Validation, reproducibility and safety of trans dermal electrical stimulation in chronic pain patients and healthy volunteers

<p>Abstract</p> <p>Background</p> <p>Surrogate pain models have been extensively tested in Normal Human Volunteers (NHV). There are few studies that examined pain models in chronic pain patients. Patients are likely to have altered pain mechanisms. It is of interest to test patient pain responses to selective pain stimuli under controlled laboratory conditions.</p> <p>Methods</p> <p>The Institutional Ethic Committee approved the study. 16 patients with chronic neuropathic radiculopathy and 16 healthy volunteers were enrolled to the study after obtaining informed consent. During electrical stimulation (150 minutes for volunteers and 75 minutes for patients) the following parameters were measured every 10 minutes:</p> <p>Ongoing pain: Visual Analogue Scale (VAS) and Numeric Rate Scale (NRS)</p> <p>Allodynia (soft foam brush)</p> <p>Hyperalgesia (von Frey monofilament 20 g)</p> <p>Flare</p> <p>For each endpoint, the area under the curve (AUC) was estimated from the start of stimulation to the end of stimulation by the trapezoidal rule. The individual AUC values for both periods were plotted to show the inter- and intra-subject variability. For each endpoint a mixed effect model was fitted with random effect subject and fixed effect visit. The estimate of intra-subject variance and the mean value were then used to estimate the sample size of a crossover study required to have a probability of 0.80 to detect a 25% change in the mean value. Analysis was done using GenStat 8^thedition.</p> <p>Results</p> <p>Each endpoint achieved very good reproducibility for patients and NHV. Comparison between groups revealed trends towards:</p> <p>Faster habituation to painful stimuli in patients</p> <p>Bigger areas of hyperalgesia in patients</p> <p>Similar area of allodynia and flare (no statistical significance)</p> <p>Conclusion</p> <p>The differences demonstrated between patients and NHVs suggest that the electrical stimulation device used here may stimulate pathways that are affected in the pathological state.</p

Foresight Review on Design for Safety

This review explores how a culture of design for safety can enhance the safety of the world around us. Design for safety goes beyond legislation, regulations and standards. These all play an important role for established products and services but their limited scope often leads to missed opportunities to enhance safety by taking a broader perspective. Design is applied to both mature industries (which have many years of experience and a good understanding of risks and how to reduce them) and emerging industries (that use new technologies requiring new ways of controlling risk which may not yet be known or understood). An example of an emerging risk is the internet that is enabling rapid innovation of new products which generate data. This data is widely shared across the internet and the risks associated with this are as yet not fully understood by the public. A design for safety culture takes a holistic approach to understanding the influences that affect safety. Such influences are varied and take into account the broader environment within which design operates, including complex interactions, behaviour and culture. It goes beyond traditional design methods and focuses on the goal of a safer design. Implementing design for safety requires an understanding of the challenges and the methods to address them. It needs multidisciplinary teams that bring together people with the relevant skills to understand the challenges and a collaborative approach of ‘designing with’ rather than the more traditional approach of ‘designing for’. This can be achieved through an international diverse community that works together to identify and share best practices

A preliminary prediction model for potentially guiding patient choices between breast conserving surgery and mastectomy in early breast cancer patients; a Dutch experience

Purpose: To guide early stage breast cancer patients to choose between breast conserving surgery (BCS) and mastectomy (MST) considering the predicted cosmetic result and quality of life (QoL). Methods: A decision model was built to compare QoL after BCS and MST. Treatment could result in BCS with good cosmesis, BCS with poor cosmesis, MST only, and MST with breast reconstruction. QoL for these treatment outcomes were obtained from a previous study and the literature and translated into EuroQoL-5D derived utilities. Chance of good cosmesis after BCS was predicted based on tumor location and tumor/breast volume ratio. The decision model determined whether the expected QoL was superior after BCS or MST based on chance of good cosmesis. Results: The mean utility for the treatments such as BCS with good cosmesis, BCS with poor cosmesis, MST only, and MST with breast reconstruction were 0.908, 0.843, 0.859, and 0.876, respectively. BCS resulted in superior QoL compared to MST in patients with a chance of good cosmesis above 36%. This 36% threshold is reached in case the tumor is located in the upper lateral, lower lateral, upper medial, lower medial, and central quadrant of the breast with a tumor/breast volume ratio below 21.6, 4.1, 15.1, 3.2, and 14.7, respectively. Conclusions: BCS results in superior QoL in patients with tumors in the upper breast quadrants or centrally and a tumor/breast volume ratio below 15. MST results in superior QoL in patients with tumors in the lower breast quadrants and a tumor/breast volume ratio above 4

Breast and Tumour Volume Measurements in Breast Cancer Patients Using 3-D Automated Breast Volume Scanner Images

Background: The resection volume in relation to the breast volume is known to influence cosmetic outcome following breast-conserving therapy. It was hypothesised that three-dimensional ultrasonography (3-D US) could be used to preoperatively assess breast and tumour volume and show high association with histopathological measurements. Methods: Breast volume by the 3D-US was compared to the water displacement method (WDM), mastectomy specimen weight, 3-D MRI and three different calculations for breast volume on mammography. Tumour volume by the 3-D US was compared to the histopathological tumour volume and 3-D MRI. Relatedness was based on the intraclass correlation coefficient (ICC) with corresponding 95% confidence interval (95% CI). Bland–Altman plots were used to graphically display the agreement for the different assessment techniques. All measurements were performed by one observer. Results: A total of 36 patients were included, 20 and 23 for the evaluation of breast and tumour volume (ductal invasive carcinomas), respectively. 3-D US breast volume showed ‘excellent’ association with WDM, ICC 0.92 [95% CI (0.80–0.97)]. 3-D US tumour volume showed a ‘excellent’ association with histopathological tumour volume, ICC 0.78 [95% CI (0.55–0.91)]. Bland–Altman plots showed an increased overestimation in lager tumour volumes measured by 3-D MRI compared to histopathological volume. Conclusions: 3-D US showed a high association with gold standard WDM for the preoperative assessment of breast volume and the histopathological measurement of tumour volume. 3-D US is an patient-friendly preoperative available technique to calculate both breast volume and tumour volume. Volume measurements are promising in outcome prediction of intended breast-conserving treatment

The performance of GridPix detectors

A GridPix detector is a gaseous detector capable of detecting individual single primary electrons from ionizing particles. Such a detector consists of a pixel chip as active anode covered with a thin layer of silicon rich silicon nitride (SiRN) for protection against discharges, an integrated amplification grid (InGrid), applied on top of the chip by wafer post processing techniques, and a cathode plane. The drift region is between the grid and cathode while the gas gain occurs between the chip and the grid. The discharge quenching properties of the SiRN layer have been determined as well as the relation on grid capacitance, grid voltage and gas mixture. Part of the detectors in this report were of the type Gossip, a GridPix detector with a drift gap of ∼1 mm. Using such thin drift layer, one may consider this detector as a replacement for a silicon pixel detector. The performance of three Gossip detectors has been investigated by measurements in a test beam at CERN

TUmor-volume to breast-volume RAtio for improving COSmetic results in breast cancer patients (TURACOS); a randomized controlled trial

Background: Cosmetic result following breast conserving surgery (BCS) for cancer influences quality of life and psychosocial functioning in breast cancer patients. A preoperative prediction of expected cosmetic result following BCS is not (yet) standard clinical practice and therefore the choice for either mastectomy or BCS is still subjective. Recently, we showed that tumour volume to breast volume ratio as well as tumour location in the breast are independent predictors of superior cosmetic result following BCS. Implementation of a prediction model including both factors, has not been studied in a prospective manner. This study aims to improve cosmetic outcome by implementation of a prediction model in the treatment decision making for breast cancer patients opting for BCS. Methods/design: Multicentre, single-blinded, randomized controlled trial comparing standard preoperative work-up to a preoperative work-up with addition of the prediction model. Tumour volume to bre

The Effect of Opioid Receptor Blockade on the Neural Processing of Thermal Stimuli

The endogenous opioid system represents one of the principal systems in the modulation of pain. This has been demonstrated in studies of placebo analgesia and stress-induced analgesia, where anti-nociceptive activity triggered by pain itself or by cognitive states is blocked by opioid antagonists. The aim of this study was to characterize the effect of opioid receptor blockade on the physiological processing of painful thermal stimulation in the absence of cognitive manipulation. We therefore measured BOLD (blood oxygen level dependent) signal responses and intensity ratings to non-painful and painful thermal stimuli in a double-blind, cross-over design using the opioid receptor antagonist naloxone. On the behavioral level, we observed an increase in intensity ratings under naloxone due mainly to a difference in the non-painful stimuli. On the neural level, painful thermal stimulation was associated with a negative BOLD signal within the pregenual anterior cingulate cortex, and this deactivation was abolished by naloxone

A network analysis to identify mediators of germline-driven differences in breast cancer prognosis.

Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies ~7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis

The CHEK2*1100delC mutation has no major contribution in oesophageal carcinogenesis

In response to DNA damage, the cell cycle checkpoint kinase 2 (CHEK2) may phosphorylate p53, Cdc25A and Cdc25C, and regulate BRCA1 function, leading to cell cycle arrest and DNA repair. The truncating germline mutation CHEK2*1100delC abrogates kinase activity and confers low-penetrance susceptibility to breast cancer. We found CHEK2*1100delC in 0.5% of 190 oesophageal squamous cell carcinomas and in 1.5% of 196 oesophageal adenocarcinomas. In addition, we observed the mutation in 3.0% of 99 Barrett's metaplasias and 1.5% of 66 dysplastic Barrett's epithelia, both known precursor lesions of oesophageal adenocarcinoma. Since CHEK2*1100delC mutation frequencies did not significantly differ among oesophageal squamous cell carcinomas, adenocarcinomas and (dysplastic) Barrett's epithelia, as compared to healthy individuals, we conclude that the CHEK2*1100delC mutation has no major contribution in oesophageal carcinogenesis