Benchmarking of surgical complications in gynaecological oncology: prospective multicentre study.

OBJECTIVE: To explore the impact of risk-adjustment on surgical complication rates (CRs) for benchmarking gynaecological oncology centres. DESIGN: Prospective cohort study. SETTING: Ten UK accredited gynaecological oncology centres. POPULATION: Women undergoing major surgery on a gynaecological oncology operating list. METHODS: Patient co-morbidity, surgical procedures and intra-operative (IntraOp) complications were recorded contemporaneously by surgeons for 2948 major surgical procedures. Postoperative (PostOp) complications were collected from hospitals and patients. Risk-prediction models for IntraOp and PostOp complications were created using penalised (lasso) logistic regression using over 30 potential patient/surgical risk factors. MAIN OUTCOME MEASURES: Observed and risk-adjusted IntraOp and PostOp CRs for individual hospitals were calculated. Benchmarking using colour-coded funnel plots and observed-to-expected ratios was undertaken. RESULTS: Overall, IntraOp CR was 4.7% (95% CI 4.0-5.6) and PostOp CR was 25.7% (95% CI 23.7-28.2). The observed CRs for all hospitals were under the upper 95% control limit for both IntraOp and PostOp funnel plots. Risk-adjustment and use of observed-to-expected ratio resulted in one hospital moving to the >95-98% CI (red) band for IntraOp CRs. Use of only hospital-reported data for PostOp CRs would have resulted in one hospital being unfairly allocated to the red band. There was little concordance between IntraOp and PostOp CRs. CONCLUSION: The funnel plots and overall IntraOp (≈5%) and PostOp (≈26%) CRs could be used for benchmarking gynaecological oncology centres. Hospital benchmarking using risk-adjusted CRs allows fairer institutional comparison. IntraOp and PostOp CRs are best assessed separately. As hospital under-reporting is common for postoperative complications, use of patient-reported outcomes is important. TWEETABLE ABSTRACT: Risk-adjusted benchmarking of surgical complications for ten UK gynaecological oncology centres allows fairer comparison.

Predictors of complications in gynaecological oncological surgery: a prospective multicentre study (UKGOSOC-UK gynaecological oncology surgical outcomes and complications).

BACKGROUND: There are limited data on surgical outcomes in gynaecological oncology. We report on predictors of complications in a multicentre prospective study. METHODS: Data on surgical procedures and resulting complications were contemporaneously recorded on consented patients in 10 participating UK gynaecological cancer centres. Patients were sent follow-up letters to capture any further complications. Post-operative (Post-op) complications were graded (I-V) in increasing severity using the Clavien-Dindo system. Grade I complications were excluded from the analysis. Univariable and multivariable regression was used to identify predictors of complications using all surgery for intra-operative (Intra-op) and only those with both hospital and patient-reported data for Post-op complications. RESULTS: Prospective data were available on 2948 major operations undertaken between April 2010 and February 2012. Median age was 62 years, with 35% obese and 20.4% ASA grade ⩾3. Consultant gynaecological oncologists performed 74.3% of operations. Intra-op complications were reported in 139 of 2948 and Grade II-V Post-op complications in 379 of 1462 surgeries. The predictors of risk were different for Intra-op and Post-op complications. For Intra-op complications, previous abdominal surgery, metabolic/endocrine disorders (excluding diabetes), surgical complexity and final diagnosis were significant in univariable and multivariable regression (P<0.05), with diabetes only in multivariable regression (P=0.006). For Post-op complications, age, comorbidity status, diabetes, surgical approach, duration of surgery, and final diagnosis were significant in both univariable and multivariable regression (P<0.05). CONCLUSIONS: This multicentre prospective audit benchmarks the considerable morbidity associated with gynaecological oncology surgery. There are significant patient and surgical factors that influence this risk.

Cognitive ability is associated with altered medial frontal cortical circuits in the LgDel mouse model of 22q11.2DS.

We established a relationship between cognitive deficits and cortical circuits in the LgDel model of 22q11 Deletion Syndrome (22q11DS)-a genetic syndrome with one of the most significant risks for schizophrenia and autism. In the LgDel mouse, optimal acquisition, execution, and reversal of a visually guided discrimination task, comparable to executive function tasks in primates including humans, are compromised; however, there is significant individual variation in degree of impairment. The task relies critically on the integrity of circuits in medial anterior frontal cortical regions. Accordingly, we analyzed neuronal changes that reflect previously defined 22q11DS-related alterations of cortical development in the medial anterior frontal cortex of the behaviorally characterized LgDel mice. Interneuron placement, synapse distribution, and projection neuron frequency are altered in this region. The magnitude of one of these changes, layer 2/3 projection neuron frequency, is a robust predictor of behavioral performance: it is substantially and selectively lower in animals with the most significant behavioral deficits. These results parallel correlations of volume reduction and altered connectivity in comparable cortical regions with diminished executive function in 22q11DS patients. Apparently, 22q11 deletion alters behaviorally relevant circuits in a distinct cortical region that are essential for cognitive function.

Patient-reporting improves estimates of postoperative complication rates: a prospective cohort study in gynaecological oncology.

BACKGROUND: Most studies use hospital data to calculate postoperative complication rates (PCRs). We report on improving PCR estimates through use of patient-reporting. METHODS: A prospective cohort study of major surgery performed at 10 UK gynaecological cancer centres was undertaken. Hospitals entered the data contemporaneously into an online database. Patients were sent follow-up letters to capture postoperative complications. Grade II-V (Clavien-Dindo classification) patient-reported postoperative complications were verified from hospital records. Postoperative complication rate was defined as the proportion of surgeries with a Grade II-V postoperative complication. RESULTS: Patient replies were received for 1462 (68%) of 2152 surgeries undertaken between April 2010 and February 2012. Overall, 452 Grade II-V (402 II, 50 III-V) complications were reported in 379 of the 1462 surgeries. This included 172 surgeries with 200 hospital-reported complications and 231 with 280 patient-reported complications. All (100% concordance) 36 Grade III-V and 158 of 280 (56.4% concordance) Grade II patient-reported complications were verified on hospital case-note review. The PCR using hospital-reported data was 11.8% (172 out of 1462; 95% CI 11-14), patient-reported was 15.8% (231 out of 1462; 95% CI 14-17.8), hospital and verified patient-reported was 19.4% (283 out of 1462; 95% CI 17.4-21.4) and all data were 25.9% (379 out of 1462; 95% CI 24-28). After excluding Grade II complications, the hospital and patient verified Grade III-V PCR was 3.3% (48 out of 1462; 95% CI 2.5-4.3). CONCLUSION: This is the first prospective study of postoperative complications we are aware of in gynaecological oncology to include the patient-reported data. Patient-reporting is invaluable for obtaining complete information on postoperative complications. Primary care case-note review is likely to improve verification rates of patient-reported Grade II complications.

Three phases of DiGeorge/22q11 deletion syndrome pathogenesis during brain development: patterning, proliferation, and mitochondrial functions of 22q11 genes.

DiGeorge, or 22q11 deletion syndrome (22q11DS), the most common survivable human genetic deletion disorder, is caused by deletion of a minimum of 32 contiguous genes on human chromosome 22, and presumably results from diminished dosage of one, some, or all of these genes--particularly during development. Nevertheless, the normal functions of 22q11 genes in the embryo or neonate, and their contribution to developmental pathogenesis that must underlie 22q11DS are not well understood. Our data suggests that a substantial number of 22q11 genes act specifically and in concert to mediate early morphogenetic interactions and subsequent cellular differentiation at phenotypically compromised sites--the limbs, heart, face and forebrain. When dosage of a broad set of these genes is diminished, early morphogenesis is altered, and initial 22q11DS phenotypes are established. Thereafter, functionally similar subsets of 22q11 genes--especially those that influence the cell cycle or mitochondrial function--remain expressed, particularly in the developing cerebral cortex, to regulate neurogenesis and synaptic development. When dosage of these genes is diminished, numbers, placement and connectivity of neurons and circuits essential for normal behavior may be disrupted. Such disruptions likely contribute to vulnerability for schizophrenia, autism, or attention deficit/hyperactivity disorder seen in most 22q11DS patients.

Cancer survival in Australia, Canada, Denmark, Norway, Sweden, and the UK, 1995-2007 (the International Cancer Benchmarking Partnership): an analysis of population-based cancer registry data.

BACKGROUND: Cancer survival is a key measure of the effectiveness of health-care systems. Persistent regional and international differences in survival represent many avoidable deaths. Differences in survival have prompted or guided cancer control strategies. This is the first study in a programme to investigate international survival disparities, with the aim of informing health policy to raise standards and reduce inequalities in survival. METHODS: Data from population-based cancer registries in 12 jurisdictions in six countries were provided for 2·4 million adults diagnosed with primary colorectal, lung, breast (women), or ovarian cancer during 1995-2007, with follow-up to Dec 31, 2007. Data quality control and analyses were done centrally with a common protocol, overseen by external experts. We estimated 1-year and 5-year relative survival, constructing 252 complete life tables to control for background mortality by age, sex, and calendar year. We report age-specific and age-standardised relative survival at 1 and 5 years, and 5-year survival conditional on survival to the first anniversary of diagnosis. We also examined incidence and mortality trends during 1985-2005. FINDINGS: Relative survival improved during 1995-2007 for all four cancers in all jurisdictions. Survival was persistently higher in Australia, Canada, and Sweden, intermediate in Norway, and lower in Denmark, England, Northern Ireland, and Wales, particularly in the first year after diagnosis and for patients aged 65 years and older. International differences narrowed at all ages for breast cancer, from about 9% to 5% at 1 year and from about 14% to 8% at 5 years, but less or not at all for the other cancers. For colorectal cancer, the international range narrowed only for patients aged 65 years and older, by 2-6% at 1 year and by 2-3% at 5 years. INTERPRETATION: Up-to-date survival trends show increases but persistent differences between countries. Trends in cancer incidence and mortality are broadly consistent with these trends in survival. Data quality and changes in classification are not likely explanations. The patterns are consistent with later diagnosis or differences in treatment, particularly in Denmark and the UK, and in patients aged 65 years and older. FUNDING: Department of Health, England; and Cancer Research UK.

Specific mesenchymal/epithelial induction of olfactory receptor, vomeronasal, and gonadotropin-releasing hormone (GnRH) neurons.

We asked whether specific mesenchymal/epithelial (M/E) induction generates olfactory receptor neurons (ORNs), vomeronasal neurons (VRNs), and gonadotropin-releasing hormone (GnRH) neurons, the major neuron classes associated with the olfactory epithelium (OE). To assess specificity of M/E-mediated neurogenesis, we compared the influence of frontonasal mesenchyme on frontonasal epithelium, which becomes the OE, with that of the forelimb bud. Despite differences in position, morphogenetic and cytogenic capacity, both mesenchymal tissues support neurogenesis, expression of several signaling molecules and neurogenic transcription factors in the frontonasal epithelium. Only frontonasal mesenchyme, however, supports OE-specific patterning and activity of a subset of signals and factors associated with OE differentiation. Moreover, only appropriate pairing of frontonasal epithelial and mesenchymal partners yields ORNs, VRNs, and GnRH neurons. Accordingly, the position and molecular identity of specialized frontonasal epithelia and mesenchyme early in gestation and subsequent inductive interactions specify the genesis and differentiation of peripheral chemosensory and neuroendocrine neurons.

Mitochondrial localization and function of a subset of 22q11 deletion syndrome candidate genes.

Six genes in the 1.5 Mb region of chromosome 22 deleted in DiGeorge/22q11 deletion syndrome-Mrpl40, Prodh, Slc25a1, Txnrd2, T10, and Zdhhc8-encode mitochondrial proteins. All six genes are expressed in the brain, and maximal expression coincides with peak forebrain synaptogenesis shortly after birth. Furthermore, their protein products are associated with brain mitochondria, including those in synaptic terminals. Among the six, only Zddhc8 influences mitochondria-regulated apoptosis when overexpressed, and appears to interact biochemically with established mitochondrial proteins. Zdhhc8 has an apparent interaction with Uqcrc1, a component of mitochondrial complex III. The two proteins are coincidently expressed in pre-synaptic processes; however, Zdhhc8 is more frequently seen in glutamatergic terminals. 22q11 deletion may alter metabolic properties of cortical mitochondria during early post-natal life, since expression complex III components, including Uqcrc1, is significantly increased at birth in a mouse model of 22q11 deletion, and declines to normal values in adulthood. Our results suggest that altered dosage of one, or several 22q11 mitochondrial genes, particularly during early post-natal cortical development, may disrupt neuronal metabolism or synaptic signaling.

When half is not enough: gene expression and dosage in the 22q11 deletion syndrome.

The 22q11 Deletion Syndrome (22q11DS, also known as DiGeorge or Velo-Cardio-Facial Syndrome) has a variable constellation of phenotypes including life-threatening cardiac malformations, craniofacial, limb, and digit anomalies, a high incidence of learning, language, and behavioral disorders, and increased vulnerability for psychiatric diseases, including schizophrenia. There is still little clear understanding of how heterozygous microdeletion of approximately 30-50 genes on chromosome 22 leads to this diverse spectrum of phenotypes, especially in the brain. Three possibilities exist: 1) 22q11DS may reflect haploinsufficiency, homozygous loss of function, or heterozygous gain of function of a single gene within the deleted region; 2) 22q11DS may result from haploinsufficiency, homozygous loss of function, or heterozygous gain of function of a few genes in the deleted region acting at distinct phenotypically compromised sites; 3) 22q11DS may reflect combinatorial effects of reduced dosage of multiple genes acting in concert at all phenotypically compromised sites. Here, we consider evidence for each of these possibilities. Our review of the literature, as well as interpretation of work from our laboratory, favors the third possibility: 22q11DS reflects diminished expression of multiple 22q11 genes acting on common cellular processes during brain as well as heart, face, and limb development, and subsequently in the adolescent and adult brain.

Gene dosage in the developing and adult brain in a mouse model of 22q11 deletion syndrome.

We evaluated the consequences of heterozygous chromosome 22q11 deletion - a significant genetic risk for schizophrenia - for expression levels and patterns of a subset of 22q11 genes implicated in schizophrenia and other phenotypes in mouse models of 22q11 deletion syndrome (22q11DS). In deleted embryos, expression levels of at least nine 22q11 orthologues decline by 40-60% in the frontonasal mass/forebrain and other 22q11DS phenotypic sites (branchial and aortic arches, limb buds); however, coincident expression patterns of 22q11 and Snail genes - diagnostic for neural crest-derived mesenchyme - are unchanged, and Snail1 expression levels do not decline. Subsequently, 22q11 mRNA levels are reduced by 40-60% in the brains of developing, adolescent and adult deleted mice without altered expression patterns, dysmorphology or reduced cell density. Apparently, in deleted individuals, 22q11 gene expression declines across otherwise stable cell populations, perhaps disrupting individual cell function via diminished dosage. Such changes might contribute to schizophrenia vulnerability in 22q11DS.

Limited influence of olanzapine on adult forebrain neural precursors in vitro.

We evaluated the activity of the atypical antipsychotic drug olanzapine on differentiation and gene expression in adult neural precursor cells in vitro. Neural precursors obtained from forebrain subventricular zone (SVZ)-derived neurospheres express a subset (13/24) of receptors known to bind olanzapine at high to intermediate affinities; in contrast, all 24 are expressed in the SVZ. In the presence of 10 nM, 100 nM or 1 microM olanzapine, there is no significant change in the frequency of oligodendrocytes, neurons, GABAergic neurons and astrocytes generated from neurosphere precursors. In parallel, there is no apparent change in cell proliferation in response to olanzapine, based upon bromodeoxyuridine incorporation. There are no major changes in cytological differentiation in response to the drug; however, at one concentration (10 nM) there is a small but statistically significant increase in the size of glial fibrillary acidic protein-labeled astrocytes derived from neurosphere precursors. In addition, olanzapine apparently modulates expression of one serotonin receptor -- 5HT2A -- in differentiating neurosphere cultures; however, it does not modify expression of several other receptors or schizophrenia vulnerability genes. Thus, olanzapine has a limited influence on differentiation and gene expression in adult neural precursor cells in vitro.

Single nucleotide polymorphisms in the leptin receptor gene: studies in anorexia nervosa.

Anorexia nervosa is an eating disorder of unknown aetiology. There is significant evidence for a genetic component in the pathogenesis of this disorder. A region on chromosome 1 has been identified as a susceptibility locus. The leptin receptor has been mapped to a similar region, further upstream of this susceptibility locus. Leptin and its receptor are known to be important factors in the control and regulation of body weight. Single nucleotide polymorphisms (SNPs) in the leptin receptor are associated with measures of body weight. In the present study, SNPs in the coding region of the leptin receptor were analysed and their possible association with anorexia nervosa was investigated. Two cohorts of young women, 176 Caucasian anorexia nervosa patients and 152 normal Caucasian females, were genotyped for three SNPs in the leptin receptor. There was no significant difference in allele or genotype frequency, for any SNP, between the normal controls and the cohort of anorexia subjects. There were no significant associations with any genotype and body mass index in either the control or anorexic cohorts. When the anorexic cohort was subdivided into restricting and bingeing/purging behaviours, we found no significant association with any genotype. Analysis of haplotypes showed no significant evidence of association with anorexia. In summary, leptin receptor SNPs do not appear to be important factors in the regulation of body weight in young, pre-menopausal women or have any significant association with anorexia nervosa.

Controlled trial of pharmacist intervention in general practice: the effect on prescribing costs.

BACKGROUND: It has been suggested that the employment of pharmacists in general practice might moderate the growth in prescribing costs. However, empirical evidence for this proposition has been lacking. We report the results of a controlled trial of pharmacist intervention in United Kingdom general practice. AIM: To determine whether intervention practices made savings relative to controls. METHOD: An evaluation of an initiative set up by Doncaster Health Authority. Eight practices agreed to take part and received intensive input from five pharmacists for one year (September 1996 to August 1997) at a cost of 163,000 Pounds. Changes in prescribing patterns were investigated by comparing these practices with eight individually matched controls for both the year of the intervention and the previous year. Prescribing data (PACTLINE) were used to assess these changes. The measures used to take account of differences in the populations of the practices included the ASTRO-PU for overall prescribing and the STAR-PU for prescribing in specific therapeutic areas. Differences between intervention and control practices were subjected to Wilcoxon matched-pairs, signed-ranks tests. RESULTS: The median (minimum to maximum) rise in prescribing costs per ASTRO-PU was 0.85 Pound (-1.95 Pounds to 2.05 Pounds) in the intervention practices compared with 2.55 Pounds (1.74 Pounds to 4.65 Pounds) in controls (P = 0.025). Had the cost growth of the intervention group been as high as that of the controls, their total prescribing expenditure would have been around 347,000 Pounds higher. CONCLUSION: This study suggests that the use of pharmacists did control prescribing expenditure sufficiently to offset their employment costs.

Identification of staphylococci by pyrolysis gas-liquid chromatography.

The identification of bacteria by pyrolysis gas-liquid chromatography (PGLC) was evaluated with the genus Staphylococcus. A matrix containing the characteristics of seven species of Staphylococcus was constructed from the results obtained with 42 named strains identified by biochemical methods. An identification program based upon this database was evaluated in tests with 100 isolates of catalase-positive oxidase-negative gram-positive cocci identified by biochemical and PGLC systems. Agreement between the two systems was 90%. Pure cultures of unknown isolates were identified within 30 min by PGLC using a microcomputer data acquisition and analysis program. A taxonomic analysis of the data is presented, and methods for quality control of PGLC, prolongation of column life, and data analysis are described and discussed.

Why does domiciliary oxygen consumption vary from area to area?

Home oxygen therapy is used mainly for chronic respiratory disease. Differences in the gross quantities of oxygen supplied for home use in eight areas in 1982 reflected differences in the user-proportions of their populations, but not the amounts consumed per user. Similar user-proportions were found among areas with markedly dissimilar levels of respiratory disease. In the majority of cases the decision to use oxygen therapy was taken by the general practitioner.To ensure that the known benefits of oxygen therapy are more widely obtained, potential recipients need to be more accurately ascertained. More frequent resort to pulmonary function testing at the primary care level is indicated.