Exploring the association between ingestion of foods with higher potential salicylate content and symptom exacerbation in chronic rhinosinusitis. Data from the National Chronic Rhinosinusitis Epidemiology Study.

INTRODUCTION: Pharmacological salicylates are known to trigger respiratory exacerbations in patients with Non-Steroidal Exacerbated Respiratory Disease (N-ERD), a specific phenotype of Chronic Rhinosinusitis (CRS) and asthma. The impact of dietary sources of salicylates across subgroups of CRS is not well understood. The hypothesis is that in patients with nasal polyps present, there is likely to be a higher incidence of symptom exacerbation due to dietary salicylates regardless of any known response to pharmacological salicylate. METHODS: The Chronic Rhinosinusitis Epidemiology Study (CRES) was a questionnaire-based case-control study which sought to characterise the UK CRS population in terms of sociological, economic and medical factors. Using specific questions to examine participant responses relating to symptom exacerbation from food groups thought to be high in salicylate content, this analysis of the CRES database sought to compare an estimate of the prevalence of dietary sensitivity due to food with higher potential salicylate content across patients with CRS with (CRSwNPs) and without nasal polyposis (CRSsNPs) and with allergic fungal rhinosinusitis (AFRS). RESULTS: The CRSwNPs group were significantly more likely than controls to report symptom exacerbation due to ingestion of food groups with higher potential dietary salicylate content. The same trend was observed amongst CRSsNPs participants to a lesser degree. Reported response to the individual specific food groups wine, nuts, spicy foods, fruit and vegetables demonstrated that a statistically significant proportion of CRSwNPs and AFRS participants reported sensitivity to wine. CONCLUSIONS: This analysis suggests that there is an association between symptom exacerbation in response to food products with higher potential salicylate content, specifically wine, in CRS patients both with and without nasal polyposis when compared to controls, but especially in the CRSwNPs and AFRS phenotypes. Further studies are needed to detail if this relationship represents a causal relationship to dietary salicylate. The data present the possibility that a wider group of CRS patients may elicit salicylate sensitivity than those with known N-ERD.

Eustachian tube symptoms are frequent in chronic rhinosinusitis and respond well to endoscopic sinus surgery.

BACKGROUND: Symptoms of Eustachian tube (ET) dysfunction are seldom assessed in patients with chronic rhinosinusitis (CRS). The Sino-Nasal Outcome Test (SNOT-22) quality-of-life tool includes two questions that specifically screen for symptoms of ET dysfunction (Ear Fullness; Ear Pain). OBJECTIVE: The purpose of this study was to determine the extent to which these ET symptoms were present in patients with CRS, and whether these symptoms respond to endoscopic sinus surgery (ESS). METHODOLOGY: SNOT-22 data collected prospectively at time of recruitment into IRB-approved clinical trials or case-control studies in CRS was pooled to provide a cross section of the frequency and severity of ET dysfunction. When applicable to the trials, the SNOT-22 was repeated at least 3 months following ESS. RESULTS: Five trials rendering 131 patients were available for assessment. The control group comprised of 251 participants from two case-control studies. Ear Fullness of equal/greather than 1 was reported in 80/131 CRS patients compared to 45/251 control patients. Ear Pain of equal/greather than 1 was reported in 39/131 CRS patients compared to 33/251 control patients. Following ESS, mean Ear Fullness and Ear Pain scores decreased to 1.17 and 0.73, respectively. CONCLUSION: Symptoms suggestive of ET dysfunction are frequent in CRS, and for most patients the symptoms will decrease post-ESS to a level comparable with a non-CRS population. Patients whose ET symptoms do not respond to ESS may represent a target population for emerging therapeutic options for ET dysfunction.

Health utility reporting in chronic rhinosinusitis patients.

OBJECTIVES: Direct comparison of different diseases allows clinicians and researchers to place the burden of symptoms and impact on quality of life of each condition in context. Generic health-related quality-of-life assessment tools allow such analysis, and limited data are available for British patients with chronic rhinosinusitis. DESIGN: As part of a larger feasibility study, patients underwent baseline assessment using the SNOT-22, SF-12 and EQ-5D-5L tools. Data were analysed using Microsoft Excel and algorithms available for the analysis of the later two tools. We plotted EQ-5D-5L VAS and utility scores and SF-12 MCS and PCS scores separately against SNOT-22 scores and quantified associations using bivariate ordinary least squares regression analysis. SETTING: Patients were prospectively recruited from six UK outpatient clinics. PARTICIPANTS: Adult patients with chronic rhinosinusitis without nasal polyps (CRSsNPs). MAIN OUTCOME MEASURES: Baseline SNOT-22, SF-12 and EQ-5D-5L scores. RESULTS: Fifty-two adults were recruited with a mean age of 55 years, 51% were male. The mean SNOT-22 score was 43.82. Mental and physical component scores of the SF-12 were 46.53 and 46, respectively. Mean index score computed form the EQ-5D-5L was 0.75. Worse (higher) SNOT-22 scores were associated with lower EQ-5D-5L VAS and utility scores and SF-12 MCS and PCS scores. CONCLUSION: The EQ-5D-5L suggests that British CRSsNPs patients are negatively impacted with regards to quality of life. We found the SF-12 to be less sensitive and conclude that the EQ-5D-5L tool is a quick and accessible method for assessing QOL in order it can be compared with other disease states.

Current use of baseline medical treatment in chronic rhinosinusitis: Data from the National Chronic Rhinosinusitis Epidemiology Study (CRES).

OBJECTIVES: According to clinical and comissioning guidelines for chronic rhinosinusitis (CRS), patients being referred to secondary care should have failed primary medical treatment with nasal douching (ND) and intranasal corticosteroids (INCS). The study objectives were to identify the rate of specific medical therapy in CRS patients and establish any differences in medication use, for both CRS and associated medical conditions, between CRS phenotypes. DESIGN AND SETTING: Case-control study in a secondary care setting. METHODS: Participant-reported study-specific questionnaire capturing free text data on current medication use at the time of study entry. Qualitative interviews with 21 participants also explored their experience of CRS and its management. PARTICPANTS: Patients both without (CRSsNPs) and with polyps (CRSwNPs). MAIN OUTCOME MEASURES: Reported use of CRS-related and non-related medications. RESULTS: Within a total of 1243 CRS participants, current INCS usage was low (18% in CRSwNPs, 12% in CRSsNPs); ND was being performed by only 1% of all participants. Bronchodilators and inhaled corticosteroids use was significantly higher in CRSwNPs participants (P < .0001). Antidepressant use was significantly higher in CRSsNPs (14% vs 7%, P < .0002). There were no significant regional variations in rates of INCS use, nor any significant influence of social deprivation. CONCLUSIONS: The current use of baseline medical therapy in CRS appears to be very low, representing a combination of poor patient compliance, possible ineffectiveness of treatment and a lack of familiarity with current guidelines amongst general practitioners and some ENT specialists. Work is needed to disseminate guidelines to all practitioners involved and reduce unnecessary burden on existing healthcare resources for this common condition by ensuring timely referral and definitive management.

Chronic rhinosinusitis and mood disturbance.

BACKGROUND: This study is part of the Chronic Rhinosinusitis Epidemiology Study (CRES). The overarching aim is to determine factors that influence the onset and severity of chronic rhinosinusitis (CRS). The aim of this analysis is to determine whether those with CRS are more likely to report psychiatric morbidity and in particular mood disturbance compared with healthy controls. METHODS: CRES consists of a study-specific questionnaire regarding demographic and socioeconomic factors and past medical history as well as a nasal symptom score (SNOT-22) and SF-36 (QoL - quality of life tool). Both of these tools contain mental health or emotional well-being domains. Participants were specifically asked whether they had ever consulted with their General Practitioner for anxiety or depression. Questionnaires were distributed to patients with CRS attending ENT outpatient clinics at 30 centres across the United Kingdom from 2007-2013. Controls were also recruited at these sites. Patients were divided into subgroups of CRS according to the absence/presence of polyps (CRSsNPs/CRSwNPs) or allergic fungal rhinosinusitis (AFRS). RESULTS: Consultations with a family physician for depression or anxiety were higher amongst those with CRS than controls, but this was only significant for those with CRSsNPs. Odds ratio (OR) for CRSsNPs vs controls: 1.89; OR for CRSwNPs: 1.40. Patients with CRS showed significantly higher mental health morbidity than controls across the mental health and emotional wellbeing domains of the SF-36 and SNOT-22. Mean difference in the mental health domain of SF-36 was 8.3 for CRSsNPs and 5.3 for CRSwNPs. For the emotional domain of SNOT-22, differences were 7.7 and 6.3 respectively. CONCLUSIONS: Depression and anxiety are significantly more common in patients with CRS compared to healthy controls, especially in those with CRSsNPs. This added mental health morbidity needs consideration when managing these patients in primary and secondary care settings.

EUFOREA Rhinology Research Forum 2016: report of the brainstorming sessions on needs and priorities in rhinitis and rhinosinusitis.

The first European Rhinology Research Forum organized by the European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA) was held in the Royal Academy of Medicine in Brussels on 17th and 18th November 2016, in collaboration with the European Rhinologic Society (ERS) and the Global Allergy and Asthma European Network (GA2LEN). One hundred and thirty participants (medical doctors from different specialties, researchers, as well as patients and industry representatives) from 27 countries took part in the multiple perspective discussions including brainstorming sessions on care pathways and research needs in rhinitis and rhinosinusitis. The debates started with an overview of the current state of the art, including weaknesses and strengths of the current practices, followed by the identification of essential research needs, thoroughly integrated in the context of Precision Medicine (PM), with personalized care, prediction of success of treatment, participation of the patient and prevention of disease as key principles for improving current clinical practices. This report provides a concise summary of the outcomes of the brainstorming sessions of the European Rhinology Research Forum 2016.

A randomised controlled trial of sodium citrate spray for non-conductive olfactory disorders.

OBJECTIVES: Previous research has suggested that sodium citrate improves hyposmia by decreasing mucus calcium levels in the nose. This study aimed to confirm or refute this effect in a single application and assess potential side-effects. DESIGN: Study design was a randomised double-blind controlled trial of sodium citrate nasal spray (intervention) vs sterile water (control). Fifty-five patients with non-conductive olfactory loss were randomised to receive the intervention or placebo. SETTING: Tertiary care clinic. MAIN OUTCOME MEASURES: The primary outcome measure was improvement in measured olfactory thresholds for phenyl ethyl alcohol (PEA) over 2 hours. Other outcome measures assessed were improvement in olfactory thresholds in 1-butanol, eucalyptol and acetic acid; number of responders with a clinically relevant response in each arm; and adverse effects. RESULTS: A significant effect was seen in the intervention arm for PEA and for 1-butanol and eucalyptol when compared to the control arm (P<.05); 32% of the intervention arm responded in terms of improved sensitivity towards some of the odours. Minor adverse effects noted included sore throat, nasal paraesthesia, slight rhinorrhoea and itching. The duration of effect of the citrate is transient, peaking at 30-60 minutes after application. CONCLUSIONS: Sodium citrate yields some potential as a treatment for non-conductive olfactory loss; however, these findings require corroboration in further clinical trials looking at longer term regular use of the spray as a viable therapeutic option for patients where it would be applied at frequent intervals such as before mealtimes.

The value of a feasibility study into long-term macrolide therapy in chronic rhinosinusitis.

OBJECTIVES: There is currently conflicting level 1 evidence in the use of long-term antibiotics for chronic rhinosinusitis without nasal polyps. The primary aim of this feasibility study was to optimise future randomised trial design by assessing recruitment and retention of patients alongside providing preliminary data on symptomatic control. DESIGN: Prospective, multicentre feasibility (cohort) study with all patients receiving macrolide therapy for 12 weeks and a further subsequent 12-week follow-up. Participants received a 12-week course of clarithromycin 250 mg alongside twice daily topical mometasone and nasal douching. Primary outcomes focused on recruitment, retention and compliance. Clinical and quality-of-life outcomes measures were also recorded. SETTING: Patients were prospectively recruited from six UK outpatient clinics. PARTICIPANTS: Adult patients with chronic rhinosinusitis without nasal polyps and no prior endoscopic sinus surgery underwent baseline assessment and then follow-up at 3 and 6 months. MAIN OUTCOME MEASURES: Six-month recruitment and retention data. RESULTS: Over 13 months, 55 adults were recruited from five centres. Four patients declined participation. 75% of patients were retained within the study. Dropouts included one medication contraindication, three unable to tolerate medication and 10 not attending full follow-up. Sino Nasal Outcome Test-22 and endoscopic scores showed statistically significant improvement. No other clinical or quality-of-life assessment improvements were seen. CONCLUSION: Retention and recruitment to a trial using long-term clarithromycin to treat chronic rhinosinusitis without nasal polyps is achievable and this data will support a future randomised controlled trial. The study provides vital insight into trial design, thus informing UK research networks and rhinology researchers internationally.

SNOT-22 in a control population.

OBJECTIVES: To assess SNOT-22 and its subscales in a non-rhinosinusitis UK-wide population. DESIGN: Self-reported questionnaire. SETTING: Based from 30 ENT departments around the UK. PARTICIPANTS: 250 Non-rhinosinusitis adults - no self-reported nasal problems in the past, no chronic conditions undergoing active treatment and no hospital admissions in the preceding 12 months. MAIN OUTCOME MEASURES: SNOT-22, SF-36. RESULTS: The mean SNOT-22 total score overall was 12.0. The mean was 10.2 for males with a median of 6.5 and a mean of 13.2 for females with a median of 9. Females scored significantly more highly than males on the sleep/fatigue and facial domains. CONCLUSIONS: Our data demonstrate differences in SNOT-22 amongst males and females. These data can be used in future studies for comparison with different disease populations with rhinosinusitis.

Management of pinna haematoma study (MaPHaeS): A multicentre retrospective observational study.

OBJECTIVES: To assess current variation in the management of pinna haematoma (PH) and its effect on outcomes. DESIGN: Multicentre retrospective observational record-based study. SETTING: Eleven hospitals around the UK. PARTICIPANTS: Eighty-three patients above the age of 16 with PH. OUTCOME MEASURES: The primary outcome measure was recurrence rate of PH over a 6-month period post-treatment, assessed by treatment type (scalpel incision vs needle aspiration). Secondary outcome measures assessed the impact of other factors on recurrence, infection and cosmetic complications of PH over a period of 6 months. RESULTS: After adjusting for confounding factors, involvement of the whole ear, and management within an operating theatre were associated with a lower rate of recurrence of pinna haematoma. The drainage technique, suspected aetiology, choice of post-drainage management, grade and specialty of practitioner performing drainage, the use of antibiotic cover and hospital admission did not affect the rate of haematoma recurrence, infection or cosmetic complications. CONCLUSIONS: Where possible PH should be drained in an operating theatre. Multicentre randomized controlled trials are required to further investigate the impact of drainage technique and post-drainage management on outcome.

A cross sectional analysis of a case-control study about quality of life in CRS in the UK; a comparison between CRS subtypes.

BACKGROUND: The Sinonasal Outcome Test (SNOT-22) has been used as a patient reported outcome measure to grade symptom severity before and after treatment for chronic rhinosinusitis (CRS). METHODOLOGY: This analysis uses data from the CRS Epidemiology Study (CRES). The overarching aim of CRES was to determine factors that influence the onset and severity of CRS. A study-specific questionnaire including SNOT-22 was distributed to patients with CRS attending ENT clinics across 30 centres in the United Kingdom. The aim of this analysis was to compare SNOT-22 scores between those with different types of CRS to determine any differences present in the total score or the subdomains and to assess whether any differences varied according to gender. RESULTS: There were a total of 1249 CRS participants in the following subgroups: CRS without nasal polyps (CRSsNPs) (n=553), CRS with nasal polyps (CRSwNPs) (n=651), allergic fungal rhinosinusitis (AFRS) (n=45). Since there were differing gender ratios in each subgroup, males and females were analysed separately. The mean and standard deviation for SNOT-22 was: males CRSsNP 41.1 (21.0), CRSwNP 41.7 (20.5); females CRSsNP 49.6 (19.7), CRSwNP 49.5 (22.9). In the nasal domain, those with CRSwNP scored more highly than those with CRSsNP; for males 18.1 (8.1) vs. 15.9 (7.9); for females 19.6 (8.0) vs 16.7 (7.5). CONCLUSIONS: Patients with CRSwNPs report higher symptom scores in the nasal domain of SNOT-22 than those with CRSsNPs with women in both subgroups reporting higher total scores than men.

Chronic rhinosinusitis: patient experiences of primary and secondary care - a qualitative study.

OBJECTIVES: To explore the experience of CRS and its management from the perspective of patients with CRS. To our knowledge, this is the first qualitative study exploring sinus disease. DESIGN: Semi-structured qualitative interviews. SETTING: ENT outpatient clinic. PARTICIPANTS: Twenty-one adult patients with CRS: 11 male, 10 female. Patients suffered from a range of types of CRS (including polyps and fungal disease) and differing durations of symptoms (1.5-47 years). Participants were purposively selected. Thematic analysis was used. OUTCOME MEASURES: Patient experience of CRS and its management. RESULTS: Patients had concerns regarding management of their symptoms by both healthcare professionals and themselves, including delays to referral and repeated medications. They reported reduced quality of life and high financial and psychosocial costs associated with living with CRS. CONCLUSIONS: Despite guidelines for CRS treatment, outcomes remain variable leading to dissatisfaction with treatment. Adherence to existing guidelines may result in fewer repeated consultations in primary care and earlier referrals to secondary care.

Psychosocial outcomes after varying risk management strategies in women at increased familial breast cancer risk: a mixed methods study of patient and partner outcomes.

INTRODUCTION: Female carriers of BRCA1/2 genes have an increased lifetime risk of breast cancer. Options for managing risk include imaging surveillance or risk-reducing surgery (RRS). This mixed methods study aimed to identify factors affecting risk-management decisions and the psychosocial outcomes of these decisions for high-risk women and their partners. METHODS: Semi-structured qualitative interviews were performed with women at high breast cancer risk who had faced these choices. Partners were also interviewed. Analysis used a framework approach. A bespoke questionnaire was developed to quantify and explore associations. RESULTS: A total of 32 women were interviewed. Of these, 27 had partners of whom 7 (26%) agreed to be interviewed. Four main themes arose: perception of risk and impact of increased risk; risk-management strategy decision-making; impact of risk-management strategy; support needs and partner relationship issues. The questionnaire response rate was 36/157 (23%). Decision satisfaction was high in both surveillance and RRS groups. Relationship changes were common but not universal. Common causes of distress following RRS included adverse body image changes. Both groups experienced generalised and cancer-specific anxiety. Drivers for surgery included having children, deaths of close family from breast cancer and higher levels of cancer anxiety. CONCLUSIONS: Levels of psychosocial and decision satisfaction were high for women choosing both RRS and surveillance but, for a minority, risk-reducing measures result in long-term psychosocial morbidity. Efforts to recognise women at increased risk of psychological morbidity may allow targeted support.

Reactions of the eco RV restriction endonuclease with fluorescent oligodeoxynucleotides: identical equilibrium constants for binding to specific and non-specific DNA.

The EcoRV restriction endonuclease cleaves DNA specifically at its recognition sequence in the presence of magnesium ions, but several studies have indicated that it binds to DNA in the absence of Mg2+ without any preference for its recognition site. However, specific binding to the recognition site has also been reported. To distinguish between these reports, oligodeoxynucleotides were tagged with either dansyl or eosin fluorophores at their 5' termini and annealed to form duplexes of 12 to 16 base-pairs. For each length of duplex, one derivative had the EcoRV recognition sequence while another lacked this sequence. For the duplexes with the recognition site, the fluorophores had no effect on DNA cleavage rates by EcoRV in the presence of Mg2+. The binding of the specific and non-specific duplexes to EcoRV in the absence of Mg2+ was measured by fluorescence resonance energy transfer and by fluorescence depolarization. In both procedures, the signal from the specific complex differed from the complex with non-specific DNA, with the depolarization data indicating that non-specific DNA bound to EcoRV retains a higher rotational freedom than specific DNA. Even so, the equilibrium constant for the binding of specific DNA was identical, within error limits, to that for non-specific DNA.

DNA cleavage by the EcoRV restriction endonuclease: roles of divalent metal ions in specificity and catalysis.

The roles of divalent metal ions in DNA cleavage by the EcoRV endonuclease were studied by using Co2+ or Mn2+ as substitutes for the natural cofactor Mg2+. In steady-state experiments with a 12 bp oligonucleotide substrate, Co2+ yielded a similar turnover rate to that with Mg2+, but Mn2+ gave a slower rate. Single turnovers of EcoRV on this substrate were analysed by stopped-flow and quench-flow methods, to determine the rates for the formation of the ternary enzyme-DNA-metal complex, the hydrolysis of the phosphodiester bonds and the dissociation of the cleaved DNA. With Co2+, all three steps had similar rates to those with Mg2+. In contrast, Mn2+ gave a faster rate for phosphodiester hydrolysis than either Mg2+ or Co2+, but a slower rate for product dissociation, thus accounting for its low turnover rate. Single turnovers on plasmids also yielded faster rates for substrate hydrolysis with Mn2+ compared to Mg2+ and Co2+. Since Mn2+ gave the most rapid rates for the hydrolytic step, despite being less electronegative than Co2+, the function of the metal ion at the active site of EcoRV cannot be just the polarisation of the scissile phosphate. Moreover, the minimal scheme for the Co2+-catalysed reaction requires two metal ions for DNA cleavage. The metal ions seem to be involved in the precise positioning of both the substrate and the water that acts as the attacking nucleophile and in activating that water molecule. A model is presented to account for how two metal ions might fulfil these functions.

Interactions of the EcoRV restriction endonuclease with fluorescent oligodeoxynucleotides.

A self-complementary dodecadeoxyribonucleotide that contains the recognition sequence for the R.EcoRV ENase was synthesised with a primary amino group at its 5' terminus. The 5' amino function was labeled with the fluorescent dye 5-[dimethylamino] napthalene-1-sulfonyl chloride. The labeled oligodeoxyribonucleotide in its duplex form was shown to be a suitable substrate for kinetic studies on the ENase and that no significant dye-DNA or dye-protein interactions occurred. Finally, the binding of R.EcoRV to the labeled DNA was followed by detecting the fluorescence resonance energy transfer between the tryptophans of the protein and the fluorescent labels of the DNA.

A general assay for restriction endonucleases and other DNA-modifying enzymes with plasmid substrates.

A procedure for measuring the activities of enzymes that alter the covalent structure of DNA is described. The assay utilizes covalently closed circles of DNA as the substrate and yields quantitative data on the fraction of this DNA converted to both open-circle and linear forms.

Refractive-index detection by interferometric backscatter in packed-capillary high-performance liquid chromatography.

A simple, inexpensive, micro-volume refractive index detector has been applied to packed capillary high-performance liquid chromatography. Nanoliter detector volumes produced by a unique optical train, based on interferometric backscatter, allows for universal solute detection at the picogram level. System utility is demonstrated by reversed-phase separation of a test mixture containing ppm levels of NaCl, phenol, ethyl benzene and toluene.

Specific rotation measurements from peak height data, with a Gaussian peak model.

A method is described whereby a sensitive laser-based polarimeter can be used to make very accurate and precise specific rotation measurements on microgram quantities of optically active materials. Flow-injection or liquid chromatography systems provide reproducible introduction of the sample into the polarimetric system. If a Gaussian distribution of the analyte concentration is assumed, the peak height can be used in the determination of specific rotation. This method provides a direct calibration with an absolute standard which yields more accurate and precise results than those obtainable by using peak area.