The effect of expectation on satisfaction in total knee replacements : a systematic review

Total knee replacement has reliably been shown to have a beneficial effect in knee osteoarthritis; however, around 17 % of patients are dissatisfied with the result. A commonly proposed mechanism driving the dissatisfaction rate is a discrepancy between expected and actual/perceived outcome. Our aim was to conduct a systematic review examining any association between pre-operative expectations and satisfaction. A comprehensive electronic search strategy was used to identify studies from MEDLINE, EMBASE, and the Cochrane Library from inception until May 2015. Data was extracted according to PRISMA guidelines and an online, published protocol. Four studies are included in this review. One study found an association between expectations and satisfaction. Different measures of expectation and satisfaction were used in all studies. To date, there is no consensus on how expectations or satisfaction should be measured, and a large number of studies that have the available information failed to conduct the relevant sub-group analysis. Further elucidation and consensus of how to measure expectations and satisfaction around joint replacement would aid this area of study greatly. On the basis of the current evidence it appears expectations have a small effect, if any, on satisfaction after knee replacement

Determining the stress biomarker profile in patients undergoing total knee replacement and the relationship with outcome at 12 months

Background: Total knee replacement (TKR) is the commonest joint arthroplasty procedure worldwide. Despite excellent outcomes, some studies have reported dissatisfaction in up to 20% of patients. There is evidence of an association between the biochemical stress response to surgery and outcomes. The objective of this study is to describe the stress biomarker profile for TKR, and correlate this with patient outcomes. Methods: A prospective cohort study of 50 patients undergoing primary TKR was conducted. Serum IL-6, TNF-α, neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were measured immediately pre- and post-operatively, and on Days 1 and 3. Follow-up questionnaires including the Oxford Knee Score (OKS) and EuroQol five dimensions (EQ-5D) were completed at 12-months. Univariate analysis was completed using a linear regression model (p < 0.05). Results: Serum IL-6, NLR, and PLR all increased to Day 1 post-operatively, and decreased by Day 3. TNF-α values increased across all time points. Statistical analysis found a significant negative correlation (r = − 0.414; p = 0.005) between pre-operative IL-6 and 12-month OKS. There was a significant positive correlation between pre-operative NLR and 12 month OKS (r = 0.272; p = 0.039) and 12 month EQ5D (r = 0.268; p = 0.043). Conclusion: This is the first study to describe the biochemical stress response to TKR. The results raise the potential for a pre-operative risk stratification tool for patients based on IL-6 and NLR measurements. Further research should be conducted to explore the underlying mechanisms involved, and investigate interventions to reduce pre-operative physiological stress with a view to improving post-operative outcomes

Hepatic transcriptional responses to copper in the three-spined stickleback are affected by their pollution exposure history

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.Some fish populations inhabiting contaminated environments show evidence of increased chemical tolerance, however the mechanisms contributing to this tolerance, and whether this is heritable, are poorly understood. We investigated the responses of two populations of wild three-spined stickleback (Gasterosteus aculeatus) with different histories of contaminant exposure to an oestrogen and copper, two widespread aquatic pollutants. Male stickleback originating from two sites, the River Aire, with a history of complex pollution discharges, and Siblyback Lake, with a history of metal contamination, were depurated and then exposed to copper (46μg/L) and the synthetic oestrogen ethinyloestradiol (22ng/L). The hepatic transcriptomic response was compared between the two populations and to a reference population with no known history of exposure (Houghton Springs, Dorset). Gene responses included those typical for both copper and oestrogen, with no discernable difference in response to oestrogen between populations. There was, however, some difference in the magnitude of response to copper between populations. Siblyback fish showed an elevated baseline transcription of genes encoding metallothioneins and a lower level of metallothionein induction following copper exposure, compared to those from the River Aire. Similarly, a further experiment with an F1 generation of Siblyback fish bred in the laboratory found evidence for elevated transcription of genes encoding metallothioneins in unexposed fish, together with an altered transcriptional response to 125μg/L copper, compared with F1 fish originating from the clean reference population exposed to the same copper concentration. These data suggest that the stickleback from Siblyback Lake have a differential response to copper, which is inherited by the F1 generation in laboratory conditions, and for which the underlying mechanism may include an elevation of baseline transcription of genes encoding metallothioneins. The genetic and/or epigenetic mechanisms contributing to this inherited alteration of metallothionein transcription have yet to be established.This work was funded by the UK NERC postgenomic and proteomic programme grant NE/C507661/1 and by a Fisheries Society of the British Isles research grant to EMS. Birmingham functional genomics facilities were funded by BBSRC grant 6/JIF13209. We thank R.E. Godfrey, S. Jondhale, A. Jones, and L. Klovrza for technical assistance, J.K. Chipman for help and support, and the Environment Agency for provision of water chemistry data

A sensorimotor control framework for understanding emotional communication and regulation

JHGW and CFH are supported by the Northwood Trust. TEVR was supported by a National Health and Medical Research Council (NHMRC) Early Career Fellowship (1088785). RP and MW were supported by the the Australian Research Council (ARC) Centre of Excellence for Cognition and its Disorders (CE110001021)Peer reviewedPublisher PD

Gender injustice in compensating injury to autonomy in English and Singaporean negligence law

The extent to which English law remedies injury to autonomy (ITA) as a stand-alone actionable damage in negligence is disputed. In this article I argue that the remedy available is not only partial and inconsistent (Keren-Paz in Med Law Rev, 2018) but also gendered and discriminatory against women. I first situate the argument within the broader feminist critique of tort law as failing to appropriately remedy gendered harms, and of law more broadly as undervaluing women’s interest in reproductive autonomy. I then show by reference to English remedies law’s first principles how imposed motherhood cases—Rees v Darlington and its predecessor McFarlane v Tayside Health Board—result in gender injustice when compared with other autonomy cases such as Chester v Afshar and Yearworth v North Bristol NHS Trust: A minor gender-neutral ITA is better remedied than the significant gendered harm of imposing motherhood on the claimant; men’s reproductive autonomy is protected to a greater extent than women’s; women’s reproductive autonomy is protected by an exceptional, derisory award. Worst of all, courts refuse to recognise imposed motherhood as detriment; and the deemed, mansplained, nonpecuniary joys of motherhood are used to offset pecuniary upkeep costs, forcing the claimant into a position she sought to avoid and thus further undermining her autonomy. The recent Singaporean case ACB v Thomson Medical Pte Ltd, awarding compensation for undermining the claimant’s genetic affinity in an IVF wrong-sperm-mix-up demonstrates some improvement in comparison to English law, and some shared gender injustices in the context of reproductive autonomy. ACB’s analysis is oblivious to the nature of reproductive autonomy harm as gendered; and prioritises the father’s interest in having genetic affinity with the baby over a woman’s interest in not having motherhood imposed upon her

Normothermic machine perfused organs as models of drug pharmacokinetics and therapeutic delivery

Less than 10% of drug candidates successfully pass through clinical trials and gain regulatory approval. One of the causes of translational failure is poor drug pharmacokinetics which are inadequately predicted by preclinical studies. Despite improvements in pharmacokinetic prediction in recent years, the circulating kinetics of many novel biologic agents, nanomedicines and drug delivery systems which exhibit transporter-mediated clearance, and size-dependent uptake by the reticuloendothelial system (RES), do not scale between species in a predictable manner and suffer with inadequate delivery to the therapeutic target. This hinders clinical translation, thus highlighting the need for more accurate preclinical testing to predict human drug disposition and facilitate improved drug delivery. Normothermic machine perfusion (NMP) is a method of organ preservation whereby oxygenation and nutrient provision to an organ is enabled via circulation of a cellular or acellular perfusate at body temperature. This maintains organs in a quasi-physiological state which we hypothesise will preserve the pharmacokinetic processes of drug distribution, metabolism and excretion, reflecting drug disposition in a close-to-man environment. The primary aim of this thesis is to determine whether human and porcine NMP clearance organs (kidney, spleen and liver) serve as a tool for predicting human drug clearance and for assessing drug delivery. Perfusion protocols were developed to support prolonged perfusion of i) human NMP liver and kidney, ii) laboratory-procured, porcine NMP liver and kidney and iii) abattoir-derived, porcine NMP liver and spleen. Systematic comparison of the different approaches demonstrated a robust physiological platform for profiling therapeutic pharmacokinetics and delivery. A small molecule therapeutic drug was delivered to the human and laboratory-procured, porcine liver and kidney models with assessment of pharmacokinetics. Both human and porcine organs were able to successfully support distribution, metabolism, hepatobiliary and renal excretion of the drug. Organ specific and total body clearance were calculated using physiological and pharmacokinetic data from the NMP organs and compared to human clinical data. Human NMP organs, which are discarded for transplantation with varying degrees of injury, did not accurately predict human clearance. However, pristine porcine NMP liver and kidney kidneys enabled accurate prediction of human intrinsic organ and total body clearance; the most important measure used to establish the safe dosing regimen when translating a novel drug into patients. This represents the first successful validation of a large mammalian normothermically preserved organ model against clinical data for an approved drug. Finally, the NMP spleen, liver and kidney were used to investigate the kinetics and delivery of a model polymeric nanoparticle and a viral vector; two classes of agent commonly captured by the RES and poorly translated from bench to bedside. PEGylated and non-PEGylated nanoparticle kinetics measured in NMP organs correspond to existing small animal data and provide evidence for nanoparticle capture in large animal organs for which data is limited. The NMP porcine liver was also able to support the circulating kinetics and integration of a viral vector into host hepatocyte DNA; a first for drug delivery studies in the ex vivo NMP liver and an exciting prospect for the delivery of hepatocyte-targeted gene therapies. In conclusion, despite limitations such as the effect of ischaemia reperfusion injury on organ physiology and the low throughput nature of the technology, this work demonstrates the utility of NMP clearance organs as a tool for predicting human pharmacokinetics and assessing drug delivery. The richness of data generated from the models has the potential to serve as an adjunct to existing preclinical technologies, for accelerating the development of novel therapeutics for patient benefit