Multidimensional Analysis of the Adult Human Heart in Health and Disease using Hierarchical Phase-Contrast Tomography (HiP-CT).

Cardiovascular diseases (CVDs) are a leading cause of death worldwide. Current clinical imaging modalities provide resolution adequate for diagnosis but are unable to provide detail of structural changes in the heart, across length-scales, necessary for understanding underlying pathophysiology of disease. Hierarchical Phase-Contrast Tomography (HiP-CT), using new (4th) generation synchrotron sources, potentially overcomes this limitation, allowing micron resolution imaging of intact adult organs with unprecedented detail. In this proof of principle study (n=2), we show the utility of HiP-CT to image whole adult human hearts ex-vivo: one 'control' without known cardiac disease and one with multiple known cardiopulmonary pathologies. The resulting multiscale imaging was able to demonstrate exemplars of anatomy in each cardiac segment along with novel findings in the cardiac conduction system, from gross (20 um/voxel) to cellular scale (2.2 um/voxel), non-destructively, thereby bridging the gap between macroscopic and microscopic investigations. We propose that the technique represents a significant step in virtual autopsy methods for studying structural heart disease, facilitating research into abnormalities across scales and age-groups. It opens up possibilities for understanding and treating disease; and provides a cardiac 'blueprint' with potential for in-silico simulation, device design, virtual surgical training, and bioengineered heart in the future.

Unexpected intraoperative hypotension in a chronic cocaine user.

It is not uncommon for patients to present for procedures under anaesthesia with a history of recent cocaine use. The acute effects of cocaine toxicity are well documented, but the pathophysiological changes caused by chronic use are complex and can result in unexpected cardiovascular responses and interactions with anaesthetic agents. In this case report, we describe an episode of hypotension under general anaesthesia, likely due to catecholamine depletion, an unusual but significant consequence of chronic cocaine use. It should be treated with intravenous fluids and direct-acting vasopressors such as phenylephrine or noradrenaline, as they are likely to be more effective than indirect acting agents. As the prevalence of cocaine use continues to increase, anaesthesia providers need to not only be familiar with the treatment of acute cocaine toxicity, but also to anticipate and manage the cardiovascular changes associated with chronic use of this drug.

Gender and immunosuppression impact on Merkel cell carcinoma diagnosis and prognosis. A population based cohort study.

Background: Merkel cell carcinoma (MCC), a rare cutaneous neuroendocrine endocrine tumour is increasing in incidence, and continues to carry a poor prognosis. Objectives: The objectives of this study were to examine all Irish cases of MCC from 1 January 1994 over 2 decades, focusing on gender and organ transplantation recipients (OTRs). Cases were identified from the National Cancer Registry of Ireland. Covariates of interest included age, body site, period of diagnosis, deprivation-status and history of non-melanoma skin cancer (NMSC). Results: In total 314 MCC cases were identified. A female predominance was noted (53.8%). Comparison between age-standardised rates between the earliest period (1994-1996) with the latest period (2012-2014) showed an increase of 105% in total. The trend in age-standardised incidence rates were noted to be increasing significantly (p = 0.0004). Average age at diagnosis was 77.6 years (male 75.1 years, female 79.7 years). Overall, the majority of MCC cases presented on the head and neck (n = 170, 54.1%). Differences in anatomical location of MCCs were noted between genders. Males were found to be more likely to have a history of previous NMSCs (males n = 73 [57.9%], females n = 53 [42.1%]). Thirty-one percentage of patients died from MCC, average survival was 3.5 years in those who died of this malignancy. Ten organ transplant recipients developed MCC. OTR who developed MCC were diagnosed at a younger average age of 65.1 years. Standardized incidence ratio for MCC in OTR was 59.96. A higher proportion of OTR died from MCC (70%), with a shorter median survival of 0.14 years. In competing risks regression, gender was not significantly associated with risk of dying, females having a non-significantly higher hazard of dying. Organ transplant recipients and patients from less deprived areas were at greater risk of dying from MCC. Conclusions: This population based study provides epidemiological, clinical and outcome data for MCC over a 20-year period.

Declining incidence of keratinocyte carcinoma in organ transplant recipients.

BACKGROUND: All organ transplant populations are predisposed to increased rates of keratinocyte carcinoma (KC). Since this increased risk was first appreciated, immunosuppressive regimens have changed and organ transplant recipients (OTRs) have been aggressively screened for KC. There is a perception that these measures have impacted on KC incidence but there is a paucity of population-based studies on post-transplant rates of basal cell carcinoma (BCC). OBJECTIVES: To identify trends in incidence rates for KC following solid organ transplantation over the past two decades. METHODS: This nationwide, population-based study included all solid OTRs transplanted between 1994 and 2014. Patient data were matched to national cancer registry data to determine the standardized incidence ratio (SIR) of KC in solid OTRs compared with the general population. RESULTS: In total 3580 solid OTRs were included. The total follow-up time was 28 407 person-years (median follow-up 7·11 years). The overall SIRs for squamous cell carcinoma (SCC) and BCC were 19·7 and 7·0, respectively. Our study documents a progressive fall in the SIRs for SCC and BCC from peak SIRs (95% confidence intervals) in 1994-1996 of 26·4 (21·5-32·4) and 9·1 (7·4-11·3) to 6·3 (2·3-16·7) and 3·2 (1·4-7·1) in 2012-2014, respectively. The ratio of SCC to BCC has remained at 3 to 1 over the last two decades. CONCLUSIONS: Our study is the first to demonstrate a significant reduction over the past two decades in the incidences of both SCC and BCC following solid organ transplantation. The SCC-to-BCC ratio was maintained, demonstrating that both are reducing equally. This trend coincided with temporal changes in immunosuppressive protocols and the introduction of skin cancer prevention programmes. What's already known about this topic? Prior studies have shown that the risk of cutaneous squamous cell carcinoma (SCC) has declined over recent decades following solid organ transplantation. It is not known whether the risk of basal cell carcinoma (BCC) has reduced in line with this. What does this study add? Our study documents a progressive fall in the risk of SCC and BCC following solid organ transplantation over the last two decades. The SCC-to-BCC ratio was maintained, demonstrating that both are reducing equally. The trends observed in our study coincided with temporal changes in immunosuppressive protocols and the introduction of cancer prevention programmes, suggesting that these factors have positively impacted on the risk of keratinocyte carcinoma in this cohort.

Temporal association between home nursing and hospital costs at end of life in three provinces.

BACKGROUND: Research has demonstrated that increases in palliative homecare nursing are associated with a reduction in the rate of subsequent hospitalizations. However, little evidence is available about the cost-savings potential of palliative nursing when accounting for both increased nursing costs and potentially reduced hospital costs. METHODS: Our retrospective cohort study included cancer decedents from British Columbia, Ontario, and Nova Scotia who received any palliative nursing in the last 6 months of life. A Poisson regression analysis was used to determine the association of increased nursing costs (in 2-week blocks) on the relative average hospital costs in the subsequent 2-week block and on the overall total cost (hospital costs plus nursing costs in the preceding 2-week block). RESULTS: The cohort included 58,022 cancer decedents. Results of the analysis for the last month of life showed an association between increased nursing costs and decreased relative hospital costs in comparisons with a reference group (>0 to 1 hour nursing in the block): the maximum decrease was 55% for Ontario, 31% for British Columbia, and 38% for Nova Scotia. Also, increased nursing costs in the last month were almost always associated with lower total costs in comparison with the reference. For example, cost savings per person-block ranged from $376 (>10 nursing hours) to $1,124 (>4 to 6 nursing hours) in British Columbia. CONCLUSIONS: In the last month of life, increased palliative nursing costs (compared with costs for >0 to 1 hour of nursing in the block) were associated with lower relative hospital costs and a lower total cost in a subsequent block. Our research suggests a cost-savings potential associated with increased community-based palliative nursing.

Effects of surgery on the cancer stem cell niche.

Recent identification of a cancer stem cell (CSC) phenotype in solid tumors has greatly enhanced the understanding of the mechanisms responsible for cancer cell metastasis. In keeping with Pagets 'seed and soil' theory, CSCs display dependence upon stromal derived factors found within the niche in which they reside. Inflammatory mediators act as a 'fertilizer' within this niche when interacting with CSCs at the tumor-stromal interface and can potentiate the metastatic ability of CSCs. Interestingly, the same components of the pro-inflammatory milieu experienced by cancer patients perioperatively are known to promote the metastagenic potential of CSCs. On the basis of this observation we discuss how surgery-induced inflammation potentiates colon CSC involvement in the metastatic process. We hypothesize that the high rates of recurrence and metastasis associated with tumor resection are potentiated by the effects of surgery-induced inflammation on CSCs. Finally we discuss potential therapeutic strategies for use in the perioperative window to protect cancer patients from the oncological effects of the pro-inflammatory milieu.

Establishing a population-based patient-reported outcomes study (PROMs) using national cancer registries across two jurisdictions: the Prostate Cancer Treatment, your experience (PiCTure) study.

OBJECTIVE: To establish an international patient-reported outcomes (PROMs) study among prostate cancer survivors, up to 18 years postdiagnosis, in two countries with different healthcare systems and ethical frameworks. DESIGN: A cross-sectional, postal survey of prostate cancer survivors sampled and recruited via two population-based cancer registries. Healthcare professionals (HCPs) evaluated patients for eligibility to participate. Questionnaires contained validated instruments to assess health-related quality of life and psychological well-being, including QLQ-C30, QLQ-PR25, EQ-5D-5L, 21-question Depression, Anxiety and Stress Scale (DASS-21) and the Decisional Regret Scale. SETTING: Republic of Ireland (RoI) and Northern Ireland (NI). PRIMARY OUTCOME MEASURES: Registration completeness, predictors of eligibility and response, data missingness, unweighted and weighted PROMs. RESULTS: Prostate cancer registration was 80% (95% CI 75% to 84%) and 91% (95% CI 89% to 93%) complete 2 years postdiagnosis in NI and RoI, respectively. Of 12,322 survivors sampled from registries, 53% (n=6559) were classified as eligible following HCP screening. In the multivariate analysis, significant predictors of eligibility were: being ≤59 years of age at diagnosis (p<0.001), short-term survivor (<5 years postdiagnosis; p<0.001) and from RoI (p<0.001). 3348 completed the questionnaire, yielding a 54% adjusted response rate. 13% of men or their families called the study freephone with queries for assistance with questionnaire completion or to talk about their experience. Significant predictors of response in multivariate analysis were: being ≤59 years at diagnosis (p<0.001) and from RoI (p=0.016). Mean number of missing questions in validated instruments ranged from 0.12 (SD 0.71; EQ-5D-5L) to 3.72 (SD 6.30; QLQ-PR25). Weighted and unweighted mean EQ-5D-5L, QLQ-C30 and QLQ-PR25 scores were similar, as were the weighted and unweighted prevalences of depression, anxiety and distress. CONCLUSIONS: It was feasible to perform PROMs studies across jurisdictions, using cancer registries as sampling frames; we amassed one of the largest, international, population-based data set of prostate cancer survivors. We highlight improvements which could inform future PROMs studies, including utilising general practitioners to assess eligibility and providing a freephone service.

A new method for automatic tracking of facial landmarks in 3D motion captured images (4D).

The aim of this study was to validate the automatic tracking of facial landmarks in 3D image sequences. 32 subjects (16 males and 16 females) aged 18-35 years were recruited. 23 anthropometric landmarks were marked on the face of each subject with non-permanent ink using a 0.5mm pen. The subjects were asked to perform three facial animations (maximal smile, lip purse and cheek puff) from rest position. Each animation was captured by the 3D imaging system. A single operator manually digitised the landmarks on the 3D facial models and their locations were compared with those of the automatically tracked ones. To investigate the accuracy of manual digitisation, the operator re-digitised the same set of 3D images of 10 subjects (5 male and 5 female) at 1 month interval. The discrepancies in x, y and z coordinates between the 3D position of the manual digitised landmarks and that of the automatic tracked facial landmarks were within 0.17mm. The mean distance between the manually digitised and the automatically tracked landmarks using the tracking software was within 0.55 mm. The automatic tracking of facial landmarks demonstrated satisfactory accuracy which would facilitate the analysis of the dynamic motion during facial animations.

Real-time perfusion echocardiography during treadmill exercise and dobutamine stress testing.

BACKGROUND: Real-time perfusion (RTP) echocardiographic imaging with a continuous infusion of microbubbles has improved the sensitivity of dobutamine stress echocardiography (DSE) in detecting coronary artery disease (CAD). The impact of RTP on treadmill exercise stress echocardiography (TESE) is unclear. Design Retrospective database review. SETTING/PATIENTS/INTERVENTIONS: RTP was utilised in 254 DSE and TESE patients being examined for the presence of significant CAD. A continuous infusion of 3% Definity (Lantheus Medical Imaging) was used for all studies, and contrast replenishment (MCR), plateau intensity (PMCE) and wall motion (WM) were examined for the detection of CAD. MAIN OUTCOME MEASURES: Sensitivity/specificity/accuracy to detect CAD. RESULTS: For DSE, the sensitivity of myocardial perfusion (MP) imaging with RTP was 85%, which was significantly higher than WM analysis (72%; p<0.05). The improvement in sensitivity with MP analysis during DSE was primarily the result of better detection of left anterior descending disease. MP sensitivity during TESE was significantly better than MP sensitivity during DSE (98% versus 85%; p<0.05), and WM sensitivity during TESE was better than WM sensitivity during DSE (89% versus 72%; p<0.05). The improvement in WM sensitivity during TESE was due to detection of subendocardial wall thickening abnormalities in 48% of the patients with induced subendocardial perfusion defects. CONCLUSION: Myocardial perfusion imaging with RTP improves the detection of CAD during both DSE and TESE. During TESE, the subendocardial perfusion defects improve WM sensitivity by delineating subendocardial WM abnormalities.

Modelling the demographics of the Irish cattle population.

In recent years, national authorities have committed very substantial resources to the creation and maintenance of databases capable of recording important animal event data, such as births, deaths and movements. This has primarily been driven by the need to ensure the quality and safety of animal products. However, it can also be used to assist policy makers in decision making. Despite the abundance of animal event data, as yet there is little published information about the use of these data to better understand the demography of cattle populations. This study reports the development of, and outputs from, a demographic model using data routinely collected from the Irish cattle population. The demographic model was based on a series of life tables detailing age-specific probabilities of survival up to a maximum of 17 years. These outputs were used to determine characteristics of the Irish cattle population, including estimated mortality rates, life expectancies and age profiles, and estimated cattle numbers by age and date. Separate life tables were developed for each of the 204 monthly birth cohorts born between January 1989 and December 2005. Within the Irish cattle population, the peak estimated mortality rate occurs at 29-33 months. The estimated life expectancy at birth of cattle in Ireland was 42 months. When the survival rates for all the cohorts within a population are calculated, then it is possible to use these rates as a model for determining future population size and answering cohort specific queries.

Splitting plaster with a scalpel blade: a safe way to allow easy splitting of a plaster.

INTRODUCTION: Splitting of a plaster cast is frequently required to accommodate post-operative limb swelling. Oscillating saws are often used but can cause injury and distress and cannot be used when the plaster is drying. At these times plaster shears are used. A safe technique is described which safely divides drying plaster using a sharp scalpel. METHOD: Plaster casts were applied to 40 modelling balloons, consisting of one roll of 3-in. and one roll of 4-in. plaster. The balloons had either two or four wool layers beneath the plaster. Ten from each group were split using our technique and 10 from each group were split with plaster shears. The number of balloons that were not burst during the splitting process was recorded. RESULTS: Of the 20 plasters split with a scalpel, all of the balloons remained inflated. The balloons underneath two of the plasters with two layers of wool that were split using plaster shears burst during splitting. When the plasters split with a scalpel were dry they could be opened easily using cast spreaders and the wool cut with scissors without the balloons bursting. CONCLUSION: This is a safe and simple technique for splitting a drying plaster without the need for extra materials. It allows easy completion of the release with scissors alone should swelling of the soft tissues become excessive. The need for plaster shears or oscillating saws with the potential trauma associated with these established methods is eliminated.

Evaluation of restenosis and extent of coronary artery disease in patients with previous percutaneous coronary interventions by dobutamine stress real-time myocardial contrast perfusion imaging.

OBJECTIVES: To assess the accuracy of real-time myocardial contrast perfusion imaging (MCPI) for the diagnosis of restenosis and extent of coronary artery disease (CAD) in patients with previous percutaneous coronary intervention (PCI). METHODS: 56 patients were studied 1.9 (SD 1.4) years after PCI. They underwent MCPI with commercially available ultrasound contrast agents (Optison or Definity) at rest and at peak dobutamine-atropine stress. Coronary angiography was performed within one month. Significant CAD was defined as >or= 50% stenosis in >or= 1 major epicardial coronary artery. Significant restenosis was defined as >or= 50% stenosis in a coronary segment with previous intervention. RESULTS: Reversible perfusion abnormalities were detected in 40 of 43 patients with significant CAD and in 4 of 13 patients without (overall sensitivity 93%, 95% CI 85% to 99%; specificity 69%, 95% CI 44% to 94%; and accuracy 88%, 95% CI 79% to 96%). Significant restenosis in >or= 1 coronary artery with previous PCI was detected in 38 (68%) patients. Reversible perfusion abnormalities were present in 35 of them (sensitivity 92%, 95% CI 84% to 99%). Reversible perfusion abnormalities were detected in >or= 2 vascular distributions in 20 of 28 patients with multivessel CAD and in 3 of 28 patients without (sensitivity 71%, 95% CI 55% to 88%; specificity 89%, 95% CI 78% to 99%; and accuracy 80%, 95% CI 70% to 91%). Restenosis was detected in 41 coronary arteries. Sensitivity of MCPI for regional diagnosis of restenosis was 73% (95% CI 60% to 87%), specificity was 75% (95% CI 60% to 90%), and accuracy was 74% (95% CI 64% to 84%). CONCLUSION: Dobutamine stress MCPI is a useful technique for the evaluation of restenosis and extent of CAD after PCI.

Acute bilateral forearm compartment syndrome of unknown aetiology.

This is the first reported case of non-traumatic, acute bilateral forearm compartment syndrome. Despite a delay of over 24 hours until surgical decompression and 50% muscle fibre necrosis in the histopathological examination, the clinical outcome was excellent after fasciotomy, delayed primary wound closure and early institution of a range of motion exercise programme. The literature on non-traumatic causes of compartment syndrome is reviewed.

Two-stage liver resection and chemotherapy for bilobar colorectal liver metastases.

BACKGROUND: A significant number of patients with colorectal metastatic disease confined to the liver are inoperable at assessment. For these patients, the outlook is poor. Chemotherapy can 'down-stage' some tumours and render them operable. The authors present a series of patients with inoperable disease despite down-staging with chemotherapy, who underwent a two-stage resection to clear their metastatic disease. METHODS: The case-notes of 11 patients who were found to have inoperable hepatic metastatic disease were identified using computerised medical records and mean hospital stay, survival and long-term follow-up data was noted. RESULTS: The mean follow-up from initial resection was 13.5 months (range of 5-20 months). Three deaths were recorded in the follow-up interval. Causes of death included recurrence of hepatic disease following completion of two-stage resection, progression of original hepatic disease leading to inoperability at second stage operation and recurrence of original primary colorectal tumour. The mean survival in the patients who died was 17 months (range of 15-19 months). The remaining patients are alive to date with six patients showing no evidence of hepatic recurrence, follow-up period of 13 months (range of 8-20 months). One patient developed de novo prostate cancer and is awaiting his second liver resection, and one patient has stable hepatic disease with no evidence of progression. CONCLUSION: Two-stage liver resection can prolong survival when compared to chemotherapy alone, with a recurrence rate equivalent to ablation techniques. Longer-term studies are needed for further evaluation.

Effects of SP500263, a novel selective estrogen receptor modulator, on bone, uterus, and serum cholesterol in the ovariectomized rat.

We describe here the activity of a novel selective estrogen receptor modulator, SP500263. When given to adult ovariectomized (OVX) rats for 28 days at doses of 0.3, 1, or 3 mg/kg/day, we found that SP500263 partially protected against OVX-induced loss of bone mineral content in the distal ends of femurs and in the whole bone. SP500263 also antagonized the OVX-induced increase in body weight. However, unlike 17beta-estradiol, SP500263 at efficacious doses did not prevent the OVX-induced loss in uterine wet weight. A small but significant effect on uterine wet weight was noted with raloxifene dosed at 1 mg/kg. As expected, SP500263 but not raloxifene acted as an estrogen antagonist on the uterus in adult rats when administered for 7 days at 30 mg/kg/day. Finally, SP500263 had no statistically significant effects on total serum cholesterol and serum triglycerides in OVX rats treated for 28 days. Raloxifene had no significant effects on body weight, bone mineral content, and serum cholesterol or triglycerides in the OVX-rat model. In summary, SP500263 is a new orally active SERM that acts in rats as an estrogen agonist on bone without causing uterine stimulatory effects.

Electromagnetic fields and breast cancer on Long Island: a case-control study.

The EMF and Breast Cancer on Long Island Study (EBCLIS) was a case-control study designed to evaluate the possible association between exposure to electromagnetic fields (EMFs) and breast cancer. Eligible women were participants in the population-based Long Island Breast Cancer Study Project, were under 75 years of age at enrollment, were residentially stable, and were identified between August 1, 1996, and June 20, 1997. Of those eligible, 576 cases and 585 controls participated in EBCLIS (87% and 83%, respectively). In-home data collection included various spot and 24-hour EMF measurements, ground-current magnetic field measurements, wire mapping of overhead power lines servicing the home, and an interview. Odds ratios and 95% confidence intervals were based on multivariate logistic regression analyses. All odds ratios were close to 1 and nonsignificant. For the highest quartile of 24-hour EMF measurements, the odds ratio was 0.97 (95% confidence interval (CI): 0.69, 1.37) in the bedroom and 1.09 (95% CI: 0.78, 1.51) in the most lived-in room. For the highest exposure category of ground-current measurements, the odds ratio was 1.13 (95% CI: 0.88, 1.44) in the bedroom and 1.08 (95% CI: 0.85, 1.38) in the most lived-in room. These and other EBCLIS results agree with other recent reports of no association between breast cancer and residential EMF exposures.

Efficiency of Dispatch and Infiltrator cardiac infusion catheters in arterial localization of nanoparticles in a porcine coronary model of restenosis.

Localized intramural delivery of sustained release biodegradable nanoparticles containing an antiproliferative agent could provide prolonged drug effect at the site of vascular injury that could inhibit the proliferation of smooth muscle cells and hence restenosis. The efficiency of arterial localization of nanoparticles is crucial in maximizing the drug effect in the target tissue. Therefore, the objective of the present study was to determine the comparative efficiency of the Dispatch and the Infiltrator cardiac infusion catheters to localize nanoparticles in the arterial wall. Following a standard balloon angioplasty procedure on the left anterior descending artery (LAD) in a porcine coronary model of restenosis, a suspension of nanoparticles containing a fluorescent marker was infused at the site of injury using either the Dispatch or the Infiltrator catheter. One hour following the infusion, animals were sacrificed and the nanoparticle levels in the LAD and other tissue were analyzed. The Dispatch catheter resulted in 3.3 folds greater efficiency of nanoparticle localization in the LAD than the Infiltrator catheter (309 +/- 124 vs. 93 +/- 43 microg/g of tissue, n = 6 for Dispatch and n = 5 for Infiltrator, p = 0.082, t-test). It is estimated that about 2% of the arterial volume can be displaced with the nanoparticle infusion. Fluorescence microscopy of the cross-sections of the LAD revealed greater fluorescence activity in the intimal layer with both the catheters, however the arteries infused using the Dispatch catheter demonstrated relatively higher degree of fluorescence activity in the medial and adventitial layers. The transmission electron microscopy of the arterial sections demonstrated infiltration of nanoparticles in the arterial wall and the histological analysis of the sections demonstrated no apparent damage to the endothelium due to the infusion of nanoparticles.