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Keele University School of Medicine opened in 2002, initially delivering the Manchester MB ChB curriculum, with the aim that from 2007 it would deliver a 'distinctive Keele curriculum' which would 'graduate excellent clinicians'. This curriculum would be spiral and integrated in design, and delivered by a 'hybrid' model of learning methods, from small group interactive (including problem-based learning) through to large group and more didactic methods. It would be student-centred and include a strong focus on community and primary care contexts, the latter reflecting the origins of the university which grew out of the Workers' Education Alliance after the Second World War as the University College of North Staffordshire, becoming the University of Keele in 1962. The university has always had strong links with the Potteries and North Staffordshire, communities with long-standing problems of poor health status and recruitment of the necessary health workforce. While there are strong local drivers for medical students learning in and with the community, this is in a broader context of primary care becoming an increasingly important resource for medical undergraduate education arising from policy, health service and andragogy. We were charged with the responsibility of developing the community element of the curriculum. This paper describes the systematic development of our general practice curriculum from 2007 to the present. We describe the decisions we made and general practice's current contribution to the curriculum. We will present our evaluation of the curriculum in a separate paper.

The use of C57BL/6 Rag2(-/-)γc(-/-) mice as recipients for xenotransplantation with human immune systems (humanization) has been problematic because C57BL/6 SIRPα does not recognize human CD47, and such recognition is required to suppress macrophage-mediated phagocytosis of transplanted human hematopoietic stem cells (HSCs). We show that genetic inactivation of CD47 on the C57BL/6 Rag2(-/-)γc(-/-) background negates the requirement for CD47-signal recognition protein α (SIRPα) signaling and induces tolerance to transplanted human HSCs. These triple-knockout, bone marrow, liver, thymus (TKO-BLT) humanized mice develop organized lymphoid tissues including mesenteric lymph nodes, splenic follicles and gut-associated lymphoid tissue that demonstrate high levels of multilineage hematopoiesis. Importantly, these mice have an intact complement system and showed no signs of graft-versus-host disease (GVHD) out to 29 weeks after transplantation. Sustained, high-level HIV-1 infection was observed via either intrarectal or intraperitoneal inoculation. TKO-BLT mice exhibited hallmarks of human HIV infection including CD4(+) T-cell depletion, immune activation, and development of HIV-specific B- and T-cell responses. The lack of GVHD makes the TKO-BLT mouse a significantly improved model for long-term studies of pathogenesis, immune responses, therapeutics, and vaccines to human pathogens.

Contains fulltext : 170105.pdf (Publisher’s version ) (Closed access) OBJECTIVE: We aimed to observe how an Option Grid decision aid for clinical encounters might be used where an interpreter is present, and to assess the impact of its use on shared decision making. METHODS: Data were available from three clinical consultations between patient, clinician (a physiotherapist), and interpreter about knee osteoarthritis. Clinicians were trained in the use of an Option Grid decision aid and the tool was used. Consultations were audio-recorded, transcribed, and translated by independent translators into English. RESULTS: Analysis revealed the difficulties with introducing a written decision aid into an interpreted consultation. The extra discussion needed between the clinician and interpreter around the principles and purpose of shared decision making and instructions regarding the Option Grid decision aid proved challenging and difficult to manage. Discussion of treatment options while using an Option Grid decision aid was predominantly done between clinician and interpreter. The patient appeared to have little involvement in discussion of treatment options. CONCLUSION: Patients were not active participants within the discussion. Further work needs to be done on how shared decision making can be achieved within interpreted consultations. PRACTICE IMPLICATIONS: Option Grid decision aids are not being used as intended in interpreted consultations.

Tauopathies are a family of neurodegenerative diseases in which fibrils of human hyperphosphorylated tau (P-tau) are believed to cause neuropathology. In Alzheimer disease, P-tau associates with A-beta amyloid and contributes to disease pathogenesis. In familial human prion diseases and variant CJD, P-tau often co-associates with prion protein amyloid, and might also accelerate disease progression. To test this latter possibility, here we compared progression of amyloid prion disease in vivo after scrapie infection of mice with and without expression of human tau. The mice used expressed both anchorless prion protein (PrP) and membrane-anchored PrP, that generate disease associated amyloid and non-amyloid PrP (PrPSc) after scrapie infection. Human P-tau induced by scrapie infection was only rarely associated with non-amyloid PrPSc, but abundant human P-tau was detected at extracellular, perivascular and axonal deposits associated with amyloid PrPSc. This pathology was quite similar to that seen in familial prion diseases. However, association of human and mouse P-tau with amyloid PrPSc did not diminish survival time following prion infection in these mice. By analogy, human P-tau may not affect prion disease progression in humans. Alternatively, these results might be due to other factors, including rapidity of disease, blocking effects by mouse tau, or low toxicity of human P-tau in this model.

Hypochlorous acid (HOCl) is produced naturally by neutrophils and other cells to kill conventional microbes in vivo. Synthetic preparations containing HOCl can also be effective as microbial disinfectants. Here we have tested whether HOCl can also inactivate prions and other self-propagating protein amyloid seeds. Prions are deadly pathogens that are notoriously difficult to inactivate, and standard microbial disinfection protocols are often inadequate. Recommended treatments for prion decontamination include strongly basic (pH ≥~12) sodium hypochlorite bleach, ≥1 N sodium hydroxide, and/or prolonged autoclaving. These treatments are damaging and/or unsuitable for many clinical, agricultural and environmental applications. We have tested the anti-prion activity of a weakly acidic aqueous formulation of HOCl (BrioHOCl) that poses no apparent hazard to either users or many surfaces. For example, BrioHOCl can be applied directly to skin and mucous membranes and has been aerosolized to treat entire rooms without apparent deleterious effects. Here, we demonstrate that immersion in BrioHOCl can inactivate not only a range of target microbes, including spores of Bacillus subtilis, but also prions in tissue suspensions and on stainless steel. Real-time quaking-induced conversion (RT-QuIC) assays showed that BrioHOCl treatments eliminated all detectable prion seeding activity of human Creutzfeldt-Jakob disease, bovine spongiform encephalopathy, cervine chronic wasting disease, sheep scrapie and hamster scrapie; these findings indicated reductions of ≥103- to 106-fold. Transgenic mouse bioassays showed that all detectable hamster-adapted scrapie infectivity in brain homogenates or on steel wires was eliminated, representing reductions of ≥~105.75-fold and >104-fold, respectively. Inactivation of RT-QuIC seeding activity correlated with free chlorine concentration and higher order aggregation or destruction of proteins generally, including prion protein. BrioHOCl treatments had similar effects on amyloids composed of human α-synuclein and a fragment of human tau. These results indicate that HOCl can block the self-propagating activity of prions and other amyloids., Author Summary Many serious diseases have been linked to pathogenic states of various proteins. These naturally occurring proteins can be corrupted to form aggregates such as prions and amyloids that propagate in and between tissues by acting as seeds that convert the normal form of the protein into more of the pathological form. For example, corrupted prion protein can cause fatal transmissible neurodegenerative diseases such as Creutzfeldt-Jakob disease in humans, chronic wasting disease in cervids and bovine spongiform encephalopathy. Other amyloid-forming protein aggregates are pathogenic in Parkinson’s, Alzheimer’s, and other diseases. The fact that prions and amyloids are composed predominantly of tough, tightly packed proteins makes them unusually resistant to conventional microbial disinfection procedures. Infectious prions can persist indefinitely in, or on, a variety of materials such as tissues, fluids, tools, instruments, and environmental surfaces, making it important to identify decontaminants that are effective without being dangerous or damaging. Here we show that hypochlorous acid, a disinfectant that is produced naturally by certain cells within the body, has strong anti-prion and anti-amyloid activity. We find that a non-irritating and broadly applicable hypochlorous acid preparation can disinfect prions in tissue homogenates and on stainless steel wires serving as surrogates for surgical instruments.

Amyloid hexapeptide molecules are effective in the treatment of the murine model of neuroinflammation, known as experimental autoimmune encephalomyelitis (EAE). Efficacy however differs between two inbred mouse strains, C57BL/6J (B6) and C57BL/10SnJ (B10). Amyloid hexapeptide treatments improved the clinical outcomes of B6, but not B10 mice, indicating that genetic background influences therapeutic efficacy. Moreover, although previous studies indicated that prion protein deficiency results in more severe EAE in B6 mice, we observed no such effect in B10 mice. In addition, we found that amyloid hexapeptide treatments of B10 and B6 mice elicited differential IL4 responses. Thus, the modulatory potential of prion protein and related treatments with other amyloid hexapeptides in EAE depends on mouse strain.

Neurodegenerative diseases are typically associated with an activation of glia and an increased level of cytokines. In our previous studies of prion disease, the cytokine response in the brains of clinically sick scrapie-infected mice was restricted to a small group of cytokines, of which IL-12p40, CCL2, and CXCL10 were present at the highest levels. The goal of our current research was to determine the relationship between cytokine responses, gliosis, and neuropathology during prion disease. Here, in time course studies of C57BL/10 mice intracerebrally inoculated with 22L scrapie, abnormal protease-resistant prion protein (PrPres), astrogliosis, and microgliosis were first detected at 40 days after intracerebral scrapie inoculation. In cytokine studies, IL-12p40 was first elevated by 60 days; CCL3, IL-1β, and CXCL1 were elevated by 80 days; and CCL2 and CCL5 were elevated by 115 days. IL-12p40 showed the most extensive increase throughout disease and was 30-fold above control levels at the terminal stage. Because of the early onset and dramatic elevation of IL-12p40 during scrapie, we investigated whether IL-12p40 contributed to the development of prion disease neuropathogenesis by using three different scrapie strains (22L, RML, 79A) to infect knockout mice in which the gene encoding IL-12p40 was deleted. We also studied knockout mice lacking IL-12p35, which combines with IL-12p40 to form active IL-12 heterodimers. In all instances, knockout mice did not differ from control mice in survival time, clinical tempo, or levels of spongiosis, gliosis, or PrPres in the brain. Thus, neither IL-12p40 nor IL-12p35 molecules were required for prion disease-associated neurodegeneration or neuroinflammation.

Prion protein (PrP) is found in all mammals, mostly as a glycoprotein anchored to the plasma membrane by a C-terminal glycosylphosphatidylinositol (GPI) linkage. Following prion infection, host protease-sensitive prion protein (PrPsen or PrPC) is converted into an abnormal, disease-associated, protease-resistant form (PrPres). Biochemical characteristics, such as the PrP amino acid sequence, and posttranslational modifications, such as glycosylation and GPI anchoring, can affect the transmissibility of prions as well as the biochemical properties of the PrPres generated. Previous in vivo studies on the effects of GPI anchoring on prion infectivity have not examined cross-species transmission. In this study, we tested the effect of lack of GPI anchoring on a species barrier model using mice expressing human PrP. In this model, anchorless 22L prions derived from tg44 mice were more infectious than 22L prions derived from C57BL/10 mice when tested in tg66 transgenic mice, which expressed wild-type anchored human PrP at 8- to 16-fold above normal. Thus, the lack of the GPI anchor on the PrPres from tg44 mice appeared to reduce the effect of the mouse-human PrP species barrier. In contrast, neither source of prions induced disease in tgRM transgenic mice, which expressed human PrP at 2- to 4-fold above normal. IMPORTANCE Prion protein (PrP) is found in all mammals, usually attached to cells by an anchor molecule called GPI. Following prion infection, PrP is converted into a disease-associated form (PrPres). While most prion diseases are species specific, this finding is not consistent, and species barriers differ in strength. The amino acid sequence of PrP varies among species, and this variability affects prion species barriers. However, other PrP modifications, including glycosylation and GPI anchoring, may also influence cross-species infectivity. We studied the effect of PrP GPI anchoring using a mouse-to-human species barrier model. Experiments showed that prions produced by mice expressing only anchorless PrP were more infectious than prions produced in mice expressing anchored PrP. Thus, the lack of the GPI anchor on prions reduced the effect of the mouse-human species barrier. Our results suggest that prion diseases that produce higher levels of anchorless PrP may pose an increased risk for cross-species infection.

Viral neuroinvasion is a critical step in the pathogenesis of viral encephalitis. Multiple mechanisms of neuroinvasion have been identified, but their relative contribution to central nervous system (CNS) infection remains unclear for many viruses. In this study, we examined neuroinvasion of the mosquito-borne bunyavirus La Crosse (LACV), the leading cause of pediatric viral encephalitis in the USA. We found that the olfactory bulb (OB) and tract were the initial areas of CNS virus infection in mice. Removal of the OB reduced the incidence of LACV-induced disease demonstrating the importance of this area to neuroinvasion. However, we determined that infection of the OB was not due to axonal transport of virus from olfactory sensory neurons as ablation of these cells did not affect viral pathogenesis. Instead, we found that OB capillaries were compromised allowing leakage of virus-sized particles into the brain. Analysis of OB capillaries demonstrated specific alterations in cytoskeletal and Rho GTPase protein expression not observed in capillaries from other brain areas such as the cortex where leakage did not occur. Collectively, these findings indicate that LACV neuroinvasion occurs through hematogenous spread in specific brain regions where capillaries are prone to virus-induced activation such as the OB. Capillaries in these areas may be “hot spots” that are more susceptible to neuroinvasion not only for LACV, but other neurovirulent viruses as well.

Gliosis is often a preclinical pathological finding in neurodegenerative diseases, including prion diseases, but the mechanisms facilitating gliosis and neuronal damage in these diseases are not understood. To expand our knowledge of the neuroinflammatory response in prion diseases, we assessed the expression of key genes and proteins involved in the inflammatory response and signal transduction in mouse brain at various times after scrapie infection. In brains of scrapie-infected mice at pre- and postclinical stages, we identified 15 previously unreported differentially expressed genes related to inflammation or activation of the STAT signal transduction pathway. Levels for the majority of differentially expressed genes increased with time postinfection. In quantitative immunoblotting experiments of STAT proteins, STAT1α, phosphorylated-STAT1α (pSTAT1α), and pSTAT3 were increased between 94 and 131 days postinfection (p.i.) in brains of mice infected with strain 22L. Furthermore, a select group of STAT-associated genes was increased preclinically during scrapie infection, suggesting early activation of the STAT signal transduction pathway. Comparison of inflammatory markers between mice infected with scrapie strains 22L and RML indicated that the inflammatory responses and gene expression profiles in the brains were strikingly similar, even though these scrapie strains infect different brain regions. The endogenous interleukin-1 receptor antagonist (IL-1Ra), an inflammatory marker, was newly identified as increasing preclinically in our model and therefore might influence scrapie pathogenesis in vivo . However, in IL-1Ra-deficient or overexpressor transgenic mice inoculated with scrapie, neither loss nor overexpression of IL-1Ra demonstrated any observable effect on gliosis, protease-resistant prion protein (PrPres) formation, disease tempo, pathology, or expression of the inflammatory genes analyzed. IMPORTANCE Prion infection leads to PrPres deposition, gliosis, and neuroinflammation in the central nervous system before signs of clinical illness. Using a scrapie mouse model of prion disease to assess various time points postinoculation, we identified 15 unreported genes that were increased in the brains of scrapie-infected mice and were associated with inflammation and/or JAK-STAT activation. Comparison of mice infected with two scrapie strains (22L and RML), which have dissimilar neuropathologies, indicated that the inflammatory responses and gene expression profiles in the brains were similar. Genes that increased prior to clinical signs might be involved in controlling scrapie infection or in facilitating damage to host tissues. We tested the possible role of the endogenous IL-1Ra, which was increased at 70 days p.i. In scrapie-infected mice deficient in or overexpressing IL-1Ra, there was no observable effect on gliosis, PrPres formation, disease tempo, pathology, or expression of inflammatory genes analyzed.

Background In humans and animals, prion protein (PrP) is usually expressed as a glycophosphatidylinositol (GPI)-anchored membrane protein, but anchorless PrP may be pathogenic in humans with certain familial prion diseases. Anchored PrP expressed on neurons mediates spread of prions along axons in the peripheral and central nervous systems. However, the mechanism of prion spread in individuals expressing anchorless PrP is poorly understood. Here we studied prion spread within brain of mice expressing anchorless or anchored PrP. Results To create a localized initial point of infection, we microinjected scrapie in a 0.5 microliter volume in the striatum. In this experiment, PrPres and gliosis were first detected in both types of mice at 40 days post-inoculation near the needle track. In mice with anchored PrP, PrPres appeared to spread via neurons to distant connected brain areas by the clinical endpoint at 150 days post-inoculation. This PrPres was rarely associated with blood vessels. In contrast, in mice with anchorless PrP, PrPres spread did not follow neuronal circuitry, but instead followed a novel slower pattern utilizing the drainage system of the brain interstitial fluid (ISF) including perivascular areas adjacent to blood vessels, subependymal areas and spaces between axons in white matter tracts. Conclusions In transgenic mice expressing anchorless PrP small amyloid-seeding PrPres aggregates appeared to be transported in the ISF, thus spreading development of cerebral amyloid angiopathy (CAA) throughout the brain. Spread of amyloid seeding by ISF may also occur in multiple human brain diseases involving CAA.

Background. Nurses in primary care, who see a large proportion of the population, are well placed to discuss weight with patients and offer management advice. Interventions to promote weight loss have shown that there are effective ways of making small changes for patients. Objectives. To use qualitative semi-structured interviews to explore how practice nurses manage obesity within primary care and to identify good practice and explore barriers to achieving effective management. Methods. Eighteen semi-structured interviews were conducted with practice nurses within two local health board areas in South Wales. Interviews were audio-recorded, transcribed and analysed qualitatively using a thematic approach. Results. Nurses described two roles. One role was providing obesity management to patients who had co-morbid conditions and were seen regularly in chronic disease clinics. All nurses perceived that these patients needed their weight addressing routinely. The other role was to broach the subject with overweight but healthy patients. Nurses were of divided opinion whether to address obesity with these patients and what primary care had to offer. Weight management advice, when given, lacked consistency of approach. Conclusions. Broaching the subject of weight opportunistically with healthy but overweight patients may require a deeper appreciation of their motivations for change and discussion beyond future health risks. These patients also need clearer follow up to monitor their progress with weight loss. All overweight patients also need clearer guidance tailored to their own particular circumstances as to how to lose weight. For patients being counselled about their weight, interventions that promote consistency of advice are advocated to improve care.

Objective To systematically review audio-visual (AV) interventions for promoting informed consent (IC) in clinical practice and to consider the impact of reading age adjustment. Methods Systematic review of randomized controlled trials (RCTs) comparing AV interventions to standard IC in clinical practice. Outcomes included recall (immediate 14 days), satisfaction and anxiety. Data were synthesized using random effects meta-analyses. Comparisons were made between studies that did and did not adjust for participant reading age. Results Of 11,813 abstracts screened, 29 RCTs were eligible (30 intervention arms). Interventions included videos (n = 17), computer programs (n = 5), electronic presentations (n = 3), compact discs (n = 3) and websites (n = 2). Meta-analysis showed AV interventions improved immediate recall (standardized mean difference [SMD] 0.64, 95% confidence interval [CI] 0.45–0.85). Results for intermediate and late recall were too heterogeneous to synthesize. AV interventions did not consistently affect either satisfaction or anxiety. Adjusting the reading age of interventions improved immediate recall (reading age interventions: adjusted SMD 1.21, 95%CI 0.81–1.61; non-reading age adjusted SMD 0.51, 95%CI 0.36–0.66). Conclusion AV interventions, especially those adjusted for participant reading age, improve immediate information recall for IC. Practice implications Wider use of AV aids is justified when obtaining IC in clinical practice.

Background: As obesity levels increase, opportunistic behaviour change counselling from primary care clinicians in consultations about healthy eating is ever more important. However, little is known about the approaches clinicians take with patients. Aim: To describe the content of simulated consultations on healthy eating in primary care, and compare this with the content of smoking cessation consultations. Design and setting: Qualitative study of 23 audiotaped simulated healthy eating and smoking cessation consultations between an actor and primary care clinicians (GPs and nurses) within a randomised controlled trial looking at behaviour change counselling. Method: Consultations were audiotaped and transcribed verbatim, then analysed inductively using thematic analysis. A thematic framework was developed by all authors and applied to the data. The content of healthy eating consultations was contrasted with that given for smoking cessation. Results: There was a lack of consistency and clarity when clinicians discussed healthy eating compared with smoking; in smoking cessation consultations, the content was clearer to both the clinician and patient. There was a lack of specificity about what dietary changes should be made, how changes could be achieved, and how progress could be monitored. Barriers to change were addressed in more depth within the smoking cessation consultations than within the healthy eating encounters. Conclusion: At present, dietary counselling by clinicians in primary care does not typically contain consistent, clear suggestions for specific change, how these could be achieved, and how progress would be monitored. This may contribute to limited uptake and efficacy of dietary counselling in primary care.

Tumor-draining lymph node (TDLN) cells develop substantial antitumor activity after activation on immobilized αCD3 and culture in low-dose IL-2. This study found that the minor subset of TDLN T cells expressing binding sites for the adhesion receptor P-selectin (Plighigh T cells) produced T lymphoblasts with the most tumor-specific IFN-γ synthesis in vitro and antitumor activity following adoptive transfer in vivo. The Plighigh T cells constituted 30-fold more active than cultured TDLN cells depleted of the Plighigh fraction before expansion (Pliglow cells). Tumor-specific IFN-γ synthesis in vitro paralleled the antitumor activities of the cultured fractions in vivo, implying that increased Tc1 and Th1 effector functions contributed to the tumor suppression. Neither nonspecific interaction with the P-selectin chimera used for sorting nor endogenous costimulatory activity in the Plighigh fraction accounted for the marked increase in antitumor activities after culture. The cultured Plighigh fraction contained a variety of potential effector cells; however, the CD8 and CD4 subsets of αβ T cells accounted for 95–97% of its antitumor activity. The authors propose that P-selectin sorting increased antitumor activities by concentrating Tc1 and Th1 pre-effector/effector cells before culture.

Background: Informed consent is required before any surgery or invasive procedure is performed. Achieving ethically valid informed consent can be difficult: too little information may leave patients poorly informed and too much information may be overwhelming. As such interventions to promote information provision for informed consent are warranted. This study aimed to evaluate the impact of such interventions on a range of outcomes including patient knowledge, anxiety, and satisfaction. Methods: Medical databases were searched using keywords and subject headings (Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, PsycINFO). Reference lists of included studies were searched. Randomised controlled trials (RCTs) of interventions to promote informed consent for patients undergoing surgical or invasive procedures were included. Studies were dual-assessed. Random effects meta-analyses were conducted for all outcomes with sufficient information. Standardised mean differences summarised the output. Narrative synthesis was also performed. Results: 65 RCTs were identified from 12 countries. In total 9,021 patients were randomised into these trials. Interventions employed various formats including written material, audio-visual tools and decision aids. Meta-analyses demonstrated statistically significant improvements in knowledge when measured immediately after interventions, shortly afterwards (between 24 hours and 15 days) and at a later date (15 days or more) (Immediate knowledge SMD 0.53 [95% CI 0.37, 0.69], I2 73%; Short-term knowledge SMD 0.68 [0.42, 0.93], I2 85%; Long-term knowledge SMD 0.78 [0.50, 1.06], I2 82%). Satisfaction with decision making also improved (SMD 2.25 [1.36, 3.15], I2 99% and decisional conflict was reduced (SMD -1.80 [-3.46, -0.14], I2 99%). No statistically significant differences were found for generalised anxiety, anxiety with the consent process or satisfaction with the consent process (generalised anxiety SMD -0.11 [-0.35, -0.01], I2 82%, anxiety with the consent process SMD 0.01 [-0.21, 0.23], I2 70%; satisfaction with the consent process SMD 0.12 [-0.09, 0.32], I2 76%). Conclusion: Interventions to promote informed consent consistently improve patient knowledge, an important prerequisite for informed consent and this is achieved without any significant harmful effects. Such interventions can thus be considered effective at promoting informed consent for invasive healthcare procedures. Further studies are necessary to investigate all aspects of informed consent as a unified concept.

Background. Achieving informed consent is a core clinical procedure and is required before any surgical or invasive procedure is undertaken. However, it is a complex process which requires patients be provided with information which they can understand and retain, opportunity to consider their options, and to be able to express their opinions and ask questions. There is evidence that at present some patients undergo procedures without informed consent being achieved. Objectives. To assess the effects on patients, clinicians and the healthcare system of interventions to promote informed consent for patients undergoing surgical and other invasive healthcare treatments and procedures. Search methods. We searched the following databases using keywords and medical subject headings: Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 5, 2012), MEDLINE (OvidSP) (1950 to July 2011), EMBASE (OvidSP) (1980 to July 2011) and PsycINFO (OvidSP) (1806 to July 2011). We applied no language or date restrictions within the search. We also searched reference lists of included studies. Selection criteria. Randomised controlled trials and cluster randomised trials of interventions to promote informed consent for patients undergoing surgical and other invasive healthcare procedures. We considered an intervention to be intended to promote informed consent when information delivery about the procedure was enhanced (either by providing more information or through, for example, using new written materials), or if more opportunity to consider or deliberate on the information was provided. Data collection and analysis. Two authors assessed the search output independently to identify potentially-relevant studies, selected studies for inclusion, and extracted data. We conducted a narrative synthesis of the included trials, and meta-analyses of outcomes where there were sufficient data. Main results. We included 65 randomised controlled trials from 12 countries involving patients undergoing a variety of procedures in hospitals. Nine thousand and twenty one patients were randomised and entered into these studies. Interventions used various designs and formats but the main data for results were from studies using written materials, audio-visual materials and decision aids. Some interventions were delivered before admission to hospital for the procedure while others were delivered on admission. Only one study attempted to measure the primary outcome, which was informed consent as a unified concept, but this study was at high risk of bias. More commonly, studies measured secondary outcomes which were individual components of informed consent such as knowledge, anxiety, and satisfaction with the consent process. Important but less commonly-measured outcomes were deliberation, decisional conflict, uptake of procedures and length of consultation. Meta-analyses showed statistically-significant improvements in knowledge when measured immediately after interventions (SMD 0.53 (95% CI 0.37 to 0.69) I2 73%), shortly afterwards (between 24 hours and 14 days) (SMD 0.68 (95% CI 0.42 to 0.93) I2 85%) and at a later date (15 days or more) (SMD 0.78 (95% CI 0.50 to 1.06) I2 82%). Satisfaction with decision making was also increased (SMD 2.25 (95% CI 1.36 to 3.15) I2 99%) and decisional conflict was reduced (SMD -1.80 (95% CI -3.46 to -0.14) I2 99%). No statistically-significant differences were found for generalised anxiety (SMD -0.11 (95% CI -0.35 to 0.13) I2 82%), anxiety with the consent process (SMD 0.01 (95% CI -0.21 to 0.23) I2 70%) and satisfaction with the consent process (SMD 0.12 (95% CI -0.09 to 0.32) I2 76%). Consultation length was increased in those studies with continuous data (mean increase 1.66 minutes (95% CI 0.82 to 2.50) I2 0%) and in the one study with non-parametric data (control 8.0 minutes versus intervention 11.9 minutes, interquartile range (IQR) of 4 to 11.9 and 7.2 to 15.0 respectively). There were limited data for other outcomes. In general, sensitivity analyses removing studies at high risk of bias made little difference to the overall results. Authors' conclusions. Informed consent is an important ethical and practical part of patient care. We have identified efforts by researchers to investigate interventions which seek to improve information delivery and consideration of information to enhance informed consent. The interventions used consistently improve patient knowledge, an important prerequisite for informed consent. This is encouraging and these measures could be widely employed although we are not able to say with confidence which types of interventions are preferable. Our results should be interpreted with caution due to the high levels of heterogeneity associated with many of the main analyses although we believe there is broad evidence of beneficial outcomes for patients with the pragmatic application of interventions. Only one study attempted to measure informed consent as a unified concept.

This paper is an attempt to answer the question of how to help undergraduate medical students learn about the principles of long-term healthcare management. The authors are concerned that undergraduate medical students are often not formally taught about this matter except from the purely technical aspects of longitudinal healthcare provision, and that it is necessary to be aware of certain issues as undergraduate students to facilitate improved expertise as they become qualified doctors. The authors suggest that the topic requires consideration in light of newer concepts of the role and value of long-term health care for patients in general. The authors propose several ideas about how to achieve this in small group settings, and this paper includes a series of points for discussion within these groups. The list of issues to be discussed includes encouragement for all teachers to discuss long-term healthcare issues with undergraduate medical students, how to develop and maintain positive working relationships over multiple clinical encounters, to be aware of the overall concepts of doctoring, holding relationships, spiritual values within long-term healthcare, and heartsink. The authors hope this novel addition to the curriculum will prove useful as an adjunct to student learning about professional roles.

Chapter 6 examines Cambridge’s performance at a regional and national level. Cambridge’s position relative to other leading towns nearby, such as Ely, Bury St Edmunds, King’s Lynn, Huntingdon and St Ives, is examined. The competitiveness of its market is evaluated through assessment of its transport connections and the local charters for market and fairs in the Cambridge area. Once again new information is brought to bear on the subject; in this case the account rolls of the Merton manor in Cambridge, previously owned by the Dunning family and subsequently acquired by Walter de Merton for the endowment of Merton College, Oxford. The chapter demonstrates the dominance of Cambridge market in the local economy. The strength of this market, combined with the town’s control of the export-oriented river trade, assured its leading position in local trade and contributed to attracting investors from the local region and beyond.

Chapter 7 connects the book to work on the subsequent history of Cambridge, including that on the development of the University. It considers the extent to which trends identified in the Hundred Rolls continued into the fourteenth century. Cambridge adjusted to the decline in its agricultural trade after the Black Death by developing its service sector, linked to university education. The role of family dynasties remained significant, but the period was characterised by the growth of three key institutions – the borough corporation, the guilds, and the colleges. College property holdings increased, driven by increasing student numbers, and the colleges gradually obtained rights to the meadows adjoining the river to the west of the town. The foundation of King’s College transformed the street plan in the west of Cambridge, obliterating many ancient streets and buildings, but providing new economic opportunities to supply the academic community.