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.

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.

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.

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.

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.

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.

A fuzzy logic based apnoea monitor for SIDS risk infants.

A unit has been designed which monitors newborn infants at risk of Sudden Infant Death Syndrome (SIDS) in a home environment. The unit monitors respiration, electrocardiogram (ECG) and haemoglobin oxygen saturation (SpO2) in combination, in order to detect any potentially life threatening event at an early stage. Provision is made for the generation of both audible and silent alarms and for the storage of signals and other information before, during and after an alarm episode for diagnostic purposes. An intelligent fuzzy logic algorithm is used to process the signals monitored and to implement several propositions concerning their status in order to determine the probability of an apnoea event and initiate the appropriate action. This has substantially reduced the number of false alarms and of undetected dangerous situations compared with previous units, which greatly improves the reliability and usefulness of such a monitor.

Freezing Characteristics of Rigid Plant Tissues (Development of Cell Tension during Extracellular Freezing).

The freezing characteristics and development of cell tension during extracellular freezing were examined in supercooling stem tissues of riverbank grapes (Vitis riparia) and cold-hardened leaves of live oak (Quercus virginiana) and mountain cranberry (Vaccinium vitis-idaea). Dormant stem xylem and pith tissues of river-bank grapes were resistant to freeze-induced dehydration above the homogeneous nucleation temperature, and they developed cell tension reaching a maximum of 27 MPa. Similarly, extracellular freezing induced cell tension in the leaves of live oak and mountain cranberry. Maximum cell tension in the leaves of live oak was 16.8 MPa and 8.3 MPa in the leaves of mountain cranberry. Following peak tensions in the leaves, a decline in the pressure was observed with progressive freezing. The results suggest that resistance to cell deformation during extracellular freezing due to cell-wall rigidity can lead to reduced cell dehydration and increased cell tension. A relationship to predict freezing behavior in plant tissues based on cell rigidity is presented. Based on cell-water relations and ice nucleation rates, cell-wall rigidity has been shown to effect the freezing characteristics of plant tissues, including freeze-induced dehydration, supercooling, and homogeneous nucleation temperatures.

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.

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.

Therapeutic drug monitoring of antidepressants: cost implications and relevance to clinical practice.

Despite evidence to support its potential benefit in clinical practice, therapeutic drug monitoring (TDM) is under-utilised and underdeveloped in the field of psychiatry. In antidepressant pharmacotherapy drug dose is emphasised as the critical treatment variable. However, dose in, and of, itself can be a strikingly misleading predictor of drug concentration and, hence, treatment effect. For antidepressant drugs, plasma concentrations at a given dose have been shown to vary in excess of 40-fold. The clinical relevance of this variability is that at a standard antidepressant dosage only some patients will have tissue drug concentrations associated with an optimal response whereas others will have either low, ineffective drug concentrations or unnecessarily high concentrations which may be poorly tolerated. Among clinicians and healthcare agencies there is an under-appreciation of the degree of pharmacokinetic variability found in patients and how that might impact on the patients response to pharmacotherapy. Hence there is a perception that TDM is an unnecessary, complicated and costly procedure. This is actually unfounded. There are data to suggest that TDM can favourably affect the outcome of antidepressant treatment by providing a rational alternative to the inherently slower, trial and error practice of dosage titration based on clinical response. It is unlikely that TDM will become a standard of care for all antidepressant agents and all patients. Therefore the question becomes for which antidepressant agents, for which patients and under what circumstances, is TDM more cost-effective than traditional dose titration. The use of TDM to optimise the efficient use of selected antidepressant agents could potentially free up healthcare resources to fund other equally deserving treatments. This article provides a discussion of the major classes of antidepressant drugs with regard to their pharmacological features that predict the utility of TDM in clinical practice. Recommendations are made for the practical application of TDM and the directions for further research.

A versatile, computer-controlled, closed-loop system for continuous infusion of muscle relaxants.

A computer-controlled, closed-loop system for continuous infusion of muscle relaxants that allows the operator to choose either atracurium besylate or vecuronium bromide to provide any desired target level of neuromuscular blockade is described. This new system offers certain advantages over computer-controlled systems described previously for continuous infusion of muscle relaxants--that is, the option to choose either of two muscle relaxants to be infused and the inclusion of monitors to provide feedback about the dosage needed to produce a target level of neuromuscular blockade. The clinical performance of this system was tested in 36 patients who were 18 to 65 years old, were classified in American Society of Anesthesiologists physical status 1 or 2, and were undergoing elective orthopedic, abdominal, or thoracic procedures. In all patients, the control algorithm rapidly induced the target level of neuromuscular blockade and maintained that level of blockade at steady state with minimal oscillation. We conclude that the automatic feedback control system described can induce and precisely maintain any predetermined target level of neuromuscular blockade.

Pharmacoeconomic considerations when evaluating treatment options for major depressive disorder.

The goal of this paper is to increase the psychiatrist's awareness of issues and methods in pharmacoeconomics with the hope that this will lead to greater physician involvement in the ongoing cost-management debates. This paper will first examine the underlying dynamics of health economics as they relate to the treatment of major depressive disorder. It will then discuss cost-benefit factors in antidepressant pharmacotherapy with special focus on the economic implications of clinically relevant differences among antidepressant drug classes. The paper ends with a review of methods for the economic analysis of drug therapies and a discussion of research needs in this area.

Carbon monoxide retinopathy.

We recently examined three family members with acute carbon monoxide intoxication resulting from a single accidental exposure--a stepfather with a normal fundus, a mother with scattered superficial retinal hemorrhages, and her child with multiple large subinternal limiting membrane hemorrhages, peripapillary hemorrhages, severe venous tortuosity, and disc edema. All three had comparable carboxyhemoglobin levels and no evidence of hypertension, diabetes, or anemia. The different fundus presentations illustrated the variable clinical manifestations of carbon monoxide retinopathy. Early detection could prevent a lethal outcome.

Negative affectivity and the reporting of stressful life events.

Maddi, Bartone, and Puccetti (1987) and Schroeder and Costa (1984) reported inconsistent findings regarding the impact of negative affectivity (NA; i.e., neuroticism) contaminated life event items on observed life event-illness relationships. Here, unlike the previous studied, such contaminated items were nonjudgmentally identified. Among a sample of managers and professionals, it was found that NA-contaminated items correlated significantly with three measures of well-being (depression, life satisfaction, and physical symptoms) and that uncontaminated items were unassociated with the well-being indicators. Moreover, in two of three cases, the correlations between contaminated items and the well-being measures were significantly different from the correlations between uncontaminated items and the well-being indicators. Therefore, we concluded that prior life event-well-being findings are inflated considerably by the use of NA-contaminated events. Suggestions for future life events research that incorporate the NA construct are detailed.

Anterior uveitis in Kawasaki's disease.

Kawasaki's disease (mucocutaneous lymph node syndrome) is an acute febrile illness primarily affecting children. Slit-lamp examinations of six children with kawasaki's disease, ranging in age from 22 months to 16 years, showed that five had anterior uveitis during the acute phase of the illness. Two of the children were treated with corticosteroids and cycloplegic drugs and three received no treatment. In all five, the anterior uveitis resolved completely within a few weeks.