Surgical treatment of drug-resistant focal epilepsy: selection, economic considerations and long-term outcomes

Epilepsy surgery can be an effective treatment for drug-resistant focal epilepsy, but requires careful selection of appropriate candidates to achieve optimal results and minimise the chance of adverse outcomes, including seizure recurrence. Long-term data on multimodal outcomes and a better appreciation of various factors influencing surgical suitability will help facilitate informed discussions between clinicians and prospective surgical candidates. This thesis includes a comprehensive analysis of a cohort of individuals who had epilepsy surgery at a tertiary neurosciences centre over the last 30 years, supplemented by data on individuals who completed presurgical evaluation at the same centre but did not proceed to surgical resection. An inability to localise the epileptogenic zone (EZ), multifocal epilepsy, or an individual choice not to have either intracranial electroencephalography or surgery were the most common reasons why people referred for presurgical evaluation did not proceed to a definitive resection. A predictive model based on demographic, imaging and electroclinical data was constructed to assist early discussions about surgical suitability. Those with normal MRI, extratemporal epilepsy and evidence of bilateral seizure onsets on video telemetry had an estimated 2.9% chance of proceeding to surgery, and people with a normal MRI brain invariably required intracranial EEG. Frontal lobe epilepsy surgery was safe and effective, with a long-term (median seven years) seizure freedom rate of 27%, and another 11% having auras only. Psychiatric comorbidity frequently improved postoperatively and paralleled seizure freedom. Focal MRI abnormality and fewer anti-seizure medications at the time of surgery could help predict a good outcome. In contrast, the site of resection and intracranial monitoring were not independently significant. Localisation of the EZ should rely on clinical features and multimodal investigation, as in our cohort frontal lobe semiology alone could correctly lateralise the EZ in only 77% and localise to a sublobar level in 52%. For those who completed presurgical evaluation but did not have surgery, under 5% had >12 months of seizure-freedom following the decision not to proceed, although a quarter had substantial improvement with further anti-seizure medication (ASM) or neurostimulation. Evaluation for epilepsy surgery was lengthy for individuals and costly for the public health system. Both duration and cost depended on what investigations were required and varied according to different routes through the presurgical pathway, especially the need for intracranial EEG. The median duration of evaluation was 29.7 months (IQR 18.6-44.1 months), with a median cost per person of £9,138 (IQR £6,984-£14,868). Approximately £123,500 was spent per additional person seizure-free

A Clinical Evaluation of a Self-Etch, Self-Adhesive Resin Cement for Bonding Indirect All-Ceramic Restorations

Master of ScienceRestorative DentistryUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/90956/1/Khoo_Anthony-THESIS_FINAL.pd

Measuring disease activity and predicting response to intravenous immunoglobulin in chronic inflammatory demyelinating polyneuropathy

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Abstract Chronic inflammatory demyelinating polyneuropathy (CIDP) is characterised by significant clinical heterogeneity and as such reliable biomarkers are required to measure disease activity and assess treatment response. Recent advances in our understanding of disease pathogenesis and the discovery of novel serum-based, electrophysiologic and imaging biomarkers allow clinicians to make more informed decisions regarding individualised treatment regimes. As a chronic immune-mediated process typified by relapse following withdrawal of immunomodulatory therapy, a substantial proportion of patients with CIDP require long term treatment with intravenous immunoglobulin (IVIg), a scarce and expensive donor-derived resource. The required duration and intensity of immunoglobulin treatment vary widely between individuals, highlighting both the heterogeneous nature of the underlying disease process as well as the variable pharmacologic properties of IVIg. This review outlines the use of multimodal biomarkers in the longitudinal evaluation of nerve injury and how recent developments have impacted our ability to predict both response to immunoglobulin administration and its withdrawal

Serum Adiponectin, Resistin, and Circulating Soluble Receptor for Advanced Glycation End Products in Colectomy Patients

Aim. Surgical trauma and associated complications are frequently related to physiological stress during colectomy. This study evaluated the response of adiponectin, resistin, and circulating soluble receptor for advanced glycation end products (sRAGE) in colectomy patients with or without an enhanced recovery protocol. Method. Serum samples were collected from 44 colectomy patients at 3 timframes. The surgical procedures were laparoscopic (LAP), hand-assisted laparoscopic (HALS), or open colectomy (OPEN). Adiponectin, resistin, and sRAGE levels were determined by ELISA. Repeated measures ANOVA was applied and P values < 0.05 were considered significant. Results. A total of 132 (44 × 3) sera were used for analysis. Levels of adiponectin was significantly decreased between PREOP and POD3 (P < 0.001). Conversely, concentrations of resistin significantly increased from PREOP to POD1 and returned to baseline value by POD3 (P < 0.001). Serum sRAGE levels were significantly higher in LAP in comparison with HALS (P = 0.004) and OPEN (P < 0.001). sRAGE levels were significantly higher in sera of patients that underwent ERP (P < 0.001). Conclusions. Serum adiponectin, resistin, and sRAGE have the potential to develop into a panel of stress markers. Higher sRAGE levels in sera of LAP and ERP patients may be indicative of a protective and syngeristic role for colectomy recovery

Pharmacodynamic modeling of bacillary elimination rates and detection of bacterial lipid bodies in sputum to predict and understand outcomes in treatment of pulmonary tuberculosis

This work was supported by a Wellcome Trust Clinical PhD Fellowship (086757/Z/08/A to D. J. S.), the Malawi Liverpool Wellcome Trust Core grant, and Medical Research Council (grant number G0300403 to M. R. B.).Background. Antibiotic-tolerant bacterial persistence prevents treatment shortening in drug-susceptible tuberculosis, and accumulation of intracellular lipid bodies has been proposed to identify a persister phenotype of Mycobacterium tuberculosis cells. In Malawi, we modeled bacillary elimination rates (BERs) from sputum cultures and calculated the percentage of lipid body-positive acid-fast bacilli (%LB + AFB) on sputum smears. We assessed whether these putative measurements of persistence predict unfavorable outcomes (treatment failure/relapse). Methods. Adults with pulmonary tuberculosis received standard 6-month therapy. Sputum samples were collected during the first 8 weeks for serial sputum colony counting (SSCC) on agar and time-to positivity (TTP) measurement in mycobacterial growth indicator tubes. BERs were extracted from nonlinear and linear mixed-effects models, respectively, fitted to these datasets. The %LB + AFB counts were assessed by fluorescence microscopy. Patients were followed until 1 year posttreatment. Individual BERs and %LB + AFB counts were related to final outcomes. Results. One hundred and thirty-three patients (56% HIV coinfected) participated, and 15 unfavorable outcomes were reported. These were inversely associated with faster sterilization phase bacillary elimination from the SSCC model (odds ratio [OR], 0.39; 95% confidence interval [CI], .22-.70) and a faster BER from the TTP model (OR, 0.71; 95% CI, .55-.94). Higher %LB + AFB counts on day 21-28 were recorded in patients who suffered unfavorable final outcomes compared with those who achieved stable cure (P = .008). Conclusions. Modeling BERs predicts final outcome, and high %LB + AFB counts 3-4 weeks into therapy may identify a persister bacterial phenotype. These methods deserve further evaluation as surrogate endpoints for clinical trials.Publisher PDFPeer reviewe

Algorithmic governance: Developing a research agenda through the power of collective intelligence

We are living in an algorithmic age where mathematics and computer science are coming together in powerful new ways to influence, shape and guide our behaviour and the governance of our societies. As these algorithmic governance structures proliferate, it is vital that we ensure their effectiveness and legitimacy. That is, we need to ensure that they are an effective means for achieving a legitimate policy goal that are also procedurally fair, open and unbiased. But how can we ensure that algorithmic governance structures are both? This article shares the results of a collective intelligence workshop that addressed exactly this question. The workshop brought together a multidisciplinary group of scholars to consider (a) barriers to legitimate and effective algorithmic governance and (b) the research methods needed to address the nature and impact of specific barriers. An interactive management workshop technique was used to harness the collective intelligence of this multidisciplinary group. This method enabled participants to produce a framework and research agenda for those who are concerned about algorithmic governance. We outline this research agenda below, providing a detailed map of key research themes, questions and methods that our workshop felt ought to be pursued. This builds upon existing work on research agendas for critical algorithm studies in a unique way through the method of collective intelligence

Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation.

Familial hypercholesterolaemia (FH) is a dominantly inherited disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL) cholesterol and causes premature coronary heart disease. There are at least 20million people with FH worldwide, but the majority remain undetected and current treatment is often suboptimal. To address this major gap in coronary prevention we present, from an international perspective, consensus-based guidance on the care of FH. The guidance was generated from seminars and workshops held at an international symposium. The recommendations focus on the detection, diagnosis, assessment and management of FH in adults and children, and set guidelines for clinical purposes. They also refer to best practice for cascade screening and risk notifying and testing families for FH, including use of genetic testing. Guidance on treatment is based on risk stratification, management of non-cholesterol risk factors, and safe and effective use of LDL lowering therapies. Recommendations are given on lipoprotein apheresis. The use of emerging therapies for FH is also foreshadowed. This international guidance acknowledges evidence gaps, but aims to make the best use of contemporary practice and technology to achieve the best outcomes for the care of FH. It should accordingly be employed to inform clinical judgement and be adjusted for country-specific and local health care needs and resources

Integrated Guidance on the Care of Familial Hypercholesterolaemia from the International FH Foundation: Executive Summary

Familial hypercholesterolaemia (FH) is a dominantly inherited disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL) cholesterol and causes premature coronary heart disease. There are at least 20 million people with FH worldwide, but the majority remains undetected and current treatment is often suboptimal. To address this major gap in coronary prevention we present, from an international perspective, consensus-based guidance on the care of FH. The guidance was generated from seminars and workshops held at an international symposium. The recommendations focus on the detection, diagnosis, assessment and management of FH in adults and children, and set guidelines for clinical purposes. They also refer to best practice for cascade screening and risk notifying and testing families for FH, including use of genetic testing. Guidance on treatment is based on risk stratification, management of non-cholesterol risk factors and safe and effective use of LDL lowering therapies. Recommendations are given on lipoprotein apheresis. The use of emerging therapies for FH is also foreshadowed. This international guidance acknowledges evidence gaps, but aims to make the best use of contemporary practice and technology to achieve the best outcomes for the care of FH. It should accordingly be employed to inform clinical judgment and be adjusted for country-specific and local healthcare needs and resources

Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD) : effectiveness results from the pilot phase of a pragmatic open-label randomised trial

Background Randomised placebo-controlled trials have shown that daily oral pre-exposure prophylaxis (PrEP) with tenofovir-emtricitabine reduces the risk of HIV infection. However, this benefit could be counteracted by risk compensation in users of PrEP. We did the PROUD study to assess this effect. Methods PROUD is an open-label randomised trial done at 13 sexual health clinics in England. We enrolled HIV-negative gay and other men who have sex with men who had had anal intercourse without a condom in the previous 90 days. Participants were randomly assigned (1:1) to receive daily combined tenofovir disoproxil fumarate (245 mg) and emtricitabine (200 mg) either immediately or after a deferral period of 1 year. Randomisation was done via web-based access to a central computer-generated list with variable block sizes (stratified by clinical site). Follow-up was quarterly. The primary outcomes for the pilot phase were time to accrue 500 participants and retention; secondary outcomes included incident HIV infection during the deferral period, safety, adherence, and risk compensation. The trial is registered with ISRCTN (number ISRCTN94465371) and ClinicalTrials.gov (NCT02065986). Findings We enrolled 544 participants (275 in the immediate group, 269 in the deferred group) between Nov 29, 2012, and April 30, 2014. Based on early evidence of effectiveness, the trial steering committee recommended on Oct 13, 2014, that all deferred participants be offered PrEP. Follow-up for HIV incidence was complete for 243 (94%) of 259 patient-years in the immediate group versus 222 (90%) of 245 patient-years in the deferred group. Three HIV infections occurred in the immediate group (1·2/100 person-years) versus 20 in the deferred group (9·0/100 person-years) despite 174 prescriptions of post-exposure prophylaxis in the deferred group (relative reduction 86%, 90% CI 64-96, p=0·0001; absolute difference 7·8/100 person-years, 90% CI 4·3-11·3). 13 men (90% CI 9-23) in a similar population would need access to 1 year of PrEP to avert one HIV infection. We recorded no serious adverse drug reactions; 28 adverse events, most commonly nausea, headache, and arthralgia, resulted in interruption of PrEp. We detected no difference in the occurrence of sexually transmitted infections, including rectal gonorrhoea and chlamydia, between groups, despite a suggestion of risk compensation among some PrEP recipients. Interpretation In this high incidence population, daily tenofovir-emtricitabine conferred even higher protection against HIV than in placebo-controlled trials, refuting concerns that effectiveness would be less in a real-world setting. There was no evidence of an increase in other sexually transmitted infections. Our findings strongly support the addition of PrEP to the standard of prevention for men who have sex with men at risk of HIV infection. Funding MRC Clinical Trials Unit at UCL, Public Health England, and Gilead Sciences

Open source clinical science for emerging infections

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