Pneumococcal carriage and disease in adults in England 2011-2019: the importance of adults as a reservoir for pneumococcus in communities.

BACKGROUND: Pneumococcal carriage in children has been extensively studied, but carriage in healthy adults and its relationship to invasive pneumococcal disease (IPD) is less understood. METHODS: Nasal wash samples from adults without close contact with young children (Liverpool, UK), 2011-2019, were cultured, and culture-negative samples tested by PCR. Pneumococcal carriage in adults 18-44 years was compared with carriage among PCV-vaccinated children 13-48 months (nasopharyngeal swabs, Thames Valley, UK) and IPD data for England for the same ages for 2014-2019. Age-group specific serotype invasiveness was calculated and used with national IPD data to estimate carriage serotype distributions for adults aged 65+ years. RESULTS: In total 98 isolates (97 carriers) were identified from 1,631 adults aged 18+ years (age and sex standardized carriage prevalence 6.4%), with only three identified solely by PCR. Despite different carriage and IPD serotype distributions between adults and children, serotype invasiveness was highly correlated (R=0.9). Serotypes 3, 37 and 8 represented a higher proportion of adult carriage than expected from direct low-level transmission from children to adults. The predicted carriage serotype distributions for 65+ years aligned more closely with the carriage serotype distribution for young adults than young children. CONCLUSIONS: The nasal wash technique is highly sensitive; additional benefit of PCR is limited. Comparison of carriage serotype distributions suggests some serotypes may be circulating preferentially within these specific young adults. Our data suggest that for some serotypes carried by adults 65+ years, other adults may be an important reservoir for transmission. Age groups such as older children should also be considered.

Carriage of multidrug-resistant Gram-negative bacilli: duration and risk factors.

Identification of risk factors influencing the duration of carriage of multidrug-resistant Gram-negative bacilli (MDR-GNB) may be useful for infection control. The aim of this study is to estimate the impact of several factors collected for routine hospital surveillance on the duration of carriage of selected MDR-GNB. From January 2015 to July 2021, patients with at least two clinical/surveillance samples positive for MDR-GNB different from ESBL-producing E. coli or AmpC - exclusively producing Enterobacterales were assessed. Microorganisms, age, number of admissions, clinical or rectal sample, sex, and admission service were evaluated as risk factors. Multivariate analysis was performed by a Cox proportional hazard model. A total of 1981 episodes of colonization were included. Involved microorganisms were ESBL-Klebsiella pneumoniae (KP) in 1057 cases (53.4%), other ESBL-non-E. coli Enterobacterales in 91 (4.6%), OXA-48-KP in 263 (13.3%), KPC-KP in 90 (4.5%), VIM-KP in 29 (1.5%), carbapenemase-producing non-KP Enterobacterales (CP-non-KP) in 124 (6.3%), and MDR Pseudomonas aeruginosa (MDR-PAER) in 327 (16.5%). No differences in duration of colonization were observed among ESBL-KP (median colonization time 320 days), ESBL-non-E. coli Enterobacterales (226 days), OXA48-KP (305 days), and MDR-PAER (321 days). For each group, duration of colonization was significantly longer than that of KPC-KP (median colonization time 60 days), VIM-KP (138 days), and CP-non-KP (71 days). Male sex (HR = 0.88; 95% CI 0.78-0.99), detection in Hepatology-Gastroenterology (HR = 0.71; 95% CI 0.54-0.93), clinical sample (HR = 0.61; 95% CI 0.53-0.69), and > 2 admissions after first detection (HR = 0.47; 95% CI 0.42-0.52) were independent predictors of longer carriage, whereas VIM-KP (HR = 1.61; 95% CI 1.04-2.48), KPC-KP (HR = 1.85; 95% CI 1.49-2.3), and CP-non-KP (HR = 1.92; 95% CI 1.49-2.47) were associated with shorter colonization time. Duration of colonization was significantly longer for ESBL-KP, other ESBL-non-E. coli Enterobacterales, OXA-48-KP, and MDR-PAER. For these microorganisms, prolonging surveillance up to 2.5-3 years should be considered. Male sex, clinical sample, multiple readmissions, admission service, and type of microorganism are independent predictors of the duration of carriage.

Methodological guidelines for preparing a structured therapeutic education program: From design to evaluation. / Guía metodológica para la elaboración de un programa estructurado de educación terapéutica: del diseño a la evaluación.

BACKGROUND AND OBJECTIVE: Therapeutic patient education (TPE) is effective and essential in the context of the growing prevalence of chronic diseases, in which tools are needed for planning structured programs. The objective of this project was to develop guidelines for designing and assessing a TPE program. METHODS: 1) We assembled a multidisciplinary group of 8 leaders in TPE, chronicity, quality and safety from the hospital and the university. 2) We conducted an exhaustive review of the scientific literature on the planning of TPE programs directed at chronically ill patients, their relatives and caregivers. 3) The final text underwent comments and suggestions by participants from the hospital and primary care centre during a course on information and TPE methodology. The recommendations were unanimously agreed upon by the writing group. RESULTS: We obtained a standardised work procedure targeted at professionals involved in planning TPE programs, based on international recommendations. The document is structured into sections: a) Definition of the health problem and analysis of the situation; b) Program structure (human resources and materials); objectives (health-related, behaviour-related and educational) and methodology; c) Path the patient and family/caregiver follows in the program; and d) Assessment and indicators. The assessment of the procedure, in the framework of the methodology courses, was favourable. CONCLUSIONS: The methodology provided by this document serves as an instrument for the standardised and systematic planning of educational programs and unifies the criteria in their drafting. However, the document needs to be adapted to the condition and population to which each program is directed.

The influence of education on the access to childhood immunization: the case of Spain.

BACKGROUND: In order to enhance childhood vaccination uptake and the health consequences for the whole society, there is a need to study predictors that might help in understanding parents' behaviour in relation to childhood vaccination schemes. The aim of this paper is to assess whether parental education has an influence on their children's public health-care use in terms of visits for vaccinations, and thus evaluate whether more educated parents use public health resources more frequently in childhood immunization schedules. METHODS: The setting was the region of Catalonia in the north-east of Spain. Three different databases, containing information about 11,415 individuals corresponding to 79,905 observations, were merged and linked: 1) observational and longitudinal administrative data for adults and children in Catalonia; 2) a database containing information on the vaccination of children in relation to the public health programme called the "Healthy Child Programme"; and 3) the governmental vaccination registration. The presence of an education gradient was explored using a logistic regression. Children's health-care use was modelled using a logistic procedure. RESULTS: The greater the mothers' educational attainment level, the higher the probability of being vaccinated in this immunization programme. The presence of an age profile for vaccinations showed that less educated parents visit their GPs more frequently for immunizations when their children are below the age of six, but that pattern is completely the opposite after that age. Hence, for children aged between six and 16, more educated parents are more likely to ensure their children are immunized. Likewise, systematic vaccinations are more likely for those parents with a lower educational attainment level. CONCLUSIONS: This paper evidenced the presence of an education gradient for specific preventive care through the public health system and visits to the GP without any particular disease or advice for specific vaccinations.

Nek9 is a Plk1-activated kinase that controls early centrosome separation through Nek6/7 and Eg5.

The NIMA-family kinases Nek9/Nercc1, Nek6 and Nek7 form a signalling module required for mitotic spindle assembly. Nek9, the upstream kinase, is activated during prophase at centrosomes although the details of this have remained elusive. We now identify Plk1 as Nek9 direct activator and propose a two-step activation mechanism that involves Nek9 sequential phosphorylation by CDK1 and Plk1. Furthermore, we show that Plk1 controls prophase centrosome separation through the activation of Nek9 and ultimately the phosphorylation of the mitotic kinesin Eg5 at Ser1033, a Nek6/7 site that together with the CDK1 site Thr926 we establish contributes to the accumulation of Eg5 at centrosomes and is necessary for subsequent centrosome separation and timely mitosis. Our results provide a basis to understand signalling downstream of Plk1 and shed light on the role of Eg5, Plk1 and the NIMA-family kinases in the control of centrosome separation and normal mitotic progression.

A systematic review and meta-analysis of willingness-to-pay values: the case of malaria control interventions.

The increasing use of willingness to pay (WTP) to value the benefits of malaria control interventions offers a unique opportunity to explore the possibility of estimating a transferable indicator of mean WTP as well as studying differences across studies. As regression estimates from individual WTP studies are often assumed to transfer across populations it also provides an opportunity to question this practice. Using a qualitative review and meta analytic methods, this article determines what has been studied and how, provides a summary mean WTP by type of intervention, considers how and why WTP estimates vary and advises on future reporting of WTP studies. WTP has been elicited mostly for insecticide-treated nets, followed by drugs for treatment. Mean WTP, including zeros, is US$2.79 for insecticide-treated nets, US$6.65 for treatment and US$2.60 for other preventive services. Controlling for a limited number of sample and design effects, results can be transferred to different countries using the value function. The main concerns are the need to account for a broader range of explanators that are study specific and the ability to transfer results into malaria contexts beyond those represented by the data. Future studies need to improve the reporting of WTP.

A hospital incident reporting system (2016-2019): Learning from notifier's perception on incidents' risk, severity and frequency of adverse events.

Incident reporting systems (IRSs) are considered safety culture promoters. Nevertheless, they have not been contemplated to monitor professionals' perception about patient safety related risks. This study aims to describe the characteristics and evolution of incident notifications reported between 2016 and 2019 in a high complexity reference hospital in Barcelona and explores the association between notifications' characteristics and notifier's perception about incidents severity, probability of occurrence and risk. The main analysis unit was notifications reported. A descriptive analysis was performed and taxes by hospital activity were calculated. Odds ratios were obtained to study the association between the type of incident, the moment of incident, notifiers' professional category, reported incident's severity, probability and incidents' calculated risk. Through the study period, a total of 6379 notifications were reported, observing an annual increase of notifications until 2018. Falls (21.22%), Medical and procedures management (18.91%) and Medication incidents (15.49%) were the most frequently notified. Departments reporting the highest number of notifications were Emergency room and Obstetrics & Gynaecology. Incident type and notifiers' characteristics were consistently included in the models constructed to assess risk perception. Pharmaceutics were the most frequent notifiers when considering the proportion of staff members. Notification patterns can inform professionals' patient risk perception and increase awareness of professionals' misconceptions regarding patient safety.

Identification of photocrosslinking peptide ligands by mRNA display.

Photoaffinity labelling is a promising method for studying protein-ligand interactions. However, obtaining a specific, efficient crosslinker can require significant optimisation. We report a modified mRNA display strategy, photocrosslinking-RaPID (XL-RaPID), and exploit its ability to accelerate the discovery of cyclic peptides that photocrosslink to a target of interest. As a proof of concept, we generated a benzophenone-containing library and applied XL-RaPID screening against a model target, the second bromodomain of BRD3. This crosslinking screening gave two optimal candidates that selectively labelled the target protein in cell lysate. Overall, this work introduces direct photocrosslinking screening as a versatile technique for identifying covalent peptide ligands from mRNA display libraries incorporating reactive warheads.

Strategic discussion on funding and access to therapies targeting rare diseases in Spain: an expert consensus paper.

BACKGROUND: In recent years, significant advances have been made in the field of rare diseases (RDs). However, there is a large number of RDs without specific treatment and half of these treatments have public funding in Spain. The aim of the FINEERR project was to carry out a multidisciplinary strategic discussion on the challenge of funding and access to RD-targeted drugs in Spain, in order to agree on specific proposals for medium-term improvement and hence support decision-making in the Spanish National Healthcare System (SNHS). RESULTS: The FINEERR Project was organized around a CORE Advisory Committee, which provided an overview, agreed on the design and scope of the project, and selected the members within each of four working groups (WG). Overall, 40 experts discussed and reached a consensus on different relevant aspects, such as conditioning factors for initial funding and access, evaluation and access to RD-targeted therapies, funding of these therapies, and implementation of a new funding and access model. From these meetings, 50 proposals were defined and classified by their level of relevance according to the experts. A descriptive analysis of responses was performed for each proposal. Thereafter, experts completed another questionnaire where they ranked the 25 most relevant proposals according to their level of feasibility of being implemented in the SNHS. The most relevant and feasible proposals were to improve: process of referral of patients with RDs, control over monitoring mechanisms, and communication between healthcare professionals and patients. CONCLUSIONS: The FINEERR project may provide a starting point for stakeholders involved in the process of funding and access to RD-targeted therapies in Spain to provide the necessary resources and implement measures to improve both the quality of life and life expectancy of patients with RDs.

DYNLL/LC8 protein controls signal transduction through the Nek9/Nek6 signaling module by regulating Nek6 binding to Nek9.

The NIMA family protein kinases Nek9/Nercc1 and the highly similar Nek6 and Nek7 form a signaling module activated in mitosis, when they are involved in the control of spindle organization and function. Here we report that Nek9, the module upstream kinase, binds to DYNLL/LC8, a highly conserved protein originally described as a component of the dynein complex. LC8 is a dimer that interacts with different proteins and has been suggested to act as a dimerization hub promoting the organization and oligomerization of partially disorganized partners. We find that the interaction of LC8 with Nek9 depends on a (K/R)XTQT motif adjacent to the Nek9 C-terminal coiled coil motif, results in Nek9 multimerization, and increases the rate of Nek9 autoactivation. LC8 binding to Nek9 is regulated by Nek9 activity through the autophosphorylation of Ser(944), a residue immediately N-terminal to the (K/R)XTQT motif. Remarkably, LC8 binding interferes with the interaction of Nek9 with its downstream partner Nek6 as well as with Nek6 activation, thus controlling both processes. Our work sheds light into the control of signal transduction through the module formed by Nek9 and Nek6/7 and uncovers a novel manner in which LC8 can regulate partner physiology by interfering with protein complex formation. We suggest that this and other LC8 functions can be specifically regulated by partner phosphorylation.

Fluorescent Amino Acid Initiated de novo Cyclic Peptides for the Label-Free Assessment of Cell Permeability*.

The major obstacle in applying peptides to intracellular targets is their low inherent cell permeability. Standard approaches to attach a fluorophore (e. g. FITC, TAMRA) can change the physicochemical properties of the parent peptide and influence their ability to penetrate and localize in cells. We report a label-free strategy for evaluating the cell permeability of cyclic peptide leads. Fluorescent tryptophan analogues 4-cyanotryptophan (4CNW) and ß-(1-azulenyl)-L-alanine (AzAla) were incorporated into in vitro translated macrocyclic peptides by initiator reprogramming. We then demonstrate these efficient blue fluorescent emitters are good tools for monitoring peptide penetration into cells.

Using a stated preference discrete choice experiment to assess societal value from the perspective of decision-makers in Europe. Does it work for rare diseases?

OBJECTIVES: To pilot the feasibility of using a discrete choice experiment (DCE) design to investigate individual preferences from the decision-maker perspective regarding the use of public funding for orphan drugs and generate prior information for future experimental designs. METHODS: A DCE was used on a convenience sample of participants from five European countries (England, France, Germany, Italy and Spain), exploring their preferences in distinct healthcare scenarios involving orphan drugs. A preliminary review of the empirical literature on distributive preferences informed the selection of attributes and their levels in the design. An online questionnaire was used to conduct the DCE survey. RESULTS: A total of 199 questionnaires were completed. The five country model showed relative preference for some attributes over others: cost of treatment, improvement in health, value for money and availability of treatment alternatives received the greatest attention. However, disease severity, beginning of life, waiting times and side effects were also shown to be important social values that should not be ignored. CONCLUSIONS: The findings presented in this study provide insight about the preferences that can influence decisions on orphan drugs in different countries. This study also provides valuable prior information that could inform future DCE designs in this area.

ASPP proteins discriminate between PP1 catalytic subunits through their SH3 domain and the PP1 C-tail.

Serine/threonine phosphatases such as PP1 lack substrate specificity and associate with a large array of targeting subunits to achieve the requisite selectivity. The tumour suppressor ASPP (apoptosis-stimulating protein of p53) proteins associate with PP1 catalytic subunits and are implicated in multiple functions from transcriptional regulation to cell junction remodelling. Here we show that Drosophila ASPP is part of a multiprotein PP1 complex and that PP1 association is necessary for several in vivo functions of Drosophila ASPP. We solve the crystal structure of the human ASPP2/PP1 complex and show that ASPP2 recruits PP1 using both its canonical RVxF motif, which binds the PP1 catalytic domain, and its SH3 domain, which engages the PP1 C-terminal tail. The ASPP2 SH3 domain can discriminate between PP1 isoforms using an acidic specificity pocket in the n-Src domain, providing an exquisite mechanism where multiple motifs are used combinatorially to tune binding affinity to PP1.

Psychiatric manifestations of 22q11.2 deletion syndrome: a literature review. / Manifestaciones psiquiátricas del síndrome de deleción 22q11.2: una revisión de la literatura.

INTRODUCTION: The 22q11.2 deletion syndrome is a genetic disorder with variable clinical manifestations. It affects one out of 5950 neonates and has an autosomal dominant inheritance pattern. The aim of this article is to review its psychiatric manifestations and any underlying genetic alterations. METHODS: We reviewed the scientific literature available as of October 2014 in the LILACS and Medline databases. RESULTS: Sixty per cent of these patients fulfilled diagnostic criteria for a mental disorder at some point in their lives, referring to psychotic disorders, attention deficit hyperactivity disorder, mood disorders, anxiety disorders, and autism spectrum disorders. Specific genes, such as COMT and PRODH, have been linked to these psychiatric manifestations. CONCLUSIONS: It is necessary to raise awareness among all health care professionals so that they understand the relevance of these manifestations, are able to anticipate them, and can provide appropriate information to patients and family members.

Analysis of the quality of patient therapeutic education and information in a high complexity reference hospital.

BACKGROUND AND OBJECTIVES: The application and monitoring of quality criteria in information and therapeutic patient education can identify areas to improve care. The objectives of this study were: (1) To analyze the characteristics of patient information materials, educational activities, and self-management programs, and (2) to determine health care provider (HCP) proposals on therapeutic patient education. MATERIALS AND METHODS: Using a cross-sectional study, an online questionnaire was sent to hospital departments in a high complexity reference hospital from September to December 2013 to record: (a) information materials, (b) patient educational activities, and self-management program characteristics, (c) HCP proposals. The materials were analyzed using Health Promoting Hospitals (HPH) recommendations. RESULTS: (1) An analysis was performed on 258 materials (leaflets [54%]) for chronic patients (86%), acute patients (7%), and the general population (7%). More than half (55%) lacked the authors, and 43% the year issued, and 69% followed HPH recommendations. (2) An evaluation was made of 70 educational activities and 37 self-management programs addressed to patients/relatives with diabetes/obesity, musculoskeletal disorders, COPD/asthma, pelvic-floor disorders, transplantation, bowel-inflammation/liver disease, hypertension, cancer, heart failure, acquired immune deficiency syndrome, chronic renal insufficiency, splenectomy, anticoagulation and older-patient dependence. The structure, process and outcome evaluation varied. (3) HCP proposals included: standardization of materials criteria, web accessibility, list of accredited websites, cross-sectional use, and HCP training in self-management education. CONCLUSIONS: The online questionnaire showed the weaknesses and strengths of patient information and education, and can be used to monitor their quantity and quality. These results help in the definition of a useful model to improve patient information and education policies.

Spanish and Catalan translation, cultural adaptation and validation of the Picker Patient Experience Questionnaire-15.

OBJECTIVE: To develop and test a culturally adapted core set of questions to measure patients' experience after in-patient care. MATERIAL AND METHODS: Following the methodology recommended by international guides, a basic set of patient experience questions, selected from Picker Institute Europe questionnaires (originally in English), was translated to Spanish and Catalan. Acceptability, construct validity and reliability of the adapted questionnaire were assessed via a cross-sectional validation study. The inclusion criteria were patients aged >18 years, discharged within one week to one month prior to questionnaire sending and whose email was available. Day cases, emergency department patients and deaths were excluded. Invitations were sent by email (N=876) and questionnaire was fulfilled through an online platform. An automatic reminder was sent 5 days later to non-respondents. RESULTS: A questionnaire, in Spanish and Catalan, with adequate conceptual and linguistic equivalence was obtained. Response rate was 44.4% (389 responses). The correlation matrix was factorable. Four factors were extracted with Parallel Analysis, which explained 43% of the total variance. First factor: information and communication received during discharge. Second factor: low sensitivity attitudes of professionals. Third factor: assessment of communication of medical and nursing staff. Fourth factor: global items. The value of the Cronbach alpha was 0.84, showing a high internal consistency. CONCLUSIONS: The obtained experience patient questionnaire, in Spanish and Catalan, shows good results in the psychometric properties evaluated and could be a useful tool to identify opportunities for health care improvement in our context. Email could become a feasible tool for greater patient participation in everything that concerns his health.

Inescapable shocks accentuate fluctuations of forced swimming immobility in different phases of the rat estrous cycle.

The forced swimming test is an animal model that is sensitive to the different antidepressant treatments. On the other hand, it is also sensitive to the characteristic changes suffered by animals that have been previously exposed to different depression models. In the present study we explored the effects of inescapable shocks on the forced swimming test, during different phases of the rat estrous cycle. There was an increase of the immobility during diestrus as compared to estrus. Furthermore, inescapable shocks increased the immobility, but only during diestrus. Thus, the differences found between both phases of the estrous cycle were accentuated. Due to the fact that during diestrus there is an absence of progesterone, and that depressed women exacerbate their symptoms during the premenstrual phase, the authors suggest that the immobility registered during the forced swimming test may be useful in the study of premenstrual depression.

[Post-transplantation vaccination of bone-marrow transplant recipients]. / Vacunación de pacientes receptores de trasplante de progenitores hematopoyéticos.

BACKGROUND: Patients subject to bone marrow transplantation (BMT) and other blood stem cell transplantations are severely immunocompromised after transplantation. Some studies have suggested that post-transplantation loss of acquired immunity may play a role. The objective of this study was to determine the susceptibility to vaccine-preventable diseases in people subject to BMT and the serologic response after vaccination. PATIENTS AND METHOD: Study population was people subject to transplantation at least 6 months before initiating vaccination and without immunosuppressive treatment at that time. A prevaccination serologic analysis was carried out, and the hepatitis B, the adult tetanus-diphtheria (Td), the IPV, the influenza and the pneumococccal vaccines were administered in accordance with standard guidelines Depending on the immune status of the patient according to the serologic analysis, the MMR vaccine was administered no sooner than 18 months after transplantation. After vaccination, a serologic analysis was carried out to determine the response. RESULTS: The mean time SD between transplant and the initiation of vaccination was 3.2 2.9 years. Of the 122 recipients of BMT (average age 35.8 13 years; 54.2% male), 51.7% received an allogenic and 48.3% an autologous transplant. Before vaccination, the susceptibility was 48.2% for tetanus, 66.7% for diphtheria, 74.1% for pertussis, 85.9% for hepatitis B, 13.4% for measles, 36.7% for rubella and 9.2% for mumps. The rates of seroconversion with protective titers after vaccination for tetanus, diphtheria and hepatitis B were 94%, 67% and 75% respectively. The response to the MMR vaccine was greater than 70%, with a second dose of the vaccine being needed in 26% of patients. CONCLUSIONS: Susceptibility to vaccine-preventable diseases in transplanted patients is high. The acceptable response to vaccination justifies the development of specific programs. Given the special characteristics of this group of patients, vaccination programs must be simple and flexible.

Economic modelling of diagnostic and treatment pathways in National Institute for Health and Care Excellence clinical guidelines: the Modelling Algorithm Pathways in Guidelines (MAPGuide) project.

BACKGROUND: National Institute for Health and Care Excellence (NICE) clinical guidelines (CGs) make recommendations across large, complex care pathways for broad groups of patients. They rely on cost-effectiveness evidence from the literature and from new analyses for selected high-priority topics. An alternative approach would be to build a model of the full care pathway and to use this as a platform to evaluate the cost-effectiveness of multiple topics across the guideline recommendations. OBJECTIVES: In this project we aimed to test the feasibility of building full guideline models for NICE guidelines and to assess if, and how, such models can be used as a basis for cost-effectiveness analysis (CEA). DATA SOURCES: A 'best evidence' approach was used to inform the model parameters. Data were drawn from the guideline documentation, advice from clinical experts and rapid literature reviews on selected topics. Where possible we relied on good-quality, recent UK systematic reviews and meta-analyses. REVIEW METHODS: Two published NICE guidelines were used as case studies: prostate cancer and atrial fibrillation (AF). Discrete event simulation (DES) was used to model the recommended care pathways and to estimate consequent costs and outcomes. For each guideline, researchers not involved in model development collated a shortlist of topics suggested for updating. The modelling teams then attempted to evaluate options related to these topics. Cost-effectiveness results were compared with opinions about the importance of the topics elicited in a survey of stakeholders. RESULTS: The modelling teams developed simulations of the guideline pathways and disease processes. Development took longer and required more analytical time than anticipated. Estimates of cost-effectiveness were produced for six of the nine prostate cancer topics considered, and for five of eight AF topics. The other topics were not evaluated owing to lack of data or time constraints. The modelled results suggested 'economic priorities' for an update that differed from priorities expressed in the stakeholder survey. LIMITATIONS: We did not conduct systematic reviews to inform the model parameters, and so the results might not reflect all current evidence. Data limitations and time constraints restricted the number of analyses that we could conduct. We were also unable to obtain feedback from guideline stakeholders about the usefulness of the models within project time scales. CONCLUSIONS: Discrete event simulation can be used to model full guideline pathways for CEA, although this requires a substantial investment of clinical and analytic time and expertise. For some topics lack of data may limit the potential for modelling. There are also uncertainties over the accessibility and adaptability of full guideline models. However, full guideline modelling offers the potential to strengthen and extend the analytical basis of NICE's CGs. Further work is needed to extend the analysis of our case study models to estimate population-level budget and health impacts. The practical usefulness of our models to guideline developers and users should also be investigated, as should the feasibility and usefulness of whole guideline modelling alongside development of a new CG. FUNDING: This project was funded by the Medical Research Council and the National Institute for Health Research through the Methodology Research Programme [grant number G0901504] and will be published in full in Health Technology Assessment; Vol. 17, No. 58. See the NIHR Journals Library website for further project information.

Nek9 phosphorylation of NEDD1/GCP-WD contributes to Plk1 control of γ-tubulin recruitment to the mitotic centrosome.

The accumulation of γ-tubulin at the centrosomes during maturation is a key mechanism that ensures the formation of two dense microtubule (MT) asters in cells entering mitosis, defining spindle pole positioning and ensuring the faithful outcome of cell division. Centrosomal γ-tubulin recruitment depends on the adaptor protein NEDD1/GCP-WD and is controlled by the kinase Plk1. Surprisingly, and although Plk1 binds and phosphorylates NEDD1 at multiple sites, the mechanism by which this kinase promotes the centrosomal recruitment of γ-tubulin has remained elusive. Using Xenopus egg extracts and mammalian cells, we now show that it involves Nek9, a NIMA-family kinase required for normal mitotic progression and spindle organization. Nek9 phosphorylates NEDD1 on Ser377 driving its recruitment and thereby that of γ-tubulin to the centrosome in mitotic cells. This role of Nek9 requires its activation by Plk1-dependent phosphorylation but is independent from the downstream related kinases Nek6 and Nek7. Our data contribute to understand the mechanism by which Plk1 promotes the recruitment of γ-tubulin to the centrosome in dividing cells and position Nek9 as a key regulator of centrosome maturation.