Tropism of engineered and evolved recombinant AAV serotypes in the rd1 mouse and ex vivo primate retina.

There is much debate on the adeno-associated virus (AAV) serotype that best targets specific retinal cell types and the route of surgical delivery-intravitreal or subretinal. This study compared three of the most efficacious AAV vectors known to date in a mouse model of retinal degeneration (rd1 mouse) and macaque and human retinal explants. Green fluorescent protein (GFP) driven by a ubiquitous promoter was packaged into three AAV capsids: AAV2/8(Y733F), AAV2/2(quad Y-F) and AAV2/2(7m8). Overall, AAV2/2(7m8) transduced the largest area of retina and resulted in the highest level of GFP expression, followed by AAV2/2(quad Y-F) and AAV2/8(Y733F). AAV2/2(7m8) and AAV2/2(quad Y-F) both resulted in similar patterns of transduction whether they were injected intravitreally or subretinally. AAV2/8(Y733F) transduced a significantly smaller area of retina when injected intravitreally compared with subretinally. Retinal ganglion cells, horizontal cells and retinal pigment epithelium expressed relatively high levels of GFP in the mouse retina, whereas amacrine cells expressed low levels of GFP and bipolar cells were infrequently transduced. Cone cells were the most frequently transduced cell type in macaque retina explants, whereas Müller cells were the predominant transduced cell type in human retinal explants. Of the AAV serotypes tested, AAV2/2(7m8) was the most effective at transducing a range of cell types in degenerate mouse retina and macaque and human retinal explants.

Signalling by melanopsin (OPN4) expressing photosensitive retinal ganglion cells.

Over the past two decades there have been significant advances in our understanding of both the anatomy and function of the melanopsin system. It has become clear that rather than acting as a simple irradiance detector the melanopsin system is in fact far more complicated. The range of behavioural systems known to be influenced by melanopsin activity is increasing with time, and it is now clear that melanopsin contributes not only to multiple non-image forming systems but also has a role in visual pathways. How melanopsin is capable of driving so many different behaviours is unclear, but recent evidence suggests that the answer may lie in the diversity of melanopsin light responses and the functional specialisation of photosensitive retinal ganglion cell (pRGC) subtypes. In this review, we shall overview the current understanding of the melanopsin system, and evaluate the evidence for the hypothesis that individual pRGC subtypes not only perform specific roles, but are functionally specialised to do so. We conclude that while, currently, the available data somewhat support this hypothesis, we currently lack the necessary detail to fully understand how the functional diversity of pRGC subtypes correlates with different behavioural responses, and ultimately why such complexity is required within the melanopsin system. What we are lacking is a cohesive understanding of how light responses differ between the pRGC subtypes (based not only on anatomical classification but also based on their site of innervation); how these diverse light responses are generated, and most importantly how these responses relate to the physiological functions they underpin.

Treatment-related problems experienced by cancer patients undergoing chemotherapy: a scoping review.

Cancer patients undergoing chemotherapy experience a range of treatment-related problems, and variations in prevalence exist between treatment centres. A scoping review was undertaken to map reported rates of problem prevalence in the literature. This will inform development of a patient-reported outcome measure (PROM) to monitor prevalence and severity of problems over time and assist service providers optimise supportive care provision. Two databases (Embase and Medline) were searched from 2002 to 2013. Fifty one published papers and conference abstracts reporting problem prevalence rates were identified. The papers reported 98 different problems, from which a typology of 27 problem domains was developed, including both physical symptoms and psychosocial issues. The problem domains most often studied were nausea, vomiting and fatigue. This review reflects the chemotherapy-associated problems to which researchers attach the most importance. The range in reported prevalence across studies was very broad (e.g. nausea: 9-74%), with even less frequently studied problems showing high prevalence in some studies (e.g. gynaecological problems: up to 94%). The wide variation in prevalence and range of problems experienced raises challenges for PROM development. Patients should therefore be involved in consensus exercises to assist selection of items to ensure any instrument is complete and robust.

Maintaining stable symptom control in inflammatory bowel disease: a retrospective analysis of adherence, medication switches and the risk of relapse.

BACKGROUND: Maintenance therapy with 5-aminosalicylic acid (5-ASA) is a key strategy for preventing relapse in many patients with inflammatory bowel disease (IBD). Factors which disrupt 5-ASA delivery, such as non-adherence and 5-ASA switches, may destabilise symptom control. AIM: To investigate the impact of non-adherence and medication switches on stable symptom control in UK patients with IBD. METHODS: A retrospective cohort study was conducted using a UK dispensing database. Adherence was analysed in randomised matched samples for each of the six leading oral mesalazine formulations, measured by medication possession ratio (MPR); MPR ≥80% was classified as adherent. Relationships among adherence, switch and relapse were analysed over 18 months in patients receiving continuous mesalazine therapy throughout a 6-month baseline period (primary subgroup analysis). Relapses of active ulcerative colitis were identified using a doubling of MPR as a proxy. RESULTS: Only 39% of patients in the matched samples (n = 1200) were classed as adherent. No significant differences in adherence were observed among mesalazine formulations. In the primary subgroup analysis (n = 568), non-adherent patients had a significantly greater risk of relapse than adherent patients (RR = 1.44, 95% CI = 1.08-1.94; P = 0.014). Among adherent patients (n = 276), those who switched had a 3.5-fold greater risk of relapse than those who did not switch (95% CI = 1.16-10.62; P = 0.008). CONCLUSIONS: Both non-adherence and mesalazine switches in adherent patients were associated with significant increases in the risk of relapse, suggesting that disruption of mesalazine maintenance therapy may destabilise symptom control. These findings provide evidence to advocate caution when considering mesalazine switches for stable patients.

Oral vs intravenous paracetamol for lower third molar extractions under general anaesthesia: is oral administration inferior?

BACKGROUND: Paracetamol formulations provide effective analgesia after surgery [Duggan ST, Scott LJ. Intravenous paracetamol (acetominophen). Drugs 2009; 69: 101-13; Toms L, McQuay HJ, Derry S, Moore RA. Single dose oral paracetamol (acetaminophen) for postoperative pain in adults. Cochrane Database Syst Rev 2008: CD004602]. I.V. paracetamol is superior to oral for pain rescue (Jarde O, Boccard E. Parenteral versus oral route increases paracetamol efficacy. Clin Drug Invest 1997; 14: 474-81). By randomized, double-blinded trial, we aimed to determine whether preoperative oral paracetamol provides inferior postoperative analgesia to preoperative i.v. paracetamol. METHODS: One hundred and thirty participants received either oral paracetamol and i.v. placebo (Group OP), or oral placebo and i.v. paracetamol (Perfalgan™) (Group IP). Oral preparations were given at least 45 min before surgery; i.v. preparations after induction of anaesthesia. Pain was assessed by a 100 mm visual analogue scale (VAS) 1 h from the end of surgery. Rescue analgesia was given on request. RESULTS: A total of 128 patients completed the study. There were no significant differences in baseline characteristics or intraoperative variables between the groups. The study was designed to reveal whether OP is inferior to IP, with an inferiority margin of 20%. The number of patients reporting satisfactory analgesia at 1 h with VAS ≤ 30 mm were 15 (OP) and 17 (IP), respectively. The secondary outcome measure of the mean (standard deviation) VAS (mm) for the whole of each group was 52 (22) for OP and 47 (22) for IP. Analysis of confidence intervals indicates that oral paracetamol is not inferior to i.v. paracetamol. The median survival (90% CI) to rescue analgesia request was 54.3 (51.2-57.4) min in Group OP and 57.3 (55.4-59.2) min in Group IP; there was no significant difference in this measure. CONCLUSIONS: In this study of lower third molar extraction, oral paracetamol is not inferior to i.v. for postoperative analgesia. ISRCTN Registration http://www.controlled-trials.com/ISRCTN77607163.

Measuring asthma-specific quality of life: structured review.

Measuring quality of life (QoL) has become an increasingly important dimension of assessing patient well-being and drug efficacy. As there are now several asthma QoL questionnaires to choose from, it is important to appreciate their strengths and weaknesses. To assist in this choice, we have reviewed the existing questionnaires in a structured way. Information relating to the conceptual and measurement model, reliability, validity, interpretability, burden, administration format and translations was extracted from the published literature. The instruments differ in almost all criteria considered, and therefore it cannot be assumed that they measure the same thing. We recommend the selection of questionnaires that are designed only for asthma and that do not assess symptoms as part of QoL. Only two of the questionnaires reviewed fulfill these requirements: the Sydney Asthma QoL Questionnaire (AQLQ-S) and the Living with Asthma Questionnaire (LWAQ). However, for multinational studies, it may be convenient or practical to use questionnaires that have been linguistically validated in many languages (AQLQ-J, SGRQ). It remains unclear which of these questionnaires best reflects patient perceptions of QoL. Our review did not involve patients, so for the time being choosing from existing questionnaires requires a compromise based on the rigor of the development process and the target patient group.

Conducting oral examinations for cancer in general practice: what are the barriers?

BACKGROUND: The incidence of oral (mouth) cancer in the UK is continuing to rise. Individuals who are at greatest risk rarely visit a dentist but do consult general medical practitioners (GMPs). Therefore, GMPs could have an important role in the early detection of oral cancer. Research has shown that GMPs do not opportunistically screen high-risk individuals; however, the barriers to screening are poorly understood. OBJECTIVES: To understand the reasons why GMPs may not screen for oral cancer. METHODS: A questionnaire was developed, using the Theory of Planned Behaviour (TPB), to measure GMPs attitudes to and screening for oral cancer. The questionnaire was designed using all the key theoretical constructs of the TPB and incorporating the themes identified in a qualitative elicitation study. The questionnaire was posted to 499 GPs in Surrey Primary Care trust. RESULTS: Two hundred and twenty-eight completed questionnaires were returned (46%). Two TPB constructs [subjective norm (e.g. peer pressure) and perceived external control factors (e.g. adequate equipment, time constraints)] were identified as significant predictors of 'intention' to perform oral screening. Intention and perceived internal control factors (e.g. self-efficacy) were predictive of actually performing oral screening with patients. CONCLUSIONS: The results of the study suggest that there is considerable potential for improving intention to perform oral cancer screening in general practice. Theory-based interventions could include further training to enhance confidence, expertise, knowledge and ease of examination, the provision of adequate equipment in the surgery and increasing the motivation to comply with significant others by introducing guidelines on opportunistic screening.

The effect of the European Clinical Trials Directive on published drug research in anaesthesia.

The clinical indications for anaesthetic drugs are developed through peer-reviewed publication of clinical trials. We performed a bibliometric analysis of all human research papers reported in nine general anaesthesia journals over 6 years (n = 6489), to determine any effects of the 2004 European Clinical Trials Directive on reported drug research in anaesthesia originating from Europe and the United Kingdom. We found 89% studies involved patients and 11% volunteers. Of 3234 (50%) drug studies, 96% were phase IV (post-marketing) trials. Worldwide, the number of research papers fell by 3.6% (p < 0.004) in the 3 years following introduction of the European Clinical Trials Directive (5% Europe, 18% United Kingdom), and drug research papers fell by 12% (p < 0.001; 15% Europe, 29% United Kingdom). The introduction of the Clinical Trials Directive has therefore coincided with a decline in European drug research, particularly that originating from the United Kingdom. We suggest a number of measures researchers could take in response, and we propose a simplification of the application process for phase IV clinical trials, emphasising patient risk assessment.

Development of a tracheostomy scoring system to guide airway management after major head and neck surgery.

The use of elective tracheostomy in major head and neck surgery is well established, although practice varies between units. There is no published method that reliably predicts the need for tracheostomy. This paper describes the development of a surgical scoring system designed to achieve that aim. The system was devised using data obtained retrospectively from 148 consecutive major head and neck procedures. These procedures were grouped according to the airway management plan in place at the end of the procedure: elective extubation (group E, 52 procedures, 50 patients); elective overnight ventilation via an endotracheal tube (group ETT, 55 procedures, 52 patients); and elective overnight ventilation via a tracheostomy (group T, 41 procedures, 41 patients). 8 patients from group ETT required a late tracheostomy for either medical or surgical indications. Using statistical methods, a threshold score was defined above which the high risk of upper airway obstruction should prompt consideration of an elective tracheostomy.

The influence of symptom experiences and attributions on adherence to highly active anti-retroviral therapy (HAART): a six-month prospective, follow-up study.

OBJECTIVE: To examine changes in individuals' experiences of symptoms over the first six months of taking highly active anti-retroviral therapy (HAART) and to assess the impact of symptom experiences and attributions on adherence to HAART. METHODS: A prospective study where consecutive HIV positive individuals initiating HAART completed validated questionnaires assessing their experiences of symptoms, depression, beliefs about HAART and adherence, before starting treatment and after one, three and six months of treatment. RESULTS: Rates of low (<95%) adherence to HAART increased over time (p<0.001). Overall, the number of HIV or HAART-related symptoms reported did not change significantly over follow-up. However, symptom experiences differed between those reporting high (> or =95%) adherence and those reporting low adherence. Individuals reporting high adherence experienced a decrease in symptoms they attributed to HIV (p<0.05), and a decrease in the symptoms they attributed to HAART-side effects (p<0.05) over time. This decrease in symptoms over time was not seen among individuals reporting low adherence. A lack of symptomatic improvement was associated with increasing doubts about the continued necessity for HAART (p<0.05). CONCLUSIONS: The findings suggest that adherence to HAART is influenced by individuals' experiences of both HIV and HAART-related symptoms. Patients who experience persistent symptoms while on HAART may begin to doubt their continued need for treatment and respond by missing doses. These findings have implications for the development of evidence-based interventions to increase adherence.

A survey of the quality and accuracy of information leaflets about skin cancer and sun-protective behaviour available from UK general practices and community pharmacies.

BACKGROUND: Better information promotes sun protection behaviour and is associated with earlier presentation and survival for malignant melanoma. Aim To assess the quality of patient information leaflets about skin cancer and sun-protective behaviour available from general practices and community pharmacies. DESIGN OF STUDY: A structured review of patient information leaflets. Setting All community pharmacies and general practices in one Primary Care Trust were invited to supply leaflets. METHODS: Readability was assessed using the SMOG scoring system. Presentation and content were reviewed using the Ensuring Quality Information for Patients (EQIP) guidelines. Three consultant dermatologists assessed each leaflet for accuracy. RESULTS: Thirty-one different patient information leaflets were returned. Thirteen (42%) were published in the previous 2 years, but 10 (32%) were over 5 years old. Nine (29%) leaflets were produced by the NHS or Health Education Authority, and 8 (27%) were linked to a commercial organization. One leaflet had readability in the primary education range (SMOG score = 6), and none with the recommended range for health education material (SMOG score < or = 5). Two leaflets (6%) were in the highest quartile of EQIP score for presentation and content. Five leaflets (17%) had a major inaccuracy such as over-reliance on sun screen products instead of shade and clothing. CONCLUSIONS: Leaflets were of variable quality in presentation and content. All required a reading age higher than recommended. All leaflets with major inaccuracies had links with commercial organizations. This study raises important issues about the potential conflict between marketing and health messages in the way sun creams are promoted.

Self-sampling for oropharyngeal and rectal specimens to screen for sexually transmitted infections: acceptability among men who have sex with men.

OBJECTIVES: To explore the feasibility and acceptability of self-sampling for oropharyngeal and rectal specimens to screen for sexually transmitted infections (STIs) among men who have sex with men (MSM). Participant's willingness to self-sample at home was also explored. METHODS: Participants of a study to evaluate the sensitivity and specificity of self versus nurse taken oropharyngeal and rectal specimens were surveyed to assess the feasibility and acceptability of self-sampling using specimen collection methods (gargle, OraSure mouth pad to collect oropharyngeal specimens and APTIMA unisex swabs to collect rectal and pharyngeal specimens). Acceptability was measured using a five-point Likert-type response scale (for example, 1 = strongly disagree; 5 = strongly agree). Open-ended questions explored participants' experiences of self-sampling. RESULTS: Of 334 eligible MSM, 301 (90%) participated in the study. Altogether, 301 participants self-sampled using gargle and rectal and pharyngeal swabs and 288 using mouth pad. Complete questionnaire data from 274 participants showed that feasibility and acceptability of self-sampling using gargle and mouth pad was higher (92%) than pharyngeal swabs (76%). Rectal swabs were acceptable to 82% participants. Despite some discomfort and difficulty in using swabs, 76% were willing to use all four methods for self-sampling in the future. Home sampling was acceptable (84%) as it was perceived to be less intrusive and more convenient than a clinic visit and likely to reduce genitourinary medicine (GUM) waiting time. CONCLUSIONS: Self-sampling for rectal and oropharyngeal specimens is feasible and acceptable to MSM. Self-sampling can be offered as an alternative to clinic-based testing and has the potential to improve choice, access and uptake of screening for STIs.

Attending an STI Foundation course increases chlamydia testing in primary care, but not HIV testing.

The Sexually Transmitted Infection Foundation course (STIF) is a recommended training course for UK general practitioners (GPs) and others delivering sexual health services in the community. We assessed the impact of attending the course on testing for HIV and chlamydia. Thirty-one GPs attending Brighton STIF courses were identified and the laboratory database was searched to identify all chlamydia and HIV tests they requested in the three months prior to attending, the first three months after attending and the subsequent three months. Three hundred and eight chlamydia tests were performed precourse, 390 postcourse and 342 in the following three months. This represented a significant increase from baseline to postcourse (P = 0.007), which was lost by three to six months (P = 0.25). The proportion of positives did not change. A total of 98, 111 and 131 HIV tests were performed in the three time periods of which; none were positive. Barriers other than training may need to be overcome to increase HIV testing in primary care.

Interventions to increase self-efficacy in the context of addiction behaviours: a systematic literature review.

This article describes the effectiveness of interventions aimed at increasing self-efficacy and consequently, changing addiction behaviours. Electronic databases were searched and bibliographies of retrieved references scanned. Ten studies targeting tobacco smoking, alcohol and illicit drug use met the inclusion criteria. The interventions ranged from computer-generated tailored letters to intensive group-based interventions. Seven of the 10 studies reported positive effects of interventions upon self-efficacy. The two that assessed behaviour change reported a significant effect but as neither performed mediation analyses, behaviour change could not reliably be attributed to self-efficacy change. In conclusion, self-efficacy can be increased using a range of methods. There is, however, little evidence to determine whether such increases change behaviour.

The impact of genetic testing for Crohn's disease, risk magnitude and graphical format on motivation to stop smoking: an experimental analogue study.

Genetic tests may motivate risk-reducing behaviour more than other types of tests because they generate higher risk magnitudes and because their results have high personal relevance. To date, trial designs have not allowed the disentangling of the effects of these two factors. This analogue study examines the independent impacts of risk magnitude and provenance, and of risk display type, on motivation to quit smoking. A total of 180 smokers were randomly allocated to one of the 18 Crohn's disease risk vignettes in a 3 (risk provenance: family history. genetic test mutation positive. genetic test mutation negative) x 3 (risk magnitude: 3%, 6%, 50%) x 2 (display: grouped or dispersed icons) design. The 50% group had significantly higher intentions to quit than the 3% group. A significant risk provenance x magnitude interaction showed that participants in 50% or 6% groups were equally motivated, regardless of risk provenance, while participants in the 3% group had higher intentions associated with a mutation negative result than with a result based on family history alone. Grouped icon displays were more motivating than the dispersed icons. Using genetic tests to estimate risks of common complex conditions may not motivate behaviour change beyond the impact of the numerical risk estimates derived from such tests.

Long-term results of a hydroxyapatite-coated femoral component in total hip replacement: a 15- to 21-year follow-up study.

Between 1986 and 1991 we implanted 331 consecutive Furlong hydroxyapatite-coated femoral components of a total hip replacement in 291 patients. A cemented acetabular prosthesis was used in 217 hips and a hydroxyapatite-coated component in 114. We describe the long-term clinical and radiological survival of the femoral component at a mean follow-up of 17.5 years (15 to 21). Only two patients (0.68%) were lost to follow-up. With revision of the femoral component for any reason as the endpoint, the survival at a mean of 17 years was 97.4% (95% confidence interval 94.1 to 99.5), and with revision for aseptic loosening as the endpoint it was 100%. The survival at a maximum of 21 years with revision of the femoral component for any reason as the endpoint was 97.4% (95% confidence interval 81.0 or 99.5). These results compare favourably with the best long-term results of cemented or uncemented femoral components used in total hip replacement.

Assessing patients' beliefs about cardiac rehabilitation as a basis for predicting attendance after acute myocardial infarction.

BACKGROUND: Some sociodemographic and psychological variables such as patients' belief about illness are associated with attendance at cardiac rehabilitation. Exploration of patients' beliefs about treatment regarding cardiac rehabilitation has been limited to qualitative studies; their role in relation to attendance at cardiac rehabilitation after acute myocardial infarction (AMI) remains speculative. OBJECTIVES: To develop a valid and reliable measure of patients' beliefs regarding cardiac rehabilitation and to ascertain the relationship between such beliefs and attendance. DESIGN: A prospective questionnaire-based study. SETTING: Coronary care unit of a London teaching hospital. PATIENTS: 130 patients with AMI; 104 (83%) men; mean age 58.4 (standard deviation (SD) 10.7) years. INTERVENTIONS: Patients completed a 26-item questionnaire consisting of statements pertaining to beliefs about cardiac rehabilitation. MAIN OUTCOME MEASURES: Cardiac rehabilitation attendance; beliefs of patients about cardiac rehabilitation. RESULTS: Four subscales pertaining to patients' beliefs about cardiac rehabilitation were produced, accounting for 65.3% of the attendance variance: perceived necessity of cardiac rehabilitation (alpha = 0.71), concerns about exercise (alpha = 0.79), practical barriers (alpha = 0.70) and perceived personal suitability (alpha = 0.74). Patients who attended were more likely to believe that cardiac rehabilitation was necessary and to understand its role compared with non-attenders (17.7 (SD 2.7) v 16.9 (SD 3.0), p = 0.029). Patients who thought cardiac rehabilitation was suitable for a younger, more active person were less likely to attend (5.6 (SD 1.9) v 4.6 (SD 1.7), p = 0.007). Patients who expressed concerns about exercise or who reported practical barriers to attendance were less likely to attend, although these did not reach statistical significance. CONCLUSION: Beliefs about cardiac rehabilitation can be quantified and differ between attenders and non-attenders of cardiac rehabilitation.