Developing an ethics support tool for dealing with dilemmas around client autonomy based on moral case deliberations.

BACKGROUND: Moral Case Deliberations (MCDs) are reflective dialogues with a group of participants on their own moral dilemmas. Although MCD is successful as clinical ethics support (CES), it also has limitations. 1. Lessons learned from individual MCDs are not shared in order to be used in other contexts 2. Moral learning stays limited to the participants of the MCD; 3. MCD requires quite some organisational effort, 4. MCD deals with one individual concrete case. It does not address other, similar cases (it is case based). These limitations warrant research into complementary ways of providing CES to healthcare professionals. Our research objective was therefore to develop a low threshold CES tool based on a series of MCDs on autonomy in long-term care. METHODS: We used a qualitative research design in which we analyzed the process and content of a series of MCDs, combined with reflections on the theoretical background of MCD. In total 28 MCDs (10 transcripts and 18 summary reports) were analyzed by means of a thematic content analysis. In various rounds of development, the results of the analysis were combined with theoretical reflections on CES. Consequently, the tool was evaluated in three focus groups and adjusted. RESULTS: The CES tool, called 'moral compass', guides the users through a series of six subsequent questions in order to methodically reflect on their concrete moral dilemma, in the form of a booklet of 23 pages. It combines a methodical element that encourages and structures a reflection process with a substantive element, including norms, values, options, strategies, and insights regarding dealing with client autonomy. CONCLUSION: By using data from a series of MCDs, combined with theoretical reflections on MCD, ethics support and moral learning, we developed a thematic, low-threshold CES tool that supports healthcare professionals in daily practice in dealing with moral questions regarding client autonomy. It integrates examples and insights from earlier MCDs on the same topic. The moral compass is not a replacement of, but can be used complementary to MCD. The feasibility and impact of the moral compass need to be investigated in an evaluative follow-up study. The methodology presented in this paper may be used to develop moral compasses on different topics in various healthcare organizations.

Verwijzen naar het hospice: verwijsgedrag van artsen en ervaren belemmeringen in Deventer en omgeving.

UNLABELLED: PHYSICIANS' REFERRAL PATTERNS AND PERCEIVED BARRIERS IN THE DEVENTER REGION IN THE NETHERLANDS: OBJECTIVE: To examine physicians' perceived referral patterns and barriers to referral of terminally ill patients to a hospice (institute). DESIGN: Survey study among physicians practicing in hospital and other settings in the region of Deventer, The Netherlands, in 2011-2012. METHOD: We translated two available American instruments into Dutch. The questionnaire assessed hospice referral, knowledge about hospice, attitudes and barriers and reasons not to refer. We queried physicians who had referred patients to the local hospice about expectations and suggested areas for improvement with two open-ended items. RESULTS: In total, 240 physicians received the questionnaire. The response rate was 47%. The physicians were generally positive about hospice care. They indicated experiencing few barriers in hospice referrals, but 32% of the physicians (21% of those practicing in the hospital, and 39% in other settings), indicated the patient being unready as a strong barrier. Half of the physicians (51%) believed that hospice is being underutilized and 22% (35% and 14%, respectively) thought that they would refer more frequently if they had more knowledge about hospice care. Of the physicians, 35% answered all six knowledge questions correctly. Communication with the hospice may be improved. CONCLUSION: Despite positive attitudes toward hospice care, it may be underutilized due to poor knowledge and communication with the hospice. Perhaps, this is also due to limited patient-physician communication on prognosis, which further research may address.

Cost-effectiveness and cost-utility of add-on, low-dose prednisolone in patients with rheumatoid arthritis aged 65+: The pragmatic, multicenter, placebo-controlled GLORIA trial.

BACKGROUND: The GLORIA placebo-controlled trial found a favorable balance of benefit and harm for two years of prednisolone (5 mg/day) as add-on treatment for rheumatoid arthritis (RA) patients aged 65+. This study evaluated the cost-effectiveness of low-dose prednisolone in the treatment of RA. METHODS: The economic evaluation had a societal perspective with a time horizon of two years. Cost data were collected with questionnaires and from recorded events, and valued with standard Dutch unit prices of 2017. The primary effectiveness outcome was the disease activity score in 28 joints (DAS28). For cost-utility, quality-adjusted life years (QALYs) were estimated from the EuroQol-5 Dimension (EQ-5D) questionnaire. Bootstrapping assessed the uncertainty around the average differences in costs and health outcomes. RESULTS: In total, 444 of 451 randomized patients were included in the modified intention-to-treat analysis. Patients had median four active comorbidities at baseline. Mean total costs over two years were k€10.8 in the prednisolone group, k€0.5 (95% CI -4.0; 1.8) lower than in the placebo group. Total direct medical costs were k€0.5 (95% CI -4.0; 1.5) lower in the prednisolone group. The mean number of QALYs was similar in both groups (difference 0.02 [-0.03; 0.06] in favor of prednisolone). The DAS28 was 0.38 lower in the prednisolone group than in the placebo group (0.19; 0.56). CONCLUSION: With greater effectiveness (DAS28) at non-significantly lower costs, low-dose, add-on prednisolone is cost-effective for RA compared to placebo over two years. QALYs were equal in both groups, most likely due to the impact of multiple comorbidities.

Adhesive and degradative properties of human placental cytotrophoblast cells in vitro.

Human fetal development depends on the embryo rapidly gaining access to the maternal circulation. The trophoblast cells that form the fetal portion of the human placenta have solved this problem by transiently exhibiting certain tumor-like properties. Thus, during early pregnancy fetal cytotrophoblast cells invade the uterus and its arterial network. This process peaks during the twelfth week of pregnancy and declines rapidly thereafter, suggesting that the highly specialized, invasive behavior of the cytotrophoblast cells is closely regulated. Since little is known about the actual mechanisms involved, we developed an isolation procedure for cytotrophoblasts from placentas of different gestational ages to study their adhesive and invasive properties in vitro. Cytotrophoblasts isolated from first, second, and third trimester human placentas were plated on the basement membrane-like extracellular matrix produced by the PF HR9 teratocarcinoma cell line. Cells from all trimesters expressed the calcium-dependent cell adhesion molecule cell-CAM 120/80 (E-cadherin) which, in the placenta, is specific for cytotrophoblasts. However, only the first trimester cytotrophoblast cells degraded the matrices on which they were cultured, leaving large gaps in the basement membrane substrates and releasing low molecular mass 3H-labeled matrix components into the medium. No similar degradative activity was observed when second or third trimester cytotrophoblast cells, first trimester human placental fibroblasts, or the human choriocarcinoma cell lines BeWo and JAR were cultured on radiolabeled matrices. To begin to understand the biochemical basis of this degradative behavior, the substrate gel technique was used to analyze the cell-associated and secreted proteinase activities expressed by early, mid, and late gestation cytotrophoblasts. Several gelatin-degrading proteinases were uniquely expressed by early gestation, invasive cytotrophoblasts, and all these activities could be abolished by inhibitors of metalloproteinases. By early second trimester, the time when cytotrophoblast invasion rapidly diminishes in vivo, the proteinase pattern of the cytotrophoblasts was identical to that of term, noninvasive cells. These results are the first evidence suggesting that specialized, temporally regulated metalloproteinases are involved in trophoblast invasion of the uterus. Since the cytotrophoblasts from first trimester and later gestation placentas maintain for several days the temporally regulated degradative behavior displayed in vivo, the short-term cytotrophoblast outgrowth culture system described here should be useful in studying some of the early events in human placen

Tumor necrosis factor and immune interferon synergistically induce cytochrome b-245 heavy-chain gene expression and nicotinamide-adenine dinucleotide phosphate hydrogenase oxidase in human leukemic myeloid cells.

Recombinant tumor necrosis factor (rTNF) and rIFN-gamma induce in the human leukemia cell lines HL-60, ML3, and U937 the accumulation of transcripts of the X chromosome-linked chronic granulomatous disease (X-CGD) gene, encoding the 91-kD heavy chain of cytochrome b-245, a component of the NADPH oxidase of phagocytic cells. The gene is induced within 6 h by either cytokine, and its accumulation is observed upon induction with rIFN-gamma up to 5 d. The combined effect of the two cytokines is more than additive. rIFN-gamma also induces accumulation of X-CGD mRNA in immature myeloid cells from peripheral blood of chronic myeloid leukemia (CML) patients, whereas rTNF has almost no effect. The cells from CML patients constitutively express TNF mRNA, suggesting that endogenously produced TNF may play a role in the effect of rIFN-gamma on these cells. rTNF induces X-CGD gene expression in the myeloid cell lines acting, at least in part, at the transcriptional level, as shown in nuclear run-on experiments. The gene encoding the 22-kD light chain of cytochrome b-245 is constitutively expressed in the human myeloid cell lines and the accumulation of its transcripts is affected by neither rTNF nor rIFN-gamma, rTNF and rIFN-gamma synergistically to induce the cell lines to express the cytochrome b-245 heterodimer (as evaluated by its visible spectrum), and to produce NADPH oxidase activity and H2O2 upon stimulation with phorbol diesters.

Hypoxia-inducible factor 1α predicts recurrence in high-grade soft tissue sarcoma of extremities and trunk wall.

BACKGROUND AND AIM: Sarcomas are of mesenchymal origin and typically show abundant tumour stroma and presence of necrosis. In search for novel biomarkers for personalised therapy, we determined the prognostic impact of stromal markers, hypoxia and neovascularity in high-grade soft tissue leiomyosarcoma and pleomorphic undifferentiated sarcoma. METHOD: We evaluated CD163, colony-stimulating factor (CSF)-1, CD16 and hypoxia-inducible factor 1 (HIF-1)α using immunohistochemical staining and assessed microvessel density using CD31 in 73 high-grade leiomyosarcomas and undifferentiated pleomorphic sarcomas of the extremities and the trunk wall. The results were correlated to metastasis-free and overall survival. RESULTS: Expression of HIF-1α was associated with the presence of necrosis and independently predicted shorter metastasis-free survival (HR 3.2, CI 1.4 to 7.0, p=0.004), whereas neither expression of the stromal markers CD163, CD16 and CSF-1 nor microvessel density was prognostically relevant in this series. CONCLUSIONS: There is increasing evidence for the prognostic role of hypoxia in high-grade soft tissue sarcoma, and these data suggest that HIF-1α expression represents a candidate prognostic biomarker for clinical application in high-grade leiomyosarcoma and undifferentiated pleomorphic sarcoma.

Induction of expression of genes encoding components of the respiratory burst oxidase during differentiation of human myeloid cell lines induced by tumor necrosis factor and gamma-interferon.

In HL-60 and ML-3 human myeloid cell lines, gamma-interferon (IFN-gamma) and/or tumor necrosis factor (TNF) induce synergistic accumulation of transcripts of the genes encoding the heavy chain (gp91-phox) of cytochrome b558 and the cytosolic factors p47-phox and p67-phox, components of the superoxide-generating NADPH oxidase system. The accumulation of transcripts for gp91-phox and p47-phox, as quantitated at the single-cell level by in situ hybridization, is extremely heterogeneous; however, when the cells are stimulated by IFN-gamma and TNF together, most or all the cells in the induced cultures express higher accumulation of gp91-phox and p47-phox transcripts than cells from uninduced culture. In situ hybridization was performed on cellular subsets separated by fluorescence-activated cell sorting on the basis of surface expression of differentiation antigens or respiratory burst activity. The accumulation of gp91-phox and p47-phox transcripts correlated positively with the expression of the CD14 and CD11b antigens, two markers expressed on mature myelomonocytic cells. Similarly, accumulation of the two transcripts correlated with respiratory burst activity in cells separated by fluorescence-activated cell sorting after being loaded with dichlorofluorescein diacetate and stimulated with 12-O-tetradecanoylphorbol-13-acetate. These results suggest that all the cells in the culture are induced to differentiate by TNF and IFN-gamma but that at the time of analysis there is heterogeneity in the level of differentiation and a proportion of cells is present that shows more mature characteristics with a coordinate expression of the various differentiation markers and functions.

The Role of Vitality in the Relationship Between a Healthy Lifestyle and Societal Costs of Health Care and Lost Productivity: A Mediation Analysis.

PURPOSE: To examine the mediating effect of vitality in the relationship between healthy lifestyle characteristics and health-care and productivity-related costs. DESIGN: Observational prospective cohort study with 2 measurements. Online questionnaires were filled out in 2013 (T0) and 2014 (T1). SETTING: A random sample of a Dutch online interview panel was obtained. SUBJECTS: Data of 4231 Dutch adults who had complete data at T0 and T1 were used in the present study. Participants were representative for the Dutch adult population in terms of age, gender, and having chronic disease(s). MEASURES: Healthy Lifestyle Index (HLI), vitality, and health-care and productivity-related costs. The HLI consisted of the sum of 6 healthy lifestyle characteristics, including a healthy BMI (yes/no), meeting physical activity, fruit, vegetable, and alcohol consumption guidelines (yes/no), and smoking status (yes: non or former smoker/no: current smoker). Health-care and productivity-related costs were measured using a utilization questionnaire. ANALYSIS: Linear regression analysis. RESULTS: The HLI was related to vitality. In addition, vitality was related to health-care costs and productivity-related costs. Furthermore, vitality was found to transmit 28.4% of the effect of HLI on health-care costs and 39.4% of the effect of HLI on productivity-related costs. CONCLUSION: Lifestyle was related to vitality and vitality to health-care and productivity-related costs. Vitality mediated the relationship between lifestyle and health-care and productivity-related costs. Therefore, we recommend to sustain and improve both vitality and lifestyle.

Influenza immunization in adults with diabetes mellitus.

The antibody responses to influenza vaccination of a group of adult diabetic patients were compared with responses in a healthy group of regular volunteer vaccinees. The initial and final geometric mean hemagglutination-inhibiting antibody titers were lower in the patient group, but the relative increase in titers was greater for each of the vaccine components. The percentage of fourfold rises in individual titers was greater in the diabetic group than in the control group. It was concluded that patients with diabetes mellitus responded normally to influenza vaccination. This was confirmed in an additional study. There was no significant difference in the antibody responses of patients treated with insulin or oral antidiabetic agents. There was no impairment of diabetic control as a result of influenza vaccination when this was evaluated by measuring the concentration of glycosylated hemoglobin, or by random blood glucose estimations. There was no significant change in the serum insulin level after immunization in patients on oral diabetic agents. It was concluded that influenza vaccination was safe and effective in adult diabetic patients.

The interface between sexual dysfunctional and marital conflict.

The author used a self-rating scale to assess marital happiness and sexual functioning in a sample of 20 couples referred to an outpatient family therapy unit. Evaluation of couples in structured interactions indicated important differences in the quality and intensity of relationship difficulties observed. Analysis of variance clearly showed that sexual dysfunction and marital distress may operate independently of one another. Thus effective treatment of marital discord may be neither a necessary nor sufficient condition for improvement in sexual functioning.

A double-blind, placebo-controlled, ascending-dose evaluation of the pharmacokinetics and tolerability of modafinil tablets in healthy male volunteers.

A randomized, double-blind, placebo-controlled, ascending-dose study was conducted to evaluate the pharmacokinetic and safety profiles of increasing modafinil doses (200 mg, 400 mg, 600 mg, 800 mg) administered orally over a 7-day period in normal healthy male volunteers. Eight subjects (six modafinil; two placebo) were randomized to each of the four dose groups. Modafinil or a placebo was administered once daily for 7 days. Serial blood samples were obtained following administration of the day 1 and day 7 doses for characterization of pharmacokinetics, and trough samples were obtained prior to dosing on days 2 through 6 to assess the time to reach the steady state. Pharmacokinetic parameters were calculated using noncompartmental methods. Modafinil steady state was reached after three daily doses. Modafinil pharmacokinetics were dose and time independent over the range of 200 mg to 800 mg. Steady-state pharmacokinetics of modafinil were characterized by a rapid oral absorption rate, a low plasma clearance of approximately 50 mL/min, a volume of distribution of approximately 0.8 L/kg, and a long half-life of approximately 15 hr. Modafinil was primarily eliminated by metabolism. Modafinil acid was the major urinary metabolite. Stereospecific pharmacokinetics of modafinil were demonstrated. The d-modafinil enantiomer was eliminated at a threefold faster rate than 1-modafinil. Modafinil 200 mg, 400 mg, and 600 mg doses were generally well tolerated. The modafinil 800 mg dose panel was discontinued after 3 days of treatment due to the observation of increased blood pressure and pulse rate. The safety data from this study suggest that the maximum tolerable single daily oral modafinil dose, without titration, may be 600 mg.

Comparison of the single-dose pharmacokinetics and tolerability of modafinil and dextroamphetamine administered alone or in combination in healthy male volunteers.

An open-label, randomized, crossover study was performed in healthy male volunteers to evaluate the potential pharmacokinetic and pharmacodynamic interactions and tolerability of single oral doses of modafinil (200 mg) and dextroamphetamine (10 mg). Blood samples were collected for determination of plasma levels of modafinil, the acid and sulfone metabolites of modafinil, and dextroamphetamine at intervals through 48 hours after administration for each treatment. Vital signs (blood pressure and pulse rate) were measured through 48 hours, and electrocardiograms were measured through 24 hours after administration. Pharmacokinetic parameters were determined using noncompartmental methods. The data collected in this study of 24 healthy volunteers suggest that concomitant administration of single oral doses of modafinil and dextroamphetamine has no clinically significant effects on the pharmacokinetic profile of either agent. Although there was a slightly greater incidence of adverse events when modafinil and dextroamphetamine were administered together, the concomitant administration of the two drugs was well tolerated.

Possible endogenous regulators of steroid inactivating enzymes and glucocorticoid-induced Na+ retention.

Various endogenous substances which bear similar structural resemblances to glycyrrhetininc acid were screened for inhibitory activity against 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) and 5 beta-reductase (5 beta-R). Among the compounds screened, 3 alpha, 5 beta-tetrahydroprogesterone (3 alpha,5 beta-THP) was a potent inhibitor of 11 beta-OHSD and a moderate inhibitor of 5 beta-R. Of the bile acids tested, chenodeoxycholic acid (CDCA) was the most potent inhibitor of both 11 beta-OHSD and 5 beta-R. Cholic acid (CA), a moderate inhibitor of 11 beta-OHSD was a weak inhibitor of 5 beta-R, whereas deoxycholic acid was a moderate inhibitor of 5 beta-R but a weak inhibitor of 11 beta-OHSD. 3 alpha, 5 beta-THP and bile acids were also tested to determine whether, like GA, they could confer mineralocorticoid actions upon corticosterone (B). In adrenalectomized rats pretreated with CDCA or 3 alpha,5 beta-THP, B caused a significant antinatriuresis; the effect of B plus CDCA was blocked by the antimineralocorticoid, RU 28318. Thus, we report on two structurally similar endogenous substances, 3 alpha, 5 beta-THP and CDCA, which inhibit both 11 beta-OHSD and 5 beta-R activity, and which can confer mineralocorticoid actions upon the glucocorticoid, B.

Bioavailability study of diphtheria immunoglobulin (human).

A diptheria immunoglobulin has been prepared from selected blood donations to the Australian Red Cross Transfusion Services. A dose of 250 I.U. has been demonstrated to raise the titre of diptheria antitoxin in non-immune subjects to protective levels within 24 h, and these levels remain protective for at least 5 wk. Supplies are available from the various branches of the Australian Red Cross Transfusion Services.

Canine intersegmental hip joint forces and moments before and after cemented total hip replacement.

Intersegmental forces and moments (i.e. resultant free body forces and moments computed at the joint centers) were studied in canine hindlimbs before and after cemented total hip replacement (THR). Five large, adult, mixed-breed dogs were selected. Their gait was recorded (while leash-walked) before surgery using high-speed cinematography and a force plate. Cemented total hip replacement was unilaterally performed on each dog. Gait was again recorded at one and four months after surgery. Segmental properties (mass, center of mass, and mass moment of inertia) of the hindlimbs were experimentally determined, and an inverse dynamics approach was used to compute intersegmental forces and moments in the sagittal plane. Significant reductions in intersegmental joint forces and moments were observed in the operated hindlimb one month after surgery, although kinematic gait parameters were unaltered. Decreases of 77.0% for vertical forces, 61.9% for craniocaudal forces, and 66.2% for extension moments were determined. Four months after surgery, the joint forces and moments had returned to their preoperative values. This experiment demonstrates that the dynamics of normal walking can be restored in a canine model by four months after THR. It also shows that kinetic (rather than kinematic) parameters are more descriptive of antalgic gait in the canine.

Orthotic collar in the treatment of intertriginous impetigo.

This article illustrates a manner in which physical therapy can provide adjunctive treatment management of an infant with intertriginous impetigo. This treatment program was an interdisciplinary approach to a difficult clinical problem. The medical staff concluded that implementation of the cervical orthosis expedited the patient's recovery and reduced the potential complications of the disease process.

Effects of pretreatment sterilization and cleaning methods on materials properties and osseoinductivity of a threaded implant.

A new endosseous titanium implant has been designed to replace skin adhesives as a method of retention of maxillofacial prostheses. The effects of various methods of preimplantation preparation on surface characteristics of the implant were analyzed with electron spectroscopy for chemical analysis. Having undergone one of several pretreatment protocols, fixtures were implanted in the crania of Yucatan miniature hairless swine. Both argon radiofrequency glow discharge and ultraviolet chamber treated implants were associated with the rapid ingrowth and maturation of new bone around the fixture. Conventional steam sterilization was associated with a paucity of neo-osteogenesis accompanied by the production of thick collagen slings at the interface. Apparently, the bulk material, fixture design, and method of surface preparation all contribute to the ultimate clinical fate of an implant.

Treatment of substance abuse by relaxation training: a review of its rationale, efficacy and mechanisms.

The efficacy of relaxation training as a treatment for alcohol and drug abuse is reviewed, and directions for future research derived. Such use of relaxation procedures, notably progressive muscular relaxation and meditation, has been widespread and is premised on the assumptions that substance abuse is causally linked to anxiety and that anxiety can be reduced by relaxation training. However, the evidence suggests that such precipitating anxiety is limited to interpersonal-stress situations involving diminished perceived personal control over the stressor, and that alcohol and other drugs are often consumed for their euphoric rather than tranquilizing effects. Consequently, the empirical support for the effectiveness of relaxation training as a treatment for substance abuse in general is equivocal. As well, the existing outcome studies suffer from numerous methodological and conceptual inadequacies. In cases of demonstrated effectiveness, increased perceived control is a more plausible explanation than is decreased anxiety.

U100 insulin and the general practitioner.

On August 1 1980, U100 insulins (100 units/mL) will be introduced and other strengths will be phased out over four months. During that period all insulin-dependent diabetics will need to be seen and helped to adjust to their new dosage volume. The new system is decimal, and provided the new appropriate syringes are used, much more simple. Experience has shown that mistakes in dosage are much fewer with U100 insulins. General practitioners will be in the forefront of the campaign to educate patients.