Healthcare professionals' attitudes toward cancer precision medicine: A systematic review.

Use of precision medicine in oncology is burgeoning and can provide patients with new treatment options. However, it is not clear how precision medicine is impacting healthcare professionals (HCPs), particularly with regards to their concerns about this new approach. We therefore synthesized the existing literature on HCPs' attitudes toward cancer precision medicine. We searched four databases for relevant articles. Two reviewers screened eligible articles and extracted data. We assessed the quality of each article using the QualSyst tool. We found 22 articles, representing 4,321 HCPs (63.7% cancer specialists). HCPs held largely positive attitudes toward cancer precision medicine, including their capacity to facilitate treatment decisions and provide prognostic information. However, they also had concerns regarding costs, insurance coverage, limited HCP knowledge about precision medicine, potential misuse, difficulties accessing the tests, and delays in receiving test results. Most HCPs felt that test-related decisions should be shared between families and HCPs. HCPs intended to disclose actionable results but were less inclined to disclose negative/secondary findings. HCPs had a strong preference for genetic counselor involvement when disclosing germline findings. Most HCPs intended to use somatic and germline tests in their future practice but the extent to which pharmacogenomic tests will be used is uncertain. HCPs indicated that additional evidence supporting test utility and increased availability of treatment guidelines could facilitate the use of testing. HCPs held generally positive attitudes toward cancer precision medicine, however there were some key concerns. Addressing concerns early, devising educational support for HCPs and developing guidelines may facilitate the successful implementation of precision medicine trials in the future.

Protein engineering and preclinical development of a GM-CSF receptor antibody for the treatment of rheumatoid arthritis.

BACKGROUND AND PURPOSE: For antibody therapies against receptor targets, in vivo outcomes can be difficult to predict because of target-mediated clearance or antigen 'sink' effects. The purpose of this work was to engineer an antibody to the GM-CSF receptor α (GM-CSFRα) with pharmacological properties optimized for chronic, s.c. treatment of rheumatoid arthritis (RA) patients. EXPERIMENTAL APPROACH: We used an in silico model of receptor occupancy to guide the target affinity and a combinatorial phage display approach for affinity maturation. Mechanism of action and internalization assays were performed on the optimized antibody in vitro before refining the modelling predictions of the eventual dosing in man. Finally, in vivo pharmacology studies in cynomolgus monkeys were carried out to inform the predictions and support future clinical development. KEY RESULTS: Antibody potency was improved 8600-fold, and the target affinity was reached. The refined model predicted pharmacodynamic effects at doses as low as 1 mg kg(-1) and a study in cynomolgus monkeys confirmed in vivo efficacy at 1 mg kg(-1) dosing. CONCLUSIONS AND IMPLICATIONS: This rational approach to antibody drug discovery enabled the isolation of a potent molecule compatible with chronic, s.c. self-administration by RA patients. We believe this general approach enables the development of optimal biopharmaceuticals.

Factors associated with non-participation in a physical activity promotion trial.

BACKGROUND: Non-participation can bias outcome in intervention studies of physical activity. OBJECTIVES: To compare characteristics, knowledge and attitudes to physical activity in participants and non-participants of a physical activity intervention trial in primary care. STUDY DESIGN: Cross-sectional survey. METHODS: Patients aged 40-64 years were recruited opportunistically during surgery visits in an inner city general practice in Newcastle upon Tyne, UK. Attitudes to physical activity, views of its health benefits, and barriers to participation were elicited in interviews with participants, and by postal questionnaire from non-participants. Data held by general practitioners were used to compare anthropometry and lifestyle between groups. RESULTS: Of 842 eligible patients, 276 (33%) refused outright (non-volunteers) and 566 volunteered for the intervention study, of which 353 (42%) attended a baseline assessment and 213 (25%) subsequently defaulted. The initial refusal rate was higher amongst men, smokers and those with addresses in more deprived areas. The response rate to the postal survey of non-volunteers was 45%. Compared with participants, the non-volunteers were more likely to be an adult carer and to report poorer health, and were less likely to have had higher education or to have children living at home. Far more non-volunteers considered that they already did enough exercise to maintain health. Non-volunteers had slightly less knowledge of the benefits of physical activity; attached far less importance to it in maintaining health; were more likely to cite 'fear of leaving their home unattended', 'do not enjoy exercise' and 'poor health' as barriers to exercise; and were less likely to cite 'no one to exercise with' as a barrier to exercise. CONCLUSION: Recruitment of 'hard to engage' individuals requires careful phrasing of the message to focus on their personal goals and to address gaps in their knowledge about physical activity and the principal barriers they perceive. Differential uptake across population subgroups could lead to a widening of health inequalities.

Managing patient demand: a qualitative study of appointment making in general practice.

BACKGROUND: Managing patients' requests for appointments is an important general practice activity. No previous research has systematically observed how patients and receptionists negotiate appointments. AIM: To observe appointment making and investigate patients' and professionals' experiences of appointment negotiations. DESIGN OF STUDY: A qualitative study using participant observation. SETTING: Three general practices on Tyneside; a single-handed practice, a practice comprising three doctors, and a seven-doctor practice. METHOD: Participant observation sessions, consisting of 35 activity recordings and 34 periods of observation and 38 patient and 15 professional interviews, were set up. Seven groups of patients were selected for interview. These included patients attending an 'open access' surgery, patients who complained about making an appointment, and patients who complimented the receptionists. RESULTS: Appointment making is a complex social process. Outcomes are dependent on the process of negotiation and factors, such as patients' expectations and appointment availability. Receptionists felt that patients in employment, patients allocated to the practice by the Health Authority, and patients who did not comply with practice appointment rules were most demanding. Appointment requests are legitimised by receptionists enforcing practice rules and requesting clinical information. Patients volunteer information to provide evidence that their complaint is appropriate and employ strategies, such as persistence, assertiveness, and threats, to try and persuade receptionists to grant appointments. CONCLUSION: Appointment making is a complex social process where outcomes are negotiated. Receptionists have an important role in managing patient demand. Practices should be explicit about how appointments are allocated, including publishing practice criteria.

Prevalence of enduring and disabling mental illness in the inner city.

Previous research identifying the long-term mentally ill in primary care has been outside areas of deprivation. We used a case finding approach by a primary care group to identify the prevalence and characteristics of people with enduring and disabling mental ill health in a disadvantaged inner-city community. We found a high point prevalence (12.9 per 1000 patients) of enduring psychotic and non-psychotic illness (36.1% and 63.9% respectively). This contributed to considerable workload and disability, and included a significant proportion of older people (24.6% aged over 65 years). The approach may be useful for local needs assessment. It highlights a need to consider disability as well as diagnosis for service development.

The Newcastle exercise project: a randomised controlled trial of methods to promote physical activity in primary care.

OBJECTIVE: To evaluate the effectiveness of combinations of three methods to promote physical activity. DESIGN: Randomised controlled trial. Baseline assessment with post-intervention follow up at 12 weeks and 1 year. SETTING: One urban general practice, 1995-7. PARTICIPANTS: 523 adults aged 40 to 64 years, randomised to four intervention groups and a control group. INTERVENTIONS: Brief (one interview) or intensive (six interviews over 12 weeks) motivational interviewing based on the stages of change model of behaviour change, with or without financial incentive (30 vouchers entitling free access to leisure facilities). MAIN OUTCOME MEASURES: Physical activity score; sessions of moderate and vigorous activity in the preceding four weeks. RESULTS: Response rate was 81% at 12 weeks and 85% at one year. More participants in the intervention group reported increased physical activity scores at 12 weeks than controls (38% v 16%, difference 22%, 95% confidence interval for difference 13% to 32%), with a 55% increase observed in those offered six interviews plus vouchers. Vigorous activity increased in 29% of intervention participants and 11% of controls (difference 18%, 10% to 26%), but differences between the intervention groups were not significant. Short term increases in activity were not sustained, regardless of intensity of intervention. CONCLUSIONS: The most effective intervention for promoting adoption of exercise was the most intensive. Even this did not promote long term adherence to exercise. Brief interventions promoting physical activity that are used by many schemes in the United Kingdom are of questionable effectiveness.

DAN is a secreted glycoprotein related to Xenopus cerberus.

We report that DAN, a potential cell cycle regulator and tumour suppressor, is a secreted glycoprotein related to Xenopus cerberus. DAN, cerberus, its mouse relative Cer-1/cer-l/Cerberus-like/Cerr1, and the recently described factor DRM/Gremlin, appear to be members of the cystine knot superfamily, which includes TGFbetas and BMPs. Like cerberus and mCer-1, DAN-induced cement glands as well as markers of anterior neural tissue and endoderm in Xenopus animal cap assays, features of BMP signalling blockade. During mouse embryogenesis, Dan was expressed from E8.5 in cranial mesenchyme and somites, then later in limb and facial mesenchyme. The pattern in somites was highly dynamic, with transcripts initially localized to the caudal half of the nascent epithelial somite, then, after maturation, to sclerotomal cells adjacent to the neural tube. Dan was also expressed in the developing myotome. The expression domains include sites in which BMP inhibition is known to be important for development. Thus, DAN appears to be a secreted factor belonging to the cystine knot superfamily, and one of a growing number of antagonists acting to modulate BMP signalling during development.

Murine cerberus homologue mCer-1: a candidate anterior patterning molecule.

Xenopus cerberus (Xcer) is a cytokine expressed in anterior mesendoderm overlapping and surrounding Spemann's gastrula organiser. When misexpressed in blastomeres, Xcer can induce ectopic heads with well-defined brain, cement gland, olfactory placodes, cyclopic eye, and occasionally liver and heart. We report here the identification of mCer-1, a murine gene related to cerberus. Both mCer-1 and Xcer appear to belong to the cystine knot superfamily, which includes TGF beta s and BMPs. In Xenopus animal cap assays, mCer-1 and Xcer induced cement glands and markers of anterior neural tissue and endoderm, characteristic of BMP inhibition. Furthermore, both antagonised the ventrolateral mesoderm-inducing activity of coexpressed BMP4. In mouse embryos, mCer-1 was expressed at early gastrulation in a stripe of primitive endoderm along the future anterior side of the egg cylinder, a region essential for anterior patterning. A second phase of expression was detected in anterior embryonic mesendoderm, and by late-streak stages most of the anterior half of the embryo was positive, except for the node and cardiac progenitors. Expression was later seen in the cranial portion of the two most-recently formed somites and in two stripes within presomitic mesoderm. In embryos lacking Otx2, a homeogene with a demonstrated role in anterior patterning, mCer-1 was still expressed in an anterior zone, although often abnormally. The data suggest that mCer-1 shares structural, functional, and expression characteristics with Xcer and may participate in patterning the anterior of the embryo and nascent somite region, in part, through a BMP-inhibitory mechanism.

The prevention of psychological morbidity following perinatal death.

In recent years, a significant volume of hospital-based literature has been produced about the management of women and their families after a perinatal death. There has also been a considerable amount of work in the voluntary sector which has recognized this as an area of unmet need. The introduction of regional neonatal intensive care units and the shift from secondary to primary care make the development of a structured community-based approach for this group of vulnerable patients increasingly important. This article documents the evidence for high levels of psychological morbidity following perinatal death, reviews a variety of interventions designed to reduce morbidity, and makes some tentative proposals about the key elements of an effective community-based support programme.

Functional inactivation in mice of the gene for the interleukin-3 (IL-3)-specific receptor beta-chain: implications for IL-3 function and the mechanism of receptor transmodulation in hematopoietic cells.

The receptors for granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 and -5 (IL-3, IL-5) share a common signaling subunit (beta c). However, in the mouse, IL-3 can also use an alternative IL-3-specific receptor beta-chain (beta IL-3). To assess the relative contributions of beta c and beta IL-3 to IL-3 receptor formation and function, mice were generated in which the beta IL-3 gene was functionally inactivated by replacement of exons 9-13 with a neomycin resistance cassette. Bone marrow cells from these mice displayed a lower affinity IL-3 receptor than normal and were hyporesponsive to IL-3, but the mice displayed no obvious hematopoietic abnormalities. The data suggested that beta c and beta IL-3 are normally coexpressed on IL-3-responsive cells and have identical qualitative signaling capacities. Receptor transmodulation studies on bone marrow cells from wild-type, beta c -/-, and beta IL-3 -/- mice showed that the previously described hierarchical pattern of transmodulation was dependent on the relative numbers of both beta IL-3 and beta c receptor chains and also provided evidence for an unexpected interaction between beta c chains and G-CSF and M-CSF receptors.

Cloning and characterization of a novel human gene related to vascular endothelial growth factor.

This paper describes the cloning and characterization of a new member of the vascular endothelial growth factor (VEGF) gene family, which we have designated VRF for VEGF-related-factor. Sequencing of cDNAs from a human fetal brain library and RT-PCR products from normal and tumor tissue cDNA pools indicate two alternatively spliced messages with open reading frames of 621 and 564 bp, respectively. The predicted proteins differ at their carboxyl ends resulting from a shift in the open reading frame. Both isoforms show strong homology to VEGF at their amino termini, but only the shorter isoform maintains homology to VEGF at its carboxyl terminus and conserves all 16 cysteine residues of VEGF165. Similarity comparisons of this isoform revealed overall protein identity of 48% and conservative substitution of 69% with VEGF189. VRF is predicted to contain a signal peptide, suggesting that it may be a secreted factor. The VRF gene maps to the D11S750 locus at chromosome band 11q13, and the protein coding region, spanning approximately 5 kb, is comprised of 8 exons that range in size from 36 to 431 bp. Exons 6 and 7 are contiguous and the two isoforms of VRF arise through alternate splicing of exon 6. VRF appears to be ubiquitously expressed as two transcripts of 2.0 and 5.5 kb; the level of expression is similar among normal and malignant tissues.

Hematopoietic and lung abnormalities in mice with a null mutation of the common beta subunit of the receptors for granulocyte-macrophage colony-stimulating factor and interleukins 3 and 5.

Gene targeting was used to create mice with a null mutation of the gene encoding the common beta subunit (beta C) of the granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 3 (IL-3; multi-CSF), and interleukin 5 (IL-5) receptor complexes (beta C-/- mice). High-affinity binding of GM-CSF was abolished in beta C-/- bone marrow cells, while cells from heterozygous animals (beta C+/- mice) showed an intermediate number of high-affinity receptors. Binding of IL-3 was unaffected, confirming that the IL-3-specific beta chain remained intact. Eosinophil numbers in peripheral blood and bone marrow of beta C-/- animals were reduced, while other hematological parameters were normal. In clonal cultures of beta C-/- bone marrow cells, even high concentrations of GM-CSF and IL-5 failed to stimulate colony formation, but the cells exhibited normal quantitative responsiveness to stimulation by IL-3 and other growth factors. beta C-/- mice exhibited normal development and survived to young adult life, although they developed pulmonary peribronchovascular lymphoid infiltrates and areas resembling alveolar proteinosis. There was no detectable difference in the systemic clearance and distribution of GM-CSF between beta C-/- and wild-type littermates. The data establish that beta C is normally limiting for high-affinity binding of GM-CSF and demonstrate that systemic clearance of GM-CSF is not mediated via such high-affinity receptor complexes.

Optimal timing of wound drain removal following total joint arthroplasty.

Closed suction drains reduce postoperative hematoma formation, but create an entry portal for bacteria and thus increase the risk of infection. This study attempts to establish when the risks of wound drainage outweigh the benefits. In a prospective clinical trial, wound drains were used in all patients having a total knee or total hip arthroplasty. Timing of drain removal and amount drained were recorded. Drain-site swabs were sent with drain tips for bacteriology. Results suggest that the likelihood of bacterial colonization increases while wound drainage decreases with time. The authors conclude that the optimal time to remove drains is 24 hours after total joint arthroplasty.

Khat chewing delays gastric emptying of a semi-solid meal.

BACKGROUND: The leaves of Khat are chewed for their central stimulant effect, but their use may cause anorexia and constipation. METHODS: Gastric emptying of a radio-labelled semi-solid meal was measured in 12 healthy volunteers on two occasions a week apart. Subjects chewed either Khat leaves (Catha edulis) or lettuce for 2 h before the study. RESULTS: Gastric emptying was significantly (P < 0.02) prolonged after chewing Khat compared with lettuce. CONCLUSION: The sympathomimetic action of cathinone in Khat may cause the observed delay in gastric emptying.

The carboxyl terminus of nerve growth factor is required for biological activity.

A series of mouse nerve growth factor (NGF) deletion mutants have been constructed using in vitro mutagenesis to define domains of the protein essential for its activity. Deletions of the amino or carboxyl termini of mature NGF or of an internal domain, which normally produces a surface-exposed reverse turn, have been analyzed. Mutants with deletions in the amino terminus or in the reverse turn retain significant biological activity, whereas, in contrast, a mutant NGF lacking the seven most carboxyl-terminal amino acids is appropriately synthesized but shows no measurable biological activity. These results suggests that the flexible carboxyl tail of NGF, and perhaps other neurotrophins, plays a crucial role in mediating receptor recognition and/or ligand binding.

The family study: a model for integrating the individual and community perspective in medical education.

The principles of and experience with a family study and survey undertaken by first-year medical students are reported. The family study is based on the observations made by pairs of students on a selected family, which includes a pregnant mother, in the Newcastle upon Tyne area. These observations include the family context, the pregnancy, the early development of the new-born baby, and the use of health and other services. The family survey records and analyses relevant data on the collective group of selected families. The family study acts as a preparation for clinical understanding by emphasizing the individual or family view. In addition, students learn that the collective epidemiological approach provided by the survey can guide the clinical impression gained from the observational study, yet each individual and family remains unique. An early opportunity is therefore provided for students to explore and integrate these two approaches.