Assessment of the current and emerging criteria for the histopathological classification of lung neuroendocrine tumours in the lungNENomics project.

BACKGROUND: Six thoracic pathologists reviewed 259 lung neuroendocrine tumours (LNETs) from the lungNENomics project, with 171 of them having associated survival data. This cohort presents a unique opportunity to assess the strengths and limitations of current World Health Organization (WHO) classification criteria and to evaluate the utility of emerging markers. PATIENTS AND METHODS: Patients were diagnosed based on the 2021 WHO criteria, with atypical carcinoids (ACs) defined by the presence of focal necrosis and/or 2-10 mitoses per 2 mm2. We investigated two markers of tumour proliferation: the Ki-67 index and phospho-histone H3 (PHH3) protein expression, quantified by pathologists and automatically via deep learning. Additionally, an unsupervised deep learning algorithm was trained to uncover previously unnoticed morphological features with diagnostic value. RESULTS: The accuracy in distinguishing typical from ACs is hampered by interobserver variability in mitotic counting and the limitations of morphological criteria in identifying aggressive cases. Our study reveals that different Ki-67 cut-offs can categorise LNETs similarly to current WHO criteria. Counting mitoses in PHH3+ areas does not improve diagnosis, while providing a similar prognostic value to the current criteria. With the advantage of being time efficient, automated assessment of these markers leads to similar conclusions. Lastly, state-of-the-art deep learning modelling does not uncover undisclosed morphological features with diagnostic value. CONCLUSIONS: This study suggests that the mitotic criteria can be complemented by manual or automated assessment of Ki-67 or PHH3 protein expression, but these markers do not significantly improve the prognostic value of the current classification, as the AC group remains highly unspecific for aggressive cases. Therefore, we may have exhausted the potential of morphological features in classifying and prognosticating LNETs. Our study suggests that it might be time to shift the research focus towards investigating molecular markers that could contribute to a more clinically relevant morpho-molecular classification.

Going where other methods cannot: A systematic mapping review of 25 years of qualitative research in Otolaryngology.

OBJECTIVE: To map the use of qualitative methods within otolaryngology, providing examples and identifying gaps in the literature. DESIGN: Systematic mapping review of journal-based literature from 1990 to 2015 using Medline, Embase, PsycINFO and CENTRAL. Included studies were categorised according to clinical subspecialty, research aims and qualitative approach. RESULTS: Of 4,061 identified articles, 388 were deemed relevant to qualitative research in ENT. The number of qualitative publications has risen markedly over the last 25 years (r = 0.802), particularly since 2010. The most commonly used method was semi-structured interviews 62.1% (241/388). Head and neck cancer (41.8% (162/388)) and otology (40.2% (156/388)) publish more qualitative research than rhinology (7.0% (27/388)) and laryngology (6.7% (26/388)). CONCLUSIONS: Qualitative research in otolaryngology has increased over time, but laryngology and rhinology remain under-represented. Most studies use interviews, underutilising the strengths of other qualitative methods. There is considerable scope for further application of qualitative methods in otolaryngology.

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.

'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.

Appropriate dosing of sugammadex to reverse deep rocuronium-induced neuromuscular blockade in morbidly obese patients.

In morbidly obese patients, the speed of reversal of neuromuscular blockade with sugammadex based on ideal body weight is still matter of debate. In this single-center, randomised, double-blinded study, neuromuscular blockade was monitored in 50 patients using acceleromyography at the adductor pollicis. At the end of surgery with deep rocuronium-induced neuromuscular blockade, patients randomly received sugammadex 4 mg.kg(-1) (high dose group), 2 mg.kg(-1) (middle dose group), or 1 mg.kg(-1) (low dose group) of ideal body weight. After administration of the first dose of sugammadex, the mean (SD) recovery time (censored at 600 s) from deep neuromuscular blockade was significantly shorter (p < 0.001) in the high-dose group (n = 14; 255 (63) s) vs the middle-dose group (n = 13; 429 (102) s), or low-dose group (n = 4; 581 (154) s). Success rate from neuromuscular blockade reversal defined by a train-of-four ≥ 0.9 within 10 min after sugammadex administration, were 93%, 77% and 22% for these high, middle and low-dose groups respectively (p < 0.05 vs low-dose group). In morbidly obese patients, 4 mg.kg(-1) of ideal body weight of sugammadex allows suitable reversal of deep rocuronium-induced neuromuscular blockade. Monitoring remains essential to detect residual curarisation or recurarisation.

Prognostic value of metabolic parameters and clinical impact of ¹8F-fluorocholine PET/CT in biochemical recurrent prostate cancer.

PURPOSE: To evaluate the therapeutic impact of (18)F-fluorocholine (FCH) PET/CT in biochemical recurrent prostate cancer (PC) and to investigate the value of quantitative FCH PET/CT parameters in predicting progression-free survival (PFS). METHODS: This retrospective study included 172 consecutive patients with PC who underwent FCH PET/CT for biochemical recurrence. Mean rising PSA was 10.7 ± 35.0 ng/ml. Patients with positive FCH PET were classified into three groups: those with uptake only in the prostatic bed, those with locoregional disease, and those with distant metastases. Referring physicians were asked to indicate the hypothetical therapeutic strategy with and without the FCH PET/CT results. Clinical variables and PET parameters including SUVmax, SUVpeak, SUVmean, total lesion choline kinase activity (TLCKA) and standardized added metabolic activity (SAM) were recorded and a multivariate analysis was performed to determine the factors independently predicting PFS. RESULTS: In 137 of the 172 patients, the FCH PET/CT scan was positive, and of these, 29.9 % (41/137) had prostatic recurrence, 42.3 % (58/137) had pelvic lymph node recurrence with or without prostatic recurrence, and 27.7 % (38/137) had distant metastases. The FCH PET/CT result led to a change in treatment plan in 43.6 % (75/172) of the 172 patients. Treatment was changed in 49.6 % (68/137) of those with a positive FCH PET/CT scan and in 20 % (7/35) of those with a negative FCH PET/CT scan. After a median follow-up of 29.3 months (95 % CI 18.9 - 45.9 months), according to multivariate analysis age <70 years, SAM ≥23 and SUVmean ≥3 were parameters independently predicting PFS. A nomogram constructed using the three parameters showed 49 months of PFS in patients with the best scores (0 or 1) and only 11 months in patients with a poor score (score 3). CONCLUSION: This study indicates that a positive FCH PET result in PC patients with biochemical recurrence predicts a shorter PFS and confirms the major impact of the FCH PET result on the management of biochemical recurrent PC.

Patients' experiences of dental implant treatment: A literature review of key qualitative studies.

OBJECTIVES: To identify and summarise the findings of previous qualitative studies relating to patients' experience of dental implant treatment (DIT) at various stages of their implant treatment, by means of textual narrative synthesis. DATA/SOURCES: Original articles reporting patients' experience with dental implant were included. A two-stage search of the literature, electronic and hand search identified relevant qualitative studies up to July 2014. An extensive electronic search was conducted of databases including PubMed, Embase, Scopus, Web of Knowledge, Cochrane Database and Google Scholar. STUDY SELECTION: Included primary studies (n=10) used qualitative research methods and qualitative analysis to investigate patients' experiences with dental implants treatment. CONCLUSIONS: While the growing interest in implant treatment for the replacement of missing dentition is evident, it is essential to investigate patients' perceptions of different aspects of implant treatment. This textual narrative synthesis conducted to review qualitative studies which provided insight into patients' experience of two types of implant prostheses namely ISOD (implant-supported overdenture) and FISP (fixed implant supported prostheses). Primary reviewed studies tended to include samples of older patients with more extensive tooth loss, and to focus on experiences prior to and post-treatment rather than on the treatment period itself. Findings across reviewed studies (n=10) suggested that patients with FISP thought of implant treatment as a process of 'normalisation'(1) and believed that such implant restorations could be similar to natural teeth, whereas patients with ISOD focused more on the functional and social advantages of their implant treatment. CLINICAL SIGNIFICANCE: The growing interest in qualitative research is evident in several branches of clinical dentistry and dental implantology is not an exception. Qualitative studies concerning the patients account of their experience of dental implants is however limited. The aim of this review is to firstly identify recent work within this field and to subsequently categorise it more consistently by means of textural narrative synthesis, thus highlighting similarities and differences and enabling identification of gaps in research knowledge thereby setting the direction of further research.

Dietary supplementation of alpha-linolenic acid in an enriched rapeseed oil diet protects from stroke.

Populations of Western countries are severely deficient in omega-3 intake, both in the form of alpha-linolenic acid (ALA) and the Long Chain derivatives (LC-n-3), Eicosa-Pentaenoic-Acid and Docosa-Hexaenoic-Acid. Omega-3 insufficiency is a risk factor for cardiovascular and cerebral diseases such as coronary heart disease and stroke. Stroke is a major cause of mortality and morbidity, and induces a significant socioeconomic cost and a marked increase in patient/family burden. To date, preventive treatments and neuroprotective drugs identified in preclinical studies failed in clinical trials, in part because of an inability to tolerate drugs at neuroprotective concentrations. Therefore testing alternative protective strategies, such as functional foods/nutraceuticals, are of considerable interest. We have previously demonstrated that a single injection of ALA reduced ischemic damage by limiting glutamate-mediated neuronal death, whereas repeated injections displayed additive protective benefits as a result of increased neurogenesis, synaptogenesis and neurotrophin expression. Because intravenous injections are not a suitable long-term strategy in humans, the present study investigated the effect of ALA supplementation by an experimental diet containing rapeseed oil (RSO, a rich source of ALA) as the only source of lipids for stroke prevention. We tested several experimental diets which included 5, 10, and 20% RSO-enriched diet and feeding paradigms (fresh diet was provided once or twice a week for 4 or 6 weeks). Our results showed that ALA supplemented diets are more sensitive to lipid peroxidation than a regular chow diet. Because the diet affected feeding behavior and animal growth, we defined concrete guidelines to investigate the effect of omega-3 supplementation on neuropathology. Among the different sets of experiments, animals fed with 10% and 20% RSO-enriched diet displayed a reduced mortality rate, infarct size and increased probability of spontaneous reperfusion in the post-ischemic period. In addition, a drastic reduction of lipid peroxidation levels was observed in the ischemic brain of RSO-fed animals. Overall, our findings provide new insights into the potential of employing rapeseed oil as a functional food/nutraceutical aiding in stroke prevention and protection.

Facilitation of implant provision in primary care.

OBJECTIVE: To investigate primary care practitioner participation in implant-supported mandibular overdenture (ISOD) provision. DESIGN: Postal questionnaire. SETTING: Primary dental care, North East England 2007. SUBJECTS AND METHODS: Two hundred and ninety-five practitioners in North East England were sent questionnaires presenting a case-based scenario of a patient unable to manage a lower denture on an atrophic ridge. The questionnaire led them through the facilitation stages of ISOD provision, asking them to state their anticipated level of participation at each stage. Demographic details were also collected. RESULTS: Two hundred and seventeen responses were received (74%). Most practitioners would consider the option of provision of ISODs (89%) in this case and all who considered would discuss the option with the patient. Of those offering to facilitate treatment, 66% (122/184) would never deliver themselves, with the majority (60%, 111/184) referring within primary care. Statistical analysis showed associations between demographics and behaviour. CONCLUSIONS: The majority of practitioners in this study area would facilitate ISOD provision in this case. Practitioners who are male and working in a practice where a framework for the provision of implants already exists are most likely to facilitate provision and/or provide an ISOD within primary care.

Hybrid epitaxial-colloidal semiconductor nanostructures.

We present a growth technique which combines wet-chemical growth and molecular beam epitaxy (MBE) to create complex semiconductor nanostructures with nanocrystals as active optical material. The obtained results show that wet-chemically prepared semiconductor nanocrystals can be incorporated in an epitaxally grown crystalline cap layer. As an exemplary system we chose CdSe nanorods and CdSe(ZnS) core-shell nanocrystals in ZnSe and discuss the two limits of thin (d approximately 2R) and thick (d>2R) ZnSe cap layers of thickness d for CdSe nanorods and nanodots of radii R between 2 and 4 nm. In contrast to the strain-induced CdSe/ZnSe Stranski-Krastanow growth of a quantum dot layer in a semiconductor heterostructure, the technique proposed here does not rely on strain and thus results in additional degrees of freedom for choosing composition, concentration, shape, and size of the nanocrystals. Transmission electron microscopy and X-ray diffractometry show that the ZnSe cap layer is of high crystalline quality and provides all parameters for a consecutive growth of Bragg structures, waveguides, or diode structures for electrical injection.

[Cerebral abscess: MRI, DWI and MRS features]. / Abcès cérébral: aspects caractéristiques en imagerie morphologique et fonctionnelle.

Although rare in non immunodeficient patients, the correct diagnosis of brain abscess is essential in order to initiate urgent medical and surgical treatment. We describe the imaging features including spectroscopy and diffusion MRI.

Evidence-based guideline for the primary care management of stable angina.

This is an updated version of the first North of England Stable Angina Guideline (1,2) and summarizes the full guideline. (3) This paper presents all the recommendations within the guideline; and where these are new or substantially altered from the original version, it also presents a summary of the supporting evidence. The aims and methods of development (summarized in Box 1) of this guideline are unchanged from the original version, to which readers are directed for more detail. The research questions raised during the development of this guideline are shown in Box 2.

Evidence-based guideline on the primary care management of asthma.

This is an updated version of the first North of England Asthma Guideline (1,2) and summarizes the full guideline. (3) This paper presents all the recommendations within the guideline and, where these are new or substantially altered from the original version, it also presents a summary of the supporting evidence. The aims and methods of development (summarized in Box 1) of this guideline are unchanged from the original version, to which readers are directed for more detail. The research questions raised during the development of this guideline are shown in Box 2.

Guidelines in professions allied to medicine.

BACKGROUND: Clinical practice guidelines aim to reduce inappropriate variations in practice and to promote the delivery of evidence-based health care. OBJECTIVES: To identify and assess the effects of studies of the introduction of clinical practice guidelines in nursing (including health visiting), midwifery and other professions allied to medicine. SEARCH STRATEGY: We searched the Cochrane Effective Practice and Organisation of Care Group specialised register, MEDLINE (1975 to 1996), EMBASE, Cinahl and Sigle to 1996, the NHS Economic Evaluations Database (1994 to 1996), DHSS-Data (1983 to 1996), the Database of Abstracts of Reviews of Effectiveness (1994 to 1996) and reference lists of articles. We also hand searched the journal Quality in Health Care, made personal contact with content experts and contacted libraries identified by an expert panel. SELECTION CRITERIA: Randomised trials, controlled before-and-after studies and interrupted time series analyses of the introduction of interventions comparing 1. Clinical guidelines plus dissemination and/or implementation strategies versus no guidelines; 2. Guidelines plus dissemination and/or implementation strategies versus guidelines plus alternative dissemination and/or implementation strategies; and 3. (post hoc) Guidelines used by professions allied to medicine versus standard physician care. The participants were nurses, midwives and other professions allied to medicine. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed study quality. MAIN RESULTS: Eighteen studies were included involving more than 467 health care professionals. The reporting of study methods was inadequate for all studies. In all but one study, nurses were the targeted professional group; one study was aimed solely at dieticians. The various behaviours targeted included the management of hypertension, low back pain and hyperlipidaemia. Nine studies were identified for comparison 1. Three out of five studies observed improvements in at least some processes of care and six out of eight studies observed improvements in outcomes of care. Only one study included a formal economic evaluation, with equivocal findings. Three studies were identified for comparison 2 but it was difficult to draw firm conclusions because of poor methods. Six studies were identified for comparison 3 (post hoc). These studies generally supported the hypothesis that there was no difference between care given by nurses using clinical guidelines and standard physician care. REVIEWER'S CONCLUSIONS: There is some evidence that guideline-driven care is effective in changing the process and outcome of care provided by professions allied to medicine. However, caution is needed in generalising findings to other professions and settings.

Local information for primary care: the St Albans WAX Project (STAPCIS).

The St. Albans Primary Care Information Service (STAPCIS) is a database of locally focused information designed to be of use for GPs and the Primary Care team as a whole in a particular area. It is currently being used by practices in the St. Albans, Dacorum and Watford & Three Rivers Primary Care Groups. STAPCIS developed from a project initiated in late 1997 to pilot the use of the WAX software to improve access to directory-type and full-text material needed for easy access by primary care staff and traditionally difficult to manage. The database is updated centrally by the STAPCIS Librarian who distributes the new editions to the practices. The WAX software itself was developed by the Cambridge Centre for Clinical Informatics. STAPCIS contains locally and nationally produced relevant information from a variety of sources, including full-text clinical guidelines and directories of Trusts. Decisions on new content are made by a Steering Group and the GPs and Primary Care teams are particularly encouraged to make suggestions regarding new content. The service is financially supported by the three primary care groups. The STAPCIS Librarian is project-managed by the Library & Information Development Unit (North Thames ), which also provides additional equipment and expertise. A new software company, WaX Info Ltd (), will soon be releasing a new version of the software, WaX. WaX consists of a WaX client and WaX ActiveLibrary server software. With the new version, the 'books' of information will still be stored on the user's PC, retaining the speed of access, but the server will enable users to 'borrow' books from remote locations and will provide automatic updates of all books. The new software will improve the management and distribution processes of STAPCIS once all of the practices have Internet connectivity.

Predicting place of discharge from hospital for patients with a stroke or hip fracture on admission.

OBJECTIVES: To determine the predictive power of patient and service characteristics on place of discharge following hospital admission for an acute stroke and for hip fracture. METHODS: Prospective cohort of 440 acute stroke and 572 hip fracture patients aged 65 years or over admitted from home to six district general hospitals and associated community hospitals, three in the North and three in the South of England. RESULTS: Age, marital status, living arrangements, mental health status at admission, pre-admission self-rated disability, pre-admission use of home-care services, post-admission staff assessments of functional dependency as measured by Barthel Index and of confusion as measured by the modified Crichton Royal Behavioural Rating Scale and nursing staffs' expectation of place of discharge are all significantly related to place of discharge for stroke and hip fracture participants. Logistic regression correctly predicted discharge destination for 87% of stroke patients from data available at time of admission and 83% of hip fracture patients. Of the 30% of stroke patients discharged to an institution, the model correctly predicted 73%. However, of the 19% of hip fracture patients discharged to an institution, only 28% were correctly predicted. CONCLUSIONS: Data about older patients admitted to hospital with an acute condition should be routinely collected by hospital staff to inform clinical management and to permit risk-adjusted audit.

Switch recombination in a transfected plasmid occurs preferentially in a B cell line that undergoes switch recombination of its chromosomal Ig heavy chain genes.

Ab class switching is induced upon B cell activation in vivo by immunization or infection or in vitro by treatment with mitogens, e. g. LPS, and results in the expression of different heavy chain constant region (CH) genes without a change in the Ab variable region. This DNA recombination event allows Abs to alter their biological activity while maintaining their antigenic specificity. Little is known about the molecular mechanism of switch recombination. To attempt to develop an assay for enzymes, DNA binding proteins, and DNA sequences that mediate switch recombination, we have constructed a plasmid DNA substrate that will undergo switch recombination upon stable transfection into the surface IgM+ B cell line (I.29 mu), a cell line capable of undergoing switch recombination of its endogenous genes. We demonstrate that recombination occurs between the two switch regions of the plasmid, as assayed by PCRs across the integrated plasmid switch regions, followed by Southern blot hybridization. Nucleotide sequence analysis of the PCR products confirmed the occurrence of S mu-S alpha recombination in the plasmid. Recombination of the plasmid in I.29 mu cells does not require treatment with inducers of switch recombination, suggesting that recombinase activity is constitutive in I.29 mu cells. Recombination does not require high levels of transcription across the switch regions of the plasmid. Fewer recombination events are detected in four different B and T cell lines that do not undergo switch recombination of their endogenous genes.

Clinical guidelines in nursing, midwifery and the therapies: a systematic review.

BACKGROUND: While nursing, midwifery and professions allied to medicine (PAMs) are increasingly using clinical guidelines to reduce inappropriate variations in practice and ensure higher quality care, there have been no rigorous overviews of their effectiveness in relation to these professions. We identified 18 evaluations of guidelines which met established quality for evaluations of interventions aimed at changing professional practice. This paper describes characteristics of guidelines evaluated and the effectiveness of different dissemination and implementation strategies used. METHODS: Guideline evaluations conducted since 1975 which used a randomized controlled trial, controlled before-and-after, or interrupted time-series design, were identified using a combination of database and hand searching. FINDINGS: It is mostly impossible to tell whether the guidelines evaluated were based on evidence. The most common method of guideline dissemination was the distribution of printed educational materials. Three studies compared different dissemination and/or implementation strategies: findings suggest educational interventions may be of value in the dissemination of guidelines and confer a benefit over passive dissemination.