnostic and psychopathological assessments were made at baseline and at follow-up. Mean follow-up period was 4.96 years. Patients with comorbid Drug Abuse exhibited higher scores in the item Unusual Content of Thought at baseline than drug-induced psychotic disorder patients: 5.48 vs 4.39 while the two patients groups did not differ in any of the BPRS items evaluated at follow-up. The primary psychosis with comorbid drug abuse and the substance induced psychosis groups were similar regarding diagnostic stability, and a diagnosis of schizophrenia at follow-up occurred similarly. There was no evidence that Drug Induced psychotic patients' symptoms tend to improve more after cessation of drug abuse. An earlier age of onset was found in primary psychotic patients, particularly for patients diagnosed as affected by schizophrenia at follow up. These results might reflect the uncertainty of the distinction between Primary and Drug Induced Psychosis and the difficulties in applying the DSM IV-TR criteria for diagnosing comorbid drug use disorders and psychotic disorders.

Paliperidone for the treatment of schizophrenia and schizoaffective disorders - a drug safety evaluation.

INTRODUCTION: Paliperidone, the major active metabolite of risperidone, is a second-generation antipsychotic that has been developed as an extended-release (ER) oral formulation and a long-acting injectable paliperidone palmitate (PP) formulation. Paliperidone has demonstrated efficacy in the reduction of acute schizophrenia symptoms and clinical benefits were maintained also in the long-term treatments. Paliperidone ER and PP are generally well tolerated with a predictable adverse event profile. Areas covered: Data from studies evaluating safety and tolerability in the acute and maintenance treatment of schizophrenia with paliperidone are reviewed. The reported treatment-emergent adverse events of these formulations are discussed. Expert opinion: In the treatment of schizophrenia and schizoaffective disorders the safety profile has a central role because it can enhance patient compliance. In fact treatment-emergent adverse events are one of the main causes of discontinuation in these patients. In particular the main limitation in the administration of paliperidone could be represented by the onset of hyperprolactinemia (especially in women) and of mild parkinsonism. Paliperidone has a high impact on current long-term drug strategies, especially given the new 3 month long-acting injectable formulation of PP.

New generation non-stationary portable neutron generators for biophysical applications of Neutron Activation Analysis.

BACKGROUND: Neutron sources are increasingly employed in a wide range of research fields. For some specific purposes an alternative to existing large-scale neutron scattering facilities, can be offered by the new generation of portable neutron devices. SCOPE OF REVIEW: This review reports an overview for such recently available neutron generators mainly addressed to biophysics applications with specific reference to portable non-stationary neutron generators applied in Neutron Activation Analysis (NAA). MAJOR CONCLUSIONS: The review reports a description of a typical portable neutron generator set-up addressed to biophysics applications. GENERAL SIGNIFICANCE: New generation portable neutron devices, for some specific applications, can constitute an alternative to existing large-scale neutron scattering facilities. Deuterium-Deuterium pulsed neutron sources able to generate 2.5MeV neutrons, with a neutron yield of 1.0×106n/s, a pulse rate of 250Hz to 20kHz and a duty factor varying from 5% to 100%, when combined with solid-state photon detectors, show that this kind of compact devices allow rapid and user-friendly elemental analysis. "This article is part of a Special Issue entitled "Science for Life" Guest Editor: Dr. Austen Angell, Dr. Salvatore Magazù and Dr. Federica Migliardo".

[Cytotoxicity mechanism of the RNase Sa cationic mutants involves inhibition of potassium current through Ca2+-activated channels].

Bacterial ribonucleases (RNases) are considered to be potential anticancer agents. One of most important determinants of RNase cytotoxicity is the net charge of the molecule. In this work a set of mutants of the RNase from Streptomyces aureofaciens (RNase Sa), differing in the net charge of the protein molecules (from -7 to +6) and localization of additional positive charge at the N- or C-terminus of the molecule is used to study inhibition of cell growth. It has been found that the mutants of RNase with increased cationicity most effectively inhibit the growth of HEKhSK4 cells. Additional positive charge at the C-terminus of the molecule also increases the cytotoxic properties of RNases. It has been shown that RNase cytotoxicity correlated with the level of inhibition of the K+-current in cells.

Drift of the HIV-1 envelope glycoprotein gp120 toward increased neutralization resistance over the course of the epidemic: a comprehensive study using the most potent and broadly neutralizing monoclonal antibodies.

Extending our previous analyses to the most recently described monoclonal broadly neutralizing antibodies (bNAbs), we confirmed a drift of HIV-1 clade B variants over 2 decades toward higher resistance to bNAbs targeting almost all the identified gp120-neutralizing epitopes. In contrast, the sensitivity to bNAbs targeting the gp41 membrane-proximal external region remained stable, suggesting a selective pressure on gp120 preferentially. Despite this evolution, selected combinations of bNAbs remain capable of neutralizing efficiently most of the circulating variants.

Forces stabilizing proteins.

The goal of this article is to summarize what has been learned about the major forces stabilizing proteins since the late 1980s when site-directed mutagenesis became possible. The following conclusions are derived from experimental studies of hydrophobic and hydrogen bonding variants. (1) Based on studies of 138 hydrophobic interaction variants in 11 proteins, burying a -CH2- group on folding contributes 1.1±0.5 kcal/mol to protein stability. (2) The burial of non-polar side chains contributes to protein stability in two ways: first, a term that depends on the removal of the side chains from water and, more importantly, the enhanced London dispersion forces that result from the tight packing in the protein interior. (3) Based on studies of 151 hydrogen bonding variants in 15 proteins, forming a hydrogen bond on folding contributes 1.1±0.8 kcal/mol to protein stability. (4) The contribution of hydrogen bonds to protein stability is strongly context dependent. (5) Hydrogen bonds by side chains and peptide groups make similar contributions to protein stability. (6) Polar group burial can make a favorable contribution to protein stability even if the polar group is not hydrogen bonded. (7) Hydrophobic interactions and hydrogen bonds both make large contributions to protein stability.

Contribution of hydrogen bonds to protein stability.

Our goal was to gain a better understanding of the contribution of the burial of polar groups and their hydrogen bonds to the conformational stability of proteins. We measured the change in stability, Δ(ΔG), for a series of hydrogen bonding mutants in four proteins: villin headpiece subdomain (VHP) containing 36 residues, a surface protein from Borrelia burgdorferi (VlsE) containing 341 residues, and two proteins previously studied in our laboratory, ribonucleases Sa (RNase Sa) and T1 (RNase T1). Crystal structures were determined for three of the hydrogen bonding mutants of RNase Sa: S24A, Y51F, and T95A. The structures are very similar to wild type RNase Sa and the hydrogen bonding partners form intermolecular hydrogen bonds to water in all three mutants. We compare our results with previous studies of similar mutants in other proteins and reach the following conclusions. (1) Hydrogen bonds contribute favorably to protein stability. (2) The contribution of hydrogen bonds to protein stability is strongly context dependent. (3) Hydrogen bonds by side chains and peptide groups make similar contributions to protein stability. (4) Polar group burial can make a favorable contribution to protein stability even if the polar groups are not hydrogen bonded. (5) The contribution of hydrogen bonds to protein stability is similar for VHP, a small protein, and VlsE, a large protein.

Sustained periodic terrestrial locomotion in air-breathing fishes.

While emergent behaviours have long been reported for air-breathing osteichthyians, only recently have researchers undertaken quantitative analyses of terrestrial locomotion. This review summarizes studies of sustained periodic terrestrial movements by air-breathing fishes and quantifies the contributions of the paired appendages and the axial body to forward propulsion. Elongate fishes with axial-based locomotion, e.g. the ropefish Erpetoichthys calabaricus, generate an anterior-to-posterior wave of undulation that travels down the axial musculoskeletal system and pushes the body against the substratum at multiple points. In contrast, appendage-based locomotors, e.g. the barred mudskipper Periophthalmus argentilineatus, produce no axial bending during sustained locomotion, but instead use repeated protraction-retraction cycles of the pectoral fins to elevate the centre of mass and propel the entire body anteriorly. Fishes that use an axial-appendage-based mechanism, e.g. walking catfishes Clarias spp., produce side-to-side, whole-body bending in co-ordination with protraction-retraction cycles of the pectoral fins. Once the body is maximally bent to one side, the tail is pressed against the substratum and drawn back through the mid-sagittal plane, which elevates the centre of mass and rotates it about a fulcrum formed by the pectoral fin and the ground. Although appendage-based terrestrial locomotion appears to be rare in osteichthyians, many different species appear to have converged upon functionally similar axial-based and axial-appendage-based movements. Based on common forms observed across divergent taxa, it appears that dorsoventral compression of the body, elongation of the axial skeleton or the presence of robust pectoral fins can facilitate effective terrestrial movement by air-breathing fishes.

Cytotoxicity of RNase Sa to the acute myeloid leukemia Kasumi-1 cells depends on the net charge.

The majority of known cytotoxic RNases are basic proteins which destroy intracellular RNA. Cationization of RNases is considered to be an effective strategy for strengthening their antitumor properties. We constructed a set of RNase Sa variants consisting of charge reversal mutants, charge neutralization mutants, and variants with positively charged cluster at the N-terminus. All constructs retain a high level of catalytic activity and differ in net charge. Using acute myeloid leukemia cells Kasumi-1 we have shown that (i) cytotoxicity of RNase Sa mutants is linearly enhanced by cationization, (ii) the ability of cytotoxic mutants to induce cell death is caused by induction of apoptosis and (iii) localization of positive charge on N-terminus does not contribute to RNase Sa cytotoxicity. Capacity to induce apoptosis in malignant cells and the absence of necrotic effects make the RNase Sa mutants with high positive charge a suitable anti-cancer agent.

Clinical pharmacology of atypical antipsychotics: an update.

This review will concentrate on the clinical pharmacology, in particular pharmacodynamic data, related to atypical antipsychotics, clozapine, risperidone, paliperidone, olanzapine, que¬tiapine, amisulpride, ziprasidone, aripiprazole, asenapine, iloperidone, lurasidone and cariprazine. A summary of their acute pharmacokinetics properties are also reported. Four new second-generation antipsychotics are available: iloperidone, asenapine, lurasidone and in the next future cariprazine. Similar to ziprasidone and aripiprazole, these new agents are advisable for the lower propensity to give weight gain and metabolic abnormalities in comparison with older second-generation antipsychotics such as olanzapine or clozapine. Actually lurasidone seems to be best in terms of minimizing unwanted alterations in body weight and metabolic variables. Therapeutic drug monitoring is not strictly necessary for all of the new antipsychotic drugs because there are no unequivocal data supporting a relationship between plasma drug levels and clinical outcomes or side effects. The exception can be represented by clozapine for which plasma levels of 350-420 ng/ml are reported to be associated with an increased probability of a good clinical response. Also for olanzapine an established therapeutic range (20-50 ng/ml) is proposed to yield an optimal response and minimize side effects.

Biogeographical patterns and determinants of invasion by forest pathogens in Europe.

A large database of invasive forest pathogens (IFPs) was developed to investigate the patterns and determinants of invasion in Europe. Detailed taxonomic and biological information on the invasive species was combined with country-specific data on land use, climate, and the time since invasion to identify the determinants of invasiveness, and to differentiate the class of environments which share territorial and climate features associated with a susceptibility to invasion. IFPs increased exponentially in the last four decades. Until 1919, IFPs already present moved across Europe. Then, new IFPs were introduced mainly from North America, and recently from Asia. Hybrid pathogens also appeared. Countries with a wider range of environments, higher human impact or international trade hosted more IFPs. Rainfall influenced the diffusion rates. Environmental conditions of the new and original ranges and systematic and ecological attributes affected invasiveness. Further spread of established IFPs is expected in countries that have experienced commercial isolation in the recent past. Densely populated countries with high environmental diversity may be the weakest links in attempts to prevent new arrivals. Tight coordination of actions against new arrivals is needed. Eradication seems impossible, and prevention seems the only reliable measure, although this will be difficult in the face of global mobility.

Sexually transmitted infections among HIV-infected heavy drinkers in St Petersburg, Russia.

The objective of this study was to estimate the prevalence and identify correlates of four sexually transmitted infections (STIs) among HIV-infected Russians reporting heavy alcohol use and recent unprotected sex, we conducted a cross-sectional analysis of baseline data from the HERMITAGE study. The primary outcome was any current STI, based on urine tests for Neisseria gonorrhoeae, Chlamydia trachomatis and Trichomonas vaginalis and serological testing for infection with Treponema pallidum. Data on potential demographic and behavioural predictors of STI were obtained from surveys administered at study entry. Of 682 participants, 12.8% (95% confidence interval [CI] 10.3, 15.3) tested positive for at least one STI. In a multivariable model adjusted for gender, age and marital status, only sex trade involvement over the last three months was significantly associated with an increased odds of STI (adjusted odds ratio [AOR] 2.00, 95% CI 1.13, 3.55). Given that STIs were common in this HIV-infected cohort, and that few patient characteristics predicted STI, the current practice of screening HIV-infected Russians for syphilis alone merits re-evaluation.

Circulating natriuretic peptide concentrations in hyperthyroid cats.

OBJECTIVES: To assess the influence of thyroid function on natriuretic peptide concentration in hyperthyroid cats before and after treatment. METHODS: Serum natriuretic peptide concentration was measured in 61 hyperthyroid cats recruited from first-opinion clinics before and after treatment. RESULTS: Following successful treatment, total thyroxine, heart rate, systolic blood pressure and packed cell volume all decreased and bodyweight and creatinine concentrations increased. Furthermore, a significant (P < 0·001) decline in NT-proBNP concentration but not NT-proANP was identified. CLINICAL SIGNIFICANCE: Thyroid function has a modest but significant effect on NT-proBNP concentration. Thyroid status should be taken into account when interpreting NT-proBNP concentrations in cats.

Toward a molecular understanding of protein solubility: increased negative surface charge correlates with increased solubility.

Protein solubility is a problem for many protein chemists, including structural biologists and developers of protein pharmaceuticals. Knowledge about how intrinsic factors influence solubility is limited due to the difficulty of obtaining quantitative solubility measurements. Solubility measurements in buffer alone are difficult to reproduce, because gels or supersaturated solutions often form, making it impossible to determine solubility values for many proteins. Protein precipitants can be used to obtain comparative solubility measurements and, in some cases, estimations of solubility in buffer alone. Protein precipitants fall into three broad classes: salts, long-chain polymers, and organic solvents. Here, we compare the use of representatives from two classes of precipitants, ammonium sulfate and polyethylene glycol 8000, by measuring the solubility of seven proteins. We find that increased negative surface charge correlates strongly with increased protein solubility and may be due to strong binding of water by the acidic amino acids. We also find that the solubility results obtained for the two different precipitants agree closely with each other, suggesting that the two precipitants probe similar properties that are relevant to solubility in buffer alone.

Continuity and discontinuity of attachment patterns: a short-term longitudinal pilot study using a sample of late-adopted children and their adoptive mothers.

This study analysed the attachment patterns of 28 late-adopted children (placed when they were between four and seven years of age) and their adoptive mothers. The change in the children's internal working models (IWMs) within seven to eight months of their placement was evaluated. In addition, we wanted to observe the influence of a secure-autonomous maternal state of mind in facilitating the change in the children's IWMs and the possible associations between the maternal IWMs and the children's IWMs in the adoptive dyads. The separation-reunion procedure (SRP) was used for the late-adopted children in order to assess their attachment behavioural patterns, and the Manchester Child Attachment Story Task (MCAST) was used to evaluate their attachment narrative patterns. The adoptive mothers completed the Adult Attachment Interview (AAI) in order to classify their state of mind with regard to attachment. The results showed a significant change in the attachment behavioural patterns of late-adopted children, from insecure to secure (p = .002). Furthermore, the children who presented this change were predominantly placed with secure-autonomous adoptive mothers (p = .047), although the link between the adoptive mothers' representations of their attachment history and their adopted children's completed narratives was not significant. In conclusion, it seems possible to revise the attachment behaviour of late-adopted children but, for about one-third of children, the adverse history will persist at a narrative/representational level.

Cryptic introgression of Dasypyrum villosum parental DNA in wheat lines derived from intergeneric hybridization.

Cytogenetic and DNA molecular analyses have been carried out in 3 wheat introgression lines (ILs; CS×V58, CS×V59, and CS×V60) derived from Triticum aestivum cv. 'Chinese Spring' (CS) × Dasypyrum villosum(Dv) intergeneric hybridization. All lines, which showed several phenotypic differences compared to CS, had the same chromosome number (2n = 42) and structure as CS, and neither chromosomes nor chromatin from Dv were apparently added to their complement. However, Feulgen/DNA cytophotometry showed that there was more nuclear DNA in the lines than in the parental wheat (by 1.85%, 2.76%, and 1.26% in CS×V58, CS×V59, and CS×V60, respectively). Molecular investigation indicated the presence of Dv DNA in the ILs. AFLP analysis of genomic DNA from the ILs, CS, and Dv detected a total of 120 polymorphic bands, of which 7 (5.8%) were present in some or all the ILs and Dv but were absent in CS. PCR amplification, sequence analysis of amplicons, and Southern blot hybridization confirmed the presence of Dv-specific sequences in each of the ILs. These results indicate cryptic introgression of Dv DNA sequences into the genome of the ILs. Some implications of this finding are discussed.