Enhanced Risk Stratification for Children and Young Adults with B-Cell Acute Lymphoblastic Leukemia: A Children's Oncology Group Report.

Current strategies to treat pediatric acute lymphoblastic leukemia rely on risk stratification algorithms using categorical data. We investigated whether using continuous variables assigned different weights would improve risk stratification. We developed and validated a multivariable Cox model for relapse-free survival (RFS) using information from 21199 patients. We constructed risk groups by identifying cutoffs of the COG Prognostic Index (PICOG) that maximized discrimination of the predictive model. Patients with higher PICOG have higher predicted relapse risk. The PICOG reliably discriminates patients with low vs. high relapse risk. For those with moderate relapse risk using current COG risk classification, the PICOG identifies subgroups with varying 5-year RFS. Among current COG standard-risk average patients, PICOG identifies low and intermediate risk groups with 96% and 90% RFS, respectively. Similarly, amongst current COG high-risk patients, PICOG identifies four groups ranging from 96% to 66% RFS, providing additional discrimination for future treatment stratification. When coupled with traditional algorithms, the novel PICOG can more accurately risk stratify patients, identifying groups with better outcomes who may benefit from less intensive therapy, and those who have high relapse risk needing innovative approaches for cure.

Targeting neural correlates of placebo effects.

Harnessing the placebo effects would prompt critical ramifications for research and clinical practice. Noninvasive brain stimulation (NIBS) techniques, such as transcranial magnetic stimulation and multifocal transcranial electric stimulation, could manipulate the placebo response by modulating the activity and excitability of its neural correlates. To identify potential stimulation targets, we conducted a meta-analysis to investigate placebo-associated regions in healthy volunteers, including studies with emotional components and painful stimuli. Using biophysical modeling, we identified NIBS solutions to manipulate placebo effects by targeting either a single key region or multiple connected areas. Moving to a network-oriented approach, we then ran a quantitative network mapping analysis on the functional connectivity profile of clusters emerging from the meta-analysis. As a result, we suggest a multielectrode optimized montage engaging the connectivity patterns of placebo-associated functional brain networks. These NIBS solutions hope to provide a starting point to actively control, modulate or enhance placebo effects in future clinical studies and cognitive enhancement studies.

Sham-derived effects and the minimal reliability of theta burst stimulation.

Theta-burst stimulation (TBS) is a patterned form of repetitive transcranial magnetic stimulation (rTMS) that has been used to induce long-term modulation (plasticity) of corticospinal excitability in a drastically shorter duration protocol than conventional rTMS protocols. In this study we tested the reliability of the effects of two well defined TBS protocols, continuous TBS (cTBS) and intermittent TBS (iTBS), especially in relation to sham TBS, within and across the same 24 participants. All TBS protocols were repeated after approximately 1 month to assess the magnitude and reliability of the modulatory effects of each TBS protocol. Baseline and post-TBS changes in motor evoked potentials (MEP-measure of corticospinal excitability) amplitudes were compared across the cTBS, iTBS and sham TBS protocols and between the initial and retest visits. Overall, across participants, at the initial visit, iTBS facilitated MEPs as compared to baseline excitability, with sham eliciting the same effect. cTBS did not show a significant suppression of excitability compared to baseline MEPs at either visit, and even facilitated MEPs above baseline excitability at a single time point during the repeat visit. Otherwise, effects of TBS were generally diminished in the repeat visit, with iTBS and sham TBS replicating facilitation of MEPs above baseline excitability at similar time points. However, no protocol demonstrated consistent intra-individual modulation of corticospinal excitability upon retest. As the first study to test both iTBS and cTBS against sham TBS across repeat visits, our findings challenge the efficacy and reliability of TBS protocols and emphasize the importance of accounting for sham effects of TBS. Furthermore, given that therapeutic effects of TBS are hypothetically derived from consistent and repeated modulation of brain activity, the non-replicability of plasticity and sham effects call into question these basic mechanisms.

Multicentre, blinded, randomised clinical trial comparing the use of flunixin meglumine with firocoxib in horses with small intestinal strangulating obstruction.

BACKGROUND: Small intestinal strangulating obstruction (SISO) is associated with endotoxaemia which leads to an increased risk of death. Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to treat signs of endotoxaemia by inhibiting cyclo-oxygenases (COX). COX-1 is expressed constitutively and promotes gut barrier function, whereas COX-2 is inducible and contributes to the signs of endotoxaemia. In preclinical SISO trials, intestinal barrier recovery was more complete with reductions in endotoxin permeability in horses treated with COX-2 selective NSAIDs as compared with horses treated with flunixin meglumine. OBJECTIVES: We hypothesised that treatment of post-surgical SISO horses with firocoxib (COX-2 selective) would reduce the signs of endotoxaemia to a greater extent than flunixin meglumine (nonselective COX inhibitor) while continuing to provide similar levels of pain control. STUDY DESIGN: Blinded randomised clinical trial. METHODS: In addition to clinical monitoring, preoperative and 12-, 24- and 48-h post-operative plasma samples were assessed for prostaglandin E2 (PGE2 ), thromboxane B2 (TXB2 ), TNF⍺ and soluble CD14 (sCD14). RESULTS: In 56 recruited SISO horses, either flunixin meglumine (1.1 mg/kg, i.v., q12h) or firocoxib (0.3 mg/kg, i.v. loading dose; 0.1 mg/kg, i.v., q24h) was given in the post-operative period in three university hospitals from 2015 to 2017. COX-2 selectivity was confirmed by a relative lack of inhibition of the COX-1 prostanoid TXB2 by firocoxib and significant inhibition by flunixin meglumine (P = 0.014). Both drugs inhibited the COX-2 prostanoid PGE2 . There were no significant differences in pain scores between groups (P = 0.2). However, there was a 3.23-fold increased risk (P = 0.04) of increased plasma sCD14 in horses treated with flunixin meglumine, a validated biomarker of equine endotoxaemia. MAIN LIMITATIONS: Horses were all treated with flunixin meglumine prior to referral. In addition, many horses were treated with lidocaine, which has been shown to mitigate the deleterious effects of flunixin meglumine. CONCLUSIONS: In SISO cases, firocoxib reduced a biomarker of endotoxaemia as compared with flunixin meglumine while continuing to provide similar levels of pain control.

Evaluation of digital cryotherapy using a commercially available sleeve style ice boot in healthy horses and horses receiving i.v. endotoxin.

BACKGROUND: Continuous digital cryotherapy experimentally prevents development and reduces severity of sepsis-associated laminitis. A sleeve style ice boot where ice is in direct contact with the skin, and water drains from the boot is being used clinically for distal limb cryotherapy. The degree of cooling achieved by this boot is unknown. OBJECTIVES: Evaluate skin and lamellar cooling after application of the ice sleeve in healthy horses, and the same horses during an endotoxaemia model. STUDY DESIGN: Prospective study, crossover design. METHODS: In eight healthy horses thermocouples were inserted into dorsal lamellae of both front feet, and under skin on both metacarpi. One forelimb received cryotherapy using sleeve style ice boot, with contralateral limb as control. Temperature was recorded on data logging devices at 5 min intervals during each cryotherapy session. Day 1: temperature data was collected for healthy horses. Day 2: data was collected for the same horses during i.v. administration of endotoxin. RESULTS: In healthy and endotoxaemic horses, the sleeve style ice boot significantly decreased mean skin (7.2°C and 5.8°C respectively) and lamellar (10.8°C and 9.6°C respectively) temperatures compared with control limbs (P<0.001). Skin and lamellar temperatures in endotoxaemic horses undergoing cryotherapy were significantly colder than in healthy horses (P = 0.01). MAIN LIMITATIONS: Order of treatment not randomised. CONCLUSIONS: The boot caused significant decreases in lamellar temperatures compared with untreated control limbs in all horses. Endotoxaemic horses had significantly colder lamellae and skin than healthy horses. This study is the first to show that a sleeve style boot, where ice does not cover the hoof, can cause significant decreases in lamellar temperatures through cooling of blood as it travels to the foot.

Non-equilibrium cobalt(iii) "click" capsules.

Cobalt(iii) tetrahedral capsules have been prepared using an assembly-followed-by-oxidation protocol from a cobalt(ii) precursor and a readily derivatizable pyridyl-triazole ligand system. Experiments designed to probe the constitutional dynamics show that these architectures are in a non-equilibrium state. A preliminary investigation into the host-guest chemistry of a water-soluble derivative shows it can bind and differentiate a range of different neutral organic molecules. The stability of this ensemble also permits the study of guest-binding at high salt concentrations.

The use of smartphone applications by urology trainees.

OBJECTIVE: Mobile phone technology is continuously advancing- the smartphone allows users instant access to information via the internet. Downloadable applications (apps) are becoming widespread across medical specialities. The aim of this study was to assess the use of smartphone apps among urology trainees in Ireland. METHODS: An anonymous electronic survey was distributed via Survey Monkey(®) to all urology trainees in Ireland assessing their ownership and use of smartphones and downloadable apps. A search of urology apps was performed using the Apple App Store and the Android Market. RESULTS: 36 (81.8%) of trainees responded with 100% ownership of smartphones. 28 (77%) report downloading apps with 11 (30.6%) reporting paying for them. The mean number of apps downloaded was 4 (Range 1-12). 16 (44.4%) trainees think apps for smartphones are very useful in clinical practice, 14 (42.4%) think they are useful. A total of 126 urology apps were available. 76 (60.3%) were designed for physicians, 46 (36.5%) for patients, 2 (1.6%) for students and 2 (1.6%) for urological nurses. CONCLUSION: There are an ever increasing number of urology apps available. Urology trainees are using smartphones as an educational and reference tool and find them a useful aide in clinical practice.

Paediatric orchidopexy: a need for dedicated paediatric surgical training among urologists?

BACKGROUND: Undescended testis (UDT) is one of the most common congenital abnormalities with a prevalence of about 1% at the age of 1 year. UDT is associated with an increased risk of testicular tumours and infertility. AIMS: The aim of this study was to assess who is carrying out paediatric orchidopexy in Ireland. METHODS: A survey was distributed via Survey Monkey to all Consultant Paediatric Surgeons and Urologists in Ireland. RESULTS: Twenty-seven (64.3%) urologists and five (71.4%) paediatric surgeons responded to our online survey. Of the urologists, 100% reported formal training in paediatric orchidopexy. Eight (29.6%) underwent a dedicated paediatric fellowship. 13 (48.1%) currently perform paediatric orchidopexy. Nine (33%) think it should be carried out by a urologist, whereas eight (29.6%) think it should be carried out by paediatric surgeon. The mean age at which urologists think an orchidopexy for UDT should be performed by was 18 months (range 1-4 years). Approximately 400 orchidopexies are performed per year by the surveyed urologists. Of the paediatric surgeons, three (60%) feel it should be carried out by a paediatric surgeon whereas two (40%) feel it does not matter. All paediatric surgeons feel it should be performed by 1 year of age. Approximately 700 orchidopexies are performed per year by the surveyed paediatric surgeons. CONCLUSION: UDT is a concerning condition which requires intervention at an early stage. Dedicated training in core paediatric procedures is required to continue to meet this need for the future to prevent delayed orchidopexy and resultant increased risk of testicular tumours.

Paediatric urology training: what does the future hold?

BACKGROUND: Paediatric urology training is not a mandatory part of higher surgical training in urology in Ireland. It is predicted there will be a shortfall of surgeons trained in paediatric surgery in the coming years leading to a reliance on specialist paediatric surgical centres. AIM: The aim of this study was to assess the attitudes of urological trainees regarding the current state of paediatric urology training and to address the potential future changes to training structures. METHODS: A voluntary anonymous internet-based survey was emailed to all urological trainees. Parameters assessed included sex, level of training, attitudes towards paediatric urology training and levels of competence regarding core paediatric urological procedures. RESULTS: 69.2 % (n = 18) responded to the survey. 94.4 % (n = 17) would favour mandatory paediatric training-of these, 52.9 % (n = 9) would favour this in a dedicated paediatric hospital with a paediatric urologist. 66.7 % (n = 12) would like to provide a paediatric urology service as a consultant. 55.6 % (n = 10) felt they were competent to perform circumcision or scrotal exploration independently and manage all associated complications. No trainee felt themselves to be competent to perform orchidopexy independently and manage all complications. CONCLUSION: Our study demonstrates a promising desire to provide paediatric services in the future. A greater emphasis on structured paediatric urology training is required to maintain the standard currently offered by adult urologists.

Use of dynamic time warping for accurate ECG signal timing characterization.

Dynamic time warping techniques have been used to characterize the timing variation of the constituent components of the human electrocardiogram (ECG). Lead II ECG recordings were obtained in 21 subjects, 10 male and 11 female aged between 13-65 years. The fiducial points in each cardiac cycle were identified in the recordings across the range of heart rate from 46-184 beats/min. A set of second order equations in the square root of the cardiac cycle time was obtained to describe the duration each of the constituent components in the ECG signal. The accuracy of the dynamic time warping technique was verified against professionally annotated clinical recordings in the on-line PhysioNet™ database. The equations obtained allow a Lead II ECG signal to be synthesized in which the variation with heart rate of the profile of each in the signal mirrors the true in-vivo behaviour.

Similar outcomes between adolescent/young adults and children with AML following allogeneic hematopoietic cell transplantation.

We recently reported that adolescents and young adults (AYAs) with B-cell ALL receiving allogeneic hematopoietic cell transplantation (allo-HCT) have inferior survival compared with children, primarily because of greater TRM. We therefore hypothesized that in the setting of allo-HCT for AML, similar inferior outcomes would be observed in AYA patients as compared with children. We reviewed outcomes of 168 consecutive patients (ages 0-30 years) with AML undergoing allo-HCT at our institution. Of these, 60% (n=101) were <15 years of age and 40% (n=67) were AYAs (15-30 years of age). We identified no significant differences in 5-year overall survival (48% vs 50%, P=0.89), disease-free (47% vs 47%, P=0.89), relapse (24% vs 33%, P=0.30) or TRM (27% vs 16%, P=0.10) between the two groups. However, AYA patients had a greater incidence of grade II-IV acute (48% vs 31%, P=0.01) and chronic GVHD (22% vs 7%, P<0.01). Based on this analysis we identified no differences in survival, relapse or TRM between AYAs and children with AML receiving allo-HCT.

Morphometry of the hippocampal microvasculature in post-stroke and age-related dementias.

BACKGROUND: Optimal vascular function is vital for prevention of dementia. We hypothesized that elderly post-stroke survivors who preserve cognitive function show unperturbed cerebral microvasculature compared with those who develop dementia. METHODS: Using stereological spherical probe software, we compared the length density (Lv, cumulative vessel length per unit tissue volume) of hippocampal microvessels in post mortem brain tissue from post-stroke survivors, Alzheimer's disease (AD), vascular dementia (VaD) and normal ageing control subjects. We also assessed microvessel diameters in the same subjects. Microvessels were identified by markers of endothelial cells (glucose transporter 1; GLUT1), basement membrane (collagen IV; COL4) and smooth muscle cell α-actin (SMA). RESULTS: We found increased Lv of both GLUT1 and COL4 immunostained microvessels (P < 0.05) in the hippocampal CA1 region of post-stroke demented (PSD) and AD cases compared with post-stroke nondemented (PSND), control and VaD subjects. However, no changes were apparent in the CA2 region. We also noted significant increase in Lv in the entorhinal cortex of AD compared with PSND and PSD subjects. The mean diameter of microvessels was decreased in PSD, compared with PSND, as well as in AD and VaD compared with controls. Cumulative frequency analysis showed PSND subjects to have significantly greater proportion of microvessels with diameters, ranging from 7 to 12 µm. CONCLUSIONS: An increase in microvascular Lv in AD and PSD suggests either an increase in angiogenesis or the formation of newer microvessel loops in response to cerebral hypoperfusion. The decreased vessel diameters found in AD and VaD suggests increased vasoconstriction in dementia.

A clofarabine-based bridging regimen in patients with relapsed ALL and persistent minimal residual disease (MRD).

In patients with relapsed ALL, minimal residual disease (MRD) identified prior to allogeneic hematopoietic cell transplantation (HCT) is a strong predictor of relapse. We report our experience using a combination of reduced-dosing clofarabine, CY and etoposide as a 'bridge' to HCT in eight patients with high risk or relapsed ALL and pre-HCT MRD. All patients had detectable MRD (>0.01%, flow cytometry) at the start of therapy with all eight achieving MRD reduction following one cycle. The regimen was well tolerated with seven grade 3/4 toxicities occurring among four of the eight patients. Five patients (62.5%) are alive, one died from relapse (12.5%) and two from transplant-related mortality (25%). The combination of reduced-dose clofarabine, CY and etoposide as bridging therapy appears to be well tolerated in patients with relapsed ALL and is effective in reducing pre-HCT MRD.

Cost-effectiveness analysis comparing epidural, patient-controlled intravenous morphine, and continuous wound infiltration for postoperative pain management after open abdominal surgery.

BACKGROUND: Continuous wound infiltration (CWI), i.v. patient-controlled analgesia (i.v.-PCA), and epidural analgesia (EDA) are analgesic techniques commonly used for pain relief after open abdominal surgery. The aim of this study was to evaluate the cost-effectiveness of these techniques. METHODS: A decision analytic model was developed, including values retrieved from clinical trials and from an observational prospective cohort of 85 patients. Efficacy criteria were based on pain at rest (VAS ≤ 30/100 mm at 24 h). Resource use and costs were evaluated from medical record measurements and published data. Probabilistic sensitivity analysis (PSA) was performed. RESULTS: When taking into account all resources consumed, the CWI arm (€ 6460) is economically dominant when compared with i.v.-PCA (€ 7273) and EDA (€ 7500). The proportion of patients successfully controlled for their postoperative pain management are 77.4%, 53.9%, and 72.9% for CWI, i.v.-PCA, and EDA, respectively, demonstrating the CWI procedure to be both economically and clinically dominant. PSA reported that CWI remains cost saving in 70.4% of cases in comparison with EDA and in 59.2% of cases when compared with PCA. CONCLUSIONS: Device-related costs of using CWI for pain management after abdominal laparotomy are partly counterbalanced by a reduction in resource consumption. The cost-effectiveness analysis suggests that CWI is the dominant treatment strategy for managing postoperative pain (i.e. more effective and less costly) in comparison with i.v.-PCA. When compared with EDA, CWI is less costly with almost equivalent efficacy. This economic evaluation may be useful for clinicians to design algorithms for pain management after major abdominal surgery.

A versatile temperature-stable ECG simulator.

The use of ECG recordings as a diagnostic tool relies heavily on the fidelity of the recorded signal. ECG signal synthesis is therefore vital in the testing and commissioning of ECG recording equipment. A number of signal generators have been previously presented in the literature, however the platforms they were developed on have become dated and more importantly their architectures do not provide a temperature-stable generator capable of operating at the necessary levels of precision in the voltage range required. The shortcomings of previous instruments are overcome here using a novel approach to the digital and analogue stages of the signal conditioning process. It offers significantly increased precision over the 100 µV-10 mV amplitude range, includes voltage offset correction and full temperature stability. The devices capability has been analysed and tested significantly more than any of its predecessors, and the results demonstrate it is a significant step forward in ECG signal synthesis.

Allogeneic hematopoietic cell transplantation outcomes for children with B-precursor acute lymphoblastic leukemia and early or late BM relapse.

Large registry studies have shown superior disease-free survival (DFS) with matched sibling donor (MSD) allogeneic hematopoietic cell transplantation (allo-HCT) over chemotherapy alone for patients with B-precursor acute lymphoblastic leukemia (ALL) and a late BM relapse. As most of these patients will not have an MSD, the decision to pursue an unrelated allo-HCT in second remission (CR2) or await a future relapse and perform HCT in third remission (CR3) continues to be debated. Between 1990 and 2006, 41 children with relapsed B-precursor ALL received a myeloablative allo-HCT at the University of Minnesota. Graft sources consisted of matched related donor (n=11), matched unrelated donor (n=9), and unrelated umbilical cord blood (n=21). Before allo-HCT, 15 patients had an early relapse (<36 months from diagnosis) and 26 had an initial late relapse (36 months from diagnosis). In all, 30 patients (73%) were in CR2 and 11 were in CR3 (27%) at time of allo-HCT. Five year OS/DFS were similar for patients with an early or late marrow relapse, but there was inferior DFS among late-relapse patients transplanted in CR3 compared with CR2 (30% vs 75%, P=0.04). These results suggest that allo-HCT should be pursued in children after a first marrow relapse, rather than waiting for subsequent recurrence.

Lower leukemia relapse in pediatric patients with pulmonary cytolytic thrombi following allogeneic transplant.

Pulmonary cytolytic thrombi (PCT) is an uncommon complication after hematopoietic cell transplantation. Although the pathogenesis is unknown, patients typically respond to systemic corticosteroid treatment. Considering corticosteroids may impair GVL reactions, we reviewed the records of 324 pediatric patients who received a transplant for leukemia and compared the outcomes of those with PCT (n=14) to those without PCT (n=310). PCT patients had a significantly more acute GVHD (aGVHD) and chronic GVHD (cGVHD). Though 3-year non-relapse mortality and OS were similar, there was significantly less relapse in patients with PCT compared to those without PCT (0 vs 28%, P=0.02), regardless of the presence or absence of aGVHD. In multivariate analysis, grade II-IV aGVHD (P=0.02), cGVHD (P=0.01) and development of PCT (P<0.01) were independently associated with less relapse. These data suggest that patients with PCT are at greater risk for GVHD, but at lower risk of leukemia relapse.

A time domain based classifier for ECG pattern recognition.

Pattern recognition, and in particular dynamic time warping has been applied to the ECG for many different purposes over the last decade. Significant research on creating adaptive, feature based, and more complex forms of the algorithm in order to increase its ability to classify an ECG signal accurately has been performed. Despite this increase in complexity and in the number of variations of the dynamic time warping algorithm there has been less focus on actually using the results of dynamic time warping to relate the reference and test signals to each other as accurately as possible. The majority of dynamic time warping algorithms published in the literature, even the most complex of them, classify the most accurate match to a reference signal based only on resulting Euclidean distance or slope difference between samples of the known reference and unknown query signal. This article demonstrates how a combination of measurements including heart-rate, amplitude and required warping time alignment can be used to reduce the resulting error in the classification of a query signal after the query and reference signals have been warped together. Its benefits are verified with significant testing.

Imatinib use either pre- or post-allogeneic hematopoietic cell transplantation (allo-HCT) does not increase cardiac toxicity in chronic myelogenous leukemia patients.

Since the introduction of imatinib mesylate, the role of allogeneic hematopoietic cell transplantation (allo-HCT) for CML has essentially been reserved for patients with advanced disease or imatinib resistance. In addition, there have been concerns regarding imatinib associated cardiac toxicity. We investigated the outcome of 61 patients with CML who received a myeloablative allo-HCT at the University of Minnesota between 1999 and 2006. The median age at HCT was 38.4 (range; 6.9-56.9) years. Thirty-seven patients were in first chronic phase and twenty-four patients in a second chronic or accelerated phase at the time of HCT. Twenty-six patients received imatinib therapy before or after HCT, and thirty-five patients either never received imatinib (n=32) or received it only at the time of relapse after HCT (n=3). OS and relapse-free survival (RFS) at 2 years was 69 and 55% for the imatinib group, and 57 and 49% for the non-imatinib group (P=0.57 and 0.95, respectively). There was no difference in the risk of relapse at 2 years between the groups. Symptomatic cardiac toxicity at 1 year was reported in three imatinib group (12%) and two non-imatinib group (6%) patients (P=0.44). Thus, patients treated with imatinib either before or after myeloablative allo-HCT had no increase in cardiac toxicity.