Effects of Social Determinants and Pharmacogenetic Medication Interactions on 90-Day Hospital Readmissions.

Context: The present study builds on our prior work that demonstrated an association between pharmacogenetic interactions and 90-day readmission. Objective: Evaluate aggregate contribution of social determinants, comorbidity, and gene-x-drug interactions to moderate 90-day hospital readmission. Study Design and Analysis: Non-concurrent cohort study; Multivariable logistic regression Setting: Hospital/integrated healthcare delivery system in northern Illinois Population Studied: 19,999 adults tracked from 2010 through 2020 who underwent testing with a 13-gene pharmacogenetic panel Outcome Measure: 90-day hospital readmission (primary outcome) Results: Univariate logistic regression analyses demonstrated that strongest associations with 90 day hospital readmissions were the number of medications prescribed within 30 days of a first hospital admission that had Clinical Pharmacogenomics Implementation Consortium (CPIC) guidance (CPIC medications) (5+ CPIC medications, odds ratio (OR) = 7.66, 95% confidence interval 5.45-10.77) (p < 0.0001), major comorbidities (5+ comorbidities, OR 3.36, 2.61-4.32) (p < 0.0001), age (65 + years, OR = 2.35, 1.77-3.12) (p < 0.0001), unemployment (OR = 2.19, 1.88-2.64) (p < 0.0001), Black/African-American race (OR 2.12, 1.47-3.07) (p < 0.0001), median household income (OR = 1.63, 1.03-2.58) (p = 0.035), male gender (OR = 1.47, 1.21-1.80) (p = 0.0001), and one or more gene-x-drug interaction (defined as a prescribed CPIC medication for a patient with a corresponding actionable pharmacogenetic variant) (OR = 1.41, 1.18-1.70). Health insurance was not associated with risk of 90-day readmission. Race, income, employment status, and gene-x-drug interactions were robust in a multivariable logistic regression model. The odds of 90-day readmission for patients with one or more identified gene-x-drug interactions after adjustment for these covariates was attenuated by 10% (OR = 1.31, 1.08-1.59) (p = 0.006). Although the interaction between race and gene-x-drug interactions was not statistically significant, White patients were more likely to have a gene-x-drug interaction (35.2%) than Black/African-American patients (25.9%) who were not readmitted (p < 0.0001). Conclusions: These results highlight the major contribution of social determinants and medical complexity to risk for hospital readmission, and that these determinants may modify the effect of gene-x-drug interactions on rehospitalization risk.

Predictors of post traumatic growth in allogeneic hematopoietic stem cell transplantation survivors: a cross-sectional survey.

AIMS: Given the increasing number of Hematopoietic Stem Cell Transplantations (HSCT) performed world-wide, the increasing likelihood of survival following HSCT, and the profound physical, psychosocial, and emotional impact of HSCT on survivors, their carers and families, it is important to identify factors that may contribute to or support post-traumatic growth (PTG) after transplant. In this study, we aimed to investigate the prevalence of PTG in an Australian cohort of long-term allogeneic HSCT survivors and describe associations between PTG and relevant clinical, sociodemographic and psychological variables. METHODS: This was a large, multi-centre, cross sectional survey of Australian HSCT-survivors inviting all those transplanted in New South Wales between 2000 and 2012. Respondents completed the PTG Inventory (PTGI), the Sydney Post-BMT Survey, FACT-BMT, DASS 21, The Chronic Graft versus Host Disease (GVHD) Activity Assessment-Patient Self-Report (Form B), the Lee Chronic GVHD Symptom Scale, and the Fear of Cancer Recurrence Scale. Data was analysed using independent t-tests, one-way analysis of variance, and pearson's correlations, and hierarchical multiple regression adjusted for potential confounders and to ascertain independent associations of explanatory variables with PTG. RESULTS: Of 441 respondents, 99% reported some level of PTG with 67% reporting moderate to high levels of PTG. Female gender, younger age, complementary therapy use, anxiety, psychological distress and psychosocial care, and higher quality of life were associated with higher levels of PTG. Importantly, we also found that PTG was not associated with either chronic GVHD or post-HSCT morbidity. CONCLUSIONS: In this study - the largest study of PTG in long-term allogeneic HSCT survivors - we found that growth appears ubiquitous, with 99% of survivors reporting some degree of PTG and 67% reporting moderate-high levels of PTG. Importantly, we found no association with GVHD or chronic physical post-HSCT morbidity, or adverse financial, occupational or sexual impacts. This suggests that it is the necessity for and experience of, HSCT itself that foments personal growth. Accordingly, healthcare professionals should be alert to the profound and wide-ranging impact of HSCT - and the degree to which survivor's may experience PTG. Identifying interventions that may assist HSCT survivors cope and building their resilience is of utmost importance.

Comprehensive ECG reference intervals in C57BL/6N substrains provide a generalizable guide for cardiac electrophysiology studies in mice.

Reference ranges provide a powerful tool for diagnostic decision-making in clinical medicine and are enormously valuable for understanding normality in pre-clinical scientific research that uses in vivo models. As yet, there are no published reference ranges for electrocardiography (ECG) in the laboratory mouse. The first mouse-specific reference ranges for the assessment of electrical conduction are reported herein generated from an ECG dataset of unprecedented scale. International Mouse Phenotyping Consortium data from over 26,000 conscious or anesthetized C57BL/6N wildtype control mice were stratified by sex and age to develop robust ECG reference ranges. Interesting findings include that heart rate and key elements from the ECG waveform (RR-, PR-, ST-, QT-interval, QT corrected, and QRS complex) demonstrate minimal sexual dimorphism. As expected, anesthesia induces a decrease in heart rate and was shown for both inhalation (isoflurane) and injectable (tribromoethanol) anesthesia. In the absence of pharmacological, environmental, or genetic challenges, we did not observe major age-related ECG changes in C57BL/6N-inbred mice as the differences in the reference ranges of 12-week-old compared to 62-week-old mice were negligible. The generalizability of the C57BL/6N substrain reference ranges was demonstrated by comparison with ECG data from a wide range of non-IMPC studies. The close overlap in data from a wide range of mouse strains suggests that the C57BL/6N-based reference ranges can be used as a robust and comprehensive indicator of normality. We report a unique ECG reference resource of fundamental importance for any experimental study of cardiac function in mice.

Influence of adrenalectomy on the gut microbiome and MDMA-induced hyperthermia.

The increased use of the stimulant drug, 3,4-methylenedioxymethamphetamine (MDMA), more commonly known as Ecstasy, Molly or X, has been linked to the development of life-threatening hyperthermia in human and animal models. The current study aimed to investigate the role of the gut-adrenal axis in MDMA-induced hyperthermia by assessing the influence of the acute exogenous supplementation with norepinephrine (NE) or corticosterone (CORT) to adrenalectomized (ADX) rats following MDMA administration. MDMA (10 mg/kg, sc) resulted in significant increase of body temperature in SHAM animals compared to ADX animals at 30-, 60- and 90-min timepoints post-MDMA treatment. The attenuated MDMA-mediated hyperthermic response seen in ADX animals was partially restored by the exogenous administration of NE (3 mg/kg, ip) or CORT (3 mg/kg, ip) 30 min after MDMA treatment. Additionally, 16 S rRNA analysis revealed distinct changes in the gut microbiome composition and diversity notable by the higher abundance of minor phyla Actinobacteria, Verrucomicrobia and Proteobacteria in ADX rats compared to control and SHAM rats. Furthermore, MDMA administration resulted in marked changes in the dominant phyla Firmicutes and Bacteroidetes and minor phyla Actinobacteria, Verrucomicrobia and Proteobacteria in ADX animals. The most notable changes in the gut microbiome upon CORT treatment were reported with increase in Bacteroidetes and decrease in Firmicutes phyla whereas NE treatment resulted in increase in Firmicutes and decrease in Bacteroidetes and Proteobacteria post treatment. These results suggest a correlation between the sympathoadrenal axis, gut microbiome structure and diversity and MDMA-mediated hyperthermia.

Influence of fecal microbial transplant (FMT) between male and female rats on methamphetamine-induced hyperthermia.

OBJECTIVE: To investigate the effect of bidirectional fecal microbial transplant (FMT) between male and female rats on methamphetamine (MA)-induced hyperthermia. METHODS: FMT was performed between male and female rats prior to MA (10 mg/kg, sc) treatment. Core body temperature, plasma drug and norepinephrine (NE) levels were measured and compared between treatment groups. 16S rRNA gene sequencing of bacterial communities between male and female rats was performed. RESULTS: MA treatment resulted in significantly higher core body temperatures in male groups (control and FMT-treated) compared to MA-treated female groups (control and FMT-treated). Plasma concentrations of MA and amphetamine were higher in females than males. Whereas, plasma norepinephrine (NE) levels were not different between male and female rats 90 minutes after MA treatment. At the phyla level, the microbiome of male and female control rats were dominated by Firmicutes and Bacteroidetes. Males had a higher relative abundance of Firmicutes and lower relative abundances of Bacteroidetes than females. The FMT procedure changed the recipient group towards their donor with males getting closer to their donors than females. In the control groups following MA treatment, Firmicutes increased and Bacteroides decreased in females and males. Conversely, in the FMT treatment groups following MA treatment, Firmicutes decreased while Bacteroidetes increased in females and males. CONCLUSIONS: Although definite differences in the structure and diversity of the gut microbiome were observed using 16S rRNA gene sequencing of bacterial communities between male and female rats, these differences do not seem to contribute to the sex-based differences in MA-induced hyperthermia.

General practitioner perspectives on factors that influence implementation of secondary care-initiated treatment in primary care: Exploring implementation beyond the context of a clinical trial.

BACKGROUND: The Beta-blockers Or Placebo for Primary Prophylaxis of oesophageal varices (BOPPP) trial is a 3-year phase IV, multi-centre clinical trial of investigational medicinal product (CTIMP) that aims to determine the effectiveness of carvedilol in the prevention of variceal bleeding for small oesophageal varices in patients with cirrhosis. Early engagement of General Practitioners (GPs) in conversations about delivery of a potentially effective secondary care-initiated treatment in primary care provides insights for future implementation. The aim of this study was to understand the implementation of trial findings by exploring i) GP perspectives on factors that influence implementation beyond the context of the trial and ii) how dose titration and ongoing treatment with carvedilol is best delivered in primary care. METHODS: This qualitative study was embedded within the BOPPP trial and was conducted alongside site opening. GP participants were purposively sampled and recruited from ten Clinical Commissioning Groups in England and three Health Boards across Wales. Semi-structured telephone individual interviews were conducted with GPs (n = 23) working in England and Wales. Data were analysed using reflexive thematic analysis. FINDINGS: Five overarching themes were identified: i) primary care is best placed for oversight, ii) a shared approach led by secondary care, iii) empower the patient to take responsibility, iv) the need to go above and beyond and v) develop practice guidance. The focus on prevention, attention to holistic care, and existing and often long-standing relationships with patients provides an impetus for GP oversight. GPs spoke about the value of partnership working with secondary care and of prioritising patient-centred care and involving patients in taking responsibility for their own health. An agreed pathway of care, clear communication, and specific, accessible guidance on how to implement the proposed treatment strategy safely and effectively are important determinants in the success of implementation. CONCLUSIONS: Our findings for implementing secondary care-initiated treatment in primary care are important to the specifics of the BOPPP trial but can also go some way in informing wider learning for other trials where work is shared across the primary-secondary care interface, and where findings will impact the primary care workload. We propose a systems research perspective for addressing implementation of CTIMP findings at the outset of research. The value of early stakeholder involvement is highlighted, and the need to consider complexity in terms of the interaction between the intervention and the context in which it is implemented is acknowledged. TRIAL REGISTRATION: ISRCTN10324656.

Preclinical Characterization of an Antibody-Drug Conjugate Targeting CS-1 and the Identification of Uncharacterized Populations of CS-1-Positive Cells.

Multiple myeloma is a hematologic cancer that disrupts normal bone marrow function and has multiple lines of therapeutic options, but is incurable as patients ultimately relapse. We developed a novel antibody-drug conjugate (ADC) targeting CS-1, a protein that is highly expressed on multiple myeloma tumor cells. The anti-CS-1 mAb specifically bound to cells expressing CS-1 and, when conjugated to a cytotoxic pyrrolobenzodiazepine payload, reduced the viability of multiple myeloma cell lines in vitro In mouse models of multiple myeloma, a single administration of the CS-1 ADC caused durable regressions in disseminated models and complete regression in a subcutaneous model. In an exploratory study in cynomolgus monkeys, the CS-1 ADC demonstrated a half-life of 3 to 6 days; however, no highest nonseverely toxic dose was achieved, as bone marrow toxicity was dose limiting. Bone marrow from dosed monkeys showed reductions in progenitor cells as compared with normal marrow. In vitro cell killing assays demonstrated that the CS-1 ADC substantially reduced the number of progenitor cells in healthy bone marrow, leading us to identify previously unreported CS-1 expression on a small population of progenitor cells in the myeloid-erythroid lineage. This finding suggests that bone marrow toxicity is the result of both on-target and off-target killing by the ADC.

Chronic dietary supplementation with soy protein improves muscle function in rats.

Athletes as well as elderly or hospitalized patients use dietary protein supplementation to maintain or grow skeletal muscle. It is recognized that high quality protein is needed for muscle accretion, and can be obtained from both animal and plant-based sources. There is interest to understand whether these sources differ in their ability to maintain or stimulate muscle growth and function. In this study, baseline muscle performance was assessed in 50 adult Sprague-Dawley rats after which they were assigned to one of five semi-purified "Western" diets (n = 10/group) differing only in protein source, namely 19 kcal% protein from either milk protein isolate (MPI), whey protein isolate (WPI), soy protein isolate (SPI), soy protein concentrate (SPC) or enzyme-treated soy protein (SPE). The diets were fed for 8 weeks at which point muscle performance testing was repeated and tissues were collected for analysis. There was no significant difference in food consumption or body weights over time between the diet groups nor were there differences in terminal organ and muscle weights or in serum lipids, creatinine or myostatin. Compared with MPI-fed rats, rats fed WPI and SPC displayed a greater maximum rate of contraction using the in vivo measure of muscle performance (p<0.05) with increases ranging from 13.3-27.5% and 22.8-29.5%, respectively at 60, 80, 100 and 150 Hz. When the maximum force was normalized to body weight, SPC-fed rats displayed increased force compared to MPI (p<0.05), whereas when normalized to gastrocnemius weight, WPI-fed rats displayed increased force compared to MPI (p<0.05). There was no difference between groups using in situ muscle performance. In conclusion, soy protein consumption, in high-fat diet, resulted in muscle function comparable to whey protein and improved compared to milk protein. The benefits seen with soy or whey protein were independent of changes in muscle mass or fiber cross-sectional area.

Epidemiology of complementary and alternative medicine therapy use in allogeneic hematopoietic stem cell transplant survivorship patients in Australia.

In addition to prescribed conventional medicines, many allogeneic hematopoietic stem cell transplant (HSCT) survivors also use complementary and alternative medical therapies (CAM), however, the frequency and types of CAMs used by allogeneic HSCT survivors remain unclear. Study participants were adults who had undergone an allogeneic HSCT between 1st January 2000 and 31st December 2012. Participants completed a 402-item questionnaire regarding the use of CAM, medical complications, specialist referrals, medications and therapies, infections, vaccinations, cancer screening, lifestyle, and occupational issues and relationship status following stem cell transplantation. A total of 1475 allogeneic HSCT were performed in the study period. Of the 669 recipients known to be alive at study sampling, 583 were contactable and were sent study packs. Of 432 participants who returned the completed survey (66% of total eligible, 76% of those contacted), 239 (54.1%) HSCT survivors used at least one form of CAM. These included dietary modification (13.6%), vitamin therapy (30%), spiritual or mind-body therapy (17.2%), herbal supplements (13.5%), manipulative and body-based therapies (26%), Chinese medicine (3.5%), reiki (3%), and homeopathy (3%). These results definitively demonstrate that a large proportion of HSCT survivors are using one or more form of CAM therapy. Given the potential benefits demonstrated by small studies of specific CAM therapies in this patient group, as well as clearly documented therapies with no benefit or even toxicity, this result shows there is a large unmet need for additional studies to ascertain efficacy and safety of CAM therapies in this growing population.

The effect of omega-3 polyunsaturated fatty acids on fibrin and thrombin generation in healthy subjects and subjects with cardiovascular disease.

Hypercoagulability plays a key role in the progression of cardiovascular disease (CVD). Although omega-3 polyunsaturated fatty acid (PUFA) intake has been inversely related to the risk of cardiovascular events, the mechanisms are not fully understood. The aim of this study was to investigate the effects of omega-3 on novel markers of global coagulation. The generation of fibrin and thrombin, measured via overall hemostasis potential (OHP) assay and calibrated automated thrombography, respectively, was determined in 40 healthy subjects and 16 patients with CVD at baseline and after 4 weeks of 640 mg/day omega-3 PUFA. In healthy subjects, fibrin generation was significantly reduced, as measured by overall coagulation potential (p = 0.013), OHP (p < 0.001), velocity of fibrin polymerization (p = 0.002), and significant increase in delay to fibrin generation (p = 0.002). The peak of generated thrombin was significantly reduced (p = 0.043). In subjects with CVD, omega-3 PUFA significantly reduced OHP and significantly increased the lag time to thrombin generation (both p < 0.001). Treatment with omega-3 PUFA had no effect on other fibrin and thrombin generation parameters in CVD patients. Four-week omega-3 PUFA supplementation reduced thrombotic potential in healthy subjects, as shown by reduced fibrin generation and peak thrombin. There was a greater effect on fibrin generation in healthy subjects compared with those with CVD.

Effects of omega-3 polyunsaturated fatty acids on platelet function in healthy subjects and subjects with cardiovascular disease.

Hyperactivation and aggregation of platelets play a major role in thrombosis and hemostasis. The aims of this study were to investigate the effects of omega-3 polyunsaturated fatty acids (PUFAs) on platelet function. Light transmission aggregometry and flow cytometric analyses of platelet activation and platelet-leukocyte aggregates were determined at baseline and after 4 weeks of omega-3 (docosahexaenoic acid 520 mg and eicosapentaenoic acid 120 mg) supplementation. In total, 40 healthy subjects and 16 patients with a history of cardiovascular disease (CVD) completed the study. In healthy subjects, omega-3 PUFA significantly reduced adenosine diphosphate (ADP)-induced (maximum amplitude, 77.0% ± 3.2% vs. 71.6% ± 3.4%, p = 0.036; maximum slope, 86.3 ± 1.8 vs. 80.7 ± 2.1, p = 0.014) and adrenaline-induced platelet aggregation (maximum slope, 42.8 ± 2.7 vs. 37.4 ± 3.0, p = 0.013; lag time, 00:21 ± 00:02 vs. 00:31 ± 00:03 s, p = 0.002). Omega-3 PUFA also reduced P-selectin expression (40.5% ± 2.9% vs. 34.4% ± 2.4%, p = 0.049) on platelets and platelet-monocyte aggregates (38.5% ± 2.6% vs. 31.4% ± 2.5%, p = 0.022) after activation with ADP 0.5 µM. There were fewer changes in platelet aggregation and activation found in subjects with CVD. Nevertheless, there was a reduction in the slope of arachidonic acid-induced platelet aggregation (13.21 ± 6.41 vs. 4.88 ± 3.01, p = 0.009) and increased lag time for U46619 (00:16 ± 00:00 vs. 00:29 ± 00:07 s, p = 0.018) induced platelet aggregation. Thus, 4-week supplementation of 640 mg omega-3 PUFA reduced measures of platelet aggregation and activation in healthy subjects but effects were less evident in patients with existing CVD. Our findings support the recommendation that the omega-3 PUFA dose be higher in CVD than among healthy subjects.

E-cadherin and, in its absence, N-cadherin promotes Nanog expression in mouse embryonic stem cells via STAT3 phosphorylation.

We have recently shown that loss of E-cadherin in mouse embryonic stem cells (mESCs) results in significant alterations to both the transcriptome and hierarchy of pluripotency-associated signaling pathways. Here, we show that E-cadherin promotes kruppel-like factor 4 (Klf4) and Nanog transcript and protein expression in mESCs via STAT3 phosphorylation and that ß-catenin, and its binding region in E-cadherin, is required for this function. To further investigate the role of E-cadherin in leukemia inhibitory factor (LIF)-dependent pluripotency, E-cadherin null (Ecad(-/-)) mESCs were cultured in LIF/bone morphogenetic protein supplemented medium. Under these conditions, Ecad(-/-) mESCs exhibited partial restoration of cell-cell contact and STAT3 phosphorylation and upregulated Klf4, Nanog, and N-cadherin transcripts and protein. Abrogation of N-cadherin using an inhibitory peptide caused loss of phospho STAT3, Klf4, and Nanog in these cells, demonstrating that N-cadherin supports LIF-dependent pluripotency in this context. We therefore identify a novel molecular mechanism linking E- and N-cadherin to the core circuitry of pluripotency in mESCs. This mechanism may explain the recently documented role of E-cadherin in efficient induced pluripotent stem cell reprogramming.

Effect of omega-3 fish oil on cardiovascular risk in diabetes.

PURPOSE: Diabetes and cardiovascular disease are major public health concerns worldwide and are leading causes of morbidity and mortality. People with type 2 diabetes are at an increased risk for cardiovascular disease. Diet has a substantial affect on the progression of many diseases, including diabetes, cardiovascular disease, osteoporosis, and arthritis. Omega-3 polyunsaturated fatty acids (long-chain polyunsaturated fatty acids [LC-PUFA]) have long been attributed to the maintenance of health and may be of benefit in reducing cardiovascular risk. The purpose of this review is to investigate the possible roles of omega-3 in reducing cardiovascular risk in patients with diabetes. METHODS: A literature search was conducted from the Medline, EBSCO, and EMBASE databases. Articles that addressed diabetes, cardiovascular disease, or omega-3 were included. RESULTS: Reviews and studies reported an association with fish and omega-3 LC-PUFA consumption and decreased total cardiovascular mortality (approximately 15%-19%), along with decreased platelet activation and aggregation, improved lipid profiles, including reduction of triglycerides and very low-density lipoprotein (VLDL), decreased inflammation, and lowered blood pressure. CONCLUSION: Diets higher in fish and omega-3 LC-PUFA may reduce cardiovascular risk in diabetes by inhibiting platelet aggregation, improving lipid profiles, and reducing cardiovascular mortality. Fish and omega-3 LC-PUFA can be recommended to people with diabetes and included into a diabetes management program.

L-tryptophan and correlates of self-injurious behavior in small-eared bushbabies (Otolemur garnettii).

Self-injurious behavior (SIB) among captive primates is a recurring problem for those who manage such facilities. Its prevalence highlights the need for research evaluating the effectiveness of potential treatment approaches. In the present study, 4 wk of dietary supplementation with L-tryptophan (100 mg daily) was evaluated for the treatment of self-inflicted wounds in 22 small-eared bushbabies, a prosimian primate, with a history of SIB. The treatment significantly reduced stereotypy and was associated with a reduction in wound area and severity. In terms of physiologic measures, preexisting high levels of cortisol were reduced in bushbabies with SIB, whereas serotonin concentrations were increased after 4 wk of treatment. Results indicate that L-tryptophan as a dietary supplement may be a viable adjunct to standard husbandry procedures for animals exhibiting maladaptive behaviors such as stereotypy and SIB.

Effects of phytoestrogens on sarcoplasmic/endoplasmic reticulum calcium ATPase 2a and Ca2+ uptake into cardiac sarcoplasmic reticulum.

Phytoestrogens are naturally occurring estrogenic compounds found in plants and plant products. These compounds are also known to exert cellular effects independent of their interactions with estrogen receptors. We studied the effects of the phytoestrogens phloretin, phloridzin, genistein, and biochanin A on Ca(2+) uptake into the cardiac muscle sarcoplasmic reticulum (SR). Genistein and biochanin A did not affect SR Ca(2+) uptake. On the other hand, phloretin and phloridzin decreased the maximum velocity of SR Ca(2+) uptake but did not affect the Hill coefficient or the Ca(2+) sensitivity of uptake. Measurements of the ATPase activity of the cardiac SR Ca(2+) pump (SERCA2a) revealed direct inhibitory effects of phloretin and phloridzin on SERCA2a. Neither compound induced a detectable change in the permeability of the SR membrane to Ca(2+). These results indicate that phloretin and phloridzin inhibit cardiac SR Ca(2+) uptake by directly inhibiting SERCA2a.

A consumer involvement model for health technology assessment in Canada.

Similar to other health policy initiatives, there is a growing movement to involve consumers in decisions affecting their treatment options. Access to treatments can be impacted by decisions made during a health technology assessment (HTA), i.e., the rigorous assessment of medical interventions such as drugs, vaccines, devices, materials, medical and surgical procedures and systems. The purpose of this paper was to empirically assess the interest and potential mechanisms for consumer involvement in HTA by identifying what health consumer organizations consider meaningful involvement, examining current practices internationally and developing a model for involvement based on identified priorities and needs. Canadian health consumer groups representing the largest disease or illness conditions reported a desire for involvement in HTA and provided feedback on mechanisms for facilitating their involvement.

Significant variations in differentiation properties between independent mouse ES cell lines cultured under defined conditions.

Mouse embryonic stem (ES) cells are isolated from the inner cell mass (ICM)/epiblast of preimplantation embryos and are widely used in cell differentiation studies. We have previously observed differences in transcript and antigen expression following differentiation of ES cells lines in vitro. We have investigated this further by comparing the differentiation characteristics of five independently derived ES cell lines cultured and differentiated under defined conditions. Undifferentiated ES cell lines exhibited similar morphology and antigen/transcript marker expression. However, upon differentiation in monolayer culture by LIF withdrawal, only two of the lines expressed similar germ layer transcript profiles, and these were significantly altered compared to differentiation in serum-supplemented media. Neurofilament-68k was the only transcript marker common to all cell lines, however, induction of neuroectoderm lineages using 1 microM all-trans retinoic acid (RA) resulted in significant variations in cell number and morphology between the lines. Furthermore, neurons were only formed from clones of the two cell lines that exhibited similar transcript profiles, although the morphology was different between the two. We conclude that the independent ES cell lines in this study differ in their response to alterations in culture conditions in vitro, and the use of an appropriate cell line enables relatively homogeneous neuronal populations to be achieved in monolayer culture under defined conditions.

Doctors' perceptions of palliative care for heart failure: focus group study.

OBJECTIVES: To identify doctors' perceptions of the need for palliative care for heart failure and barriers to change. DESIGN: Qualitative study with focus groups. SETTING: North west England. PARTICIPANTS: General practitioners and consultants in cardiology, geriatrics, palliative care, and general medicine. RESULTS: Doctors supported the development of palliative care for patients with heart failure with the general practitioner as a central figure. They were reluctant to endorse expansion of specialist palliative care services. Barriers to developing approaches to palliative care in heart failure related to three main areas: the organisation of health care, the unpredictable course of heart failure, and the doctors' understanding of roles. The health system was thought to work against provision of holistic care, exacerbated by issues of professional rivalry and control. The priorities identified for the future were developing the role of the nurse, better community support for primary care, and enhanced communication between all the health professionals involved in the care of patients with heart failure. CONCLUSIONS: Greater consideration should be given to the care of patients dying with heart failure, clarifying the roles of doctors and nurses in different specialties, and reshaping the services provided for them. Many of the organisational and professional issues are not peculiar to patients dying with heart failure, and addressing such concerns as the lack of coordination and continuity in medical care would benefit all patients.