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An editorial is presented on the mitigating the July effect. Topics include the arrival of a crop of newly graduated medical students beginning their internships, the influx of so many freshly trained physicians arriving at the same time always triggers concern, and the belief in a July effect with presumed adverse consequences for patient safety and quality of care.

During the safety and feasibility 'Study of Intravenous Autologous Marrow in Multiple Sclerosis (SIAMMS)', intravenous infusion of autologous marrow was well tolerated. The efficacy of the approach is being explored in a placebo-controlled randomised controlled trial (ACTiMuS, NCT01815632) but it is not known whether repeated infusions will be required to optimise benefit. The objective of the current study was to explore the safety and feasibility of repeat treatment with intravenous autologous bone marrow for patients with progressive multiple sclerosis (MS).'SIAMMS II' was a prospective, single centre phase I extension study in which participants in the SIAMMS study were offered repeat bone marrow harvest and infusion of autologous, unfractionated bone marrow as a day-case procedure. The primary outcome measure was number of adverse events and secondary outcome measures included change in clinical rating scales of disability, global evoked potential and cranial magnetic resonance imaging (MRI).In total, 4 of the 6 participants in the SIAMMS study had repeat bone marrow harvest and infusion of filtered autologous marrow as a day case procedure which was well tolerated. There were no serious adverse effects. Additional outcome measures including clinical scales, global evoked potentials and cranial MRI were stable.SIAMMS II demonstrates the safety and feasibility of repeated, non-myeloablative autologous bone marrow-derived cell therapy in progressive MS.

Alternating Hemiplegia of Childhood (AHC) is a rare neurological disease characterized by early-onset recurrent paroxysmal events and persistent neurological deficits. TBC1D24 gene variants have been associated with a phenotypic spectrum having epilepsy as the main clinical manifestation. Herein, we report the case of a child affected by developmental delay, polymorphic seizures, and nonepileptic episodes characterized by hemiplegia or bilateral plegia, pallor, hypotonia, and dystonic postures without loss of consciousness that resolved with sleep. Noteworthy, the patient fulfills all the diagnostic criteria for AHC. An epilepsy gene panel revealed a novel TBC1D24 mutation. This variant may be considered a PM5, according to the American College of Medical Genetics and Genomics guidelines. TBC1D24 gene variants are associated with various clinical features, and increasing data confirms the association with permanent and paroxysmal movement disorders. Our report suggests that the TBC1D24 molecular analysis could be considered in the diagnostic workup of AHC patients.

Objectives Selective dorsal rhizotomy (SDR) is used to improve spasticity, gait, and pain in children with spastic diplegia. There is growing evidence supporting its long-term benefits in terms of functional outcomes, independence, and quality of life. There is, however, little contemporary work describing the surgical morbidity of this irreversible procedure. The purpose of this study is to evaluate the surgical outcomes and complications of SDR at a single United Kingdom center. Methods Demographics, surgical, postoperative, and follow-up data for all patients undergoing SDR between 2011 and 2016 were collected from medical records. Results Preoperative Gross Motor Function Classification System levels in 150 consecutive patients were II (35%), III (65%), and IV (1%). Median age was 6 years and 58% were male patients. There were no deaths, cerebrospinal fluid leaks, returns to theater, or readmissions within 30 days. There were no new motor or sphincter deficits. Postoperative neuropathic pain was reported by 5.3% and sensory symptoms by 8.7%. Other complications included: postoperative nausea and vomiting (19.3%), superficial wound infection (3.3%), urinary retention (1.3%), headache (6.7%), and urine or chest infection (4.7%). Follow-up data were available for all patients (93% to 12 months, 72% to 24 months). Persistent neuropathic symptoms were reported in 6.5% at 24 months. Conclusions SDR using a single-level approach is a safe procedure with low surgical morbidity. This study complements the growing evidence base in support of SDR for spastic diplegia and should help inform decisions when considering treatment options.

Damage to the cerebellum during posterior fossa surgery can lead to ataxia and in paediatric cases, the risk of cerebellar mutism syndrome. Animal electrophysiological and human imaging studies have shown compartmentalisation of sensorimotor and cognitive functions within the cerebellum. In the present study, electrophysiological monitoring of sensory and motor pathways was carried out to assess the location of limb sensorimotor representation within the human cerebellum, as a potential approach for real time assessment of neurophysiological integrity to reduce the incidence of cerebellar surgical morbidities.Thirteen adult and paediatric patients undergoing posterior fossa surgery were recruited. For sensory mapping (n=8), electrical stimulation was applied to the median nerves, the posterior tibial nerves, or proximal and distal limb muscles and evoked field potential responses were sought on the cerebellar surface. For motor mapping (n=5), electrical stimulation was applied to the surface of the cerebellum and evoked EMG responses were sought in facial and limb muscles.Evoked potentials on the cerebellar surface were found in two patients (25% of cases). In one patient, the evoked response was located on the surface of the right inferior posterior cerebellum in response to stimulation of the right leg. In the second patient, stimulation of the extensor digitorum muscle in the left forearm evoked a response on the surface of the left inferior posterior lobe. In the motor mapping cases no evoked EMG responses could be found.Intraoperative electrophysiological mapping, therefore, indicates it is possible to record evoked potentials on the surface of the human cerebellum in response to peripheral stimulation.

The use of an aqueous-based surrogate solution in at-scale process development for biopharmaceutical drug products enables significant reduction in the usage of costly drug substance and improves confidence in initial drug product production runs performed using active biotherapeutic. Strategies for the formulation design of a surrogate solution that is representative of the unit operations in a typical drug product manufacturing process for a biopharmaceutical are presented herein, and a case study for the development of a surrogate solution for an example protein drug product is discussed. The surrogate was shown to have similar physical attributes to the drug product, including viscosity, surface tension, and density. The surrogate was used in at-scale process development of compounding, filling, and lyophilization operations in a single technical run, and the performance was shown to be similar to that of the drug product solution, providing a cost-effective and readily available option for process development while minimizing operator exposure to potentially hazardous drug solution and limiting drug wastage.

Aim A new-onset seizure clinic (NOSC) was established at our hospital in 2011, with the aim to provide accurate diagnosis and appropriate management to children with new-onset seizures or seizure mimics. Methods We report on the data analysis of the first 200 children seen in NOSC. A paediatric neurologist or paediatric/neurology trainee under supervision of a neurologist reviewed all the children. A detailed history and clinical examination were undertaken. Electroencephalogram (EEGs) were undertaken prior to clinic review in most emergency departments. Children were classified as 'epilepsy positive' (EP+) or 'epilepsy negative' (EP-) after the first consultation. Results Of 200 patients, 109 were classified as EP+: generalised epilepsy in 57 of 109, focal in 36, childhood seizure susceptibility syndrome in 26 and epileptic encephalopathy in 5. EEG was available in 192: in 117, it was abnormal - 23 with background abnormalities and 109 with epileptiform activity. Of the 109 patients, 80 were commenced on anti-epileptic drugs (AEDs): 12 were able to come off medication after seizure-free period, 61 were controlled on AEDs and 7 were refractory. Children were followed up for 12-48 months. None of the children had diagnosis revised on follow-up. Conclusions This is the first Australian study to report on a large cohort of children from a NOSC. An EEG and a paediatric neurologist assessment is a good combination to enable diagnostic accuracy: In the first 200 patients seen, there were no revisions of the initial diagnosis on follow-up.

Stroke is among the top 10 causes of death in children and survivors carry resulting disabilities for decades, at substantial cost to themselves and their families. Children are not currently able to access reperfusion therapies, due to limited evidence supporting safety and efficacy and long diagnostic delays. The Australian Clinical Consensus Guideline for the Diagnosis and Acute Management of Childhood Stroke was developed to minimize unwarranted variations in care and document best evidence on the risk factors, etiologies, and conditions mimicking stroke that differ from adults. Clinical questions were formulated to inform systematic database searches from 2007 to 2017, limited to English and pediatric studies. SIGN methodology and the National Health and Medical Research Council system were used to screen and classify the evidence. The Grades of Recommendation, Assessment, Development, and Evaluation system (GRADE) was used to grade evidence as strong or weak. The Guideline provides more than 60 evidence-based recommendations to assist prehospital and acute care clinicians in the rapid identification of childhood stroke, choice of initial investigation, to confirm diagnosis, determine etiology, selection of the most appropriate interventions to salvage brain at risk, and prevent recurrence. Recommendations include advice regarding the management of intracranial pressure and congenital heart disease. Implementation of the Guideline will require reorganization of prehospital and emergency care systems, including the development of regional stroke networks, pediatric Code Stroke, rapid magnetic resonance imaging and accreditation of primary pediatric stroke centers with the capacity to offer reperfusion therapies. The Guideline will allow auditing to benchmark timelines of care, access to acute interventions, and outcomes. It will also facilitate the development of an Australian childhood stroke registry, with data linkage to international registries, to allow for accurate data collection on stroke incidence, treatment, and outcomes.

This study aimed to explore, articulate and expand on existing concepts of recovery and paid peer support within consumer-operated mental health organizations. Focus groups and interviews were cond...

The Brassington Formation of the Pennines is the most extensive onshore Miocene succession in the UK. It is preserved as outliers in Lower Carboniferous Limestone. During the Cenozoic, central England underwent uplift, with erosion of post-Mississippian strata from the Pennine axis in the Peak District. The Brassington Formation is hence significant in reconstructing Cenozoic geological history. It is non-marine, derived from Triassic sandstone and of Mid–Late Miocene age. The c. 60 outliers occur in three clusters over c. 220 km2. They are remnants of a sedimentary prism at least 75 m thick and with a volume of c. 10 km3. Suffosion of bedrock, conditioned by aggressive precursor fluids of hypogenic origin, was the major control on subsidence. The calculated volume of the fills in the Bees Nest and Green Clay outliers is 3.7–5.0 × 106 m3. Referenced to a sub-Miocene surface at c. 450 m OD in pre-subsidence times, the original volume of this subsidence complex was c. 21.8 × 106 m3 and the aggregated volume of the Late Neogene White Peak palaeokarst was at least 0.66 km3. Subsidence was concomitant with Pliocene uplift of the Pennine Axis, suggesting suffosion accommodation of 3 × 106 m3 per km2 or 244 m3 per annum.

Forest management activities have the potential to significantly modify large wood loads in riparian areas, and thus the availability of material for recruitment into the stream channel, hence it is important that forest management practices take account of the role wood supplied from riparian areas play in the development of channel structure and sediment retention capacity. In this study the cellular landscape and river reach process model CAESAR LISFLOOD (C-L) was used to simulate the effect of in-channel obstructions created by large wood on the distribution of erosion and deposition within a small headwater channel and suspended sediment yield at the catchment outlet. The process model was parameterised and calibrated against an observed discharge and suspended sediment record. Following calibration, 12 discharge and large wood obstruction scenarios were carried out to model erosion and suspended sediment transport over a timber harvesting cycle. The inclusion of obstructions into the model runs to simulate in-channel LW pieces substantially reduced suspended sediment yields in all three discharge scenarios and increased sediment storage along the channel. The modelled location of channel bed degradation and aggradation generally coincided with the pattern of sediment storage along the channel bed demonstrating that C_L was predicting the pattern of erosion and deposition in the channel reasonably well. Modelled erosion rates were extremely low for the respective discharge and large wood model scenarios, with the highest rates ranging from 0.02 t ha−1 year−1 to 0.1 t ha−1 year−1 for the no large wood model over the 22-year period. These findings reinforce the importance of maintaining sufficient volume of standing wood in buffer strips alongside small headwater channels to ensure ongoing recruitment of large wood to the channel network in forests managed for timber production.

Copy Number Variations (CNVs) comprising the distal 1q region 1q43-q44 are associated with neurological impairments, structural brain disorder, and intellectual disability. Here, we report an extremely rare, de novo case of a 1q43-q44 deletion with an adjacent duplication, associated with severe seizures, microcephaly, agenesis of the corpus callosum, and pachygyria, a consequence of defective neuronal migration disorder. We conducted a literature survey to find that our patient is only the second case of such a 1q43-q44 CNV ever to be described. Our data support an association between 1q43-q44 deletions and microcephaly, as well as an association between 1q43-q44 duplications and macrocephaly. We compare and contrast our findings with previous studies reporting on critical 1q43-q44 regions and their constituent genes associated with seizures, microcephaly, and corpus callosum abnormalities [Ballif et al., 2012; Hum Genet 131:145-156; Nagamani et al., 2012; Eur J Hum Genet 20:176-179]. Taken together, our study reinforces the association between 1q43-q44 CNVs and brain disorder.

The promising utility of multi-modality evoked potential batteries to objectively measure multi-tract dysfunction has been evaluated by several groups using different methods.To independently evaluate the use of multi-modality evoked potential batteries as surrogate biomarkers for both physical and cognitive status in a cohort of Primary Progressive Multiple Sclerosis patients and identify the most potentially useful scoring method of those described.28 Patients with Primary Progressive Multiple Sclerosis underwent clinical evaluation with Kurtzke's Modified EDSS and the Multiple Sclerosis Functional Composite (MSFC). 19 Participants also underwent the Minimal Assessment of Cognitive Function in Multiple Sclerosis. Visual, Brainstem Auditory, Somatosensory and Motor Evoked Potentials were recorded on all. Results were graded by variants of the Global Evoked Potential Score, Multiple Evoked Potential Score and Summation of Z transformed Evoked Potential Latencies for correlation against the clinical scores.Multi-modal evoked potential batteries generally show moderate and useful correlation with clinical status as measured by the regulatory standard of EDSS (r = .65 vs. mEPS p.005) and MSFC (r = .39 vs. mEPS p.05). The graded qualitative mEPS scoring system displayed the strongest relationship although the influence of scoring system applied appeared reassuringly minimal. Non-association with cognitive impairment is an important limitation however.

Purpose To assess the role of resective brain surgery in childhood epilepsy. Methodology We retrospectively analysed the seizure outcomes in 55 children with epilepsy who had resective brain surgery between 1997 and 2012, at our centre. The children were 1.5–18 years at the time of surgery; their seizure onset was between 0.2 andto 15 years of age. 48 had refractory epilepsy. One child died of tumour progression. Follow-up duration in the survivors ranged from 2 to −16 years (mean: 9).Presurgical evaluation included clinical profiles, non-invasive V-EEG monitoring, neuroimaging with MRIs in all; SPECT and PET in selected patients. 54 had intraoperative ECoG. Results An Engel Class 1 outcome was seen in 78% of the cohort, with 67% being off all AEDs at the most recent follow-up. Children with tumours constituted the majority (56%), with 87% of this group showing a Class 1 outcome and 84% being off AEDs. Children with cortical dysplasia had a Class 1 outcome in 56%. Conclusion Resective brain surgery is an efficacious option in some children with epilepsy. We found ECoG useful to tailor the cortical resection and in our opinion ECoG contributed to the good seizure outcomes.

The development of “child aware” practice is about the capacity and capability of adult health and social service providers to identify and respond to the needs of children. A scoping review of the literature considered five adult adversities associated with family stress and reduced parenting capacity: mental illness, alcohol and substance abuse, homelessness, intellectual disability, and domestic violence. Although there are specific needs for children pertaining to particular adversities, there was substantial commonality of potential effects. These included emotional and psychological difficulties, physical and mental health problems, academic difficulties, language delays, peer difficulties, stigma, trauma reactions, loss and grief, instability, and social exclusion. How children react to difficulties in their family depends upon various protective factors, a child's frame of reference, and other dynamics within the family that can offset risks. The findings aim to inform policy, program deve...

City planning draws out relationships between land use patterns, housing form and density, transport, energy provision and other infrastructures. While commonly struggling with the task, a city’s planning system could be one of the key integrating forces for tackling the sustainability challenge. As it happens, these particular systems are quite regularly subject to coordinated and relatively well resourced reform efforts, usually not generated from a sustainability viewpoint. This chapter raises the question of whether, and how, transition management ideas might more directly enter and influence this “turbulent” reform space. Sydney provides the case-setting for the introduction of transition management, and related conceptions, to a recent major planning system reform project for that city. Working from a theoretical meshing of planning, relational-institutional and transitions studies, a new process model for planning system reform projects is introduced: the Planning System Transition (PST) framework. This framework’s development and testing, through empirical research, is explained. This chapter suggests positive prospects for transition management in city planning reform, but also highlights the critical requirement for contextualisation with practical and scholarly planning insights, as exemplified in the PST framework.

Aims Lacosamide (LCM) is a novel anti-epileptic drug (AED) that enhances the slow inactivation of voltage-gated sodium channels. Its efficacy as adjunctive therapy for focal seizures is confirmed in adult placebo controlled trials with >50% reduction in seizure frequency in up to 50% patients. There is paucity of data on its efficacy and tolerance in treatment-resistant epilepsy in childhood (TREC). This study aims to assess efficacy and tolerance of LCM as adjunct therapy in TREC. Methods Audit of medical records and seizure diaries in children with TREC on LCM. A response (RR) was defined as ≥50% reduction in seizure frequency. Results Forty children (age range: 2–19 years) with TREC received LCM as add-on therapy. All had abnormal electroencephalograms, and 36 had abnormal neuroimaging. All children failed >2 AED trials, nine had trialled the ketogenic diet, five had failed the vagal nerve stimulator and 11 had failed resective epilepsy surgery. Median dose and duration of LCM therapy were 5.7 mg/kg/day and 10.5 months, respectively. RR was seen in 20% with persistence of RR in 8/36, 8/30 and 8/26 children on LCM at 3-, 6- and 9-month follow-up. Two children became seizure free. Retention on LCM was 65% at 9 months. LCM was well tolerated with minor side effects in seven children; no child discontinued LCM because of side effects. Conclusion LCM is a well-tolerated AED with RR in 20%: in 5%, it resulted in seizure freedom. LCM may be useful even in TREC when seizures have not responded to intervention with multiple modalities.

Background: Vincristine is a chemotherapeutic agent frequently used in the treatment of childhood cancer. Peripheral neuropathy is an important side effect of Vincristine. We assessed the incidence, severity and type of peripheral neuropathy in children on Vincristine using clinical parameters and nerve conduction studies. Methods : Children with cancer treated with Vincristine were enrolled. Symptoms and signs of motor, sensory and autonomic peripheral neuropathy at baseline and at 3, 6 and 12 month follow up were documented. A modified total neuropathy score grading was undertaken. Nerve conduction studies (NCS) were undertaken and vitamin E levels measured at the time of these assessments. Results: 28 patients were enrolled over 12 months. 93% had evidence of neuropathy clinically and/or electrophysiologically. Weakness, pain and constipation were the most common symptoms and the most common sign was loss of ankle reflexes. The peripheral neuropathy was mild in most cases. Plasma levels of vitamin E remained in the normal range, however they dropped significantly from the baseline value. Conclusions: Peripheral neuropathy assessed clinically and electrophysiologically, occurs in the majority of children on Vincristine treatment. The neuropathy is sensory-motor and generally mild. There was a statistically significant drop in average vitamin E levels during treatment. Keywords: Vincristine, peripheral neuropathy, vitamin E