SFX-01 in hospitalised patients with community-acquired pneumonia during the COVID-19 pandemic: a double-blind, randomised, placebo-controlled trial.

Introduction: Sulforaphane can induce the transcription factor, Nrf2, promoting antioxidant and anti-inflammatory responses. In this study, hospitalised patients with community-acquired pneumonia (CAP) were treated with stabilised synthetic sulforaphane (SFX-01) to evaluate impact on clinical status and inflammation. Methods: Double-blind, randomised, placebo-controlled trial of SFX-01 (300 mg oral capsule, once daily for 14 days) conducted in Dundee, UK, between November 2020 and May 2021. Patients had radiologically confirmed CAP and CURB-65 (confusion, urea >7 mmol·L-1, respiratory rate ≥30 breaths·min-1, blood pressure <90 mmHg (systolic) or ≤60 mmHg (diastolic), age ≥65 years) score ≥1. The primary outcome was the seven-point World Health Organization clinical status scale at day 15. Secondary outcomes included time to clinical improvement, length of stay and mortality. Effects on Nrf2 activity and inflammation were evaluated on days 1, 8 and 15 by measurement of 45 serum cytokines and mRNA sequencing of peripheral blood leukocytes. Results: The trial was terminated prematurely due to futility with 133 patients enrolled. 65 patients were randomised to SFX-01 treatment and 68 patients to placebo. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was the cause of CAP in 103 (77%) cases. SFX-01 treatment did not improve clinical status at day 15 (adjusted OR 0.87, 95% CI 0.41-1.83; p=0.71), time to clinical improvement (adjusted hazard ratio (aHR) 1.02, 95% CI 0.70-1.49), length of stay (aHR 0.84, 95% CI 0.56-1.26) or 28-day mortality (aHR 1.45, 95% CI 0.67-3.16). The expression of Nrf2 targets and pro-inflammatory genes, including interleukin (IL)-6, IL-1ß and tumour necrosis factor-α, was not significantly changed by SFX-01 treatment. At days 8 and 15, respectively, 310 and 42 significant differentially expressed genes were identified between groups (false discovery rate adjusted p<0.05, log2FC >1). Conclusion: SFX-01 treatment did not improve clinical status or modulate key Nrf2 targets in patients with CAP primarily due to SARS-CoV-2 infection.

The Impact of Methylphenidate on Pubertal Maturation and Bone Age in ADHD Children and Adolescents: Results from the ADHD Drugs Use Chronic Effects (ADDUCE) Project.

OBJECTIVE: The short-term safety of methylphenidate (MPH) has been widely demonstrated; however the long-term safety is less clear. The aim of this study was to investigate the safety of MPH in relation to pubertal maturation and to explore the monitoring of bone age. METHOD: Participants from ADDUCE, a two-year observational longitudinal study with three parallel cohorts (MPH group, no-MPH group, and a non-ADHD control group), were compared with respect to Tanner staging. An Italian subsample of medicated-ADHD was further assessed by the monitoring of bone age. RESULTS: The medicated and unmedicated ADHD groups did not differ in Tanner stages indicating no higher risk of sexual maturational delay in the MPH-treated patients. The medicated subsample monitored for bone age showed a slight acceleration of the bone maturation after 24 months, however their predicted adult height remained stable. CONCLUSION: Our results do not suggest safety concerns on long-term treatment with MPH in relation to pubertal maturation and growth.

Methylphenidate and Sleep Difficulties in Children and Adolescents With ADHD: Results From the 2-Year Naturalistic Pharmacovigilance ADDUCE Study.

OBJECTIVE: Short-term RCTs have demonstrated that MPH-treatment significantly reduces ADHD-symptoms, but is also associated with adverse events, including sleep problems. However, data on long-term effects of MPH on sleep remain limited. METHODS: We performed a 2-year naturalistic prospective pharmacovigilance multicentre study. Participants were recruited into three groups: ADHD patients intending to start MPH-treatment (MPH-group), those not intending to use ADHD-medication (no-MPH-group), and a non-ADHD control-group. Sleep problems were assessed with the Children's-Sleep-Habits-Questionnaire (CSHQ). RESULTS: 1,410 participants were enrolled. Baseline mean CSHQ-total-sleep-scores could be considered clinically significant for the MPH-group and the no-MPH-group, but not for controls. The only group to show a significant increase in any aspect of sleep from baseline to 24-months was the control-group. Comparing the MPH- to the no-MPH-group no differences in total-sleep-score changes were found. CONCLUSION: Our findings support that sleep-problems are common in ADHD, but don't suggest significant negative long-term effects of MPH on sleep.

Environmental risk factors for respiratory infection and wheeze in young children: A multicentre birth cohort study.

INTRODUCTION: Respiratory infections and wheeze have a considerable impact on the health of young children and consume significant healthcare resources. We aimed to evaluate the effect of environmental factors on respiratory infections and symptoms in early childhood. METHODS: Environmental risk factors including: daycare attendance; breastfeeding; siblings; damp within the home; environmental tobacco smoke (ETS); child's bedroom flooring; animal exposure; road traffic density around child's home; and solid fuel pollution within home were assessed in children recruited to the GO-CHILD multicentre prospective birth cohort study. Follow-up information on respiratory infections (bronchiolitis, pneumonia, otitis media and cold or flu), wheeze and cough symptoms, healthcare utilisation and medication prescription was collected by postal questionnaires at 12 and 24 months. Log binomial and ordered logistic regression models were fitted to the data. RESULTS: Follow-up was obtained on 1344 children. Daycare was associated with increased odds of pneumonia (odds ratio [OR] = 2.39, 95% confidence interval [CI]: 1.04-5.49), bronchiolitis (OR = 1.40, 1.02-1.90), otitis media (OR = 1.68, 1.32-2.14) and emergency department attendance for wheeze (RR = 1.81, 1.17-2.80). Breastfeeding beyond 6 months was associated with a reduced odds of bronchiolitis (OR = 0.55, 0.39-0.77) and otitis media (OR = 0.75, 0.59-0.99). Siblings at home was associated with an increased odds of bronchiolitis (OR = 1.65, 1.18-2.32) and risk of reliever inhaler prescription (RR = 1.37, 1.02-1.85). Visible damp was associated with an increased odds of wheeze (OR = 1.85, 1.11-3.19), and risk of reliever inhaler (RR = 1.73, 1.04-2.89) and inhaled corticosteroid prescription (RR = 2.61, 1.03-6.59). ETS exposure was associated with an increased odds of primary care attendance for cough or wheeze (OR = 1.52, 1.11-2.08). Dense traffic around the child's home was associated with an increased odds of bronchiolitis (OR = 1.32, 1.08-2.29). CONCLUSION: Environmental factors likely influence the wide variation in infection frequency and symptoms observed in early childhood. Larger population studies are necessary to further inform and guide public health policy to decrease the burden of respiratory infections and wheeze in young children.

Long-term safety of methylphenidate in children and adolescents with ADHD: 2-year outcomes of the Attention Deficit Hyperactivity Disorder Drugs Use Chronic Effects (ADDUCE) study.

BACKGROUND: Methylphenidate is the most frequently prescribed medication for the treatment of ADHD in children and adolescents in many countries. Although many randomised controlled trials support short-term efficacy, tolerability, and safety, data on long-term safety and tolerability are scarce. The aim of this study was to investigate the safety of methylphenidate over a 2-year period in relation to growth and development, psychiatric health, neurological health, and cardiovascular function in children and adolescents. METHODS: We conducted a naturalistic, longitudinal, controlled study as part of the ADDUCE research programme in 27 European child and adolescent mental health centres in the UK, Germany, Switzerland, Italy, and Hungary. Participants aged 6-17 years were recruited into three cohorts: medication-naive ADHD patients who intended to start methylphenidate treatment (methylphenidate group), medication-naive ADHD patients who did not intend to start any ADHD medication (no-methylphenidate group), and a control group without ADHD. Children with ADHD diagnosed by a qualified clinician according to the DSM-IV criteria and, in the control group, children who scored less than 1·5 on average on the Swanson, Nolan, and Pelham IV rating scale for ADHD items, and whose hyperactivity score on the parent-rated Strengths and Difficulties Questionnaire was within the normal range (<6) were eligible for inclusion. Participants were excluded if they had previously taken any ADHD medications but remained eligible if they had previously taken or were currently taking other psychotropic drugs. The primary outcome was height velocity (height velocity SD score; estimated from at least two consecutive height measurements, and normalised with reference to the mean and SD of a population of the same age and sex). FINDINGS: Between Feb 01, 2012, and Jan 31, 2016, 1410 participants were enrolled (756 in methylphenidate group, 391 in no-methylphenidate group, and 263 in control group). 1070 (76·3%) participants were male, 332 (23·7%) were female, and for eight gender was unknown. The average age for the cohort was 9·28 years (SD 2·78; IQR 7-11). 1312 (93·0%) of 1410 participants were White. The methylphenidate and no-methylphenidate groups differed in ADHD symptom severity and other characteristics. After controlling for the effects of these variables using propensity scores, there was little evidence of an effect on growth (24 months height velocity SD score difference -0·07 (95% CI -0·18 to 0·04; p=0·20) or increased risk of psychiatric or neurological adverse events in the methylphenidate group compared with the no-methylphenidate group. Pulse rate and systolic and diastolic blood pressure were higher in the methylphenidate group compared with the no-methylphenidate group after 24 months of treatment. No serious adverse events were reported during the study. INTERPRETATION: Our results suggest that long-term treatment with methylphenidate for 2 years is safe. There was no evidence to support the hypothesis that methylphenidate treatment leads to reductions in growth. Methylphenidate-related pulse and blood pressure changes, although relatively small, require regular monitoring. FUNDING: EU Seventh Framework Programme.

Laying the foundations for hepatitis C elimination: evaluating the development and contribution of community care pathways to diagnostic efforts.

BACKGROUND: Hepatitis C Virus (HCV) is a public health threat which contributes substantially to the global burden of liver disease. There is much debate about effective approaches to scaling up diagnosis of HCV among risk groups. Tayside, a region in the East of Scotland, developed low-threshold community pathways for HCV to lay the foundations of an elimination strategy. In this retrospective study, we sought to: quantify the contribution of community pathways to increasing HCV diagnosis; understand if shifting diagnosis to community settings led to a higher proportion of individuals tested for HCV being actively infected; and describe functional characteristics of the care pathways. METHODS: Descriptive statistics were used to for analysis of routinely-collected HCV testing data from 1999 to 2017, and a review of the development of the care pathways was undertaken. Community-based testing was offered through general practices (GP); nurse outreach clinics; prisons; drug treatment services; needle and syringe provision (NSP) sites; community pharmacies; and mosques. RESULTS: Anti-HCV screening was undertaken on 109,430 samples, of which 5176 (4.7%) were reactive. Of all samples, 77,885 (71.2%) were taken in secondary care; 25,044 (22.9%) in GPs; 2970 (2.7%) in prisons; 2415 (2.2%) in drug services; 753 (0.7%) in NSPs; 193 (0.2%) pharmacies; and 170 (0.1%) in mosques. The highest prevalence of HCV infection among those tested was in NSP sites (26%), prisons (14%), and drug treatment centres (12%). CONCLUSIONS: Decentralised care pathways, particularly in harm reduction and other drug service settings, were key to increasing diagnosis of HCV in the region, but primary and secondary care remain central to elimination efforts.

Mannose-binding lectin genotype is associated with respiratory disease in young children: A multicenter cohort study.

BACKGROUND: Mannose-binding lectin (MBL) is an important component of the innate immune system. Polymorphisms in the MBL2 gene and promoter region are directly associated with MBL-deficiency. We sought to determine the association between MBL genotype on the frequency of common childhood respiratory infections, respiratory symptoms, and atopic outcomes in early childhood. METHODS: MBL2 gene variants were analyzed in newborns recruited to the GO-CHILD multicenter prospective cohort study. Follow-up for respiratory infection and atopy diagnoses and symptoms, healthcare utilization, and medication prescription were conducted by postal questionnaires at 12 and 24 months. RESULTS: Genotyping and follow-up were completed in 1004 children. Genotypes associated with MBL-deficiency were associated with an increased risk of bronchiolitis (relative risk [RR] 1.95, 95% confidence interval [CI] 1.33-2.85) and pneumonia (RR 2.46, 95% CI 1.16-5.22). MBL-deficient genotypes were associated with an increased risk of wheeze with shortness of breath episodes (RR 1.22, 95% CI 1.04-1.43), emergency department attendance (RR 1.90 95% CI 1.13-3.19), and hospital admission (RR 2.01, 95% CI 1.04-3.89) for wheeze. MBL-deficient genotypes were associated with a reduced risk of developing atopic dermatitis (RR 0.72, 95% CI 0.53-0.98). CONCLUSION: The positive association between MBL-deficient genotypes and bronchiolitis and pneumonia, as well as a severe wheeze phenotype in some young children, supports the hypothesis that MBL is an important component of innate immunity in the vulnerable period before the maturation of the adaptive immune system. Identification of disease-modifying genotypes may help target preventative strategies in high-risk infants.

Reaching people receiving opioid agonist therapy at community pharmacies with hepatitis C virus: an international randomised controlled trial.

BACKGROUND: Conventional healthcare models struggle to engage those at risk of hepatitis C virus (HCV) infection. This international study evaluated point-of-care (PoC) HCV RNA diagnostic outreach and direct-acting antiviral (DAA) treatment for individuals receiving opioid agonist therapy (OAT) in community pharmacies. AIMS: We assessed the effectiveness of a roving nurse-led pathway offering PoC HCV RNA testing to OAT clients in community pharmacies relative to conventional care. METHODS: Pharmacies in Scotland, Wales, and Australia were randomised to provide PoC HCV RNA testing or conventional referral. Pharmacists directed OAT clients to on-site nurses (intervention) or local clinics (control). Infected participants were treated with DAAs, alongside OAT. Primary outcome was the number of participants with sustained virologic response at 12 weeks (SVR) and analysed using mixed effects logistic regression in the intention-to-treat (ITT) population. RESULTS: Forty pharmacies were randomised. The ITT population contained 1410 OAT clients. In the conventional arm (n = 648), 62 (10%) agreed to testing, 17 (27%) were tested, 6 (35%) were positive and 5 (83%) initiated treatment. In the intervention arm (n = 762), 148 (19%) agreed to testing, 144 (97%) were tested, 23 (16%) were positive and 22 (96%) initiated treatment. SVR was obtained by 2 (40%; conventional) and 18 (82%; intervention). Intervention arm participants had higher odds of testing, OR 16.95 (7.07-40.64, p < 0.001); treatment, OR 4.29 (1.43-12.92, p = 0.010); and SVR, OR 8.64 (1.82-40.91, p = 0.007). CONCLUSIONS: Nurse-led PoC diagnosis in pharmacies made HCV care more accessible for OAT clients relative to conventional care. However, strategies to improve testing uptake are required. TRIAL REGISTRATION: NCT03935906.

Real-world outcomes of rapid regional hepatitis C virus treatment scale-up among people who inject drugs in Tayside, Scotland.

BACKGROUND: In 2017, Tayside, a region in the East of Scotland, rapidly scaled-up Hepatitis C Virus (HCV) outreach and treatment among People Who Inject Drugs (PWID) using novel community care pathways. AIMS: We aimed to determine treatment outcomes for PWID during the scale-up against pre-determined targets; and assess re-infection, mortality, and post-treatment follow up. METHODS: HCV treatment was delivered in community pharmacies, drug treatment centres, nurse-led outreach clinics, prisons, and needle exchanges, alongside conventional hospital care. We retrospectively analysed clinical outcomes and compared pathways using logistic regression models. RESULTS: Of 800 estimated HCV-infected PWID, 718 (90%) were diagnosed. 713 treatments commenced among 662 (92%) PWID, delivering 577 (81%) Sustained Virologic Responses (SVR). SVR was 91% among those who attended for testing. Forty-six individuals were treated more than once. Needle exchanges and community pharmacies initiated 49% of all treatments. Regression analyses implied pharmacies had superior follow-up, but there was no difference in likelihood of achieving SVR in community pathways relative to hospital care. Re-infection occurred 39 times over 256.57 person years (PY), yielding a rate of 15.20 per 100 PY (95% CI 10.81-20.78). 54 deaths occurred (29 drug related) over 1,553.04 PY, yielding a mortality rate of 3.48 per 100 PY (95% CI 2.61-4.54). Drug-related mortality was 1.87 per 100 PY (95% CI 1.25-2.68). CONCLUSIONS: Rapid HCV treatment scale-up to PWID in community settings, whilst maintaining high SVR, is achievable. However, other interventions are required to minimise re-infection; reduce drug-related deaths; and improve post-SVR follow-up testing regionally.

Clinical effectiveness of pharmacist-led versus conventionally delivered antiviral treatment for hepatitis C virus in patients receiving opioid substitution therapy: a pragmatic, cluster-randomised trial.

BACKGROUND: Highly effective direct-acting antiviral drugs provide the opportunity to eliminate hepatitis C virus (HCV) infection, but established pathways can be ineffective. We aimed to examine whether a community pharmacy care pathway increased treatment uptake, treatment completion, and cure rates for people receiving opioid substitution therapy, compared with conventional care. METHODS: This cluster-randomised trial was done in Scottish community pharmacies. Before participants were recruited, pharmacies were randomly assigned (1:1) to refer patients with evidence of HCV antibodies to conventional care or offered them care in the pharmacy (pharmacist-led care). Pharmacies were stratified by location. All pharmacies were trained to offer dried blood spot testing. All eligible participants had received opioid substitution therapy for approximately 3 months, and those eligible to receive treatment in the pharmacist-led care pathway were HCV PCR positive, were infected with HCV genotype 1 or 3, and were willing to have a pharmacist supervise their antiviral drug administration. Neither pharmacists nor patients were masked to treatment allocation. In both groups, assessment blood samples were taken, infection with HCV was confirmed, and daily oral ledipasvir-sofosbuvir (90 mg ledipasivir plus 400 mg sofosbuvir) for 8 weeks for genotype 1 or daily oral sofosbuvir (400 mg) plus oral daclatasvir (60 mg) for 12 weeks for genotype 3 was prescribed by a nurse (conventional care group) or pharmacist (pharmacist-led care group). In the conventional care group, the patient received care at a treatment centre. Once prescribed, medication in both groups was delivered as daily modified directly observed therapy alongside opioid substitution therapy in the participants' pharmacy where treatment was observed on 6 days per week. The primary outcome was the number of patients with sustained virological response 12 weeks after completion of treatment (SVR12) as a proportion of the number of people receiving opioid substitution therapy at participating pharmacies. Participants were monitored at each visit for nausea and fatigue; other adverse events were recorded as free text. Secondary outcomes compared key points on treatment pathway between the two groups. These key points were the proportion of patients having dry blood spot testing, the proportion of patients initiating HCV treatment, the proportion of patients completing the 8 or 12 week HCV course of treatment, and the proportion of patients with sustained virological response at 12 months. This study is registered with ClinicalTrials.gov, NCT02706223. FINDINGS: 56 pharmacies were randomly assigned (28 to each group; one pharmacy withdrew from the conventional care group). The 55 participating pharmacies included 2718 patients receiving opioid substitution therapy (1365 in the pharmacist-led care group and 1353 in the conventional care group). More patients met the primary endpoint of SVR12 in the pharmacist-led care group (98 [7%] of 1365) than in the conventional care group (43 [3%] of 1353; odds ratio 2·375, 95% CI 1·555-3·628, p<0·0001). More users of opioid substitution therapy in the pharmacist-led care group versus the conventional care group agreed to dry blood spot testing (245 [18%] of 1365 vs 145 [11%] of 1353, 2·292, 0·968-5·427, p=0·059); initiated treatment (112 [8%] of 1365 vs 61 [4%] of 1353, 1·889, 1·276-2·789, p=0·0015) and completed treatment (108 [8%] of 1365 vs 58 [4%] of 1353, 1·928, 1·321-2·813, p=0·0007). The data for sustained virological response at 12 months are not reported in this study: patients remain in follow-up for this outcome. No serious adverse events were recorded. INTERPRETATION: Using pharmacists to deliver an HCV care pathway made testing and treatment more accessible for patients, improved engagement, and maintained high treatment success rates. The use of this pathway could be a key part of an integrated and effective approach to HCV elimination at a community level. FUNDING: Partnership between the Scottish Government, Gilead Sciences, and Bristol-Myers Squib.

Neurological and psychiatric adverse effects of long-term methylphenidate treatment in ADHD: A map of the current evidence.

Methylphenidate (MPH), the most common medication for children with Attention Deficit/Hyperactivity Disorder (ADHD) in many countries, is often prescribed for long periods of time. Any long-term psychotropic treatment in childhood raises concerns about possible adverse neurological and psychiatric outcomes. We aimed to map current evidence regarding neurological and psychiatric outcomes, adverse or beneficial, of long-term MPH (> 1 year) treatment in ADHD. We coded studies using a "traffic light" system: Green: safe/favours MPH; Amber: warrants caution; Red: not safe/not well-tolerated. Un-categorisable study findings were coded as "Unclear". Although some evidence suggests an elevated risk of psychosis and tics, case reports describe remission on discontinuation. Several studies suggest that long-term MPH may reduce depression and suicide in ADHD. Evidence suggests caution in specific groups including pre-school children, those with tics, and adolescents at risk for substance misuse. We identified a need for more studies that make use of large longitudinal databases, focus on specific neuropsychiatric outcomes, and compare outcomes from long-term MPH treatment with outcomes following shorter or no pharmacological intervention.

Randomised controlled trial conducted in injecting equipment provision sites to compare the effectiveness of different hepatitis C treatment regimens in people who inject drugs: A Direct obserVed therApy versus fortNightly CollEction study for HCV treatment-ADVANCE HCV protocol study.

INTRODUCTION: Hepatitis C is a blood-borne virus (HCV) that can seriously damage the liver and is spread mainly through blood-to-blood contact with an infected person. Over 85% of individuals who have HCV in Scotland became infected following injecting drug use. Since people who inject drugs (PWID) are the main source of new infections, theoretical modelling has suggested that treatment of HCV infection in PWID may effectively reduce HCV prevalence and accomplish elimination. This protocol describes a clinical trial delivering HCV treatment within injecting equipment provision sites (IEPS) in Tayside, Scotland. METHODS AND ANALYSIS: PWID attending IEPS are tested for HCV and, if they are chronically infected with HCV and eligible, invited to receive treatment within the IEPS. They are randomised to one of three treatment regimens; daily observed treatment, treatment dispensed every 2 weeks and treatment dispensed every 2 weeks together with an adherence psychological intervention (administered before treatment begins). The primary outcome is comparison of the rate of successful treatment (SVR12) in each treatment group. Secondary analyses include assessment of adherence, reinfection rates, viral resistance to treatment and interaction of the treatment with illicit drugs. ETHICS AND DISSEMINATION: The ADVANCE (A Direct obserVed therApy versus fortNightly CollEction) HCV trial was given favourable opinion by East of Scotland Research Ethics Committee (LR/17/ES/0089) prior to commencement. TRIAL REGISTRATION NUMBERS: European Clinical Trials Database (EudraCT) (2017-001039-38) and ClinicalTrials.gov (NCT03236506).

Clinical effectiveness of pharmacy-led versus conventionally delivered antiviral treatment for hepatitis C in patients receiving opioid substitution therapy: a study protocol for a pragmatic cluster randomised trial.

INTRODUCTION: Hepatitis C virus (HCV) infection affects 0.7% of the general population, and up to 40% of people prescribed opioid substitution therapy (OST) in Scotland. In conventional care, less than 10% of OST users are tested for HCV and less than 25% of these initiate treatment. Community pharmacists see this group frequently to provide OST supervision. This study examines whether a pharmacist-led 'test & treat' pathway increases cure rates for HCV. METHODS AND ANALYSIS: This protocol describes a cluster-randomised trial where 60 community pharmacies provide either conventional or pharmacy-led care. All pharmacies offer dried blood spot testing (DBST) for HCV. Participants have attended the pharmacy for OST for 3 months; are positive for HCV genotype 1 or 3; are not co-infected with HIV and/or hepatitis B; have no decompensated liver disease; are not pregnant. For conventional care, pharmacists refer HCV-positive participants to a local centre for assessment. In the pharmacy-led arm, pharmacists assess participants themselves in the pharmacy. Drug prescribing is by nurse prescribers (conventional arm) or pharmacist prescribers (pharmacy-led arm). Treatment in both arms is delivered as daily modified directly observed therapy in a pharmacy. Primary trial outcome is number of sustained virological responses at 12 weeks after treatment completion. Secondary trial outcomes are number of tests taken; treatment uptake; completion; adherence; re-infection. An economic evaluation will assess potential cost-effectiveness. Qualitative research interviews with clients and health professionals assess acceptability of a pharmacist-led pathway. ETHICS AND DISSEMINATION: This protocol has been ethically approved by the East of Scotland Research Ethics Committee 2 (15/ES/0086) and complies with the Declaration of Helsinki and principles of Good Clinical Practice. Caldicott guardian approval was given on 16 December 2016 to allow NHS Tayside to pass information to the cluster community pharmacies about the HCV test status of patients that they are seeing to provide OST supervision. NHS R&D approvals have been obtained from each health board taking part in the study. Informed consent is obtained before study enrolment and only anonymised data are stored in a secured database, enabling an audit trail. Results will be submitted to international peer-reviewed journals and presented at international conferences. TRIAL REGISTRATION NUMBER: NCT02706223; Pre-results.

Association of Risk of Suicide Attempts With Methylphenidate Treatment.

Importance: Patients with attention-deficit/hyperactivity disorder (ADHD) are at an increased risk of attempting suicide. Stimulants, such as methylphenidate hydrochloride, are the most common treatment for ADHD, but the association between their therapeutic use and suicide is unclear. Objective: To investigate the association between methylphenidate and the risk of suicide attempts. Design, Setting, and Participants: A population-based, electronic medical records database from the Hong Kong Clinical Data Analysis & Reporting System was used to identify 25 629 individuals aged 6 to 25 years who were treated with methylphenidate between January 1, 2001, and December 31, 2015. Those who had attempted suicide were included in the analysis. A self-controlled case series design was used to control for time-invariant characteristics of the patients. Main Outcomes and Measures: Relative incidence of suicide attempt during periods when patients were exposed to methylphenidate compared with nonexposed periods. Results: Among 25 629 patients with methylphenidate prescriptions, 154 had their first recorded suicide attempt within the study period; of these individuals, 111 (72.1%) were male; mean (SD) age at baseline was 7.15 (2.19) years. The overall incidence of suicide attempts during methylphenidate treatment was 9.27 per 10 000 patient-years. An increased risk of suicide attempts was detected during the 90-day period before methylphenidate was initiated, with an incidence rate ratio (IRR) of 6.55 (95% CI, 3.37-12.72). The IRR remained elevated during the first 90 days of treatment (IRR, 3.91; 95% CI, 1.62-9.42) before returning to baseline levels during ongoing treatment (IRR, 1.35; 95% CI, 0.77-2.38). When the risk during the first 90 days of treatment was compared with the 90 days preceding first treatment, the incidence of suicide attempts was not elevated (IRR, 0.78; 95% CI, 0.26-2.35). Conclusions and Relevance: The incidence of suicide attempts was higher in the period immediately before the start of methylphenidate treatment. The risk remained elevated immediately after the start of methylphenidate treatment and returned to baseline levels during continuation of methylphenidate treatment. The observed higher risk of suicide attempts before treatment may reflect emerging psychiatric symptoms that trigger medical consultations that result in a decision to begin ADHD treatment. Therefore, this study's results do not support a causal association between methylphenidate treatment and suicide attempts.

Personalized Medication Response Prediction for Attention-Deficit Hyperactivity Disorder: Learning in the Model Space vs. Learning in the Data Space.

Attention-Deficit Hyperactive Disorder (ADHD) is one of the most common mental health disorders amongst school-aged children with an estimated prevalence of 5% in the global population (American Psychiatric Association, 2013). Stimulants, particularly methylphenidate (MPH), are the first-line option in the treatment of ADHD (Reeves and Schweitzer, 2004; Dopheide and Pliszka, 2009) and are prescribed to an increasing number of children and adolescents in the US and the UK every year (Safer et al., 1996; McCarthy et al., 2009), though recent studies suggest that this is tailing off, e.g., Holden et al. (2013). Around 70% of children demonstrate a clinically significant treatment response to stimulant medication (Spencer et al., 1996; Schachter et al., 2001; Swanson et al., 2001; Barbaresi et al., 2006). However, it is unclear which patient characteristics may moderate treatment effectiveness. As such, most existing research has focused on investigating univariate or multivariate correlations between a set of patient characteristics and the treatment outcome, with respect to dosage of one or several types of medication. The results of such studies are often contradictory and inconclusive due to a combination of small sample sizes, low-quality data, or a lack of available information on covariates. In this paper, feature extraction techniques such as latent trait analysis were applied to reduce the dimension of on a large dataset of patient characteristics, including the responses to symptom-based questionnaires, developmental health factors, demographic variables such as age and gender, and socioeconomic factors such as parental income. We introduce a Bayesian modeling approach in a "learning in the model space" framework that combines existing knowledge in the literature on factors that may potentially affect treatment response, with constraints imposed by a treatment response model. The model is personalized such that the variability among subjects is accounted for by a set of subject-specific parameters. For remission classification, this approach compares favorably with conventional methods such as support vector machines and mixed effect models on a range of performance measures. For instance, the proposed approach achieved an area under receiver operator characteristic curve of 82-84%, compared to 75-77% obtained from conventional regression or machine learning ("learning in the data space") methods.

Mucous solids and liquid secretion by airways: studies with normal pig, cystic fibrosis human, and non-cystic fibrosis human bronchi.

To better understand how airways produce thick airway mucus, nonvolatile solids were measured in liquid secreted by bronchi from normal pig, cystic fibrosis (CF) human, and non-CF human lungs. Bronchi were exposed to various secretagogues and anion secretion inhibitors to induce a range of liquid volume secretion rates. In all three groups, the relationship of solids concentration (percent nonvolatile solids) to liquid volume secretion rate was curvilinear, with higher solids concentration associated with lower rates of liquid volume secretion. In contrast, the secretion rates of solids mass and water mass as functions of liquid volume secretion rates exhibited positive linear correlations. The y-intercepts of the solids mass-liquid volume secretion relationships for all three groups were positive, thus accounting for the higher solids concentrations in airway liquid at low rates of secretion. Predictive models derived from the solids mass and water mass linear equations fit the experimental percent solids data for the three groups. The ratio of solids mass secretion to liquid volume secretion was 5.2 and 2.4 times higher for CF bronchi than for pig and non-CF bronchi, respectively. These results indicate that normal pig, non-CF human, and CF human bronchi produce a high-percent-solids mucus (>8%) at low rates of liquid volume secretion (≤1.0 µl·cm(-2)·h(-1)). However, CF bronchi produce mucus with twice the percent solids (~8%) of pig or non-CF human bronchi at liquid volume secretion rates ≥4.0 µl·cm(-2)·h(-1).

Effects of peroxisome proliferator-activated receptor gamma agonists on Na+ transport and activity of the kinase SGK1 in epithelial cells from lung and kidney.

BACKGROUND AND PURPOSE: Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, such as rosiglitazone and pioglitazone, sensitize cells to insulin, and are therefore used to treat type 2 diabetes. However, in some patients, these drugs induce oedema, and the present study tests the hypothesis that this side effect reflects serum and glucocorticoid-inducible kinase 1 (SGK1)-dependent enhancement of epithelia Na(+) absorption. EXPERIMENTAL APPROACH: Na(+) absorbing epithelial cells (H441 cells, mpkCCD cells) on permeable membranes were mounted in Ussing chambers, and the effects of rosiglitazone (2 microM) and pioglitazone (10 microM) on transepithelial Na(+) absorption were quantified electrometrically. Changes in SGK1 activity were assessed by monitoring phosphorylation of residues within an endogenous protein. KEY RESULTS: Both cell types absorbed Na(+) via an electrogenic process that was enhanced by insulin. In mpkCCD cells, this stimulation of Na(+) transport was associated with increased activity of SGK1, whereas insulin regulated Na(+) transport in H441 cells through a mechanism that did not involve activation of this kinase. Rosiglitazone and pioglitazone had no discernible effect on transepithelial Na(+) absorption in unstimulated or insulin-stimulated cells and failed to alter cellular SGK1 activity. CONCLUSIONS AND IMPLICATIONS: Our results do not support the view that PPARgamma agonists stimulate epithelial Na(+) absorption or alter the control of cellular SGK1 activity. It is therefore likely that other mechanisms are involved in PPARgamma-mediated fluid retention, and a better understanding of these mechanisms may help with the identification of patients likely to develop oedema or heart failure when treated with these drugs.

A Ba2+-resistant, acid-sensitive K+ conductance in Na+-absorbing H441 human airway epithelial cells.

By analysis of whole cell membrane currents in Na(+)-absorbing H441 human airway epithelial cells, we have identified a K(+) conductance (G(K)) resistant to Ba(2+) but sensitive to bupivacaine or extracellular acidification. In polarized H441 monolayers, we have demonstrated that bupivacaine, lidocaine, and quinidine inhibit basolateral membrane K(+) current (I(Bl)) whereas Ba(2+) has only a weak inhibitory effect. I(Bl) was also inhibited by basolateral acidification, and, although subsequent addition of bupivacaine caused a further fall in I(Bl), acidification had no effect after bupivacaine, demonstrating that cells grown under these conditions express at least two different bupivacaine-sensitive K(+) channels, only one of which is acid sensitive. Basolateral acidification also inhibited short-circuit current (I(SC)), and basolateral bupivacaine, lidocaine, quinidine, and Ba(2+) inhibited I(SC) at concentrations similar to those needed to inhibit I(Bl), suggesting that the K(+) channels underlying I(Bl) are part of the absorptive mechanism. Analyses using RT-PCR showed that mRNA encoding several two-pore domain K(+) (K2P) channels was detected in cells grown under standard conditions (TWIK-1, TREK-1, TASK-2, TWIK-2, KCNK-7, TASK-3, TREK-2, THIK-1, and TALK-2). We therefore suggest that K2P channels underlie G(K) in unstimulated cells and so maintain the driving force for Na(+) absorption. Since this ion transport process is vital to lung function, K2P channels thus play an important but previously undocumented role in pulmonary physiology.

Ionic mechanism of forskolin-induced liquid secretion by porcine bronchi.

cAMP-elevating agents such as forskolin and vasoactive intestinal peptide induce liquid secretion by tracheobronchial submucosal glands. This pathway is thought to be CFTR dependent and thus defective in cystic fibrosis; however, the ionic mechanism that drives this secretion process is incompletely understood. To better define this mechanism, we studied the effects of ion transport inhibitors on the forskolin-induced liquid secretion response (Jv) of porcine distal bronchi. The forskolin-induced Jv was driven by a combination of bumetanide-sensitive Cl- secretion and DIDS-sensitive HCO3- secretion. When Cl- secretion was inhibited with bumetanide, Na+/H+ exchange-dependent HCO3- secretion was apparently induced to compensate for the loss of Cl- secretion. The forskolin-induced Jv was significantly inhibited by the anion channel blockers 5-nitro-2-(3-phenylpropylamino)benzoic acid, diphenylamine-2-carboxylate, and glibenclamide. We conclude that the forskolin-induced Jv shares many characteristics of cholinergically induced secretion except for the presence of a DIDS-sensitive component. Although the identity of the DIDS-sensitive component is unclear, we speculate that it represents a basolateral membrane Na+ -HCO3- cotransporter or an Na+-dependent anion exchanger, which could account for transepithelial HCO3- secretion.