Atypical back pain in a child: subcutaneous lumbar abscess associated with chickenpox

Back pain in children has numerous possible causes. Although chickenpox is an extremely common and contagious condition in the paediatric population, it can be associated with potentially life-threatening musculoskeletal complications. We discuss the extremely unusual case of a child with an extensive subcutaneous lumbar abcess who presented with severe back pain associated with active chickenpox infection.Keywords: abscess, back pain, chickenpox, group A  β-haemolytic streptococcus, varicella zoster viru

Known or potential threats from pests and diseases to prospective tree species for high value timber plantings in northern Australia

The development of a high value timber industry in northern Australia requires high-level, long-term investment. To secure such a commitment, potential investors and growers must be confident of achieving high productivity and/or high quality end product. Pests and diseases, and their effect on tree health, can be major limiting factors to tree establishment and performance. This is especially true where native or endemic species are to be grown. Timber plantings in northern Australia are likely to be at risk from a number of pests and diseases. This includes both native and exotic species already present within the region, and species not yet present but which have potential to cause problems should they arrive. Existing and potential threats are listed and the more serious problems reviewed

Towards an understanding of the burdens of medication management affecting older people: the MEMORABLE realist synthesis

Background More older people are living in the community with multiple diagnoses and medications. Managing multiple medications produces issues of unrivalled complexity for those involved. Despite increasing literature on the subject, gaps remain in understanding how, why and for whom complex medication management works, and therefore how best to improve practice and outcomes. MEMORABLE, MEdication Management in Older people: Realist Approaches Based on Literature and Evaluation, aimed to address these gaps. Methods MEMORABLE used realism to understand causal paths within medication management. Informed by RAMESES (Realist And Meta-narrative Evidence Synthesis: and Evolving Standards) guidelines, MEMORABLE involved three overlapping work packages: 1) Realist Review of the literature (24 articles on medication management exploring causality); 2) Realist Evaluation (50 realist-informed interviews with older people, family carers and health and care practitioners, explaining their experiences); and 3) data synthesis and theorising from 1) and 2). Results Medication management was viewed from the perspective of ‘implementation’ and structured into five stages: identifying a problem (Stage 1), getting a diagnosis and/or medications (Stage 2), starting, changing or stopping medications (Stage 3), continuing to take medications (Stage 4), and reviewing/reconciling medications (Stage 5). Three individual stages (1, 3 and 4) are conducted by the older person sometimes with family carer support when they balance routines, coping and risk. Stages 2 and 5 are interpersonal where the older person works with a practitioner-prescriber-reviewer, perhaps with carer involvement. Applying Normalisation Process Theory, four steps were identified within each stage: 1) sense making: information, clarification; 2) action: shared-decision-making; 3) reflection/monitoring; and 4) enduring relationships, based on collaboration and mutual trust. In a detailed analysis of Stage 5: Reviewing/reconciling medications, adopting the lens of ‘burden’, MEMORABLE identified five burdens amenable to mitigation: ambiguity, concealment, unfamiliarity, fragmentation and exclusion. Two initial improvement propositions were identified for further research: a risk screening tool and individualised information. Conclusions Older people and family carers often find medication management challenging and burdensome particularly for complex regimens. Practitioners need to be aware of this potential challenge, and work with older people and their carers to minimise the burden associated with medication management. Trial registration PROSPERO 2016:CRD42016043506

Medication management in older people: the MEMORABLE realist synthesis

Background The number and proportion of older people in the UK are increasing, as are multimorbidity (potentially reducing quality of life) and polypharmacy (increasing the risk of adverse drug events). Together, these complex factors are challenging for older people, informal carers, and health and care practitioners. Objectives MEMORABLE (MEdication Management in Older people: Realist Approaches Based on Literature and Evaluation) aimed to understand how medication management works and propose improvements. Design A realist approach informed three work packages, combining a realist review of secondary data with a realist evaluation of primary interview data, in a theory-driven, causal analysis. Setting The setting was in the community. Participants Older people, informal carers, and health and care practitioners. Interventions Studies relating to medication management and to reviewing and reconciling medications; and realist-informed interviews. Main outcome measures Not applicable. Data sources MEDLINE, CINAHL (Cumulative Index of Nursing and Allied Health Literature) and EMBASE were searched (all searched from January 2009 to July 2017; searched on 1 August 2017). Supplementary articles were identified by the Research Team. Data were also obtained through interviews. Review methods Searches of electronic databases were supplemented by citation-tracking for explanatory contributions, as well as accessing topic-relevant grey literature. Following RAMESES (Realist And Meta-narrative Evidence Syntheses: Evolving Standards) guidelines, articles were screened and iteratively analysed with interview data, to generate theory-informed (normalisation process theory) explanations. Results Developing a framework to explain medication management as a complex intervention across five stages: identifying problem (Stage 1), starting, changing or stopping medications (Stage 3) and continuing to take medications (Stage 4), where older people, sometimes with informal carers, make individual decisions and follow routines that fit medication management into their day-to-day lives, engendering a sense of control. In getting diagnosis and/or medications (Stage 2) and reviewing/reconciling medications (Stage 5), older people and practitioners share decision-making in time-limited contacts: involving four steps – sense-making, relationships, action and reflection/monitoring (normalisation process theory); and conceptualising burden – through a detailed analysis of Stage 5, generating a theoretical framework and identifying five burden types amendable to mitigation: ambiguity, concealment, unfamiliarity, fragmentation and exclusion. Proposing interventions: risk identification – a simple way of identifying older people and informal carers who are not coping, at risk and who need appropriate help and support; and individualised information – a short, personalised record and reference point, co-produced and shared by older people, informal carers and practitioners that addresses the experience of living with multimorbidities and polypharmacy. Limitations Few studies directly address the complexity of medication management as a process and how it works. Limitations included, having identified the overall complexity, the need to focus the analysis on reviewing/reconciling medications (Stage 5), the exclusion of non-English-language literature, the focus on non-institutionalised populations and the broad definition of older people. Conclusions MEMORABLE explored the complexity of medication management. It highlighted the way interpersonal stages in the medication management process, notably reviewing/reconciling medications, contribute to the mitigation of burdens that are often hidden. Future work Co-produced studies to scope and trial the two proposed interventions; studies to extend the detailed understanding of medication management, linked to burden mitigation; and a study to clarify the medication management outcomes wanted by older people, informal carers and practitioners. Study registration This study is registered as PROSPERO CRD42016043506

Assessing the outcomes of participatory research: protocol for identifying, selecting, appraising and synthesizing the literature for realist review

<p>Abstract</p> <p>Background</p> <p>Participatory Research (PR) entails the co-governance of research by academic researchers and end-users. End-users are those who are affected by issues under study (<it>e.g.</it>, community groups or populations affected by illness), or those positioned to act on the knowledge generated by research (<it>e.g.</it>, clinicians, community leaders, health managers, patients, and policy makers). Systematic reviews assessing the generalizable benefits of PR must address: the diversity of research topics, methods, and intervention designs that involve a PR approach; varying degrees of end-user involvement in research co-governance, both within and between projects; and the complexity of outcomes arising from long-term partnerships.</p> <p>Methods</p> <p>We addressed the above mentioned challenges by adapting realist review methodology to PR assessment, specifically by developing inductively-driven identification, selection, appraisal, and synthesis procedures. This approach allowed us to address the non-uniformity and complexity of the PR literature. Each stage of the review involved two independent reviewers and followed a reproducible, systematic coding and retention procedure. Retained studies were completed participatory health interventions, demonstrated high levels of participation by non-academic stakeholders (<it>i.e.</it>, excluding studies in which end-users were not involved in co-governing throughout the stages of research) and contained detailed descriptions of the participatory process and context. Retained sets are being mapped and analyzed using realist review methods.</p> <p>Results</p> <p>The librarian-guided search string yielded 7,167 citations. A total of 594 citations were retained after the identification process. Eighty-three papers remained after selection. Principle Investigators (PIs) were contacted to solicit all companion papers. Twenty-three sets of papers (23 PR studies), comprising 276 publications, passed appraisal and are being synthesized using realist review methods.</p> <p>Discussion</p> <p>The systematic and stage-based procedure addressed challenges to PR assessment and generated our robust understanding of complex and heterogeneous PR practices. To date, realist reviews have focussed on evaluations of relatively uniform interventions. In contrast our PR search yielded a wide diversity of partnerships and research topics. We therefore developed tools to achieve conceptual clarity on the PR field, as a beneficial precursor to our theoretically-driven synthesis using realist methods. Findings from the ongoing review will be provided in forthcoming publications.</p

The SANAD II study of the effectiveness and cost-effectiveness of levetiracetam, zonisamide, or lamotrigine for newly diagnosed focal epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial

Background: Levetiracetam and zonisamide are licensed as monotherapy for patients with focal epilepsy, but there is uncertainty as to whether they should be recommended as first-line treatments because of insufficient evidence of clinical effectiveness and cost-effectiveness. We aimed to assess the long-term clinical effectiveness and cost-effectiveness of levetiracetam and zonisamide compared with lamotrigine in people with newly diagnosed focal epilepsy. Methods: This randomised, open-label, controlled trial compared levetiracetam and zonisamide with lamotrigine as first-line treatment for patients with newly diagnosed focal epilepsy. Adult and paediatric neurology services across the UK recruited participants aged 5 years or older (with no upper age limit) with two or more unprovoked focal seizures. Participants were randomly allocated (1:1:1) using a minimisation programme with a random element utilising factor to receive lamotrigine, levetiracetam, or zonisamide. Participants and investigators were not masked and were aware of treatment allocation. SANAD II was designed to assess non-inferiority of both levetiracetam and zonisamide to lamotrigine for the primary outcome of time to 12-month remission. Anti-seizure medications were taken orally and for participants aged 12 years or older the initial advised maintenance doses were lamotrigine 50 mg (morning) and 100 mg (evening), levetiracetam 500 mg twice per day, and zonisamide 100 mg twice per day. For children aged between 5 and 12 years the initial daily maintenance doses advised were lamotrigine 1·5 mg/kg twice per day, levetiracetam 20 mg/kg twice per day, and zonisamide 2·5 mg/kg twice per day. All participants were included in the intention-to-treat (ITT) analysis. The per-protocol (PP) analysis excluded participants with major protocol deviations and those who were subsequently diagnosed as not having epilepsy. Safety analysis included all participants who received one dose of any study drug. The non-inferiority limit was a hazard ratio (HR) of 1·329, which equates to an absolute difference of 10%. A HR greater than 1 indicated that an event was more likely on lamotrigine. The trial is registered with the ISRCTN registry, 30294119 (EudraCt number: 2012-001884-64). Findings: 990 participants were recruited between May 2, 2013, and June 20, 2017, and followed up for a further 2 years. Patients were randomly assigned to receive lamotrigine (n=330), levetiracetam (n=332), or zonisamide (n=328). The ITT analysis included all participants and the PP analysis included 324 participants randomly assigned to lamotrigine, 320 participants randomly assigned to levetiracetam, and 315 participants randomly assigned to zonisamide. Levetiracetam did not meet the criteria for non-inferiority in the ITT analysis of time to 12-month remission versus lamotrigine (HR 1·18; 97·5% CI 0·95–1·47) but zonisamide did meet the criteria for non-inferiority in the ITT analysis versus lamotrigine (1·03; 0·83–1·28). The PP analysis showed that 12-month remission was superior with lamotrigine than both levetiracetam (HR 1·32 [97·5% CI 1·05 to 1·66]) and zonisamide (HR 1·37 [1·08–1·73]). There were 37 deaths during the trial. Adverse reactions were reported by 108 (33%) participants who started lamotrigine, 144 (44%) participants who started levetiracetam, and 146 (45%) participants who started zonisamide. Lamotrigine was superior in the cost-utility analysis, with a higher net health benefit of 1·403 QALYs (97·5% central range 1·319–1·458) compared with 1·222 (1·110–1·283) for levetiracetam and 1·232 (1·112, 1·307) for zonisamide at a cost-effectiveness threshold of £20 000 per QALY. Cost-effectiveness was based on differences between treatment groups in costs and QALYs. Interpretation: These findings do not support the use of levetiracetam or zonisamide as first-line treatments for patients with focal epilepsy. Lamotrigine should remain a first-line treatment for patients with focal epilepsy and should be the standard treatment in future trials. Funding: National Institute for Health Research Health Technology Assessment programme

The SANAD II study of the effectiveness and cost-effectiveness of valproate versus levetiracetam for newly diagnosed generalised and unclassifiable epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial

Background: Valproate is a first-line treatment for patients with newly diagnosed idiopathic generalised or difficult to classify epilepsy, but not for women of child-bearing potential because of teratogenicity. Levetiracetam is increasingly prescribed for these patient populations despite scarcity of evidence of clinical effectiveness or cost-effectiveness. We aimed to compare the long-term clinical effectiveness and cost-effectiveness of levetiracetam compared with valproate in participants with newly diagnosed generalised or unclassifiable epilepsy. Methods: We did an open-label, randomised controlled trial to compare levetiracetam with valproate as first-line treatment for patients with generalised or unclassified epilepsy. Adult and paediatric neurology services (69 centres overall) across the UK recruited participants aged 5 years or older (with no upper age limit) with two or more unprovoked generalised or unclassifiable seizures. Participants were randomly allocated (1:1) to receive either levetiracetam or valproate, using a minimisation programme with a random element utilising factors. Participants and investigators were aware of treatment allocation. For participants aged 12 years or older, the initial advised maintenance doses were 500 mg twice per day for levetiracetam and valproate, and for children aged 5–12 years, the initial daily maintenance doses advised were 25 mg/kg for valproate and 40 mg/kg for levetiracetam. All drugs were administered orally. SANAD II was designed to assess the non-inferiority of levetiracetam compared with valproate for the primary outcome time to 12-month remission. The non-inferiority limit was a hazard ratio (HR) of 1·314, which equates to an absolute difference of 10%. A HR greater than 1 indicated that an event was more likely on valproate. All participants were included in the intention-to-treat (ITT) analysis. Per-protocol (PP) analyses excluded participants with major protocol deviations and those who were subsequently diagnosed as not having epilepsy. Safety analyses included all participants who received one dose of any study drug. This trial is registered with the ISRCTN registry, 30294119 (EudraCt number: 2012-001884-64). Findings: 520 participants were recruited between April 30, 2013, and Aug 2, 2016, and followed up for a further 2 years. 260 participants were randomly allocated to receive levetiracetam and 260 participants to receive valproate. The ITT analysis included all participants and the PP analysis included 255 participants randomly allocated to valproate and 254 randomly allocated to levetiracetam. Median age of participants was 13·9 years (range 5·0–94·4), 65% were male and 35% were female, 397 participants had generalised epilepsy, and 123 unclassified epilepsy. Levetiracetam did not meet the criteria for non-inferiority in the ITT analysis of time to 12-month remission (HR 1·19 [95% CI 0·96–1·47]); non-inferiority margin 1·314. The PP analysis showed that the 12-month remission was superior with valproate than with levetiracetam. There were two deaths, one in each group, that were unrelated to trial treatments. Adverse reactions were reported by 96 (37%) participants randomly assigned to valproate and 107 (42%) participants randomly assigned to levetiracetam. Levetiracetam was dominated by valproate in the cost-utility analysis, with a negative incremental net health benefit of −0·040 (95% central range −0·175 to 0·037) and a probability of 0·17 of being cost-effectiveness at a threshold of £20 000 per quality-adjusted life-year. Cost-effectiveness was based on differences between treatment groups in costs and quality-adjusted life-years. Interpretation: Compared with valproate, levetiracetam was found to be neither clinically effective nor cost-effective. For girls and women of child-bearing potential, these results inform discussions about benefit and harm of avoiding valproate. Funding: National Institute for Health Research Health Technology Assessment Programme

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Effectiveness of a national quality improvement programme to improve survival after emergency abdominal surgery (EPOCH): a stepped-wedge cluster-randomised trial

Background: Emergency abdominal surgery is associated with poor patient outcomes. We studied the effectiveness of a national quality improvement (QI) programme to implement a care pathway to improve survival for these patients. Methods: We did a stepped-wedge cluster-randomised trial of patients aged 40 years or older undergoing emergency open major abdominal surgery. Eligible UK National Health Service (NHS) hospitals (those that had an emergency general surgical service, a substantial volume of emergency abdominal surgery cases, and contributed data to the National Emergency Laparotomy Audit) were organised into 15 geographical clusters and commenced the QI programme in a random order, based on a computer-generated random sequence, over an 85-week period with one geographical cluster commencing the intervention every 5 weeks from the second to the 16th time period. Patients were masked to the study group, but it was not possible to mask hospital staff or investigators. The primary outcome measure was mortality within 90 days of surgery. Analyses were done on an intention-to-treat basis. This study is registered with the ISRCTN registry, number ISRCTN80682973. Findings: Treatment took place between March 3, 2014, and Oct 19, 2015. 22 754 patients were assessed for elegibility. Of 15 873 eligible patients from 93 NHS hospitals, primary outcome data were analysed for 8482 patients in the usual care group and 7374 in the QI group. Eight patients in the usual care group and nine patients in the QI group were not included in the analysis because of missing primary outcome data. The primary outcome of 90-day mortality occurred in 1210 (16%) patients in the QI group compared with 1393 (16%) patients in the usual care group (HR 1·11, 0·96–1·28). Interpretation: No survival benefit was observed from this QI programme to implement a care pathway for patients undergoing emergency abdominal surgery. Future QI programmes should ensure that teams have both the time and resources needed to improve patient care. Funding: National Institute for Health Research Health Services and Delivery Research Programme