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Fatigue seems deeply associated with Autism Spectrum Disorders (ASD) as reflected by the preferred terms ‘autistic fatigue’ and ‘autistic burnout’. In ASD there is also a greater prevalence of sens...

Purpose Chronic obstructive pulmonary disease (COPD) limits respiration, which may negatively impact airway safety during swallowing. It is unknown how differences in lung volume in COPD may alter swallowing physiology. This exploratory study aimed to determine how changes in lung volume impact swallow duration and coordination in persons with stable state COPD compared with older healthy volunteers (OHVs). Method Volunteers ≥ 45 years with COPD (VwCOPDs; n = 9) and OHVs ( n = 10) were prospectively recruited. Group and within-participant differences were examined when swallowing at different respiratory volumes: resting expiratory level (REL), tidal volume (TV), and total lung capacity (TLC). Participants swallowed self-administered 20-ml water boluses by medicine cup. Noncued (NC) water swallows were followed by randomly ordered block swallowing trials at three lung volumes. Estimated lung volume (ELV) and respiratory–swallow patterning were quantified using spirometry and respiratory inductive plethysmography. Manometry measured pharyngeal swallow duration from onset of base of tongue pressure increase to offset of negative pressure in the pharyngoesophageal segment. Results During NC swallows, the VwCOPDs swallowed at lower lung volumes than OHVs ( p = .011) and VwCOPDs tended to inspire after swallows more often than OHVs. Pharyngeal swallow duration did not differ between groups; however, swallow duration significantly decreased as the ELV increased in VwCOPDs ( p = .003). During ELV manipulation, the COPD group inspired after swallowing more frequently at REL than at TLC ( p = .001) and at TV ( p = .002). In conclusion, increasing respiratory lung volume in COPD should improve safety by reducing the frequency of inspiration after a swallow.

Whilst attendance in mainstream school helps encourage inclusivity, these environments are recognised as being particularly challenging for young people with an autism spectrum disorder (ASD). The ...

Very little is known about the use of nutritional supplements in children with Tourette syndrome. The current study aimed to address the frequency of nutritional supplements and the use of special diets in children with Tourette syndrome and typically developing children. Additional data also sought to address the motivations behind using them, their cost and perceived benefits. A total of 76 responses from an anonymous online survey (Tourette syndrome = 42; typically developing = 34) were completed and analyzed. Fifty-six per cent of children with Tourette syndrome compared to 15% of typically developing children were currently taking nutritional supplements, with the majority take two or more. Thirty-five per cent of the Tourette syndrome compared to 6% typically developing were currently or had previously adopted a special diet. Supplements most used for children with TS included probiotics, omega-3, multivitamins and magnesium. For children with TS, supplementation often began around the age of eight, for a duration on average of 35 months. The average cost was £32.44 a month compared to £8.25 for typically developing children. Seventy-five per cent of supplement users in the Tourette syndrome group noted improvement, mainly in motor and vocal tics, sleep quality and anxiety reduction. Most caregivers learned of supplements through the Internet. In almost 42% of the Tourette syndrome group, their pediatrician was unaware of the supplement use and this rose to 65% for special diets. Given the popularity of nutritional supplements, more research on the effectiveness and safety of such interventions is crucial.

Cryptorchidism causes spermatogenic failure and reduced serum androgen levels, as well as testicular oedema and fibrosis, which are hallmarks of inflammation. However, the role of inflammation and the effects of cryptorchidism on Sertoli cell and Leydig cell function at the molecular level remain ill-defined. Bilateral cryptorchidism was surgically induced in adult rats for 7 and 14 weeks. Testis weights decreased to 40% of normal within 7 weeks, due to loss of all developing spermatogenic cells except spermatogonia, but did not decrease further at 14 weeks. Serum FSH and LH were increased at both time points, consistent with a loss of feedback by inhibin and testosterone. This damage was accompanied by progressive accumulation of interstitial fluid and peritubular fibrosis, and a progressive decline of several critical Sertoli cell genes (Sox9, Inha (inhbin α-subunit), Cldn11 (claudin 11), Gja1 (connexin 43), and Il1a (interleukin-1α)) and the Leydig cell steroidogenic enzymes, Cyp11a1, Hsd3b1, and Hs17b3. Activin B and the activin-binding protein, follistatin, also declined, but the intratesticular concentration of activin A, which is a regulator of inflammatory responses, was largely unaffected at either time point. Expression of genes involved in inflammation (Tnf, Il10, Il1b, Mcp1) and fibrosis (Acta2, Col1a1) were considerably elevated at both time points. These data indicate that induction of experimental cryptorchidism, which causes complete failure of spermatogenesis in the adult rat, also induces chronic testicular inflammation, manifesting in oedema and fibrosis, and a progressive decline of Sertoli and Leydig cell gene expression and function.

Introduction Dry needling of the periscapular musculature is a procedure commonly performed by physical therapists. Needling of the deep musculature may be challenging, and use of a thoracic rib as a “backstop” is often applied to prevent inadvertent puncture of the pleura. The aim of this study was to: 1) To examine the accuracy rate of experienced physical therapists in identifying a mid-scapular thoracic rib using palpation, 2) to understand patient characteristics that affect the accuracy rate, and 3) to examine if therapist confidence levels were associated with palpatory accuracy. Methods Two experienced physical therapists attempted to palpate a thoracic rib in the mid-scapular region of healthy participants (n = 101 subjects, 202 ribs), and self-reported their level of confidence in an accurate palpation. Their accuracy was verified with ultrasonography. Results The two physical therapists were accurate on 73.3% of palpations and did not differ in accuracy (72.0% vs. 75.0%, p = 0.747). The only ultrasonographic or subject characteristic measurement that correlated with improved accuracy was a reduced muscle thickness (p = 0.032). Therapists’ self-reported confidence levels did not correlate to actual accuracy (p = 0.153). Discussion Physical therapists should be aware that palpation of a thoracic rib may not be as accurate as it may seem. The greater thickness of muscle in the area reduces the accuracy of accurate palpation. Conclusion Dry needling of the periscapular muscles should be done with caution if using a rib as a “blocking” technique.

Cancer therapy related cardiac dysfunction (CTRCD) is an area of increasing focus, particularly during the survivorship period, for paediatric, adolescent and adult cancer survivors. With the advent of immunotherapy and targeted therapy, there is a new set of mechanisms from which paediatric and young adult patients with cancer may suffer cardiovascular injury. Furthermore, cardiovascular disease is the leading cause of morbidity and mortality in the survivorship period. The recently established Australian Cardio-Oncology Registry is the largest and only population-based cardiotoxicity database of paediatric and adolescent and young adult oncology patients in the world, and the first paediatric registry that will document cardiotoxicity caused by chemotherapy and novel targeted therapies using a prospective approach. The database is designed for comprehensive data collection and evaluation of the Australian practice in terms of diagnosis and management of CTRCD. Using the Australian Cardio-Oncology Registry critical clinical information will be collected regarding predisposing factors for the development of CTRCD, the rate of subclinical left ventricular dysfunction and transition to overt heart failure, further research into protectant molecules against cardiac dysfunction and aid in the discovery of which genetic variants predispose to CTRCD. A health economic arm of the study will assess the cost/benefit of both the registry and cardio-oncology clinical implementation. Finally, an imaging arm will establish if exercise cardiac magnetic resonance imaging and VO2 max testing is a more sensitive predictor of cardiac reserve in paediatric and adolescent and young adult oncology patients exposed to cardiac toxic therapies.

Study Objective The aim of this study was to validate temporally and externally the ultrasound-based endometriosis staging system (UBESS) to predict the level of complexity of laparoscopic surgery for endometriosis. Design A multicenter, international, retrospective, diagnostic accuracy study was carried out between January 2016 and April 2018 on women with suspected pelvic endometriosis. Setting Four different centers with advanced ultrasound and laparoscopic services were recruited (1 for temporal validation and 3 for external validation). Patients Women with pelvic pain and suspected endometriosis. Interventions All women underwent a systematic transvaginal ultrasound and were staged according to the UBESS system, followed by classification of laparoscopic level of complexity according to the Royal College of Obstetricians and Gynaecologists (RCOG) levels 1 to 3. Measurements and Main Results UBESS I, II, and III were then correlated with RCOG levels 1, 2, and 3, respectively. A comparison between temporal and external sites (skipping “A”) and between each site was performed in terms of the diagnostic accuracy of UBESS to predict RCOG laparoscopic skill level. A total of 317 consecutive women who underwent laparoscopy with suspected endometriosis were included. Complete transvaginal ultrasound and laparoscopic surgical outcomes were available for 293/317 (92.4%). At the temporal site, the accuracy, sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio of UBESS I to predict RCOG level 1 were 80.0%,73.8%, 94.9%, 97.2%, 60.2%, 14.5%, and 0.3%, respectively; of UBESS II to predict RCOG level 2 were 81.0%, 70.6%, 82.0%, 26.7%, 96.8%, 3.9%, and 0.3%, respectively; of UBESS III to predict RCOG level 3 were 91.0%, 85.7%, 92.4%, 75.0%, 96.1%, 11.3%, and 0.2%, respectively. At the external sites, the results of UBESS I to predict RCOG level 1 were 90.3%, 92.0%, 88.4%, 90.2%, 90.5%, 7.9%, and 0.1% respectively; UBESS II to predict RCOG level 2 were 89.2%, 100.0%, 88.5%, 37.5%, 100.0%, 8.7%, and 0.0%, respectively; and UBESS III to predict RCOG level 3 were 86.0%, 67.6%, 98.2%, 96.2%, 82.1%, 37.8%, and 0.3%, respectively. When patients requiring ureterolysis (i.e., RCOG level 3) in the absence of bowel endometriosis were excluded (n = 54), the sensitivity of UBESS III to correctly classify RCOG level 3 increased from 85.7% to 96.7% at the temporal site (n = 42) and from 67.6% to 96.0% at the external sites (n = 12) (p Conclusion The results from this external validation study suggest that UBESS in its current form is not generalizable unless there is either or both bowel deep endometriosis and cul-de-sac obliteration present. The major limitation appears to be the misclassification of women who require surgical ureterolysis in the absence of bowel endometriosis.

Diamond-Blackfan anemia (DBA) is a rare bone marrow failure syndrome usually caused by heterozygous variants in ribosomal proteins (RP) and which leads to severe anemia. Genetic studies in DBA rely primarily on multigene panels that often result in variants of unknown significance. Our objective was to optimize polysome profiling to functionally validate new large subunit RP variants. We determined the optimal experimental conditions for B-cell polysome profiles then performed this analysis on 2 children with DBA and novel missense RPL5 (uL18) and RPL26 (uL24) variants of unknown significance. Both patients had reduced 60S and 80S fractions when compared with an unaffected parent consistent with a large ribosomal subunit defect. Polysome profiling using primary B-cells is an adjunctive tool that can assist in validation of large subunit RP variants of uncertain significance. Further studies are necessary to validate this method in patients with known DBA mutations, small RP subunit variants, and silent carriers.

Introduction: The COVID-19 pandemic has resulted in unprecedented changes to the delivery of maternity care across Australia, including RANZCOG-endorsed measures to reduce antenatal visits, and implement telehealth. We analysed trends in maternity consultations and the uptake of telehealth in VIC and NSW since the first COVID-19 pandemic restrictions were introduced in late March 2020. Methods: Episodes of outpatient antenatal and post-natal consultations and obstetric ultrasounds from January 2018 to September 2020 were obtained using Australian Government Medicare Statistics data from NSW and VIC. Run charts using pre-pandemic median from January 2018 were generated. A significant trend was defined as five consecutive months of numbers all going up or down.1 Utilisation of telehealth consultations was compared between VIC and NSW using the z-test for difference in proportions. Results: Despite a decline in monthly face-to-face consultations in Victoria and NSW (16% and 12% decline from pre-COVID medians of 32,413 and 41,848, respectively), there was no significant downward trend in total attendances during the first lockdown. A higher proportion of antenatal and post-natal care was delivered via telehealth/telephone in Victoria compared to NSW (19.4% vs 9.4%, respectively, p < 0.0001). From March 2020 in Victoria, the run chart showed a trend towards increased ultrasound examinations for women with a singleton pregnancy after 22 weeks. Discussion: Widespread uptake of telehealth has been a major contributor to maintaining maternity consultations during Victorian pandemic restrictions. Further research is required to understand the increase in ultrasound billings during lockdown in Victoria.

This is the fourth and final article in a series on the gastrointestinal (GI) symptoms of pelvic radiation disease (PRD). Published studies and patient reports suggest that health professionals lack of awareness of PRD. This professional awareness can be improved with third-sector advocacy and provision of simple screening tools, such as Assessment of Late Effects of Radiotherapy-Bowel (ALERT-B). In South Wales, patients with suspected PRD are referred to a PRD specialist nurse in either a gastroenterology clinic or a gynae-oncology follow-up clinic. These two nurse-led clinics demonstrate different ways to identify, assess and manage patients with late GI effects of PRD. Data from these clinics suggest that systematic investigations based on appropriate guidance are effective in identifying these symptoms, many of which can be managed or treated. The rising incidence of PRD and lack of specialist services suggests that the NHS needs to provide more funding to care for patients beyond the end of their cancer treatment.

A masked randomised control design compared the effectiveness of precision ophthalmic tints in improving the recognition of emotion in Autism Spectrum Disorders (ASD). Fourteen children aged 10-14 with ASD and 14 control children matched on verbal and non-verbal IQ, wore spectacles with coloured lenses to complete two tasks that involved the observation of coloured video sequences in which social interactions were depicted. On one occasion (randomly first or second) the coloured lenses provided light of a colour that the child had one month previously selected as optimal for the clarity of text. On the other occasion the lenses differed in CIE UCS chromaticity by 0.077. Performance in the ASD group was superior in both social interaction tasks with the lenses that provided the optimal colour of light.

Background Salpingectomy may damage ovarian reserve by direct vascular interruption to the ovary or thermal vascular injury from electrosurgery. It is plausible that this risk may increase in the context of salpingectomy conducted for ectopic pregnancy due to the distension of the fallopian tube and vascular changes associated with pregnancy. Aim To report anti-Mullerian hormone (AMH) concentrations before and after laparoscopic salpingectomy for ectopic pregnancy as an indicator of change in ovarian reserve. Materials and methods Women aged 18-44 years scheduled for salpingectomy for tubal ectopic pregnancy were prospectively recruited. Serum AMH concentrations were measured immediately prior to surgery, then repeated four months post-operatively. In all cases, salpingectomy was conducted laparoscopically using bipolar electrosurgery and mechanical scissors. A group of women scheduled for uterine curettage for first trimester miscarriage was recruited to ensure any observed change in AMH concentration in the women undergoing salpingectomy was secondary to surgery, rather than an effect of pregnancy. Results Paired pre- and post-operative serum AMH concentrations were obtained from 32 women with tubal ectopic pregnancy. The mean age of the women was 33.6 ± 4.6 years. There was no significant difference in the median pre- and post-operative AMH concentrations (13.00 pmol/L (range 5-67 pmol/L) vs 15.25 pmol/L (range 3-96 pmol/L), P = 0.575). Median AMH concentrations also remained stable in women experiencing a first trimester miscarriage (10.40 pmol/L (range 3.9-37.8 pmol/L) vs 13.67 pmol/L (range 2.8-30.5 pmol/L), P = 0.185). Conclusion Laparoscopic salpingectomy using electrosurgery and mechanical scissors does not damage ovarian reserve. AMH concentrations do not fluctuate from baseline in the first trimester of pregnancy.

Type 2 diabetes (T2D) manifests from inadequate glucose control due to insulin resistance, hypoinsulinemia, and deteriorating pancreatic β-cell function. The pro-inflammatory factor Activin has been implicated as a positive correlate of severity in T2D patients, and as a negative regulator of glucose uptake by skeletal muscle, and of pancreatic β-cell phenotype in mice. Accordingly, we sought to determine whether intervention with the Activin antagonist Follistatin can ameliorate the diabetic pathology. Here, we report that an intravenous Follistatin gene delivery intervention with tropism for striated muscle reduced the serum concentrations of Activin B and improved glycemic control in the db/db mouse model of T2D. Treatment reversed the hyperglycemic progression with a corresponding reduction in the percentage of glycated-hemoglobin to levels similar to lean, healthy mice. Follistatin gene delivery promoted insulinemia and abundance of insulin-positive pancreatic β-cells, even when treatment was administered to mice with advanced diabetes, supporting a mechanism for improved glycemic control associated with maintenance of functional β-cells. Our data demonstrate that single-dose intravascular Follistatin gene delivery can ameliorate the diabetic progression and improve prognostic markers of disease. These findings are consistent with other observations of Activin-mediated mechanisms exerting deleterious effects in models of obesity and diabetes, and suggest that interventions that attenuate Activin signaling could help further understanding of T2D and the development of novel T2D therapeutics.

Radiotherapy used to treat cancers in the pelvic region can have lasting side effects, and the persistence of these symptoms for 3 months or more is described as pelvic radiation disease (PRD). The growing number of pelvic cancer patients being diagnosed and successfully treated is increasing the incidence of PRD. This review examines the literature on the gastrointestinal symptoms of PRD. This includes how PRD is defined, how it is identified and how it relates specifically to the three pelvic cancers in which it most commonly manifests (prostate, gynaecological and colorectal). It pays particular attention to the impact of PRD on patient experience and quality of life. This review is the first part in a series on the GI symptoms of PRD.

Deficits in empathy have been considered hallmarks in individuals with autism spectrum disorders (ASD) but are also considered to underlie antisocial behaviour associated with individuals with callous unemotional traits (CU). Research has suggested that individuals with autism spectrum disorders show more difficulties with cognitive empathy, and that individuals diagnosed with behaviours difficulties, characterised by CU traits and antisocial behaviour, demonstrate low affective empathy. In the current manuscript we present findings of two studies. The first study describes the validation of a new stimulus set developed for the empathic accuracy task, focused on its cognitive component. The second study compares the performance of 27 adolescents with ASD, 27 age matched typically developing adolescents and 17 adolescents with behavioural difficulties on the empathic accuracy task and a self-report measure of empathy. While, no differences were observed between the three groups across the empathy accuracy task, the adolescents with ASD and CD showed deficits in their cognitive empathy across the self-report measure. Adolescents with ASD showed lower scores in particularly their perspective taking abilities, whereas the adolescences with behavioural difficulties showed more difficulties with their online simulation. No differences in self-reported affective empathy across the three groups were observed. Clinical implications of the findings are discussed.

Despite the recognition that a high proportion of individuals with an Autism Spectrum Disorder (ASD) will also reach the diagnostic threshold for at least one other mental health condition, many families struggle to access the appropriate mental health support. This study aimed to systematically explore the lived experiences of raising a child with an Autism Spectrum Disorder (ASD) and comorbid mental health condition and describes their attempts to access support via mental health services in the UK. Seven mothers of children aged between 11 to 15 years with ASD and who were referred for mental health issues, took part in semi-structured interviews. Interpretative Phenomenological Analysis (IPA) of the transcribed interviews revealed gaps and inconsistencies within the process of gaining access to mental health services, in addition to the impact it had on the mothers’ own mental health. The themes generated were psychological impact on caregiver; negative experience accessing mental health services, and breakdown in relationships with professionals. Managing the impact of their child’s mental health condition, including suicidal ideation and self-harm, alongside their child’s neurological condition, commonly led to feelings of isolation, self-blame, guilt and powerlessness; impacting on the mother’s own mental health. The themes emphasised the importance of ensuring appropriate referrals are made, enhancing the therapeutic alliance with both the child and parent during the referral process, and in providing continuity of care.

Tourette syndrome (TS) is a neurodevelopmental disorder characterised by involuntary, repetitive and non-rhythmic motor and vocal tics. Despite suggestion that diet may affect tics, and the substantial research into children's diet, eating behaviours and sensory processing in comorbid disorders (e.g. ASD), research in TS is lacking. The present study examined differences between children with and without TS in parental reports of child selective eating, food preferences and sensitivity, and aimed to examine sensory sensitivity as a predictor of food selectivity outcomes in children with and without TS. Thirty caregivers of children with TS (M = 10 years 8 months [SD = 2.40]) and the caregivers of 30 age- and sex-matched typically developing (TD) children (M = 9 years 9 months [SD = 2.50]) completed the following measures online: Short Sensory Profile, Food Preference Questionnaire for Children, Child Eating Behaviour Questionnaire. Children with TS were reported to have significantly higher levels of food selectivity and sensory sensitivity, and less preference for fruit and vegetables than TD children. Importantly, while higher levels of overall sensory sensitivity predicted eating outcomes in the TS group, only sensitivity to taste/smell was found to be a predictor of food selectivity and preference for vegetables for both groups of children. The findings suggest that efforts to address food selectivity in children with TS may be enhanced by including strategies that address atypical sensory processing.

Simple Summary DNA-damaging chemotherapeutics, such as platinum drugs, are cornerstones in cancer treatment. The efficacy of such treatment is intimately linked to the DNA repair capacity of the cancer cells, as DNA damage above a tolerable threshold culminates in cell death. Cancer cells often have deregulated DNA repair mechanisms, making them initially more sensitive to DNA-damaging chemotherapies. Unfortunately, over time, cancer cells often develop resistance to such treatments by rewiring their DNA damage response pathways. Here, we identify that targeting the recognized anti-cancer target 6-phosphofructo-2-kinase/fructose-2,6,-bisphophatase 3 (PFKFB3), commonly overexpressed in cancer, with the small molecule inhibitor KAN0438757, selectively sensitizes cancer cells to platinum drugs, including treatment-resistant cancer cells, while sparing normal cells. Mechanistically, PFKFB3 promotes tolerance to and the repair of platinum-induced DNA interstrand crosslinks (ICLs) through modulation of the Fanconi anemia (FA) DNA repair pathway. Thus targeting PFKFB3 opens up therapeutic possibilities to improve the efficacy of ICL-inducing cancer treatments. Abstract Replicative repair of interstrand crosslinks (ICL) generated by platinum chemotherapeutics is orchestrated by the Fanconi anemia (FA) repair pathway to ensure resolution of stalled replication forks and the maintenance of genomic integrity. Here, we identify novel regulation of FA repair by the cancer-associated glycolytic enzyme PFKFB3 that has functional consequences for replication-associated ICL repair and cancer cell survival. Inhibition of PFKFB3 displays a cancer-specific synergy with platinum compounds in blocking cell viability and restores sensitivity in treatment-resistant models. Notably, the synergies are associated with DNA-damage-induced chromatin association of PFKFB3 upon cancer transformation, which further increases upon platinum resistance. FA pathway activation triggers the PFKFB3 assembly into nuclear foci in an ATR- and FANCM-dependent manner. Blocking PFKFB3 activity disrupts the assembly of key FA repair factors and consequently prevents fork restart. This results in an incapacity to replicate cells to progress through S-phase, an accumulation of DNA damage in replicating cells, and fork collapse. We further validate PFKFB3-dependent regulation of FA repair in ex vivo cultures from cancer patients. Collectively, targeting PFKFB3 opens up therapeutic possibilities to improve the efficacy of ICL-inducing cancer treatments.

OBJECTIVES: To evaluate patient factors associated with post-ureteroscopy opioid prescriptions, provider-level variation in opioid prescribing, and the relationship between opioid-free discharges and ED visits. METHODS: This is a retrospective analysis of a prospective cohort study of adults age 18 years and older who underwent primary ureteroscopy for urinary stones from June 2016 to September 2019 within the Michigan Urological Surgery Improvement Collaborative (MUSIC) Reducing Operative Complications from Kidney Stones (ROCKS) quality improvement initiative. Postoperative opioid prescription trends and variation among practices and surgeons were examined. Multivariable logistic regression models defined risk factors for receipt of opioid prescriptions. The association among opioid prescriptions and postoperative ED visits within 30 days of surgery was assessed among complete case and propensity matched cohorts, matched on all measured characteristics other than opioid receipt. RESULTS: 13,143 patients underwent ureteroscopy with 157 urologists across 28 practices. Post-ureteroscopy opioid prescriptions and ED visits declined (86% to 39%, p

Ribosome dysfunction is implicated in multiple abnormal developmental and disease states in humans. Heterozygous germline mutations in genes encoding ribosomal proteins are found in most individuals with Diamond-Blackfan anemia (DBA), whereas somatic mutations have been implicated in a variety of cancers and other disorders. Ribosomal protein-deficient animal models show variable phenotypes and penetrance, similar to human patients with DBA. In this study, we characterized a novel ENU mouse mutant (Skax23m1Jus) with growth and skeletal defects, cardiac malformations, and increased mortality. After genetic mapping and whole-exome sequencing, we identified an intronic Rpl5 mutation, which segregated with all affected mice. This mutation was associated with decreased ribosome generation, consistent with Rpl5 haploinsufficiency. Rpl5Skax23-Jus/+ animals had a profound delay in erythroid maturation and increased mortality at embryonic day (E) 12.5, which improved by E14.5. Surviving mutant animals had macrocytic anemia at birth, as well as evidence of ventricular septal defect (VSD). Surviving adult and aged mice exhibited no hematopoietic defect or VSD. We propose that this novel Rpl5Skax23-Jus/+ mutant mouse will be useful in studying the factors influencing the variable penetrance that is observed in DBA.

Ribosome dysfunction is implicated in multiple abnormal developmental and disease states in humans. Heterozygous germline mutations in genes encoding ribosomal proteins (RPs) are found in the majority of individuals with Diamond Blackfan anemia (DBA) while somatic mutations have been implicated in a variety of cancers and other disorders. Ribosomal protein-deficient animal models show variable phenotypes and penetrance, similar to human DBA patients. The spontaneous anemia remission observed in some DBA patients occurs via unknown mechanism(s) and has not been previously described in animal models. Here we characterized a novel ENU mouse mutant (Skax23m1Jus) with growth and skeletal defects, cardiac malformations and increased mortality. Following genetic mapping and whole exome sequencing, we identified an intronicRpl5mutation, which segregated with all affected mice. This mutation was associated with decreased ribosome generation, consistent withRpl5haploinsufficiency.Rpl5Skax23-Jusmutant animals had a profound delay in erythroid maturation and increased mortality at embryonic day E12.5, which improved by E14.5. Surviving mutant animals had a macrocytic anemia at birth as well as evidence of ventricular septal defect (VSD). Surviving adult and aged mice exhibited no hematopoietic defect or VSD. We propose that this novelRpl5Skax23-Jusmutant mouse will be useful to study the factors influencing the variable penetrance and anemia remission that are observed in DBA.

Glyoxalase I (GLOI) is the primary enzyme for detoxifying the reactive dicarbonyl methylglyoxal. Pre-clinical models demonstrate that loss of GLOI promotes the development of diabetes in obesogenic conditions. To determine if GLOI is attenuated with human obesity, we compared GLOI expression in skeletal muscle biopsy samples from 5 obese (OB) and 15 age-matched lean, healthy individuals (LH). GLOI protein was ~50% lower (p Disclosure E.R. Miranda: None. J. Shadiow: None. D.B. Lombard: None. A.T. Ludlow: None. J.M. Haus: None. Funding National Institutes of Health (R01DK109948)

Active telomerase is essential for stem cells and most cancers to maintain telomeres. The enzymatic activity of telomerase is related but not equivalent to the expression of TERT, the catalytic subunit of the complex. Here we show that telomerase enzymatic activity can be robustly estimated from the expression of a 13-gene signature. We demonstrate the validity of the expression-based approach, named EXTEND, using cell lines, cancer samples, and non-neoplastic samples. When applied to over 9,000 tumors and single cells, we find a strong correlation between telomerase activity and cancer stemness. This correlation is largely driven by a small proliferating cancer cell population that exhibits both high telomerase activity and cancer stemness. This study establishes a novel computational framework for quantifying telomerase enzymatic activity and provides new insights into the relationships among telomerase, cancer proliferation, and stemness.

Active telomerase is essential for stem cells and most cancers to maintain telomeres. The enzymatic activity of telomerase is related but not equivalent to the expression of TERT, the catalytic subunit of the complex. Here we show that telomerase enzymatic activity can be robustly estimated from the expression of a 13-gene signature. We demonstrate the validity of the expression-based approach, named EXTEND, using cell lines, cancer samples, and non-neoplastic samples. When applied to over 9,000 tumors and single cells, we find a strong correlation between telomerase activity and cancer stemness. This correlation is largely driven by a small population of proliferating cancer cells that exhibits both high telomerase activity and cancer stemness. This study establishes a computational framework for quantifying telomerase enzymatic activity and provides new insights into the relationships among telomerase, cancer proliferation, and stemness., Telomerase activity correlates with distinct cell states, but can be challenging to quantify. Here the authors quantify telomerase activity across a range of biological samples using the expression of 13 genes, and show it correlates with cancer cell proliferation and stemness.

This chapter examines a number of comics to determine whether texts about abortion, miscarriage, and birthing exceed normative discourses of maternity (which frequently frame such life-events as horrific and monstrous), or if, despite their potential to perform otherwise, certain comics perpetuate the characterization of maternity as abject. This chapter provides an analysis of how particular comics do, or do not, make use of monstrosity in order to imagine im/possibilities relating to birth.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative illness that is unremittingly fatal and for which no effective treatment exists. All forms of ALS are characterized by protein aggregation. In familial forms of ALS, specific and heritable aggregation-prone proteins have been identified, such as mutant superoxide dismutase (SOD1). It has been suggested that a factor capable of preventing mutant SOD1 protein aggregation and/or disassembling mutant SOD1 protein aggregates would ameliorate SOD1-associated forms of familial ALS. Here we identify Fas Apoptosis Inhibitory Molecule (FAIM), a highly evolutionarily conserved 20 kDa protein, as an agent with this activity. We show FAIM counteracts intracellular accumulation of mutant SOD1 protein aggregates, which is increased in the absence of FAIM, as determined by pulse-shape analysis and filter trap assays. In a cell-free system, FAIM inhibits aggregation of mutant SOD1, and further disassembles and solubilizes established mutant SOD1 protein aggregates, as determined by thioflavin T (ThT), filter trap, and sedimentation assays. In sum, we report here a previously unknown activity of FAIM that opposes ALS disease-related protein aggregation and promotes proteostasis of an aggregation-prone ALS protein.

Purpose: Diffuse intrinsic pontine glioma is the most aggressive form of high grade glioma in children with no effective therapies. There have been no improvements in survival in part due poor understanding of underlying biology, and lack of representative in vitro and in vivo models. Recently, it has been found feasible to use both biopsy and autopsy tumors to generate cultures and xenograft models. Methods: To further model development, we evaluated the collective international experience from 8 collaborating centers to develop DIPG pre-clinical models from patient-derived autopsies and biopsies. Univariate and multivariate analysis was performed to determine key factors associated with the success of in vitro and in vivo PDX development. Results: In vitro cultures were successfully established from 57% of samples (84.2% of biopsies and 38.2% of autopsies). Samples transferred in DMEM media were more likely to establish successful culture than those transported in Hibernate A. In vitro cultures were more successful from biopsies (84.2%) compared with autopsies (38.2%) and as monolayer on laminin-coated plates than as neurospheres. Primary cultures successfully established from autopsy samples were more likely to engraft in animal models than cultures established from biopsies (86.7% vs. 47.4%). Collectively, tumor engraftment was more successful when DIPG samples were directly implanted in mice (68%), rather than after culturing (40.7%). Conclusion: This multi-center study provides valuable information on the success rate of establishing patient-derived pre-clinical models of DIPG. The results can lead to further optimization of DIPG model development and ultimately assist in the investigation of new therapies for this aggressive pediatric brain tumor.

Regionalised interaction of the activins, follistatin and inhibin was investigated in the male reproductive tract of mice lacking the inhibin α-subunit (Inha-/-). Serum and intratesticular activin B, although not activin A and follistatin, were increased in Inha-/- mice at 25 days of age, but all three proteins were elevated at 56 days. None of these proteins were altered within the epididymis and vas deferens at either age. At 25 days, histology of the epididymis and vas deferens was similar to wild-type. At 56 days, the testis contained extensive somatic cell tumours, leading to Leydig cell regression and testosterone deficiency. The epididymis and vas deferens showed epithelial regression and increased prominence of the interstitial stroma. Immunoregulatory and fibrotic gene expression in the epididymis and vas deferens were unchanged. Thus, absence of the inhibin α-subunit has marginal effects on activins in the epididymis and vas deferens, and regression of these tissues is associated with androgen deficiency.

Research has shown the transition planning of young people with autism spectrum disorders from child to adult-directed services to be both problematic and limited in function. Mothers of children w...

Food selectivity has been shown to be more persistent and severe in children with Tourette syndrome (TS) compared to their typically developing peers. The current study aimed to examine differences in food selectivity, food neophobia and Avoidant Restrictive Food Intake Disorder (ARFID)-associated behaviours, between adults with and without TS. Fifty-three adults diagnosed with TS were compared to 53 neurotypical adults and completed the following measures online: Adult Eating Behaviour Questionnaire (AEBQ), Nine-Item Avoidant/Restrictive Food Intake disorder screen (NIAS), Food Neophobia Scale (FNS) and the Sensory Perception Quotient (SPQ). Higher levels of food avoidant behaviours, in terms of food fussiness, food neophobia and ARFID-associated behaviours, were identified in adults with TS compared to adults without TS. While heightened sensory sensitivity failed to predict food fussiness, greater sensitivity to taste was found to be predictive of food neophobia in TS. These are the first findings to suggest that food avoidant behaviours are more prevalent for adults with TS and signal a need to address health implications.

Herein, we report the synthesis of zeolite composites with core–shell structure via a secondary growth technique and evaluation of their catalytic performance in ethanol dehydration. In particular, SAPO-34 particles were functionalized by TPA+, followed by dispersion in ZMS-5 or silicalite-1 to form SAPO-34@ZSM-5 and SAPO-34@silicalite-1 core–shell materials showed a hierarchical porous structure consisting of both micropores and mesopores. The active sites in the developed composites were found to have a mild acidity. Compared to conventional zeolite catalysts in ethanol dehydration reaction, the silicalite-1 composites. The novel core–shell materials showed a hierarchical porous structure consisting of both micropores and mesopores. The active sites in the developed composites were found to have a mild acidity. Compared to conventional zeolite catalysts in ethanol dehydration reaction, the core–shell SAPO-34@ZSM-5 improved the selectivity toward light olefins. In addition, our catalyst test results reve...

Aim To investigate hepatitis C virus (HCV) testing patterns and engagement with health care for women positive for HCV antibodies (anti-HCV) in pregnancy and their children through pregnancy and the first 2 years of the child's life. Methods At a large inner-city Australian hospital from 2010 to 2012, anti-HCV positive pregnant women were recruited into a cohort study from pregnancy to 2 years post-delivery. Maternal and child data were collected by questionnaire and medical record extraction. Results During the study 29 women participants delivered 31 children. HCV RNA was detected in 64% (18/28) of pregnancies, with injecting drug use, the most likely route of maternal infection. Relatively high maternal health-care engagement during pregnancy reduced after delivery. There was evidence of ongoing illicit drug use in the majority of women. Of the children, 58% (18/31) had some HCV testing confirmed but complete testing was confirmed for only 10% (3/31). Largely, testing was incomplete or unknown. No vertical transmission was identified. Forty-two percent (13/31) of children were placed in out-of-home-care. Conclusions Potentially, there is a high risk of inadequate or incomplete HCV testing of vulnerable children. Ongoing maternal drug use, poor maternal health-care engagement and placement in out-of-home-care may increase the risk. Complete testing of all children at risk of vertically acquired HCV needs to be ensured.

Anecdotal reports frequently suggest some dietary involvement in the maintenance of tics in children with Tourette syndrome (TS). This scoping review aimed to (1) understand the possible influence of diet as a trigger of tics and (2) map out the existing studies documenting dietary interventions in children with TS. Current evidence suggests no single diet to benefit individuals with TS. However, reports from parents of children with TS suggest that certain allergens in food may exacerbate tic-related symptoms. For example, an increase in tics has been related to the consumption of caffeine and refined sugar. Moreover, oligoantigenic diets and sugar-free diets have been identified as significantly reducing tics. More research is urgently needed to develop more accurate guidance for parents and children with TS, as many have reported using dietary and nutritional supplements, despite the lack of evidence detailing any benefits, side effects and recommended doses.

Aim: Speech and language therapists (SLTs) provide intervention for communication and swallowing to patients with life-limiting conditions, such as dementia and head and neck cancer. The role of the SLT in palliative care is difficult to define. Much is known about the clinical aspects of this role; however, little is known about the core values, beliefs and expectations of SLTs working in this sector, particularly with regard to their role in supporting patients' communication. Through a series of semi-structured interviews and a follow-up focus group, this report aimed to form a picture of the experiences and views of SLTs about their communication role in palliative care. Results suggest that SLTs are forging a self-identity in a sector that is itself constantly evolving, which causes difficulties in defining their role. Participants report that other health professionals have a poor understanding of the SLT's role. SLTs may benefit from palliative care-specific guidelines and increased interprofessional awareness of their role in order to become better integrated into the palliative care sector.

SummaryBackground Corticosteroids are central to inducing remission in inflammatory bowel disease (IBD) but are ineffective maintenance agents. Aim To benchmark steroid usage in British outpatients and assess factors associated with excess exposure. Methods We recorded steroid use in unselected IBD outpatients. Cases meeting criteria for steroid dependency or excess were blind peer reviewed to determine whether steroid prescriptions were avoidable. Associations between steroid use and patient/institutional factors were analysed. Results Of 1176 patients, 30% received steroids in the prior 12 months. 14.9% had steroid dependency or excess, which was more common in moderate/severe ulcerative colitis (UC) than Crohn's disease (CD) (42.6% vs 28.1%; P = .027). Steroid dependency or excess was deemed avoidable in 49.1%. The annual incidence of inappropriate steroid excess was 7.1%. Mixed-effects logistic regression analysis revealed independent predictors of inappropriate steroid excess. The odds ratio (OR, 95%CI) for moderate/severe compared to mild/quiescent disease activity was 4.59 (1.53-20.64) for UC and 4.60 (2.21-12.00) for CD. In CD, lower rates of inappropriate steroid excess were found in centres with an IBD multi-disciplinary team (OR 0.62 [0.46-0.91]), whilst dedicated IBD clinics protected against inappropriate steroid excess in UC (OR 0.64, 95% CI 0.21-0.94). The total number of GI trainees was associated with rates of inappropriate steroid excess. Conclusion Steroid dependency or excess occurred in 14.9% of British IBD patients (in 7.1% potentially avoidable). We demonstrated positive effects of service configurations (IBD multi-disciplinary team, dedicated IBD clinics). Routine recording of steroid dependency or excess is feasible and should be considered a quality metric.

Objective The purpose of this review is to describe the recent advances in identifying possible factors involved in the pathogenesis of spasmodic dysphonia. Spasmodic dysphonia is a task-specific focal laryngeal dystonia characterized by irregular and uncontrolled voice breaks. Pathogenesis of the disorder is poorly understood. Data Sources PubMed, Google Scholar, and Cochrane Library. Review Methods The data sources were searched using the following search terms: ( spasmodic dysphonia or laryngeal dystonia) and ( etiology, aetiology, diagnosis, pathogenesis, or pathophysiology). Conclusions Several potential etiological factors have been proposed by epidemiological, genetic, and neuropathological studies. Spasmodic dysphonia is a rare disorder primarily affecting females beginning in their 40s. Vocal tremor co-occurs in 30% to 60%. Large cohort studies identified risk factors such as a family history of neurological disorders including dystonia and tremor, recent viral illness, and heavy voice use. As none are rare events, a complex interactive process may contribute to pathogenesis in a small proportion of those at risk. Consequences to pathogenesis are neurological processes found in spasmodic dysphonia: loss of cortical inhibition, sensory processing disturbances, and neuroanatomical and physiological differences in the laryngeal motor control system. Implications for Practice Diagnosis of spasmodic dysphonia usually includes speech and laryngoscopic assessment. However, as diagnosis is sometimes problematic, measurement of neurophysiological abnormalities may contribute useful adjuncts for the diagnosis of spasmodic dysphonia in the future.

PURPOSEEvaluation of 12 ccRCC publicly-available ccRCC gene expression datasets showed that previously proposed discrete molecular subtypes are unstable. To reflect the continuous nature of gene expression observed, we developed a quantitative score (Continuous Linear Enhanced Assessment of Renal cell carcinoma, or CLEAR) using expression analysis founded on pathologic parameters.MATERIALS AND METHODS265 ccRCC gene expression profiles were used to develop the CLEAR score, representing a genetic correlate of the continuum of morphological tumor grade. A signature derivation method based on correlation of CLEAR score with gene expression ranking was used to derive an 18-transcript signature. External validation was conducted in multiple public expression datasets.ResultsAs a measure of intertumoral gene expression heterogeneity, the CLEAR score demonstrated both superior prognostic estimates (94% vs 83% adequacy index in TCGA dataset) and inverse correlation with anti-angiogenic tyrosine-kinase inhibition (65% vs 55% adequacy index) in comparison to previously proposed discrete subtyping classifications. Inverse correlation with high-dose interleukin-2 outcomes was also observed for the CLEAR score (p=0.05). Multiple somatic mutations (VHL, PBRM1, SETD2, KDM5C, TP53, BAP1, PTEN, MTOR) were associated with the CLEAR score. Application of the CLEAR score to independent expression profiling of intratumoral ccRCC regions demonstrated its ability to reflect intratumoral expression heterogeneity and further analysis showed average intertumoral heterogeneity exceeded intratumoral heterogeneity.ConclusionsThe CLEAR score, a gene expression signature developed on histopathology, outperformed discrete subtype-classification in prognostic estimates and correlated better with treatment outcomes. Recognizing cancer as a continuum has important implications for laboratory and clinical research.

Introduction Palpation of a thoracic rib is a common method for reducing the risk of pneumothorax during electromyographic examination of the rhomboid major muscle, but its accuracy is unknown. Methods Two physicians palpated healthy subjects to attempt to identify the center of a rib located beneath the rhomboid major muscle. The identified location was examined with ultrasonography to examine its accuracy and the subject's anatomical depths. Results Forty-four subjects (88 ribs) were studied. Palpation demonstrated a 66.3% accuracy rate, with significantly more incorrect palpations seen with greater muscle thickness (P = 0.004) and body mass index (P = 0.037), but not adipose thickness, age, or skin thickness (P > 0.05). Discussion Palpation of the ribs in an attempt to avoid inadvertent pneumothorax while examining the rhomboid major may be inaccurate, primarily in patients with large muscle bulk. We suggest a brief ultrasound evaluation before electromyography to gauge correct needle depth. Muscle Nerve 57: 61-64, 2018.

Type 1 diabetes (T1D) is associated with subfertility in men. We hypothesised that this results from inhibitory effects of chronic hyperglycemia on testicular function and used the Ins2Akita+/- mouse model to investigate this. Diabetic mice exhibited progressive testicular dysfunction, with a 30% reduction in testis weight at 24 weeks of age. Diabetic mice showed significantly reduced seminiferous tubule diameters and increased spermatogenic disruption, although testes morphology appeared grossly normal. Unexpectedly, serum LH and intra-testicular testosterone were similar in all groups. Ins2Akita+/- mice displayed elevation of the testicular inflammatory cytokines activin A and IL-6. Intratesticular activin B was downregulated, while the activin regulatory proteins, follistatin and inhibin, were unchanged. Activin signalling, measured by pSmad3 and Smad4 production, was enhanced in diabetic mice only. These results suggest that prolonged exposure to hyperglycemia in the Ins2Akita+/- mice leads to progressive testicular disruption mediated by testicular activin activity, rather than hormonal dysregulation.

There are currently at least 2 million people in the UK living with and following a cancer diagnosis. Typically four out of every ten people with cancer will receive radiotherapy, but a large proportion of people who have pelvic radiotherapy may go on to develop gastrointestinal (GI) symptoms. This includes rectal bleeding and faecal incontinence, which can have a huge impact on quality of life. These problems often go under-reported by patients and are also under-recognised or under-treated by health professionals. Cancer survivorship is a growing topic that is likely to have a major impact on the NHS, with increasing numbers of patients presenting. A late GI effects of pelvic radiotherapy clinic was set up to address these growing needs of patients with GI symptoms following radiotherapy. This article also shares insights from a doctoral study that is underway looking at people's experiences of living with symptoms following their treatment, in order to improve awareness of the major impact that this can have.

BACKGROUND Medical management of miscarriage allows women to avoid the risks associated with surgical intervention. In 2011 the early pregnancy assessment service (EPAS) at the Royal Prince Alfred Hospital (RPAH) in Sydney, Australia introduced medical management of miscarriage with single-dose 800 μg vaginal misoprostol. AIMS We sought to investigate the impact of the introduction of medical management had on the proportion of women having surgery and conservative management and to examine the success and complication rates of medical management. MATERIALS AND METHODS We undertook a retrospective cohort study that included all women diagnosed with a miscarriage from 12 months prior to and 18 months after the introduction of medical management. Successful management was defined as the absence of retained products of conception or endometrial thickness less than 15 mm on ultrasound at two weeks. The change in management choices over time, the success rates and complication rates were measured. RESULTS Of 1102 women in the final analysis, 446 were in Group A (before medical management) and 656 in Group B (after medical management). Primary surgical procedures fell significantly for missed miscarriages from 68 to 48% (P

Cancer cells balance with the equilibrium of cell death and growth to expand and metastasize. The activity of mammalian sterile20-like kinases (MST1/2) has been linked to apoptosis and tumor suppression via YAP/Hippo pathway-independent and -dependent mechanisms. Using a kinase substrate screen, we identified here MST1 and MST2 among the top substrates for fibroblast growth factor receptor 4 (FGFR4). In COS-1 cells, MST1 was phosphorylated at Y433 residue in an FGFR4 kinase activity-dependent manner, as assessed by mass spectrometry. Blockade of this phosphorylation by Y433F mutation induced MST1 activation, as indicated by increased threonine phosphorylation of MST1/2, and the downstream substrate MOB1, in FGFR4-overexpressing T47D and MDA-MB-231 breast cancer cells. Importantly, the specific knockdown or short-term inhibition of FGFR4 in endogenous models of human HER2(+) breast cancer cells likewise led to increased MST1/2 activation, in conjunction with enhanced MST1 nuclear localization and generation of N-terminal cleaved and autophosphorylated MST1. Unexpectedly, MST2 was also essential for this MST1/N activation and coincident apoptosis induction, although these two kinases, as well as YAP, were differentially regulated in the breast cancer models analyzed. Moreover, pharmacological FGFR4 inhibition specifically sensitized the HER2(+) MDA-MB-453 breast cancer cells, not only to HER2/EGFR and AKT/mTOR inhibitors, but also to clinically relevant apoptosis modulators. In TCGA cohort, FGFR4 overexpression correlated with abysmal HER2(+) breast carcinoma patient outcome. Therefore, our results uncover a clinically relevant, targetable mechanism of FGFR4 oncogenic activity via suppression of the stress-associated MST1/2-induced apoptosis machinery in tumor cells with prominent HER/ERBB and FGFR4 signaling-driven proliferation.

Background and aim Patients are referred to our complex breathlessness service due to a clinical suspicion of Inducible Laryngeal Obstruction (ILO) and/or Breathing Pattern Disorder (BPD). We wanted to understand the prevalence of these disorders and their association with other respiratory co-morbidities. If a diagnosis was made we investigated if patients were seen for Speech and Language Therapy (SLT), Physiotherapy (PT), joint therapy or if their other respiratory diagnosis was treated first. Method Data from all patients over a six month period who attended the Manchester Airways ‘one stop day assessment’ were analysed. Investigations included: full clinical history from SLT, PT, clinical nurse specialist, clinical psychologist and respiratory physician, a provocation laryngoscopy and lung function tests. Results One hundred and fifty seven patients were seen in our complex breathlessness clinic between December 2018 and June 2019. Eighty-eight (56%) of these [67 female, median (range) 54 (17–83) years] had confirmed ILO (n=32), BPD (20) or both (36). Other relevant co-morbidities are shown in table 1. Of the patients diagnosed with ILO, most occurred on inspiration (91%) and at the glottic level (87%). All six patients with a diagnosis of tracheobronchomalacia also had a BPD. The majority of patients with a diagnosis of COPD were diagnosed with a BPD (6/7, 86%); with a high proportion also having expiratory ILO (3/7, 43%). A high percentage of patients had concurrent diagnoses of asthma, ILO and BPD (28%). Of the patients diagnosed with ILO, BPD or both; 46 were referred for SLT (52%), 20 for PT (23%) and 15 for joint SLT and PT (17%). Seven of the patients were not given therapy due to other co-morbidities needing to be medically managed first. Eight patients (9%) were referred for clinical psychology on this initial visit. Conclusion A high proportion of patients referred to the complex breathlessness service received a diagnosis of ILO and/or BPD, and many also had a diagnosis of asthma or other respiratory disease. Few were referred for clinical psychology at the initial assessment, but these issues are often discussed during SLT/PT sessions and referrals made at a later date.

Background Cough hypersensitivity syndrome is associated with significant physical and psychological morbidity and impacts patient’s quality of life. We aimed to evaluate the prevalence of anxiety and depression symptoms in our patients with cough hypersensitivity syndrome and to assess patients’ awareness of the association. Method All patients over a three month period who attended a Respiratory Speech and Language Therapy-led cough assessment clinic were asked to complete the Leicester Cough Questionnaire (LCQ), Generalised Anxiety Disorder Assessment (GAD-7), Patient Health Questionnaire depression module (PHQ-9) and cough severity Visual Analogue Scale (VAS, 0–10 scale). Patients were asked if they believed anxiety, depression or stress were triggers for their cough. Results Data from 32 patients (24 female) with a median (range) age of 57 (31–73) years and average cough duration of 10 (2–40) years who attended the clinic between April and June 2019 were analysed (table). Other relevant co-morbidities included asthma (16%), inducible laryngeal obstruction (13%), reflux (38%) and nasal disease (28%). Several patients were taking (38%) or had taken (38%) anti-tussive medications for their cough. On the GAD-7, 12 patients reported anxiety symptoms (38%); seven mild (22%), three moderate (9%) and two severe (6%). On the PHQ-9, 15 patients reported depression symptoms (47%); ten mild (31%), four moderate (13%) and one severe (3%). Several patients who recognised stress to be a trigger of their cough scored highly on the anxiety and depression questionnaires (12/17, 70%). Cough scores (VAS and LCQ) correlated strongly with each other, as did GAD7 and PHQ9 scores. PHQ9 also correlated with the LCQ-physical domain (Spearman’s rho=-0.397, p=0.025) supporting the relationship between depression and increased physical symptoms related to cough. Conclusion A high proportion of patients with cough hypersensitivity syndrome had symptoms of anxiety and depression. The direction of cough and psychological problems is difficult to determine from these results. When taking a medical history from a patient, physicians should note psychological as well as physical complications. Failure to recognise this may influence treatment outcomes. Clinical psychology input into cough multi-disciplinary teams may be beneficial.

Purpose: Rhabdoid tumors are devastating pediatric cancers in need of improved therapies. We sought to identify small molecules that exhibit in vitro and in vivo efficacy against preclinical models of rhabdoid tumor. Experimental Design: We screened eight rhabdoid tumor cell lines with 481 small molecules and compared their sensitivity with that of 879 other cancer cell lines. Genome-scale CRISPR–Cas9 inactivation screens in rhabdoid tumors were analyzed to confirm target vulnerabilities. Gene expression and CRISPR–Cas9 data were queried across cell lines and primary rhabdoid tumors to discover biomarkers of small-molecule sensitivity. Molecular correlates were validated by manipulating gene expression. Subcutaneous rhabdoid tumor xenografts were treated with the most effective drug to confirm in vitro results. Results: Small-molecule screening identified the protein-translation inhibitor homoharringtonine (HHT), an FDA-approved treatment for chronic myelogenous leukemia (CML), as the sole drug to which all rhabdoid tumor cell lines were selectively sensitive. Validation studies confirmed the sensitivity of rhabdoid tumor to HHT was comparable with that of CML cell lines. Low expression of the antiapoptotic gene BCL2L1, which encodes Bcl-XL, was the strongest predictor of HHT sensitivity, and HHT treatment consistently depleted Mcl-1, the synthetic-lethal antiapoptotic partner of Bcl-XL. Rhabdoid tumor cell lines and primary-tumor samples expressed low BCL2L1, and overexpression of BCL2L1 induced resistance to HHT in rhabdoid tumor cells. Furthermore, HHT treatment inhibited rhabdoid tumor cell line and patient-derived xenograft growth in vivo. Conclusions: Rhabdoid tumor cell lines and xenografts are highly sensitive to HHT, at least partially due to their low expression of BCL2L1. HHT may have therapeutic potential against rhabdoid tumors.