Tumour, narrow pelvis and surgery specific factors for total mesorectal excision quality and morbidity following rectal cancer resection.

BACKGROUND: Pelvic anatomy is critical in challenging rectal resections. This study investigated how pelvic anatomy relates to total mesorectal excision (TME) quality, anastomotic leakage rate, and long-term oncological outcomes. METHODS: Patients undergoing elective rectal cancer resection from 2008 to 2017 in an Austrian institution were retrospectively reviewed regardless of the surgical approach. CT scans were analysed for pelvic measurements and volumes. The primary outcomes of interest were the correlation between pelvic dimensions and the TME quality and anastomotic leakage. Subanalysis was done by surgical approach (open, laparoscopic, transanal TME). Secondary outcomes were overall and disease-free survivals. RESULTS: Among 154 eligible patients, 112 were included. The angle between pubic symphysis and promontory significantly correlated with worse TME grades (TME grade 1: mean(s.d.) 102.7(5.7)°; TME grade 2: 92.0(4.4)°; TME grade 3: 91.4(3.6)°; P < 0.001). A significantly lower distance between tumour and circumferential resection margin (CRM) was observed in grade 3 resections, whereas no difference appeared in grade 1 and grade 2 resection (TME grade 1: mean(s.d.) 11.92(9.4) mm; TME grade 2: 10.8(8.1) mm; TME grade 3: 3.1(4.1) mm; P = 0.003). The anastomotic leakage rate was significantly higher in case of a lower CRM (patients with anastomotic leakage: mean(s.d.) 6.8(5.8) mm versus others: 12.6(9.8) mm, P = 0.027), but not associated with pelvimetry measurements. The transanal TME (TaTME) subgroup displayed a wider angle between the pubic symphysis and promontory, younger age and improved TME quality compared to others (respectively, mean TME grades in TaTME versus open versus laparoscopic: 1.0 ± 0.0, 1.5 ± 0.7 and 1.3 ± 0.5, P = 0.013). Finally, oncological survival was not impacted by pelvic measurements or worse TME quality. CONCLUSION: The angle between the pubic symphysis and promontory and the distance between tumour and CRM were associated with worse TME grades. The anastomotic leakage was associated with a lower CRM but not with pelvimetric measures.

Sarcopenic Obesity Is a Risk Factor for Worse Oncological Long-Term Outcome in Locally Advanced Rectal Cancer Patients: A Retrospective Single-Center Cohort Study.

BACKGROUND: Malnutrition and skeletal muscle waste (sarcopenia) are known as predictive factors for a poor postoperative outcome. Paradoxically, obesity seems to be associated with a survival advantage in wasting diseases such as cancer. Thus, the interpretation of body composition indices and their impact on rectal cancer therapy has become more and more complex. The aim of this study was to evaluate body composition indices in locally advanced rectal cancer patients prior to therapy and their impact on short- and long-term outcomes. METHODS: Between 2008 and 2018, 96 patients were included in this study. Pre-therapeutic CT scans were used to evaluate visceral and subcutaneous fat mass, as well as muscle mass. Body composition indices were compared to body mass index, morbidity, anastomotic leakage rate, local recurrency rate, and oncological long-term outcomes. RESULTS: Increased visceral fat (p < 0.01), subcutaneous fat (p < 0.01), and total fat mass (p = 0.001) were associated with overweight. Skeletal muscle waste (sarcopenia) (p = 0.045), age (p = 0.004), comorbidities (p < 0.01), and sarcopenic obesity (p = 0.02) were significantly associated with increased overall morbidity. The anastomotic leakage rate was significantly influenced when comorbidities were present (p = 0.006). Patients with sarcopenic obesity showed significantly worse disease-free (p = 0.04) and overall survival (p = 0.0019). The local recurrency rate was not influenced by body composition indices. CONCLUSION: Muscle waste, older age, and comorbidities were demonstrated as strong risk factors for increased overall morbidity. Sarcopenic obesity was associated with worse DFS and OS. This study underlines the role of nutrition and appropriate physical activity prior to therapy.

Art and craft material use patterns by pre-school and elementary school children at home and school: a year long survey for refining exposure assessments.

BACKGROUND: Use frequency and times are critical parameters for estimating realistic chemical exposures associated with the use of consumer products. Very limited information is available in the published literature for children's use patterns of art and craft materials at home and school. OBJECTIVE: Conduct a year-long survey of art materials use at home and school by pre-school and elementary school children, teachers, and parents which can be used to refine chemical exposure assessments for these consumer products. METHODS: Parent and teacher online surveys were conducted on the daily use of markers and monthly use of fifteen additional art and craft materials. RESULTS: Daily marker use by elementary children was widespread at home and school (65% and 80%, respectively). On average, pre-school and elementary students used markers for 27 min per day, more than double daily home use. Adults used markers for longer durations relative to their children/students with teachers reporting the highest average daily usage time. School use of general art materials exceeded home use for both age groups, with elementary children using art materials more frequently than their pre-school counterparts. Examples of how these data can be used to refine exposure estimates are provided. SIGNIFICANCE: Accurate art material usage data contributes to refined estimates of chemical exposure for these consumer products. IMPACT STATEMENT: A year-long online survey was conducted which measured daily frequency and duration use for markers and comparable monthly use of other art materials for pre-school and elementary school children, their parents and teachers. Such use information is critical for estimating chemical exposures associated with this class of consumer products.

Identification of Risk Factors for Sexual Dysfunction after Multimodal Therapy of Locally Advanced Rectal Cancer and Their Impact on Quality of Life: A Single-Center Trial.

PURPOSE: Sexual function is crucial for the quality of life and can be highly affected by preoperative therapy and surgery. The aim of this study was to identify potential risk factors for poor sexual function and quality of life. METHODS: Female patients were asked to complete the Female Sexual Function Index (FSFI-6). Male patients were demanded to answer the International Index of Erectile Function (IIEF-5). RESULTS: In total, 79 patients filled in the questionary, yielding a response rate of 41.57%. The proportion of women was represented by 32.91%, and the median age was 76.0 years (66.0-81.0). Sexual dysfunction appeared in 88.46% of female patients. Severe erectile dysfunction occurred in 52.83% of male patients. Univariate analysis showed female patients (OR: 0.17, 95%CI: 0.05-0.64, p = 0.01), older age (OR: 0.34, 95%CI 0.11-1.01, p = 0.05), tumor localization under 6cm from the anal verge (OR: 4.43, 95%CI: 1.44-13.67, p = 0.01) and extension of operation (APR and ISR) (OR: 0.13, 95%CI: 0.03-0.59, p = 0.01) as significant risk factors for poor outcome. Female patients (OR: 0.12, 95%CI: 0.03-0.62, p = 0.01) and tumors below 6 cm from the anal verge (OR: 4.64, 95%CI: 1.18-18.29, p = 0.03) were shown to be independent risk factors for sexual dysfunction after multimodal therapy in the multivariate analysis. Quality of life was only affected in the case of extensive surgery (p = 0.02). CONCLUSION: Higher Age, female sex, distal tumors and extensive surgery (APR, ISR) are revealed risk factors for SD in this study. Quality of life was only affected in the case of APR or ISR.

Are risk factors for anastomotic leakage influencing long-term oncological outcomes after low anterior resection of locally advanced rectal cancer with neoadjuvant therapy? A single-centre cohort study.

PURPOSE: Anastomotic leakage (AL) poses the most serious problem following low anterior resection in patients with rectal cancer independent of surgical approach or technique. The aim of this study was to evaluate risk factors for the occurrence of AL and how they affect the oncological long-term outcome of patients who received neoadjuvant therapy. METHODS: A single centre cohort study of 163 consecutive locally advanced rectal cancer patients (cT3, cT4, N +) that received neoadjuvant therapy followed by resection with primary anastomosis between January 1998 and December 2020 were included in this study. Short- and long-term findings were compared between patients with AL (Leakage +) and without AL (Leakage -). RESULTS: A complete follow-up was obtained from 163 patients; thereby, 33 patients (20%) developed an AL. We observed more patients with comorbidities (38% vs. 61%, p = 0.049) which developed a leakage in the course. Permanent stoma rate (36% vs. 18%, p = 0.03) was higher, and time between primary operation and stoma reversal was longer (219 days [172-309] vs. 93 days [50-182], p < 0.001) in this leakage group as well. Tumour distance lower than 6 cm from the anal verge (OR: 2.81 [95%CI: 1.08-7.29], p = 0.04) and comorbidities (OR: 2.22 [95%CI: 1.01-4.90], p = 0.049) was evaluated to be independent risk factors for developing an AL after rectal cancer surgery. Oncological outcome was not influenced by AL nor by other associated risk factors. CONCLUSION: We could clearly detect the distance of tumour from the anal verge and comorbidities independent risk factors for the occurrence of AL. Oncological findings and long-term outcome were not influenced by these particular risk factors.

Is Robotic Assisted Colorectal Cancer Surgery Equivalent Compared to Laparoscopic Procedures during the Introduction of a Robotic Program? A Propensity-Score Matched Analysis.

BACKGROUND: Robotic surgery represents a novel approach for the treatment of colorectal cancers and has been established as an important and effective method over the last years. The aim of this work was to evaluate the effect of a robotic program on oncological findings compared to conventional laparoscopic surgery within the first three years after the introduction. METHODS: All colorectal cancer patients from two centers that either received robotic-assisted or conventional laparoscopic surgery were included in a comparative study. A propensity-score-matched analysis was used to reduce confounding differences. RESULTS: A laparoscopic resection (LR Group) was performed in 82 cases, and 93 patients were treated robotic-assisted surgery (RR Group). Patients' characteristics did not differ between groups. In right-sided resections, an intracorporeal anastomosis was significantly more often performed in the RR Group (LR Group: 5 (26.31%) vs. RR Group: 10 (76.92%), p = 0.008). Operative time was shown to be significantly shorter in the LR Group (LR Group: 200 min (150-243) vs. 204 min (174-278), p = 0.045). Conversions to open surgery did occur more often in the LR Group (LR Group: 16 (19.51%) vs. RR Group: 5 (5.38%), p = 0.004). Postoperative morbidity, the number of harvested lymph nodes, quality of resection and postoperative tumor stage did not differ between groups. CONCLUSION: In this study, we could clearly demonstrate robotic-assisted colorectal cancer surgery as effective, feasible and safe regarding postoperative morbidity and oncological findings compared to conventional laparoscopy during the introduction of a robotic system.

A tiered approach to investigate the inhalation toxicity of cobalt substances. Tier 3: Inflammatory response following acute inhalation exposure correlates with lower tier data.

In vitro studies have shown that cobalt substances predominantly induce pre-inflammatory biomarkers, resulting in a grouping of substances either predicted to cause inflammation following inhalation, or those with a different reactivity profile (poorly-reactive). There is a lack of data on whole-organ lung responses following inhalation of these substances, especially relating to the poorly-reactive group. It is of interest to generate tissue-specific histopathological correlation to better ascertain the predictive nature of the lower tier tests (i.e. tier 1 - bioelution, tiers 2a and b - in vitro markers and ToxTracker testing), in order to understand the type of effects caused by the poorly-reactive group and to gauge long-term effects. Eight cobalt substances were tested in vivo in a customized 4-h toxicity test; with animals sacrificed up to 14-days post-exposure. Histopathological severity scores were assigned based on inflammatory and pre-carcinogenic markers. A clear pattern emerged, with the reactive substances causing a persistent increase in one or more of the selected markers, and absence of these markers with poorly-reactive substances. Longer-term studies should be conducted to investigate the repeated dose effects of the poorly-reactive substances.

Shortening the preparation time of the single prolonged breath-hold for radiotherapy sessions.

OBJECTIVE: Single prolonged breath-holds of >5 min can be obtained in cancer patients. Currently, however, the preparation time in each radiotherapy session is a practical limitation for clinical adoption of this new technique. Here, we show by how much our original preparation time can be shortened without unduly compromising breath-hold duration. METHODS: 44 healthy subjects performed single prolonged breath-holds from 60% O2 and mechanically induced hypocapnia. We tested the effect on breath-hold duration of shortening preparation time (the durations of acclimatization, hyperventilation and hypocapnia) by changing these durations and or ventilator settings. RESULTS: Mean original breath-hold duration was 6.5 ± 0.2 (standard error) min. The total original preparation time (from connecting the facemask to the start of the breath-hold) was 26 ± 1 min. After shortening the hypocapnia duration from 16 to 5 min, mean breath-hold duration was still 6.1 ± 0.2 min (ns vs the original). After abolishing the acclimatization and shortening the hypocapnia to 1 min (a total preparation time now of 9 ± 1 min), a mean breath-hold duration of >5 min was still possible (now significantly shortened to 5.2 ± 0.6 min, p < 0.001). After shorter and more vigorous hyperventilation (lasting 2.7 ± 0.3 min) and shorter hypocapnia (lasting 43 ± 4 s), a mean breath-hold duration of >5 min (5.3 ± 0.2 min, p < 0.05) was still possible. Here, the final total preparation time was 3.5 ± 0.3 min. CONCLUSIONS: These improvements may facilitate adoption of the single prolonged breath-hold for a range of thoracic and abdominal radiotherapies especially involving hypofractionation. ADVANCES IN KNOWLEDGE: Multiple short breath-holds improve radiotherapy for thoracic and abdominal cancers. Further improvement may occur by adopting the single prolonged breath-hold of >5 min. One limitation to clinical adoption is its long preparation time. We show here how to reduce the mean preparation time from 26 to 3.5 min without compromising breath-hold duration.

The Influence of VE-Cadherin on Adhesion and Incorporation of Breast Cancer Cells into Vascular Endothelium.

During metastasis, cancer cells that originate from the primary tumor circulate in the bloodstream, extravasate, and form micrometastases at distant locations. Several lines of evidence suggest that specific interactions between cancer cells and endothelial cells, in particular tumor cell adhesion to the endothelium and transendothelial migration, play a crucial role in extravasation. Here we have studied the role of vascular endothelial (VE)-cadherin which is expressed aberrantly by breast cancer cells and might promote such interactions. By comparing different human breast cancer cell lines, we observed that the number of cancer cells that adhered to endothelium correlated with VE-cadherin expression levels. VE-cadherin silencing experiments confirmed that VE-cadherin enhances cancer cell adhesion to endothelial cells. However, in contrast, the number of cancer cells that incorporated into the endothelium was not dependent on VE-cadherin. Thus, it appears that cancer cell adhesion and incorporation are distinct processes that are governed by different molecular mechanisms. When cancer cells incorporated into the endothelial monolayer, they formed VE-cadherin positive contacts with endothelial cells. On the other hand, we also observed tumor cells that had displaced endothelial cells, reflecting either different modes of incorporation, or a temporal sequence where cancer cells first form contact with endothelial cells and then displace them to facilitate transmigration. Taken together, these results show that VE-cadherin promotes the adhesion of breast cancer cells to the endothelium and is involved in the initial phase of incorporation, but not their transmigration. Thus, VE-cadherin might be of relevance for therapeutic strategies aiming at preventing the metastatic spread of breast cancer cells.

Safely achieving single prolonged breath-holds of > 5 minutes for radiotherapy in the prone, front crawl position.

OBJECTIVE: Breast cancer radiotherapy is increasingly delivered supine with multiple, short breath-holds. There may be heart and lung sparing advantages for locoregional breast cancer of both prone treatment and in a single breath-hold. We test here whether single prolonged breath-holds are possible in the prone, front crawl position. METHODS: 19 healthy volunteers were trained to deliver supine, single prolonged breath-holds with pre-oxygenation and hypocapnia. We tested whether all could achieve the same durations in the prone, front crawl position. RESULTS: 19 healthy volunteers achieved supine, single prolonged breath-holds for mean of 6.2 ± 0.3 min. All were able to hold safely for the same duration while prone (6.1 ± 0.2 min ns. by paired ANOVA). With prone, the increased weight on the chest did not impede chest inflation, nor the ability to hold air in the chest. Thus, the rate of chest deflation (mean anteroposterior deflation movement of three craniocaudally arranged surface markers on the spinal cord) was the same (1.2 ± 0.2, 2.0 ± 0.4 and 1.2 ± 0.4 mm/min) as found previously during supine prolonged breath-holds. No leakage of carbon dioxide or air was detectable into the facemask. CONCLUSION: Single prolonged (>5 min) breath-holds are equally possible in the prone, front crawl position. ADVANCES IN KNOWLEDGE: Prolonged breath-holds in the front crawl position are possible and have the same durations as in the supine position. Such training would therefore be feasible for some patients with breast cancer requiring loco-regional irradiation. It would have obvious advantages for hypofractionation.

Positive effects of lumbar puncture simulation training for medical students in clinical practice.

BACKGROUND: Lumbar puncture (LP) is an invasive medical procedure that can be done by any doctor. Several simulation-based trainings have been built however the evaluations of the theoretical knowledge and the impact of the simulation-based training have never been performed in real life. The objective was to evaluate the impact of a LP training on the theoretical knowledge improvement and the performance of a LP in clinical practice. METHODS: Before and after medical students' training, theoretical knowledge and confidence level were assessed. Over a 6 months period, the impact of simulation training was evaluated by the success rate of students' first LP carried out in hospitalized patients and compared to the results of a no-training control. RESULTS: Students' theoretical knowledge and confidence level showed significant improvement after simulation training on 115 students (p < 0.0001). The evaluation in real life based on 41 students showed that the success rate of the first LP in patients was higher in the LP simulation group compared to the control group (67% vs 14%, p = 0.0025). The technical assistance was also less frequently needed in the LP simulation group (19% vs 57%, respectively, p = 0.017). The rate of students who participated in this educational study was low. DISCUSSION: Simulation-based teaching was an effective way to improve students' theoretical and practical knowledge. Whether this approach translates to other procedural skills in real clinical settings merits further study. The low participation rate in the study is due to the fact that students are not used to be included in educational studies and to the complexity of evaluation in routine clinical practice.

The feasibility, safety and optimization of multiple prolonged breath-holds for radiotherapy.

BACKGROUND & PURPOSE: Multiple, short breath-holds are now used in single radiotherapy treatment sessions. Here we investigated the feasibility and safety of multiple prolonged breath-holds in a single session. We measured how long is a second breath-hold if we prematurely terminate a single, prolonged breath-hold of >5 min either by using a single breath of oxygen (O2), or by reintroducing preoxygenation and hypocapnia. We also investigated the feasibility and safety of undertaking 9 prolonged breath-holds in a row. MATERIALS & METHODS: 30 healthy volunteers with no previous breath-holding experience were trained to perform single prolonged breath-holds safely. RESULTS: Their mean single, prolonged breath-hold duration was 6.1 ±â€¯0.3 se minutes (n = 30). In 18/18 subjects, premature termination (at 5.1 ±â€¯0.2 min) with a single breath of 60% O2, enabled a 2nd safe breath-hold lasting 3.3 ±â€¯0.2 min. In 18/18 subjects, premature termination at 5.3 ±â€¯0.2 min) by reintroducing preoxygenation and hypocapnia, enabled a 2nd safe breath-hold lasting 5.8 ±â€¯0.3 min. 17/17 subjects could safely perform 9 successive prolonged breath-holds, each terminated (at 4.3 ±â€¯0.2 min) by reintroducing preoxygenation and hypocapnia for 3.1 ±â€¯0.2 min. The 9th unconstrained breath-hold (mean of 6.0 ±â€¯0.3 min) lasted as long as their single breath-hold. CONCLUSIONS: Multiple prolonged breath-holds are possible and safe. In a ∼19 min treatment session, it would therefore be possible to have ∼13 min for radiotherapy treatment (3 breath-holds) and ∼6 min for setup and recovery. In a 65 min session, it would be possible to have 41 min for radiotherapy and 25 min for setup and recovery.

Hypocapnia Alone Fails to Provoke Important Electrocardiogram Changes in Coronary Artery Diseased Patients.

BACKGROUND: There is still an urgent clinical need to develop non-invasive diagnostic tests for early ischemic heart disease because, once angina occurs, it is too late. Hypocapnia has long been known to cause coronary artery vasoconstriction. Some new cardiology tests are accompanied by the claim that they must have potential diagnostic value if hypocapnia enhances their cardiac effects in healthy subjects. But no previous study has tested whether hypocapnia produces bigger cardiac effects in patients with angina than in healthy subjects. METHODS: Severe hypocapnia (a PetCO2 level of 20 mmHg) lasting >15 min was mechanically induced by facemask, while conscious and unmedicated, in 18 healthy subjects and in 10 patients with angina and angiographically confirmed coronary artery disease, awaiting by-pass surgery. Each participant was their own control in normocapnia (where CO2 was added to the inspirate) and the order of normocapnia and hypocapnia was randomized. Twelve lead electrocardiograms (ECG) were recorded and automated measurements were made on all ECG waveforms averaged over >120 beats. 2D echocardiography was also performed on healthy subjects. RESULTS: In the 18 healthy subjects, we confirm that severe hypocapnia (a mean PetCO2 of 20 ± 0 mmHg, P < 0.0001) consistently increased the mean T wave amplitude in leads V1-V3, but by only 31% (P < 0.01), 15% (P < 0.001) and 11% (P < 0.05), respectively. Hypocapnia produced no other significant effects (p > 0.05) on their electro- or echocardiogram. All 10 angina patients tolerated the mechanical hyperventilation well, with minimal discomfort. Hypocpania caused a similar increase in V1 (by 39%, P < 0.05 vs. baseline, but P > 0.05 vs. healthy controls) and did not induce angina. Its effects were no greater in patients who did not take ß-blockers, or did not take organic nitrates, or had the worst Canadian Cardiovascular Society scores. CONCLUSION: Non-invasive mechanical hyperventilation while awake and unmedicated is safe and acceptable, even to patients with angina. Using it to produce severe and prolonged hypocapnia alone does produce significant ECG changes in angina patients. But its potential diagnostic value for identifying patients with coronary stenosis requires further evaluation.

Role of Payers in the Development of Cardiovascular Therapeutics: Misalignment Between Approval and Reimbursement.

Regulators and payers have contrasting priorities that can lead to divergent decisions and delays in patient access to new treatments. Those involved in coverage decisions have not routinely been integrated in the drug development process. Theoretically, inclusion of payer representatives early in development could help discern discordance among stakeholder priorities; facilitate cooperation to align objectives; foster agreement on the evidence required for approval and reimbursement; improve transparency, accountability, and consistency of payer decision making; and ideally, minimize delays in patient access to new therapies. However, early participation by payers may not provide these expected benefits if payers' decision-making processes are not evidence based or cannot be reliably predicted. This paper describes current interactions among regulatory agencies, payers, sponsors, and investigators and proposes collaboration among all stakeholders earlier in the development process. The premise that a priori discussions might facilitate the delivery of advances in cardiovascular care is a hypothesis worth testing.

Safely prolonging single breath-holds to >5 min in patients with cancer; feasibility and applications for radiotherapy.

OBJECTIVE: Multiple, short and deep inspiratory breath-holds with air of approximately 20 s are now used in radiotherapy to reduce the influence of ventilatory motion and damage to healthy tissue. There may be further clinical advantages in delivering each treatment session in only one single, prolonged breath-hold. We have previously developed techniques enabling healthy subjects to breath-hold for 7 min. Here, we demonstrate their successful application in patients with cancer. METHODS: 15 patients aged 37-74 years undergoing radiotherapy for breast cancer were trained to breath-hold safely with pre-oxygenation and mechanically induced hypocapnia under simulated radiotherapy treatment conditions. RESULTS: The mean breath-hold duration was 5.3 ± 0.2 min. At breakpoint, all patients were normocapnic and normoxic [mean end-tidal partial pressure of carbon dioxide was 36 ± 1 standard error millimetre of mercury, (mmHg) and mean oxygen saturation was 100 ± 0 standard error %]. None were distressed, nor had gasping, dizziness or disturbed breathing in the post-breath-hold period. Mean blood pressure had risen significantly from 125 ± 3 to 166 ± 4 mmHg at breakpoint (without heart rate falling), but normalized within approximately 20 s of the breakpoint. During breath-holding, the mean linear anteroposterior displacement slope of the L breast marker was <2 mm min(-1). CONCLUSION: Patients with cancer can be trained to breath-hold safely and under simulated radiotherapy treatment conditions for longer than the typical beam-on time of a single fraction. We discuss the important applications of this technique for radiotherapy. ADVANCES IN KNOWLEDGE: We demonstrate for the first time a technique enabling patients with cancer to deliver safely a single prolonged breath-hold of >5 min (10 times longer than currently used in radiotherapy practice), under simulated radiotherapy treatment conditions.

Reducing the within-patient variability of breathing for radiotherapy delivery in conscious, unsedated cancer patients using a mechanical ventilator.

OBJECTIVE: Variability in the breathing pattern of patients with cancer during radiotherapy requires mitigation, including enlargement of the planned treatment field, treatment gating and breathing guidance interventions. Here, we provide the first demonstration of how easy it is to mechanically ventilate patients with breast cancer while fully conscious and without sedation, and we quantify the resulting reduction in the variability of breathing. METHODS: 15 patients were trained for mechanical ventilation. Breathing was measured and the left breast anteroposterior displacement was measured using an Osiris surface-image mapping system (Qados Ltd, Sandhurst, UK). RESULTS: Mechanical ventilation significantly reduced the within-breath variability of breathing frequency by 85% (p < 0.0001) and that of inflation volume by 29% (p < 0.006) when compared with their spontaneous breathing pattern. During mechanical ventilation, the mean amplitude of the left breast marker displacement was 5 ± 1 mm, the mean variability in its peak inflation position was 0.5 ± 0.1 mm and that in its trough inflation position was 0.4 ± 0.0 mm. Their mean drifts were not significantly different from 0 mm min(-1) (peak drift was -0.1 ± 0.2 mm min(-1) and trough drift was -0.3 ± 0.2 mm min(-1)). Patients had a normal resting mean systolic blood pressure (131 ± 5 mmHg) and mean heart rate [75 ± 2 beats per minute (bpm)] before mechanical ventilation. During mechanical ventilation, the mean blood pressure did not change significantly, mean heart rate fell by 2 bpm (p < 0.05) with pre-oxygenation and rose by only 4 bpm (p < 0.05) during pre-oxygenation with hypocapnia. No patients reported discomfort and all 15 patients were always willing to return to the laboratory on multiple occasions to continue the study. CONCLUSION: This simple technique for regularizing breathing may have important applications in radiotherapy. ADVANCES IN KNOWLEDGE: Variations in the breathing pattern introduce major problems in imaging and radiotherapy planning and delivery and are currently addressed to only a limited extent by asking patients to breathe to auditory or visual guidelines. We provide the first demonstration that a completely different technique, of using a mechanical ventilator to take over the patients' breathing for them, is easy for patients who are conscious and unsedated and reduces the within-patient variability of breathing. This technique has potential advantages in radiotherapy over currently used breathing guidance interventions because it does not require any active participation from or feedback to the patient and is therefore worthy of further clinical evaluation.

Inter-laboratory validation of bioaccessibility testing for metals.

Bioelution assays are fast, simple alternatives to in vivo testing. In this study, the intra- and inter-laboratory variability in bioaccessibility data generated by bioelution tests were evaluated in synthetic fluids relevant to oral, inhalation, and dermal exposure. Using one defined protocol, five laboratories measured metal release from cobalt oxide, cobalt powder, copper concentrate, Inconel alloy, leaded brass alloy, and nickel sulfate hexahydrate. Standard deviations of repeatability (sr) and reproducibility (sR) were used to evaluate the intra- and inter-laboratory variability, respectively. Examination of the sR:sr ratios demonstrated that, while gastric and lysosomal fluids had reasonably good reproducibility, other fluids did not show as good concordance between laboratories. Relative standard deviation (RSD) analysis showed more favorable reproducibility outcomes for some data sets; overall results varied more between- than within-laboratories. RSD analysis of sr showed good within-laboratory variability for all conditions except some metals in interstitial fluid. In general, these findings indicate that absolute bioaccessibility results in some biological fluids may vary between different laboratories. However, for most applications, measures of relative bioaccessibility are needed, diminishing the requirement for high inter-laboratory reproducibility in absolute metal releases. The inter-laboratory exercise suggests that the degrees of freedom within the protocol need to be addressed.

Assessment of the performance of the Marsh model in effect site mode for target controlled infusion of propofol during the maintenance phase of general anaesthesia in an unselected population of neurosurgical patients.

BACKGROUND: Propofol target-controlled infusion (TCI) in effect site mode has become popular since it became commercially available. OBJECTIVE: We have performed a study to assess the pharmacokinetic performance of the Marsh model in effect site mode in an unselected group of patients during neurosurgery during the maintenance phase of anaesthesia. DESIGN: Fifty American Society of Anesthesiologists (ASA) physical status classes 1 to 3 adults underwent elective neurosurgery receiving propofol TCI using the Marsh model in effect site mode. Propofol dose titration and level of patient monitoring was determined by the attending anaesthesiologist. Arterial blood was sampled at regular intervals during the maintenance phase of anaesthesia and measured plasma propofol concentrations were compared with those estimated using TCI. SETTING: Large tertiary referral centre in Birmingham, UK, with a specialist neuroanaesthesia service. PATIENTS: Fifty ASA status I to III adult patients undergoing elective neurosurgery. MAIN OUTCOME MEASURES: Performance of Marsh model as assessed by median performance error (bias) and median absolute performance error (imprecision). RESULTS: Performance of the Marsh model showed a positive bias (median performance error) of 27.6%, and imprecision (median absolute performance error) of 29.4%. Analysis of pooled data demonstrated greatest bias in the early phase (15 to 30 min) of anaesthesia (mean prediction error of 51.6%). Analysis of covariates demonstrated that obesity (BMI >30 kg m(-2)) contributed around half of the bias detected (mean prediction error 47 vs. 23%, P < 0.001). Patients with advanced age and significant comorbidity (ASA physical status class >2) actually demonstrated significantly lower prediction errors. CONCLUSION: Pharmacokinetic analysis suggests that the performance of the Marsh model in effect site mode is poor in this broad patient population. The greatest bias demonstrated occurred in the early maintenance phase of anaesthesia. Of the covariates analysed, obesity contributed most significantly to an increased bias. Despite overall poor performance of the Marsh model, attending anaesthesiologists modified targeted propofol concentrations only 0.3 times per hour on average, using remifentanil dose modification nine times more frequently, with good surgical conditions in all patients.