Ischaemic stroke with multi-focal venous and arterial thrombosis due to hyperhomocysteinemia: anabolic androgenic steroid use and MTHFR c.667 C > T variant - a case report.

BACKGROUND: Severely elevated serum homocysteine is a rare cause of ischaemic stroke and extra-cranial arterial and venous thrombosis. Several factors can lead to mild elevation of homocysteine including dietary folate and B12 deficiency, and genetic variants of the methylenetetrahydrofolate reductase (MTHFR) enzyme. The use of Anabolic androgenic steroid (AAS) is under-reported, but increasingly linked to ischaemic stroke and can raise homocysteine levels. CASE REPORT: We present a case of a man in his 40s with a large left middle cerebral artery (MCA) territory ischaemic stroke and combined multifocal, extracranial venous, and arterial thrombosis. His past medical history was significant for Crohn's disease and covert use of AAS. A young stroke screen was negative except for a severely elevated total homocysteine concentration, folate and B12 deficiencies. Further tests revealed he was homozygous for the methylenetetrahydrofolate reductase enzyme thermolabile variant (MTHFR c.667 C > T). The etiology of this stroke was a hypercoagulable state induced by raised plasma homocysteine. Raised homocysteine in this case was likely multifactorial and related to chronic AAS use in combination with the homozygous MTHFR c.677 C > T thermolabile variant, folate deficiency and, vitamin B12 deficiency. CONCLUSION: In summary, hyperhomocysteinemia is an important potential cause of ischaemic stroke and may result from genetic, dietary, and social factors. Anabolic androgenic steroid use is an important risk factor for clinicians to consider, particularly in cases of young stroke with elevated serum homocysteine. Testing for MFTHR variants in stroke patients with raised homocysteine may be useful to guide secondary stroke prevention through adequate vitamin supplementation. Further studies looking into primary and secondary stroke prevention in the high-risk MTHFR variant cohort are necessary.

Hybrid-integrated diode laser in the visible spectral range.

Generating visible light with wide tunability and high coherence based on photonic integrated circuits is of high interest for applications in biophotonics, precision metrology, and quantum technology. Here we present, to our knowledge, the first demonstration of a hybrid-integrated diode laser in the visible spectral range. Using an AlGaInP optical amplifier coupled to a low-loss Si3N4 feedback circuit based on microring resonators, we obtain a spectral coverage of 10.8 nm around 684.4 nm wavelength with up to 4.8 mW output power. The measured intrinsic linewidth is 2.3±0.2kHz.

Udder firmness as a possible indicator for clinical mastitis.

Swelling of the mammary gland is an important sign to detect clinical mastitis (CM) in dairy cows. The overall objective of this study was to evaluate if udder firmness can be used as a cow-side indicator for mastitis and to evaluate how CM affects firmness within 14 d after diagnosis. A dynamometer was used to objectively determine udder firmness before and after milking in 45 cows with CM and 95 healthy cows. Udder firmness of both hind quarters was measured daily on 3 locations (upper, middle, lower measuring point) from the day of mastitis diagnosis until d 7 and again on d 14. Firmness of the middle measuring point was highest before and after milking in all cows. Udder firmness before milking was similar in quarters without and with CM. Subsequently, we concentrated on firmness measured on the middle point after milking. After milking, quarters with CM were firmer than healthy quarters. An increase of firmness of a quarter with mastitis did not affect firmness of the healthy neighboring quarter, nor did firmness of all healthy quarters differ. One firmness value per cow [i.e., Δ firmness (difference in udder firmness between both hind quarters)] was used for all further calculations. After fitting a generalized mixed model, CM affected Δ firmness in all cases. In multiparous cows, Δ firmness was also affected by continuous milk yield per day and DIM. Firmness thresholds for detection of CM were calculated using receiver operation characteristic curves. The threshold for detection of CM using Δ firmness was 0.282 kg (area under the curve: 0.722, sensitivity: 64.3%, specificity: 89.7%) and 0.425 kg (area under the curve: 0.817, sensitivity: 62.5%, specificity: 96.7%) in primiparous cows and multiparous cows, respectively. Linear mixed-model ANOVA were used to evaluate how CM affects udder firmness within 14 d after diagnosis. Cows with CM had a higher Δ firmness compared with cows without CM throughout the 14 d after the mastitis diagnoses. Parity had an effect on Δ firmness. Depending on systemic signs of sickness, mastitic cows were divided into cows having mild to moderate (n = 21) or severe mastitis (n = 24). Cows with severe mastitis suffered from a firmer udder on all measuring days. Bacteriological cure was defined based on 2 milk samples taken at 7 and 14 d after enrollment. An effect of parity and bacteriological cure on Δ firmness of cows with CM did not exist within the 14 d. Cows not clinically cured showed an increased Δ firmness of 0.560 kg compared with cured cows. In conclusion, udder firmness can be a useful indicator for CM. Further research is warranted to evaluate if udder firmness can be used as a predictor for the prognosis of a CM or the cure of inflammation.

Adhesion of Escherichia coli under flow conditions reveals potential novel effects of FimH mutations.

FimH-mediated adhesion of Escherichia coli to bladder epithelium is a prerequisite for urinary tract infections. FimH is also essential for blood-borne bacterial dissemination, but the mechanisms are poorly understood. The purpose of this study was to assess the influence of different FimH mutations on bacterial adhesion using a novel adhesion assay, which models the physiological flow conditions bacteria are exposed to. We introduced 12 different point mutations in the mannose binding pocket of FimH in an E. coli strain expressing type 1 fimbriae only (MSC95-FimH). We compared the bacterial adhesion of each mutant across several commonly used adhesion assays, including agglutination of yeast, adhesion to mono- and tri-mannosylated substrates, and static adhesion to bladder epithelial and endothelial cells. We performed a comparison of these assays to a novel method that we developed to study bacterial adhesion to mammalian cells under flow conditions. We showed that E. coli MSC95-FimH adheres more efficiently to microvascular endothelium than to bladder epithelium, and that only endothelium supports adhesion at physiological shear stress. The results confirmed that mannose binding pocket mutations abrogated adhesion. We demonstrated that FimH residues E50 and T53 are crucial for adhesion under flow conditions. The coating of endothelial cells on biochips and modelling of physiological flow conditions enabled us to identify FimH residues crucial for adhesion. These results provide novel insights into screening methods to determine the effect of FimH mutants and potentially FimH antagonists.

Effect of Heat Stress on Concentrations of Faecal Cortisol Metabolites in Dairy Cows.

The negative impact of heat stress on health and productivity of dairy cows is well known. Heat stress can be quantified with the temperature-humidity index (THI) and is defined as a THI ≥ 72. Additionally, animal welfare is affected in cows living under heat stress conditions. Finding a way to quantify heat stress in dairy cows has been of increasing interest over the past decades. Therefore, the objective of this study was to evaluate concentrations of faecal glucocorticoid metabolites [i.e. 11,17-dioxoandrostanes (11,17-DOA)] as an indirect stress parameter in dairy cows without heat stress (DOA 0), with heat stress on a single day (acute heat stress, DOA 1) or with more than a single day of heat stress (chronic heat stress, DOA 2). Cows were housed in five farms under moderate European climates. Two statistical approaches (approach 1 and approach 2) were assessed. Using approach 1, concentrations of faecal 11,17-DOA were compared among DOA 0, DOA 1 and DOA 2 samples regardless of their origin (i.e. cow, unpaired comparison with a one-way anova). Using approach 2, a cow was considered as its own control; that is 11,17-DOA was treated as a cow-specific factor and only paired samples were included in the analysis for this approach (paired comparison with t-tests). In approach 1 (p = 0.006) and approach 2 (p = 0.038), 11,17-DOA values of cows under acute heat stress were higher compared to those of cows without heat stress. Our results also indicate that acute heat stress has to be considered as a confounder in studies measuring faecal glucocorticoid metabolites in cows to evaluate other stressful situations.

Certifications for sight impairment due to age related macular degeneration in England.

OBJECTIVES: To examine variability across England in certification rates for age related macular degeneration (AMD) between 1st April 2011 and 31st March 2012. STUDY DESIGN: Cross-sectional survey. METHODS: An electronic version of the CVI, the ECVI, was used at the Certifications Office, London, to transfer information from paper based certificates into a database. The electronic certifications data set was queried for all certificates completed in England between April 1st 2011 and March 31st 2012 with the main cause of certifiable visual loss being AMD or with the main cause of certifiable visual loss being multiple pathology but a contributory cause being AMD. Data were explored by type of AMD, visual status, age and sex and then directly standardized rates were computed by English region. RESULTS: The Certifications Office received 23,616 CVIs for England between April 2011 and March 2012, of which 10,481 (44%) were people certified severely sight-impaired (blind) (SSI) and 12,689 (54%) were certified as sight-impaired (partial sight) (SI). The remainder did not have visual status classified. AMD contributed to 11546 causes of certification on the CVI forms during this period, 53% of forms being for geographic atrophy (GA)/dry AMD which is currently mostly untreatable. The median (interquartile) age at certification for AMD was 86 (81, 90) years and women were more commonly certified than men (66%). Considerable variability was seen across English regions, although there was consistency in that GA was the more common form in all areas. CONCLUSIONS: There is considerable regional variability in CVI rates in England, which are not attributable to differences in age or sex. Reasons for such variability need examination yet this should not undermine the value of these data in terms of describing those newly registered with sight impairment due to AMD who are predominantly female and over 85 years of age.

How many people in England and Wales are registered partially sighted or blind because of age-related macular degeneration?

PURPOSE: The purpose of the study was to determine what proportion of new certifications between 1 April 2007 and 31 March 2008 could be attributed to age-related macular degeneration (AMD) and to describe the AMD-certified population in England and Wales. METHODS: An electronic version of the Certificate of Vision Impairment form (CVI), the ECVI, was used at the certifications office to transfer information from the paper-based certificates into a database. The electronic certifications data set was queried for all certificates completed between 1 April 2007 and 31 March 2008 with the main cause of certifiable visual loss being AMD or with the main cause of certifiable visual loss being multiple pathology but a contributory cause being AMD. The electronic data set was adapted so that a distinction could be made between geographic atrophy (GA) and neovascular AMD (nAMD). RESULTS: The Certifications Office received 23 185 CVIs between April 2007 and March 2008, of whom 9823 (42%) were people registered severely sight impaired (SSI) and 12 607 (52%) were certified as sight impaired (SI). AMD contributed to 13 000 causes of registration on the CVI forms during this period and was the main cause in 11 015 people. In these 11 015 people, GA accounted for 49.3%, nAMD 35.1%, and AMD not specified 15.7%. CONCLUSIONS: The data in this report provide detailed information on CVI registration due to AMD before the widespread adoption of ranibizumab therapy in NHS practice and provide an insight into the burden of vision loss due to AMD at a time of great change in the management of nAMD.

Evaluation of udder firmness by palpation and a dynamometer.

Swelling of the mammary gland is an important health status sign for clinical exploration and palpation is a routine diagnostic tool for mastitis detection in dairy cows. Data on repeatability or validity of specific methods of udder palpation are rare. The overall objective was to study the validity of estimates of udder firmness generated by palpation and by using a validated dynamometer. Specifically, we set out to determine within-observer repeatability and between-observer repeatability in 2 specific experiments. Additionally, we compared a 4-point palpation scoring system with estimates obtained with a dynamometer in this study. In a pilot trial, we determined the range of udder firmness of 25 cows and developed an in vitro model for udder firmness. This model enabled training of the observers and allowed investigating a 4-point palpation scoring system. In vivo, udder firmness was determined before and after milking by palpation and by using a dynamometer. Within-observer repeatability based on estimates of udder firmness of 25 cows obtained by 3 observers on a single day by palpation was 0.968. Within-observer repeatability of estimates of udder firmness of 25 cows obtained with the dynamometer by a single observer was 0.997. The coefficient of variation of the same measures was 9.1%. To determine between-observer repeatability (palpation: 0.932; dynamometer: 0.898), udder firmness of 100 cows was measured on 4 different days by 9 observers in experiment 2. Udder firmness in dairy cows could be measured repeatably with the dynamometer and by palpation, especially when performed by a single observer. Estimates of udder firmness generated by palpation and with the dynamometer were moderately related (correlation coefficient = 0.54). Training of observers through the pilot trial or practical experience in the 4 d of the study in experiment 2 did not improve the correlation. Further research is warranted to understand how udder firmness develops in infected udders.

Differences between men and women in the regulation of adipose 11ß-HSD1 and in its association with adiposity and insulin resistance.

This study explored sex differences in 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) activity and gene expression in isolated adipocytes and adipose tissue (AT), obtained via subcutaneous biopsies from non-diabetic subjects [58 M, 64 F; age 48.3 ± 15.3 years, body mass index (BMI) 27.2 ± 3.9 kg/m²]. Relationships with adiposity and insulin resistance (IR) were addressed. Males exhibited higher 11ß-HSD1 activity in adipocytes than females, but there was no such difference for AT. In both men and women, adipocyte 11ß-HSD1 activity correlated positively with BMI, waist circumference, % body fat, adipocyte size and with serum glucose, triglycerides and low-density lipoprotein:high-density lipoprotein (LDL:HDL) ratio. Positive correlations with insulin, HOMA-IR and haemoglobin A1c (HbA1c) and a negative correlation with HDL-cholesterol were significant only in males. Conversely, 11ß-HSD1 activity in AT correlated with several markers of IR and adiposity in females but not in males, but the opposite pattern was found with respect to 11ß-HSD1 mRNA expression. This study suggests that there are sex differences in 11ß-HSD1 regulation and in its associations with markers of obesity and IR.

What is the clinical effectiveness and cost-effectiveness of using drugs in treating obese patients in primary care? A systematic review.

BACKGROUND: Obesity [defined as a body mass index (BMI) ≥ 30 kg/m(2)] represents a considerable public health problem and is associated with a significant range of comorbidities and an increased mortality risk. The primary aim of the management of obesity is to achieve weight reduction in the interests of health. For obese patients who cannot achieve or maintain a healthy weight by non-pharmacological means, drug therapy is recommended in combination with non-pharmacological interventions such as dietary modifications and exercise. OBJECTIVE: To evaluate the clinical effectiveness and cost-effectiveness of three pharmacological interventions in obese patients. DATA SOURCES: Clinical effectiveness data used in the meta-analysis were sourced from articles identified in a systematic review of the literature. Data used to inform transitions to obesity-related comorbidities were derived from the General Practice Research Database (GPRD). The results of the meta-analysis and GPRD analyses informed the economic model supplemented by data from the Health Survey for England and other UK-specific data sourced from the literature. REVIEW METHODS: A systematic literature review was conducted of the clinical effectiveness and cost-effectiveness of orlistat, sibutramine and rimonabant within their licensed indications for the treatment of obese patients. Electronic bibliographic databases including MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, The Cochrane Library databases and Cumulative Index to Nursing and Allied Health Literature (CINAHL) were searched in January 2009, and the reference lists of relevant articles were checked. Studies were included if they compared orlistat, sibutramine or rimonabant with lifestyle and/or exercise advice (standard care), placebo or metformin. RESULTS: Overall, 94 studies involving 24,808 individuals were included in the clinical meta-analysis. Eighty-three trials included data on weight change, 41 included data on BMI change and 45 and 36 studies reported on 5% and 10% body weight loss, respectively. Overall, the results show that the active drug interventions are all effective at reducing weight and BMI compared with placebo. In the case of sibutramine, the higher dose (15 mg) resulted in a greater reduction than the lower dose (10 mg). Generally, the data quality of the trials included was low with poor reporting of standard errors and standard deviations. Results from the BMI risk models derived from the GPRD showed consistent increases in risk with increasing BMI. Adjustments for key confounders, such as age, sex and smoking status, were found to be statistically significant at the 5% level, in all risk models. Applying linear models to estimate BMI trajectories, for the diabetic cohort, an average increase in BMI of 0.040 per year for both men and women was observed. The non-diabetic cohort model showed an increase in BMI of 0.175 per year for women and 0.145 per year for men. The results of the cost-effectiveness analyses suggest that sibutramine 15 mg dominates the other three active interventions and the net benefit analyses show that sibutramine 15 mg is the most cost-effective alternative for thresholds > £2000 per quality-adjusted life-year (QALY). However, both sibutramine and rimonabant have been withdrawn because of safety concerns relating to potential treatment-induced fatal adverse events. If the proportion of patients who experienced a fatal adverse event was > 1.8% (1.5%, 1.0%) for sibutramine 15 mg (sibutramine 10 mg, rimonabant) the treatment would not be considered cost-effective when using a threshold of £20,000 per QALY. LIMITATIONS: The clinical review did not include all possible lifestyle comparators, with the inclusion limited to only those trials included one of the active drug interventions. We also excluded all studies not reported in English. Although the clinical review included data from 94 studies, the quality of data was generally low, particularly in terms of the reporting of standard deviation. There was also inconsistency between the results of the mixed-treatment comparison (MTC) and the pair-wise analyses. CONCLUSION: The MTC of anti-obesity treatments shows that all the active treatments are effective at reducing weight and BMI. The economic results show that, compared with placebo, the treatments are all cost-effective when using a threshold of £20,000 per QALY, and, within the limitations of the data available, sibutramine 15 mg dominates the other three interventions. This work has highlighted many areas of methodological research that could be explored, including assessing inconsistencies within a network to determine differences between the results of pair-wise and MTC analyses; the use of meta-regression methods to look for effect modifiers; exploring the effect of local publication bias; and the use of joint models to analyse the repeated measures of BMI and the time-to-event processes simultaneously. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

What is the value of routinely testing full blood count, electrolytes and urea, and pulmonary function tests before elective surgery in patients with no apparent clinical indication and in subgroups of patients with common comorbidities: a systematic review of the clinical and cost-effective literature.

BACKGROUND: The evidence base which supported the National Institute for Health and Clinical Excellence (NICE) published Clinical Guideline 3 was limited and 50% was graded as amber. However, the use of tests as part of pre-operative work-up remains a low-cost but high-volume activity within the NHS, with substantial resource implications. The objective of this study was to identify, evaluate and synthesise the published evidence on the clinical effectiveness and cost-effectiveness of the routine use of three tests, full blood counts (FBCs), urea and electrolytes tests (U&Es) and pulmonary function tests, in the pre-operative work-up of otherwise healthy patients undergoing minor or intermediate surgery in the NHS. OBJECTIVE: The aims of this study were to estimate the clinical effectiveness and cost-effectiveness of routine pre-operative testing of FBC, electrolytes and renal function and pulmonary function in adult patients classified as American Society of Anaesthesiologists (ASA) grades 1 and 2 undergoing elective minor (grade 1) or intermediate (grade 2) surgical procedures; to compare NICE recommendations with current practice; to evaluate the cost-effectiveness of mandating or withdrawing each of these tests in this patient group; and to identify the expected value of information and whether or not it has value to the NHS in commissioning further primary research into the use of these tests in this group of patients. DATA SOURCES: The following electronic bibliographic databases were searched: (1) BIOSIS; (2) Cumulative Index to Nursing and Allied Health Literature; (3) Cochrane Database of Systematic Reviews; (4) Cochrane Central Register of Controlled Trials; (5) EMBASE; (6) MEDLINE; (7) MEDLINE In-Process & Other Non-Indexed Citations; (8) NHS Database of Abstracts of Reviews of Effects; (9) NBS Health Technology Assessment Database; and (10) Science Citation Index. To identify grey and unpublished literature, the Cochrane Register of Controlled Trials, National Research Register Archive, National Institute for Health Research Clinical Research Network Portfolio database and the Copernic Meta-search Engine were searched. A large routine data set which recorded the results of tests was obtained from Leeds Teaching Hospitals Trust. REVIEW METHODS: A systematic review of the literature was carried out. The searches were undertaken in March to April 2008 and June 2009. Searches were designed to retrieve studies that evaluated the clinical effectiveness and cost-effectiveness of routine pre-operative testing of FBC, electrolytes and renal function and pulmonary function in the above group of patients. A postal survey of current practice in testing patients in this group pre-operatively was undertaken in 2008. An exemplar cost-effectiveness model was constructed to demonstrate what form this would have taken had there been sufficient data. A large routine data set that recorded the results of tests was obtained from Leeds Teaching Hospitals Trust. This was linked to individual patient data with surgical outcomes, and regression models were estimated. RESULTS: A comprehensive and systematic search of both the clinical effectiveness and cost-effectiveness literature identified a large number of potentially relevant studies. However, when these studies were subjected to detailed review and quality assessment, it became clear that the literature provides no evidence on the clinical effectiveness and cost-effectiveness of these specific tests in the specific patient groups. The postal survey had a 17% response rate. Results reported that in ASA grade 1, patients aged < 40 years with no comorbidities undergoing minor surgery did not have routine tests for FBC, electrolytes and renal function and pulmonary function. The results from the regression model showed that the frequency of test use was not consistent with the hypothesis of their routine use. FBC tests were performed in only 58% of patients in the data set and U&E testing was carried out in only 57%. LIMITATIONS: Systematic searches of the clinical effectiveness and cost-effectiveness literature found that there is no evidence on the clinical effectiveness or cost-effectiveness of these tests in this specific clinical context for the NHS. A survey of NHS hospitals found that respondent trusts were implementing current NICE guidance in relation to pre-operative testing generally, and a de novo analysis of routine data on test utilisation and post-operative outcome found that the tests were not be used in routine practice; rather, use was related to an expectation of a more complex clinical case. The paucity of published evidence is a limitation of this study. The studies included relied on non-UK health-care systems data, which may not be transferable. The inclusion of non-randomised studies is associated with an increased risk of bias and confounding. Scoping work to establish the likely mechanism of action by which tests would impact upon outcomes and resource utilisation established that the cause of an abnormal test result is likely to be a pivotal determinant of the cost-effectiveness of a pre-operative test and therefore evaluations would need to consider tests in the context of the underlying risk of specific clinical problems (i.e. risk guided rather than routine use). CONCLUSIONS: The time of universal utilisation of pre-operative tests for all surgical patients is likely to have passed. The evidence we have identified, though weak, indicates that tests are increasingly utilised in patients in whom there is a reason to consider an underlying raised risk of a clinical abnormality that should be taken into account in their clinical management. It is likely that this strategy has led to substantial resource savings for the NHS, although there is not a published evidence base to establish that this is the case. The total expenditure on pre-operative tests across the NHS remains significant. Evidence on current practice indicates that clinical practice has changed to such a degree that the original research question is no longer relevant to UK practice. Future research on the value of these tests in pre-operative work-up should be couched in terms of the clinical effectiveness and cost-effectiveness in the identification of specific clinical abnormalities in patients with a known underlying risk. We suggest that undertaking a multicentre study making use of linked, routinely collected data sets would identify the extent and nature of pre-operative testing in this group of patients. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Prescribing high-dose lipid-lowering therapy early to avoid subsequent cardiovascular events: is this a cost-effective strategy?

BACKGROUND: While evidence shows high-dose statins reduce cardiovascular events compared with moderate doses in individuals with acute coronary syndrome (ACS), many primary care trusts (PCT) advocate the use of generic simvastatin 40 mg/day for these patients. METHODS AND RESULTS: Data from 28 RCTs were synthesized using a mixed treatment comparison model. A Markov model was used to evaluate the cost-effectiveness of treatments taking into account adherence and the likely reduction in cost for atorvastatin when the patent expires. There is a clear dose-response: rosuvastatin 40 mg/day produces the greatest reduction in low-density lipoprotein cholesterol (56%) followed by atorvastatin 80 mg/day (52%), and simvastatin 40 mg/day (37%). Using a threshold of £20,000 per QALY, if adherence levels in general practice are similar to those observed in RCTs, all three higher dose statins would be considered cost-effective compared to simvastatin 40 mg/day. Using the net benefits of the treatments, rosuvastatin 40 mg/day is estimated to be the most cost-effective alternative. If the cost of atorvastatin reduces in line with that observed for simvastatin, atorvastatin 80 mg/day is estimated to be the most cost-effective alternative. CONCLUSION: Our analyses show that current PCT policies intended to minimize primary care drug acquisition costs result in suboptimal care.

Diagnostic management strategies for adults and children with minor head injury: a systematic review and an economic evaluation.

BACKGROUND: Patients with minor head injury [Glasgow Coma Scale (GCS) score 13-15] have a small but important risk of intracranial injury (ICI) that requires early identification and neurosurgical treatment. Diagnostic assessment can use either a clinical decision rule or unstructured assessment of individual clinical features to identify those who are at risk of ICI and in need of computerised tomography (CT) scanning and/or hospital admission. Selective use of CT investigations helps minimise unnecessary radiation exposure and resource use, but can lead to missed opportunities to provide early treatment for ICI. OBJECTIVES: To determine the diagnostic accuracy of decision rules, individual clinical characteristics, skull radiography and biomarkers, and the clinical effectiveness and cost-effectiveness of diagnostic management strategies for minor head injury (MHI). DATA SOURCES: Several electronic databases [including MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, Cumulative Index to Nursing and Allied Health Literature (CINAHL), EMBASE and The Cochrane Library] were searched from inception to April 2009 (updated searches to March 2010 were conducted on the MEDLINE databases only). Searches were supplemented by hand-searching relevant articles (including citation searching) and contacting experts in the field. For each of the systematic reviews the following studies were included (1) cohort studies of patients with MHI in which a clinical decision rule or individual clinical characteristics (including biomarkers and skull radiography) were compared with a reference standard test for ICI or need for neurosurgical intervention and (2) controlled trials comparing alternative management strategies for MHI. REVIEW METHODS: Study quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool (for the assessment of diagnostic accuracy) or criteria recommended by the Effective Practice and Organisation of Care Review Group (for the assessment of management practices). Where sufficient data existed, a meta-analysis was undertaken to generate pooled estimates of diagnostic parameters. A decision-analysis model was developed using Simul8 2008 Professional software (Simul8 Corporation, Boston, MA, USA) to estimate the costs and quality-adjusted life-years (QALYs) accrued by management strategies for MHI. The model took a lifetime horizon and NHS perspective. Estimates of the benefits of early treatment, harm of radiation exposure and long-term costs were obtained through literature reviews. Initial analysis was deterministic, but probabilistic sensitivity analysis was also performed. Secondary analyses were undertaken to explore the trade-off between sensitivity and specificity in diagnostic strategies and to determine the cost-effectiveness of scenarios involving hospital admission. RESULTS: The literature searches identified 8003 citations. Of these, 93 full-text papers were included for the assessment of diagnostic accuracy and one for the assessment of management practices. The quality of studies and reporting was generally poor. The Canadian CT Head Rule (CCHR) was the most widely validated adult rule, with sensitivity of 99-100% and 80-100% for neurosurgical and any ICI, respectively (high- or medium-risk criteria), and specificity of 39-51%. Rules for children had high sensitivity and acceptable specificity in derivation cohorts, but limited validation. Depressed, basal or radiological skull fracture and post-traumatic seizure (PTS) [positive likelihood ratio (PLR) > 10]; focal neurological deficit, persistent vomiting, decrease in GCS and previous neurosurgery (PLR 5-10); and fall from a height, coagulopathy, chronic alcohol use, age > 60 years, pedestrian motor vehicle accident (MVA), any seizure, undefined vomiting, amnesia, GCS < 14 and GCS < 15 (PLR 2-5) increased the likelihood of ICI in adults. Depressed or basal skull fracture and focal neurological deficit (PLR > 10), coagulopathy, PTS and previous neurosurgery (PLR 5-10), visual symptoms, bicycle and pedestrian MVA, any seizure, loss of consciousness, vomiting, severe or persistent headache, amnesia, GCS < 14, GCS < 15, intoxication and radiological skull fracture (PLR 2-5) increased the likelihood of ICI in children. S100 calcium-binding protein B had pooled sensitivity of 96.8% [95% highest-density region (HDR) 93.8% to 98.6%] and specificity of 42.5% (95% HDR 31.0% to 54.2%). The only controlled trial showed that early CT and discharge is cheaper and at least as effective as hospital admission. Economic analysis showed that selective CT use dominated 'CT all' and 'discharge all' strategies. The optimal strategies were the CCHR (adults) and the CHALICE (Children's Head injury Algorithm for the prediction of Important Clinical Events) or NEXUS II (National Emergency X-Radiography Utilization Study II) rule (children). The sensitivity and specificity of the CCHR (99% and 47%, respectively) represented an appropriate trade-off of these parameters. Hospital admission dominated discharge home for patients with non-neurosurgical injury, but cost £39 M per QALY for clinically normal patients with a normal CT. CONCLUSIONS: The CCHR is widely validated and cost-effective for adults. Decision rules for children appear cost-effective, but need further validation. Hospital admission is cost-effective for patients with abnormal, but not normal, CT. The main research priorities are to (1) validate decision rules for children; (2) determine the prognosis and treatment benefit for non-neurosurgical injuries; (3) evaluate the use of S100B alongside a validated decision rule; (4) evaluate the diagnosis and outcomes of anticoagulated patients with MHI; and (5) evaluate the implementation of guidelines, clinical decision rules and diagnostic strategies. Formal expected value of sample information analysis would be recommended to appraise the cost-effectiveness of future studies. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

The clinical effectiveness and safety of prophylactic retinal interventions to reduce the risk of retinal detachment and subsequent vision loss in adults and children with Stickler syndrome: a systematic review.

BACKGROUND: Stickler syndrome, also known as hereditary progressive arthro-ophthalmopathy, is an inherited progressive disorder of the collagen connective tissues. Manifestations include short-sightedness, cataracts, retinal problems leading to retinal detachment and possible blindness. This is principally the case among individuals with type 1 Stickler Syndrome. It is the most commonly identified inherited cause of retinal detachment in childhood. However, there is no consensus regarding best practice and no current guidelines on prophylactic interventions for this population. OBJECTIVES: The aim of this systematic review was to assess the evidence for the clinical effectiveness and safety of primary prophylactic interventions for the prevention of retinal detachment in previously untreated eyes without retinal detachment in patients with Stickler syndrome. The primary outcome of interest was retinal detachment post prophylaxis. DATA SOURCES: A systematic search was made of 11 databases of published and unpublished literature, which included MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing and Allied Health Literature and The Cochrane Library. There was no restriction by language or date. The references of all included studies were checked for further relevant citations and authors of studies with potentially relevant data were also contacted. REVIEW METHODS: Two reviewers double-screened all titles and abstracts of the citations retrieved by the search to identify studies that satisfied the inclusion criteria. Both reviewers also independently extracted and quality assessed all included studies. A narrative synthesis was performed. RESULTS: The literature search identified 1444 unique citations, of which four studies satisfied the inclusion criteria. The two principal studies were both retrospective cohort studies with control groups in populations with type 1 Stickler syndrome. One study evaluated 360° cryotherapy (n = 204) and the other focal or circumferential laser treatment (n = 22). Both studies reported a statistically significant difference in the rate of retinal detachment per eye between the groups receiving prophylaxis and the controls. However, both studies were subject to a high risk of bias. The results of the two supporting studies of Wagner-Stickler patients were either relatively inconsistent or unreliable. No study reported any major or long-term complications associated with the interventions. Despite the weaknesses of the evidence, the rate of retinal detachment in the intervention groups, especially the cryotherapy group, was lower than the rate either experienced in the study control groups or reported in other studies of untreated Stickler syndrome populations not exposed to prophylaxis. CONCLUSIONS: Only 360° cryotherapy and focal and circumferential laser treatment have been evaluated for the type 1 Stickler syndrome population, and then only by a single retrospective, controlled, cohort study in each case. Both of these studies report a significant difference between intervention and control groups (principally no treatment) and no major or long-term side effects or complications. However, there is a high risk of bias within these two studies, so the relative effectiveness of either intervention is uncertain. FUTURE WORK: A service priority is to determine reliably the prevalence of Stickler syndrome, i.e. how many individuals have type 1 or type 2 Stickler syndrome, and their risk of retinal detachment and subsequent blindness. A non-randomised, prospective cohort comparison study, in which eligible participants are treated, followed-up and analysed in one of three study arms, for no treatment, laser therapy or cryotherapy, would potentially offer further certainty in terms of the relative efficacy of both prophylaxis versus no prophylaxis and cryotherapy versus laser therapy than is possible with the currently available data. Alternatively, continued follow-up and analysis of existing study data, and data collection from relevant sample populations, are required to assess the long-term risks of blindness, retinal detachment and prophylaxis. FUNDING: This study was funded by the National Institute for Health Research Health Technology Assessment programme.

Standard haemostatic tests following major obstetric haemorrhage.

BACKGROUND: Postpartum haemorrhage is an important cause of maternal morbidity and mortality. It is associated with haemostatic impairment which may exacerbate bleeding. METHODS: All deliveries over a 3-year period in a large UK unit were reviewed and cases of haemorrhage of 1500 mL or more identified. Laboratory records were reviewed and the lowest value for haemoglobin, platelet count and fibrinogen, and longest value for prothrombin time and activated partial thromboplastin time within 24h of delivery were recorded. RESULTS: Of 18,501 deliveries there were 456 bleeds of 1500 mL or more (2.5%). Fibrinogen levels correlated best with blood loss (r -0.48 P<0.01) and fell progressively as volume increased. Activated partial thromboplastin time was less sensitive (r 0.4 P<0.01) to increasing blood loss. Prothrombin time did not correlate with blood loss (r 0.01). Activated partial thromboplastin time and prothrombin time remained within the normal range in most women despite large bleeds. Similar results were observed in women who received four or more units of red blood cells. Haemoglobin level was adequately maintained irrespective of blood loss. Based on UK national guidelines only 13 of 456 (3%) women should have received fresh frozen plasma, although it was given to 45; despite this, fibrinogen levels below the pregnancy-related normal range were observed in most cases. CONCLUSION: Fibrinogen level was the parameter that best correlated with increasing volume of haemorrhage and was the most useful marker of developing haemostatic impairment. Guidelines for fresh frozen plasma use in major postpartum haemorrhage were rarely followed and should be reviewed.