Anxiety-like behavior and anxiolytic treatment in the Rett syndrome natural history study

BACKGROUND: Rett syndrome (RTT) is a neurodevelopmental disorder most often related to a pathogenic variant in the X-linked MECP2 gene. Internalizing behaviors appear to be common, but standard methods of diagnosing anxiety are not readily applied in this population which typically has cognitive impairment and limited expressive language. This study aims to describe the frequency of anxiety-like behavior and anxiolytic treatments along with associated clinical features in individuals with RTT. METHODS: Parental reports and medication logs provided data from 1380 females with RTT participating in two iterations of the multicenter U.S. RTT Natural History Study (RNHS) from 2006 to 2019. RESULTS: Most participants with RTT (77.5%) had at least occasional anxious or nervous behavior. Anxiety was reported to be the most troublesome concern for 2.6%, and within the top 3 concerns for 10.0%, of participants in the second iteration. Parents directly reported treatment for anxious or nervous behavior in 16.6% of participants in the second iteration with most reporting good control of the behavior (71.6%). In the medication logs of both RNHS iterations, the indication of anxiety was listed for a similar number of participants (15% and 14.5%, respectively). Increased use of anxiolytics and selective serotonin reuptake inhibitors (SSRIs) was related to more frequent anxiety-like behaviors (P \u3c 0.001), older age (P \u3c 0.001), and mild MECP2 variants (P = 0.002). CONCLUSION: Anxiety-like behavior is frequent at all ages and is a significant parental concern in RTT. Older individuals and those with mild MECP2 variants are more likely to be treated with medications. Better diagnosis and treatment of anxiety in RTT should be a goal of both future studies and clinical care. TRIAL REGISTRATION: NCT00299312 and NCT02738281

Preparation and Preliminary Dielectric Characterization of Structured C\u3csub\u3e60\u3c/sub\u3e-Thiol-Ene Polymer Nanocomposites Assembled Using the Thiol-Ene Click Reaction

Fullerene-containing materials have the ability to store and release electrical energy. Therefore, fullerenes may ultimately find use in high-voltage equipment devices or as super capacitors for high electric energy storage due to this ease of manipulating their excellent dielectric properties and their high volume resistivity. A series of structured fullerene (C60) polymer nanocomposites were assembled using the thiol-ene click reaction, between alkyl thiols and allyl functionalized C60 derivatives. The resulting high-density C60-urethane-thiol-ene (C60-Thiol-Ene) networks possessed excellent mechanical properties. These novel networks were characterized using standard techniques, including infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), dynamic mechanical analysis (DMA), and thermal gravimetric analysis (TGA). The dielectric spectra for the prepared samples were determined over a broad frequency range at room temperature using a broadband dielectric spectrometer and a semiconductor characterization system. The changes in thermo-mechanical and electrical properties of these novel fullerene-thiol-ene composite films were measured as a function of the C60 content, and samples characterized by high dielectric permittivity and low dielectric loss were produced. In this process, variations in chemical composition of the networks were correlated to performance characteristics

Quantitative planar and volumetric cardiac measurements using 64 mdct and 3t mri vs. Standard 2d and m-mode echocardiography: does anesthetic protocol matter?

Cross‐sectional imaging of the heart utilizing computed tomography and magnetic resonance imaging (MRI) has been shown to be superior for the evaluation of cardiac morphology and systolic function in humans compared to echocardiography. The purpose of this prospective study was to test the effects of two different anesthetic protocols on cardiac measurements in 10 healthy beagle dogs using 64‐multidetector row computed tomographic angiography (64‐MDCTA), 3T magnetic resonance (MRI) and standard awake echocardiography. Both anesthetic protocols used propofol for induction and isoflourane for anesthetic maintenance. In addition, protocol A used midazolam/fentanyl and protocol B used dexmedetomedine as premedication and constant rate infusion during the procedure. Significant elevations in systolic and mean blood pressure were present when using protocol B. There was overall good agreement between the variables of cardiac size and systolic function generated from the MDCTA and MRI exams and no significant difference was found when comparing the variables acquired using either anesthetic protocol within each modality. Systolic function variables generated using 64‐MDCTA and 3T MRI were only able to predict the left ventricular end diastolic volume as measured during awake echocardiogram when using protocol B and 64‐MDCTA. For all other systolic function variables, prediction of awake echocardiographic results was not possible (P = 1). Planar variables acquired using MDCTA or MRI did not allow prediction of the corresponding measurements generated using echocardiography in the awake patients (P = 1). Future studies are needed to validate this approach in a more varied population and clinically affected dogs

SRSS: A New Chaos-Based Single-Round Single S-Box Image Encryption Scheme for Highly Auto-Correlated Data

With the advent of digital communication, securing digital images during transmission and storage has become a critical concern. The traditional s-box substitution methods often fail to effectively conceal the information within highly auto-correlated regions of an image. This paper addresses the security issues presented by three prevalent S-box substitution methods, i.e., single S-box, multiple S-boxes, and multiple rounds with multiple S-boxes, especially when handling images with highly auto-correlated pixels. To resolve the addressed security issues, this paper proposes a new scheme SRSS-the Single Round Single S-Box encryption scheme. SRSS uses a single S-box for substitution in just one round to break the pixel correlations and encrypt the plaintext image effectively. Additionally, this paper introduces a new Chaos-based Random Operation Selection System-CROSS, which nullifies the requirement for multiple S-boxes, thus reducing the encryption scheme's complexity. By randomly selecting the operation to be performed on each pixel, driven by a chaotic sequence, the proposed scheme effectively scrambles even high auto-correlation areas. When compared to the substitution methods mentioned above, the proposed encryption scheme exhibited exceptionally well in just a single round with a single S-box. The close-to-ideal statistical security analysis results, i.e., an entropy of 7.89 and a correlation coefficient of 0.007, validate the effectiveness of the proposed scheme. This research offers an innovative path forward for securing images in applications requiring low computational complexity and fast encryption and decryption speeds.Comment: 6 Page

Physiological levels of lipoxin A4 inhibit ENaC and restore airway surface liquid height in cystic fibrosis bronchial epithelium.

In cystic fibrosis (CF), the airway surface liquid (ASL) is depleted. We previously demonstrated that lipoxin A4 (LXA4) can modulate ASL height (ASLh) through actions on Cl(-) transport. Here, we report novel effects of lipoxin on the epithelial Na(+) channel ENaC in this response. ASL dynamics and ion transport were studied using live-cell confocal microscopy and short-circuit current measurements in CF (CuFi-1) and non-CF (NuLi-1) cell cultures. Low physiological concentrations of LXA4 in the picomolar range produced an increase in ASLh which was dependent on inhibition of an amiloride-sensitive Na(+) current and stimulation of a bumetanide-sensitive Cl(-) current. These ion transport and ASLh responses to LXA4 were blocked by Boc-2 an inhibitor of the specific LXA4 receptor ALX/FPR2. LXA4 affected the subcellular localization of its receptor and enhanced the localization of ALX/FPR2 at the apical membrane of CF cells. Our results provide evidence for a novel effect of low physiological concentrations of LXA4 to inhibit airway epithelial Na(+) absorption that results in an ASL height increase in CF airway epithelia

Episode-like pulse testosterone supplementation induces tumor senescence and growth arrest down-modulating androgen receptor through modulation of p-ERK1/2, pAR ser81 and CDK1 signaling: biological implications for men treated with testosterone replacement therapy

Despite the growing body of knowledge showing that testosterone (T) may not significantly affect tumor progression in hypogonadal patients treated for prostate cancer (Pca), the use of this hormone in this population still remains controversial. The effects of continuous or pulsed T stimulation were tested in vitro and in vivo on androgen-sensitive Pca cell lines in order to assess the differential biological properties of these two treatment modalities. Pulsed T treatment resulted in a greater inhibition than continuous T supplementation of tumor growth in vitro and in vivo. The effects of pulsed T treatment on tumor growth inhibition, G0/G1 cell cycle arrest, and tumor senescence was more pronounced than those obtained upon continuous T treatments. Mechanistic studies revealed that G0/G1 arrest and tumor senescence upon pulsed T treatment were associated with a marked decrease in cyclin D1, c-Myc and SKp2, CDK4 and p-Rb levels and upregulation of p27 and p-ERK1/2. Pulsed, but not continuous, T supplementation decreased the expression levels of AR, p-AR ser81 and CDK1 in both cellular models. The in vitro results were confirmed in an in vivo xenografts, providing evidence of a greater inhibitory activity of pulsed supraphysiological T supplementation than continuous treatment, both in terms of tumor volume and decreased AR, p-AR ser81 , PSA and CDK1 staining. The rapid cycling from hypogonadal to physiological or supra-physiological T intraprostatic concentrations results in cytostatic and senescence effects in preclinical models of androgen-sensitive Pca. Our preclinical evidence provides relevant new insights in the biology of Pca response to pulsed T supplementation

Antidepressant Controlled Trial For Negative Symptoms In Schizophrenia (ACTIONS): a double-blind, placebo-controlled, randomised clinical trial

Background Negative symptoms of schizophrenia represent deficiencies in emotional responsiveness, motivation, socialisation, speech and movement. When persistent, they are held to account for much of the poor functional outcomes associated with schizophrenia. There are currently no approved pharmacological treatments. While the available evidence suggests that a combination of antipsychotic and antidepressant medication may be effective in treating negative symptoms, it is too limited to allow any firm conclusions. Objective To establish the clinical effectiveness and cost-effectiveness of augmentation of antipsychotic medication with the antidepressant citalopram for the management of negative symptoms in schizophrenia. Design A multicentre, double-blind, individually randomised, placebo-controlled trial with 12-month follow-up Setting Adult psychiatric services, treating people with schizophrenia. Participants Inpatients or outpatients with schizophrenia, on continuing, stable antipsychotic medication, with persistent negative symptoms at a criterion level of severity. Interventions Eligible participants were randomised 1 : 1 to treatment with either placebo (one capsule) or 20 mg of citalopram per day for 48 weeks, with the clinical option at 4 weeks to increase the daily dosage to 40 mg of citalopram or two placebo capsules for the remainder of the study. Main Outcome Measures The primary outcomes were quality of life measured at 12 and 48 weeks assessed using the Heinrich’s Quality of Life Scale, and negative symptoms at 12 weeks measured on the negative symptom subscale of the Positive and Negative Syndrome Scale. Results No therapeutic benefit in terms of improvement in quality of life or negative symptoms was detected for citalopram over 12 weeks or at 48 weeks, but secondary analysis suggested modest improvement in the negative symptom domain, avolition/amotivation, at 12 weeks (mean difference –1.3, 95% confidence interval–2.5 to–0.09). There were no statistically significant differences between the two treatment arms over 48-week follow-up in either the health economics outcomes or costs, and no differences in the frequency or severity of adverse effects, including corrected QT interval prolongation. Limitations The trial under-recruited, partly because cardiac safety concerns about citalopram were raised, with the 62 participants recruited falling well short of the target recruitment of 358. Although this was the largest sample randomised to citalopram in a randomised controlled trial of antidepressant augmentation for negative symptoms of schizophrenia and had the longest follow-up, the power of statistical analysis to detect significant differences between the active and placebo groups was limited. Conclusion Although adjunctive citalopram did not improve negative symptoms overall, there was evidence of some positive effect on avolition/amotivation, recognised as a critical barrier to psychosocial rehabilitation and achieving better social and community functional outcomes. Comprehensive assessment of side-effect burden did not identify any serious safety or tolerability issues. The addition of citalopram as a long-term prescribing strategy for the treatment of negative symptoms may merit further investigation in larger studies. Future Work Further studies of the viability of adjunctive antidepressant treatment for negative symptoms in schizophrenia should include appropriate safety monitoring and use rating scales that allow for evaluation of avolition/amotivation as a discrete negative symptom domain. Overcoming the barriers to recruiting an adequate sample size will remain a challenge.</p

Dentists' use of validated child dental anxiety measures in clinical practice: a mixed methods study

Background: Assessing anxiety is an important part of the assessment of a child presenting for dental treatment; however, the use of dental anxiety scales in practice is not well-documented. Aims: To introduce child dental anxiety scales, and to monitor the extent to which dentists used them; to explore the experience and views of dentists regarding anxiety assessment. Design: A mixed-methods design was employed. Method: A protocol for child anxiety assessment was introduced to paediatric dentists in Eastman Dental Hospital. After 6 months, 100 patient files were audited to examine compliance with the protocol. Fourteen dentists were interviewed to explore their experience and views regarding anxiety assessment. Results: Only five patients were assessed using the scales. Thematic analysis of the dentist interviews revealed three themes: ‘Clinical observations and experience: The gold standard’; ‘Scales as an estimate or adjunct’; and ‘Shortcomings and barriers to using scales’. Conclusions: The dentists in our study did not use anxiety scales, instead they rely on their own experience/judgement. Therefore, scales should be recommended as an adjunct to judgement. Brief scales are recommended as clinicians lack time and expertise in administering anxiety questionnaires. Advantages of using scales and hands-on experience could be incorporated more in undergraduate training

Tracking and re-finding printed material using a personal digital library

Most web searches aim to re-find previously known information or documents. Keeping track of one’s digital and printed reading material is known to be a challenging and costly task. We describe the design, implementation and evaluation of our Human-centred workplace (HCW) – a system that supports the tracking of physical document printouts. HCW embeds QR codes in the document printout, stores the documents in a personal Digital Library, and uses cameras in the office to track changes in the document locations. We explored the HCW in three evaluations, using the system over several weeks in an office setting, a user study in a lab environment, and extensive functional tests