Development of an intervention to manage knee osteoarthritis risk and symptoms following anterior cruciate ligament injury.

INTRODUCTION: Anterior cruciate ligament (ACL) injury is a risk factor for developing knee osteoarthritis (OA). We developed an intervention to support people manage risk factors for OA. METHODS: We conducted one-on-one interviews with 20 individuals with OA symptoms 6-15 years post ACL injury and used a nominal group process during a workshop with 40 patients and healthcare professionals (HCPs) to elicit information on the intervention content and delivery characteristics (timing, HCPs, and methods). Interview data were analyzed using content analysis. Nominal group ideas with importance ratings ≥5 of 7 met criteria for inclusion. Results were integrated, considering similarities and differences. RESULTS: Eight content categories were identified: 1. understanding knee injury and expectations about recovery; 2. understanding OA risk; 3. understanding OA signs and symptoms; 4. managing OA risk; 5. managing knee OA symptoms; 6. information for influencers; 7. credible sources; and, 8. updates on new evidence and treatments. Delivery timing reflected a lifespan approach from time of injury through symptomatic knee OA management. Although multiple media for delivery were identified, introductory face-to-face discussions and opportunity for re-accessing HCPs were critical. All HCPs who treat people with ACL should be familiar with and able to deliver the intervention. CONCLUSIONS: This co-development approach identified that an intervention to support people with ACL injury to limit and manage knee OA requires content embedded within an easily accessible, multi-media delivery model with capacity for check-back with HCPs that is appealing to different age groups and personal preferences over the lifespan post injury.

Microarray analysis of primary epithelial and fibroblast cells in chronic rhinosinusitis without nasal polyps.

BACKGROUND: Chronic rhinosinusitis is an inflammatory condition with an as yet unknown pathophysiology. We aimed to detect clusters of differentially regulated genes in the epithelial and fibroblast cells of patients with Chronic Rhinosinusitis without nasal polyposis (CRSsNP) and healthy controls. METHODOLOGY: Carefully phenotyped CRSsNP and healthy control participants were recruited. Primary cultures of isolated epithelial and fibroblast cells were established. Whole transcriptome analysis of the cells was performed using microarrays and replicated with quantitative RT-PCR and immunohistochemistry. RESULTS: Fibroblast cells from CRSsNP patients showed a significant upregulation (more than 2x) of the transcription factor NFE2L3 when compared to healthy controls by microarray with multiple hypothesis testing correction, qRT-PCR and immunohistochemistry. CONCLUSIONS: Here we have utilized microarray analysis to search for differentially expressed genes in isolated patient derived epithelial and fibroblast cells. The transcription factor NFE2L3 has been shown to be upregulated in fibroblast cells consistent with increasing evidence that fibroblasts play a key role in tissue specific inflammation within the paranasal sinuses.

General illness and psychological factors in patients with chronic nasal symptoms.

OBJECTIVES: Only a minority of patients referred to specialists with sinonasal symptoms have clear evidence of chronic rhinosinusitis (CRS). This study aims to estimate the prevalence of and associations between (i) general illness factors (fatigue, autonomic dysfunction) and (ii) psychological factors (anxiety, depression, somatisation, personality traits) in patients presenting with sinonasal symptoms. DESIGN: The following validated questionnaires were administered to patients: the Sino-Nasal Outcome Test-22 (SNOT-22) identifying symptom burden, Composite Autonomic Symptom Score-31 (COMPASS-31) measuring autonomic function, Chalder Fatigue Questionnaire, Patient Health Questionnaire-15 (PHQ-15) addressing somatisation symptoms, Hospital Anxiety and Depression Scale (HADS), and the International Personality Item Pool-50 (IPIP-50). Comparisons were made with normative and general population data, and relationships were analysed using nonparametric correlation. SETTING: Secondary care ENT outpatients. PARTICIPANTS: Adults referred with chronic sinonasal symptoms. MAIN OUTCOME MEASURES: SNOT-22, COMPASS-31, Chalder, PHQ-15, HADS, and IPIP-50 questionnaire scores. RESULTS: Sixty-one patients were included. There was a high prevalence of all general and psychological factors assessed compared with controls. Total SNOT-22 scores showed significant correlation with Chalder fatigue scores, total autonomic dysfunction score, anxiety, depression, somatisation tendencies and the emotionally unstable personality trait. Emotional instability and psychological dysfunction correlated significantly with sleep and psychological subscales of SNOT-22 but not the rhinological or ear/facial subscales. CONCLUSION: Patients with sinonasal symptoms demonstrate high prevalence and complex associations of general illness factors, psychological distress and certain personality traits. The SNOT-22 is a valuable tool, but its utility is limited by correlations with these confounding factors (eg psychological factors) that may exaggerate the total score. The use of the SNOT-22 component subscales is likely to provide more clinically meaningful and discriminant information.

A comparison of attitudes to laryngeal cancer treatment outcomes: A time trade-off study.

DESIGN: Time trade-off choice experiment. SETTING: Two large head and neck cancer centres. PARTICIPANTS: Patients who have received treatment for head and neck cancer and members of the head and neck cancer multidisciplinary team. MAIN OUTCOME MEASURES: Participants were asked to rank the outcome scenarios, assign utility values using time trade-off and rate the importance of survival on treatment choice. RESULTS: A total of 49 patients with head and neck cancer and 73 staff members were recruited. Chemoradiotherapy (CRT) optimal outcome was the most preferred health state (34 of 49, 69% patients, and 50 of 73, 68% staff), and CRT with complications was least preferred (27 of 49, 55% patients, and 51 of 73, 70% staff). Using time trade-off, mean utility values were calculated for CRT optimal outcome (0.73 for patients, 0.77 for staff), total laryngectomy (TL) optimal outcome (0.67 for patients, 0.69 for staff), TL outcome with complications (0.46 for patients, 0.51 for staff) and CRT with complications (0.36 for patients, 0.49 for staff). The average survival advantage required for a participant to change their preferred choice was 2.6 years. CONCLUSIONS: We have demonstrated that a significant proportion of patients with head and neck cancer and staff members would not choose CRT to manage locally advanced laryngeal cancer. Staff members rated the health states associated with laryngeal cancer treatment higher than patients who have experienced them, and this is particularly evident when considering the poorer outcomes. The head and neck cancer community should develop methods of practice and decision-making which incorporate elicitation and reporting of patient values as a central principle.

Synthesis and biological assessment of 3,7-dihydroxytropolones.

3,7-Dihydroxytropolones (3,7-dHTs) are highly oxygenated troponoids that have been identified as lead compounds for several human diseases. To date, structure-function studies on these molecules have been limited due to a scarcity of synthetic methods for their preparation. New synthetic strategies towards structurally novel 3,7-dHTs would be valuable in further studying their therapeutic potential. Here we describe the successful adaptation of a [5 + 2] oxidopyrilium cycloaddition/ring-opening for 3,7-dHT synthesis, which we apply in the synthesis of a plausible biosynthetic intermediate to the natural products puberulic and puberulonic acid. We have also tested these new compounds in several biological assays related to human immunodeficiency virus (HIV), hepatitis B virus (HBV) and herpes simplex virus (HSV) in order to gain insight into structure-functional analysis related to antiviral troponoid development.

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.

Stakeholders' views of recurrent sore throat, tonsillitis and their management: a qualitative interview study for the NAtional Trial of Tonsillectomy IN Adults (NATTINA Part 1).

OBJECTIVES: To determine the impact of recurrent sore throats and tonsillitis in adults and stakeholder views of treatment pathways. DESIGN: Qualitative semistructured interview design reporting novel data from a feasibility study for a UK national trial of tonsillectomy in adults. SETTING: Nine study sites linked to ear, nose and throat departments in National Health Service hospitals located across the United Kingdom. PARTICIPANTS: Fifteen patients, 11 general practitioners and 22 ear, nose and throat staff consented to in-depth interviews, which were analysed using a framework analysis approach. MAIN OUTCOME MEASURES: Views of stakeholder groups. RESULTS: Recurrent sore throats were reported to severely impact patients' family, work and social life. Ear, nose and throat staff stated that patients faced increasing barriers to secondary care service access. General practitioners were under pressure to reduce 'limited clinical value' surgical procedures. CONCLUSIONS: The findings from this study suggest that there is a disconnect between the attitudes of the stakeholders and the reality of recurrent sore throat, tonsillectomy procedures and service provision. More evidence for the role of tonsillectomy is needed from randomised controlled trials to determine whether it should continue to be ranked as a procedure of limited clinical effectiveness.

The effect of tonsillectomy on the morbidity from recurrent tonsillitis.

BACKGROUND: Tonsillitis is a common condition with an incidence in UK general practice of 37 per 1000 population a year.1 Recurrent tonsillitis results in significant morbidity and impacts on individuals' quality of life. This study assesses the morbidity and quality of life of adults with recurrent tonsillitis, and the impact of surgical intervention on their health state. OBJECTIVES: To describe disease-specific and global quality of life for adults with recurrent tonsillitis 6 months after tonsillectomy, using two instruments: the health impact of throat problems (HITP) and EuroQol-visual analogue scale questionnaire. To assess the overall health benefit from tonsillectomy as an intervention using the Glasgow Benefit Inventory (GBI). To assess potential predictors of tonsillectomy benefit. DESIGN: A prospective, observational cohort audit of patients who have fulfilled Scottish Intercollegiate Guideline Network (SIGN) criteria for tonsillectomy.2 SETTING: Secondary care, teaching hospital. PARTICIPANTS: Seventy patients (57 female), median age 20 years (range 13-41). RESULTS: Median preoperative HITP was 47 (range 15-67), compared to 4 (0-72), (P<.001) 6 months following surgery. Median HITP difference was 39.5 (range -20 to 75). There was no significant change in global Quality of Life. Median overall 6 months GBI was 39 (-3 to 100). Patients had an average of 27 episodes of tonsillitis over a period of seven years before "achieving" tonsillectomy, significantly higher than the SIGN guidelines of three or more episodes over three years. CONCLUSIONS: Recurrent tonsillitis causes a poor disease-specific quality of life. Patients experienced a median of three episodes per year for seven years before tonsillectomy. Following tonsillectomy, patients had a significant improvement in their disease-specific quality of life. Baseline HITP significantly improved after tonsillectomy. The results imply patients with recurrent acute tonsillitis may be experiencing undue delay.

'Thinking that somebody's going to delay [a tonsillectomy] for one to two years is quite horrifying really': a qualitative feasibility study for the NAtional Trial of Tonsillectomy IN Adults (NATTINA Part 2).

OBJECTIVES: Level one evidence on the value of adult tonsillectomy versus non-surgical management remains scarce. Before embarking on a costly national randomised controlled trial, it is essential to establish its feasibility. DESIGN: Feasibility study with in-depth qualitative and cognitive interviews. SETTING: ENT staff and patients were recruited from nine hospital centres across England and Scotland. PARTICIPANTS: Patients who were referred for tonsillectomy (n = 15), a convenience sample of general practitioners (n = 11) and ear, nose and throat staff (n = 22). MAIN OUTCOME MEASURES: To ascertain whether ear, nose and throat staff would be willing to randomise patients to the treatment arms. To assess general practitioners' willingness to refer patients to the NAtional Trial of Tonsillectomy IN Adults (NATTINA) centres. To assess patients' willingness to be randomised and the acceptability of the deferred surgery treatment arm. To ascertain whether the study could progress to the pilot trial stage. RESULTS: Ear, nose and throat staff and general practitioners were willing to randomise patients to the proposed NATTINA. Not all ENT staff were in equipoise concerning the treatment pathways. Patients were reluctant to be randomised into the deferred surgery group if they had already waited a substantial time before being referred. CONCLUSIONS: Findings suggest that the NATTINA may not be feasible. Proposed methods could not be realistically assessed without a pilot trial. Due to the importance of the question, as evidenced by NATTINA clinicians, and strong support from ENT staff, the pilot trial proceeded, with modifications.

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.

Pragmatic detection of anxiety and depression in a prospective cohort of voice outpatient clinic attenders.

OBJECTIVE: To evaluate diagnostic performance of the emotional domain of the VoiSS questionnaire compared with the Hospital Anxiety and Depression Scale (HADS). DESIGN: Cross-sectional questionnaire study. SETTING: Tertiary referral centre voice clinic. PARTICIPANTS: 210 consecutive voice clinic patients. MAIN OUTCOME MEASURES: Screening with VoiSS and HADS questionnaires. Paired comparison, correlation, multinomial logistic regression and receiver-operating characteristic (ROC) curve analysis. RESULTS: A total of 177 returned complete data sets. Ninety-six patients (54.2%) had functional dysphonia, and 81 (45.8%) had organic laryngeal disorders. Mean total VoiSS score = 39.7/120 (standard deviation (sd) 22.2). Mean emotional VoiSS subscale = 7.6/22 (sd 7.5). Mean HADS anxiety = 6.5/21 (sd 5.2) and depression mean = 7.1/21 (sd 4.8). There were 35 (20%) borderline anxiety and/or depression scores and 30 (17%) scores considered positive for 'caseness'. There was strong correlation between emotional VoiSS and HADS anxiety (Spearman's Rho = 0.68, P < 0.001) and HADS depression (Spearman's Rho = 0.62, P < 0.001). ROC curve analysis exhibited significant association between emotional VoiSS and HADS 'caseness' (area under curve = 0.88). In addition, functional dysphonia patients had lower mean VoiSS and HADS scores than patients with identifiable laryngeal abnormalities. CONCLUSION: The VoiSS emotional subscale strongly correlates with HADS anxiety and depression scores and could be used as a measure of psychological distress. This could allow targeted psychological strategies, without additional psychometric questionnaires. Functional dysphonia has less association with psychological distress than certain organic laryngological disorders.

Indolamine 2,3-dioxygenase expression by monocytes and dendritic cell populations in hepatitis C patients.

Dendritic cells (DCs) play an important role in the induction of the primary immune response to infection. DCs may express the tryptophan-catabolizing enzyme indolamine2,3-dioxygenase (IDO), which is an inducer of immune tolerance. Because there is evidence that chronic hepatitis C virus (HCV) infection leads to functional impairment of certain DC populations, we analysed IDO expression in DCs and monocytes from chronically infected and recovered HCV patients. The IDO1 and -2 expression was increased significantly in the monocytes of chronic HCV patients but, interestingly, not in those from recovered patients. The myeloid DCs from chronically infected HCV patients also showed enhanced IDO1 expression, while no change in either IDO1 or -2 was found for plasmacytoid DCs. Up-regulation of IDO1 gene expression was confirmed by the presence of enhanced kynurenine/tryptophan ratios in the plasma from chronic HCV patients. Increased IDO1 and -2 expression was also observed in monocytes from healthy donors infected with an adapted mutant of the HCV JFH-1 strain ex vivo, confirming a direct effect of HCV infection. These changes in IDO expression could be prevented by treatment with the IDO inhibitor 1-methyl tryptophan (1-mT). Furthermore, maturation of monocyte-derived DCs from chronically infected HCV patients, as well as well as monocyte-derived DCs infected ex vivo with HCV, was impaired, but this was reversed by 1-mT treatment. This suggests that IDO inhibitors may be used to treat chronic HCV patients in vivo, in conjunction with current therapies, or to activate DCs from patients ex vivo, such that they can be administered back as a DC-based therapeutic vaccine.

Injection laryngoplasty in the outpatient clinic under local anaesthetic: a case series of sixty-eight patients.

OBJECTIVES: We aimed to assess self-report and perceptual voice outcomes in patients undergoing local anaesthetic injection laryngoplasty in our outpatient clinic. DESIGN: Prospective case series. SETTING: Department of Otolaryngology-Head and Neck Surgery, Freeman Hospital, Newcastle-upon-Tyne, UK. PARTICIPANTS: Sixty-eight patients underwent local anaesthetic injection laryngoplasty in the outpatient clinic over the 2-year study period. MAIN OUTCOME MEASURE: Voice Performance Questionnaire (patient-rated), and perceptual voice analysis (observer-rated) Grade, Roughness, Breathiness, Aesthenia and Strain scores were recorded before and 2 weeks after injection laryngoplasty. RESULTS: Fifty-seven patients had sufficient pre- and post-procedure data to be included in the analysis. These included 32 men and 25 women, age range 26-97 years. Of the remaining patients, they were excluded due to failed procedure (n = 3), too unwell to proceed (n = 1), died before follow-up was complete (n = 3) and incomplete data (n = 4). The median Voice Performance Questionnaire score improved from 42 to 21; (P < 0.0001). Significant improvements were seen in all parameters of Grade, Roughness, Breathiness, Aesthenia, Strain. CONCLUSION: Injection laryngoplasty under local anaesthetic in the outpatient clinic generates improvements in subjective and perceptual voice outcomes similar to those obtained in the operating room under general anaesthetic or sedation. Complication rates between these procedures were also comparable. Injection laryngoplasty under local anaesthetic is timely, cost-effective and obviates need for general anaesthesia in patients, many of whom have comorbidities and diminished life expectancy.

Transnasal oesophagoscopy: diagnostic and management outcomes in a prospective cohort of 257 consecutive cases and practice implications.

OBJECTIVES: To determine the success rate, patient tolerability and impact of introducing transnasal oesophagoscopy on clinical practices. DESIGN: Prospective cohort with review of electronic patient records for outcomes. SETTING: UK tertiary centre Otolaryngology Department. PARTICIPANTS: The cohort comprised of two hundred and fifty-seven patients, 128 females (50%) and 129 males (50%) with an age range of 20-91 years; mean age 59 years (sd 13.6). MAIN OUTCOME MEASURES: Success rates, indications, findings and outcomes of patients undergoing transnasal oesophagoscopy and impact on rigid examinations of the pharynx and oesophagus were also considered. RESULTS: Transnasal oesophagoscopy has a high success rate of 97%; it is well tolerated by patients, and poor views are uncommon. Pathology was detected in 44% of patients. The most common indications for transnasal oesophagoscopy were unexplained throat symptoms (50%) and dysphagia (25%). Common positive findings were hiatus hernia (7%), Barrett's oesophagus (5%), dysmotility (5%) and oesophageal candidiasis (5%). Following transnasal oesophagoscopy, 59% of patients were discharged to their referring clinician, 17% continued to undergo otolaryngology follow-up, and 13% were referred to our gastrointestinal colleagues. Following the introduction of transnasal oesophagoscopy, there was a reduction in the number of rigid examinations of the pharynx and oesophagus in the subsequent years, despite an increase in total referrals. CONCLUSIONS: Transnasal oesophagoscopy is a well-tolerated procedure that allows otolaryngologists to make management decisions on common referrals swiftly in the clinic setting avoiding unnecessary investigations, follow-up and referral.

Head and neck cancer and dysphagia; caring for carers.

OBJECTIVES: A diagnosis of head and neck cancer (HNC) is a profound event for patients and family members who play a crucial role in their care. Eating and drinking difficulties affect patients' quality of life (QOL), but the impact on the carers' QOL has not been explored. This preliminary mixed method study reports on carer QOL over time and investigates the relationship with dysphagia. METHODS: Two hundred and eight HNC patients referred for (chemo)radiotherapy were asked to identify a carer and complete a health-related QOL and a swallowing QOL questionnaire at pre-treatment, 3 and 12 months post-treatment. Carers were given the Caregiver QOL-Cancer (CQOL-C) questionnaire at the same time points. A purposive sample of patient and carer dyads was observed over mealtimes and interviewed. RESULTS: Seventy per cent of carers returned a questionnaire at least once. There was no change in CQOL-C scores between pre-treatment and 3 months, but a significant improvement was found between 3 and 12 months post-treatment (p = 0.012). Patient-reported outcomes accounted for 52% of variance in carer QOL measurements (R(2) = 0.52, p < 0.001). Four themes emerged from the qualitative data food provision, monitoring, motivation and changes to lifestyle. CONCLUSIONS: Findings suggest a relationship between carer and patient QOL. Elsewhere, these two characteristics have been associated such that the greater the patients' physical care needs, the poorer the carers' and patients' QOL. Living with someone with dysphagia not only involves managing the physical swallowing difficulties but is also likely to impact on social activities such as participation in shared meals, leading to permanent lifestyle changes.

An evidence-based review of peritonsillar abscess.

OBJECTIVE OF REVIEW: We present the current literature surrounding peritonsillar abscess management highlighting areas of controversy. TYPE OF REVIEW AND SEARCH STRATEGY: Literature review using Medline and Embase databases (search terms 'peritonsillar abscess', 'peritonsillar infection' and 'quinsy') limited to articles published from 1991 to 2011 (English language). RESULTS: (i) INVESTIGATIONS: Intraoral ultrasound has a sensitivity and specificity of between 89-95% and 79-100%, respectively, for correctly diagnosing peritonsillar abscess and is underutilised currently. (ii) Medical management: Steroids can effectively aid recovery, reducing hospitalisation time and improving symptom relief; however, further study is needed, especially related to risk and cost benefit. Penicillin and metronidazole are an effective combination in 98-99% of cases of peritonsillar abscess. (iii) Surgical management: Overall, there is no convincing evidence in favour of either aspiration or incision & drainage. Quinsy tonsillectomy is subject to great geographical variation, however, is a safe procedure and reduces overall recovery time when compared with interval tonsillectomy. (iv) Admission: peritonsillar abscess can be effectively managed as an outpatient in many cases. (v) Further management: Overall, the recurrence rate of peritonsillar abscess is poorly defined but estimated as 9-22% based on current evidence. Interval tonsillectomy may be indicated in selected groups of patients at high risk of recurrence. CONCLUSIONS: Peritonsillar abscess is a common condition with increasing incidence. We demonstrate the potential for evidence-based modifications in clinical management. However, lack of national consensus may mean that this evidence base is not being adequately exploited in current practice. A national audit of peritonsillar abscess management, in particular looking at recurrence rates and patient experience with different management strategies, appears indicated.

Perspectives on paediatric sleep-disordered breathing in the UK: a qualitative study.

OBJECTIVE: There is limited understanding of treatment pathways for paediatric sleep-disordered breathing. This study explored current UK pathways and what is important to well-being for parents and children. METHOD: The study comprised in-depth qualitative interviews (n = 22) with parents of children (2-9 years) with symptoms of sleep-disordered breathing referred to a regional ENT clinic (n = 11), general practitioners who might refer these children to ENT (n = 5) and hospital doctors involved in treating these children (n = 6). Interviews were audio recorded, transcribed verbatim, anonymised and analysed thematically. RESULTS: General practitioners rarely identify seeing children with sleep-disordered breathing; conversely hospital doctors identify unsuspected issues. Parents are worried their child will stop breathing, but routes to referral and diagnosis are not straightforward. Modern technology can aid investigation and diagnosis. Patient weight is an issue for general practitioners and hospital doctors. Adenotonsillectomy is the treatment of choice, and information on paediatric sleep-disordered breathing is needed. CONCLUSION: Guidelines for the management of paediatric sleep-disordered breathing are needed.

Otitis externa: what is the problem with getting it right? A mixed-methods study in primary and secondary care.

OBJECTIVE: Otitis externa accounts for 1.1-1.3 per cent of patient presentations in primary care and 25 per cent of urgent referrals to ENT. This study aimed to explore otitis externa clinical decision-making at the primary-secondary care interface, otitis externa prevalence and recent trends in antimicrobial resistance in otitis externa related bacterial isolates and ototopical prescribing. METHOD: This is a mixed-methods study drawing on data from primary and secondary care and open National Health Service sources. RESULTS: A total of 101 general practitioner survey respondents reported frequently prescribing oral antibiotics for otitis externa. General practitioner consultations for otitis externa increased 25 per cent over 15 years. General practitioner ototopical preparations cost the National Health Service £7 410 440 in 2006 and £11 325 241 in 2016. A total of 162 consecutive hospital otitis externa-related bacterial isolates yielded 128 pseudomonas species, with 18 that were resistant to gentamicin and 7 that were resistant to ciprofloxacin. Ten guidelines reviewed showed systematic inconsistencies. CONCLUSION: General practitioners reported regularly prescribing oral antibiotics for otitis externa. Antimicrobial drug resistance is common in otitis externa. The available guidance is suboptimal.

Decreased levels of the cell-cycle inhibitor p27Kip1 protein: prognostic implications in primary breast cancer.

Breast cancer is the second leading cause of cancer death in North American women. There is considerable need for reliable prognostic markers to assist clinicians in making management decisions. Although a variety of factors have been tested, only tumor stage, grade, size, hormone receptor status, and S-phase fraction are used on a routine basis. The cell cycle is governed by a family of cyclin-dependent kinases (cdks), which are regulated by associated cyclins and by phosphorylation. p27Kip1, a cyclin-dependent kinase inhibitor, regulates progression from G1 into S phase by binding and inhibiting cyclin/cdks. p27Kip1 protein levels and/or activity are upregulated by growth inhibitory cytokines including transforming growth factor-beta (TGF-beta) and, thus, provide an important link between extracellular regulators and the cell cycle. Loss of p27Kip1, a negative cell-cycle regulator, may contribute to oncogenesis and tumor progression. However, p27Kip1 mutations in human tumors are extremely rare. We have demonstrated by immunohistochemistry that p27Kip1 protein levels are reduced in primary breast cancers and that this is associated with tumor progression in both in situ and invasive lesions. This was confirmed by western analysis, reflected in increased G1/S-phase cyclin-dependent kinase activities and shown to be regulated posttranscriptionally by in situ hybridization. Furthermore, on multivariate analysis, low p27Kip1 is a predictor of reduced disease-free survival. This simple and reliable immunohistochemical assay may become a routine part of breast cancer evaluation and may influence patient management.