How are reasons for encounter associated with influenza-like illness and acute respiratory infection diagnoses and interventions? A cohort study in eight Italian general practice populations.

BACKGROUND: Influenza-like illness (ILI) and Acute Respiratory Infections (ARI) are a considerable health problem in Europe. Most diagnoses are made by family physicians (FPs) and based on symptoms and clinical signs rather than on diagnostic testing. The International Classification of Primary Care (ICPC) advocates that FPs record patients' 'Reasons for Encounters' (RfEs) as they are presented to them. This study analyses the association of patients' RfEs with FPs' diagnoses of ILI and ARI diagnoses and FPs' management of those patients. METHODS: Cohort study of practice populations. Over a 4-month period during the winter season 2013-14, eight FPs recorded ILI and ARI patients' RfEs and how they were managed. FPs recorded details of their patients using the ICPC format, collecting data in an Episode of Care (EoC) structure. RESULTS: There were 688 patients diagnosed as having ILI; between them they presented with a total of 2,153 RfEs, most commonly fever (79.7%), cough (59.7%) and pain (33.0%). The 848 patients with ARI presented with a total of 1,647 RfEs, most commonly cough (50.4%), throat symptoms (25.9%) and fever (19.9%). For patients with ILI, 37.0% of actions were related to medication for respiratory symptoms; this figure was 38.4% for patients with ARI. FPs referred six patients to specialists or hospitals (0.39% of all patients diagnosed with ILI and ARI). CONCLUSIONS: In this study of patients with ILI and ARI, less than half received a prescription from their FPs, and the illnesses were mainly managed in primary care, with few patients' needing referral. The ICPC classification allowed a standardised data collection system, providing documentary evidence of the management of those diseases.

Unburdening dementia - a basic social process grounded theory based on a primary care physician survey from 25 countries.

OBJECTIVE: To explore dementia management from a primary care physician perspective. DESIGN: One-page seven-item multiple choice questionnaire; free text space for every item; final narrative question of a dementia case story. Inductive explorative grounded theory analysis. Derived results in cluster analyses. Appropriateness of dementia drugs assessed by tertiary care specialist. SETTING: Twenty-five European General Practice Research Network member countries. SUBJECTS: Four hundred and forty-five key informant primary care physician respondents of which 106 presented 155 case stories. MAIN OUTCOME MEASURES: Processes and typologies of dementia management. Proportion of case stories with drug treatment and treatment according to guidelines. RESULTS: Unburdening dementia - a basic social process - explained physicians' dementia management according to a grounded theory analysis using both qualitative and quantitative data. Unburdening starts with Recognizing the dementia burden by Burden Identification and Burden Assessment followed by Burden Relief. Drugs to relieve the dementia burden were reported for 130 of 155 patients; acetylcholinesterase inhibitors or memantine treatment in 89 of 155 patients - 60% appropriate according to guidelines and 40% outside of guidelines. More Central and Northern primary care physicians were allowed to prescribe, and more were engaged in dementia management than Eastern and Mediterranean physicians according to cluster analyses. Physicians typically identified and assessed the dementia burden and then tried to relieve it, commonly by drug prescriptions, but also by community health and home help services, mentioned in more than half of the case stories. CONCLUSIONS: Primary care physician dementia management was explained by an Unburdening process with the goal to relieve the dementia burden, mainly by drugs often prescribed outside of guideline indications. Implications: Unique data about dementia management by European primary care physicians to inform appropriate stakeholders. Key points Dementia as a syndrome of cognitive and functional decline and behavioural and psychological symptoms causes a tremendous burden on patients, their families, and society. •We found that a basic social process of Unburdening dementia explained dementia management according to case stories and survey comments from primary care physicians in 25 countries. •First, Burden Recognition by Identification and Assessment and then Burden Relief - often by drugs. •Prescribing physicians repeatedly broadened guideline indications for dementia drugs. The more physicians were allowed to prescribe dementia drugs, the more they were responsible for the dementia work-up. Our study provides unique data about dementia management in European primary care for the benefit of national and international stakeholders.

ELOVL5 mutations cause spinocerebellar ataxia 38.

Spinocerebellar ataxias (SCAs) are a heterogeneous group of autosomal-dominant neurodegenerative disorders involving the cerebellum and 23 different genes. We mapped SCA38 to a 56 Mb region on chromosome 6p in a SCA-affected Italian family by whole-genome linkage analysis. Targeted resequencing identified a single missense mutation (c.689G>T [p.Gly230Val]) in ELOVL5. Mutation screening of 456 independent SCA-affected individuals identified the same mutation in two further unrelated Italian families. Haplotyping showed that at least two of the three families shared a common ancestor. One further missense variant (c.214C>G [p.Leu72Val]) was found in a French family. Both missense changes affect conserved amino acids, are predicted to be damaging by multiple bioinformatics tools, and were not identified in ethnically matched controls or within variant databases. ELOVL5 encodes an elongase involved in the synthesis of polyunsaturated fatty acids of the ω3 and ω6 series. Arachidonic acid and docosahexaenoic acid, two final products of the enzyme, were reduced in the serum of affected individuals. Immunohistochemistry on control mice and human brain demonstrated high levels in Purkinje cells. In transfection experiments, subcellular localization of altered ELOVL5 showed a perinuclear distribution with a signal increase in the Golgi compartment, whereas the wild-type showed a widespread signal in the endoplasmic reticulum. SCA38 and SCA34 are examples of SCAs due to mutations in elongase-encoding genes, emphasizing the importance of fatty-acid metabolism in neurological diseases.

Exploring dementia management attitudes in primary care: a key informant survey to primary care physicians in 25 European countries.

BACKGROUND: Strategies for the involvement of primary care in the management of patients with presumed or diagnosed dementia are heterogeneous across Europe. We wanted to explore attitudes of primary care physicians (PCPs) when managing dementia: (i) the most popular cognitive tests, (ii) who had the right to initiate or continue cholinesterase inhibitor or memantine treatment, and (iii) the relationship between the permissiveness of these rules/guidelines and PCP's approach in the dementia investigations and assessment. METHODS: Key informant survey. SETTING: Primary care practices across 25 European countries. SUBJECTS: Four hundred forty-five PCPs responded to a self-administered questionnaire. Two-step cluster analysis was performed using characteristics of the informants and the responses to the survey. MAIN OUTCOME MEASURES: Two by two contingency tables with odds ratios and 95% confidence intervals were used to assess the association between categorical variables. A multinomial logistic regression model was used to assess the association of multiple variables (age class, gender, and perceived prescription rules) with the PCPs' attitude of "trying to establish a diagnosis of dementia on their own." RESULTS: Discrepancies between rules/guidelines and attitudes to dementia management was found in many countries. There was a strong association between the authorization to prescribe dementia drugs and pursuing dementia diagnostic work-up (odds ratio, 3.45; 95% CI 2.28-5.23). CONCLUSIONS: Differing regulations about who does what in dementia management seemed to affect PCP's engagement in dementia investigations and assessment. PCPs who were allowed to prescribe dementia drugs also claimed higher engagement in dementia work-up than PCPs who were not allowed to prescribe.

INFORMEG, a new evaluation system for family medicine trainees: feasibility in an Italian rural setting.

INTRODUCTION: In Italy the course to become a general practitioner (GP) lasts 3 years and includes both theoretical and practical study. Different from the theoretical part, until recently the practical activity has not been assessed at all. The Emilia Romagna Regional Health Authority has developed a special program called INFORMEG (Management of Tutoring during the Triennial Specific Training in General Practice), aimed at assessing primary doctor trainees' practical skills. INFORMEG includes a list of pre-defined cases of specific diseases, conditions or health problem, a web application and a smartphone app, aimed at assisting trainee self-management and helping the tutor in the assessment of trainee performance. The Emilia Romagna Regional Health Authority divided the pre-defined cases into three categories (A, B and C) according to their relevance to a trainee's education and coded them using the International Classification of Primary Care (ICPC). The aim of this project report is to illustrate the implementation of INFORMEG in a rural setting. METHODS: Program evaluation took place from 2 May to 31 October 2013 during GPs' routine clinical activities. The following steps were accomplished during every meeting: (1) consultation recording; (2) identification of the reason for the encounter (RfE); (3) classification of the diagnostic procedure(s) performed (diagnostic/therapeutic/test results/administrative/advice); (4) classification of special procedures called 'practical clinical skills' and (5) elaboration of the final diagnosis after the encounter. RESULTS: The number of cases of specific disease or condition encountered by the trainee were 98 for type A, 57 for type B and 22 for type C. A total of 605 RfEs were collected: 376 for type A cases, 147 for type B cases and 82 for type C cases. A total of 976 procedures were performed during the 6 months: 590 procedures for the type A cases, 271 for type B and 115 for type C. CONCLUSIONS: The pre-selected health problems were almost all addressed, thus confirming the good degree of representativeness of these clinical cases even in a rural setting. The ICPC coding helped the trainee in the construction of the case according to the logical process of family medicine. Two things to amend in INFORMEG are the absence of common arrhythmic conditions such as atrial fibrillation and the absence of means to assess the patient-trainee relationship.

Binding of CD157 protein to fibronectin regulates cell adhesion and spreading.

CD157/BST-1 behaves both as an ectoenzyme and signaling receptor and is an important regulator of leukocyte trafficking and ovarian cancer progression. However, the molecular interactions underpinning the role of CD157 in these processes remain obscure. The biological functions of CD157 and its partnership with members of the integrin family prompted us to assume the existence of a direct interaction between CD157 and an unknown component of the extracellular matrix. Using solid-phase binding assays and surface plasmon resonance analysis, we demonstrated that CD157 binds fibronectin with high affinity within its heparin-binding domains 1 and 2. Furthermore, we found that CD157 binds to other extracellular matrix proteins containing heparin-binding domains. Finally, we proved that the CD157-fibronectin interaction occurs with living cells, where it elicits CD157-mediated cell responses. Indeed, knockdown of CD157 in Met-5A mesothelial cells changed their morphology and cytoskeleton organization and attenuated the activation of intracellular signaling pathways triggered by fibronectin. This led to impaired cell spreading and adhesion to selected extracellular matrix proteins. Collectively, these findings indicate a central role of CD157 in cell-extracellular matrix interactions and make CD157 an attractive therapeutic target in inflammation and cancer.

A Quick Test of Cognitive Speed: norm-referenced criteria for 121 Italian adults aged 45 to 90 years.

ABSTRACT Background: A Quick Test of Cognitive Speed (AQT) is a brief test that can identify cognitive impairment. AQT has been validated in Arabic, English, Greek, Japanese, Norwegian, Spanish, and Swedish. The aim of this study was to develop Italian criterion-referenced norms for AQT. Methods: AQT consists of three test plates where the patient shall rapidly name (1) the color of 40 blue, red, yellow, or black squares (AQT color), (2) the form of 40 black figures (circles, squares, triangles, or rectangles; AQT form), (3) the color and form of 40 figures (consisting of previous colors and forms; AQT color-form). The AQT test was administered to 121 Italian cognitively healthy primary care patients (age range: 45-90 years). Their mean Mini-Mental State Examination (MMSE) score was 28.8 ± 0.9 points (range 26-30 points). AQT naming times in seconds were used for developing preliminary criterion cut-off times for different age groups. Results: Age was found to have a significant moderate positive correlation with AQT naming times color (r = 0.65, p < 0.001), form (r = 0.53, p < 0.001), color-form (r = 0.63, p < 0.001) and a moderate negative correlation with MMSE score (r = -0.44, p < 0.001) and AQT naming times differed significantly between younger (45-55 years old), older (56-70 years old), and the oldest (71-90 years old) participants. Years of education correlated positively but weakly with MMSE score (r = 0.27, p = 0.003) and negatively but weakly with AQT color (r = -0.16, p = ns), form (r = -0.24, p = 0.007), and color-form (r = -0.19, p = 0.005). We established preliminary cut-off times for the AQT test based on +1 and +2 standard deviations according to the approach in other languages and settings. Conclusions: This is the first Italian normative AQT study. Future studies of AQT - a test useful for dementia screening in primary care - will eventually refine cut-off times for normality balancing sensitivity and specificity in cognitive diagnostics.

40 years of biannual family medicine research meetings--the European General Practice Research Network (EGPRN).

OBJECTIVE: To document family medicine research in the 25 EGPRN member countries in 2010. DESIGN: Semi-structured survey with open-ended questions. SETTING: Academic family medicine in 23 European countries, Israel, and Turkey. SUBJECTS: 25 EGPRN national representatives. MAIN OUTCOME MEASURES: Demographics of the general population and family medicine. Assessments, opinions, and suggestions. RESULTS: EGPRN has represented family medicine for almost half a billion people and > 300,000 general practitioners (GPs). Turkey had the largest number of family medicine departments and highest density of GPs, 2.1/1000 people, Belgium had 1.7, Austria 1.6, and France 1.5. Lowest GP density was reported from Israel 0.17, Greece 0.18, and Slovenia 0.4 GPs per 1000 people. Family medicine research networks were reported by 22 of 25 and undergraduate family medicine research education in 20 of the 25 member countries, and in 10 countries students were required to do research projects. Postgraduate family medicine research was reported by 18 of the member countries. Open-ended responses showed that EGPRN meetings promoted stimulating and interesting research questions such as comparative studies of chronic pain management, sleep disorders, elderly care, healthy lifestyle promotion, mental health, clinical competence, and appropriateness of specialist referrals. Many respondents reported a lack of interest in family medicine research related to poor incentives and low family medicine status in general and among medical students in particular. It was suggested that EGPRN exert political lobbying for family medicine research. CONCLUSION: Since 1974, EGPRN organizes biannual conferences that unite and promote primary care practice, clinical research and academic family medicine in 25 member countries.

Audit of cholesterol management among primary care patients in rural southern Italy.

INTRODUCTION: There has not yet been an audit of achievement rates of therapeutic targets for cholesterol management in the rural Italian primary care setting. The purpose of this study was to measure the percentage of patients with hypercholesterolaemia in a rural primary care setting in southern Italy, classify their risk category and measure the proportions of those patients who achieved optimal cholesterol levels according to the Adult Treatment Panel III guidelines. METHODS: The audit was completed using records from 1 January 2005 to 31 December 2007. An electronic search key was entered into the electronic clinical records of 10 family doctors in a rural area of southern Italy for subjects with a diagnosis of or being treated for hypercholesterolaemia. A total of 194 hypercholesterolaemic patients were randomly selected from a cohort of patients registered with these family doctors. The low density lipoprotein cholesterol (LDL-C) target level was 100 mg/dL (2.6 mmol/L) in patients with existing cardiovascular disease, 130 mg/dL (3.3 mmol/L) for patients with ≥2 risk factors, and 160 mg/dL (4.1 mmol/L) for all other patients. The results regarding the efficacy of the therapy were categorised as follows: (1) on target, LDL-C lower or equal to levels of affiliated class; (2) poor control, 1-30 mg/dL (0.03-0.78 mmol/L) above the target level of LDL-C; (3) very poor control, ≥31 mg/dL (≥0.8 mmol/L) above the LDL-C target level. RESULTS: The average age of the hypercholesterolaemic patients included in the study was 62.0 ± 9.0 years; 55% were males, 30% were smokers, 71.3% suffered from hypertension, 46.3% had diabetes, 39.9% were obese and 31.9% had a family history of coronary disease. There were 114 subjects in Class I (personal history of coronary disease, cardiovascular risk ≥ 20, diabetes mellitus) LDL-C target level. Of these patients, 24.6% were at target, 30.7% had poor control and 44.7% had very poor control. A total of 42.3% of the subjects examined with the score system adopted by the Italian Heart Project showed levels of cardiovascular risk between 5% and 19% and were not eligible for a free prescription of lipid-lowering drugs. CONCLUSIONS: These data suggest that cholesterol management in this rural area is not always optimal in patients with high cardiovascular risk. Italian healthcare regulation seems to be a barrier to drug prescription and it may influence optimal LDL-C control.

The fractured lens: a controversial revision of the International Classification of Primary Care.

Background: The International Classification of Primary Care (ICPC) has represented the international standard reduction for measuring the content of primary care for over 30 years. In the process of its third revision, its authors, the Wonca International Classification Committee (WICC), delegated a major part of the technical work to a purposely formed Consortium. However, in the process of such revision, standard classification principles and rules have been inconsistently applied with the result that ICPC-3 has been published with major errors and an inconsistent structure. Objectives: To formally describe and critically appraise the revision process of ICPC-3. Methods: The formal review of ICPC-3 performed by an expert group within WICC and commissioned by the Executive Council of Wonca Europe is presented in abridged form. Results: ICPC-3 as currently presented introduces major departures from formal classification principles and rules, besides other major errors and inconsistencies, all of which are listed and described. Conclusion: Major changes in ICPC-3 defy categorisation and conceptualisation standards. ICPC-3 now represents an untested departure from international standard presentations, without a formal academic base. The direct inclusion of measures of functioning in a classification of reasons for encounter and health problems fails to address the dichotomy of these domains, the boundaries of and relationships between which are not satisfactorily resolved by the system. Analysis of ICPC-3 data will require the development and implementation of alternative, as yet undefined, models of the relationships between disease and health. By including different domains without resolving ambiguity, and by splitting function from other body systems, ICPC-3 becomes an internally fractured instrument.

Translation of the working alliance inventory short revised into Italian using a Delphi procedure and a forward-backward translation.

Introduction: Enhancing treatment adherence, especially for chronic diseases, can be achieved through therapeutic alliance, potentially elevating the quality of care. An instrument to evaluate the therapeutic alliance could be beneficial in routine clinical settings, educational environments, and extensive research efforts at national and European levels. In this study, we translated therapist and patient versions of the Working Alliance Inventory Short Revised (WAI-SR) into Italian. Methodology: An email-based Delphi method was employed for the English-to-Italian translation, incorporating a forward-backward process. The initial translation team comprised two Italian family physicians proficient in English, a linguist, and a psychiatrist. The forward translation was then reviewed by 18 Italian family physicians through a Delphi process and was subjected to a backward translation by two Italian English teachers. A cultural correspondence was subsequently identified to adjust translations within a national and international framework. Results: All 18 experts fully engaged in the Delphi process, and consensus was achieved by the second Delphi round. A cultural check checked for discrepancies regarding linguistic consistency with other translations and found no difference. Conclusion: This Italian translation of the WAI-SR is expected to support Italian family physicians aiming to enhance their clinical practice and therapeutic outcomes. It could also be a valuable tool for Italian medical students to foster therapeutic relationships and improve their communication skills.

Exploring why European primary care physicians sometimes do not think of, or act on, a possible cancer diagnosis. A qualitative study.

BACKGROUND: While primary care physicians (PCPs) play a key role in cancer detection, they can find cancer diagnosis challenging, and some patients have considerable delays between presentation and onward referral. AIM: To explore European PCPs' experiences and views on cases where they considered that they had been slow to think of, or act on, a possible cancer diagnosis. DESIGN & SETTING: A multicentre European qualitative study, based on an online survey with open-ended questions, asking PCPs for their narratives about cases when they had missed a diagnosis of cancer. METHOD: Using maximum variation sampling, PCPs in 23 European countries were asked to describe what happened in a case where they were slow to think of a cancer diagnosis, and for their views on why it happened. Thematic analysis was used to analyse the data. RESULTS: A total of 158 PCPs completed the questionnaire. The main themes were as follows: patients' descriptions did not suggest cancer; distracting factors reduced PCPs' cancer suspicions; patients' hesitancy delayed the diagnosis; system factors not facilitating timely diagnosis; PCPs felt that they had acted wrongly; and problems with communicating adequately. CONCLUSION: The study identified six overarching themes that need to be addressed. Doing so should reduce morbidity and mortality in the small proportion of patients who have a significant, avoidable delay in their cancer diagnosis. The 'Swiss cheese' model of accident causation showed how the themes related to each other.

The CD157-integrin partnership controls transendothelial migration and adhesion of human monocytes.

CD157, a member of the CD38 gene family, is an NAD-metabolizing ectoenzyme and a signaling molecule whose role in polarization, migration, and diapedesis of human granulocytes has been documented; however, the molecular events underpinning this role remain to be elucidated. This study focused on the role exerted by CD157 in monocyte migration across the endothelial lining and adhesion to extracellular matrix proteins. The results demonstrated that anti-CD157 antibodies block monocyte transmigration and adhesion to fibronectin and fibrinogen but that CD157 cross-linking is sufficient to overcome the block, suggesting an active signaling role for the molecule. Consistent with this is the observation that CD157 is prevalently located within the detergent-resistant membrane microdomains to which, upon clustering, it promotes the recruitment of ß(1) and ß(2) integrin, which, in turn, leads to the formation of a multimolecular complex favoring signal transduction. This functional cross-talk with integrins allows CD157 to act as a receptor despite its intrinsic structural inability to do so on its own. Intracellular signals mediated by CD157 rely on the integrin/Src/FAK (focal adhesion kinase) pathway, resulting in increased activity of the MAPK/ERK1/2 and the PI3K/Akt downstream signaling pathways, which are crucial in the control of monocyte transendothelial migration. Collectively, these findings indicate that CD157 acts as a molecular organizer of signaling-competent membrane microdomains and that it forms part of a larger molecular machine ruled by integrins. The CD157-integrin partnership provides optimal adhesion and transmigration of human monocytes.

What factors empower general practitioners for early cancer diagnosis? A 20-country European Delphi Study.

BACKGROUND: Some symptoms are recognised as red flags for cancer, causing the General Practitioner (GP) to refer the patient for investigation without delay. However, many early symptoms of cancer are vague and unspecific, and in these cases, a delay in referral risks a diagnosis of cancer that is too late. Empowering GPs in their management of patients that may have cancer is likely to lead to more timely cancer diagnoses. AIM: To identify the factors that affect European GPs' empowerment in making an early diagnosis of cancer. METHODS: This was a Delphi study involving GPs in 20 European countries. We presented GPs with 52 statements representing factors that could empower GPs to increase the number of early cancer diagnoses. Over three Delphi rounds, we asked GPs to indicate the clinical relevance of each statement on a Likert scale.The final list of statements indicated those that were considered by consensus to be the most relevant. RESULTS: In total, 53 GPs from 20 European countries completed the Delphi process, out of the 68 GPs who completed round one. Twelve statements satisfied the pre-defined criteria for relevance. Five of the statements related to screening and four to the primary/secondary care interface. The other selected statements concerned information technology (IT) and GPs' working conditions. Statements relating to training, skills and working efficiency were not considered priority areas. CONCLUSION: GPs consider that system factors relating to screening, the primary-secondary care interface, IT and their working conditions are key to enhancing their empowerment in patients that could have cancer. These findings provide the basis for seeking actions and policies that will support GPs in their efforts to achieve timely cancer diagnosis.

Quality of care for hypertensive patients with type 2 diabetes in a rural area of Southern Italy: is the recording of patient data and the achievement of quality indicators targets satisfactory?

INTRODUCTION: Type 2 diabetes mellitus and hypertension are commonly associated chronic conditions which require regular structured treatment. In the UK many quality markers have been improved through an incentivisation scheme. The aim of this study was to discover if there is potential for improving the quality of care for patients with type 2 diabetes and hypertension in rural Italy, through a quality and outcome incentivisation scheme. METHODS: The study was conducted in a rural practice context in Southern Italy and seven family doctors were involved. The main outcome measures were glycated haemoglobin A1c (HbA1c), LDL cholesterol, and systolic and diastolic blood pressure. The patient characteristics examined were age, sex, educational level, behaviour-related factors such as smoking and BMI, and the presence of comorbidities. RESULTS: A poor level of registration was found for important variables such as HBA1c (61.4% compared with the UK Quality Indicator of 90%). An adequate level of registration and control was found only for blood pressure (95.7% and 82.1%, respectively), while an acceptable but not optimal level of control for HBA1c was also achieved (88.4% &#8804;10%). In comparison with levels in UK practices, the Italian district studied performed much less favorably, especially regarding process indicators. Intermediate outcome and treatment indicators were slightly better for blood pressure control but slightly worse for HBA1c and cholesterol control. CONCLUSION: The data confirm a poor registration level for important healthcare indicators in the study area, and that optimal levels are rarely reached for many quality indicators. A quality and outcome incentivisation scheme similar to the UK Quality and Outcomes Framework may offer a tool for achieving improvements.

In vitro dexamethasone treatment does not induce alternative ATM transcripts in cells from Ataxia-Telangiectasia patients.

Short term treatment with low doses of glucocorticoid analogues has been shown to ameliorate neurological symptoms in Ataxia-Telangiectasia (A-T), a rare autosomal recessive multisystem disease that mainly affects the cerebellum, immune system, and lungs. Molecular mechanisms underlying this clinical observation are unclear. We aimed at evaluating the effect of dexamethasone on the induction of alternative ATM transcripts (ATMdexa1). We showed that dexamethasone cannot induce an alternative ATM transcript in control and A-T lymphoblasts and primary fibroblasts, or in an ATM-knockout HeLa cell line. We also demonstrated that some of the reported readouts associated with ATMdexa1 are due to cellular artifacts and the direct induction of γH2AX by dexamethasone via DNA-PK. Finally, we suggest caution in interpreting dexamethasone effects in vitro for the results to be translated into a rational use of the drug in A-T patients.

Primary care practitioners' diagnostic action when the patient may have cancer: an exploratory vignette study in 20 European countries.

OBJECTIVES: Cancer survival rates vary widely between European countries, with differences in timeliness of diagnosis thought to be one key reason. There is little evidence on the way in which different healthcare systems influence primary care practitioners' (PCPs) referral decisions in patients who could have cancer.This study aimed to explore PCPs' diagnostic actions (whether or not they perform a key diagnostic test and/or refer to a specialist) in patients with symptoms that could be due to cancer and how they vary across European countries. DESIGN: A primary care survey. PCPs were given vignettes describing patients with symptoms that could indicate cancer and asked how they would manage these patients. The likelihood of taking immediate diagnostic action (a diagnostic test and/or referral) in the different participating countries was analysed. Comparisons between the likelihood of taking immediate diagnostic action and physician characteristics were calculated. SETTING: Centres in 20 European countries with widely varying cancer survival rates. PARTICIPANTS: A total of 2086 PCPs answered the survey question, with a median of 72 PCPs per country. RESULTS: PCPs' likelihood of immediate diagnostic action at the first consultation varied from 50% to 82% between countries. PCPs who were more experienced were more likely to take immediate diagnostic action than their peers. CONCLUSION: When given vignettes of patients with a low but significant possibility of cancer, more than half of PCPs across Europe would take diagnostic action, most often by ordering diagnostic tests. However, there are substantial between-country variations.

How European primary care practitioners think the timeliness of cancer diagnosis can be improved: a thematic analysis.

BACKGROUND: National European cancer survival rates vary widely. Prolonged diagnostic intervals are thought to be a key factor in explaining these variations. Primary care practitioners (PCPs) frequently play a crucial role during initial cancer diagnosis; their knowledge could be used to improve the planning of more effective approaches to earlier cancer diagnosis. OBJECTIVES: This study sought the views of PCPs from across Europe on how they thought the timeliness of cancer diagnosis could be improved. DESIGN: In an online survey, a final open-ended question asked PCPs how they thought the speed of diagnosis of cancer in primary care could be improved. Thematic analysis was used to analyse the data. SETTING: A primary care study, with participating centres in 20 European countries. PARTICIPANTS: A total of 1352 PCPs answered the final survey question, with a median of 48 per country. RESULTS: The main themes identified were: patient-related factors, including health education; care provider-related factors, including continuing medical education; improving communication and interprofessional partnership, particularly between primary and secondary care; factors relating to health system organisation and policies, including improving access to healthcare; easier primary care access to diagnostic tests; and use of information technology. Re-allocation of funding to support timely diagnosis was seen as an issue affecting all of these. CONCLUSIONS: To achieve more timely cancer diagnosis, health systems need to facilitate earlier patient presentation through education and better access to care, have well-educated clinicians with good access to investigations and better information technology, and adequate primary care cancer diagnostic pathway funding.

Generation of potent neutralizing human monoclonal antibodies against cytomegalovirus infection from immune B cells.

BACKGROUND: Human monoclonal antibodies (mAbs) generated as a result of the immune response are likely to be the most effective therapeutic antibodies, particularly in the case of infectious diseases against which the immune response is protective.Human cytomegalovirus (HCMV) is an ubiquitous opportunistic virus that is the most serious pathogenic agent in transplant patients. The available therapeutic armamentarium (e.g. HCMV hyperimmune globulins or antivirals) is associated with severe side effects and the emergence of drug-resistant strains; therefore, neutralizing human mAb may be a decisive alternative in the prevention of primary and re-activated HCMV infections in these patients. RESULTS: The purpose of this study was to generate neutralizing mAb against HCMV from the immunological repertoire of immune donors. To this aim, we designed an efficient technology relying on two discrete and sequential steps: first, human B-lymphocytes are stimulated with TLR9-agonists and IL-2; second, after both additives are removed, the cells are infected with EBV. Using this strategy we obtained 29 clones secreting IgG neutralizing the HCMV infectivity; four among these were further characterized. All of the mAbs neutralize the infection in different combinations of HCMV strains and target cells, with a potency approximately 20 fold higher than that of the HCMV hyperimmune globulins, currently used in transplant recipients. Recombinant human monoclonal IgG1 suitable as a prophylactic or therapeutic tool in clinical applications has been generated. CONCLUSION: The technology described has proven to be more reproducible, efficient and rapid than previously reported techniques, and can be adopted at low overall costs by any cell biology laboratory for the development of fully human mAbs for immunotherapeutic uses.