Semaphorin-plexin signaling: From axonal guidance to a new X-linked intellectual disability syndrome

BACKGROUND: Semaphorins and plexins are ligands and cell surface receptors that regulate multiple neurodevelopmental processes such as axonal growth and guidance. PLXNA3 is a plexin gene located on the X chromosome that encodes the most widely expressed plexin receptor in fetal brain, plexin-A3. Plexin-A3 knockout mice demonstrate its role in semaphorin signaling in vivo. The clinical manifestations of semaphorin/plexin neurodevelopmental disorders have been less widely explored. This study describes the neurological and neurodevelopmental phenotypes of boys with maternally inherited hemizygous PLXNA3 variants. METHODS: Data-sharing through GeneDx and GeneMatcher allowed identification of individuals with autism or intellectual disabilities (autism/ID) and hemizygous PLXNA3 variants in collaboration with their physicians and genetic counselors, who completed questionnaires about their patients. In silico analyses predicted pathogenicity for each PLXNA3 variant. RESULTS: We assessed 14 boys (mean age, 10.7 [range 2 to 25] years) with maternally inherited hemizygous PLXNA3 variants and autism/ID ranging from mild to severe. Other findings included fine motor dyspraxia (92%), attention-deficit/hyperactivity traits, and aggressive behaviors (63%). Six patients (43%) had seizures. Thirteen boys (93%) with PLXNA3 variants showed novel or very low allele frequencies and probable damaging/disease-causing pathogenicity in one or more predictors. We found a genotype-phenotype correlation between PLXNA3 cytoplasmic domain variants (exons 22 to 32) and more severe neurodevelopmental disorder phenotypes (P \u3c 0.05). CONCLUSIONS: We report 14 boys with maternally inherited, hemizygous PLXNA3 variants and a range of neurodevelopmental disorders suggesting a novel X-linked intellectual disability syndrome. Greater understanding of PLXNA3 variant pathogenicity in humans will require additional clinical, computational, and experimental validation

A psychometric evaluation of the Female Sexual Function Index in women treated for breast cancer.

BACKGROUND: We aimed to determine the psychometric properties and factor structure of the 19-item Female Sexual Function Index (FSFI) in 132 sexually active women previously treated for breast cancer. METHODS: Confirmatory factor analysis explored three models: (a) second-order six-factor, (b) six-factor, and (c) five-factor models combining the desire and arousal subscales. RESULTS: Results revealed excellent reliability for the total score (Cronbach's α = 0.94), and domain scores (all Cronbach's αs > 0.90), and good convergent and discriminant validity. The six-factor model provided the best fit of the models assessed, but a marginal overall fit (Tucker-Lewis index = 0.91, comparative fit index = 0.93, root mean square error of approximation = 0.09). Exploratory factor analyses (EFA) supported a four-factor structure, revealing an arousal/orgasm factor alongside the original pain, lubrication, and satisfaction domains. CONCLUSION: The arousal/orgasm factor suggests a "sexual response" construct, potentially arising from an underlying latent factor involving physical and mental stimulation in conceptualizations of arousal and orgasm in women treated for breast cancer. Finally, the EFA failed to capture an underlying desire factor, potentially due to measurement error associated with the small number of items (two) in this domain. Despite evidence that the FSFI has sound psychometric properties, our results suggest that the current conceptualizations of the FSFI might not accurately represent sexual functioning in women previously treated for breast cancer. Further research is required to elucidate the factors that influence desire, arousal, and orgasm in sexually active women in this population, and the reasons underlying sexual inactivity. Practical and theoretical implications for FSFI use in this population are discussed

Classifying Periodic Astrophysical Phenomena from non-survey optimized variable-cadence observational data

Modern time-domain astronomy is capable of collecting a staggeringly large amount of data on millions of objects in real time. Therefore, the production of methods and systems for the automated classification of time-domain astronomical objects is of great importance. The Liverpool Telescope has a number of wide-field image gathering instruments mounted upon its structure, the Small Telescopes Installed at the Liverpool Telescope. These instruments have been in operation since March 2009 gathering data of large areas of sky around the current field of view of the main telescope generating a large dataset containing millions of light sources. The instruments are inexpensive to run as they do not require a separate telescope to operate but this style of surveying the sky introduces structured artifacts into our data due to the variable cadence at which sky fields are resampled. These artifacts can make light sources appear variable and must be addressed in any processing method. The data from large sky surveys can lead to the discovery of interesting new variable objects. Efficient software and analysis tools are required to rapidly determine which potentially variable objects are worthy of further telescope time. Machine learning offers a solution to the quick detection of variability by characterising the detected signals relative to previously seen exemplars. In this paper, we introduce a processing system designed for use with the Liverpool Telescope identifying potentially interesting objects through the application of a novel representation learning approach to data collected automatically from the wide-field instruments. Our method automatically produces a set of classification features by applying Principal Component Analysis on set of variable light curves using a piecewise polynomial fitted via a genetic algorithm applied to the epoch-folded data. The epoch-folding requires the selection of a candidate period for variable light curves identified using a genetic algorithm period estimation method specifically developed for this dataset. A Random Forest classifier is then used to classify the learned features to determine if a light curve is generated by an object of interest. This system allows for the telescope to automatically identify new targets through passive observations which do not affect day-to-day operations as the unique artifacts resulting from such a survey method are incorporated into the methods. We demonstrate the power of this feature extraction method compared to feature engineering performed by previous studies by training classification models on 859 light curves of 12 known variable star classes from our dataset. We show that our new features produce a model with a superior mean cross-validation F1 score of 0.4729 with a standard deviation of 0.0931 compared with the engineered features at 0.3902 with a standard deviation of 0.0619. We show that the features extracted from the representation learning are given relatively high importance in the final classification model. Additionally, we compare engineered features computed on the interpolated polynomial fits and show that they produce more reliable distributions than those fit to the raw light curve when the period estimation is correct

Improving health-related quality of life in women with breast, blood, and gynaecological Cancer with an eHealth-enabled 12-week lifestyle intervention: the women's wellness after Cancer program randomised controlled trial.

BACKGROUND: The residual effects of cancer and its treatment can profoundly affect women's quality of life. This paper presents results from a multisite randomized controlled trial that evaluated the clinical benefits of an e-health enabled health promotion intervention (the Women's Wellness after Cancer Program or WWACP) on the health-related quality of life of women recovering from cancer treatment. METHODS: Overall, 351 women previously treated for breast, blood or gynaecological cancers were randomly allocated to the intervention (WWACP) or usual care arms. The WWACP comprised a structured 12-week program that included online coaching and an interactive iBook that targeted physical activity, healthy diet, stress and menopause management, sexual wellbeing, smoking cessation, alcohol intake and sleep hygiene. Data were collected via a self-completed electronic survey at baseline (t0), 12 weeks (post-intervention, t1) and 24 weeks (to assess sustained behaviour change, t2). The primary outcome, health-related quality of life (HRQoL), was measured using the Short Form Health Survey (SF-36). RESULTS: Following the 12-week lifestyle program, intervention group participants reported statistically significant improvements in general health, bodily pain, vitality, and global physical and mental health scores. Improvements were also noted in the control group across several HRQoL domains, though the magnitude of change was less. CONCLUSIONS: The WWACP was associated with improved HRQoL in women previously treated for blood, breast, and gynaecological cancers. Given how the synergy of different lifestyle factors influence health behaviour, interventions accounting for the reciprocity of multiple health behaviours like the WWACP, have real potential for immediate and sustainable change. TRIAL REGISTRATION: The protocol for this randomised controlled trial was submitted to the Australian and New Zealand Clinical Trials Registry on 15/07/2014 and approved on 28/07/2014 ( ACTRN12614000800628 )

Cause of Death, Mortality and Occult Blood in Colorectal Cancer Screening

SIMPLE SUMMARY: Colorectal cancer (CRC) screening participants with significant traces of hemoglobin in their stool have been reported to have higher mortality and different causes of death (other than CRC) compared to those without. We aimed to investigate these differences among screening participants after 33 years of follow-up. We confirmed that participants with detectable fecal hemoglobin were more likely to die in the study period and to die from different causes, such as cardiovascular and endocrine and hematological diseases, compared to those without detectable fecal hemoglobin. This confirms that fecal hemoglobin may have potential as a marker for diseases not directly related to the colon and rectum and may represent a target for future preventive measures. ABSTRACT: Fecal hemoglobin (f-Hb) detected by the guaiac fecal occult blood test (gFOBT) may be associated with mortality and cause of death in colorectal cancer (CRC) screening participants. We investigated this association in a randomly selected population of 20,694 participants followed for 33 years. We followed participants from the start of the Hemoccult-II CRC trial in 1985–1986 until December 2018. Data on mortality, cause of death and covariates were retrieved using Danish national registers. We conducted multivariable Cox regressions with time-varying exposure, reporting results as crude and adjusted hazard ratios (aHRs). We identified 1766 patients with at least one positive gFOBT, 946 of whom died in the study period. Most gFOBT-positive participants (93.23%) died of diseases unrelated to CRC and showed higher non-CRC mortality than gFOBT-negative participants (aHR: 1.20, 95% CI 1.10–1.30). Positive gFOBT participants displayed a modest increase in all-cause (aHR: 1.28, 95% CI: 1.18–1.38), CRC (aHR: 4.07, 95% CI: 3.00–5.56), cardiovascular (aHR: 1.22, 95% CI: 1.07–1.39) and endocrine and hematological mortality (aHR: 1.58, 95% CI: 1.19–2.10). In conclusion, we observed an association between positive gFOBT, cause of death and mortality. The presence of f-Hb in the gFOBT might indicate the presence of systemic diseases

Grip strength and pen pressure are not key contributors to handwriting difficulties in children with Developmental Coordination Disorder

Copyright © The Author(s) 2020. Introduction Children with developmental coordination disorder have significant difficulties with handwriting. Factors such as hand grip strength and pen pressure are often assumed by clinicians to play a role, although empirical evidence is lacking. The aim of this study was to measure grip strength and pen pressure to examine their relationships with handwriting performance in children with developmental coordination disorder. Method Sixteen 8–14-year-old children with developmental coordination disorder were compared with 20 typically developing age- and gender-matched controls. Palmar, pinch and tripod grip strength were measured using hand dynamometers. The mean pressure exerted on a writing tablet by the pen was obtained during a handwriting task. Group comparisons were made and correlations conducted between grip strength and pen pressure and a range of handwriting product and process measures. Results There were no group differences on the three measures of grip strength. However, the developmental coordination disorder group exerted less pressure on the writing surface compared to typically developing peers. There were no significant correlations between grip strength or pen pressure and handwriting performance in children with developmental coordination disorder. Conclusion Clinicians should be cautious when using measures of grip strength or pen pressure to inform them about aspects of handwriting skill in children with developmental coordination disorder.UK Occupational Therapy Research Foundation (UKOTRF) Research Development Grant (2016)

Carbon Monoxide Effects on Electrophysiological Mechanisms of Ventricular Arrhythmogenesis

Increased dissolved carbon monoxide decreases ICa,L IK1 and IKr, and increases late INa currents in rat and guinea pig patch-clamped isolated ventricular myocytes. Action potentials are prolonged. These effects are reproduced by scaling the currents in the Gattoni et al., 2016 (rat) and Luo and Rudy, 1994 (guinea-pig) cell models. Using the same scaling of currents in the O’Hara-Rudy (2011) models the endo-, mid-myo- and epi-cardial APD90 is prolonged. CO abolishes alternans in endo-, and induces alternans in mid-myo -cardial cell models at cycle lengths < 280ms. In the homogenous human ventricular tissue models these CO effects decrease epi-, endocardial conduction velocities from 0.4 to 0.32m/s, and increase the widths of the vulnerable windows by +9%, +8% . In the ventricular wall model (a third each of endo-, mid-myo- and epicardial) CO increased transmural propagation times from 44 to 55 ms and maximal difference in propagating APD from 68 to 73 ms. The computed effects of CO on human ventricular tissue are pro-arrhythmogenic