Caveolae in ventricular myocytes are required for stretch-dependent conduction slowing.

Mechanical stretch of cardiac muscle modulates action potential propagation velocity, causing potentially arrhythmogenic conduction slowing. The mechanisms by which stretch alters cardiac conduction remain unknown, but previous studies suggest that stretch can affect the conformation of caveolae in myocytes and other cell types. We tested the hypothesis that slowing of action potential conduction due to cardiac myocyte stretch is dependent on caveolae. Cardiac action potential propagation velocities, measured by optical mapping in isolated mouse hearts and in micropatterned mouse cardiomyocyte cultures, decreased reversibly with volume loading or stretch, respectively (by 19±5% and 26±4%). Stretch-dependent conduction slowing was not altered by stretch-activated channel blockade with gadolinium or by GsMTx-4 peptide, but was inhibited when caveolae were disrupted via genetic deletion of caveolin-3 (Cav3 KO) or membrane cholesterol depletion by methyl-ß-cyclodextrin. In wild-type mouse hearts, stretch coincided with recruitment of caveolae to the sarcolemma, as observed by electron microscopy. In myocytes from wild-type but not Cav3 KO mice, stretch significantly increased cell membrane capacitance (by 98±64%), electrical time constant (by 285±149%), and lipid recruitment to the bilayer (by 84±39%). Recruitment of caveolae to the sarcolemma during physiologic cardiomyocyte stretch slows ventricular action potential propagation by increasing cell membrane capacitance.

A novel computational model of mouse myocyte electrophysiology to assess the synergy between Na+ loading and CaMKII.

Ca(2+)-calmodulin-dependent protein kinase II (CaMKII) hyperactivity in heart failure causes intracellular Na(+) ([Na(+)]i) loading (at least in part by enhancing the late Na(+) current). This [Na(+)]i gain promotes intracellular Ca(2+) ([Ca(2+)]i) overload by altering the equilibrium of the Na(+)-Ca(2+) exchanger to impair forward-mode (Ca(2+) extrusion), and favour reverse-mode (Ca(2+) influx) exchange. In turn, this Ca(2+) overload would be expected to further activate CaMKII and thereby form a pathological positive feedback loop of ever-increasing CaMKII activity, [Na(+)]i, and [Ca(2+)]i. We developed an ionic model of the mouse ventricular myocyte to interrogate this potentially arrhythmogenic positive feedback in both control conditions and when CaMKIIδC is overexpressed as in genetically engineered mice. In control conditions, simulation of increased [Na(+)]i causes the expected increases in [Ca(2+)]i, CaMKII activity, and target phosphorylation, which degenerate into unstable Ca(2+) handling and electrophysiology at high [Na(+)]i gain. Notably, clamping CaMKII activity to basal levels ameliorates but does not completely offset this outcome, suggesting that the increase in [Ca(2+)]i per se plays an important role. The effect of this CaMKII-Na(+)-Ca(2+)-CaMKII feedback is more striking in CaMKIIδC overexpression, where high [Na(+)]i causes delayed afterdepolarizations, which can be prevented by imposing low [Na(+)]i, or clamping CaMKII phosphorylation of L-type Ca(2+) channels, ryanodine receptors and phospholamban to basal levels. In this setting, Na(+) loading fuels a vicious loop whereby increased CaMKII activation perturbs Ca(2+) and membrane potential homeostasis. High [Na(+)]i is also required to produce instability when CaMKII is further activated by increased Ca(2+) loading due to ß-adrenergic activation. Our results support recent experimental findings of a synergistic interaction between perturbed Na(+) fluxes and CaMKII, and suggest that pharmacological inhibition of intracellular Na(+) loading can contribute to normalizing Ca(2+) and membrane potential dynamics in heart failure.

Randomized clinical trial of intraoperative superficial cervical plexus block versus incisional local anaesthesia in thyroid and parathyroid surgery.

BACKGROUND: Moderate wound pain and opiate analgesia requirement is reported following thyroid and parathyroid surgery. A randomized clinical trial was performed to investigate whether intraoperative superficial cervical plexus block (SCPB) would decrease postoperative pain and analgesia use. METHODS: Patients were randomized to incisional local anaesthesia (control) or incisional local anaesthesia plus intraoperative SCPB. The primary outcome measure was pain, assessed by a visual analogue scale (VAS). Secondary outcome measures were analgesia use (strong opiates defined as having potency at least as strong as that of oral morphine), respiratory rate and sedation score. Primary outcome measures were analysed with non-parametric tests, as well as with receiver operating characteristic (ROC) curves calculated as area under the curve (AUC) to discriminate between trial limbs. RESULTS: Twenty-nine patients were randomized to each group. Pain (VAS) scores were lower in patients who received intraoperative SCPB than in controls 30 min after surgery and subsequently (P < 0·020 at all time points), with a median pain score of zero on the day of operation in the SCPB group. Corresponding analysis of ROC curves showed differences between groups at 30 min (AUC = 0·722, P = 0·012), 90 min (AUC = 0·747, P = 0·005), 150 min (AUC = 0·803, P < 0·001) and 210 min (AUC = 0·849, P < 0·001) after surgery, and at 07.00 hours on postoperative day 1 (AUC = 0·710, P = 0·017). Fewer patients in the SCPB group required strong opiates (5 of 29 versus 16 of 29 in the control group; P = 0·003) and rescue opiates (6 of 29 versus 20 of 29; P < 0·001). CONCLUSION: Intraoperative SCPB reduces pain scores following thyroid and parathyroid surgery, and reduces the requirement for strong and rescue opiates. REGISTRATION NUMBER: 2009-012671-98 (https://www.clinicaltrialsregister.eu).

Culturally appropriate health education for Type 2 diabetes in ethnic minority groups: a systematic and narrative review of randomized controlled trials.

To determine if culturally appropriate health education is more effective than 'usual' health education for people with diabetes from ethnic minority groups living in high- and upper-middle-income countries. A systematic review with meta-analysis, following the methodology of the Cochrane Collaboration. Electronic literature searches of nine databases were made, with hand searching of three journals and 16 author contacts. The criteria for inclusion into the analysis were randomized controlled trials of a specified diabetes health education intervention, and a named ethnic minority group with Type 2 diabetes. Data were collected on HbA(1c), blood pressure, and quality-of-life measures. A narrative review was also performed. Few studies fitted the selection criteria, and were heterogeneous in methodologies and outcome measures, making meta-analysis difficult. HbA(1c) showed an improvement at 3 months [weighted mean difference (WMD) -0.32%, 95% confidence interval (CI) -0.63, -0.01] and 6 months post intervention (WMD -0.60%, 95% CI -0.85, -0.35). Knowledge scores also improved in the intervention groups at 6 months (standardized mean difference 0.46, 95% CI 0.27, 0.65). There was only one longer-term follow-up study, and one formal cost-effectiveness analysis. Culturally appropriate health education was more effective than 'usual' health education in improving HbA(1c) and knowledge in the short to medium term. Due to poor standardization between studies, the data did not allow determination of the key elements of interventions across countries, ethnic groups and health systems, or a broad view of their cost-effectiveness. The narrative review identifies learning points to direct future research.

Sonographic identification of lower limb venous hypoplasia in the prenatal diagnosis of Klippel-Trénaunay syndrome.

We report the prenatal identification of lower-limb venous hypoplasia to support a provisional prenatal diagnosis of Klippel-Trénaunay syndrome (KTS). Ultrasound assessment of a fetus with marked lower-limb edema, cystic areas in the abdomen/pelvis/lower limbs and abnormal development of the feet demonstrated bilateral hypoplasia of the femoral and popliteal veins. The external iliac veins and the great saphenous veins were seen to be normal. The lower limb arterial system was present. These findings supported KTS as the most likely provisional diagnosis, and postnatal clinical evaluation confirmed that the infant is best classified in the spectrum of KTS. Venous hypoplasia was confirmed with a postnatal ultrasound examination of the lower limbs. This case suggests that careful examination of the lower-limb venous system may be helpful in making the prenatal diagnosis of KTS.

Management of varicose veins: a survey of current practice by members of the Vascular Society of Great Britain and Ireland.

INTRODUCTION: In 1999, a survey was published detailing the management of varicose veins by members of the then Vascular Surgical Society (VSS). Since then, newer methods for treating varicose veins have been developed and far more explicit rationing has been introduced in the NHS. SUBJECTS AND METHODS: In order to examine whether there had been a significant change in established practice in the UK, a questionnaire was sent to all Vascular Society of Great Britain and Ireland (VSGBI) members in the 2004 yearbook by E-mail or post. RESULTS: Of the 426 questionnaires distributed, a 69% response rate was achieved. Of respondents, 97% treated varicose veins in their NHS practice, whilst 88% did so in private practice. Some 73% used hand-held Doppler assessment in the clinic and 96% used duplex ultrasound assessment selectively. Despite UK National Institute for Health and Clinical Excellence (NICE) guidelines, only 68% said that their primary care trusts funded treatment of symptomatic varicose veins, while 93% did so for complications. In either NHS or private practice, respectively, 83% or 72% of responders offered surgery as preferred treatment for primary varicose veins, while 14% or 20% preferred endovascular treatments (endovascular laser treatment, radiofrequency ablation and foam sclerotherapy). Of responders, 17% did not follow-up patients after treatment. CONCLUSIONS: This survey suggests that there is rationing of access to care for symptomatic varicose veins. Despite publicity for endovenous techniques, surgery remains the preferred treatment for varicose veins in the UK.

Antigen receptor V-segment usage in mucosal T cells.

In the accepted model of lymphocyte intestinal homing, naïve T cells recirculate via organized lymphoid tissues, whilst induced effector/memory cells home to the intestinal mucosa. In order to assess the T-cell-receptor repertoire in the intestine and gut-associated lymphoid tissue (GALT), spectratyping was performed on the proximal and the distal intestine, spleen and mesenteric lymph node tissue from six PVG rats. The products were analysed with an automated sequencer and statistical analyses were performed with hierarchical cluster analysis. This demonstrated the presence of a restricted T-cell repertoire in the small intestine compared with that in the mesenteric lymph nodes and the spleen. It also demonstrated marked differences in repertoire between individual, fully inbred rats maintained under apparently identical conditions in the same cage and fed identical diets. In addition, this work demonstrated marked differences between repertoires in the proximal and the distal intestine. Such marked differences are likely to reflect the end result of increasing divergence over time produced by relatively subtle effects of environment and antigenic load. Equally, marked differences in repertoire between small intestinal segments within individual rats indicate selective recruitment or retention of specific clones, presumably antigen-driven.

Personalised risk communication for informed decision making about taking screening tests.

BACKGROUND: There is a trend towards greater patient involvement in healthcare decisions. Adequate discussion of the risks and benefits associated with different choices is often required if involvement is to be genuine and effective. Achieving both the adequate involvement of consumers and informed decision making are now seen as important goals for any screening programme. Personalised risk estimates have been shown to be effective methods of risk communication in general, but the effectiveness of different strategies has not previously been examined. OBJECTIVES: To assess the effects of different types of personalised risk communication for consumers making decisions about taking screening tests. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 4, 2004), MEDLINE (1985 to December 2005), EMBASE (1985 to December 2005), CINAHL (1985 to December 2005), and PsycINFO (1989 to December 2005). Follow-up searches involved hand searching Preventive Medicine, citation searches on seven authors, and searching reference lists of articles. For the original version of this review (Edwards 2003c) we also searched CancerLit (1985 to 2001) and Science Citation Index Expanded (searched March 2002). SELECTION CRITERIA: Randomised controlled trials addressing the decision by consumers of whether or not to undergo screening, incorporating an intervention with a 'personalised risk communication element' and reporting cognitive, affective, or behavioural outcomes. A 'personalised risk communication element' is based on the individual's own risk factors for a condition (such as age or family history). It may be calculated from an individual's risk factors using formulae derived from epidemiological data, and presented as an absolute or relative risk or as a risk score, or it may be categorised into, for example, high, medium or low risk groups. It may be less detailed still, involving a listing, for example, of a consumer's risk factors as a focus for discussion and intervention. DATA COLLECTION AND ANALYSIS: Two authors independently assessed each trial for quality and extracted data. We extracted data about the nature and setting of the intervention, and relevant outcome data, along with items relating to methodological quality. We then used standard statistical methods of the Consumers and Communication Review Group to combine data using MetaView, including analysis according to different levels of detail of personalised risk communication, different condition for screening, and studies based only on high risk participants rather than people at 'average' risk. MAIN RESULTS: Twenty-two studies were included, nine of which were added in the 2006 update of this review. There was weak evidence, consistent with a small effect, that personalised risk communication (whether written, spoken or visually presented) increases uptake of screening tests (odds ratio (OR) 1.31 (random effects, 95% confidence interval (CI) 0.98 to 1.77). In three studies the interventions showed a trend towards more accurate risk perception (OR 1.65 (95% CI 0.96 to 2.81), and three other trials with heterogenous outcome measures showed improvements in knowledge with personalised risk interventions. There was little other evidence from these studies that the interventions promoted or achieved informed decision making by consumers about participation in screening. More detailed personalised risk communication may be associated with a smaller increase in uptake of tests. That is, for personalised risk communication which used and presented numerical calculations of risk, the OR for test uptake was 0.82 (95% CI 0.65 to 1.03). For risk estimates or calculations which were categorised into high, medium or low strata of risk, the OR was 1.42 (95% CI 1.07 to 1.89). For risk communication that simply listed personal risk factors the OR was 1.42 (95% CI 0.95 to 2.12). Over half of the included studies assessed interventions in the context of mammography. These studies showed similar effects to the overall dataset. The five studies examining risk communication in high risk individuals (individuals at higher risk due to, for example, a family history of breast cancer or other conditions) showed larger odds ratios for uptake of tests than the other studies (random effects OR 1.74; 95% CI 1.05 to 2.88). There were insufficient data from the included studies to report odds ratios on other key outcomes such as: intention to take tests, anxiety, satisfaction with decisions, decisional conflict, knowledge and resource use. AUTHORS' CONCLUSIONS: Personalised risk communication (as currently implemented in the included studies) may have a small effect on increasing uptake of screening tests, and there is only limited evidence that the interventions have promoted or achieved informed decision making by consumers.

From meeting presentation to peer-review publication--a UK review.

INTRODUCTION: Annual academic surgical meetings provide a forum for the discussion of research. For the wide-spread dissemination of this information, peer-reviewed publication is required. The aim of this study was to compare the amount of presentations which go on to publication from 4 UK-based surgical meetings. MATERIALS AND METHODS: We determined whether a presentation had led to a successful publication using PubMed, a median of 28 months following each meeting. We compared the ASGBI publication rate with the meetings of the Vascular Surgical Society (VSSGBI), the Association of Coloproctology of Great Britain and Ireland (ACPGBI) and the British Transplantation Society (BTS). We also compared the median impact factor of journals used. RESULTS: The ASGBI and BTS had a similar rate of presentations resulting in publication, with 35% and 36% at 2 years, respectively. The VSS had a significantly greater proportion of presentations resulting in publication (54% at 2 years; P = 0.004), whilst the ACPGBI had significant fewer (24% at 2 years; P = 0.006). There was no difference in the median impact factors of the journals used between the meetings (Kruskal Wallis P = 0.883). CONCLUSIONS: There is a significant variation between meetings in terms of turning presentations into publications. However, the majority of abstracts have still not been fully published within 2 years of presentation at the meeting.

Intestinal adaptation after massive intestinal resection.

Patients with short bowel syndrome require long term parenteral nutrition support. However, after massive intestinal resection the intestine undergoes adaptation and nutritional autonomy may be obtained. Given that the complications of parenteral nutrition may be life threatening or result in treatment failure and the need for intestinal transplantation, a more attractive option is to wean patients off nutrition support by optimising the adaptive process. The article examines the evidence that after extensive small bowel resection adaptation occurs in humans and focuses on the factors that influence adaptation and the strategies that have been used to optimise this process. The review is based on an English language Medline search with secondary references obtained from key articles. There is evidence that adaptation occurs in humans. Adaptation is a complex process that results in response to nutrient and non-nutrient stimuli. Successful and reproducible strategies to improve adaptation remain elusive despite an abundance of experimental data. Nevertheless given the low patient survival and quality of life associated with other treatments for irreversible intestinal failure it is imperative that clinical research continues into the optimisation of the adaptation.

Informed consent in renal transplantation.

PURPOSE: This study was performed to assess how well completed the new consent forms are for patients undergoing renal transplantation. METHODOLOGY: 100 patients were randomly selected from the 160 who had a renal transplantation, at a single centre in the UK, over an 18 month period. The notes were located and the consent forms scrutinised. FINDINGS: Seven sets of notes could not be traced and 10 did not contain a relevant consent form. Forty eight per cent of completed forms mentioned the source of organ while 8% mentioned on which side the operation was to be performed. Twelve risks and complications were identified as being relevant to this procedure but no single form mentioned all 12. In most cases a senior member of the surgical team obtained consent. IMPLICATIONS: The demonstrated variability in the amount of detail on consent forms lends weight to the call for the use of procedure specific forms. While such variability does not necessarily equate with not gaining valid, informed consent, this form, at present, serves as the only record of what has been discussed with the patient. These findings should encourage all surgeons to complete the forms themselves, be as detailed as possible, and ensure that the form is filed in the patients' notes.

Psychological interventions for women with metastatic breast cancer.

BACKGROUND: There have been conflicting results from systematic reviews of psychological interventions for patients with cancer, some showing benefits for patients and others not. One early study appeared to show significant survival benefits as well as psychological benefits from a psychological intervention given to women with metastatic breast cancer. Some further studies have been undertaken, again with conflicting results. OBJECTIVES: To assess the effects of psychological interventions (educational, individual cognitive behavioural or psychotherapeutic, or group support) on psychological and survival outcomes for women with metastatic breast cancer. SEARCH STRATEGY: We searched the Cochrane Breast Cancer Group Trials Register (September 2003), the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 4, 2003), MEDLINE (1966-October 2003), CancerLit (1983-2000), CINAHL (1982-October 2003), PsycInfo (1974-November 2003), and SIGLE (1980-November 2003). SELECTION CRITERIA: Randomised controlled trials (RCTs) of psychological interventions for women with metastatic breast cancer. Studies were included even if they were not 'intention to treat', owing to the nature of the patient group under study and the likely high loss of follow-up data. DATA COLLECTION AND ANALYSIS: Data were extracted independently by two reviewers. Data about the nature and setting of the intervention, and the relevant outcome data were extracted, along with items relating to methodological quality. MAIN RESULTS: Five primary studies were identified, all group psychological interventions. Two of these were cognitive behavioural interventions and three evaluated support-expressive group therapy. The five studies of group psychological therapies for women with metastatic breast cancer showed very limited evidence of benefit arising from these interventions. Although there was evidence of short-term benefit for some psychological outcomes, in general these were not sustained at follow-up. A clearer pattern of psychological outcomes could not be discerned as a wide variety of outcome measures and durations of follow-up were used in the included studies. The possible longer survival times in women allocated to receive psychological intervention in the early study have not been replicated in the subsequent four studies (including one by members of the first study group), and overall the effects of these interventions on survival are not statistically significant (for example, odds ratio for 5 year survival 0.83 (95% confidence interval [CI] 0.53 - 1.28). REVIEWERS' CONCLUSIONS: There is insufficient evidence to advocate that group psychological therapies (either cognitive behavioural or supportive-expressive) should be made available to all women diagnosed with metastatic breast cancer. Any benefits of the interventions are only evident for some of the psychological outcomes and in the short term. The possibility of the interventions causing harm is not ruled out by the available data.

Unexplained extra visits to general practitioners before the diagnosis of first urinary tract infection: a case-control study.

AIMS: To determine: (1) whether children diagnosed with a urinary tract infection (UTI) visited their general practitioner (GP) more frequently before the diagnosis of UTI was established compared to children never diagnosed with a UTI; and (2) whether those children with evidence of renal scarring at their first diagnosed UTI visited their GPs more frequently before diagnosis compared to children who did not have evidence of renal scarring when their first UTI was investigated. METHODS: Case-control study of 77 children with a UTI identified from a hospital radiology database (37 with and 40 without renal scarring), and 77 age, sex, and general practice matched controls. Main outcome measures were entries in general practice clinical records for types of illness, antibiotic prescriptions, and urine samples requested prior to the diagnosis of first UTI (cases) or equivalent time periods for controls. RESULTS: Cases had a mean 2.94 additional visits or 21% more visits (95% CI 1% to 41%) in the period (mean 2.4 years) prior to the visit at which their first UTI was diagnosed, including a mean 2.5 additional visits or 23% more visits for infectious illness (95% CI 1% to 45%). The cases had 114% (95% CI 41% to 184%) more visits for symptoms relating to the genitourinary tract, though the actual number of these visits was small. They were febrile at 49% more visits (95% CI 1% to 99%) and received significantly more courses of antibiotics than controls (5.2 v 4.1). They had more urine samples requested (37 v 3). Both the cases with and without renal scarring had similar excess GP visits. CONCLUSION: Compared to controls, children diagnosed with a first UTI had more visits at which symptoms of infection were recorded and more antibiotics prescribed prior to the visit at which the first UTI was diagnosed. These excess visits may have included undiagnosed UTIs. Both those with and without renal scarring had a similar degree of excess visits; additional aetiological factors must have played a role in scar formation.

The development of a new site-specific measure of quality of life for breast problems: the Cardiff breast scales.

The management of women presenting to primary care with symptoms of breast disease is of increasing interest given recent organisational changes aimed at improving accuracy and speed of referrals. As part of a randomised controlled trial, 1063 women were recruited following a primary care consultation for a variety of breast-related problems. In the absence of a suitable outcome measure for such women, a site-specific instrument was developed to complement a generic quality of life scale (SF-36). Items were generated using key informant interviews with health professionals. Draft scale items were piloted using a postal questionnaire and subsequent patient debrief interviews. A sample of respondents were also sent the same questionnaire I month later to assess test-retest reliability. Across the whole sample (n = 848), three factors were identified: 'general well-being', 'concerns' and 'relationships'. These factors accounted for 60% of total variance. Evidence of scale validity, reliability and responsiveness are reported for this new outcome measure for use in women presenting with breast problems.

Efficiency of searching the grey literature in palliative care.

A systematic review into palliative care team effectiveness was undertaken which has, inherent in its methodology, grey literature searching. Over 100 letters were written to a systematically chosen range of service providers, commissioners, and experts in combination with requests for information in six UK national cancer/palliative care organization newsletters. In addition, the System for Information on Grey Literature (SIGLE ) database was searched. As a result, 25 document hard copies were received. The documents were, in all but one case (this one study was also highlighted by the SIGLE search), not relevant as they were predominated by annual reports, service descriptions, and needs assessments. In terms of obtaining unpublished studies for possible inclusion in the review, this comprehensive search was unsuccessful and, therefore, it would appear that grey literature searching is not a useful tool in palliative care systematic reviews.

Efficient literature searching in diffuse topics: lessons from a systematic review of research on communicating risk to patients in primary care.

Using the example of communication about risk in a primary care setting, this paper puts forward a method of developing and evaluating a detailed search strategy for locating the literature for a systematic review of a 'diffuse' subject. The aim of this paper is to show how to develop a search strategy that maximizes both recall and precision while keeping search outputs manageable. Six different databases were used, namely Medline, Embase, PsychLIT, CancerLIT, Cinahl and Social Science Citation Index (SSCI). The searches were augmented by hand-searching, contacting authors, citation searching and reference lists from included papers. Other databases were searched but yielded no extra references for this subject matter. Of the 99 papers included, 80 were indexed on Medline. The Medline search strategy identified 54 of them and the remaining 26 were located on other databases. The 19 further unique references were found using the other databases and methods of retrieval. A combination of several databases must be used to maximize recall and to increase the precision of searches on individual databases, thus improving the overall efficiency of the search.

Ovarian dermoid cyst leakage--a cautionary tale.

This case illustrates that when a dermoid cyst is punctured, an immediate operative laparoscopy or laparotomy should be performed, along with lavage, to avoid the problems associated with dermoid cyst contents spillage.

Signal versus noise in the evidence base for medicine: an alternative to hierarchies of evidence?

Clinical practice frequently generates questions that are not easily answered by randomized trials. On conventional hierarchies of evidence, 'weaker' study designs are often more feasible. Also, much research is not well designed. Yet we still need to make best use of the available evidence. Systematic reviews must therefore address the danger of underestimating the evidence from relevant literature if it includes only that of a certain methodological quality. This would run the risk of missing or distorting the true message that the review is trying to identify. We propose a classification of research which does not reject studies on the basis of design alone, but recognizes the importance of assessing the message or 'signal' within each piece of research. It explicitly introduces judgement into the appraisal and synthesis of evidence, and affords more flexibility in attaching weight to evidence that might otherwise be lost. It includes an assessment of methodological quality, balancing this against the weight of its message, rather than rejecting studies which are below a certain threshold for quality. Fundamentally flawed research will still be rejected, but more commonly papers can still be used, tempering the importance that we attach to their signal by the amount of 'noise' around that signal. The balance of these two elements may be termed the 'signal to noise ratio'.