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Objectives: To investigate how the symptoms of mucus and cough impact adults living with laryngotracheal stenosis, and to use this information to guide future research and treatment plans. Methods: A survey was developed with the support of patient advisors and distributed to people suffering with laryngotracheal stenosis. The survey comprised 15 closed and open questions relating to mucus and cough and included the Leicester Cough Questionnaire (LCQ). Descriptive statistics, X2 and thematic analyses were completed. Results: In total, 641 participants completed the survey, with 83.62% (n = 536) reporting problems with mucus; 79% having daily issues of varying severity that led to difficulties with cough (46.18%) and breathing (20.90%). Mucus affected voice and swallowing to a lesser degree. Respondents described a range of triggers; they identified smoky air as the worst environmental trigger. Strategies to manage mucus varied widely with drinking water (72.26%), increasing liquid intake in general (49.35%) and avoiding or reducing dairy (45.32%) the most common approaches to control symptoms. The LCQ showed a median total score of 14 (interquartile range 11-17) indicative of cough negatively affecting quality of life. Thematic analysis of free text responses identified 4 key themes—the Mucus Cycle, Social impact, Psychological impact, and Physical impact. Conclusion: This study shows the relevance of research focusing on mucus and cough and its negative impact on quality of life, among adults with laryngotracheal stenosis. It demonstrates the inconsistent advice and management strategies provided by clinicians for this issue. Further research is required to identify clearer treatment options and pathways.

Acquired laryngotracheal stenosis (LTS) is a rare condition causing dyspnea and stridor. Patients often require multiple surgical procedures with no guarantee of a definitive outcome. Difficulty swallowing is a recognised problem associated with LTS and the reconstructive surgeries required to manage the condition. The breathlessness patient’s experience impacts on swallowing, and the vulnerable structures of the larynx are implicated during complex surgeries. This leads to dysphagia post-surgery, with some patients experiencing more chronic symptoms depending on the biomechanical impact of the surgery, or a pre-existing dysphagia. Despite this there is limited observational research about the dysphagia associated with LTS, with no exploration of the patient experience. Our aim was to investigate patient experience of living with LTS focussing on dysphagia in order to guide clinical practice. A qualitative study was completed using focus groups and semi-structured interviews with 24 patients who have had reconstructive surgery for LTS. Thematic analysis was used to identify three over-arching themes: The Physical Journey, The Emotional Journey and The Medical Journey. Key sub-themes included the importance of self-management and control, presence of symptoms, benefits of therapy, living with a life-long condition, fear and anxiety, autonomy, medicalisation of normal processes and the dichotomy between staff expertise and complacency. Swallowing was connected to all themes. The results are reviewed with consideration of the wider literature of lived experience particularly in relation to other chronic conditions and those that carry a high symptom burden such as head and neck cancer. Future clinical and research recommendations have been made. Akin to other clinical groups, adults with LTS are keen that management of their swallowing is person-centred and holistic.

Objectives Mindfulness-based programs (MBPs) such as the ‘Soles of the Feet’ (SoF) meditation have been shown to be effective for reducing aggressive behavior in people with intellectual disabilities (ID). Research on SoF has shown promising results in the USA but there is an absence of evidence for the approach in the United Kingdom (UK). The aim of this research was to adapt SoF for the UK and to assess the feasibility and cost of implementing the SoF intervention in a UK healthcare setting (UK SoF). Methods The UK SoF intervention consisted of a manualized protocol delivered over a six-week period by National Health Service staff to people with ID and their carers. This was a single-arm study with three measurement time points (baseline and 2- and 6-month follow-ups). Results The UK SoF intervention was shown to be feasible, with recruitment, retention, and adherence figures exceeding the minimum cut-off of 50%. Costs were £2426 per participant, or £2766 when including set-up costs such as therapist training. Although not a primary aim, data suggest that at 6-month follow-up, there was a reduction in scores for anger and aggressive behavior, and depression and anxiety showed improvement. In addition, people with ID were able to self-report on their health-related quality of life. Conclusions This study has indicated areas where the protocol could be further improved, and it is recommended that the research should move to a pilot trial before the development of a full randomized control trial.

Mindfulness-Based Cognitive Therapy (MBCT) was lightly adapted for participants diagnosed with chronic fatigue syndrome (CFS). The aim of the study was to explore participants’ experiences of the MBCT course, with a particular focus on how they applied MBCT to living with and coping with the symptoms of CFS. Nine participants with CFS who completed the MBCT course were interviewed using semi-structured interview methods. Inductive thematic analysis, a methodology designed to generate themes from the “bottom up,” was used. Four superordinate themes were generated from the data: (1) awareness of unhelpful behavioral patterns associated with CFS, (2) benefits of group solidarity, (3) use of mindfulness tools to facilitate shifts in behavioral patterns, and (4) a sense of change and agency. Participants became aware of three specific transformative changes that contributed to a more skillful way of living with CFS: development of acceptance, improved self-care and self-compassion, and reduction in heightened stress response. MBCT appears to enable people with CFS to actively work with their symptoms, and make transformative changes in their behavioral patterns, resulting in benefits to well-being.

Rationale & Objective More than 50% of hemodialysis patients experience sleep disturbance and most have coexisting sleep apnea. However, how sleep apnea affects sleep and the overall experience of patients with chronic kidney disease treated by hemodialysis has not been evaluated. Study Design A mixed-methods design, incorporating cross-sectional observational and descriptive qualitative methodologies. Setting & Participants Patients receiving maintenance hemodialysis in Newcastle, New South Wales, Australia, with newly diagnosed sleep apnea (apnea-hypopnea index ≥ 5 per hour). Assessments In-laboratory polysomnography to assess sleep apnea and objective sleep parameters. Epworth Sleepiness Scale to assess daytime symptoms. A semi-structured qualitative interview to explore patient experience. Analytical Approach Descriptive and iterative thematic analysis. Results We analyzed 36 patients with newly diagnosed sleep apnea and interviewed 26 (mean age, 62 years, median apnea-hypopnea index, 32 per hour). Severity of sleep apnea did not affect patients’ sleep duration, sleep efficiency, or self-reported Epworth Sleepiness Scale score. From the qualitative interviews, 4 themes emerged: “broken sleep” related to short sleep duration, with waking and dozing off a common sleep cycle, caused by uncontrolled pain and dialysis. Many participants reported regularly “feeling unrefreshed” on waking. “Impact of sleep disturbance” included reduced physical, mental, and self-management capacity. Finally, interviewees described the need to use strategies to “soldier on” with symptoms. Limitations Participants’ views are only transferrable to hemodialysis patients with sleep apnea. Conclusions Our findings suggest that severity of sleep apnea does not affect sleep time or patient-reported daytime sleepiness; however, hemodialysis patients with sleep apnea report disturbed and unrefreshed sleep and the debilitating effects of sleep disturbance is profound. Broken and unrefreshed sleep were the dominant symptoms of sleep apnea and should be assessed routinely to identify patients with sleep apnea and improve quality of life in patients with chronic kidney disease treated with hemodialysis., Graphical abstract

PurposeRadiopharmaceuticals targeting poly(ADP-ribose) polymerase (PARP) have emerged as promising agents for cancer diagnosis and therapy. PARP enzymes are expressed in both cancerous and normal tissue. Hence, the injected mass, molar activity and potential pharmacological effects are important considerations for the use of radiolabelled PARP inhibitors for diagnostic and radionuclide therapeutic applications. Here, we performed a systematic evaluation by varying the molar activity of [18F]olaparib and the injected mass of [TotalF]olaparib to investigate the effects on tumour and normal tissue uptake in two subcutaneous human glioblastoma xenograft models.Methods[18F]Olaparib uptake was evaluated in the human glioblastoma models: in vitro on U251MG and U87MG cell lines, and in vivo on tumour xenograft-bearing mice, after administration of [TotalF]olaparib (varying injected mass: 0.04-8.0 µg, and molar activity: 1-320 GBq/μmol).ResultsSelective uptake of [18F]olaparib was demonstrated in both models. Tumour uptake was found to be dependent on the injected mass of [TotalF]olaparib (µg), but not the molar activity per sé. An injected mass of 1 μg resulted in the highest tumour uptake (up to 6.9 ± 1.3%ID/g), independent of the molar activity. In comparison, both the lower and higher injected masses of [TotalF]olaparib resulted in lower relative tumour uptake (%ID/g; PEx vivo analysis of U87MG xenograft sections showed that the heterogeneity in [18F]olaparib intratumoural uptake correlated with PARP1 expression. Substantial upregulation of PARP1-3 expression was observed after administration of [TotalF]olaparib (>0.5 µg).Conclusion Our findings show that the injected mass of [TotalF]olaparib has significant effects on tumour uptake. Moderate injected masses of PARP inhibitor-derived radiopharmaceuticals may lead to improved relative tumour uptake and tumour-to-background ratio for cancer diagnosis and radionuclide therapy.

The consumption of caffeine has been linked to osteoporosis, believed to be due to enhanced bone resorption as a result of increased calcium excretion in the urine. However, the amount of calcium in the urine may not necessarily reflect the true effect of caffeine on calcium clearance. This study therefore examined the impact of high-dose, short-term caffeine intake on renal clearance of calcium, sodium and creatinine in healthy adults. In a double-blind clinical study, participants chewed caffeine (n = 12) or placebo (n = 12) gum for 5 minutes at 2-hour intervals over a 6-hour treatment period (800 mg total caffeine). Caffeine increased renal calcium clearance by 77%. Furthermore, the effect was positively correlated with sodium clearance and urine volume, suggesting that caffeine may act through inhibition of sodium reabsorption in the proximal convoluted tubule. This study confirmed that caffeine does increase renal calcium clearance and fosters further investigation into safe consumption of caffeine. Refereed/Peer-reviewed

OBJECTIVE:\ud We estimated the cost consequence of Italian National Health System (NHS) investment in direct-acting antiviral (DAA) therapy according to hepatitis C virus (HCV) treatment access policies in Italy.\ud \ud METHODS:\ud A multistate, 20-year time horizon Markov model of HCV liver disease progression was developed. Fibrosis stage, age and genotype distributions were derived from the Italian Platform for the Study of Viral Hepatitis Therapies (PITER) cohort. The treatment efficacy, disease progression probabilities and direct costs in each health state were obtained from the literature. The break-even point in time (BPT) was defined as the period of time required for the cumulative costs saved to recover the Italian NHS investment in DAA treatment. Three different PITER enrolment periods, which covered the full DAA access evolution in Italy, were considered.\ud \ud RESULTS:\ud The disease stages of 2657 patients who consecutively underwent DAA therapy from January 2015 to December 2017 at 30 PITER clinical centres were standardized for 1000 patients. The investment in DAAs was considered to equal €25 million, €15 million, and €9 million in 2015, 2016, and 2017, respectively. For patients treated in 2015, the BPT was not achieved, because of the disease severity of the treated patients and high DAA prices. For 2016 and 2017, the estimated BPTs were 6.6 and 6.2 years, respectively. The total cost savings after 20 years were €50.13 and €55.50 million for 1000 patients treated in 2016 and 2017, respectively.\ud \ud CONCLUSIONS:\ud This study may be a useful tool for public decision makers to understand how HCV clinical and epidemiological profiles influence the economic burden of HCV.

Objectives Airway reconstruction for laryngotracheal stenosis (LTS) encompasses several procedures. Dysphagia is a well-recognised sequela of LTS and airway surgery, however studies have employed mostly non-validated assessments post-operatively in small, heterogenous samples, perpetuating uncertainty around the contributions of LTS and its management to impaired deglutition. Consequently, considerable variation in LTS perioperative nutritional management exists. Our objective was to characterise baseline and post-operative dysphagia with instrumental assessment in an LTS cohort undergoing airway reconstruction and provide a gold-standard management framework for its management. Design, setting, participants and main outcome measures We performed a retrospective cohort study of adult airway reconstruction procedures from 2016-2020 at our quaternary centre. Patient background, LTS aetiology, procedure type, tube feeding duration, length of stay and serial Functional Oral Intake Scale (FOIS) and International Dysphagia Diet Standardisation Initiative (IDDSI) scores were noted. Baseline, post-operative day one and post-stent removal Fibreoptic Endoscopic Evaluation of Swallow (FEES) generated Penetration Aspiration Scale (PAS) scores. Results Forty-four patients underwent forty-six reconstructions. Baseline incidence of penetration-aspiration was considerably higher than the general population and worsened in the immediate post-operative period, however FOIS and PAS scores generally returned to baseline by discharge. Post-operative FOIS correlated negatively with tracheostomy or airway stent placement. At discharge, 80% tolerated soft or normal diet and 93% were feeding tube independent. Conclusions We present the largest adult airway reconstruction cohort with instrumental swallow assessment perioperatively. LTS patients have a higher incidence of underlying dysphagia but swallowing tends to return to baseline with appropriate postoperative rehabilitation. Such practice may avoid the complications, costs and morbidity of prolonged nutritional support.

Introduction Sarcoidosis is a chronic granulomatous disease of unknown aetiology and laryngeal involvement is seen in a small percentage of cases. Dysphagia is a common but under-reported symptom. Little is known about how dysphagia typically presents or is managed in the context of this fluctuating disease. We present our case series using an SLT-led model of assessment and management. Methods A literature search was conducted for any articles that reported both laryngeal sarcoidosis and dysphagia. We then analysed a case series of laryngeal sarcoidosis patients treated at Charing Cross Hospital. We report on multidimensional swallowing evaluation and rehabilitative interventions. Results Seventeen papers report both laryngeal sarcoidosis and dysphagia, with only one paper giving details on the nature of the dysphagia and the treatment provided. In our case series (n = 7), patients presented with FOIS Scores ranging from 5 to 7 pre-operatively (median = 6). Aspiration (median PAS Score = 6 and Range = 3–8) and pharyngeal residue were common. Sensory issues were also prevalent with most unaware of the extent of their difficulties. Management interventions included safe swallowing advice, compensatory strategies, exercises and close surveillance given their potential for repeated surgical interventions. Conclusion Laryngeal sarcoidosis is a rare condition. Dysphagia is under-reported and our experience highlights the need for specialist dysphagia intervention. Further research is required to understand dysphagia management requirements in the context of this fluctuating disease process.

Background: There is a common perception that smoking generally helps people to manage stress, and may be a form of 'self‐medication' in people with mental health conditions. However, there are biologically plausible reasons why smoking may worsen mental health through neuroadaptations arising from chronic smoking, leading to frequent nicotine withdrawal symptoms (e.g. anxiety, depression, irritability), in which case smoking cessation may help to improve rather than worsen mental health. Objectives: To examine the association between tobacco smoking cessation and change in mental health. Search Methods: We searched the Cochrane Tobacco Addiction Group's Specialised Register, Cochrane Central Register of Controlled Trials, MEDLINE, Embase, PsycINFO, and the trial registries clinicaltrials.gov and the International Clinical Trials Registry Platform, from 14 April 2012 to 07 January 2020. These were updated searches of a previously‐conducted non‐Cochrane review where searches were conducted from database inception to 13 April 2012. Selection Criteria: We included controlled before‐after studies, including randomised controlled trials (RCTs) analysed by smoking status at follow‐up, and longitudinal cohort studies. In order to be eligible for inclusion studies had to recruit adults who smoked tobacco, and assess whether they quit or continued smoking during the study. They also had to measure a mental health outcome at baseline and at least six weeks later. Data Collection and Analysis: We followed standard Cochrane methods for screening and data extraction. Our primary outcomes were change in depression symptoms, anxiety symptoms or mixed anxiety and depression symptoms between baseline and follow‐up. Secondary outcomes included change in symptoms of stress, psychological quality of life, positive affect, and social impact or social quality of life, as well as new incidence of depression, anxiety, or mixed anxiety and depression disorders. We assessed the risk of bias for the primary outcomes using a modified ROBINS‐I tool. For change in mental health outcomes, we calculated the pooled standardised mean difference (SMD) and 95% confidence interval (95% CI) for the difference in change in mental health from baseline to follow‐up between those who had quit smoking and those who had continued to smoke. For the incidence of psychological disorders, we calculated odds ratios (ORs) and 95% CIs. For all meta‐analyses we used a generic inverse variance random‐effects model and quantified statistical heterogeneity using I2. We conducted subgroup analyses to investigate any differences in associations between sub‐populations, i.e. unselected people with mental illness, people with physical chronic diseases. We assessed the certainty of evidence for our primary outcomes (depression, anxiety, and mixed depression and anxiety) and our secondary social impact outcome using the eight GRADE considerations relevant to non‐randomised studies (risk of bias, inconsistency, imprecision, indirectness, publication bias, magnitude of the effect, the influence of all plausible residual confounding, the presence of a dose‐response gradient). Main Results: We included 102 studies representing over 169,500 participants. Sixty‐two of these were identified in the updated search for this review and 40 were included in the original version of the review. Sixty‐three studies provided data on change in mental health, 10 were included in meta‐analyses of incidence of mental health disorders, and 31 were synthesised narratively. For all primary outcomes, smoking cessation was associated with an improvement in mental health symptoms compared with continuing to smoke: anxiety symptoms (SMD −0.28, 95% CI −0.43 to −0.13; 15 studies, 3141 participants; I2 = 69%; low‐certainty evidence); depression symptoms: (SMD −0.30, 95% CI −0.39 to −0.21; 34 studies, 7156 participants; I2 = 69%' very low‐certainty evidence); mixed anxiety and depression symptoms (SMD −0.31, 95% CI −0.40 to −0.22; 8 studies, 2829 participants; I2 = 0%; moderate certainty evidence). These findings were robust to preplanned sensitivity analyses, and subgroup analysis generally did not produce evidence of differences in the effect size among subpopulations or based on methodological characteristics. All studies were deemed to be at serious risk of bias due to possible time‐varying confounding, and three studies measuring depression symptoms were judged to be at critical risk of bias overall. There was also some evidence of funnel plot asymmetry. For these reasons, we rated our certainty in the estimates for anxiety as low, for depression as very low, and for mixed anxiety and depression as moderate. For the secondary outcomes, smoking cessation was associated with an improvement in symptoms of stress (SMD −0.19, 95% CI −0.34 to −0.04; 4 studies, 1792 participants; I2 = 50%), positive affect (SMD 0.22, 95% CI 0.11 to 0.33; 13 studies, 4880 participants; I2 = 75%), and psychological quality of life (SMD 0.11, 95% CI 0.06 to 0.16; 19 studies, 18,034 participants; I2 = 42%). There was also evidence that smoking cessation was not associated with a reduction in social quality of life, with the confidence interval incorporating the possibility of a small improvement (SMD 0.03, 95% CI 0.00 to 0.06; 9 studies, 14,673 participants; I2 = 0%). The incidence of new mixed anxiety and depression was lower in people who stopped smoking compared with those who continued (OR 0.76, 95% CI 0.66 to 0.86; 3 studies, 8685 participants; I2 = 57%), as was the incidence of anxiety disorder (OR 0.61, 95% CI 0.34 to 1.12; 2 studies, 2293 participants; I2 = 46%). We deemed it inappropriate to present a pooled estimate for the incidence of new cases of clinical depression, as there was high statistical heterogeneity (I2 = 87%). Authors' Conclusions: Taken together, these data provide evidence that mental health does not worsen as a result of quitting smoking, and very low‐ to moderate‐certainty evidence that smoking cessation is associated with small to moderate improvements in mental health. These improvements are seen in both unselected samples and in subpopulations, including people diagnosed with mental health conditions. Additional studies that use more advanced methods to overcome time‐varying confounding would strengthen the evidence in this area.

BackgroundSmoking rates are significantly higher in people with mental health problems, compared to those without. Negative attitudes towards smoking cessation are widespread in inpatient settings towards patients with severe and enduring mental illness. It is not clear if the same attitudes operate in psychological services towards people with common mental illness. We aimed to understand the concerns and views that patients, therapists, and smoking cessation practitioners may have about integrating smoking cessation treatment into psychological treatment for common mental illness and how these concerns may be overcome.MethodsThematic analysis of 23 in-depth interviews. Interviews took place in Improving Access to Psychological Therapies (IAPT) and smoking cessation services in England. Participants were 11 psychological wellbeing practitioners (PWPs), six IAPT patients with common mental illness, and six smoking cessation advisors.OutcomesNone.FindingsIAPT patients reported psychological benefits from smoking, but also described smoking as a form of therapeutic self-harm. PWPs seem positive towards smoking cessation treatment for people with common mental illness. IAPT PWPs and patients accept evidence that smoking tobacco may harm mental health, and quitting might benefit mental health. PWPs report expertise in helping people with common mental illness to make behavioural changes in the face of mood disturbances and poor motivation. IAPT appears to be a natural environment for smoking cessation intervention. PWPs felt confident to offer smoking cessation treatments to IAPT patients, but thought that a reduction in caseload was required to deliver smoking cessation support in an already pressed service.

Tobacco-related health disparities disproportionately affect smokers with major depression (MD). Although tobacco simulation models have been applied to general populations, to date they have not considered populations with a comorbid mental health condition. We developed and calibrated a simulation model of smoking and MD comorbidity for the US adult population using the 2005–2018 National Surveys on Drug Use and Health. We use this model to evaluate trends in smoking prevalence, smoking-attributable mortality and life-years lost among adults with MD, and changes in smoking prevalence by mental health status from 2018 to 2060. The model integrates known interaction effects between smoking initiation and cessation, and MD onset and recurrence. We show that from 2018 to 2060, smoking prevalence will continue declining among those with current MD. In the absence of intervention, people with MD will be increasingly disproportionately affected by smoking compared to the general population; our model shows that the smoking prevalence ratio between those with current MD and those without a history of MD increases from 1.54 to 2.42 for men and from 1.81 to 2.73 for women during this time period. From 2018 to 2060, approximately 484,000 smoking-attributable deaths will occur among adults with current MD, leading to 11.3 million life-years lost. Ambitious tobacco control efforts could alter this trajectory. With aggressive public health efforts, up to 264,000 of those premature deaths could be avoided, translating into 7.5 million life years gained. This model can compare the relative health gains across different intervention strategies for smokers with MD.

BackgroundSmoking prevalence is higher amongst individuals with schizophrenia and depression compared with the general population. Mendelian randomisation (MR) can examine whether this association is causal using genetic variants identified in genome-wide association studies (GWAS).MethodsWe conducted two-sample MR to explore the bi-directional effects of smoking on schizophrenia and depression. For smoking behaviour, we used (1) smoking initiation GWAS from the GSCAN consortium and (2) we conducted our own GWAS of lifetime smoking behaviour (which captures smoking duration, heaviness and cessation) in a sample of 462690 individuals from the UK Biobank. We validated this instrument using positive control outcomes (e.g. lung cancer). For schizophrenia and depression we used GWAS from the PGC consortium.ResultsThere was strong evidence to suggest smoking is a risk factor for both schizophrenia (odds ratio (OR) 2.27, 95% confidence interval (CI) 1.67–3.08, p < 0.001) and depression (OR 1.99, 95% CI 1.71–2.32, p < 0.001). Results were consistent across both lifetime smoking and smoking initiation. We found some evidence that genetic liability to depression increases smoking (β = 0.091, 95% CI 0.027–0.155, p = 0.005) but evidence was mixed for schizophrenia (β = 0.022, 95% CI 0.005–0.038, p = 0.009) with very weak evidence for an effect on smoking initiation.ConclusionsThese findings suggest that the association between smoking, schizophrenia and depression is due, at least in part, to a causal effect of smoking, providing further evidence for the detrimental consequences of smoking on mental health.

Background and aimsVarenicline and nicotine replacement therapy (NRT) are the most commonly used medications to quit smoking. Given their widespread use, monitoring adverse risks remains important. This study aimed to estimate the neuropsychiatric and cardiovascular risks associated with varenicline and NRT as used in routine UK care.DesignCase–cross‐over study.SettingUK‐based electronic primary care records in the Clinical Practice Research Datalink from 2006 to 2015 linked to hospital and mortality data sets.ParticipantsAdult smokers observed during periods when exposed and not exposed to either varenicline or NRT.MeasurementsMain outcomes included suicide, self‐harm, myocardial infarction (MI), all‐cause death and cause‐specific death [MI, chronic obstructive pulmonary disease (COPD)]. In primary analyses, conditional logistic regression was used to compare the chance of varenicline or NRT exposure during the risk period (90 days prior to the event) with the chance of exposure during an earlier single reference period (91–180 days prior to the event) or multiple 90‐day reference periods to increase statistical power.FindingsIn the primary analyses, findings were inconclusive for the associations between varenicline and the main outcomes using a single reference period, while NRT was associated with MI [odds ratio (OR) = 1.40, 95% confidence interval (CI) = 1.18–1.67]. Using multiple reference periods, varenicline was associated with an increased risk of self‐harm (OR = 1.32, 95% CI = 1.12–1.56) and suicide (OR = 3.56, 95% CI = 1.32–9.60) but a reduction in all‐cause death (OR = 0.75, 95% CI = 0.61–0.93). NRT was associated with MI (OR = 1.54, 95% CI = 1.36–1.74), self‐harm (OR = 1.30, 95% CI = 1.18–1.44) and deaths from MI (OR = 1.53, 95% CI = 1.11–2.10), COPD (OR = 1.33, 95% CI = 1.14–1.56) and all causes (OR = 1.28, 95% CI = 1.18–1.40) when using multiple reference periods.ConclusionsThere appear to be positive associations between (1) nicotine replacement therapy (NRT) and myocardial infarction, death and risk of self‐harm and (2) varenicline and increased risk of self‐harm and suicide, as well as a negative association between varenicline and all‐cause death. The associations may not be causal. They may reflect health changes at the time of smoking cessation (nicotine replacement therapy is prescribed for people with cardiac problems) or be associated with quit attempts (exposure to both medicines was associated with self‐harm).

Rationale: Despite its widespread use in oncology, the PET radiotracer 18F-FDG is ineffectivefor improving early detection of pancreatic ductal adenocarcinoma (PDAC). An alternative strategy for early detection of pancreatic cancer involves visualisation of high-grade pancreatic intraepithelial neoplasias (PanIN-3), generally regarded as the non-invasive precursors of PDAC. The DNA damage response is known to be hyper-activated in late-stage PanINs. Therefore, we investigated whether the SPECT imaging agent, 111In-anti-γH2AX-TAT, allows visualisation of the DNA damage repair marker γH2AX in PanIN-3s in an engineered mouse model of PDAC, to facilitate early detection of PDAC. Methods: Genetically engineered KPC mice (KRasLSL.G12D/+; p53LSL.R172H/+; PdxCre) were imaged with 18F-FDG and 111In-anti-γH2AX-TAT. PanIN/PDAC presence visualised by histology was compared with autoradiography and immunofluorescence. Separately, the survival of KPC mice imaged with 111In-anti-γH2AX-TAT was evaluated. Results: In KPC mouse pancreata, γH2AX expression was increased in high-grade PanINs, but not in PDAC, corroborating earlier results obtained from human pancreas sections. Uptake of 111In-anti-γH2AX-TAT, but not 111In-IgG-TAT or 18F-FDG, within the pancreas was positively correlated with the age of KPC mice, which was correlated with the number of highgrade PanINs. 111In-anti-γH2AX-TAT localises preferentially in high-grade PanIN lesions, but not in established PDAC. Younger, non-tumour-bearing KPC mice that show uptake of 111Inanti-γH2AX-TAT in the pancreas survive significantly shorter than mice with physiological 111In-anti-γH2AX-TAT uptake. Conclusion: 111In-anti-γH2AX-TAT imaging allows non-invasive detection of DNA damage repair signalling upregulation in pre-invasive PanIN lesions and is a promising new tool to aid in the early detection and staging of pancreatic cancer.

Objectives Laryngotracheal stenosis is a rare condition characterized by upper airway narrowing. Reconstructive surgical treatment aims to manage the area of stenosis to improve dyspnea and can impact voice and swallowing function. This article critically evaluates the literature about voice and swallowing outcomes in adults with laryngotracheal stenosis who undergo reconstructive surgery. Study design Systematic review. Methods Six databases were searched for articles referring to voice and swallowing outcome measures following reconstruction procedures in adults with laryngotracheal stenosis. Screening was completed using predefined inclusion/exclusion criteria. Results A total of 143 abstracts were reviewed, with 67 articles selected for full-text review. Twenty studies met the inclusion criteria. Data extraction was completed with the Strengthening Reporting of Observational Studies in Epidemiology checklist with Oxford Centre for Evidence-Based Medicine Level of Evidence used to indicate quality. Risk of bias was assessed using the Risk of Bias Assessment Tool for Non-Randomized Studies. All studies scored a high risk of bias in at least one of the domains. Selection and timing of outcome measures was heterogenous, and there was limited information provided about rationale or reliability. Conclusions The literature acknowledges the importance of voice and swallowing outcomes following airway reconstruction. Studies show correlation between reconstructive surgery and deterioration in vocal function; there are no consistent data about swallowing outcomes. The lack of a core outcome measures set for adults with laryngotracheal stenosis limits the findings of this review. Further research is needed to establish clear criteria for robust and clinically relevant outcome measurement. Laryngoscope, 131:146-157, 2021.

Children with intellectual and developmental disabilities (IDD) are more likely to engage in behavior problems than children without IDD. In the present study, we explored whether adverse life experiences and events were related to child behavioral and emotional problems. We also examined whether child resilience would act as a protective factor in this putative association between adverse experiences and child behavioral and emotional problems. Mothers of 310 children with IDD aged between 4 and 15 years old completed a cross-sectional online survey including measures of exposure to adverse life experiences, child resilience, and behavior and emotional problems. In moderated multiple regression models, we found that exposure to adverse life experiences had a positive association with child behavior problems and peer problems and that these associations were moderated by child resilience. Resilience served a protective function—lowering risk of problems for children exposed to adversity. Child resilience also served a compensatory function, being directly associated with fewer conduct and emotional problems and increased pro-social behavior. Child resilience may be an important factor in understanding the behavior and emotional problems of children with IDD. Further, especially longitudinal, research is needed. Interventions designed to increase children’s resilience may be beneficial for children with IDD.

There is variability in the extent to which mothers are affected by the behavior problems of their children with developmental disabilities (DD). We explore whether maternal resilience functions as a protective or compensatory factor. In Studies 1 and 2, using moderated multiple regression models, we found evidence that maternal resilience functioned as a compensatory factor-having a significant independent main effect relationship with well-being outcomes in mothers of children with DD and autism spectrum disorder. However, there was no longitudinal association between resilience and maternal well-being outcomes. There was little evidence of the role of resilience as a protective factor between child behavior problems and maternal well-being in both studies.

Background & Aims Premenopausal women who are HCV positive (HCV+) have failing ovarian function, which is likely to impact their fertility. Thus, we investigated the reproductive history, risk of infertility, and pregnancy outcomes in women of childbearing age who were HCV+. Methods Three different groups were studied: (1) Clinical cohort: 100 women who were HCV+ and also had chronic liver disease (CLD), age matched with 50 women who were HBV+ with CLD and with 100 healthy women; all women were consecutively observed in three gastroenterology units in hospitals in Italy; (2) 1,998 women who were HCV+ and enrolled in the Italian Platform for the Study of Viral Hepatitis Therapies (PITER); (3) 6,085 women, who were mono-infected with HCV, and 20,415 women, who were HCV−, from a large de-identified insurance database from the USA. Measurements: total fertility rate (TFR) defined as the average number of children that a woman would bear during her lifetime. To define the reproductive stage of each participant, levels of anti-Müllerian hormone (AMH) and 17β-estradiol were measured. Results Clinical cohort: women who were either HCV+ or HBV+ had similar CLD severity and age at first pregnancy. Based on a multivariate analysis, women who were HCV+ had a higher risk of miscarriage than those who were HBV+ (odds ratio [OR] 6,905; 95% CI 1.771–26.926). Among women who were HCV+, incidence of miscarriage was correlated with median AMH level (1.0 ng/ml). Achieving a sustained virologic response (SVR) after antiviral treatment reduced the risk of miscarriage (OR 0.255; 95% CI 0.090–0.723). In the PITER-HCV cohort, miscarriage occurred in 42.0% of women (44.6% had multiple miscarriages). TFR for women who were HCV+ and between 15 and 49 years of age was 0.7 vs. 1.37 of Italian population of the same age range. In the US cohort: compared with women who were HCV−, women who were HCV+ positive were significantly more likely to have infertility (OR 2.439; 95% CI 2.130–2.794), premature birth (OR 1.34; 95% CI 1.060–1.690), gestational diabetes (OR 1.24; 95% CI 1.020–1.510), and pre-eclampsia (OR 1.206; 95% CI 0.935–1.556), and were less likely to have a live birth (OR 0.754; 95% CI 0.622–0.913). Conclusions Ovarian senescence in women of childbearing age who are HCV+ is associated with a lower chance of live birth, greater risk of infertility, gestational diabetes, pre-eclampsia and miscarriage. Such risks could be positively influenced by successful HCV cure. Lay summary Most new cases of HCV infection are among people who inject drugs, many of whom are young women in their childbearing years. Women of reproductive age who are HCV+ display markers of ovarian senescence. This is associated with an increased burden in terms of infertility and adverse pregnancy outcomes, including stillbirth, miscarriage, fewer live births, and gestational diabetes. Early viral suppression with therapy is likely to mitigate these risks.

This study utilized a mixed methods approach to examine the feasibility and acceptability of group compassion focused therapy for adults with intellectual disabilities (CFT-ID). Six participants with mild ID participated in six sessions of group CFT, specifically adapted for adults with ID. Session-by-session feasibility and acceptability measures suggested that participants understood the group content and process and experienced group sessions and experiential practices as helpful and enjoyable. Thematic analysis of focus groups identified three themes relating to (1) direct experiences of the group, (2) initial difficulties in being self-compassionate and (3) positive emotional changes. Pre- and post-group outcome measures indicated significant reductions in both self-criticism and unfavourable social comparisons. Results suggest that CFT can be adapted for individuals with ID and provide preliminary evidence that people with ID and psychological difficulties may experience a number of benefits from this group intervention.

Background Little is known about the experiences of parents whose sons or daughters are diagnosed with autism spectrum disorder (ASD) during adulthood.Method In this exploratory study, 6 mothers of...

Objectives Considerable variation has been reported in the prevalence and correlates of challenging behaviour (CB) in adults with intellectual disabilities (ID). To provide a robust estimate of prevalence, we identified the entire administrative population of adults with ID in a defined geographical area and used a behaviour assessment tool with good psychometric properties. Methods Data from 265 adults who were known to services were collected using a demographic survey tool and the Behavior Problems Inventory – Short Form. The prevalence of self-injurious, aggressive/destructive, stereotyped, and overall CB was evaluated. We explored the potential of developing cumulative risk indices (CRI) to inform longitudinal research and clinical practice. Results The prevalence of overall CB was 18.1% (95% CI: 13.94–23.19%). The prevalence of self-injurious behaviour was 7.5% (95% CI: 4.94–11.37%), aggressive–destructive behaviour 8.3% (95% CI: 5.54–12.25%), and stereotyped behaviour 10.9% (95% CI: 7.73–15.27%). Communication problems and severity of ID were consistently associated with higher risk of CBs. CRIs were significantly associated with CBs, and the five methods of CRI development produced similar results. Conclusions Findings suggest a multi-element response to CB is likely to be required that includes interventions for communication and daytime activity. Exploratory analyses of CRIs suggested these show promise as simple ways to capture cumulative risk in this population. Subject to longitudinal replication, such a tool may be especially useful in clinical practice to identify adults who are priority for interventions and predict future demand on services. Practitioner points The prevalence of challenging behaviour (CB) was 18.1% in this total population study. Stereotypy was the most frequent type of CB. Communication difficulties and severe-profound intellectual disabilities were most systematically related to the presence of CB. Establishing the effect of multiple risk factors is likely to identify people who are priority for interventions. Addressing multiple, rather than singular risks, is likely to be more efficacious. We tested five different methods of putting together a multiple risk index. All methods provided a reasonable association with CB. The most user-friendly method was the additive cumulative risk index (CRI). Limitations This is a cross-sectional design which enabled factors currently associated with CB to be identified for the whole cohort, but these variables may not be those conferring risk for the development or maintenance of CB over time. Future longitudinal research is required to replicate these CRI analyses before concluding about the CRI method with the highest predictive validity.

Background: Sleep apnoea is prevalent in dialysis patients. Previous studies identified excessive inflammation in ­patients with sleep apnoea. Online haemodiafiltration ­(OL-HDF) may reduce systematic inflammation through better clearance of middle molecules. We aimed to determine the feasibility of OL-HDF in sleep apnoea management. Methods: Eligible dialysis patients were screened for risk of sleep apnoea by nocturnal oximetry followed by a diagnostic sleep study to assess apnoea-hypopnea index (AHI). Patients with AHI ≥15/h were invited to a randomized crossover trial. The intervention was 2-month high-flux haemodialysis (HF-HD) followed by 2-month OL-HDF or vice versa with 1-month washout via HF-HD. Feasibility was assessed by patient recruitment and the primary outcome, severity of sleep apnoea (AHI). Secondary outcomes were pro-inflammatory cytokines, patient-reported daytime sleepiness, quality of sleep and health-related quality of life. Results: Of 65 participants at risk of sleep apnoea, only 15 were consented and randomized (mean age 70 years, 80% male, mean AHI 42.2/h). AHI was not statistically different between OL-HDF versus HF-HD (55.6/h vs. 48.3/h, p = 0.134); however, when sleep apnoea was stratified into obstructive and central apnoea, patients had less obstructive episodes after treated by OL-HDF (23.2/h vs. 18.6/h, p = 0.178); a sensitivity analysis was performed excluding outliers, and the treatment effect for obstructive episodes was found to be statistically significant (11.1 vs. 18.2/h, p = 0.019). Pro-inflammatory biomarkers and patient-reported outcomes were similar between OL-HDF and HF-HD. Conclusion: Patient recruitment was a major challenge in this feasibility study. OL-HDF may reduce obstructive sleep apnoea; however, the result needs to be confirmed by larger studies.

IntroductionSmoking among persons with a mental health disorder is associated with inequitable health, social and economic burden. Randomised controlled trials (RCTs) are considered the gold standard design for the assessment of healthcare intervention efficacy/effectiveness. However, many RCTs of smoking interventions for persons with a mental health disorder lack rigour due to low participant retention. No systematic review has pooled retention rates in randomised trials of smoking interventions for persons with a mental health disorder or explored associated factors. The aims of the systematic review will therefore be to: (1) summarise overall rates of participant retention in smoking cessation and reduction trials involving persons with a mental health disorder (including for experimental and control groups separately) and (2) determine if retention rates vary according to participant, environmental, researcher and study factors.Methods and analysisPsycINFO, EMBASE, MEDLINE, CENTRAL and The Cochrane Tobacco Addiction Review Group Specialised Register will be searched for reports of RCTs of outpatient smoking cessation or reduction interventions for adults with a mental health disorder. The search terms will include MeSH terms and free text words, and there will be no language or date restrictions. All databases will be searched from inception to present. Data will be analysed using the Mantel-Haenszel fixed-effect model, and where substantial heterogeneity (I2>50%) is detected, DerSimonian & Laird inverse-variance random effects model. Pooled estimates and 95% CIs will be calculated for overall participant retention rates and for intervention and control trial arms separately. Associations between participant retention and participant, environmental, researcher and study factors will be assessed via subgroup analyses and, where sufficient data are obtained, meta-regression.Ethics and disseminationThis study does not require ethical approval. The findings of this review will be disseminated via publication in a peer-reviewed open access medical journal and presentations at international scientific meetings.

ObjectivesOur primary objective was to estimate smoking prevalence and prescribing rates of varenicline and nicotine replacement therapy (NRT) in people with and without general practitioner (GP)-recorded dementia. Our secondary objective was to assess and compare quit rates of smokers with versus without GP-recorded dementia who were prescribed varenicline or NRT for smoking cessation.DesignA retrospective cohort study based on the analysis of electronic medical records within the Clinical Practice Research Datalink (2007–2015).Setting683 general practices in England.ParticipantsPeople with and without GP-recorded dementia, aged 18 years and have a code indicating that they are a current smoker.InterventionIndex prescription of varenicline or NRT (from 1 September 2006).Outcome measuresThe primary outcomes were smoking prevalence and prescribing rates of varenicline and NRT (2007–2015). The secondary outcome was smoking cessation at 2 years.ResultsAge and sex-standardised prevalence of smoking was slightly higher in people with GP-recorded dementia than in those without. There were 235 314 people aged 18 years and above prescribed NRT or varenicline. Among smokers with GP-recorded dementia (N=447), 409 were prescribed NRT and 38 varenicline. Smokers with GP-recorded dementia were 74% less likely (95% CI 64% to 82%) to be prescribed varenicline than NRT, compared with smokers without GP-recorded dementia. Compared with people without GP-recorded dementia, people with GP-recorded dementia had consistently lower prescribing rates of varenicline from 2007 to 2015. Two years after prescription, there was no clear evidence for a difference in the likelihood of smoking cessation after prescription of these medications between individuals with and without dementia (OR 1.0, 95% CI 0.8 to 1.2).ConclusionsBetween 2007 and 2015, people with GP-recorded dementia were less likely to be prescribed varenicline than those without dementia. Quit rates following prescription of either NRT or varenicline were similar in those with and without dementia.

Objective We conducted a prospective cohort study of the Clinical Practice Research Database to estimate rates of varenicline and nicotine replacement therapy (NRT) prescribing and the relative effects on smoking cessation, and mental health. Methods We used multivariable logistic regression, propensity score matched regression, and instrumental variable analysis. Exposure was varenicline or NRT prescription. Mental disorders were bipolar, depression, neurotic disorder, schizophrenia, or prescriptions of antidepressants, antipsychotics, hypnotics/anxiolytics, mood stabilizers. Outcomes were smoking cessation, and incidence of neurotic disorder, depression, prescription of antidepressants, or hypnotics/anxiolytics. Follow-ups were 3, 6, and 9 months, and at 1, 2, and 4 years. Results In all patients, NRT and varenicline prescribing declined during the study period. Seventy-eight thousand four hundred fifty-seven smokers with mental disorders aged ≥18 years were prescribed NRT (N = 59 340) or varenicline (N = 19 117) from September 1, 2006 to December 31, 2015. Compared with smokers without mental disorders, smokers with mental disorders had 31% (95% CI: 29% to 33%) lower odds of being prescribed varenicline relative to NRT, but had 19% (95% CI: 15% to 24%) greater odds of quitting at 2 years when prescribed varenicline relative to NRT. Overall, varenicline was associated with decreased or similar odds of worse mental health outcomes than NRT in patients both with and without mental disorders, although there was some variation when analyses were stratified by mental disorder subgroup. Conclusions Smoking cessation medication prescribing may be declining in primary care. Varenicline was more effective than NRT for smoking cessation in patients with mental disorders and there is not clear consistent evidence that varenicline is adversely associated with poorer mental health outcomes. Implications Patients with mental disorders were less likely to be prescribed varenicline than NRT. We triangulated results from three analytical techniques. We found that varenicline was more effective than NRT for smoking cessation in patients with mental disorders. Varenicline was generally associated with similar or decreased odds of poorer mental health outcomes (ie, improvements in mental health) when compared with NRT. We report these findings cautiously as our data are observational and are at risk of confounding.

The dysconnection hypothesis of schizophrenia (SZ) proposes that psychosis is best understood in terms of aberrant connectivity. Specifically, it suggests that dysconnectivity arises through aberrant synaptic modulation associated with deficits in GABAergic inhibition, excitation–inhibition balance and disturbances of high-frequency oscillations. Using a computational model combined with a graded-difficulty visual orientation discrimination paradigm, we demonstrate that, in SZ, perceptual performance is determined by the balance of excitation–inhibition in superficial cortical layers. Twenty-eight individuals with a DSM-IV diagnosis of SZ, and 30 age- and gender-matched healthy controls participated in a psychophysics orientation discrimination task, a visual grating magnetoencephalography (MEG) recording, and a magnetic resonance spectroscopy (MRS) scan for GABA. Using a neurophysiologically informed model, we quantified group differences in GABA, gamma measures, and the predictive validity of model parameters for orientation discrimination in the SZ group. MEG visual gamma frequency was reduced in SZ, with lower peak frequency associated with more severe negative symptoms. Orientation discrimination performance was impaired in SZ. Dynamic causal modeling of the MEG data showed that local synaptic connections were reduced in SZ and local inhibition correlated negatively with the severity of negative symptoms. The effective connectivity between inhibitory interneurons and superficial pyramidal cells predicted orientation discrimination performance within the SZ group; consistent with graded, behaviorally relevant, disease-related changes in local GABAergic connections. Occipital GABA levels were significantly reduced in SZ but did not predict behavioral performance or oscillatory measures. These findings endorse the importance, and behavioral relevance, of GABAergic synaptic disconnection in schizophrenia that underwrites excitation–inhibition balance.

Highlights • Beta rebound (PMBR) is reduced in recent-onset and established schizophrenia cases • In established cases, PMBR is negatively correlated with disorganisation symptoms • Hidden Markov model shows different transient pan-spectral bursts underlying PMBR., Magnetoencephalography (MEG) measures magnetic fields generated by synchronised neural current flow and provides direct inference on brain electrophysiology and connectivity, with high spatial and temporal resolution. The movement-related beta decrease (MRBD) and the post-movement beta rebound (PMBR) are well-characterised effects in magnetoencephalography (MEG), with the latter having been shown to relate to long-range network integrity. Our previous work has shown that the PMBR is diminished (relative to controls) in a group of schizophrenia patients. However, little is known about how this effect might differ in patients at different stages of illness and degrees of clinical severity. Here, we extend our previous findings showing that the MEG derived PMBR abnormality in schizophrenia exists in 29 recent-onset and 35 established cases (i.e., chronic patients), compared to 42 control cases. In established cases, PMBR is negatively correlated with severity of disorganization symptoms. Further, using a hidden Markov model analysis, we show that transient pan-spectral oscillatory ”bursts”, which underlie the PMBR, differ between healthy controls and patients. Results corroborate that PMBR is associated with disorganization of mental activity in schizophrenia.

A major barrier to clinicians referring service users with psychosis for psychological therapies is the belief that they will not engage. We investigated therapy receipt after discharge, in a sample of service users who had already demonstrated willingness to engage in psychological therapy during an inpatient admission. Only one-third of service users (33%; 16/48) received at least 1 session of evidence-based therapy at 6-month follow-up after discharge. Therapy receipt was more common for service users with (i) lower delusional distress at discharge, (ii) Black and Minority Ethnic (BME) background, and (iii) discharged to an Early Intervention (EI) service.

The spinal cord is vital for the processing of sensorimotor information and for its propagation to and from both the brain and the periphery. Spinal cord function is affected by aging, however, the mechanisms involved are not well-understood. To characterize molecular mechanisms of spinal cord aging, microarray analyses of gene expression were performed on cervical spinal cords of aging rats. Of the metabolic and signaling pathways affected, cholesterol-associated pathways were the most comprehensively altered, including significant downregulation of cholesterol synthesis-related genes and upregulation of cholesterol transport and metabolism genes. Paradoxically, a significant increase in total cholesterol content was observed-likely associated with cholesterol ester accumulation. To investigate potential mechanisms for the perturbed cholesterol homeostasis, we quantified the expression of myelin and neuroinflammation-associated genes and proteins. Although there was minimal change in myelin-related expression, there was an increase in phagocytic microglial and astrogliosis markers, particularly in the white matter. Together, these results suggest that perturbed cholesterol homeostasis, possibly as a result of increased inflammatory activation in spinal cord white matter, may contribute to impaired spinal cord function with aging.

Introduction Heparin is commonly used after hemodialysis treatments as a locking solution to prevent catheter thrombosis. The comparative efficacy and safety of different heparin concentrations to maintain catheter patency has been previously reported in retrospective studies. We conducted a prospective, randomised, controlled study of 1000 U/mL heparin (low dose) versus 5000 U/mL heparin (high dose) locking solution to maintain patency of tunnelled catheters. Methods One hundred patients receiving chronic, unit-based hemodialysis with newly placed tunnelled hemodialysis catheters (less than 1 week) were randomly assigned to either a low dose (n = 48) or high dose heparin (n=52). The primary intention-to-treat analysis examined time to malfunction in both groups over a 90 day period. A secondary analysis compared baseline patient characteristics in relation to catheter malfunction. Findings Overall rate of catheter patency loss was 32% of catheters by 90 days. There was no significant difference in time to malfunction of catheters locked with low dose or high dose heparin (P = 0.5770). Time to catheter malfunction was not associated with diabetic, hypertensive or smoking status. There was no difference in mean delivered blood flow rate, venous and arterial pressure, and dialysis adequacy between low dose and high dose groups. No patient suffered a hemorrhagic complication requiring hospitalisation during the study period. Discussion Low dose heparin is adequate to maintain tunnelled hemodialysis catheter patency when compared with high dose heparin. The study also suggests that there is no relationship between catheter malfunction and diabetic, hypertensive or smoking status.

Background Diagnosing attention deficit/hyperactivity disorder (ADHD) in children and young people typically relies on clinical observation and subjective parent, teacher and self-reports. The subjective nature of reports combined with contradictory or missing data can result in diagnostic uncertainty and delay. The aim of this study was to assess whether the addition of an objective test of attention, impulsivity and activity (QbTest) as an adjunct to standard ADHD assessment could accelerate the diagnostic process in routine National Health Service (NHS) settings. Method In a pre vs. post-test audit design, case records were examined in 40 cases diagnosed without the QbTest [pre-QbTest group] and 40 cases diagnosed with the QbTest [QbTest group], recording the number of consultations until a confirmed ADHD diagnosis was reached. Results Using Poisson regression, significantly fewer clinician consultations (mean 2.18 vs. 3.05; p < .02) were required to confirm the diagnosis of ADHD when the QbTest was used to augment assessment in comparison to standard assessment as usual. Conclusions The findings suggest that the addition of the QbTest to standard clinical assessment may reduce time to diagnosis and potentially result in cost savings to the NHS. These preliminary data suggest that there is a potentially clinically meaningful benefit of adding the QbTest to routine clinical ADHD assessment and this should be examined next in the context of a randomised controlled trial.

Purpose: This article presents a detailed review of the etiology of laryngotracheal stenosis, common surgical procedures, and typical pathophysiological changes affecting swallowing function. We describe the redundancy in airway protection and the possibility of safe swallowing in suboptimal conditions. Conclusion: Comprehensive understanding of unique patient factors and swallowing physiology in this complex population facilitates targeted and patient-specific rehabilitation.

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© 2018 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health. Background: Diagnosis of attention deficit hyperactivity disorder (ADHD) relies on subjective methods which can lead to diagnostic uncertainty and delay. This trial evaluated the impact of providing a computerised test of attention and activity (QbTest) report on the speed and accuracy of diagnostic decision-making in children with suspected ADHD. Methods: Randomised, parallel, single-blind controlled trial in mental health and community paediatric clinics in England. Participants were 6–17years-old and referred for ADHD diagnostic assessment; all underwent assessment-as-usual, plus QbTest. Participants and their clinician were randomised to either receive the QbTest report immediately (QbOpen group) or the report was withheld (QbBlind group). The primary outcome was number of consultations until a diagnostic decision confirming/excluding ADHD within 6-months from baseline. Health economic cost-effectiveness and cost utility analysis was conducted. Assessing QbTest Utility in ADHD: A Randomised Controlled Trial was registered at ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT02209116). Results: One hundred and thirty-two participants were randomised to QbOpen group (123 analysed) and 135 to QbBlind group (127 analysed). Clinicians with access to the QbTest report (QbOpen) were more likely to reach a diagnostic decision about ADHD (hazard ratio 1.44, 95% CI 1.04–2.01). At 6-months, 76% of those with a QbTest report had received a diagnostic decision, compared with 50% without. QbTest reduced appointment length by 15% (time ratio 0.85, 95% CI 0.77–0.93), increased clinicians’ confidence in their diagnostic decisions (odds ratio 1.77, 95% CI 1.09–2.89) and doubled the likelihood of excluding ADHD. There was no difference in diagnostic accuracy. Health economic analysis showed a position of strict dominance; however, cost savings were small suggesting that the impact of providing the QbTest report within this trial can best be viewed as ‘cost neutral’. Conclusions: QbTest may increase the efficiency of ADHD assessment pathway allowing greater patient throughput with clinicians reaching diagnostic decisions faster without compromising diagnostic accuracy.

Background Evidence shows that the relationship between depression and smoking may be bi-directional, with smoking increasing the risk for subsequent depression, and vice versa—translating into significantly higher smoking rates among those with depression compared to the general population. Computational models can be used to assess trends in smoking but have not been utilized to examine populations with behavioral health comorbidities. We develop the first joint model of smoking and depression, projecting future smoking patterns under a 'status quo' scenario. Methods We use a compartmental model to simulate individuals transitioning across smoking and depressive states from birth to age 99 or death. The model is calibrated to reproduce smoking and depression data from the 2005-2014 U.S. National Survey on Drug Use and Health. Current smokers report smoking within the past year and smoked at least 100 cigarettes in their lifetime while those with depression report a major depressive episode in the past year. Parameters for the effects of smoking and depression on each other were drawn from existing literature. [Smoking and depression model diagram] Results From 2015 to 2050, smoking prevalence among women with depression is projected to decline by 43.5% (27.6% to 15.6%), compared to 46.9% (17.9% to 9.5%) for women who report never having had a depressive episode. Among men with depression, smoking prevalence is expected to decline by 32.0% (34.4% to 23.4%), compared to 39.0% (24.1% to 14.7%) for men who report never being depressed. The likelihood of smoking among those with depression is projected to increase. Conclusions This model can be used to examine trends and identify optimal interventions to address smoking disparities by depressive status. Smoking prevalence among people with depression is expected to decline, though not as rapidly as for those without depression. In the absence of population-level strategies, smoking and tobacco-related diseases will continue to further disproportionately burden people with depression.

Research exploring the experiences of families during the process of seeking out-of-home accommodation for an adult son or daughter with intellectual disability is scarce. A study was undertaken to examine this process. Nine families currently seeking out-of-home accommodation for their adult son or daughter were interviewed and interview data were analyzed using thematic analysis. Two main themes were identified: (1) reasons for seeking housing and (2) experiences of seeking housing. Parents' aging and increased health problems along with the offspring's wish for greater independence were the main reasons for seeking out-of home accommodation. Experiences of looking for a house were not straightforward in that parents often wanted to plan ahead but were prevented from doing so as the housing system prioritizes “housing crises.” Findings showed that families experienced seeking housing as stressful and frustrating and would like to see social care and housing professionals acknowledge them as collaborative partners in the process. The authors conclude there also needs to be greater clarity of expectation of the duration of finding suitable accommodation, a process that needs to be started early in a young adult's life.

Research evaluations of Applied Behaviour Analysis (ABA)-based interventions for children with autism demonstrate positive outcomes. However, little research has focused on the translation of these evidence-based interventions into service delivery models within existing education systems. In the present article, we provide a description of the comprehensive ABA-based educational model used within TreeHouse School, London, UK. In addition, we analyse progress data over 12 months for a group of learners attending the school. Fifty-three students with autism were tested and then re-tested with the Assessment of Basic Language and Learning Skills (ABLLS-R). For 23 of these students a repeated Vineland Adaptive Behavior Scales (VABS) assessment was also available. Repeated measures t-tests revealed statistically significant improvements over time on all ABLLS domains and for all VABS scores. These data provide preliminary evidence that an ABA-based educational model can be integrated into the UK system and produce positive outcomes for children.

Background: Expressed emotion (EE) is a construct used to measure the emotional climate within families. EE is of interest to researchers in the field of autism spectrum disorder (ASD) because of its putative implications for child development. The aim was to explore whether maternal EE differs towards a child with ASD and a non-disabled sibling. Methods: We adopted a within-family design with 143 mothers of children with ASD and a non-disabled sibling. EE was measured using the Five-Minute Speech Sample. Results: Wilcoxon signed-rank tests were utilised. Mothers were coded as significantly more critical and less warm towards their child with ASD than towards the sibling. There were no significant differences in maternal emotional overinvolvement or overall EE towards the child with ASD and a sibling. Conclusions: The data support the results of previous research suggesting that EE is linked to the relationship a mother has with individual children, rather than being evidence of the character disposition of mothers. More research is needed to understand the emotional dimensions of parent–child relationships in families with children with ASD.

Purpose of review Adult laryngotracheal stenosis is a rare, multifactorial condition which carries a significant physical and psychosocial burden. Surgical approaches have developed in recent years, however, voice and swallowing function can be affected prior to treatment, in the immediate postoperative phase, and as an ongoing consequence of the condition and surgical intervention. In this study we discuss: the nature of the problem; surgical interventions to address airway disorders; optimal patterns of care to maximize voice and swallowing outcomes. Recent findings Studies in this field are limited and focused on surgical outcomes and airway status with voice and swallowing a secondary consideration. Retrospective studies of swallowing have focused on factors such as the duration of dysphagia symptoms following airway surgery and made comparisons between type of surgery, use of stent, and length of swallowing problems. The literature suggests that patients are likely to return to their preoperative diet. There has been a focus on voice outcomes following cricotracheal resection which results in a postoperative decrease in the fundamental frequency. However, study comparisons are limited by the use of inconsistent outcome measures (for both voice and swallowing) which are often not validated, with heterogeneous groups and varying surgical techniques. Summary The limited literature suggests that swallowing function is more likely to recover to presurgical status than voice function. Further prospective studies incorporating consistent instrumental, clinician, and patient-reported outcome measurement are required to understand the nature and extent of dysphagia and dysphonia resulting from this condition and its treatment.

The diagnosis and monitoring of Attention deficit hyperactivity disorder (ADHD) typically relies on subjective reports and observations. Objective continuous performance tests (CPTs) have been incorporated into some services to support clinical decision making. However, the feasibility and acceptability of adding such a test into routine practice is unknown. The study aimed to investigate the feasibility and acceptability of adding an objective computerised test to the routine assessment and monitoring of attention deficit hyperactivity disorder (ADHD). Semi-structured interviews were conducted with clinicians (n = 10) and families (parents/young people, n = 20) who participated in a randomised controlled trial. Additionally, the same clinicians (n = 10) and families (n = 76) completed a survey assessing their experience of the QbTest. The study took place in child and adolescent mental health and community paediatric clinics across the UK. Interview transcripts were thematically analysed. Interviewed clinicians and families valued the QbTest for providing an objective, valid assessment of symptoms. The QbTest was noted to facilitate communication between clinicians, families and schools. However, whereas clinicians were more unanimous on the usefulness of the QbTest, survey findings showed that, although the majority of families found the test useful, less than half felt the QbTest helped them understand the clinician’s decision making around diagnosis and medication. The QbTest was seen as a potentially valuable tool to use early in the assessment process to streamline the care pathway. Although clinicians were conscious of the additional costs, these could be offset by reductions in time to diagnosis and the delivery of the test by a Healthcare Assistant. The findings indicate the QbTest is an acceptable and feasible tool to implement in routine clinical settings. Clinicians should be mindful to discuss the QbTest results with families to enable their understanding and engagement with the process. Further findings from definitive trials are required to understand the cost/benefit; however, the findings from this study support the feasibility and acceptability of integrating QbTest in the ADHD care pathway. The findings form the implementation component of the Assessing QbTest Utility in ADHD (AQUA) Trial which is registered with the ISRCTN registry ( ISRCTN11727351 , retrospectively registered 04 July 2016) and clinicaltrials.gov ( NCT02209116 , registered 04 August 2014).

Background: Little is known about the work-related well-being of applied behaviour analysis (ABA) therapists who work in school-based contexts and deliver ABA interventions to children with autism. Methods: A questionnaire on work-related stress (burnout), general distress, perceived supervisor support and coping was completed by 45 ABA therapists across six schools in the UK. Results: Around 42% of ABA therapists reported low levels of personal accomplishment at work, 13% reported high levels of emotional exhaustion and 40% met criteria for experiencing high levels of general distress. Wishful thinking coping was predictive of higher emotional exhaustion burnout and depersonalisation, and lower personal accomplishment. Conclusions: Given that a wishful thinking approach to coping may contribute to experiencing stress at work, it is important to consider support interventions for ABA therapists that may enhance their well-being. Mindfulness and acceptance-based strategies in particular may be relevant to ...

Motile cilia are an essential component of the mouse, zebrafish, and Xenopus laevis Left Right Organizers, generating nodal flow and allowing the reception and transduction of mechanosensory signals. Nonmotile primary cilia are also an important component of the Left Right Organizer's chemosensory mechanism. It has been proposed in the chicken that signaling in Hensen's node, the Left Right Organizer of the chicken, is independent of cilia, based on a lack of evidence of motile cilia or nodal flow. It is speculated that the talpid3 chicken mutant, which has normal left–right patterning despite lacking cilia at many stages of development, is proof of this hypothesis. Here, we examine the evidence for cilia in Hensen's node and find that although cilia are present; they are likely to be immotile and incapable of generating nodal flow. Furthermore, we find that early planar cell polarity patterning and ciliogenesis is normal in early talpid3 chicken embryos. We conclude that patterning and development of the early talpid3 chicken is normal, but not necessarily independent of cilia. Although it appears that Hensen's node does not require motile cilia or the generation of motile flow, there may remain a requirement for cilia in the transduction of SHH signaling. Results FOXJ1 is expressed at low levels in the chicken node incompatible with motile cilia generation Short cilia are present in the mesodermal cells of the chicken node Talpid3 chicken embryos have normal VANGL2 localization early in development Talpid3 chicken embryos have primary cilia early in development

BackgroundSleep-disordered breathing (SDB) is common in patients with kidney disease; but often underdiagnosed as it is infrequently assessed in clinical practice. The objective of this study was to assess the risk factors of SDB in haemodialysis patients, and to identify useful assessment tools to detect SDB in this population.MethodsWe used nocturnal oximetry, Epworth Sleepiness Scale (ESS) and STOPBANG questionnaire to screen for SDB in haemodialysis patients. Presence of SDB was defined by Oxygen desaturation index (ODI≥5/h), and further confirmed by apnoea-hypopnea index (AHI) from an in-laboratory polysomnography. Blood samples were collected prior to commencing a haemodialysis treatment.ResultsSDB was detected in 70% of participants (N = 107, mean age 67 years). STOPBANG revealed that 89% of participants were at risk of SDB; however, only 17% reported daytime sleepiness on the ESS. Of the participants who underwent polysomnography (n = 36), obstructive sleep apnoea was identified in 86%, and median AHI was 34.5/h. Oximetry and AHI results were positively correlated (r = 0.62, P = 0.0001), as were oximetry and STOPBANG (r = 0.48; PConclusionDialysis patients with a large neck circumference and anaemia are at risk of SDB; using nocturnal oximetry is practical and reliable to screen for SDB and should be considered in routine management of dialysis patients, particularly for those who demonstrate risk factors.

Transactivation of epidermal growth factor receptor (EGFR) signaling by G protein-coupled receptors has been implicated in several cardiovascular (CV) conditions, including hypertension, heart failure, and cardiac and vascular hypertrophy. However, the therapeutic potential of EGFR inhibition in these conditions is currently unknown. The main objective of the present study was to investigate cardiac, vascular, and renal effects of EGFR inhibition by 4-[4-[[(1R)-1-phenylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenol (PKI-166) in the hypertensive chronic kidney disease model. Rats underwent 5/6 nephrectomy (5/6Nx) and were treated with PKI-166, lisinopril or vehicle from week 6 after disease induction until week 12. Sham animals received either PKI-166 or vehicle. Treatment with PKI-166 did not affect the development of the characteristic renal features in 5/6Nx, including proteinuria, diminished creatinine clearance, and increased glomerulosclerosis, whereas these were attenuated by lisinopril. Despite absence of effects on progressive renal damage, PKI-166 attenuated the progression of hypertension and maintained cardiac function (left ventricle end-diastolic pressure) to a similar extent as lisinopril. Also, PKI-166 attenuated the increase in phosphorylated EGFR in the heart as induced by 5/6Nx. Moreover, PKI-166 and lisinopril restored the impaired contraction of isolated thoracic aortic rings to phenylephrine and angiotensin II and impaired myogenic constriction of small mesenteric arteries in 5/6Nx rats. Blockade of the EGFR displays a CV benefit independent of limiting the progression of renal injury. Our findings extend the evidence on EGFR signaling as a target in CV disorders.

Knowledge on cross-cultural quality of life (QOL) and illness perceptions may help women with breast cancer cope more effectively. The self regulation model (SRM) guided the current exploratory longitudinal pilot-study. Central to SRM is the perception of health threats and their effects on QOL. Illness perceptions and QOL were assessed in 22 Dutch and 21 Japanese patients with breast cancer who filled out questionnaires before, 1 week, and 8 weeks after the first chemotherapy course. The questionnaires assessed QOL and illness perceptions. Patients' scores were compared with groups of patients with other chronic somatic illnesses (asthma, diabetes). Patients in both samples reported major impact of chemotherapy on global health status, physical functioning, role functioning, emotional functioning, constipation and diarrhea. Differences between Japanese and Dutch patients were limited to social functioning and financial problems. Japanese patients expressed stronger concerns about their illness than Dutch patients. Results of the Japanese and Dutch patients with breast cancer differed from data in patients with asthma on consequences, timeline, concern and emotional response. Results of Japanese patients differed from patients with type 2 diabetes on timeline and concern, whereas Dutch patients differed on timeline and consequences. Japanese and Dutch breast cancer patients have-overall-similar illness perceptions and QOL responses and are aware of the typical characteristics of their disease. The results support the feasibility of cross-cultural psychosocial research in oncology and offer implications for clinical interventions which impact on self-efficacy to empower patients with breast cancer.

Approximately 10–20 % of adults with intellectual disabilities engage in challenging behaviours such as aggression, destructiveness, and self-injury, which are often accompanied by feelings of anger. The inability to manage anger can reduce quality of life. For example, aggression is a strong predictor of out-of-area placements and is a risk variable for abuse. Recent research suggests that mindfulness-based therapies (specifically, Singh’s Soles of the Feet meditation) can help people with intellectual disabilities manage angry emotions, with resultant reductions in challenging behaviour. However, previous research has been single-case design studies, and no group studies have been published with people with intellectual disabilities and aggressive behaviour. For this feasibility study, a UK protocol will be developed for use by health professionals within National Health Service (NHS) Intellectual Disability (ID) teams, based upon Singh’s Soles of the Feet manual. Twenty adults with intellectual disabilities and identified problems with anger control will be recruited and six sessions will be delivered by a trained ID clinician. The study will monitor participant’s aggressive behaviour, health-related quality of life, anxiety, depression, and use of support services (medication, hospital appointments etc.). These will be measured at three time points: (1) Baseline (within 2 weeks prior to the first session of the intervention), (2) 2 months post-baseline, and (3) 6 months post-baseline. Qualitative interviews will be conducted with participants, their carers, and the therapists who delivered the intervention. In order to help design an economic evaluation alongside a future full trial, we will cost the intervention and test the acceptability and validity of health economics measures to record resource use and health-related quality of life outcomes. The data from this study will inform the feasibility of the project protocol and intervention, which will help develop future research and to determine whether a larger, randomised controlled trial with concurrent economic evaluation is feasible. UKCERN: 16743 .

This study is based on extensive studies in the mouse of the role of CSF1 in monocyte-macrophage production and differentiation and the function of macrophages in the control of hepatocyte proliferation. We use a novel form of CSF1, an Fc fusion protein, to demonstrate that the findings in mice can be extended to large animals. We discuss the possible role for CSF1 in homeostatic control of the size of the liver., Macrophage colony-stimulating factor (CSF1) is an essential growth and differentiation factor for cells of the macrophage lineage. To explore the role of CSF1 in steady-state control of monocyte production and differentiation and tissue repair, we previously developed a bioactive protein with a longer half-life in circulation by fusing pig CSF1 with the Fc region of pig IgG1a. CSF1-Fc administration to pigs expanded progenitor pools in the marrow and selectively increased monocyte numbers and their expression of the maturation marker CD163. There was a rapid increase in the size of the liver, and extensive proliferation of hepatocytes associated with increased macrophage infiltration. Despite the large influx of macrophages, there was no evidence of liver injury and no increase in circulating liver enzymes. Microarray expression profiling of livers identified increased expression of macrophage markers, i.e., cytokines such as TNF, IL1, and IL6 known to influence hepatocyte proliferation, alongside cell cycle genes. The analysis also revealed selective enrichment of genes associated with portal, as opposed to centrilobular regions, as seen in hepatic regeneration. Combined with earlier data from the mouse, this study supports the existence of a CSF1-dependent feedback loop, linking macrophages of the liver with bone marrow and blood monocytes, to mediate homeostatic control of the size of the liver. The results also provide evidence of safety and efficacy for possible clinical applications of CSF1-Fc.