Radiomics analysis of ultrasound images to discriminate between benign and malignant adnexal masses with solid ultrasound morphology.

OBJECTIVE: Our primary aim was to identify radiomic ultrasound features that can distinguish benign from malignant adnexal masses with solid ultrasound morphology, and primary invasive from metastatic solid ovarian masses, and to develop ultrasound-based machine learning models that include radiomics features to discriminate between benign and malignant solid adnexal masses. Our secondary aim was to compare the diagnostic performance of our radiomics models with that of the ADNEX model and subjective assessment by an experienced ultrasound examiner. METHODS: This is a retrospective observational single center study. Patients with a histological diagnosis of an adnexal tumor with solid morphology at preoperative ultrasound examination performed between 2014 and 2021 were included. The patient cohort was split into training and validation sets with a ratio of 70:30 and with the same proportion of benign and malignant (borderline, primary invasive and metastatic) tumors in the two subsets. The extracted radiomic features belonged to two different families: intensity-based statistical features and textural features. Models to predict malignancy were built based on a random forest classifier, fine-tuned using 5-fold cross-validation over the training set, and tested on the held-out validation set. The variables used in model building were patient's age, and those radiomic features that were statistically significantly different between benign and malignant adnexal masses (Wilcoxon-Mann-Whitney Test with Benjamini-Hochberg correction for multiple comparisons) and assessed as not redundant based on the Pearson correlation coefficient. We describe discriminative ability as area under the receiver operating characteristics curve (AUC) and classification performance as sensitivity and specificity. RESULTS: 326 patients were identified and 775 preoperative ultrasound images were analyzed. 68 radiomic features were extracted, 52 differed statistically significantly between benign and malignant tumors in the training set, and 18 features were selected for inclusion in model building. The same 52 radiomic features differed statistically significantly between benign, primary invasive malignant and metastatic tumors. However, the values of the features manifested overlap between primary malignant and metastatic tumors and did not differ statistically significantly between them. In the validation set, 25/98 tumors (25.5%) were benign, 73/98 (74.5%) were malignant (6 borderline, 57 primary invasive, 10 metastases). In the validation set, a model including only radiomics features had an AUC of 0.80, and 78% sensitivity and 76% specificity at its optimal risk of malignancy cutoff (68% based on Youden's index). The corresponding results for a model including age and radiomics features were 0.79, 86% and 56% (cutoff 60% based on Youden's method), while those of the ADNEX model were 0.88, 99% and 64% (at 20% malignancy cutoff). Subjective assessment had sensitivity 99% and specificity 72%. CONCLUSIONS: Even though our radiomics models had discriminative ability inferior to that of the ADNEX model, our results are promising enough to justify continued development of radiomics analysis of ultrasound images of adnexal masses. This article is protected by copyright. All rights reserved.

Pharmacokinetics and Pharmacodynamics of Murepavadin in Neutropenic Mouse Models.

Murepavadin (POL7080) represents the first member of a novel class of outer membrane protein-targeting antibiotics. It specifically interacts with LptD and inhibits lipopolysaccharide (LPS) transport. Murepavadin is being developed for the treatment of serious infections by Pseudomonas aeruginosa We determined the plasma protein binding and the pharmacokinetics of murepavadin in plasma and epithelial lining fluid (ELF; pulmonary) in infected animals, and we determined the exposure-response relationship. Treatment of CD-1 neutropenic mice was started 2 h after infection using murepavadin at different dosing frequencies for 24 h, and the number of CFU per lung was determined. The sigmoid maximum-effect model was used to fit the dose-response, and the pharmacodynamic index (PDI) response was used to determine the PDI values, resulting in a static effect and 1-log kill reduction. Using R2 as an indicator of the best fit, the area under the concentration-time curve for the unbound fraction of the drug (fAUC)/MIC ratio correlated best with efficacy. The mean AUC required to provide a static effect was 36.83 mg h/liter (fAUC = 8.25 mg h/liter), and that to provide a 1-log reduction was 44.0 mg h/liter (fAUC = 9.86 mg h/liter). The mean static fAUC/MIC was determined to be 27.78, and that for a 1-log reduction was 39.85. These data may serve to determine doses in humans that are likely to be efficacious.

Recent progress in the discovery of macrocyclic compounds as potential anti-infective therapeutics.

Novel therapeutic strategies are urgently needed for the treatment of serious diseases caused by viral, bacterial and parasitic infections, because currently used drugs are facing the problem of rapidly emerging resistance. There is also an urgent need for agents that act on novel pathogen-specific targets, in order to expand the repertoire of possible therapies. The high throughput screening of diverse small molecule compound libraries has provided only a limited number of new lead series, and the number of compounds acting on novel targets is even smaller. Natural product screening has traditionally been very successful in the anti-infective area. Several successful drugs on the market as well as other compounds in clinical development are derived from natural products. Amongst these, many are macrocyclic compounds in the 1-2 kDa size range. This review will describe recent advances and novel drug discovery approaches in the anti-infective area, focusing on synthetic and natural macrocyclic compounds for which in vivo proof of concept has been established. The review will also highlight the Protein Epitope Mimetics (PEM) technology as a novel tool in the drug discovery process. Here the structures of naturally occurring antimicrobial and antiviral peptides and proteins are used as starting points to generate novel macrocyclic mimetics, which can be produced and optimized efficiently by combinatorial synthetic methods. Several recent examples highlight the great potential of the PEM approach in the discovery of new anti-infective agents.

Multiband superconductivity in Pb, H under pressure and CaBeSi from ab initio calculations.

Superconductivity in Pb, H under extreme pressure and CaBeSi, in the framework of the density functional theory for superconductors, is discussed. A detailed analysis on how the electron-phonon and electron-electron interactions combine together to determine the superconducting gap and critical temperature of these systems is presented. Pb, H under pressure and CaBeSi are multigap superconductors. We will address the question under which conditions does a system exhibits this phenomenon. The presented results contribute to the understanding of multiband and anisotropic superconductivity, which has received a lot of attention since the discovery of MgB(2), and show how it is possible to describe the superconducting properties of real materials on a fully ab initio basis.

Air pollutants and daily number of admissions to psychiatric emergency services: evidence for detrimental mental health effects of ozone.

AIMS: Aim of the current study is to investigate the associations between daily levels of air pollutants (particulate matter, ozone, carbon monoxide, nitrogen dioxide) and daily admissions for mental disorders to the emergency department of two general hospitals in Umbria region (Italy). METHODS: We collected data about daily admissions to psychiatric emergency services of two general hospitals, air pollutants' levels and meteorological data for the time period 1 January 2015 until 31 December 2016. We assessed the impact of an increase in air pollutants on the number of daily admissions using a time-series econometric framework. RESULTS: A total of 1860 emergency department admissions for mental disorders were identified. We observed a statistically significant impact of ozone levels on daily admissions. The estimated coefficient of O3 is statistically significant at the 1% level. All other pollutants were not significantly associated with the number of daily admissions. CONCLUSIONS: Short-term exposure to ozone may be associated with increased psychiatric emergency services admissions. Findings add to previous literature on existing evidence for air pollution to have an impact on mental health. Ozone may be considered a potential environmental risk factor for impaired mental health.

Treatment decision-making capacity in non-consensual psychiatric treatment: a multicentre study.

AIMS: To evaluate treatment decision-making capacity (DMC) to consent to psychiatric treatment in involuntarily committed patients and to further investigate possible associations with clinical and socio-demographic characteristics of patients. METHODS: 131 involuntarily hospitalised patients were recruited in three university hospitals. Mental capacity to consent to treatment was measured with the MacArthur Competence Assessment Tool for Treatment (MacCAT-T); psychiatric symptoms severity (Brief Psychiatric Rating Scale, BPRS-E) and cognitive functioning (Mini Mental State Examination, MMSE) were also assessed. RESULTS: Mental capacity ratings for the 131 involuntarily hospitalised patients showed that patients affected by bipolar disorders (BD) scored generally better than those affected by schizophrenia spectrum disorders (SSD) in MacCAT-T appreciation (p < 0.05) and reasoning (p < 0.01). Positive symptoms were associated with poorer capacity to appreciate (r = -0.24; p < 0.01) and reason (r = -0.27; p < 0.01) about one's own treatment. Negative symptoms were associated with poorer understanding of treatment (r = -0.23; p < 0.01). Poorer cognitive functioning, as measured by MMSE, negatively affected MacCAT-T understanding in patients affected by SSD, but not in those affected by BD (SSD r = 0.37; p < 0.01; BD r = -0.01; p = 0.9). Poorer MacCAT-T reasoning was associated with more manic symptoms in the BD group of patients but not in the SSD group (BD r = -0.32; p < 0.05; SSD r = 0.03; p = 0.8). Twenty-two per cent (n = 29) of the 131 recruited patients showed high treatment DMC as defined by having scored higher than 75% of understanding, appreciating and reasoning MacCAT-T subscales maximum sores and 2 at expressing a choice. The remaining involuntarily hospitalised patients where considered to have low treatment DMC. Chi-squared disclosed that 32% of BD patients had high treatment DMC compared with 9% of SSD patients (p < 0.001). CONCLUSIONS: Treatment DMC can be routinely assessed in non-consensual psychiatric settings by the MacCAT-T, as is the case of other clinical variables. Such approach can lead to the identification of patients with high treatment DMC, thus drawing attention to possible dichotomy between legal and clinical status.

Analysis of the chaotic component of the sinusal R-R intervals as a tool for detecting a silent cardiac dysautonomia in type 2 diabetes mellitus.

This study explores the heart rate (HR) variability (V) in order to detect whether the chaotic component of the sinusal R-R intervals (SRRI) can be interpreted as an early indicator of a silent cardiac neurovegetative dysautonomia in apparently uncomplicated Type 2 diabetic patients (DP). The SRRI were provided by the 24-h Holter ECG of 10 Type 2 DP (5 M and 5 F, mean age = 41 +/- 5 years). Control data were obtained by the 24-h Holter ECG of 10 clinically healthy subjects (CHS, 5 M and 5 F, mean age = 38 +/- 6 years). The chaotic component of HRV was investigated via the correlation dimension (CD) analysis (A) of the SRRI, performed per each hour of the ECG recording. The hourly-qualified series of SRRI, HR and CD index (I) were, in turn, analyzed via methods of conventional statistics and chronobiology, the latter ones for assessing the circadian rhythm (CR). The CDI CR was found to peak during the night in CHS, and to be unphysiologically rotated to the diurnal hours of the day in Type 2 DP. The diurnal inversion of the CDI CR in Type 2 DP suggests that the chaotic component of HRV shows an abnormal rhythnic pattern over the day-night period. Considering that the investigated Type 2 DP were lacking of documentable signs of cardiac neuropathy, it is hypothesized that the diurnal phase of shift CDI CR might be a potential indicator of a silent autonomic cardiac dysfunction in Type 2 DP. Such a hypothesis waits for further confirmations.

The specificity of lysosomal tripeptidyl peptidase-I determined by its action on angiotensin-II analogues.

Tripeptidyl peptidase-I (TPP-I) is a lysosomal peptidase which cleaves tripeptides from the N-terminus of peptides. The function of the enzyme is unclear but its importance is demonstrated by the fact that mutations in TPP-I are responsible for late infantile neuronal ceroid lipofuscinosis, a lethal lysosomal storage disease. As a step towards identifying its natural substrates, we have used a series of synthetic peptides, based on angiotensin-II, to explore the effects of peptide chain length and the effects of amino acid substitutions at the P1 and P1' positions on the rate of catalysis. With the exception of angiotensin-(1-8) (angiotensin-II), which is a relatively poor substrate for TPP-I, the rate of catalysis increases with increasing chain length. K(cat)/K(m) values increase 50-fold between angiotensin-(1-5) and angiotensin-(1-14). TPP-I shows little specificity for the nature of the amino acids in the P1 and P1' positions, K(cat)/K(m) values varying only 5-fold for a range of substitutions. However, Pro or Lys in the P1 position and Pro in the P1' positions are incompatible with TPP-I activity. These observations suggest that TPP-I is a non-specific, but essential, peptidase involved in the latter stages of lysosomal protein degradation.

Estimation of fungal biomass and transcript levels in Tilia platyphyllos-Tuber borchii ectomycorrhizae.

Very little information is available to date about the complex truffle life cycle which involves the succession of three developmental phases. In order to gain more knowledge about ectomycorrhizal formation and fruit body development an ectomycorrhizal model system was used to study fungal biomass and plant and fungal transcript levels. They were evaluated in ectomycorrhizal development using the ergosterol assay and the internal transcribed spacer-5.8S ribosomal DNA from Tilia platyphyllos and Tuber borchii as molecular probes respectively. The results obtained from different approaches revealed a decrease in fungal biomass, transcript and protein levels during ectomycorrhizal development.

The substrate range of tripeptidyl-peptidase I.

Tripeptidyl-peptidase I (TPP-I) is an exopeptidase which removes tripeptides from the N-terminus of peptides. Mutations in TPP-I are responsible for late infantile neuronal ceroid lipofuscinosis (CLN2). The nature of the physiological substrates and the range and specificity of the enzyme are unclear. Previous experiments suggest that the enzyme can degrade small peptides but not proteins. Digestion of a range of peptides of different size by TTP-I suggests that the enzyme will degrade small peptides with an extended N-terminal domain but not structured peptides. In general, this cut-off occurs between masses of 4.5 kDa and 6 kDa. Reference to the structures of other peptidases suggests a mechanism for this size selectivity.

Hydrophobins in ectomycorrhizas: heterologous transcription of the Pisolithus HydPt-1 gene in yeast and Hebeloma cylindrosporum.

Hydrophobins are fungal cell wall proteins involved in aggregation of hyphae. Upon the development of the ectomycorrhizal symbiosis between tree roots and fungal hyphae, the transcripts of hydrophobin genes markedly accumulated. As the precise role of these proteins in symbiosis is not yet known, we develop heterologous expression system of the Pisolithus hydrophobin HYDPt-1. This gene has been introduced in Saccharomyces cerevisiae and in the ectomycorrhizal basidiomycete Hebeloma cylindrosporum. Introns were required for hydPt-1 transcript accumulation in the basidiomycete H. cylindrosporum. Heterologous transcript accumulation did not alter the phenotype of either species. The lack of altered phenotype resulted from the absence of HYDPt-1 polypeptide accumulation in transformed strains.

Haemodialysis in acute renal failure.

Haemodialysis in acute renal failure differs from chronic uraemia. We describe our clinical experience comparing tolerance to dialysis and dialysis efficacy of bicarbonate haemodialysis in comparison to haemofiltration. Both provide adequate treatment for ARF, Kt/v 0.6 +/- 0.1, URR 56% in bicarbonate haemodialysis compared to Kt/v 0.4 +/- 0.06, URR 60% in haemofiltration. Clinical outcome was the same in both groups, in particular the overall survival was satisfactory at about 70%. These results are likely to reflect close control of these patients by nursing staff committed to haemodialysis in acute renal failure.

The chaotic component of human heart rate variability shows a circadian periodicity as documented by the correlation dimension of the time-qualified sinusal R-R intervals.

OBJECTIVE: This study investigates the hypothesis that the nonlinear component of human heart rate (HR) variability might show a periodic structure over the 24-h span. Such a postulate could explain how the chaotic component might coexist with the deterministic periodic variability of instantaneous HR in beat per minute. MATERIALS AND METHODS: The sinusal R-R intervals (sRRi) of the Holter EKG of 10 clinically healthy subjects (5 M, 5 F, 23-30 years) were analyzed per each hour of the day-night span according to two methods for the nonlinear chaotic variability, i.e., the correlation dimension method, and the linear periodic variability, i.e., periodic regression analysis. RESULTS: The hourly-qualified correlation integrals were found to show a significant circadian rhythm, with an acrophase located during the night in coincidence with the longest duration of the sRRi and the lowest rate of cardiac pulse. CONCLUSIONS: The rhythmic structure of the chaotic component of the human HR variability let us to think that a deterministic periodic chaos of fractal type regulates the nonlinear cardiac dynamics. Such a periodic structure allows the chaos to be compatible with the deterministic linear periodicity of circadian type which characterizes the within-day variability of human HR.

A magnetic glassy phase in Fe(1+y)Se(x)Te(1-x) single crystals.

The evolution of magnetic order in Fe1+ySexTe1-x crystals as a function of Se content was investigated by means of ac/dc magnetometry and muon-spin spectroscopy. Experimental results and self-consistent density functional theory calculations both indicate that muons are implanted in vacant iron-excess sites, where they probe a local field mainly of dipolar origin, resulting from an antiferromagnetic (AFM) bicollinear arrangement of iron spins. This long-range AFM phase becomes progressively disordered with increasing Se content. At the same time all the tested samples manifest a marked glassy character that vanishes for high Se contents. The presence of local electronic/compositional inhomogeneities most likely favours the growth of clusters whose magnetic moment 'freezes' at low temperature. This glassy magnetic phase justifies both the coherent muon precession seen at short times in the asymmetry data, as well as the glassy behaviour evidenced by both dc and ac magnetometry.

Effect of magnetic impurities in a two-band superconductor: a point-contact study of mn-substituted single crystals.

We present the first results of directional point-contact measurements in Mg1-xMnxB2 single crystals, with x up to 0.015 and bulk Tc down to 13.3 K. The order parameters Deltasigma and Deltapi were obtained by fitting the conductance curves with the two-band Blonder-Tinkham-Klapwijk model. BothDeltapi and Deltasigma decrease with the critical temperature of the junctions TAC, but remain clearly distinct up to the highest Mn content. Once analyzed within the Eliashberg theory, the results indicate that spin-flip scattering is dominant in the sigma band, as also confirmed by first-principles band-structure calculations.