Immersive virtual reality and psychological well-being in adult chronic physical illness: systematic review.

INTRODUCTION: Individuals with chronic physical illness are at increased risk of negative psychological sequelae. Immersive virtual reality (VR) is an emerging treatment that might reduce these negative effects and increase quality of life in individuals with chronic physical illness. OBJECTIVE: To systematically review literature examining the use of immersive VR in adult populations with chronic physical illness to understand: (1) how immersive VR is used to improve psychological well-being of adults with chronic physical illness (2) what effect this immersive VR has on the psychological well-being of adults with chronic physical illness. DESIGN: Systematic literature review and meta-analysis. Searches of Ovid Medline/PubMed, PsycINFO, Embase, Web of Science and Scopus between July 1993 and March 2023 inclusive. RESULTS: 12 811 texts were identified; 31 met the inclusion criteria. Relaxing and engaging immersive VR interventions were shown to be acceptable and feasible among adults with cancer, dementia, cardiovascular disease, kidney disease and multiple sclerosis. Many of the studies reviewed were feasibility or pilot studies and so the evidence about effectiveness is more limited. The evidence, mostly from studies of people with cancer, suggests that immersive VR can have a positive effects on anticipatory anxiety symptoms and pain. CONCLUSIONS: Environment-based and game-based relaxing immersive VR offer novel interventions, with beneficial effects among people with cancer and, potentially, beneficial effects in those with other long-term physical illness.

Multi-cancer early detection test in symptomatic patients referred for cancer investigation in England and Wales (SYMPLIFY): a large-scale, observational cohort study.

BACKGROUND: Analysis of circulating tumour DNA could stratify cancer risk in symptomatic patients. We aimed to evaluate the performance of a methylation-based multicancer early detection (MCED) diagnostic test in symptomatic patients referred from primary care. METHODS: We did a multicentre, prospective, observational study at National Health Service (NHS) hospital sites in England and Wales. Participants aged 18 or older referred with non-specific symptoms or symptoms potentially due to gynaecological, lung, or upper or lower gastrointestinal cancers were included and gave a blood sample when they attended for urgent investigation. Participants were excluded if they had a history of or had received treatment for an invasive or haematological malignancy diagnosed within the preceding 3 years, were taking cytotoxic or demethylating agents that might interfere with the test, or had participated in another study of a GRAIL MCED test. Patients were followed until diagnostic resolution or up to 9 months. Cell-free DNA was isolated and the MCED test performed blinded to the clinical outcome. MCED predictions were compared with the diagnosis obtained by standard care to establish the primary outcomes of overall positive and negative predictive value, sensitivity, and specificity. Outcomes were assessed in participants with a valid MCED test result and diagnostic resolution. SYMPLIFY is registered with ISRCTN (ISRCTN10226380) and has completed follow-up at all sites. FINDINGS: 6238 participants were recruited between July 7 and Nov 30, 2021, across 44 hospital sites. 387 were excluded due to staff being unable to draw blood, sample errors, participant withdrawal, or identification of ineligibility after enrolment. Of 5851 clinically evaluable participants, 376 had no MCED test result and 14 had no information as to final diagnosis, resulting in 5461 included in the final cohort for analysis with an evaluable MCED test result and diagnostic outcome (368 [6·7%] with a cancer diagnosis and 5093 [93·3%] without a cancer diagnosis). The median age of participants was 61·9 years (IQR 53·4-73·0), 3609 (66·1%) were female and 1852 (33·9%) were male. The MCED test detected a cancer signal in 323 cases, in whom 244 cancer was diagnosed, yielding a positive predictive value of 75·5% (95% CI 70·5-80·1), negative predictive value of 97·6% (97·1-98·0), sensitivity of 66·3% (61·2-71·1), and specificity of 98·4% (98·1-98·8). Sensitivity increased with increasing age and cancer stage, from 24·2% (95% CI 16·0-34·1) in stage I to 95·3% (88·5-98·7) in stage IV. For cases in which a cancer signal was detected among patients with cancer, the MCED test's prediction of the site of origin was accurate in 85·2% (95% CI 79·8-89·3) of cases. Sensitivity 80·4% (95% CI 66·1-90·6) and negative predictive value 99·1% (98·2-99·6) were highest for patients with symptoms mandating investigation for upper gastrointestinal cancer. INTERPRETATION: This first large-scale prospective evaluation of an MCED diagnostic test in a symptomatic population demonstrates the feasibility of using an MCED test to assist clinicians with decisions regarding urgency and route of referral from primary care. Our data provide the basis for a prospective, interventional study in patients presenting to primary care with non-specific signs and symptoms. FUNDING: GRAIL Bio UK.

LID study: Plasma lidocaine levels following airway topicalisation for paediatric microlaryngobronchoscopy (MLB).

OBJECTIVES: A dose of 5 mg/kg lidocaine is considered appropriate for paediatric airway topicalisation. Existing literature suggests that younger children are susceptible to toxic lidocaine plasma levels and achieve this at a faster rate. MAIN OUTCOME MEASURES: The primary outcome of this study was to ascertain peak plasma lidocaine levels after topicalisation for airway endoscopy. Secondary endpoints included: time to peak lidocaine plasma levels, signs of lidocaine toxicity (restricted to ECG changes or seizures when under anaesthesia) and clinical adverse events of laryngospasm, coughing or desaturation during the procedure. SETTING: Data were collected prospectively over 18 months at Royal Manchester Children's Hospital. PARTICIPANTS: Children aged 0-8 years undergoing elective diagnostic or therapeutic airway endoscopy were included within the study. DESIGN: Standardised 2% lidocaine was used for airway topicalisation. Dose varied depending upon the practitioner's usual practice. Venous bloodsampling occurred at 5, 10, 15 and 20 min post-administration and plasma lidocaine levels (ng/ml) were analysed. RESULTS: A significant relationship exists between higher peak plasma levels and ages <18 months (p = .00973). Strong linear correlation exists between body weight and age for our cohort (r = .88). Higher peak plasma lidocaine levels occur with total dose volumes between 2 and 3 mls of 2% lidocaine local anaesthetic (p = .03) compared with <2 ml total dose volumes. Data suggest a potential relationship of lower body weights achieving higher peak plasma levels (p = .0516). Reduced interquartile variation of peak plasma lidocaine levels exists when lidocaine dosing is <5 mg/kg. CONCLUSIONS: Age and total dose volume of topicalised lidocaine have a significant relationship with plasma lidocaine levels. A dose of 5 mg/kg topicalised lidocaine for paediatric airway endoscopy is safe and provides good operating conditions. Lower patient body weights trend towards higher peak lidocaine plasma concentrations and require further investigation.

Surgical Emphysema in a Pediatric Tertiary Referral Center.

BACKGROUND: Laryngeal trauma in pediatrics is extremely rare; however, because of the smaller pediatric larynx, it can have catastrophic consequences. Following laryngeal trauma, surgical emphysema is a relatively common presentation. In pediatrics, it can be a life-threatening condition. Here we describe 2 cases of laryngeal trauma resulting in extensive surgical emphysema. CASES: The first case described involves bilateral pneumothoraces, airway compromise, and respiratory arrest and was managed with bilateral chest drains, intubation, and tracheostomy. The second case resulted in widespread surgical emphysema in a stable patient and was managed conservatively. Both cases were monitored closely for a period of time to ensure there were no further sequelae. DISCUSSION: Patients with laryngeal trauma resulting in surgical emphysema have the potential to deteriorate rapidly. Furthermore, surgical emphysema degrades the quality of ultrasound images, which may delay the diagnosis. If there are any concerns about the safety of the airway, then it should be secured definitively with either endotracheal intubation or emergency tracheostomy depending on clinical judgment. It is acceptable to monitor patients closely in a high-dependency unit setting if they are stable and do not show any evidence of laryngeal edema. CONCLUSIONS: We present 2 cases of laryngeal trauma that were dealt with effectively so that both patients made a full recovery. It is important to act quickly to secure the airway if there are any concerns about its patency. Stable patients with no evidence of laryngeal edema can be managed conservatively. Close monitoring is essential to prevent any potential airway compromise.

An International Interprofessional Study of Mental Models and Factors Delaying Neuroimaging of Critically Head-Injured Children Presenting to Emergency Departments.

OBJECTIVES: Thousands of head-injured children are cared for by interprofessional teams in emergency departments every day. Teams must balance performing time-consuming interventions with safe transport for neuroimaging. This study aims to describe and compare providers' perspectives on the transfer of head-injured children to neuroimaging and factors contributing to delays. METHODS: Participants were interprofessional health care providers involved in the care of head-injured children at sites in the United Kingdom, the United States, and New Zealand. They first viewed a 3-minute video of a child with a severe head injury presenting to their resuscitation bay. Next, they were presented with 5 physiologically different simulated scenarios and asked to report whether interventions were required before transporting each patient to neuroimaging. Then, they reported team and system factors contributing to delays in neuroimaging. RESULTS: Two hundred forty of 296 providers completed the intervention. The percentage of providers reporting that they would directly transport to neuroimaging without intervention was 89% for "stable," 49% for "Cushing's triad," 26% for "hypoxic," 25% for "tachycardic," and 5% for "extremis." There were differences noted in responses by profession for the hypoxia and tachycardia cases. No differences were noted between trainees and attending physicians for any cases. The most frequent factors reported as delaying neuroimaging were team decision making and waiting for equipment, medications, and scanner availability. CONCLUSIONS: There is variability in providers' perspectives on the interventions required before transporting severely head-injured patients for imaging. Diverse team and system factors contribute to delays in imaging.

A Randomized Controlled Trial of Atorvastatin in Patients With Bronchiectasis Infected With Pseudomonas Aeruginosa: A Proof of Concept Study.

BACKGROUND: There are no randomized controlled trials of statin therapy in patients with severe bronchiectasis who are chronically infected with Pseudomonas aeruginosa. METHODS: Thirty-two patients chronically infected with P aeruginosa were recruited in this double-blind cross-over randomized controlled trial. Sixteen patients were recruited in each arm, were given atorvastatin 80 mg or placebo for 3 months followed by a washout period for 6 weeks, and then crossed over and administered the alternative therapy for 3 months. RESULTS: Twenty-seven patients completed the study. Atorvastatin did not significantly improve the primary end point of cough as measured by the Leicester Cough Questionnaire (mean difference, 1.92; 95% CI for difference, -0.57-4.41; P = .12). However, atorvastatin treatment resulted in an improved St. Georges Respiratory Questionnaire (-5.62 points; P = .016) and reduced serum levels of CXCL8 (P = .04), tumor necrosis factor (P = .01), and intercellular adhesion molecule 1 (P = .04). There was a trend toward improvement in serum C-reactive protein and serum neutrophil counts (P = .07 and P = .06, respectively). We demonstrated in vitro that atorvastatin 10 µM reduced formyl-methionyl-leucyl phenylalanine-induced upregulation of CD11b expression and changes in calcium flux, reflecting an ability to decrease neutrophil activation. CONCLUSIONS: We demonstrated that atorvastatin reduced systemic inflammation and improved quality of life in patients with bronchiectasis who were infected with P aeruginosa. These effects may be due to an ability of atorvastatin to modulate neutrophil activation. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01299194; URL: www.clinicaltrials.gov.

Pseudomonas expression of an oxygen sensing prolyl hydroxylase homologue regulates neutrophil host responses in vitro and in vivo.

Background: Pseudomonas species are adapted to evade innate immune responses and can persist at sites of relative tissue hypoxia, including the mucus-plugged airways of patients with cystic fibrosis and bronchiectasis.  The ability of these bacteria to directly sense and respond to changes in local oxygen availability is in part consequent upon expression of the 2-oxoglutarate oxygenase, Pseudomonas prolyl hydroxylase (PPHD), which acts on elongation factor Tu (EF-Tu), and is homologous with the human hypoxia inducible factor (HIF) prolyl hydroxylases. We report that PPHD expression regulates the neutrophil response to acute pseudomonal infection. Methods:In vitro co-culture experiments were performed with human neutrophils and PPHD-deficient and wild-type bacteria and supernatants, with viable neutrophil counts determined by flow cytometry. In vivo consequences of infection with PPHD deficient P. aeruginosa were determined in an acute pneumonia mouse model following intra-tracheal challenge. Results: Supernatants of PPHD-deficient bacterial cultures contained higher concentrations of the phenazine exotoxin pyocyanin and induced greater acceleration of neutrophil apoptosis than wild-type PAO1 supernatants in vitro.  In vivo infection with PPHD mutants compared to wild-type PAO1 controls resulted in increased levels of neutrophil apoptosis and impaired control of infection, with higher numbers of P. aeruginosa recovered from the lungs of mice infected with the PPHD-deficient strain.  This resulted in an overall increase in mortality in mice infected with the PPHD-deficient strain. Conclusions: Our data show that Pseudomonas expression of its prolyl hydroxylase influences the outcome of host-pathogen interactions in vitro and in vivo, demonstrating the importance of considering how both host and pathogen adaptations to hypoxia together define outcomes of infection. Given that inhibitors for the HIF prolyl hydroxylases are in late stage trials for the treatment of anaemia and that the active sites of PPHD and human HIF prolyl hydroxylases are closely related, the results are of current clinical interest.

Putting recommendations into practice: Australian rheumatologists' opinions on leflunomide use in rheumatoid arthritis.

Leflunomide is the most recently introduced conventional disease-modifying anti-rheumatic drugs in Australia. It has several unique methods for initiation, unique monitoring recommendations and a distinctive cessation protocol in the event of serious toxicity. The aim of this study was to evaluate initiation and monitoring practices of Australian rheumatologists using leflunomide. A survey was emailed twice, approximately 3 months apart to 332 rheumatologist members of the Australian Rheumatology Association. Wave analysis was used to assess evidence of non-response bias. The response rate to the survey was 20% and there was no difference between the responses of waves 1 and 2. Fifty percent of the respondents indicated that 20 mg once daily was the initial dose of leflunomide that they most commonly prescribed, 45% indicated 10 mg once daily, whilst only 3% preferred to initiate leflunomide at 100 mg daily for 2-3 days followed by 10 mg once a day as recommended when first marketed. Of the responders, 12% had used doses above 20 mg daily and 70% had used alternate daily dosing with leflunomide. In a patient taking leflunomide with an ALT or AST >3 times the ULN on two or more blood tests, 75% of responders indicated they would stop leflunomide immediately and 20% would follow cessation by administering a cholestyramine washout. The choice of initial leflunomide dose among responding Australian rheumatologists varied considerably, although most preferred not to use the loading dose. Despite the recommendation of clinical guidelines, the use of a cholestyramine washout procedure for hepatic toxicity is not universal.

Genetic polymorphism of CYP1A2 but not total or free teriflunomide concentrations is associated with leflunomide cessation in rheumatoid arthritis.

AIM: Leflunomide, via its active metabolite teriflunomide, is used in rheumatoid arthritis (RA) treatment, yet approximately 20 to 40% of patients cease due to toxicity. The aim was to develop a time-to-event model describing leflunomide cessation due to toxicity within a clinical cohort and to investigate potential predictors of cessation such as total and free teriflunomide exposure and pharmacogenetic influences. METHODS: This study included individuals enrolled in the Early Arthritis inception cohort at the Royal Adelaide Hospital between 2000 and 2013 who received leflunomide. A time-to-event model in nonmem was used to describe the time until leflunomide cessation and the influence of teriflunomide exposure and pharmacogenetic variants. Random censoring of individuals was simultaneously described. The clinical relevance of significant covariates was visualized via simulation. RESULTS: Data from 105 patients were analyzed, with 34 ceasing due to toxicity. The baseline dropout hazard and baseline random censoring hazard were best described by step functions changing over discrete time intervals. No statistically significant associations with teriflunomide exposure metrics were identified. Of the screened covariates, carriers of the C allele of CYP1A2 rs762551 had a 2.29 fold increase in cessation hazard compared with non-carriers (95% CI 2.24, 2.34, P = 0.016). CONCLUSIONS: A time-to-event model described the time between leflunomide initiation and cessation due to side effects. The C allele of CYP1A2 rs762551 was linked to increased leflunomide toxicity, while no association with teriflunomide exposure was identified. Future research should continue to investigate exposure-toxicity relationships, as well as potentially toxic metabolites.

Lung Microbiota Changes Associated with Chronic Pseudomonas aeruginosa Lung Infection and the Impact of Intravenous Colistimethate Sodium.

BACKGROUND: Exacerbations associated with chronic lung infection with Pseudomonas aeruginosa are a major contributor to morbidity, mortality and premature death in cystic fibrosis. Such exacerbations are treated with antibiotics, which generally lead to an improvement in lung function and reduced sputum P. aeruginosa density. This potentially suggests a role for the latter in the pathogenesis of exacerbations. However, other data suggesting that changes in P. aeruginosa sputum culture status may not reliably predict an improvement in clinical status, and data indicating no significant changes in either total bacterial counts or in P. aeruginosa numbers in sputum samples collected prior to pulmonary exacerbation sheds doubt on this assumption. We used our recently developed lung segmental model of chronic Pseudomonas infection in sheep to investigate the lung microbiota changes associated with chronic P. aeruginosa lung infection and the impact of systemic therapy with colistimethate sodium (CMS). METHODOLOGY/PRINCIPAL FINDINGS: We collected protected specimen brush (PSB) samples from sheep (n = 8) both prior to and 14 days after establishment of chronic local lung infection with P aeruginosa. Samples were taken from both directly infected lung segments (direct) and segments spatially remote to such sites (remote). Four sheep were treated with daily intravenous injections of CMS between days 7 and 14, and four were treated with a placebo. Necropsy examination at d14 confirmed the presence of chronic local lung infection and lung pathology in every direct lung segment. The predominant orders in lung microbiota communities before infection were Bacillales, Actinomycetales and Clostridiales. While lung microbiota samples were more likely to share similarities with other samples derived from the same lung, considerable within- and between-animal heterogeneity could be appreciated. Pseudomonadales joined the aforementioned list of predominant orders in lung microbiota communities after infection. Whilst treatment with CMS appeared to have little impact on microbial community composition after infection, or the change undergone by communities in reaching that state, when Gram negative organisms (excluding Pseudomonadales) were considered together as a group there was a significant decrease in their relative proportion that was only observed in the sheep treated with CMS. With only one exception the reduction was seen in both direct and remote lung segments. This reduction, coupled with generally increasing or stable levels of Pseudomonadales, meant that the proportion of the latter relative to total Gram negative bacteria increased in all bar one direct and one remote lung segment. CONCLUSIONS/SIGNIFICANCE: The proportional increase in Pseudomonadales relative to other Gram negative bacteria in the lungs of sheep treated with systemic CMS highlights the potential for such therapies to inadvertently select or create a niche for bacteria seeding from a persistent source of chronic infection.

Beverage- and Brand-Specific Binge Alcohol Consumption among Underage Youth in the U.S.

BACKGROUND AND OBJECTIVES: Binge drinking is a common and risky pattern of alcohol consumption among youth; beverage and brand-specific consumption during binge drinking is poorly understood. The objective was to characterize beverage- and brand-specific consumption associated with binge drinking among underage youth in the U.S. METHODS: An internet panel was used to obtain a sample of 1,032 underage youth aged 13-20, who drank alcohol in the past 30 days. For each brand consumed, youth reported drinking quantity and frequency, and whether they engaged in binge drinking with that brand (≥5 drinks for males, ≥4 for females). Each youth reporting binge drinking with a brand constituted a binge drinking report. RESULTS: Overall, 50.9% of youth binge drank with ≥1 brand, and 36.5% of youth who consumed any particular brand reported binge drinking with it. Spirits accounted for 43.8% of binge drinking reports. Twenty-five brands accounted for 46.2% of binge drinking reports. Many of these brands were disproportionately associated with binge drinking relative to their youth market share. CONCLUSIONS: Binge drinking among youth is most commonly involves spirits, and binge drinking is concentrated within a relatively small number of brands. Understanding factors underlying beverage and brand preference among binge drinking youth could assist prevention efforts.

Fitness for purpose study of the Field Assessment Conditioning Tool (FACT): a research protocol.

INTRODUCTION: As part of a programme of research aiming to improve the outcomes of traumatically injured children, a multisource healthcare advocacy tool has been developed to allow trauma team members and hospital governance administrators to reflect and to act on complex trauma team-hospital systems interactions. We have termed this tool a Field Assessment Conditioning Tool (FACT). The FACT draws on quantitative data including clinical care points in addition to self-reflective qualitative data. The FACT is designed to provide feedback on this assessment data both horizontally across fellow potential team members and vertically to the hospital/organisation governance structure, enabling process gap identification and allowing an agenda of improvements to be realised. The aim of the study described in this paper is to explore the perceived fitness for purpose of the FACT to provide an opportunity for healthcare advocacy by healthcare professionals caring for traumatically injured children. METHODS AND ANALYSIS: The FACT will be implemented and studied in three district hospitals, each around a major trauma centre in the UK, USA and New Zealand. Using a qualitative approach with standardised semi-structured interviews and thematic analysis we will explore the following question: Is the FACT fit for purpose in terms of providing a framework to evaluate, reflect and act on the individual hospital's own performance (trauma team-hospital interactions) in terms of readiness to receive traumatically injured children? ETHICS AND DISSEMINATION: Ethics opinion was sought for each research host organisation participating and deemed not required. The results will be disseminated to participating sites, networks and published in high-impact journals.

Garlic revisited: antimicrobial activity of allicin-containing garlic extracts against Burkholderia cepacia complex.

The antimicrobial activities of garlic and other plant alliums are primarily based on allicin, a thiosulphinate present in crushed garlic bulbs. We set out to determine if pure allicin and aqueous garlic extracts (AGE) exhibit antimicrobial properties against the Burkholderia cepacia complex (Bcc), the major bacterial phytopathogen for alliums and an intrinsically multiresistant and life-threatening human pathogen. We prepared an AGE from commercial garlic bulbs and used HPLC to quantify the amount of allicin therein using an aqueous allicin standard (AAS). Initially we determined the minimum inhibitory concentrations (MICs) of the AGE against 38 Bcc isolates; these MICs ranged from 0.5 to 3% (v/v). The antimicrobial activity of pure allicin (AAS) was confirmed by MIC and minimum bactericidal concentration (MBC) assays against a smaller panel of five Bcc isolates; these included three representative strains of the most clinically important species, B. cenocepacia. Time kill assays, in the presence of ten times MIC, showed that the bactericidal activity of AGE and AAS against B. cenocepacia C6433 correlated with the concentration of allicin. We also used protein mass spectrometry analysis to begin to investigate the possible molecular mechanisms of allicin with a recombinant form of a thiol-dependent peroxiredoxin (BCP, Prx) from B. cenocepacia. This revealed that AAS and AGE modifies an essential BCP catalytic cysteine residue and suggests a role for allicin as a general electrophilic reagent that targets protein thiols. To our knowledge, we report the first evidence that allicin and allicin-containing garlic extracts possess inhibitory and bactericidal activities against the Bcc. Present therapeutic options against these life-threatening pathogens are limited; thus, allicin-containing compounds merit investigation as adjuncts to existing antibiotics.

Metabolic and safety issues for multiple sclerosis pharmacotherapy--opportunities for personalised medicine.

INTRODUCTION: A number of disease-modifying therapies have become available to treat multiple sclerosis (MS) in recent years. As the effects of these medications are unpredictable and they are generally used for a number of years, the selection of the most appropriate disease-modifying agent must be based on the long-term efficacy and toxicity profile, thus strategies to personalise treatment to optimise responses may be potentially very useful. AREAS COVERED: This review provides an overview of the efficacy and toxicity of disease-modifying agents used in MS and specifically discusses any metabolic side effects and advances in personalising the use of each of these agents. Medline and EMBASE were searched for any articles regarding the efficacy, toxicity and personalised use of the medicines discussed in this review. EXPERT OPINION: Disease-modifying agents used to treat MS differ substantially in their efficacy and toxicity profile, but metabolic side effects appear to be limited to alemtuzumab, teriflunomide and IFN-ß. Although personalised treatment strategies to assist in selection of the most appropriate disease-modifying agent for MS are limited, there is substantial potential to use genetic sub-studies of the many recent trials investigating disease-modifying agents to develop personalised treatment strategies.

Atorvastatin as a stable treatment in bronchiectasis: a randomised controlled trial.

BACKGROUND: Bronchiectasis is characterised by chronic cough, sputum production, and recurrent chest infections. Pathogenesis is poorly understood, but excess neutrophilic airway inflammation is seen. Accumulating evidence suggests that statins have pleiotropic effects; therefore, these drugs could be a potential anti-inflammatory treatment for patients with bronchiectasis. We did a proof-of-concept randomised controlled trial to establish if atorvastatin could reduce cough in patients with bronchiectasis. METHODS: Patients aged 18-79 years were recruited from a secondary-care clinic in Edinburgh, UK. Participants had clinically significant bronchiectasis (ie, cough and sputum production when clinically stable) confirmed by chest CT and two or more chest infections in the preceding year. Individuals were randomly allocated to receive either high-dose atorvastatin (80 mg) or a placebo, given orally once a day for 6 months. Sequence generation was done with a block randomisation of four. Random allocation was masked to study investigators and patients. The primary endpoint was reduction in cough from baseline to 6 months, measured by the Leicester Cough Questionnaire (LCQ) score, with a lower score indicating a more severe cough (minimum clinically important difference, 1·3 units). Analysis was done by intention-to-treat. The trial is registered with ClinicalTrials.gov, number NCT01299181. FINDINGS: Between June 23, 2011, and Jan 30, 2011, 82 patients were screened for inclusion in the study and 22 were excluded before randomisation. 30 individuals were assigned atorvastatin and 30 were allocated placebo. The change from baseline to 6 months in LCQ score differed between groups, with a mean change of 1·5 units in patients allocated atorvastatin versus -0·7 units in those assigned placebo (mean difference 2·2, 95% CI 0·5-3·9; p=0·01). 12 (40%) of 30 patients in the atorvastatin group improved by 1·3 units or more on the LCQ compared with five (17%) of 30 in the placebo group (difference 23%, 95% CI 1-45; p=0·04). Ten (33%) patients assigned atorvastatin had an adverse event versus three (10%) allocated placebo (difference 23%, 95% CI 3-43; p=0·02). No serious adverse events were recorded. INTERPRETATION: 6 months of atorvastatin improved cough on a quality-of-life scale in patients with bronchiectasis. Multicentre studies are now needed to assess whether long-term statin treatment can reduce exacerbations. FUNDING: Chief Scientist's Office.

Pharmacogenomics of interferon beta and glatiramer acetate response: a review of the literature.

Multiple sclerosis (MS) is one of the most common inflammatory and degenerative autoimmune diseases of the central nervous system with considerable heterogeneity in all aspects, including response to therapy. A number of disease modifying drugs, including traditional first line agents such as, interferon-beta (IFN-ß) and glatiramer acetate (GA) are available for disease management. However, a considerable number of patients fail to achieve adequate response at therapeutic doses of IFN-ß or GA. This variability in response to treatment has prompted the search for prognostic markers in order to personalize and optimize therapy so as to treat MS more efficiently. This review will summarize the existing literature examining the pharmacogenomics of IFN-ß and GA response in MS patients.

Individualization of leflunomide dosing in rheumatoid arthritis patients.

Leflunomide is largely considered to be a second-line treatment option for rheumatoid arthritis (RA). Those who fail to respond, tend to progress to treatment with expensive biological agents, which can also be associated with serious toxicities. Optimizing leflunomide treatment to meet the needs of individuals would hence be beneficial in terms of patient outcomes and health care expenditure. In this respect, therapeutic drug monitoring (TDM) may be useful, as plasma concentrations of leflunomide's active metabolite, teriflunomide, correlate with response to treatment, but are highly variable between patients. A number of pharmacogenetic markers have also been identified that influence response and toxicity. Incorporation of these findings into clinical practice could facilitate more efficient use of leflunomide.