Enzyme replacement improves survival among patients with pancreatic cancer: Results of a population based study.

BACKGROUND: Pancreatic exocrine insufficiency (PEI) and malnutrition are prevalent among patients with pancreatic adenocarcinoma. Pancreatic enzyme replacement therapy (PERT) can correct PEI but its use among patients with pancreatic cancer is unclear as are effects upon survival. This population-based study sought to address these issues METHODS: Subjects with pancreatic adenocarcinoma were identified from the UK Clinical Practice Research Datalink (CPRD). Propensity score matching generated matched pairs of subjects who did and did not receive PERT. Progression to all-cause mortality was compared using parametric survival models that included a range of relevant co-variables RESULTS: PERT use among the whole cohort (987/4554) was 21.7%. Some 1614 subjects generated 807 matched pairs. This resulted in a total, censored follow-up period of 1643 years. There were 1403 deaths in total, representing unadjusted mortality rates of 748 and 994 deaths per 1000 person-years for PERT-treated cases and their matched non-PERT-treated controls, respectively. With reference to the observed survival in pancreatic adenocarcinoma patients, adjusted median survival time was 262% greater in PERT-treated cases (survival time ratio (STR) = 2.62, 95% CI 2.27-3.02) when compared with matched, non-PERT-treated controls. Survival remained significantly greater among subjects receiving PERT regardless of the studied subgroup with respect to use of surgery or chemotherapy CONCLUSIONS: This population based study observes that the majority of patients with pancreatic adenocarcinoma do not receive PERT. PERT is associated with increased survival among patients with pancreatic adenocarcinoma suggesting a lack of clinical awareness and potential benefit of addressing malnutrition among these patients.

Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls.

AIMS: Clinical and observational studies have shown an increased risk of cardiovascular events and death associated with sulphonylureas versus metformin. However, it has never been determined whether this was due to the beneficial effects of metformin or detrimental effects of sulphonylureas. The objective of this study was therefore to compare all-cause mortality in diabetic patients treated first-line with either sulphonylurea or metformin monotherapy with that in matched individuals without diabetes. METHODS: We used retrospective observational data from the UK Clinical Practice Research Datalink (CPRD) from 2000. Subjects with type 2 diabetes who progressed to first-line treatment with metformin or sulphonylurea monotherapy were selected and matched to people without diabetes. Progression to all-cause mortality was compared using parametric survival models that included a range of relevant co-variables. RESULTS: We identified 78,241 subjects treated with metformin, 12,222 treated with sulphonylurea, and 90,463 matched subjects without diabetes. This resulted in a total, censored follow-up period of 503,384 years. There were 7498 deaths in total, representing unadjusted mortality rates of 14.4 and 15.2, and 50.9 and 28.7 deaths per 1000 person-years for metformin monotherapy and their matched controls, and sulphonylurea monotherapy and their matched controls, respectively. With reference to observed survival in diabetic patients initiated with metformin monotherapy [survival time ratio (STR) = 1.0], adjusted median survival time was 15% lower (STR = 0.85, 95% CI 0.81-0.90) in matched individuals without diabetes and 38% lower (0.62, 0.58-0.66) in diabetic patients treated with sulphonylurea monotherapy. CONCLUSIONS: Patients with type 2 diabetes initiated with metformin monotherapy had longer survival than did matched, non-diabetic controls. Those treated with sulphonylurea had markedly reduced survival compared with both matched controls and those receiving metformin monotherapy. This supports the position of metformin as first-line therapy and implies that metformin may confer benefit in non-diabetes. Sulphonylurea remains a concern.

A survey of Core Medical Trainees' opinions on the ePortfolio record of educational activities: beneficial and cost-effective?

OBJECTIVES: To evaluate Core Medical Trainees' (CMTs) opinions on the role of the ePortfolio in postgraduate education. DESIGN AND SETTING: Cross-sectional survey of 91 CMTs in five NHS trusts within the South Thames Deanery. PARTICIPANTS: Completed surveys were received from 80 Core Medical Trainees. RESULTS: A total of 84% agreed that an ongoing record of progress is necessary, only 5% felt the ePortfolio represents value for money; 78% of respondents were unclear as to how the Freedom of Information Act (2000) impacts on the ePortfolio, and most were uninformed of the extent to which their entries can be accessed by third parties. CONCLUSIONS: Trainees recognise the importance of recording ongoing progress, but most consider the ePortfolio to be poor value for money. There is uncertainty regarding ownership of information held on ePortfolio, and to what extent it can be accessed. There are inadequate opportunities to discuss concerns. This requires further deliberation and until things are clarified, trainees may not fully engage with the resource.

Awareness in children: a secondary analysis of five cohort studies.

Five recent cohort studies have shown a frequency of awareness in paediatric anaesthesia of between 0.2% and 1.2%, but they were not individually large enough to identify risk factors. This study pooled raw data from these five studies to identify factors associated with awareness in children. The outcome of awareness was taken as the cases judged to be most likely awareness cases in each study. Logistic regression was used to identify awareness-associated factors. A combined sample of 4486 anaesthetics revealed 33 cases of awareness. Unadjusted analysis demonstrated weak evidence that nitrous oxide used as an anaesthetic maintenance adjunct was associated with awareness (OR 2.04 (95% CI 0.97-4.33), p=0.06), and some evidence that use of a tracheal tube was associated with awareness (OR 2.78 (95% CI 1.11-6.94), p=0.03). Multivariable regression analysis revealed that nitrous oxide maintenance and use of a tracheal tube were independently associated with awareness (nitrous oxide, OR 2.4 (95% CI 1.08-5.32), p=0.03; tracheal tube, OR 3.0 (95% CI 1.20-7.56), p=0.02).

A study of prenatal ultrasound and postnatal magnetic imaging in the diagnosis of central nervous system abnormalities.

Accurate prenatal diagnosis of central nervous system (CNS) abnormalities is essential in counselling parents, as they are the most common developmental abnormalities causing considerable mortality. Currently, the standard in prenatal imaging is ultrasound scanning (USS). The introduction of fast acquisition magnetic resonance imaging (MRI) has lead to increased diagnostic confidence and information available for parents. Frequently USS initially identifies CNS abnormalities as ventriculomegaly alone. However, it is known that ventriculomegaly is commonly associated with other CNS pathology, which may adversely affect the prognosis. As MRI has superior soft tissue resolution and can be used at any time postnatally, it is expected to identify disorders of myelination that may result from prenatal ventriculomegaly. This study will evaluate the role of MRI as a postnatal imaging tool in patients that had a prenatal USS diagnosis of isolated ventriculomegaly. This was a retrospective review of patient notes and scan reports. The postnatal MRI study group consisted of 9 patients that had been diagnosed initially with prenatal isolated ventriculomegaly on USS, and followed up with postnatal MRI (cases of spina bifida and Dandy-Walker malformations were excluded). Findings from the scan reports were recorded and analysed. Both MRI and prenatal USS gave the same information in 55.6 % of the patients. In the remaining 44.4 %, MRI added to the information provided by the prenatal USS. An interesting finding was that MRI missed a small fluid-filled cyst and an arachnoid cyst in 2 cases. 55.6 % of patients went on to develop other CNS abnormalities prenatally, whereas 33.3 % showed prenatal regression of VM with no other pathology. 11.1 % showed postnatal persistence of isolated VM. As USS has the advantage of being cheap and easy to perform, it will remain as the primary imaging tool in obstetric care. MRI can provide significant additional information that can affect parent counselling, prenatal intervention, and postnatal management. Postnatally, MRI can give some idea of prognosis by evaluating myelination patterns, which is not possible with USS.

Study of the motor corticospinal system in the developing rat fetus: comparison of Wistar and normal and hydrocephalic HTx rats.

The motor corticospinal system can be identified from day E14 in Wistar and HTx fetuses. There are no significant anatomical differences between the two species of rats. In addition, in day E17 Wistar and HTx fetuses cell counts in the cortical mantle (cortical plate, intermediate zone and germinal matrix) are similar. However, in day E20 fetuses there are significant differences in the number of cells in the cortical mantle of the hydrocephalic HTx fetuses compared to that in the Wistar and normal HTx fetuses, their total number of cells being reduced compared to that of the normal HTx and Wistars. Breakdown of the numbers of cells in the different layers shows that in the hydrocephalics there is a significant reduction in the number of cells in the germinal matrix and intermediate zone but, although the number of cells is also reduced in the cortical plate, the reduction is not significant. Measurements of the anterior/posterior width of the pyramid show that its growth is almost complete by day E17 and that on day E20 the measurements are similar in Wistar and normal and hydrocephalic HTx fetuses. These findings suggest that it is only cells generated after day E17 that are missing from the cortex of day E20 hydrocephalic rats. It is known that the motor corticospinal tract axons arise from pyramidal cells in layers 6, 5 and 4 of the cortical plate. These layers are generated earlier than layers 3 and 2 and are almost certainly in place by day E17 and account for why motor corticospinal tract function is spared in younger animals with established hydrocephalus.

Effect of oral midazolam premedication on the awakening concentration of sevoflurane, recovery times and bispectral index in children.

BACKGROUND: We sought to determine the influence of preoperative oral midazolam on: (i) measures of anaesthetic emergence; (ii) recovery times and (iii) intraoperative bispectral index (BIS) measurements during sevoflurane/N2O anaesthesia in paediatric patients. METHODS: Fifty-two patients, aged 1-10 years, ASA I-II, were enrolled in a prospective double-blinded study. Patients were randomized to receive either midazolam 0.5 mg.kg(-1) (M) or midazolam vehicle (P) as premedication. After inhalation induction and intubation, expired sevoflurane was stabilized at 3% in 60% N2O and the corresponding BIS (BIS I) recorded. At the completion of surgery, sevoflurane was stabilized at 0.5% and the BIS (BIS E) again recorded. Awakening time, expired sevoflurane/N2O awakening concentrations and recovery times were recorded. RESULTS: There were no significant differences between groups in awakening time, sevoflurane or N2O awakening concentrations, time to PACU discharge, time to hospital discharge or in BIS I and BIS E measurements.

Outcome in prenatally diagnosed fetal agenesis of the corpus callosum.

This study of the outcome and prognostic factors in prenatally diagnosed agenesis of the corpus callosum (ACC) was undertaken to see if there are any differences between subgroups, what relationship they have to neurodevelopmental outcome and whether this information aids the counselling of parents of fetuses with the condition. The outcome of 14 prenatally diagnosed fetuses with ACC and 61 postnatally diagnosed patients was assessed in terms of clinical problems, developmental milestones and neurological signs; each patient was then given a score out of 10, 0 being a normal outcome and 10 being the worst outcome, i.e. death or termination of pregnancy. Comparing patients diagnosed pre- and postnatally, several similarities were found indicating that the postnatal group can provide useful information about the prenatal group. There was a higher incidence of ACC in males than females. In the prenatally diagnosed patients complete ACC was more common than partial ACC, although this might be because partial ACC was easily missed. Complete ACC has a worse prognosis than partial ACC (p = 0.001), and when associated with other anomalies, especially of the central nervous system, the outcome is very bad (p < 0.01). The only neurodevelopmentally normal patients were in the isolated partial ACC group. This study highlights the need to perform a detailed review of fetal anatomy and the desirability of determining the karyotype of the fetus in all newly diagnosed cases of ACC so that as much information as possible is available before parents are counselled about the likely outcome.

The effect of bispectral index monitoring on anesthetic use and recovery in children anesthetized with sevoflurane in nitrous oxide.

UNLABELLED: The utility of bispectral index (BIS) monitoring to guide anesthetic administration has been demonstrated in adults. This prospective, randomized observer-blinded study was designed to evaluate the effect of BIS monitoring on anesthetic use and recovery characteristics in pediatric patients. After data collection in 38 historical controls, 202 patients age 0-18 yr were randomized into one of two groups: standard practice (SP) and BIS guided (BIS). Patients age 0-3 yr undergoing inguinal hernia repair (IH) and patients age 3-18 yr undergoing tonsillectomy and/or adenoidectomy (TA) were selected. All patients were anesthetized with sevoflurane in 60% N(2)O/O(2). Hernia patients also received a caudal epidural anesthetic before surgery. In the BIS group, anesthetic delivery was adjusted in an effort to achieve a target BIS of 45-60 during maintenance and 60-70 during the last 15 min of the procedure. BIS was recorded throughout surgery in all patients, but data were unavailable to the anesthesiologist in the SP group. In the TA patients, BIS monitoring was associated with a significant reduction in end-tidal sevoflurane concentration during maintenance (2.4 +/- 0.6%, SP and 1.8 +/- 0.4% BIS, mean +/- SD) and during the last 15 min of the procedure (2.1 +/- 0.7, SP and 1.6 +/- 0.6, BIS). There was a 25%-40% decrease in measured recovery times. In the patients 0-6 mo of age undergoing IH, sevoflurane concentrations during maintenance (2.0 +/- 0.4% SP, 0.9 +/- 0.8 BIS), during the last 15 min (1.6 +/- 0.4% SP, 0.6 +/- 0.6% BIS), and at the end of the procedure (1.1 +/- 0.6% SP, 0.3 +/- 0.3% BIS) were smaller in the BIS group. Emergence and recovery measures were unaffected by BIS titration. In the children 6 mo-3 yr of age, there were no significant differences between the SP and BIS groups in anesthetic use or recovery measures. IMPLICATIONS: Bispectral index monitoring in children results in less anesthetic use and faster recovery than standard practice.

Problems with interhemispheric transfer of information in complete or partial agenesis of the corpus callosum.

OBJECTIVE: We assessed the presence of poor interhemispheric communication in agenesis of the corpus callosum (ACC) and hydrocephalus. METHODS: With specially designed tests, nine children with ACC were investigated and compared with 11 controls to see the degree of impairment present. Two subjects with a stretched corpus callosum due to hydrocephalus also were tested. A subject with the corpus callosum divided was tested for comparison. RESULTS: Significant differences were found in tests of coordination and stereognosis both with ACC patients and the callosotomy subject. No impairments were found in the hydrocephalics. CONCLUSIONS: When compared with controls, ACC patients perform poorly in several tests. The callosotomy patient also showed evidence of impairment similar to that of the ACC patients.

Changes in the CSF fluid pathways in the developing rat fetus with early onset hydrocephalus.

Interest in the factors involved in the abnormal cortical development of the HTx rat fetus have led us to re-examine the structural and morphological changes in the CSF pathways preceding constriction and blockage of the cerebral aqueduct. Histological analysis was carried out on coronal and sagittal sections from HTx and Wistar fetuses. The aqueduct is found to be a broad channel extending from the posterior end of the third ventricle that ends in a blind pouch above the developing cerebellum. The aqueduct drains into the fourth ventricle via a vertically orientated, narrow channel lying between the posterior aspect of the pontine flexure and the anterior surface of the cerebellum. On Day E18 the connecting channel between the aqueduct and the fourth ventricle is blocked by apposition of its walls. 24 hours later the lateral ventricles begin to dilate and the anterior end of the aqueduct is blocked and the connecting channel between the aqueduct and the fourth ventricle reopens. The cause of these sequential changes in the CSF fluid pathways remains speculative.

The case for and against intrauterine surgery for myelomeningoceles.

The case for and against intrauterine surgery on a myelomeningocele depends on how and in what order the malformations in the spinal cord and brain are thought to develop. If the brain defects arise in the embryonic period and undergo no further change and if the spinal cord is so deformed that it is functionless from the start, then operative intervention before birth will have no significant effect on the ultimate neurological defect. If, on the other hand, the brain lesions evolve during gestation and the deformed spinal cord has some useful function that can be lost by contact with the amniotic fluid or is susceptible to mechanical damage, then intrauterine surgery may have a beneficial role. Long-term follow-up of children who have already undergone intrauterine surgery should answer whether this novel form of treatment imparts significant benefit to justify the risks it imposes on the mother and fetus.

Pre-natal ventriculomegaly and hydrocephalus.

Ultrasonic imaging of the human fetal brain has allowed ventriculomegaly and hydrocephalus to be categorized. In this study 40 fetuses with ventriculomegaly and 21 with an Arnold-Chiari malformation and a myelomeningocele had ventriculomegaly that resolved, stabilised or progressed in utero. Within the progressive group were those with hydrocephalus, hydrocephalus being defined as expansion of the cerebral ventricular atria together with disproportionate increase in the head circumference. The prognosis for fetuses with resolving and stable ventriculomegaly was good, reflecting the fact that the ventricular dilatation in these cases was probably caused by delayed parenchymal and cerebrospinal fluid pathway development. Whereas the prognosis for progressive ventriculomegaly was generally poor, suggesting that the causes were likely to have been chromosomal, genetic, an infective agent or a catastrophic event which had an adverse effect on parenchymal development. The causes of hydrocephalus also adversely affected brain development but additional damage was caused by raised intracranial pressure.

Can prognostic indicators be identified in a fetus with an encephalocele?

Encephaloceles, like other congenital malformations of the brain diagnosable in utero, can be either complicated (there being an associated chromosomal abnormality, abnormalities in the remainder of the central nervous system (CNS) and/or other organs), or isolated (no abnormalities in the chromosomes, the remainder of the CNS or other organs). Complicated cases invariably have a poor prognosis but amongst those with isolated lesions the outcome is variable with some affected children having poor mental and physical development but others who are only mildly or moderately disabled. To be able to make an informed decision about how to manage their pregnancy parents need to know what the prognosis is likely to be for their fetus with an encephalocele. To see if the necessary information could be reliably gathered by prenatal assessment of affected fetuses, a review was carried out of the medical records and ultrasound scans of 31 fetuses with encephaloceles referred to the Fetal Management Unit at St. Mary's Hospital in Manchester between January 1991 and December 1997. Eighteen of the cohort were classified as having a complicated encephalocele. Thirteen of the pregnancies were terminated; there were three intrauterine deaths, and one neonatal death. There is only one surviving child who is severely disabled. Thirteen fetuses were classified as having isolated encephaloceles, six had a mass of neural tissue in the encephalocele sac and were terminated, one died in utero and six had a cystic lesion or only a nubbin and have survived with few or no abnormalities. This study has shown that it is possible to identify fetuses with an encephalocele with a favourable outcome.