Factors predicting outcome from enhanced recovery programmes in laparoscopic colorectal surgery: a systematic review.

OBJECTIVE: To perform a systematic review of published literature for the factors reported to predict outcomes of enhanced recovery after surgery (ERAS) programmes following laparoscopic colorectal surgery. BACKGROUND: ERAS programmes and the use of laparoscopy have been widely adopted in colorectal surgery bringing short-term patient benefit. However, there is a minority of patients that do not benefit from these strategies and their identification is not well characterised. The factors that underpin outcomes from ERAS programmes for laparoscopic patients are not understood. METHODS: A systematic search of the MEDLINE, Embase and Cochrane databases was conducted to identify suitable articles published between 2000 and 2015. The search strategy captured terms for ERAS, colorectal resection, prediction and outcome measures. RESULTS: Thirty-four studies containing 10,861 laparoscopic resections were included. Thirty-one (91 %) studies were confined to elective cases. Predictive analysis of outcome was most frequently based on length of stay (LOS), morbidity and readmission which were the main outcome measures of 29 (85 %), 26 (76 %) and 18 (53 %) of the included studies, respectively. Forty-seven percentage of included studies investigated the impact of ERAS programme compliance on these outcomes. Reduced protocol compliance was the most frequently identified modifiable predictive factor for adverse LOS, morbidity and readmission. CONCLUSION: Protocol compliance is the most frequently reported predictive factor for outcomes of ERAS programmes following laparoscopic colorectal resection. Reduced compliance increases LOS, morbidity and readmission to hospital. The impact of compliance with individual ERAS protocol elements is insufficiently studied, and the lack of a standardised framework for evaluating ERAS programmes makes it difficult to draw definite conclusions about which factors exert the greatest impact on outcome after laparoscopic colorectal resection.

How Well Is Quality Improvement Described in the Perioperative Care Literature? A Systematic Review.

BACKGROUND: Quality improvement (QI) approaches are widely used across health care, but how well they are reported in the academic literature is not clear. A systematic review was conducted to assess the completeness of reporting of QI interventions and techniques in the field of perioperative care. METHODS: Searches were conducted using Medline, Scopus, the Cochrane Central Register of Controlled Trials, the Cochrane Effective Practice and Organization of Care database, and PubMed. Two independent reviewers used the Template for Intervention Description and Replication (TIDieR) check list, which identifies 12 features of interventions that studies should describe (for example, How: the interventions were delivered [e. g., face to face, internet]), When and how much: duration, dose, intensity), to assign scores for each included article. Articles were also scored against a small number of additional criteria relevant to QI. RESULTS: The search identified 16,103 abstracts from databases and 19 from other sources. Following review, full-text was obtained for 223 articles, 100 of which met the criteria for inclusion. Completeness of reporting of QI in the perioperative care literature was variable. Only one article was judged fully complete against the 11 TIDieR items used. The mean TIDieR score across the 100 included articles was 6.31 (of a maximum 11). More than a third (35%) of the articles scored 5 or lower. Particularly problematic was reporting of fidelity (absent in 74% of articles) and whether any modifications were made to the intervention (absent in 73% of articles). CONCLUSIONS: The standard of reporting of quality interventions and QI techniques in surgery is often suboptimal, making it difficult to determine whether an intervention can be replicated and used to deliver a positive effect in another setting. This suggests a need to explore how reporting practices could be improved.

Specific collagen XVIII isoforms promote adipose tissue accrual via mechanisms determining adipocyte number and affect fat deposition.

Collagen XVIII is an evolutionary conserved ubiquitously expressed basement membrane proteoglycan produced in three isoforms via two promoters (P). Here, we assess the function of the N-terminal, domain of unknown function/frizzled-like sequences unique to medium/long collagen XVIII by creating P-specific null mice. P2-null mice, which only produce short collagen XVIII, developed reduced bulk-adiposity, hepatic steatosis, and hypertriglyceridemia. These abnormalities did not develop in P1-null mice, which produce medium/long collagen XVIII. White adipose tissue samples from P2-null mice contain larger reserves of a cell population enriched in early adipocyte progenitors; however, their embryonic fibroblasts had ∼ 50% lower adipocyte differentiation potential. Differentiating 3T3-L1 fibroblasts into mature adipocytes produced striking increases in P2 gene-products and dramatic falls in P1-transcribed mRNA, whereas Wnt3a-induced dedifferentiation of mature adipocytes produced reciprocal changes in P1 and P2 transcript levels. P2-derived gene-products containing frizzled-like sequences bound the potent adipogenic inhibitor, Wnt10b, in vitro. Previously, we have shown that these same sequences bind Wnt3a, inhibiting Wnt3a-mediated signaling. P2-transcript levels in visceral fat were positively correlated with serum free fatty acid levels, suggesting that collagen α1 (XVIII) expression contributes to regulation of adipose tissue metabolism in visceral obesity. Medium/long collagen XVIII is deposited in the Space of Disse, and interaction between hepatic apolipoprotein E and this proteoglycan is lost in P2-null mice. These results describe a previously unidentified extracellular matrix-directed mechanism contributing to the control of the multistep adipogenic program that determines the number of precursors committing to adipocyte differentiation, the maintenance of the differentiated state, and the physiological consequences of its impairment on ectopic fat deposition.

Polymorphisms in BACE2 may affect the age of onset Alzheimer's dementia in Down syndrome.

It is known that Alzheimer's disease (AD) presents at an early age in people with Down syndrome (DS). The trisomy 21 in DS provides an opportunity to study the effect of duplicated genes in AD. APP and BACE2 are 2 genes located in chromosome 21 and related to AD. We looked into our cohort of 67 DS cases with dementia for the effect of BACE2 variants in age of onset of dementia. Of the 83 single-nucleotide polymorphisms (SNPs), 6 were associated with age of onset and another 8 SNPs were borderline associated. Our finding also replicated a previous study showing association of rs2252576 with AD.

TEN RILLINGTON PLACE AND THE CHANGING POLITICS OF ABORTION IN MODERN BRITAIN.

This article addresses the social, cultural, and political history of backstreet abortion in post-war Britain, focusing on the murders of Beryl Evans and her daughter Geraldine, at Ten Rillington Place in 1949. It shows how the commonplace connection of John Christie to abortion and Beryl Evan's death was not a given in the wider public, legal, political, and forensic imagination of the time, reflecting the multi-layered and shifting meanings of abortion from the date of the original trials in the late 1940s and 1950s, through the subsequent judicial and literary reinvestigations of the case in the 1960s, to its cinematic interpretation in the 1970s. Exploring the language of abortion used in these different contexts, the article reveals changes in the gendering of abortionists, the increasing power and presence of abortion activists and other social reformers, the changing representation of working-class women and men, and the increasing critique of the practice of backstreet abortion. The case is also made for a kind of societal blind spot on abortion at the time of both the Evans and Christie trials; in particular, a reluctance to come to terms with the concept of the male abortionist, which distorted the criminal investigations and the trials themselves. Only when public acceptance for legalizing abortion grew in the more liberal climate of the 1960s and beyond did a revisionist understanding of the murder of Beryl Evans, in which abortion came to be positioned as a central element, gain a sustained hearing.

Association of a polymorphism in mitochondrial transcription factor A (TFAM) with Parkinson's disease dementia but not dementia with Lewy bodies.

The single nucleotide polymorphism (SNP) A>G rs2306604 in the gene encoding mitochondrial transcription factor A (TFAM) has been associated with Alzheimer's disease, with the A allele being recognised as a risk factor, but has not been studied in other types of dementia. We hypothesised that TFAM SNP rs2306604 might also be associated with Lewy body dementias. To test this hypothesis rs2306604 genotype was determined in 141 controls and 135 patients with dementia with Lewy bodies (DLB) or Parkinson's disease dementia (PDD). rs2306604 genotype frequencies were significantly different to controls in PDD (p=0.042), but not in DLB (p=0.529). The A allele was also associated with PDD (p=0.024, OR=2.092), but not DLB (p=0.429, OR=1.308). Moreover, the A allele was strongly associated with PDD in males (p=0.001, OR=5.570), but not in females (p=0.832, OR=1.100). Mitochondrial DNA copy number in the prefrontal cortex was also significantly reduced in PDD patients, but this reduction was not associated with rs2306604 genotype. These data show that the TFAM SNP rs2306604 A allele may be a risk factor for PDD, particularly in males, but not for DLB. Therefore, the genetic factors that predispose individuals to develop dementia may differ in PDD and DLB.

CDKN2B expression in adipose tissue of familial combined hyperlipidemia patients.

The purpose of this study was to determine the core biological processes perturbed in the subcutaneous adipose tissue of familial combined hyperlipidemia (FCHL) patients. Annotation of FCHL and control microarray datasets revealed a distinctive FCHL transcriptome, characterized by gene expression changes regulating five overlapping systems: the cytoskeleton, cell adhesion and extracellular matrix; vesicular trafficking; lipid homeostasis; and cell cycle and apoptosis. Expression values for the cell-cycle inhibitor CDKN2B were increased, replicating data from an independent FCHL cohort. In 3T3-L1 cells, CDKN2B knockdown induced C/EBPα expression and lipid accumulation. The minor allele at SNP site rs1063192 (C) was predicted to create a perfect seed for the human miRNA-323b-5p. A miR-323b-5p mimic significantly reduced endogenous CDKN2B protein levels and the activity of a CDKN2B 3'UTR luciferase reporter carrying the rs1063192 C allele. Although the allele displayed suggestive evidence of association with reduced CDKN2B mRNA in the MuTHER adipose tissue dataset, family studies suggest the association between increased CDKN2B expression and FCHL-lipid abnormalities is driven by factors external to this gene locus. In conclusion, from a comparative annotation analysis of two separate FCHL adipose tissue transcriptomes and a subsequent focus on CDKN2B, we propose that dysfunctional adipogenesis forms an integral part of FCHL pathogenesis.

Timing of surgery after long-course neoadjuvant chemoradiotherapy for rectal cancer: a systematic review of the literature.

BACKGROUND: Neoadjuvant long-course chemoradiotherapy is commonly used to improve the local control and resectability of locally advanced rectal cancer, with surgery performed after an interval of a number of weeks. OBJECTIVE: We report an evidence-based systematic review of published data supporting the optimal time to perform surgical resection after long-course neoadjuvant therapy. DATA SOURCES: A systematic literature search was undertaken of the MEDLINE and Embase electronic databases from 1995 to 2012. STUDY SELECTION: English language articles were included that compared outcomes following rectal cancer surgery performed at different times after a long course of neoadjuvant radiation-based therapy. INTERVENTIONS: : Patients received a long course of neoadjuvant therapy followed by radical surgical resection after an interval period. MAIN OUTCOME MEASURES: The rates of tumor response, R0 resection, sphincter preservation, surgical complications, and disease recurrence were the primary outcomes measured. RESULTS: Fifteen studies were identified: 1 randomized controlled trial, 1 prospective nonrandomized interventional study, and 13 observational studies. Studies compared time intervals that varied between <5 days and >12 weeks, with a large degree of variation in what the standard interval length was considered to be. Four of the 7 studies that reported rates of pathological complete response identified significantly higher rates with an extended interval between chemoradiotherapy and surgery; 3 of 8 studies demonstrated increased primary tumor downstaging with a longer interval. No significant differences have been consistently demonstrated in rates of surgical complications, sphincter preservation, or long-term recurrence and survival. LIMITATIONS: Neoadjuvant regimes, indications for neoadjuvant therapy, and time intervals after chemoradiotherapy were heterogeneous between studies; consequently, meta-analysis could not be performed. CONCLUSIONS: There is limited evidence to support decisions regarding when to resect rectal cancer following chemoradiotherapy. There may be benefits in prolonging the interval between chemoradiotherapy and surgery beyond the 6 to 8 weeks that is commonly practiced. However, outcomes need to be studied further in robust randomized studies.

Evidence that PICALM affects age at onset of Alzheimer's dementia in Down syndrome.

It is known that individuals with Down syndrome develop Alzheimer's disease with an early age at onset, although associated genetic risk factors have not been widely studied. We tested whether genes that increase the risk of late-onset Alzheimer's disease influence the age at onset in Down syndrome using genome-wide association data for age at onset of dementia in a small sample of individuals (N = 67) with Down syndrome. We tested for association with loci previously associated with Alzheimer's disease risk and, despite the small size of the study, we detected associations with age at onset of Alzheimer's disease in Down syndrome with PICALM (ß = 3.31, p = 0.011) and the APOE loci (ß = 3.58, p = 0.014). As dementia in people with Down syndrome is relatively understudied, we make all of these data publicly available to encourage further analyses of the problem of Alzheimer's disease in Down syndrome.

Analysis of neuron-specific enolase and S100B as biomarkers of cognitive decline following surgery in older people.

BACKGROUND/AIMS: Post-operative cognitive decline is frequent in older individuals following major surgery; however, biomarkers of this decline are less clearly defined. METHODS: Sixty-eight participants over the age of 60 provided blood samples at baseline and 24 h post-surgery. Cognitive decline was measured at baseline and 52 weeks post-surgery using the Cambridge Assessment for Mental Disorder in the Elderly, section B (CAMCOG) score. Plasma levels of neuron-specific enolase (NSE) and S100B were measured by ELISA. RESULTS: Baseline NSE and the change in NSE levels between baseline and 24 h were correlated with the change in CAMCOG score between baseline and 52 weeks. CONCLUSION: NSE concentrations may be a useful predictor of individuals at risk of more severe long-term cognitive decline.

A pilot study examining associations between DYRK1A and α-synuclein dementias.

BACKGROUND: DYRK1A is a kinase targeting several proteins associated with the pathology of dementias, including α-synuclein and amyloid precursor protein. It is not clear if DYRK1A genetics are associated with neurodegenerative conditions. OBJECTIVE: To determine if DYRK1A also has a genetic association with α-synuclein dementias such as dementia with Lewy bodies and Parkinson's disease dementia. METHODS: DNA samples from prospectively followed cohorts of control and dementia individuals were genotyped for the DYRK1A rs8126696 polymorphism. RESULTS: The rs8126696 polymorphism altered the risk of developing an α-synuclein-associated dementia. CONCLUSION: DYRK1A could prove to be an important therapeutic target as it interacts with several proteins associated with the development of pathology in dementia.

Memantine for dementia in adults older than 40 years with Down's syndrome (MEADOWS): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Prevalence of Alzheimer's disease in people with Down's syndrome is very high, and many such individuals who are older than 40 years have pathological changes characteristic of Alzheimer's disease. Evidence to support treatment with Alzheimer's drugs is inadequate, although memantine is beneficial in transgenic mice. We aimed to assess safety and efficacy of memantine on cognition and function in individuals with Down's syndrome. METHODS: In our prospective randomised double-blind trial, we enrolled adults (>40 years) with karyotypic or clinically diagnosed Down's syndrome, with and without dementia, at four learning disability centres in the UK and Norway. We randomly allocated participants (1:1) to receive memantine or placebo for 52 weeks by use of a computer-generated sequence and a minimisation algorithm to ensure balanced allocation for five prognostic factors (sex, dementia, age group, total Down's syndrome attention, memory, and executive function scales [DAMES] score, and centre). The primary outcome was change in cognition and function, measured with DAMES scores and the adaptive behaviour scale (ABS) parts I and II. We analysed differences in DAMES and ABS scores between groups with analyses of covariance or quantile regression in all patients who completed the 52 week assessment and had available follow-up data. This study is registered, number ISRCTN47562898. FINDINGS: We randomly allocated 88 patients to receive memantine (72 [82%] had DAMES data and 75 [85%] had ABS data at 52 weeks) and 85 to receive placebo (74 [87%] and 73 [86%]). Both groups declined in cognition and function but rates did not differ between groups for any outcomes. After adjustment for baseline score, there were non-significant differences between groups of -4·1 (95% CI -13·1 to 4·8) in DAMES scores, -8·5 (-20·1 to 3·1) in ABS I scores, and 2·0 (-7·2 to 11·3) in ABS II scores, all in favour of controls. 10 (11%) of 88 participants in the memantine group and six (7%) of 85 controls had serious adverse events (p=0·33). Five participants in the memantine group and four controls died from serious adverse events (p=0·77). INTERPRETATION: There is a striking absence of evidence about pharmacological treatment of cognitive impairment and dementia in people older than 40 years with Down's syndrome. Despite promising indications, memantine is not an effective treatment. Therapies that are effective for Alzheimer's disease are not necessarily effective in this group of patients. FUNDING: Lundbeck.

Synaptic protein expression is regulated by a pro-oxidant diet in APPxPS1 mice.

Dietary factors may play a role in Alzheimer's disease (AD) pathogenesis. In an effort to recapitulate some of the synaptic protein changes observed in the disease, AD transgenic and wild-type mice were fed either a normal or pro-oxidant diet for 3 months from three months of age. Pro-oxidant diet treatment resulted in altered expression of vesicular glutamate transporter-1 and glutamine synthetase, suggesting changes in glutamatergic synaptic function, and increased expression of urokinase plasminogen activator receptor, possibly reflecting oxidative stress.

Attitudes to abortion in the era of reform: evidence from the Abortion Law Reform Association correspondence.

This article examines letters sent by members of the general public to the Abortion Law Reform Association (ALRA) in the decade immediately before the 1967 Abortion Act. It shows how a voluntary organisation, in their aim of supporting a specific cause of unclear legality, called forth correspondence from those in need. In detailing the personal predicaments of those facing an unwanted pregnancy, this body of correspondence was readily deployed by ALRA in their efforts to mobilise support for abortion law reform, thus exercising a political function. A close examination of the content of the letters and the epistolary strategies adopted by their writers reveals that as much as they were a lobbying tool for changes in abortion law, these letters were discursively shaped by debates surrounding that very reform.

Genetic associations of autopsy-confirmed vascular dementia subtypes.

BACKGROUND/AIMS: Genetic risk factors have not been clearly established for vascular dementias (VaD) related to stroke and cerebrovascular disease. METHODS: Samples were genotyped for APOE, MTHFR and ICAM. Aß levels and choline acetyltransferase (ChAT) activities were assayed in controls and individuals with VaD. RESULTS: Associations were found between the APOE-ε4 allele and mixed dementia, infarct/stroke dementia and subcortical ischemic vascular dementia (SIVD), and higher Aß1-42 levels and decreased ChAT activity. MTHFR was more associated with SIVD, mixed dementia, and lower ChAT activity. CONCLUSIONS: The study demonstrates important differences in the genetic associations of VaD and begins to clarify the genetic basis of key pathological substrates.

Antipsychotic medication is associated with selective alterations in ventricular cerebrospinal fluid Aß 40 and tau in patients with intractable unipolar depression.

OBJECTIVE: Alterations in plasma and in lumbar cerebrospinal fluid amyloid-B peptide (Aß) levels have been reported in Alzheimer's disease. Studies have also suggested similar changes in depressed patients. No information is available on the impact of psychotropic drugs on this in patients with depression. We therefore quantified Aß in ventricular cerebrospinal fluid (CSF) in a population of patients with treatment-resistant depression, with and without antipsychotic medication. METHOD: A cross-sectional study of 32 patients undergoing subcaudate tractotomy for major (unipolar) depressive disorder. Ventricular CSF concentrations of Aß peptide 1-40 and 1-42, also p-tau and total tau were determined by Western blotting or enzyme-linked immunosorbent assay. RESULTS: Patients taking antipsychotic medication in the 2 weeks prior to surgery demonstrated significantly higher levels of Aß 1-40 (mean ± SD: 727.3 ± 382.3 vs. 440.9 ± 337.2 pg/ml; p = 0.032, Student's t-test) but unaltered Aß 1-42 (mean 72.1 ± 67.5 vs. 60.0 ± 56.7 pg/ml; p = 0.587) compared to a matched sample not treated with antipsychotic drugs. The same group demonstrated elevated total tau (mean 945.0 ± 422.2 vs. 534.3 ± 388.3 pg/ml; p = 0.010) but not p-tau (mean 98.6 ± 71.5 vs. 88.1 ± 70.5 pg/ml; p = 0.694). No similar effect was found with lithium, antidepressants, carbamazepine or benzodiazepines. CONCLUSIONS: This preliminary study suggests antipsychotic drugs, widely used in patients with severe depression across all age ranges, may be associated with alteration of Aß 1-40 and total tau, indices strongly linked with progressive organic brain disease. Further confirmatory work is needed.