[Primary Prevention in General Medical Practice: A Survey]. / Primärprävention in der Allgemeinarztpraxis: Eine Befragung.

AIM OF THE STUDY: According to the German social insurance code §20 Sec. 1, statutory health insurance companies can reimburse up to 80% of costs incurred by primary prevention programs in physical activity, nutrition, stress management and drug consumption. Whether and how many general practitioners (GPs) provide their patients with information on such programs as part of their own practice is unknown. In this study, we investigate to which primary prevention programs primary care physicians refer their patients and whether they take into account reimbursability of programs. METHODS: Between November 2010 and February 2011, all GPs with a practice in Berlin (n=1 168) received a questionnaire that assessed if patients were referred to prevention programs and the type of programs they were referred to, if they ensured they are reimbursable and if they themselves offered prevention programs. Descriptive statistics and multivariate logistic regression was used for analysis. RESULTS: Of 474 respondents (response rate: 41%), 67% were female. Of the respondents, 22% offered reimbursable prevention programs and 42% at out-of-pocket expense. Patients were referred to reimbursable programs by 63%. GPs younger than 50 were twice as likely to offer reimbursable programs in their practice compared to those older than 50 (OR=1.7; 95% KI 1.1-2,8; p-value 0.025). CONCLUSION: A successful implementation of the new German prevention law needs awareness among GPs about reimbursable prevention programs, which may be lacking in some groups.

Physician cooperation in outpatient cancer care. An amplified secondary analysis of qualitative interview data.

The importance of outpatient cancer care services is increasing due to the growing number of patients having or having had cancer. However, little is known about cooperation among physicians in outpatient settings. To understand what inter- and multidisciplinary care means in community settings, we conducted an amplified secondary analysis that combined qualitative interview data with 42 general practitioners (GPs), 21 oncologists and 21 urologists that mainly worked in medical practices in Germany. We compared their perspectives on cooperation relationships in cancer care. Our results indicate that all participants regarded cooperation as a prerequisite for good cancer care. Oncologists and urologists mainly reported cooperating for tumour-specific treatment tasks, while GPs' reasoning for cooperation was more patient-centred. While oncologists and urologists reported experiencing reciprocal communication with other physicians, GPs had to gather the information they needed. GPs seldom reported engaging in formal cooperation structures, while for specialists, participation in formal spaces of cooperation, such as tumour boards, facilitated a more frequent and informal discussion of patients, for instance on the phone. Further research should focus on ways to foster GPs' integration in cancer care and evaluate if this can be reached by incorporating GPs in formal cooperation structures such as tumour boards.

[Qualitative Research in Health Services Research - Discussion Paper, Part 3: Quality of Qualitative Research]. / Qualitative Studien in der Versorgungsforschung - Diskussionspapier, Teil 3: Qualität qualitativer Studien.

The third and final discussion paper of the German Network of Health Services Research's (DNVF) "Qualitative Methods Working Group" demonstrates methods for the evaluation and quality of qualitative research in health services research. In this paper we discuss approaches described in evaluating qualitative studies, including: an orientation to the general principles of empirical research, an approach-specific course of action, as well as procedures based on the research-process and criteria-oriented approaches. Divided into general and specific aspects to be considered in a qualitative study quality evaluation, the central focus of the discussion paper undertakes an extensive examination of the process and criteria-oriented approaches. The general aspects include the participation of relevant groups in the research process as well as ethical aspects of the research and data protection issues. The more specific aspects in evaluating the quality of qualitative research include considerations about the research interest, research questions, and the selection of data collection methods and types of analyses. The formulated questions are intended to guide reviewers and researchers to evaluate and to develop qualitative research projects appropriately. The intention of this discussion paper is to ensure a transparent research culture, and to reflect on and discuss the methodological and research approach of qualitative studies in health services research. With this paper we aim to initiate a discussion on high quality evaluation of qualitative health services research.

Mutations of the Down-regulated in adenoma (DRA) gene cause congenital chloride diarrhoea.

A major transport function of the human intestine involves the absorption of chloride in exchange for bicarbonate. We have studied a recessively inherited defect of this exchange, congenital chloride diarrhoea (CLD; MIM 214700). The clinical presentation of CLD is a lifetime, potentially fatal diarrhoea with a high chloride content. The CLD locus was previously mapped to 7q3 adjacent to the cystic fibrosis gene (CFTR). By refined genetic and physical mapping, a cloned gene having anion transport function, Down-regulated in adenoma (DRA), was implicated as a positional and functional candidate for CLD. In this study, we report segregation of two missense mutations, delta V317 and H124L, and one frameshift mutation, 344delT, of DRA in 32 Finnish and four Polish CLD patients. The disease-causing nature of delta V317 is supported by genetic data in relation to the population history of Finland. By mRNA in situ hybridization, we demonstrate that the expression of DRA occurs preferentially in highly differentiated colonic epithelial cells, is unchanged in Finnish CLD patients with delta V317, and is low in undifferentiated (including neoplastic) cells. We conclude that DRA is an intestinal anion transport molecule that causes chloride diarrhoea when mutated.

Variations in the definition and perceived importance of positive resection margins in patients with colorectal cancer - an EYSAC international survey.

INTRODUCTION: Microscopically positive resection margins (R1) are associated with poorer outcomes in patients with colorectal cancer. However, different definitions of R1 margins exist. It is unclear to what extent the definitions used in everyday clinical practice differ within and between nations. This study sought to investigate variations in the definition of R1 margins in colorectal cancer and the importance of margin status in clinical decision-making. MATERIALS AND METHODS: A 14-point survey was developed by members of The European Society of Surgical Oncology (ESSO) Youngs Surgeons and Alumni Club (EYSAC) Research Academy targeting all members of the multidisciplinary team (MDT) treating patients with colorectal cancer. The survey was distributed on social media, in ESSO's monthly newsletter and via national societies. RESULTS: In total, 137 responses were received. Most respondents were from Europe (89.7%), with the majority from Denmark (56.9%). Less than 2/3 of respondents defined R1 margins as the presence of viable cancer cells ≤1 mm of the margin. Only 60% reported that subdivisions of R1 margins (primary tumour vs tumour deposit vs metastatic lymph node) are routinely available. More than 20% of respondents reported that pathology reports are not routinely reviewed at MDT meetings. Less than half of respondents considered margin status in decision-making for type and duration of adjuvant chemotherapy in Stage III colon cancer. CONCLUSION: The definitions and perceived clinical importance of microscopically positive margins in patients with colorectal cancer appear to vary. Adoption of an international dataset for pathology reporting may help to standardise current practices.

[Qualitative research in health services research - discussion paper, Part 1: What is the idea?]. / Qualitative Studien in der Versorgungsforschung - Diskussionspapier, Teil 1: Gegenstandsbestimmung.

In this first part of a 3-part discussion paper the working group "Qualitative Methods" in the German Network of Health Services Research (DNVF) identifies the potentials and opportunities qualitative research methods provide for health services research. Many research questions relevant for health services research require the use of qualitative methods. However, the potential of and need for qualitative research in health services research has not yet received sufficient attention from funding bodies. We discuss the applicability and importance of qualitative research for the field of health services research. We then move on to describe the key characteristics of qualitative research that need to be taken into account in health services research. We discuss characteristics such as open-ended (qualitative) data, interpretation of meanings, the search for contradictions, closeness to everyday life, openness towards change or modification of the research question and processes in the context of health services research. To ensure a high-quality approach in qualitative methods for the health services research, sufficient competency in methods and appropriate settings that account for the peculiarities of qualitative methods need to be developed. These include an appropriate time frame and sufficient and qualified personnel to conduct qualitative research. Qualitative research is not a research paradigm in itself rather it comprises of many different and diverging approaches. The goal of this paper is to show the diversity of qualitative research methods, its importance for health services research, and to open up the discussion on strategies for integrating qualitative methods into health services research.

[Qualitative research in health services research - discussion paper, Part 2: Qualitative research in health services research in Germany - an overview]. / Qualitative Studien in der Versorgungsforschung - Diskus-sionspapier, Teil 2: Stand qualitativer Versorgungsforschung in Deutschland - ein exemplarischer Überblick.

BACKGROUND: This is the second part of a 3-part discussion paper by the working group on "Qualitative Methods" in the German network of health services research (DNVF) that shall contribute to the development of a memorandum concerning qualitative health services research. It aims to depict the different types of qualitative research that are conducted in health services research in Germany. In addition, the authors present a specific set of qualitative data collection and analysis tools to demonstrate the potential of qualitative research for health services research. QUALITATIVE RESEARCH IN HEALTH SERVICES RESEARCH - AN OVERVIEW: To give an overview of the types of qualitative research conducted in German health services research, the abstracts of the 8th German Conference on Health Services Research were filtered to identify qualitative or mixed-methods studies. These were then analysed by looking at the context which was studied, who was studied, the aims of the studies, and what type of methods were used. Those methods that were mentioned most often for data collection and analysis are described in detail. QUALITATIVE RESEARCH AT THE CONFERENCE FOR HEALTH SERVICES RESEARCH 2009: Approximately a fifth of all abstracts (n=74) had a qualitative (n=47) or a mixed-methods approach combining quantitative and qualitative methods (n=27). Research aims included needs assessment (41%), survey development (36%), evaluation (22%), and theorizing (1%). Data collection mostly consisted of one-on-one interviews (n=45) and group discussions (n=29). Qualitative content analysis was named in 35 abstracts, 30 abstracts did not reference their method of analysis. In addition to a quantitative summary of the abstract findings, the diversity of fields addressed by qualitative methods is highlighted. CONCLUSION: Although drawing conclusions on the use of qualitative methods in German health services research from the analysis of conference abstracts is not possible, the overview we present demonstrates the diversity of methods used for data collection and analysis and showed that a few select methods are extensively used. One of the tasks a memorandum of qualitative health services research should accomplish is to highlight underutilized research methods, which may help to develop the potential of qualitative methodology in German health services research.

[Epidemiology and surgical treatment of pancreatic cancer in the State of Brandenburg : Analysis of 5418 cases]. / Epidemiologie und operative Behandlung des Pankreaskarzinoms im Flächenland Brandenburg : Analyse von 5418 Fällen.

BACKGROUND: Pancreatic cancer is the second most frequent cause of death among all forms of cancer in Germany with more than 19,000 deaths per year. The evaluation of the nationwide clinical cancer register aims to depict the reality of treatment and to improve the quality of treatment in the future by targeted analyses. METHOD: The data from the clinical cancer register of Brandenburg-Berlin for the diagnosis years 2001-2017 were analyzed with respect to the treatment of pancreatic cancer. Data from patients resident in the State of Brandenburg were evaluated with respect to epidemiological and therapeutic parameters. RESULTS: A total of 5418 patients with pancreatic cancer were documented in the register from 2001 to 2017 and 49.6% of the patients were diagnosed as having the Union for International Cancer Control (UICC) stage IV. A pancreas resection was carried out in 26.4% of the cases. In cases of cancer of the head of the pancreas the most frequent procedure was a pylorus-preserving resection with 51.8% and a pancreatectomy was carried out in 9.4%. The R0 resection rate of all pancreatic cancers in the period from 2014 to 2017 was 61.9%. After R0 resection the 5­year survival was 19%. Relevant multivariate survival factors were age, UICC stage and the residual (R) tumor classification. The case numbers per hospital had no influence on the absolute survival of patients operated on in the State of Brandenburg. CONCLUSION: The treatment reality in the State of Brandenburg for patients with pancreatic cancer corresponds to the results of international publications with respect to the key performance indicators investigated. A qualitative internationally comparable treatment of these patients is also possible in nonmetropolitan regions.

Thoughts, beliefs and concepts concerning infectious childhood diseases of physicians practicing homeopathic, anthroposophic and conventional medicine - a qualitative study.

BACKGROUND: Physicians who include complementary medicine in their practice are thought to have an understanding of health and disease different from that of colleagues practicing conventional medicine. The aim of this study was to identify and compare the thoughts and concepts concerning infectious childhood diseases (measles, mumps, rubella, chickenpox, pertussis and scarlet fever) of physicians practicing homeopathic, anthroposophic and conventional medicine. METHODS: This qualitative study used semistructured interviews. Participating physicians were either general practitioners or pediatricians. Data collection and analysis were guided by a grounded theory approach. RESULTS: Eighteen physicians were interviewed (6 homeopathic, 6 anthroposophic and 6 conventional). All physicians agreed that while many classic infectious childhood diseases such as measles, mumps and rubella are rarely observed today, other diseases, such as chickenpox and scarlet fever, are still commonly diagnosed. All interviewed physicians vaccinated against childhood diseases. A core concern for physicians practicing conventional medicine was the risk of complications of the diseases. Therefore, it was considered essential for them to advise their patients to strictly follow the vaccination schedule. Homeopathic-oriented physicians viewed acute disease as a biological process necessary to strengthen health, fortify the immune system and increase resistance to chronic disease. They tended to treat infectious childhood diseases with homeopathic remedies and administered available vaccines as part of individual decision-making approaches with parents. For anthroposophic-oriented physicians, infectious childhood diseases were considered a crucial factor in the psychosocial growth of children. They tended to treat these diseases with anthroposophic medicine and underlined the importance of the family's resources. Informing parents about the potential benefits and risks of vaccination was considered important. All physicians agreed that parent-delivered loving care of a sick child could benefit the parent-child relationship. Additionally, all recognized that existing working conditions hindered parents from providing such care for longer durations of time. CONCLUSIONS: The interviewed physicians agreed that vaccines are an important aspect of modern pediatrics. They differed in their approach regarding when and what to vaccinate against. The different conceptual understandings of infectious childhood diseases influenced this decision-making. A survey with a larger sample would be needed to verify these observations.

Impaired bone health in adolescents after liver transplantation.

Long-term complications related to immunosuppressive medication are an important problem after liver transplantation (OLT). This study was carried out to evaluate the bone health and risk factors for osteoporosis and fractures in 40 pediatric liver transplant recipients. The results of 208 longitudinal bone mineral density (BMD) measurements were analyzed retrospectively. In addition, a dual-energy X-ray absorptiometry was performed to assess the bone mineral content more precisely and to detect subclinical vertebral fractures (VF). The median age of the patients was 14 years and mean postoperative follow-up 7.0 years. The results showed that over half (58%) had lumbar spine (LS) Z-score

Successful liver-kidney transplantation in two children with aHUS caused by a mutation in complement factor H.

A 12-month-old boy and his 16-year-old aunt became acutely ill 6 months apart and were diagnosed to have atypical hemolytic uremic syndrome (aHUS). Genetic analysis revealed heterozygous R1215Q mutation in complement factor H (CFH) in both patients. The same mutation was found in five healthy adult relatives indicating incomplete penetrance of the disease. The patients developed terminal renal failure and experienced reversible neurological symptoms in spite of plasma exchange (PE) therapy. In both cases, liver-kidney transplantation was successfully performed 6 months after the onset of the disease. To minimize complement activation and prevent thrombotic microangiopathy or overt thrombotic events due to the malfunctioning CFH, extensive PE with fresh frozen plasma was performed pre- and perioperatively and anticoagulation was started a few hours after the operation. No circulatory complications appeared and all four grafts started to function immediately. Also, no recurrence or other major clinical setbacks have appeared during the postoperative follow-up (15 and 9 months) and the grafts show excellent function. While more experience is needed, it seems that liver-kidney transplantation combined with pre- and perioperative PE is a rational option in the management of patients with aHUS caused by CFH mutation.

Colonic electrolyte transport in health and in congenital chloride diarrhea.

Congenital chloride diarrhea (CCD) is a rare autosomal recessive disorder, characterized by watery stools with C1- concentration around 150 meq/liter. We have perfused the colon of three patients and their three healthy siblings with different salt solutions containing 36C1- to determine the nature of the colonic defect in CCD. In the controls, net absorption of Na+ and C1- occurred against steep concentration gradients. The influx (lumen-to-plasms flux) of C1- was twice the effux. Omission of HCO3- from the perfusate caused a clear decrease in C1- efflux which suggests a coupling of C1- effux to HCO3- influx. In CCD, net Na+ absorption occurred normally when HCO3- was present in the lumen. However, Na+ absorption was always impaired when the luminal contents were acid, a situation that prevails in CCD. Net K+ secretion was clearly increased. Both influx and efflux of C1- were practically absent. Only slight net secretion occurred along a steep gradient. Net appearance of HCO3- was not observed, in contrast to controls. These findings and earlier studies of ileal function in CCD are best explained by a defect in the C1-/HCO3- exchange mechanism, which operates in both directions in the normal ileum and colon.

Depletion of the AP-1 repressor JDP2 induces cell death similar to apoptosis.

JDP2 is a ubiquitously expressed nuclear protein that efficiently represses the activity of the transcription factor AP-1. Thus far, all studies of JDP2 function have relied on the ectopic expression of the protein. In this study, we use a different approach: depletion of JDP2 from cells. Specific depletion of JDP2 resulted in p53-independent cell death that resembles apoptosis and was evident at 72 h. The death mechanism was caspase dependent as the cells could be rescued by treatment with caspase inhibitor zVAD. Our studies suggest that JDP2 functions as a general survival protein, not only following UV-irradiation, as reported earlier, but also under normal culture conditions. Thus, our data support that JDP2 is a cellular survival protein whose presence is necessary for normal cellular function.

Canine malignant lymphomas: comparison of morphologic and immunologic parameters.

Twenty-three canine malignant lymphomas were studied to correlate morphologic and immunologic properties of the neoplastic cells. Morphotologic characterization included histologic classification of cell type and growth pattern, anatomic distribution of lesions, and transmission electron microscopic examination. Parameters examined to indicate B- or T-cell nature of lymphoma cells included demonstration of mitogen responsiveness, cell-surface Ig, spontaneous rosette formation with human red blood cells, and scanning electron microscope (SEM) examination of cell-surface features. Results indicated that the cells from histiocytic lymphomas were lymphocytes rather than histiocytes or macrophages. Most cells from lymphomas examined possessed cell-surface ig, indicating B-cell nature. The cell types represented by the different Ig-positive lymphomas were compatible with maturation arrest at different stages in normal lymphocyte differentiation. For the two most common histiologic cell types, nitogen responsiveness and the presence of cell-surface Ig indicated that diffuse, poorly differentiated lymphocytic cases were biologically heterogenous, whereas nodular histiocytic lymphomas were biologically homogenous. Most canine lymphomas had a multicentric anatomic distribution; however, one thymic and two alimentary forms were observed. Lymphomas with a nodular pattern in lymph nodes had multifocal splenic involvement centered on small arteries, whereas lymphomas with a diffuse pattern in lymph nodes had diffuse involvement of splenic white pulp. The cells of Ig-positive and Ig-negative neoplasms examined by SEM were predominantly of the smooth-cell type.

Antibodies to bovine leukemia virus and presence of malignant lymphoma in slaughtered California dairy cattle.

Rates of malignant lymphoma (ML) in California dairy cattle and relationships between ML and presence of antibodies to bovine leukemia virus (BLV) were investigated. An excessively high rate of lymphoma was found in the population studied and a previously unknown relationship between ML and p-24 antibodies to BLV was identified. Sera from slaughtered California holstein dairy cows were tested by agar gel immunodiffusion for presence of antibodies to the gp-51 and p-24 antigens of BLV. Of the 7,760 cows slaughtered, 32% and 10% had gp-51 and p-24 antibodies, respectively, and 52 cows (0.67%) were condemned for ML. Lymphoma was diagnosed histopathologically in 37 (86%) of 43 cows sampled from those 52 condemned. Highly elevated prevalence rates of ML in gp-51 and p-24 antibody-positive cows were 172.6 and 511.5 per 10,000 cows, respectively. A prevalence rate of lymphoma not associated with presence of BLV antibodies was estimated for the first time to be 1.55 per 10,000 cows. A highly significant (P less than .00001) and strong (odds ratio = 26.0) association was found between presence of p-24 antibodies and presence of ML for cows with gp-51 antibodies. When results of serologic tests were compared in regard to diagnosis of ML, the highest sensitivity was with use of gp-51 serology alone (97.3%) and highest specificity was with use of p-24 serology alone (90.4%). False-negative and false-positive rates of diagnosis of ML for gp-51-positive, p-24-negative and gp-51-positive, p-24-positive cows were 0.21 and 94.8%, respectively.

Inhibition of human lymphoma DNA-dependent RNA polymerase activity by 6-mercaptopurine ribonucleoside triphosphate.

6-Mercaptopurine was found to inhibit the growth of cultured human lymphoma P3HR-1 cells and the incorporation of [3H]-uridine into trichloroacetic acid-precipitable materials of the cells. One of the derivatives of 6-mercaptopurine, 6-mercaptopurine ribonucleoside triphosphate (6-thio-ITP), was found to inhibit in vitro RNA synthesis (both engaged and free enzyme activities) of the isolated nuclei from P3HR-1 cells. The alpha-amanitin-resistant RNA polymerase (polymerase I) and alpha-amanitin-sensitive RNA polymerase (polymerase II) of the cells were isolated and partially purified by either diethylaminoethyl cellulose or diethylaminoethyl Sephadex column chromatography, followed by DNA-cellulose affinity chromatography. It was found that these partially purified enzymes were also sensitive to 6-thio-ITP inhibition. Kinetic studies showed that the inhibition of RNA polymerase activities by 6-thio-ITP could be reversed by increasing concentrations of guanosine 5'-triphosphate in the reaction mixture, indicating that 6-thio-ITP may act as a competitive inhibitor of the enzymes by competing with guanosine 5'-triphosphate for its enzyme-binding site. These data suggest that inhibition of RNA transcription by 6-thio-ITP may be considered as one of the mechanisms of the cytotoxic action of 6-mercaptopurine in human tumor cells.

E2F-1-induced p53-independent apoptosis in transgenic mice.

The E2F transcription factors are key targets for the retinoblastoma protein, pRB. By inactivation of E2Fs, pRB prevents progression to the S phase. To test proliferative functions of E2F, we generated transgenic mice expressing human E2F-1 and/or human DP-1. When the hydroxymethyl glutaryl coenzyme A reductase promoter was used to express DP-1, overexpression occurred in a variety of tissues and did not confer phenotypic changes. In contrast, expression of E2F-1 from the same promoter was obtained only in testicles, in which E2F-1 overexpression caused atrophy and sterility through a process involving increased apoptosis in the germinal epithelium. This effect was potentiated by simultaneous overexpression of DP-1. Testicular atrophy as a result of overexpression of E2F-1 and DP-1 is independent of functional p53, since p53-nullizygous transgenic mice overexpressing E2F-1 and DP-1 also suffered testicular atrophy.

JNK2 mediates TNF-induced cell death in mouse embryonic fibroblasts via regulation of both caspase and cathepsin protease pathways.

Recent studies strongly suggest an active involvement of the c-Jun N-terminal kinase (JNK) signaling pathway in tumor necrosis factor (TNF)-induced apoptosis. The direct evidence for the role of JNK and its isoforms has been missing and the mechanism of how JNK actually could facilitate this process has remained unclear. In this study, we show that Jnk2-/- primary mouse embryonic fibroblasts (pMEFs) exhibit resistance towards TNF-induced apoptosis as compared to corresponding wild-type and Jnk1-/- pMEFs. JNK2-deficient pMEFs could be resensitized to TNF via retroviral transduction of any of the four different JNK2 splicing variants. Jnk2-/- pMEFs displayed deficient and delayed effector caspase activation as well as impaired cytosolic cystein cathepsin activity: processes that both were needed for efficient TNF-induced apoptosis in pMEFs. Our work demonstrates that JNK has a central role in the promotion of TNF-induced apoptosis in pMEFs, and that the JNK2 isoform can regulate both mitochondrial and lysosomal death pathways in these cells.

Substantial increase in cadaveric organ donors in hospitals implementing the donor action program in Finland.

The results of solid organ transplantation have improved during the last decade. Five-year patient survivals over 80% and graft survivals over 70% are common in many transplant centers. Also, quality-of-life assessments show that not only adults but even small children have a good quality of life after successful organ transplantation. Furthermore, transplantation programs have proved to be cost-effective. However, the organ shortage is a worldwide problem, which has in many countries led to prolonged waiting times, deaths on the waiting list, increased living related donations, acceptance of lower-quality organs, and in some instances even commercialization of the organ supply. Thus, it is extremely important to find strategies that increase the number of cadaveric organs for donation. In Finland organ transplantation is concentrated in one center with about 250 transplantations of different organs performed annually. The number of patients needing a new cadaveric organ is steadily increasing, but the number of donors has remained the same during the last decade. To improve cadaveric organ procurement the Donor Action (DA) program, which consists of a Hospital Attitude Survey and a medical records review performed by the donor hospital, has proved to increase the number of cadaveric donors. We introduced the DA program in Finland in 2000. Here in we report the results of this program in terms of its impact on the availability of cadaveric donors.