Abstract Background Comorbidity is increasingly important in the medical literature, with ever-increasing implications for diagnosis, treatment, prognosis, management and health care. The objective ...of this study is to measure casual versus causal comorbidity in primary care in three family practice populations. Methods This is a longitudinal observational study using the Transition Project datasets. Transition Project family doctors in the Netherlands, Malta and Serbia recorded details of all patient contacts in an episode of care structure using electronic medical records and the International Classification of Primary Care, collecting data on all elements of the doctor-patient encounter, including diagnoses (1,178,178 in the Netherlands, 93,606 in Malta, 405,150 in Serbia), observing 158,370 patient years in the Netherlands, 43,577 in Malta, 72,673 in Serbia. Comorbidity was measured using the odds ratio of both conditions being incident or rest-prevalent in the same patient in one-year dataframes, as against not, corrected for the prior probability of such co-occurrence, between the 41 joint most prevalent (joint top 20) episode titles in the three populations. Specific associations were explored in different age groups to observe the changes in odds ratios with increasing age as a surrogate for a temporal or biological gradient. Results The high frequency of observed comorbidity with low consistency in both clinically and statistically significant odds ratios across populations indicates more casual than causal associations. A causal relationship would be expected to be manifest more consistently across populations. Even in the minority of cases where odds ratios were consistent between countries and numerically larger, those associations were observed to weaken with increasing patient age. Conclusion After applying accepted criteria for testing the causality of associations, most observed primary care comorbidity is due to chance, likely as a result of increasing illness diversity. Trial registration This study was performed on electronic patient record datasets made publicly available by the University of Amsterdam Department of General Practice, and did not involve any patient intervention.
ELOVL5 Mutations Cause Spinocerebellar Ataxia 38 Di Gregorio, Eleonora; Borroni, Barbara; Giorgio, Elisa ...
American journal of human genetics,
08/2014, Letnik:
95, Številka:
2
Journal Article
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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.
CD157 is a member of the ADP-ribosyl cyclase gene family that is involved in the metabolism of NAD. CD157 behaves both as an ectoenzyme and as a receptor. Though CD157 is anchored to the membrane by ...a glycosylphosphatidylinositol moiety, which makes it unsuitable to transduce signals on its own, it exploits its localization in selected membrane microdomains and its proclivity to interact with integrins to accomplish receptor functions. Initially characterized as a stromal and myeloid antigen involved in the control of leukocyte adhesion, migration and diapedesis, CD157 was subsequently found to have a far wider distribution. In particular, CD157 was found to be expressed by epithelial ovarian cancer cells where it is involved in interactions among tumor cells, extracellular matrix proteins and mesothelium. The overall picture inferred from experimental and clinical observations is that CD157 is a critical player both in leukocyte trafficking and in ovarian cancer invasion and metastasis formation. In this review, we will discuss the biological mechanisms underpinning the role of CD157 in the control of leukocyte migration and ovarian cancer dissemination.
•Gemcitabine is an active cytotoxic agent in ACC cells in vitro.•Mitotane/gemcitabine cytotoxicity differs in mitotane-sensitive and insensitive cells.•Sequential use of mitotane→gemcitabine was ...antagonistic in both cell lines.•Single/combinatory treatment response correlated to RRM1 gene modulation profiles.
We aimed at investigating in vitro the cytotoxic activity (determined using WST-1, apoptosis and cell cycle assays) of gemcitabine, alone or in combination with mitotane, in mitotane-sensitive H295R and mitotane-insensitive SW-13 cells. Results of these experiments were compared with drug-induced modulation of RRM1 gene, the specific target of gemcitabine. In H295R cells, mitotane and gemcitabine combinations showed antagonistic effects and interfered with the gemcitabine-mediated inhibition of the S phase of the cell cycle. By contrast, in SW-13 cells, except when mitotane was sequentially administered prior to gemcitabine, the combination of the two drugs was synergistic. Such opposite effects were associated with opposite expression profiles of the target gene, with significant up-modulation in H295R but not in SW-13 under gemcitabine and mitotane combination treatment.
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.
To formally describe and critically appraise the revision process of ICPC-3.
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.
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.
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.
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.
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.
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.
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.
To explore dementia management from a primary care physician perspective.
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.
Twenty-five European General Practice Research Network member countries.
Four hundred and forty-five key informant primary care physician respondents of which 106 presented 155 case stories.
Processes and typologies of dementia management. Proportion of case stories with drug treatment and treatment according to guidelines.
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.
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.
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.
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.
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.
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.
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.
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.
CD157/Bst1 is a dual-function receptor and β-NAD
-metabolizing ectoenzyme of the ADP-ribosyl cyclase family. Expressed in human peripheral blood neutrophils and monocytes, CD157 interacts with ...extracellular matrix components and regulates leukocyte diapedesis via integrin-mediated signalling in inflammation. CD157 also regulates cell migration and is a marker of adverse prognosis in epithelial ovarian cancer and pleural mesothelioma. One form of CD157 is known to date: the canonical sequence of 318 aa from a 9-exon transcript encoded by BST1 on human chromosome 4. Here we describe a second BST1 transcript, consisting of 10 exons, in human neutrophils. This transcript includes an unreported exon, exon 1b, located between exons 1 and 2 of BST1. Inclusion of exon 1b in frame yields CD157-002, a novel proteoform of 333 aa: exclusion of exon 1b by alternative splicing generates canonical CD157, the dominant proteoform in neutrophils and other tissues analysed here. In comparative functional analyses, both proteoforms were indistinguishable in cell surface localization, specific mAb binding, and behaviour in cell adhesion and migration. However, NAD glycohydrolase activity was detected in canonical CD157 alone. Comparative phylogenetics indicate that exon 1b is a genomic innovation acquired during primate evolution, pointing to the importance of alternative splicing for CD157 function.
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