De novo and inherited mutations in the X-linked gene CLCN4 are associated with syndromic intellectual disability and behavior and seizure disorders in males and females.

Variants in CLCN4, which encodes the chloride/hydrogen ion exchanger CIC-4 prominently expressed in brain, were recently described to cause X-linked intellectual disability and epilepsy. We present detailed phenotypic information on 52 individuals from 16 families with CLCN4-related disorder: 5 affected females and 2 affected males with a de novo variant in CLCN4 (6 individuals previously unreported) and 27 affected males, 3 affected females and 15 asymptomatic female carriers from 9 families with inherited CLCN4 variants (4 families previously unreported). Intellectual disability ranged from borderline to profound. Behavioral and psychiatric disorders were common in both child- and adulthood, and included autistic features, mood disorders, obsessive-compulsive behaviors and hetero- and autoaggression. Epilepsy was common, with severity ranging from epileptic encephalopathy to well-controlled seizures. Several affected individuals showed white matter changes on cerebral neuroimaging and progressive neurological symptoms, including movement disorders and spasticity. Heterozygous females can be as severely affected as males. The variability of symptoms in females is not correlated with the X inactivation pattern studied in their blood. The mutation spectrum includes frameshift, missense and splice site variants and one single-exon deletion. All missense variants were predicted to affect CLCN4's function based on in silico tools and either segregated with the phenotype in the family or were de novo. Pathogenicity of all previously unreported missense variants was further supported by electrophysiological studies in Xenopus laevis oocytes. We compare CLCN4-related disorder with conditions related to dysfunction of other members of the CLC family.

Impact of a GP-led walk-in centre on NHS emergency departments.

OBJECTIVE: To determine the impact of the GP-led walk-in centre (WIC) in Sheffield (England) on the demand for emergency department (ED) care. METHODS: A survey of patients visiting the Sheffield GP WIC was conducted over 3 weeks during September and October 2011. A short, postvisit questionnaire was also sent to those who agreed to determine if the patient had used another NHS service for the same problem. Routine data were obtained from the adult and children's EDs and minor injuries unit in Sheffield, 1 year before and 1 year after the opening of the GP WIC. A linear model of the number of minor daytime attendances (GP type) per month was used to estimate the impact of opening the GP WIC, after controlling for seasonal variation and a linear time trend. RESULTS: A total of 529 patients responded to the survey (response rate 51%). Based on their self-reported intentions, 64 of these patients (53 adults and 11 children) were diverted from going to ED in the 3-week survey period as a result of the establishment of the GP WIC. From this we would have expected around a 26% monthly reduction in GP-type attendances at adult ED, and 7% reduction at children's ED. However, routine data only showed an 8% (95% CI 1% to 16%) reduction at the adult ED. Reductions in GP-type attendances at the children's ED and the minor injury unit at the time of the opening of the GP WIC were also found, but were not statistically significant. The estimated impact on children's ED was a 14% reduction (95% CI -38% to 8%), and for minor injuries unit (MIU) a 4% reduction (95% CI -18 to 9%). CONCLUSIONS: There was a statistically significant reduction in GP-type daytime attendances at the adult ED after the opening of the GP WIC. Since this reduction was not mirrored in changes in night-time attendances (when the GP WIC was closed), and our survey responses suggested some people were diverted from going to the ED, it is possible that the opening of the GP WIC caused this reduction.

Management of scaphoid fractures with CT scanning and virtual fracture clinic pathway reduces need for face-to-face clinic appointments.

INTRODUCTION: Early diagnosis is key to managing scaphoid fractures effectively. Computed tomography (CT) imaging can be effective if plain radiographs are negative. With increasing pressure on face-to-face clinics, consultant-led virtual fracture clinics (VFCs) are becoming increasingly popular. This study evaluates the management of patients with suspected scaphoid fractures using a standardised treatment protocol involving CT imaging and VFC evaluation. METHODS: The study was conducted at a busy district general hospital. The pathway began in February 2018. Patients presenting to the emergency department with a clinically suspected scaphoid fracture but an indeterminate radiograph had a CT scan, which was then reviewed in the VFC. Patients with a confirmed fracture were seen in a face-to-face clinic; patients without a confirmed fracture were discharged. Patient pathway outcome measures were analysed pre- and post-pathway, and a cost analysis was performed. RESULTS: A total of 164 pre-pathway patients (93%) were given a face-to-face fracture clinic appointment; 76 were discharged after their first visit. Nine patients seen in clinic had a CT scan and were discharged with no fracture. If these patients had been referred to the VFC, had CT scans and been directly discharged, it would have saved £1,629. A total of 41 patients from the post-pathway group (37%) had a CT scan and were discharged from the VFC. Avoiding face-to-face clinic appointments saved £7,421. Extrapolating, the annual savings would be £29,687. CONCLUSIONS: This study shows that a VFC/CT pathway to manage patients with a suspected scaphoid fracture is cost-effective. It limits face-to-face appointments by increasing use of CT to exclude fractures.

A 1q44 deletion, paternal UPD of chromosome 2 and a deletion due to a complex translocation detected in children with abnormal phenotypes using new SNP array technology.

Children with intellectual disability, dysmorphic features, malformations and/or growth abnormalities frequently display normal karyotypes. Recent studies have shown that genome-wide single nucleotide polymorphism (SNP) arrays can be effective in detecting abnormalities involving copy number variation (CNV), deletions, duplications and loss of heterozygosity (LOH) that routine cytogenetic tests fail to identify. Five patients with various degrees of intellectual disability and/or dysmorphic features and other malformations were whole-genome genotyped using the Human-1 Genotyping BeadChip--Exon-Centrix 100K SNP arrays (Illumina). All patients had undergone routine cytogenetic testing; four patients had normal karyotypes, while one patient had an apparently balanced complex translocation involving chromosomes 1q25, 1q32, 2q23, 7q22 and 16q24. We detected deletions on chromosome 1q44 and 13q31.1 in one patient, and LOH of the entire chromosome 2 in another patient, both with cytogenetically normal karyotypes. The patient with the complex translocation had a deletion on chromosome 7q22.2-22.3, which is in conjunction with one of the translocation breakpoints. Our findings provide further evidence of there being a critical region for the development of microcephaly and corpus callosum abnormalities in children with distal 1q deletions. We have also shown that apparently balanced complex translocations might not be balanced at the DNA level, and we report the fourth case of paternal uniparental disomy of chromosome 2. The results of this study suggest that it may be desirable to investigate idiopathic mental retardation using genome-wide SNP arrays, in conjunction with other cytogenetic and molecular techniques.

Is it cost effective to introduce paramedic practitioners for older people to the ambulance service? Results of a cluster randomised controlled trial.

BACKGROUND: A scheme to train paramedics to undertake a greater role in the care of older people following a call for an emergency ambulance was developed in a large city in the UK. OBJECTIVES: To assess the cost effectiveness of the paramedic practitioner (PP) scheme compared with usual emergency care. METHODS: A cluster randomised controlled trial was undertaken of PP compared with usual care. Weeks were allocated to the study group at random to the PP scheme either being active (intervention) or inactive (control). Resource use data were collected from routine sources, and from patient-completed questionnaires for events up to 28 days. EQ-5D data were also collected at 28 days. RESULTS: Whereas the intervention group received more PP contact time, it reduced the proportion of emergency department (ED) attendances (53.3% vs 84.0%) and time in the ED (126.6 vs 211.3 minutes). There was also some evidence of increased use of health services in the days following the incident for patients in the intervention group. Overall, total costs in the intervention group were 140 UK pounds lower when routine data were considered (p = 0.63). When the costs and QALY were considered simultaneously, PP had a greater than 95% chance of being cost effective at 20 000 UK pounds per QALY. CONCLUSION: Several changes in resource use are associated with the use of PP. Given these economic results in tandem with the clinical, operational and patient-related benefits, the wider implementation and evaluation of similar schemes should be considered.

The gap after trapeziectomy: a prospective study.

Thirteen patients with basal joint arthritis of the thumb were treated by simple trapeziectomy. All patients underwent radiological assessment pre-operatively and at 2, 4 and 12 weeks after surgery. Special standardised views were taken to assess changes in the 'trapezial gap'. Collapse of this was noticed up to 4 weeks following surgery but no significant change occurred thereafter. In respect of this collapse, prolonging immobilisation after 4 weeks is probably unnecessary.

Effectiveness of measures to reduce emergency department waiting times: a natural experiment.

OBJECTIVES: To determine what measures were introduced by emergency departments in response to the national monitoring week in March 2003, and which, if any, of these were most effective in reducing waiting times. METHODS: A postal survey of all emergency departments in England was undertaken to gather data on measures taken. Department waiting times before, during, and after monitoring week were determined from data held by the Department of Health and linked to the survey data for analysis. RESULTS: A total of 111/198 responses (56%) were received. Departments had taken a wide range of measures to improve waiting times. The commonest were additional senior doctor hours (39%), creation of a "four hour monitor" role (37%), improved access to emergency beds (36%), additional non-clinical staff hours (33%), additional junior doctor hours (32%), additional nursing hours (29%), and triage by senior staff (28%). In 35 departments (32%) no changes were made at all to usual practice. The biggest influence on improved performance during monitoring week was the number of measures that a department took, rather than any specific measure, although there was weak evidence that additional junior medical and non-clinical staff time may have contributed more than other measures. CONCLUSIONS: Improved waiting time performance may depend, at least in the short term, more on the amount of effort expended than on introducing a single effective change. In addition, those measures most likely to be helpful are likely also to require additional resources.

Prediction of mortality among emergency medical admissions.

BACKGROUND: The Rapid Acute Physiology Score (RAPS) and Rapid Emergency Medicine Score (REMS) are risk adjustment methods for emergency medical admissions developed for use in audit, research, and clinical practice. Each predicts in hospital mortality using four (RAPS) or six (REMS) variables that can be easily recorded at presentation. We aimed to evaluate the predictive value of REMS, RAPS, and their constituent variables. METHODS: Age, heart rate, respiratory rate, blood pressure, Glasgow Coma Score (GCS) and oxygen saturation were recorded for 5583 patients who were transported by emergency ambulance, admitted to hospital and then followed up to determine in hospital mortality. The discriminant power of each variable, RAPS, and REMS were compared using the area under the receiver operator characteristic curve (AROCC). Multivariate analysis was used to identify which variables were independent predictors of mortality. RESULTS: REMS (AROCC 0.74; 95% CI 0.70 to 0.78) was superior to RAPS (AROCC 0.64; 95% CI 0.59 to 0.69) as a predictor of in hospital mortality. Although all the variables, except blood pressure, were associated with mortality, multivariate analysis showed that only age (odds ratio 1.74, p < 0.001), GCS (2.10, p < 0.001), and oxygen saturation (OR 1.36, p = 0.01) were independent predictors. A combination of age, oxygen saturation, and GCS (AROCC 0.80, 95% CI 0.77 to 0.83) was superior to REMS in our population. CONCLUSION: REMS is a better predictor of mortality in emergency medical admissions than RAPS. Age, GCS, and oxygen saturation appear to be the most useful predictor variables. Inclusion of other variables in risk adjustment scores, particularly blood pressure, may reduce their value.

The evolution of the emergency care practitioner role in England: experiences and impact.

BACKGROUND: The emergency care practitioner (ECP) is a generic practitioner who combines extended nursing and paramedic skills. The "new" role emerged out of changing workforce initiatives intended to improve staff career opportunities in the National Health Service and ensure that patients' health needs are assessed appropriately. OBJECTIVE: To describe the development of ECP Schemes in 17 sites, identify criteria contributing to a successful operational framework, analyse routinely collected data and provide a preliminary estimate of costs. METHODS: There were three methods used: (a) a quantitative survey, comprising a questionnaire to project leaders in 17 sites, and analysis of data collected routinely; (b) qualitative interpretation based on telephone interviews in six sites; and (c) an economic costing study. RESULTS: Of 17 sites, 14 (82.5%) responded to the questionnaire. Most ECPs (77.4%) had trained as paramedics. Skills and competencies have been extended through educational programmes, training, and assessment. Routine data indicate that 54% of patient contacts with the ECP service did not require a referral to another health professional or use of emergency transport. In a subset of six sites, factors contributing to a successful operational framework were strategic visions crossing traditional organisational boundaries and appropriately skilled workforce integrating flexibly with existing services. Issues across all schemes were patient safety, appropriate clinical governance, and supervision and workforce issues. On the data available, the mean cost per ECP patient contact is 24.00 pounds sterling, which is less than an ED contact of 55.00 pounds sterling. CONCLUSION: Indications are that the ECP schemes are moving forward in line with original objectives and could be having a significant impact on the emergency services workload.

Effect of a national urgent care telephone triage service on population perceptions of urgent care provision: controlled before and after study.

OBJECTIVE: To measure the effect of an urgent care telephone service NHS 111 on population perceptions of urgent care. DESIGN: Controlled before and after population survey, using quota sampling to identify 2000 respondents reflective of the age/sex profile of the general population. SETTING: England. 4 areas where NHS 111 was introduced, and 3 control areas where NHS 111 had yet to be introduced. PARTICIPANTS: 28 071 members of the general population, including 2237 recent users of urgent care. INTERVENTION: NHS 111 offers advice to members of the general population seeking urgent care, recommending the best service to use or self-management. Policymakers introduced NHS 111 to improve access to urgent care. OUTCOMES MEASURES: The primary outcome was change in satisfaction with recent urgent care use 9 months after the launch of NHS 111. Secondary outcomes were change in satisfaction with urgent care generally and with the national health service. RESULTS: The overall response rate was 28% (28 071/100 408). 8% (2237/28 071) had used urgent care in the previous 3 months. Of the 652 recent users of urgent care in the NHS 111 intervention areas, 9% (60/652) reported calling NHS 111 in the 'after' period. There was no evidence that the introduction of NHS 111 was associated with a changed perception of recent urgent care. For example, the percentage rating their experience as excellent remained at 43% (OR 0.97, 95% CI 0.69 to 1.37). Similarly, there was no change in population perceptions of urgent care generally (1.06, 95% CI 0.95 to 1.17) or the NHS (0.94, 95% CI 0.85 to 1.05) following the introduction of NHS 111. CONCLUSIONS: A new telephone triage service did not improve perceptions of urgent care or the health service. This could be explained by the small amount of NHS 111 activity in a large emergency and urgent care system.

Longer term clinical and economic benefits of offering acupuncture care to patients with chronic low back pain.

OBJECTIVES: To test whether patients with persistent non-specific low back pain, when offered access to traditional acupuncture care alongside conventional primary care, gained more long-term relief from pain than those offered conventional care only, for equal or less cost. Safety and acceptability of acupuncture care to patients, and the heterogeneity of outcomes were also tested. DESIGN: A pragmatic, two parallel group, randomised controlled trial. Patients in the experimental arm were offered the option of referral to the acupuncture service comprising six acupuncturists. The control group received usual care from their general practitioner (GP). Eligible patients were randomised in a ratio of 2:1 to the offer of acupuncture to allow between-acupuncturist effects to be tested. SETTING: Three non-NHS acupuncture clinics, with referrals from 39 GPs working in 16 practices in York, UK. PARTICIPANTS: Patients aged 18-65 years with non-specific low back pain of 4-52 weeks' duration, assessed as suitable for primary care management by their general practitioner. INTERVENTIONS: The trial protocol allowed up to ten individualised acupuncture treatments per patient. The acupuncturist determined the content and the number of treatments according to patient need. MAIN OUTCOME MEASURES: The Short Form 36 (SF-36) Bodily Pain dimension (range 0-100 points), assessed at baseline, and 3, 12 and 24 months. The study was powered to detect a 10-point difference between groups at 12 months post-randomisation. Cost--utility analysis was conducted at 24 months using the EuroQoL 5 Dimensions (EQ-5D) and a preference-based single index measure derived from the SF-36 (SF-6D). Secondary outcomes included the McGill Present Pain Index (PPI), Oswestry Pain Disability Index (ODI), all other SF-36 dimensions, medication use, pain-free months in the past year, worry about back pain, satisfaction with care received, and safety and acceptability of acupuncture care. RESULTS: A total of 159 patients were in the 'acupuncture offer' arm and 80 in the 'usual care' arm. All 159 patients randomised to the offer of acupuncture care chose to receive acupuncture treatment, and received an average of eight acupuncture treatments within the trial. Analysis of covariance, adjusting for baseline score, found an intervention effect of 5.6 points on the SF-36 Pain dimension [95% confidence interval (CI) -1.3 to 12.5] in favour of the acupuncture group at 12 months, and 8 points (95% CI 0.7 to 15.3) at 24 months. No evidence of heterogeneity of effect was found for the different acupuncturists. Patients receiving acupuncture care did not report any serious or life-threatening events. No significant treatment effect was found for any of the SF-36 dimensions other than Pain, or for the PPI or the ODI. Patients receiving acupuncture care reported a significantly greater reduction in worry about their back pain at 12 and 24 months compared with the usual care group. At 24 months, the acupuncture care group was significantly more likely to report 12 months pain free and less likely to report the use of medication for pain relief. The acupuncture service was found to be cost-effective at 24 months; the estimated cost per quality-adjusted (QALY) was 4241 pounds sterling (95% CI 191 pounds sterling to 28,026 pounds sterling) using the SF-6D scoring algorithm based on responses to the SF-36, and 3598 pounds sterling (95% CI 189 pounds sterling to 22,035 pounds sterling) using the EQ-5D health status instrument. The NHS costs were greater in the acupuncture care group than in the usual care group. However, the additional resource use was less than the costs of the acupuncture treatment itself, suggesting that some usual care resource use was offset. CONCLUSIONS: Traditional acupuncture care delivered in a primary care setting was safe and acceptable to patients with non-specific low back pain. Acupuncture care and usual care were both associated with clinically significant improvement at 12- and 24-month follow-up. Acupuncture care was significantly more effective in reducing bodily pain than usual care at 24-month follow-up. No benefits relating to function or disability were identified. GP referral to a service providing traditional acupuncture care offers a cost-effective intervention for reducing low back pain over a 2-year period. Further research is needed to examine many aspects of this treatment including its impact compared with other possible short-term packages of care (such as massage, chiropractic or physiotherapy), various aspects of cost-effectiveness, value to patients and implementation protocols.

The gene for the human interleukin-11 receptor alpha chain locus is highly homologous to the murine gene and contains alternatively spliced first exons.

The gene for the murine interleukin-11 receptor alpha chain (mIL-11R alpha) contains two loci (1 and 2), of which locus 2 is restricted to only some mouse strains. Two alternatively spliced exons (1a and 1b) encode the 5' untranslated region (5'UTR) of the murine locus 1. We have characterized the gene for the human interleukin-11 receptor alpha chain locus (hIL-11R alpha), examined its expression by Northern analysis and determined its chromosomal location by fluorescence in situ hybridization. The presence of exon(s) encoding the 5'UTR and mapping of transcription initiation sites was determined by reverse-transcriptase polymerase chain reaction and 5' rapid amplification of cDNA ends (5'RACE) techniques. The human locus spanned 10 kilobasepairs (kb) and consisted of 14 exons. Two alternatively spliced first exons (1a and 1b) encoding the 5'UTR were identified and shared 76 and 73% nucleotide identity with murine exons 1a and 1b. Multiple transcription start sites were demonstrated for human exon 1a. The promoter regions of both human exons 1a and 1b did not display a canonical TATA box. A predominant 1.8 kb transcript for the hIL-11R alpha was present in heart, brain, skeletal muscle, lymph nodes, thymus, appendix, pancreas and foetal liver. The hIL-11R alpha gene was localized to chromosome 9p13. In summary, the hIL-11R alpha gene was highly related to locus 1 of the murine gene and there was no evidence of a second hIL-11R alpha locus.

Isolation and identification of homeobox genes from the human placenta including a novel member of the Distal-less family, DLX4.

We have carried out a DNA binding site screen of a 32-week human placental cDNA library using a consensus homeodomain binding site as a probe. This study represents the first library screen carried out to isolate homeobox genes from the human placenta. We have shown that three homeobox genes known to be expressed in the embryo, HB24, GAX and MSX2 are also expressed in the placenta. We have also identified a novel homeobox gene, DLX4, that shows 85% sequence identity with the homeodomain encoded by the Drosophila Distal-less (Dll) gene. DLX4 therefore represents a new member of the Distal-less family of homeobox genes. This is the first evidence that members of the Distal-less family of homeobox genes are expressed in the placenta. Using fluorescence in situ hybridisation (FISH), DLX4 has been assigned to human chromosome 17q21-q22. This places DLX4 in the same region of chromosome 17 as another member of the Distal-less family, DLX3 (Scherer et al., 1995), and the HOX-B homeobox gene cluster (Acampora et al., 1989: Boncinelli et al., 1991). Members of the Distal-less family (DLX1 and DLX2; DLX5 and DLX6) are found as closely linked pairs on human chromosomes (Simeone et al., 1994). We predict that DLX3 and DLX4 are closely linked and have arisen through gene duplication and divergence from a common ancestral precursor.

AMP-activated protein kinase isoenzyme family: subunit structure and chromosomal location.

The AMP-activated protein kinase (AMPK) consists of catalytic alpha and non-catalytic, beta and gamma (38 kDa) subunits and is responsible for acting as a metabolic sensor for AMP levels. There are multiple genes for each subunit and we find that rat liver AMPK-alpha2 isoform catalytic subunit is associated with beta1 and gamma1 and not with beta2 or gamma2 subunit isoforms. The beta1 and gamma1 isoforms are also subunits of the alpha1 isoform. The sequence of cloned human AMPK-beta1 is 95% identical in amino acid sequence with rat beta1. Human chromosomal localizations were determined for AMPK-alpha1 (5p11-p14), AMPK-beta1 (12q24.1-24.3) and AMPK-gamma1 (12q12-q14), respectively.

A randomized, prospective, blinded comparison of postoperative pain, metabolic response, and perceived health after laparoscopic and small incision cholecystectomy.

BACKGROUND: We have previously shown that in a randomized comparison of laparoscopic (LC) versus small incision (SC) cholecystectomy, postoperative hospital stay is comparable. This randomized prospective study compares the postoperative pain, analgesic and antiemetic consumption, perceived health, and metabolic and respiratory responses after these two procedures. METHODS: Two hundred patients were recruited; postoperative stay, pain scores, analgesic and antiemetic consumption were recorded. Nottingham Health Profile questionnaires were completed by a subgroup of 100 patients, and the metabolic and respiratory responses were also compared in a further subgroup of 20 patients. RESULTS: Pain scores in both groups were low. LC, however, was associated with lower postoperative pain scores and analgesic requirements compared with SC, but the antiemetic requirements were greater after LC. The duration of hospital stay and the perceived health after operation were the same in both groups, and both procedures were associated with a similar reduction of respiratory function. Twenty-four hours after operation the inflammatory (C-reactive protein, CRP) response to LC (22 +/- 20 mg/L) was significantly lower than after SC (68 +/- 30 mg/L), but the neuroendocrine (cortisol) response was similar (LC, 475 +/- 335 nmol/L, compared with SC, 710 +/- 410 nmol/L). Independent of the technique used, the duration of postoperative hospital stay correlated significantly with the magnitude of both the 24-hour postoperative cortisol and CRP responses (cortisol: rs = 0.678, p < 0.001; CRP: rs = 0.566, p = 0.011). CONCLUSIONS: LC appears to be associated with less tissue destruction and pain than SC, but this did not confer any advantage in the degree of postoperative respiratory impairment, length of hospital stay, or postoperative perceived health. The neuroendocrine component of the metabolic response evoked by each procedure was similar and had a significant correlation to patient's postoperative hospital stay. This finding may explain the similar postoperative recovery after LC and SC.

Cloning, characterisation and chromosomal assignment of the human adenosine A3 receptor (ADORA3) gene.

The gene for the inhibitory G-protein coupled human A3 adenosine receptor (ADORA3) was isolated and sequence analysis shows that the coding region is interrupted by a single intron of size 2.4 kb. The location of this intron in the second intracellular loop is conserved with respect to the A1, A2a and A2b adenosine receptor subtype genes. The ADORA3 gene was mapped to 1p13.3 by fluorescence in situ hybridisation. Northern blot studies show that the gene is widely expressed and is most abundant in brain and some endocrine tissues. We have mapped multiple transcription start sites in two cell lines and lung tissue by primer extension and 5' RACE (rapid amplification of cDNA ends). The ADORA3 gene promoter lacks CAAT and TATA boxes but has putative binding sites for multiple transcription factors. In contrast to the A1 adenosine receptor gene we find no evidence of alternate splicing in the 5' untranslated region of the ADORA3 gene.

Routine preoperative testing: a systematic review of the evidence.

OBJECTIVES. To review the available evidence on the value of routine preoperative testing in healthy or asymptomatic adults. To assess the completeness of existing reviews of preoperative testing and how applicable their conclusions are to the UK. To identify areas for further research. HOW THE RESEARCH WAS CONDUCTED. The databases Medline, Embase, Biological Abstracts, Science Citation Index and HealthSTAR were thoroughly searched for relevant articles which were then classified and appraised. The databases of the Centre for Reviews and Dissemination (DARE and NHS Economic Evaluations Database) and the Cochrane Collaboration (the Cochrane Library) were also used to verify the completeness of the search. In this review, 'routine' tests are defined as those ordered for an asymptomatic, apparently healthy individual in the absence of any specific clinical indication, to identify conditions undetected by clinical history and examination. RESEARCH FINDINGS. No controlled trials of the value of the following routine preoperative tests have been published. All available evidence reports the results of case-series. CHEST X-RAY. Few studies allow the outcome of routine chest X-rays to be distinguished from those of indicated chest X-rays, and fewer have gone beyond abnormality yields to examine the impact on clinical management. Findings from routine preoperative chest X-ray are reported as abnormal in 2.5-37.0% of cases, and lead to a change in clinical management in 0-2.1% of patients. The effect on patient outcomes is unknown. Both abnormality yield and impact on patient management rise with age and poorer American Society of Anesthesiologists (ASA) status. The limited evidence on the value of a chest X-ray as a baseline measure suggests that it will be of value in less than 9% of patients. ELECTROCARDIOGRAPHY. The findings from routine preoperative electrocardiograms (ECGs) are abnormal in 4.6-31.7% of cases, and lead to a change of management in 0-2.2% of patients. The effect on patient outcomes is unknown. The proportion of abnormal tests rises with age and worsening ASA status. The predictive power of preoperative ECGs for postoperative cardiac complications in non-cardiopulmonary surgery is weak. There is no evidence to support the value of recording a preoperative ECG as a 'baseline.' HAEMOGLOBIN MEASUREMENT AND BLOOD COUNTS. Routine preoperative measurement shows that the haemoglobin level may be lower than 10-10.5 g/dl in up to 5% of patients, but that it is rarely lower than 9 g/dl. The routine test leads to a change of management in 0.1% to 2.7% of patients. Routine preoperative measurement shows that the platelet count is abnormally low in less than 1.1% of patients, and that platelet count results rarely if ever lead to change in management of patients. Routine preoperative white blood cell count is abnormal in less than 1% of patients, and rarely if ever leads to change in management of patients. TESTS OF HAEMOSTASIS. Abnormalities of bleeding time, prothrombin time and partial thromboplastin time are found in up to 3.8%, 4.8% and 15.6% of routine preoperative tests, respectively. The results of these tests very rarely lead to change in the clinical management of patients. BIOCHEMISTRY. In routine preoperative tests of serum biochemistry, abnormal levels of sodium or potassium are found in up to 1.4% of patients, and abnormal levels of urea or creatinine are found in up to 2.5% of patients. Abnormal levels of glucose are found in up to 5.2% of patients. These abnormalities rarely lead to change in clinical management of patients. URINE TESTING. Routine preoperative urinalysis finds abnormal results in 1-34.1% of patients, and leads to a change of management in 0.1-2.8% of patients. The only abnormality that leads to a change in management of patients is the finding of white blood cells in the urine. There is no good evidence that preoperative abnormal urinalysis is associated with any postoperative complication in non-urinary tract surgery. (ABSTRACT TRUNCATED)

A randomised controlled trial of prehospital intravenous fluid replacement therapy in serious trauma.

RESULTS: In total 1309 patients were entered in the study: 699 (53.4%) were treated by paramedics operating protocol A and 610 (46.6%) were treated by paramedics operating protocol B. The randomisation worked well and there were no significant differences between treatment groups in incident characteristics, ambulance performance times, or patient or injury characteristics, apart from slightly more moderate or severe head injuries in the protocol A group (25.3% versus 20.3%). Protocol compliance was poor, with only 31% of protocol A patients receiving prehospital fluids and only 80% of protocol B patients not given fluids. The estimated odds ratio for being given prehospital fluids when treated by protocol A compared to protocol B was 2.09 (95% confidence interval (CI), 1.53 to 2.81). MORTALITY: There were 73 deaths within 6 months in the 699 patients in the protocol A group (10.4%), and 60/610 (9.8%) in the protocol B group. Thus the crude odds ratio for deaths when managed by protocol A was 1.07 (95% CI, 0.73 to 1.54). Excluding 26 patients whose cause of death may not have been trauma related, the odds ratio was 1.04 (95% CI, 0.69 to 1.55). Excluding 17 patients who may have been dead on arrival of the ambulance at the scene the odds ratio was 1.04 (95% CI, 0.70 to 1.53). Adjustment for age, injury severity and whether the patient was unconscious at the scene did not significantly alter these odds ratios. COMPLICATIONS: A total of 106 patients were identified from hospital notes as having at least one of eight major complications (adult respiratory distress syndrome, sepsis, acute renal failure, coagulopathy, wound infection, pneumonia, fat embolism or pulmonary embolism). The proportions with recorded complications were similar in the two groups: 60/699 (8.5%) in the protocol A group versus 46/610 (7.5%) in the protocol B group. HEALTH STATUS: A total of 878 questionnaires were sent to patients, and 559 (64%) usable replies were received. The response rate was similar in the two groups (62.9% versus 64.6%). In all eight dimensions of the SF-36 health status measure patients who had been managed by paramedics operating protocol A reported better average health than did patients in the protocol B group. However, none of the differences were at a level considered clinically important and only for one of the eight dimensions was the difference statistically significant. COMPOSITE OUTCOMES: No significant differences in outcome were found between the two protocol groups in terms of patients who either died or had serious complications, nor for patients who either died or had known poor health. SUBGROUPS: Subgroups of patients were defined on eight characteristics (ambulance service area, whether a doctor was on scene, paramedic-patient contact time, injury severity, whether taken to theatre for emergency surgery, type of injuries, type of area, and whether the patient was treated before or after protocol cross-over). There was no evidence of any difference in mortality rates or composite outcomes between any subgroups, or between protocols within any subgroup. Time to A&E department The analysis suggests that patients given fluids spent 12-13 minutes longer at the accident scene than did patients not given fluids. However, because only one-quarter of patients were given fluids, and the specific protocol used made little difference to this, average on-scene times were largely unaffected by protocols. COSTS: In the prehospital and immediate-care phase (including A&E treatment), the mean costs of the protocol A and protocol B groups were ¿419 and ¿416, respectively. This small difference reflects two small and offsetting effects of protocol B: reduced on-scene time (p = 0.08) and increased use of blood in the A&E department (p = 0.03). There were no other statistically significant differences in costs, with the mean total costs being ¿2706 and ¿2678 in the protocol A and protocol B groups, respectively (p = 0.52). (ABSTRACT TRUNCA

Neonatal screening for inborn errors of metabolism: cost, yield and outcome.

OBJECTIVES. To systematically review the literature on inborn errors of metabolism, neonatal screening technology and screening programmes in order to analyse the costs and benefits of introducing screening based on tandem mass-spectrometry (tandem MS) for a wide range of disorders of amino acid and organic acid metabolism in the UK. To evaluate screening for cystic fibrosis, Duchenne muscular dystrophy and other disorders which are tested on an individual basis. HOW THE RESEARCH WAS CONDUCTED. Systematic searches were carried out of the literature on inborn errors of metabolism, neonatal screening programmes, tandem MS-based neonatal screening technology, economic evaluations of neonatal screening programmes and psychological aspects of neonatal screening. Background material on the biology of inherited metabolic disease, the basic philosophy, and the history and current status of the UK screening programme was also collected. Relevant papers in the grey literature and recent publications were identified by hand-searching. Each paper was graded. For each disease an aggregate grade for the state of knowledge in six key areas was awarded. Additional data were prospectively collected on activity and costs in UK neonatal screening laboratories, and expert clinical opinion on current treatment modalities and outcomes. These data were used to construct a decision-analysis model of neonatal screening technologies, comparing tandem MS with the existing phenylketonuria screening methods. This model determined the cost per additional case identified and, for each disease, the additional treatment costs per case, and the cost per life-year saved. All costs and benefits were discounted at 6% per annum. One-way sensitivity analysis was performed showing the effect of varying the discount rate, the incidence rate of each disorder, the number of neonates screened and the cost of tandem MS, on the cost per life-year gained. RESEARCH FINDINGS. The UK screening programmes for phenylketonuria and congenital hypothyroidism have largely achieved the expected objectives and are cost-effective. Current concerns are the difficulty of maintaining adequate coverage, perceived organisational weaknesses, and a lack of overview. For many of the organic acid disorders it was necessary to rely on data obtained from clinically-diagnosed cases. Many of these diseases can be treated very effectively and a sensitive screening test was available for most of the diseases. Except for cystic fibrosis, there have been no randomised controlled trials of the overall effectiveness of neonatal screening. Despite the anxiety generated by the screening process, there is strong parental support for screening. The effects of diagnosis through screening on subsequent reproductive behaviour is less clear. Conflicts exist between current concepts and the traditional principles of screening. The availability of effective treatment is not an absolute prerequisite: early diagnosis is of value to the family concerned and, to the extent that is leads to increased use of prenatal diagnosis, may help to reduce the overall burden of disease. Neonatal screening is also of value in diseases which present early but with non-specific symptoms. Indeed, almost all of the diseases considered could merit neonatal screening. The majority of economic evaluations failed to incorporate the health benefits from screening, and therefore failed to address the value of the information which the screening programmes provided to parents. The marginal cost of changing from present technology to tandem MS would be approximately 0.60 pounds per baby at a workload of 100,000 samples a year, and 0.87 pounds at 50,000 samples per year. The ability to screen for a wider range of diseases would lead to the identification of some 20 additional cases per 100,000 infants screened, giving a laboratory cost per additional diagnosis of 3000 pounds at an annual workload of 100,000 babies per year.(ABSTRACT TRUNCATED)

Epidemiology of babies dying at different ages from the sudden infant death syndrome.

An analysis of data from the United Kingdom multicentre study of postneonatal mortality has been made to assess whether there are causally distinct groups of babies dying from the Sudden Infant Death Syndrome (SIDS), and to develop explicit risk factor profiles for the subgroups. The 303 SIDS babies in the multicentre study were divided into four subgroups by age at death: weeks 1-7, 8-15, 16-23, and 24 or more weeks. Contrasts between these subgroups with respect to 28 epidemiological characteristics and to pathology findings were investigated. Significant contrasts in the number of previous pregnancies, duration of the 2nd stage of labour, gestational length, family finances and repair of housing were found. Overall, very strong evidence of epidemiological differences was found (chi 2(9) = 29.3, p less than 0.001), and of contrasts in the nature and degree of any acquired terminal disease. It is concluded that there are different causes of SIDS with different distributions according to age at death.