A Core outcome set for childhood epilepsy treated with ketogenic diet therapy (CORE-KDT study): international parent and health professional consensus.

OBJECTIVE: Ketogenic diet therapy (KDT) can result in benefits (seizure and non-seizure related) for children with drug resistant epilepsy. However, clinical trials report a wide range of outcomes making synthesis of evidence difficult, and do not adequately reflect parent views on important outcomes for their child. To address this, we established the first international parent, health professional and researcher consensus to develop a core outcome set, guided by the Core Outcome Measures in Effectiveness Trials (COMET) Initiative (COMET registration #1116). METHODS: Ethical approval was granted (London-Surrey REC19/LO/1680). A scoping review and interviews with parents identified a comprehensive list of potentially important outcomes, followed by a two-round online Delphi survey of parents and health professionals to prioritise outcomes of importance for inclusion in a core outcome set. This informed a stakeholder consensus meeting and consultation process to finalise the core outcome set. RESULTS: In total, 97 outcomes were identified; 90 from the scoping review and seven from parent interviews. These were rationalised to 77 by the study advisory group, then rated in the first Delphi round by 49 parents and 96 health professionals who suggested 12 new outcomes for rating in round two. 66% of participants (30 parents and 66 professionals) completed round two, where 22 outcomes met criteria for inclusion. In the consensus meeting (9 parents and 13 professionals), 27 undecided outcomes were discussed and scored; one further outcome reached consensus for inclusion. After consultation and ratification, 14 outcomes across five domains were included in the core outcome set. SIGNIFICANCE: A core outcome set for childhood epilepsy treated with KDT has been developed, incorporating the views of international parents and professionals. Implementation in research and clinical settings will standardise outcome selection and reporting, facilitate data synthesis and ultimately enhance the relevance of outcomes to parents, researchers and health professionals

The CORE-KDT study: a mixed methods protocol to establish core outcomes for refractory childhood epilepsy treated with ketogenic diet therapy

Background: A core outcome set defines the minimum outcomes that should be included in clinical trials, audit or practice. The aim being to increase the quality and relevance of research by ensuring consistency in the measurement and reporting of outcomes. Core outcome sets have been developed for a variety of disease states and treatments. However, there is no established set of core outcomes for refractory childhood epilepsy treated with ketogenic diet therapy. This should be developed using a patient-centred approach to ensure the outcomes measured are relevant to patients and clinical practice. Methods: This is a mixed methods study of four phases to develop a core outcome set for refractory childhood epilepsy treated with ketogenic diet therapy. In phase 1, a systematic scoping review of the literature will establish which outcomes are measured in trials of refractory epilepsy treated with ketogenic diet therapy. In phase 2, qualitative interviews with parents and carers will aim to identify the outcomes of importance to these stakeholders. Phase 3 will see a comprehensive list of outcomes collated from the first two phases, grouped into domains according to an outcome taxonomy. Phase 4 will invite parents, health care professionals and researchers to participate in a two-round Delphi study to rate the importance of the presented outcomes. Following which, the core outcome set will be ratified at a face to face consensus meeting. Discussion: This study will guide outcome measurement in future studies of childhood epilepsy treated with ketogenic diet therapy and clinical practice through audit and service evaluation

Drug-resistant epilepsy and ketogenic diet therapy – a qualitative study of families’ experiences.

Abstract Background A diagnosis of drug-resistant epilepsy is life changing for a family. Ketogenic diet therapy (KDT) can offer hope when other treatments have failed. However, it often requires a significant change in daily routine and dietary habits. This qualitative descriptive study aimed to explore families’ experiences of epilepsy and KDT. Methods Parents of a child aged ≤18 years with epilepsy, currently or recently treated with KDT, were recruited from the UK and internationally via UK Ketogenic Diet (KD) centres, charities, and social media. Semi-structured interviews were audio recorded, transcribed verbatim, anonymised, coded using Nvivo (V12), and inductive thematic analysis undertaken. Results Twenty-one parents participated. Four themes and 12 subthemes emerged: 1. ‘Epilepsy is all consuming’ explored the impact of epilepsy on the family. 2. ‘KD provides a window to new opportunities’ explores the motivators for KDT and positive outcomes. 3. ‘The reality of KD’ explores day to day life and how families adapt to KD. 4. ‘Looking to the future’ explores the factors that may make KD easier for families. All were glad their child trialled KD, even when less successful. The importance of a support network including family, friends, charity organisations and the KD team was evident across all themes. Conclusions We conclude with five recommendations to help support families in their management of KDT; Improved access to KDT and transition to adult services, access to quality education and support, enhanced variety of KD foods, regular social education and finally consideration of peer mentoring

Investigating CXCR4 expression of tumor cells and the vascular compartment: A multimodal approach

The C-X-C chemokine receptor 4 (CXCR4) is G protein-coupled receptor that upon binding to its cognate ligand, can lead to tumor progression. Several CXCR4-targeted therapies are currently under investigation, and with it comes the need for imaging agents capable of accurate depiction of CXCR4 for therapeutic stratification and monitoring. PET agents enjoy the most success, but more cost-effective and radiation-free approaches such as ultrasound (US) imaging could represent an attractive alternative. In this work, we developed a targeted microbubble (MB) for imaging of vascular CXCR4 expression in cancer. A CXCR4-targeted MB was developed through incorporation of the T140 peptide into the MB shell. Binding properties of the T140-MB and control, non-targeted MB (NT-MB) were evaluated in MDA-MB-231 cells where CXCR4 expression was knocked-down (via shRNA) through optical imaging, and in the lymphoma tumor models U2932 and SuDHL8 (high and low CXCR4 expression, respectively) by US imaging. PET imaging of [18F]MCFB, a tumor-penetrating CXCR4-targeted small molecule, was used to provide whole-tumor CXCR4 readouts. CXCR4 expression and microvessel density were performed by immunohistochemistry analysis and western blot. T140-MB were formed with similar properties to NT-MB and accumulated sensitively and specifically in cells according to their CXCR4 expression. In NOD SCID mice, T140-MB persisted longer in tumors than NT-MB, indicative of target interaction, but showed no difference between U2932 and SuDHL8. In contrast, PET imaging with [18F]MCFB showed a marked difference in tumor uptake at 40–60 min post-injection between the two tumor models (p<0.05). Ex vivo analysis revealed that the large differences in CXCR4 expression between the two models are not reflected in the vascular compartment, where the MB are restricted; in fact, microvessel density and CXCR4 expression in the vasculature was comparable between U2932 and SuDHL8 tumors. In conclusion, we successfully developed a T140-MB that can be used for imaging CXCR4 expression in the tumor vasculature

Mycobacterium tuberculosis ClpP Proteases Are Co-transcribed but Exhibit Different Substrate Specificities

PMCID: PMC3613350This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Unconventional motional narrowing in the optical spectrum of a semiconductor quantum dot

Motional narrowing refers to the striking phenomenon where the resonance line of a system coupled to a reservoir becomes narrower when increasing the reservoir fluctuation. A textbook example is found in nuclear magnetic resonance, where the fluctuating local magnetic fields created by randomly oriented nuclear spins are averaged when the motion of the nuclei is thermally activated. The existence of a motional narrowing effect in the optical response of semiconductor quantum dots remains so far unexplored. This effect may be important in this instance since the decoherence dynamics is a central issue for the implementation of quantum information processing based on quantum dots. Here we report on the experimental evidence of motional narrowing in the optical spectrum of a semiconductor quantum dot broadened by the spectral diffusion phenomenon. Surprisingly, motional narrowing is achieved when decreasing incident power or temperature, in contrast with the standard phenomenology observed for nuclear magnetic resonance

ATF6 is essential for human cone photoreceptor development

Endoplasmic reticulum (ER) stress and Unfolded Protein Response (UPR) signaling promote the pathology of many human diseases. Loss-of-function variants of the UPR regulator Activating Transcription Factor 6 (ATF6) cause severe congenital vision loss diseases such as achromatopsia by unclear pathomechanisms. To investigate this, we generated retinal organoids from achromatopsia patient induced pluripotent stem cells carrying ATF6 disease variants and from gene-edited ATF6 null hESCs. We found that achromatopsia patient and ATF6 null retinal organoids failed to form cone structures concomitant with loss of cone phototransduction gene expression, while rod photoreceptors developed normally. Adaptive optics retinal imaging of achromatopsia patients carrying ATF6 variants also showed absence of cone inner/outer segment structures but preserved rod structures, mirroring the defect in cone formation observed in our retinal organoids. These results establish that ATF6 is essential for human cone development. Interestingly, we find that a selective small molecule ATF6 signaling agonist restores the transcriptional activity of some ATF6 disease-causing variants and stimulates cone growth and gene expression in patient retinal organoids carrying these variants. These findings support that pharmacologic targeting of the ATF6 pathway can promote human cone development and should be further explored for blinding retinal diseases

Charged Dilatonic AdS Black Branes in Arbitrary Dimensions

We study electromagnetically charged dilatonic black brane solutions in arbitrary dimensions with flat transverse spaces, that are asymptotically AdS. This class of solutions includes spacetimes which possess a bulk region where the metric is approximately invariant under Lifshitz scalings. Given fixed asymptotic boundary conditions, we analyze how the behavior of the bulk up to the horizon varies with the charges and derive the extremality conditions for these spacetimes.Comment: References update

A step-wise approach to developing indicators to compare the performance of maternity units using hospital administrative data.

Hospital administrative data are attractive for comparing performance of maternity units because of their often large sample sizes, lack of selection bias and the relatively low costs of accessing these data compared with conducting primary data collection. However, using administrative data to develop indicators can also present challenges including varying data quality, the limited detail on clinical risk factors and a lack of structural and user experience measures. This review illustrates how to develop performance indicators for maternity units using hospital administrative data, including methods to address the challenges that administrative data pose. TWEETABLE ABSTRACT: How to develop maternity indicators from administrative data

Uncovering treatment burden as a key concept for stroke care: a systematic review of qualitative research

&lt;b&gt;Background&lt;/b&gt; Patients with chronic disease may experience complicated management plans requiring significant personal investment. This has been termed ‘treatment burden’ and has been associated with unfavourable outcomes. The aim of this systematic review is to examine the qualitative literature on treatment burden in stroke from the patient perspective.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Methods and findings&lt;/b&gt; The search strategy centred on: stroke, treatment burden, patient experience, and qualitative methods. We searched: Scopus, CINAHL, Embase, Medline, and PsycINFO. We tracked references, footnotes, and citations. Restrictions included: English language, date of publication January 2000 until February 2013. Two reviewers independently carried out the following: paper screening, data extraction, and data analysis. Data were analysed using framework synthesis, as informed by Normalization Process Theory. Sixty-nine papers were included. Treatment burden includes: (1) making sense of stroke management and planning care, (2) interacting with others, (3) enacting management strategies, and (4) reflecting on management. Health care is fragmented, with poor communication between patient and health care providers. Patients report inadequate information provision. Inpatient care is unsatisfactory, with a perceived lack of empathy from professionals and a shortage of stimulating activities on the ward. Discharge services are poorly coordinated, and accessing health and social care in the community is difficult. The study has potential limitations because it was restricted to studies published in English only and data from low-income countries were scarce.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Conclusions&lt;/b&gt; Stroke management is extremely demanding for patients, and treatment burden is influenced by micro and macro organisation of health services. Knowledge deficits mean patients are ill equipped to organise their care and develop coping strategies, making adherence less likely. There is a need to transform the approach to care provision so that services are configured to prioritise patient needs rather than those of health care systems