A case of multiple sclerosis—like relapsing remitting encephalomyelitis following allogeneic hematopoietic stem cell transplantation and a review of the published literature

Complications involving the central nervous system (CNS) occur in 9–14% of patients following allogeneic hematopoietic stem cell transplantation (HSCT), including stroke-like episodes, demyelination, encephalitis, and nonspecific neurological symptoms. Here we report a case of multiple sclerosis (MS) like relapsing remitting encephalomyelitis following allogeneic HSCT, which did not respond to disease modifying therapies (DMTs) and “domino” autologous HSCT. A 53-year-old male was treated with allogeneic HSCT for lymphoid blast transformation of chronic myeloid leukemia. Ten months later he presented with confusion, slurred speech, left sided facial weakness and ataxia. A magnetic resonance imaging brain scan showed multiple enhancing tumefactive lesions. Neuromyelitis optica (NMO) and myelin oligodendrocyte glycoprotein (MOG) antibodies were negative. After extensive investigations for infections, autoimmune disorders and recurrence of malignancy, he underwent brain biopsy, which showed a macrophage rich lesion with severe myelin loss but axonal preservation indicating a demyelinating pathology. Although his symptoms improved with corticosteroids, he relapsed five months later. In the absence of any systemic features suggesting graft versus host disease (GvHD), his presentation was thought to be compatible with MS. The illness followed an aggressive course that did not respond to glatiramer acetate and natalizumab. He was therefore treated with “domino” autologous HSCT, which also failed to induce long-term remission. Despite further treatment with ocrelizumab, he died of progressive disease. An autopsy limited to the examination of brain revealed multifocal destructive leukoencephalopathy with severe myelin and axonal loss. Immunohistochemistry showed macrophage located in the perivascular area, with no T or B lymphocytes. The appearance was unusual and not typical for chronic MS plaques. Reported cases of CNS demyelination following allogeneic HSCT are very limited in the literature, especially in relation to histopathological examination. Although the clinical disease course of our patient following allogeneic HSCT resembled an “MS-like” relapsing remitting encephalomyelitis, the autopsy examination did not show any evidence of active inflammation. The impact of DMTs and HSCT on the histological appearance of “MS-like” CNS pathologies is unknown. Therefore, reporting this and similar cases will improve our awareness and understanding of underlying disease mechanisms

Development of ST:REAM: A reach-based stream power balance approach for predicting alluvial river channel adjustment

River channel sediment dynamics are important in integrated catchment management because changes in channel morphology resulting from sediment transfer have important implications for many river functions. However, application of existing approaches that account for catchment-scale sediment dynamics has been limited, largely due to the difficulty in obtaining data necessary to support them. It is within this context that this study develops a new, reach-based, stream power balance approach for predicting river channel adjustment.The new approach, named ST:REAM (sediment transport: reach equilibrium assessment method), is based upon calculations of unit bed area stream power (ω) derived from remotely sensed slope, width and discharge datasets. ST:REAM applies a zonation algorithm to values of ω that are spaced every 50m along the catchment network in order to divide the branches of the network up into relatively homogenous reaches. ST:REAM then compares each reach’s ω value with the ω of its upstream neighbour in order to predict whether or not the reach is likely to be either erosion dominated or deposition dominated.The paper describes the application of ST:REAM to the River Taff in South Wales, UK. This test study demonstrated that ST:REAM can be rapidly applied using remotely sensed data that are available across many river catchments and that ST:REAM correctly predicted the status of 87.5% of sites within the Taff catchment that field observations had defined as being either erosion or deposition dominated. However, there are currently a number of factors that limit the usefulness of ST:REAM, including inconsistent performance and the need for additional, resource intensive, data to be collected to both calibrate the model and aid interpretation of its result

3D Echo systematically underestimates right ventricular volumes compared to cardiovascular magnetic resonance in adult congenital heart disease patients with moderate or severe RV dilatation

<p>Abstract</p> <p>Background</p> <p>Three dimensional echo is a relatively new technique which may offer a rapid alternative for the examination of the right heart. However its role in patients with non-standard ventricular size or anatomy is unclear. This study compared volumetric measurements of the right ventricle in 25 patients with adult congenital heart disease using both cardiovascular magnetic resonance (CMR) and three dimensional echocardiography.</p> <p>Methods</p> <p>Patients were grouped by diagnosis into those expected to have normal or near-normal RV size (patients with repaired coarctation of the aorta) and patients expected to have moderate or worse RV enlargement (patients with repaired tetralogy of Fallot or transposition of the great arteries). Right ventricular end diastolic volume, end systolic volume and ejection fraction were compared using both methods with CMR regarded as the reference standard</p> <p>Results</p> <p>Bland-Altman analysis of the 25 patients demonstrated that for both RV EDV and RV ESV, there was a significant and systematic under-estimation of volume by 3D echo compared to CMR. This bias led to a mean underestimation of RV EDV by -34% (95%CI: -91% to + 23%). The degree of underestimation was more marked for RV ESV with a bias of -42% (95%CI: -117% to + 32%). There was also a tendency to overestimate RV EF by 3D echo with a bias of approximately 13% (95% CI -52% to +27%).</p> <p>Conclusions</p> <p>Statistically significant and clinically meaningful differences in volumetric measurements were observed between the two techniques. Three dimensional echocardiography does not appear ready for routine clinical use in RV assessment in congenital heart disease patients with more than mild RV dilatation at the current time.</p

Developing and testing the urban sustainable development goal’s targets and indicators – a five-city study

The campaign for the inclusion of a specifically urban goal within the United Nations’ Sustainable Development Goals (SDGs) was challenging. Numerous divergent interests were involved, while urban areas worldwide are also extremely heterogeneous. It was essential to minimize the number of targets and indicators while still capturing critical urban dimensions relevant to human development. It was also essential to test the targets and indicators. This paper reports the findings of a unique comparative pilot project involving co-production between researchers and local authority officials in five diverse secondary and intermediate cities: Bangalore (Bengaluru), India; Cape Town, South Africa; Gothenburg, Sweden; Greater Manchester, United Kingdom; and Kisumu, Kenya. Each city faced problems in providing all the data required, and each also proposed various changes to maximize the local relevance of particular targets and indicators. This reality check provided invaluable inputs to the process of finalizing the urban SDG prior to the formal announcement of the entire SDG set by the UN Secretary-General in late September 2015

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

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

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)