Specific Endpoints Research Articles

The Application of Toxicogenomics for (Drinking) Water Quality Assessment

Due to anthropogenic activities, freshwater systems worldwide are exposed to thousands of compounds. Monitoring of priority pollutants is important, however, monitoring of all individual compounds would be practically impossible. Moreover, the effects on human health remains mostly unknown since compound toxicity data is often absent. With the release of increasing amounts of new (emerging) chemicals into the environment, new monitoring strategies are required to assess the effects of (drinking water relevant) chemicals on human health. Therefore, sensitive in-vitro bioassays have been developed which focus on specific physiological effects such as endocrine disruption or mutagenicity. The advantages of bioassays are that they directly determine the effect of (an entire mixture of) compounds present in an environmental sample instead of identifying single compounds. These bioassays are able to detect known and unknown compounds as long as they trigger the bioassay response. However, a disadvantage of applying these assays may be that they each focus on a (relatively narrow selection of) specific physiological endpoint and that the human relevance is often obscure. The evolution of new technologies and the recent advances in the knowledge on DNA sequences and organisation (i.e. genomics) have enabled the development of new holistic tools, such as DNA microarrays. This report provides an overview of innovative omic methods and the mechanisms behind certain genomics technologies are explained. The main focus is on the potential application of DNA microarrays that are able to measure the impact of toxic substances on gene expression, i.e. transcription of DNA to mRNA (transcriptomics). Practical information on this method, such as sensitivity, analysis time, responsiveness, specificity, etc. is discussed. An overview is presented of the potential applications of this technology with regard to water quality assessment. In addition, the limitations and challenges that need to be overcome are discussed. The following potential applications for genomics in water quality assessment are foreseen: This title belongs to KWR Watercycle Research Institute Series . ISBN: 9781780406671 (eBook)

Benefit in regionalization of care for patients treated with nephrectomy: a Nationwide Inpatient Sample

To provide in absolute terms a quantification of regionalization of care from low- to high-volume hospitals in patients treated with nephrectomy for non-metastatic renal cell carcinoma. Relying on the Nationwide Inpatient Sample, 48,172 patients with non-metastatic renal cell carcinoma undergoing nephrectomy were identified. All analyses focused on five specific endpoints: intraoperative complications, postoperative complications, blood transfusions, prolonged hospitalization, and in-hospital mortality. First, multivariable logistic regression models for prediction of the aforementioned endpoints were fitted among high-volume hospitals treated patients. Second, obtained coefficients from such models were applied onto low-volume hospitals treated individuals. Potentially avoidable events were computed through differences between observed and predicted adverse events. The number needed to treat was generated. Low-volume hospitals treated individuals were between 11 and 28 % more likely to succumb to an adverse outcome (all P < 0.001). Differences between observed and predicted adverse outcome rates were all in favor of high-volume hospitals, except for in-hospital mortality. Potentially avoidable intraoperative complications, postoperative complications, blood transfusions, prolonged hospitalization, and in-hospital mortality rates were 1.4, 5.6, 7.6, 24.0, and 0.7 %, respectively. Thus, for every 71, 18, 13, 4, and 143 nephrectomies that are redirected to high-volume hospitals, 1 intraoperative complication, postoperative complication, blood transfusion, prolonged hospitalization, and in-hospital mortality could be potentially avoided. Regionalization from low- to high-volume hospitals for patients undergoing a nephrectomy is associated with important benefits, for both the payer and patient's perspectives.

Abstract 216: Risk of Thrombosis Remains Elevated for 12 Weeks After Labor and Delivery

Background: The risk of arterial and venous thrombosis remains elevated during the conventionally defined 6-week postpartum period, but it is unknown whether heightened risk persists beyond this point. Given the magnitude of postpartum thrombotic risk, we hypothesized that it remains elevated beyond 6 weeks after labor and delivery. Methods: Using administrative claims data from all nonfederal acute care EDs and hospitals in California, we compared the risk of thrombotic events during sequential 6-week periods after delivery. We used validated ICD-9-CM codes to identify women hospitalized for ischemic stroke, acute MI, PE, or DVT; in a sensitivity analysis we included a broader list of thrombosis codes, including cerebral sinus thrombosis. We compared each patient’s likelihood of labor and delivery in the 0-to-6 week period before a thrombotic event (case period) versus a 6-week period exactly 1 year prior (control period). We repeated this case-crossover analysis for the 6-to-12 week, 12-to-18 week, and 18-to-24 week periods before the thrombotic event. Odds ratios for each time period were calculated with conditional logistic regression because each patient was matched to her own control period. Results: Of 648,148 women with a first documented thrombotic event between 2007 and 2011, 1,620 had delivered during the prior 24 weeks. Their mean age was 30 (±7) years; 16% were black and 35% Hispanic. The risk of thrombosis was markedly higher in the 0-to-6 week period after delivery (OR, 6.6; 95% CI, 5.1-8.4) versus 1 year prior. Notably, thrombotic risk remained elevated during the 6-to-12 week period after delivery (OR, 2.3; 95% CI, 1.8-3.1). The risk then essentially normalized in the 12-to-18 week period (OR, 1.2; 95% CI, 0.9-1.6) and fully resolved in the 18-to-24 week period (OR, 0.9; 95% CI, 0.7-1.2). This pattern was similar in our sensitivity analysis and when we assessed the specific endpoints of stroke, acute MI, and PE or DVT. Conclusions: The risk of thrombosis remains elevated beyond the traditional 6-week postpartum period, and persists for at least 12 weeks after delivery. This should be considered when evaluating postpartum women with symptoms of possible thrombosis, or making recommendations about postpartum thrombosis prophylaxis or treatment.

Neuropsychiatric Adverse Events Associated with Statins: Epidemiology, Pathophysiology, Prevention and Management

Statins, or 3-hydroxy-3-methyl-glutaryl coenzymeA reductase inhibitors, such as lovastatin, atorvastatin, simvastatin, pravastatin, fluvastatin, rosuvastatin and pitavastatin, are cholesterol-lowering drugs used in clinical practice to prevent coronary heart disease. These drugs are generally well tolerated and have been rarely associated with severe adverse effects (e.g. rhabdomyolysis). Over the years, case series and data from national registries of spontaneous adverse drug reaction reports have demonstrated the occurrence of neuropsychiatric reactions associated with statin treatment. They include behavioural alterations (severe irritability, homicidal impulses, threats to others, road rage, depression and violence, paranoia, alienation, antisocial behaviour); cognitive and memory impairments; sleep disturbance (frequent awakenings, shorter sleep duration, early morning awakenings, nightmares, sleepwalking, night terrors); and sexual dysfunction (impotence and decreased libido). Studies designed to investigate specific neuropsychiatric endpoints have yielded conflicting results. Several mechanisms, mainly related to inhibition of cholesterol biosynthesis, have been proposed to explain the detrimental effects of statins on the central nervous system. Approaches to prevent and manage such adverse effects may include drug discontinuation and introduction of dietary restrictions; maintenance of statin treatment for some weeks with close patient monitoring; switching to a different statin; dose reduction; use of ω-3fatty acids or coenzymeQ10 supplements; and treatment with psychotropic drugs. The available information suggests that neuropsychiatric effects associated with statins are rare events that likely occur in sensitive patients. Additional data are required, and further clinical studies are needed.

Dexmedetomidine vs propofol in intensive care unit patients

Dexmedetomidine is indicated as a sedative agent in intensive care units (ICUs). While several clinical trials and two meta-analyses have compared this agent with propofol or midazolam, the results were variable depending on the specific end-point (e.g., duration of mechanical ventilation, ICU mortality, maintaining a target depth of sedation, incidence of delirium episodes, length of hospital stay). Hence, the effectiveness of this new agent vs the comparators seems to be controversial. Trial sequential analysis (TSA) is a statistical technique that can estimate the optimal, cumulative number of patients that would be needed to generate a conclusive result. We therefore applied a TSA model to the most recent meta-analysis evaluating dexmedetomidine. A total of 10 randomized controlled trials were included in our analysis. According to our results, the comparison of dexmedetomidine vs propofol showed no proof of incremental effectiveness for the end-points of length of ICUs stay and incidence of delirium episodes. In contrast, futility (i.e., proof of no incremental effectiveness) was demonstrated for the end-point of mechanical ventilation. Hence, the results for the comparison of dexmedetomidine vs propofol were inconclusive for the first two end-points; on the other hand, conclusiveness was reached for the third end-point advantage. We conclude that the place of dexmedetomidine in therapy in critically ill patients is still very uncertain and further controlled trials are still needed.

Can early therapy reduce inflammation?

Serious non-AIDS events or noninfectious complications of HIV infection far outnumber AIDS events in the current combination antiretroviral therapy (ART) era and are attributed to chronic inflammation. Thus, a better understanding of why inflammation persists on ART will assist in developing better therapeutic strategies, including optimal timing of ART initiation. Markers of inflammation and coagulation, such as D-dimer, interleukin-6, C-reactive protein, soluble CD14, and soluble CD163, predict end-organ disease and mortality, whereas markers of T-cell activation appear more predictive of CD4 T-cell decline, AIDS events, or response to therapy. Initiating ART at high CD4 T-cell counts can result in less inflammation as supported by studies in acute and early HIV infection, but antiretroviral drugs may differentially affect inflammatory pathways. Decreasing inflammation in HIV-uninfected individuals may decrease morbidity, but long-term outcomes studies in HIV-infected individuals are lacking. Circulating biomarkers of inflammation are among the strongest predictors of non-AIDS outcomes in treated HIV infection. With additional investigation, they may serve in the future as specific end-organ disease surrogate endpoints and may help identify those patients at highest risk of non-AIDS events who may benefit from either early ART and/or potential adjuvant anti-inflammatory therapies.

Competency-based Education in Anesthesiology

Abstract The Accreditation Council for Graduate Medical Education is transitioning to a competency-based system with milestones to measure progress and define success of residents. The confines of the time-based residency will be relaxed. Curriculum must be redesigned and assessments will need to be precise and in-depth. Core anesthesiology faculty will be identified and will be the “trained observers” of the residents’ progress. There will be logistic challenges requiring creative management by program directors. There may be residents who achieve “expert” status earlier than the required 36 months of clinical anesthesia education, whereas others may struggle to achieve acceptable status and will require additional education time. Faculty must accept both extremes without judgment. Innovative new educational opportunities will need to be created for fast learners. Finally, it will be important that residents embrace this change. This will require programs to clearly define the specific aims and measurement endpoints for advancement and success.

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<i>Circulation</i> Editors’ Picks

Ketamine NMDA receptor-independent toxicity during zebrafish (Danio rerio) embryonic development

Concerns have been raised that the effect of anaesthetic drugs on the central nervous system may result in long-term impairment, namely when ketamine is used during embryogenesis. In addition, the cell and molecular basis of anaesthetics teratology and toxicity are still uncertain and its implications in the development remain to be clarified. More recently, the potential risks for human, and animal, exposure through environmental contamination also became an important question. In this study, the effects of sub- and over anaesthetic doses of ketamine were investigated during zebrafish (Danio rerio) embryonic development by exposing zebrafish embryos to ketamine concentrations (0.2, 0.4 and 0.8mgmL−1) for a period of 20min during the blastula stage. Ethanol 2% was used as a positive control. Morphological parameters, the overall pattern of cell death using acridine orange and overall degree of oxidative stress levels by 2,7-dichlorodihydrofluorescein-diacetate were determined. Lethality and/or developmental anomalies were measured based on specific time endpoints until 144h post fertilisation. Results showed a concentration-dependent increase in anomalies and mortality. Cephalic disorders, enlarged organs and tail/spine anomalies were the most prominent deformities observed at 144hpf. Acridine orange images revealed no differences in cellular death pattern in exposed embryos at 24hpf. At the same time point, the cellular redox processes were found to be similar among groups. In summary, this study shows that ketamine is teratogen and toxic, interfering with the normal developmental pathways of embryogenesis, suggesting that ketamine exerts an independent NMDA receptor action during the zebrafish blastula stage.

Deep phenotyping of the unselected COPSAC2010 birth cohort study

We hypothesize that perinatal exposures, in particular the human microbiome and maternal nutrition during pregnancy, interact with the genetic predisposition to cause an abnormal immune modulation in early life towards a trajectory to chronic inflammatory diseases such as asthma and others. The aim of this study is to explore these interactions by conducting a longitudinal study in an unselected cohort of pregnant women and their offspring with emphasis on deep clinical phenotyping, exposure assessment, and biobanking. Exposure assessments focus on the human microbiome. Nutritional intervention during pregnancy in randomized controlled trials are included in the study to prevent disease and to be able to establish causal relationships. Pregnant women from eastern Denmark were invited during 2008-2010 to a novel unselected 'COPSAC2010 ' cohort. The women visited the clinic during pregnancy weeks 24 and 36. Their children were followed at the clinic with deep phenotyping and collection of biological samples at nine regular visits until the age of 3 and at acute symptoms. Randomized controlled trials of high-dose vitamin D and fish oil supplements were conducted during pregnancy, and a trial of azithromycin for acute lung symptoms was conducted in the children with recurrent wheeze. Seven hundred and thirty-eight mothers were recruited from week 24 of gestation, and 700 of their children were included in the birth cohort. The cohort has an over-representation of atopic parents. The participant satisfaction was high and the adherence equally high with 685 children (98%) attending the 1 year clinic visit and 667 children (95%) attending the 2 year clinic visit. The COPSAC2010 birth cohort study provides longitudinal clinical follow-up with highly specific end-points, exposure assessments, and biobanking. The cohort has a high adherence rate promising strong data to elucidate the interaction between genomics and the exposome in perinatal life leading to lifestyle-related chronic inflammatory disorders such as asthma.

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Effects of a chronic lower range of triclosan exposure on a stream mesocosm community

Triclosan (5-chloro-2-(2,4-dichlorophenoxy)phenol) is an antimicrobial found in consumer soaps and toothpaste. It is in treated wastewater effluents at low parts-per-billion concentrations, representing a potentially chronic exposure condition for biota inhabiting receiving streams. For the present study, a naturally colonized benthos was created using flow-through indoor mesocosms; then, the benthic communities were dosed to achieve different in-stream triclosan concentrations (control, 0.1 μg/L, 0.5 μg/L, 1.0 μg/L, 5.0 μg/L, and 10 μg/L) for 56 d. Water quality parameters and endpoints from bacteria to macroinvertebrates, as well as interacting abiotic components, were measured. Effects of triclosan on specific microbial endpoints were observed at all doses, including an effect on litter decomposition dynamics at doses of 1.0 μg/L and higher. Resistance of periphytic bacteria to triclosan significantly increased at doses of 0.5 μg/L and above. By the end of dosing, the antimicrobial appeared to stimulate the stream periphyton at the 3 lowest doses, while the 2 highest doses exhibited decreased stocks of periphyton, including significantly lower bacteria cell densities and cyanobacteria abundance compared with the control. Other than an effect on benthic ostracods, the changes that occurred in the periphyton did not translate to significant change in the colonizing nematodes, the macroinvertebrate community as a whole, or other measurements of stream function. The results shed light on the role a low, chronic exposure to triclosan may play in effluent-dominated streams.

Effectiveness of seasonal influenza vaccine in preventing medically attended influenza infection in England and Wales during the 2010/2011 season: a primary care-based cohort study

Estimates of seasonal influenza vaccine effectiveness (VE) are affected by factors such as the strain of the current circulating influenza virus and characteristics of the host. The objective of this study was to provide VE estimates for the 2010/2011 seasonal trivalent influenza vaccine (TIV) in preventing medically attended influenza in England and Wales for the season 2010/2011. A cohort study design was employed using electronic health records extracted from 104 GP practices in the Royal College of General Practitioners (RCGP) primary care sentinel network. Endpoints included influenza-like illness (ILI), lower respiratory tract infection (LTRI) as well as PCR-confirmed influenza from patients swabbed from practices participating in a swabbing scheme. Adjustment was made for age, month, underlying chronic condition, region and number of consultations in the 12months prior to the study period. In addition to the cohort analysis, a nested test-negative case-control analysis (TNCC) was carried out using the swab-negative results as controls. In the cohort analysis, VE against LRTI was -0·5% [95% CI: (-7·0%, 7·5%)], against ILI was 37·8% [95% CI: (32·3%, 43·0%)] and against PCR-confirmed influenza was 50·0% [95% CI:(25·9%, 65·6%)] for type A and 44·4% [95% CI: (10·1%, 65·6%)] for type B. Using the TNCC design, the type A VE was 56·5% [95% CI: (30·4%, 72·7%)] and for type B was 54·0% [95% CI: (21·0%, 73·3%)]. This study shows that the 2010/2011 TIV provided moderate protection against the circulating influenza strains for the 2010/2011 season. It also suggests that VE against the less specific diagnosis of ILI can be found, but less specific endpoints such as LRTI are not useful.

Overweight and Severe Acute Maternal Morbidity in a Low-Risk Pregnant Population in The Netherlands

ObjectiveTo investigate the association between overweight and severe acute maternal morbidity (SAMM) in a low-risk pregnant population.DesignNationwide case-control study.SettingThe Netherlands, august 2004 to august 2006.Population1567 cases from initially primary care and 2994 women from primary care practices as controls, out of 371 012 women delivering in the Netherlands during the study periodMethodsCases were women with SAMM obtained from a nationwide prospective study. All women in this cohort who initially had low-risk pregnancies were compared with low-risk women without SAMM to calculate odd ratios (ORs) to develop SAMM by body mass index (BMI) category. We divided body mass index in three overweight categories and calculated the ORs (95% CI) of total SAMM and per specific endpoint by logistic regression, with normal weight as reference. We adjusted for age, parity and socio-economic status.Main Outcome MeasuresSAMM, defined as Intensive Care Unit (ICU)-admission, Uterine Rupture, Eclampsia or Major Obstetric Haemorrhage (MOH)ResultsSAMM was reported in 1567 cases which started as low-risk pregnancies. BMI was available in 1097 (70.0%) cases and 2994 control subjects were included. Analysis showed a dose response relation for overweight (aOR, 1.3; 95% CI, 1.0-1.5), obese (aOR, 1.4; 95% CI, 1.1-1.9) and morbidly obese (aOR, 2.1; 95% CI, 1.3-3.2) women to develop SAMM compared to normal weight. Sub analysis showed the same dose response relation for ICU-admission, Uterine Rupture and Eclampsia. We found no association for MOH.ConclusionOverweight without pre-existent co-morbidity is an important risk-indicator for developing SAMM. This risk increases with an increasing body mass index.

End Points and Trial Design in Geriatric Oncology Research: A Joint European Organisation for Research and Treatment of Cancer–Alliance for Clinical Trials in Oncology–International Society of Geriatric Oncology Position Article

Selecting the most appropriate end points for clinical trials is important to assess the value of new treatment strategies. Well-established end points for clinical research exist in oncology but may not be as relevant to the older cancer population because of competing risks of death and potentially increased impact of therapy on global functioning and quality of life. This article discusses specific clinical end points and their advantages and disadvantages for older individuals. Randomized or single-arm phase II trials can provide insight into the range of efficacy and toxicity in older populations but ideally need to be confirmed in phase III trials, which are unfortunately often hindered by the severe heterogeneity of the older cancer population, difficulties with selection bias depending on inclusion criteria, physician perception, and barriers in willingness to participate. All clinical trials in oncology should be without an upper age limit to allow entry of eligible older adults. In settings where so-called standard therapy is not feasible, specific trials for older patients with cancer might be required, integrating meaningful measures of outcome. Not all questions can be answered in randomized clinical trials, and large observational cohort studies or registries within the community setting should be established (preferably in parallel to randomized trials) so that treatment patterns across different settings can be compared with impact on outcome. Obligatory integration of a comparable form of geriatric assessment is recommended in future studies, and regulatory organizations such as the European Medicines Agency and US Food and Drug Administration should require adequate collection of data on efficacy and toxicity of new drugs in fit and frail elderly subpopulations.

Onset and Progression of Peripapillary Retinal Nerve Fiber Layer (RNFL) Retardance Changes Occur Earlier Than RNFL Thickness Changes in Experimental Glaucoma

Longitudinal measurements of peripapillary RNFL thickness and retardance were compared in terms of time to reach onset of damage and time to reach a specific progression endpoint. A total of 41 rhesus macaques with unilateral experimental glaucoma (EG) each had three or more weekly baseline measurements in both eyes of peripapillary RNFL thickness (RNFLT) and retardance. Laser photocoagulation was then applied to the trabecular meshwork of one eye to induce chronic elevation of intraocular pressure and weekly imaging continued. Pairwise differences between baseline observations were sampled by bootstrapping to determine the 95% confidence limits of each measurement's repeatability. The first two sequential measurements below the lower confidence limit defined the endpoint for each parameter. Segmented linear and exponential decay functions were fit to each RNFL-versus-time series to determine the time to damage onset. In all, 29 (71%) of the EG eyes reached endpoint by RNFL retardance and 25 (61%) reached endpoint by RNFLT. In total, 33 (80%) reached endpoint by at least one of the RNFL parameters and 21 (51%) reached endpoint by both RNFL parameters. Of the 33 EG eyes reaching any endpoint, a larger proportion reached endpoint first by retardance (n = 26, 79%) than did by RNFLT (n = 7, 21%; P = 0.002). Survival analysis indicated a shorter time to reach endpoint by retardance than by RNFLT (P < 0.001). Of the 21 EG eyes that reached endpoint by both measures, the median duration to endpoint was 120 days for retardance and 223 days for RNFLT (P = 0.003, Wilcoxon test). The time to onset was faster for retardance than that for RNFLT based on either segmented fits (by 31 days; P = 0.008, average R(2) = 0.89) or exponential fits (by 102 days; P = 0.01, average R(2) = 0.89). The onset of progressive loss of RNFL retardance occurs earlier than the onset of RNFL thinning. Endpoints of progressive loss from baseline also occurred more frequently and earlier for RNFL retardance as compared with RNFLT.

Clinical impact of biologic therapy in the treatment of SLE

Biologic therapies have generated substantial research interest for treating autoimmune diseases, resulting in several US Food and Drug Administration approvals. However, clinical trial results in systemic lupus erythematosus (SLE) populations have failed to meet efficacy expectations, primarily owing to methodological flaws in design, especially outcome measures. To address these issues, the US Food and Drug Administration published a guidance document for clinical trial design in SLE that included specific efficacy endpoints for measuring disease severity. Belimumab was the first biologic approved for SLE based on positive responses measured with the SLE Responder Index, which required a decrease in inflammation, no new organ domains being involved, and improvement in physician global assessment. Trials of other biologics have used other versions of SLE Responder Index responder indices. In addition to belimumab, a score of other biologic agents are being investigated, primarily those targeting T cells, B cells, complement, and tolerogen-targeting agents. Their development stages and clinical trial results vary. Belimumab has generated the greatest amount of clinical trials, as investigators try to further define its role in clinical practice. Results have been shared in many forums, including annual meetings of the American College of Rheumatology and European League Against Rheumatism, along with publications in the medical literature. These findings indicate that belimumab is effective in patients with more active disease who are able to wait up to 3 months for improvement. Additionally, it can be considered for patients with active disease despite therapy with NSAIDs, antimalarials, immunosuppressives, or corticosteroids, especially if the benefits of treatment outweigh its risks or if the patient is intolerant to steroids or immunosuppressives. Additional file 1 contains an edited transcript of the full presentation.

The impact of the Harmonic FOCUS™ on complications in thyroid surgery: a prospective multicenter study

In recent years, newer tools have been developed and used in thyroid surgery. This study compared patients with multinodular goiter undergoing thyroidectomy using the Harmonic FOCUS™ with patients undergoing the clamp-and-tie technique. Medical records of 268 patients with multinodular goiter undergoing thyroidectomy from December 2006 to July 2011 in two centers in Italy, the Department of Surgery of Pisa and the General Surgery Unit of Grosseto, were prospectively evaluated. Patients were divided into group A (Harmonic FOCUS™ Shear), and group B (clamp-and-tie technique). Patient demographics and specific end points analyzed included age, sex, diagnosis, thyroid gland volume, operative time, complications, need for clips and hemostatic agents, need for suction balloon, postoperative blood loss, and postoperative hospital length of stay. 141 patients were included in group A, and 127 patients were included in group B. The two groups were similar in age, sex ratio, indication for surgery, and thyroid volume. Mean operative time was significantly shorter with the Harmonic FOCUS™ Shear (51.8 min) than with the clamp-and-tie technique (70.9 min). The mean postoperative amount obtained from the suction balloon was similar. Vascular clips were needed significantly more frequently in group A (26.2 %) than in group B (12.5 %), whereas the need for hemostatic agents was significantly reduced in group A (4.2 %) compared with group B (14.9 %). The decision to leave a suction drain at the end of the operation occurred significantly more frequently in group B (96 %) than in group A (78 %). Mean postoperative hospital length of stay was 2.02 days in group A compared with 3.1 days in group B, which was significant. No definitive postoperative complications were documented in either group, except a higher rate, but not statistically significant, of permanent hypoparathyroidism in group B versus Group A. Transient laryngeal nerve injury was similar in both groups, whereas transient hypoparathyroidism occurred more frequently in Group B (4.7 %) than in Group A (2.4 %). Harmonic FOCUS device was significantly associated with lower rate of postoperative transient hypocalcemia, decreased operative time, shorter hospitalization, and lesser need for hemostatic agents and postoperative drain balloon. These results might be considered "indirect" money-saving factors, despite the cost of the device, especially in countries where the cost of thyroidectomy is influenced also by the hospital length of stay.

Importance of Idiopathic Pulmonary Fibrosis Staging for Clinical Trial Endpoints

We welcome the Pulmonary Perspective on the evaluation of clinically meaningful primary endpoints for idiopathic pulmonary fibrosis (IPF) (1). However, the logic of this discussion is weakened by the failure to acknowledge that the disease progression is influenced by the burden of disease at presentation. The burden of disease is normally described by a staging system, which is currently absent for IPF. One specific endpoint will clearly be insufficient if applied to “all comers with IPF.” Therefore, the definition of endpoints is heavily dependent on the staging of the disease (2). Regrettably, we have not seen a formal staging system emerge from the American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association guideline publication (3). We have learned from randomized controlled studies that change in FVC is a very pragmatic endpoint to be applied in patients with “mild to moderate disease,” which equates with a limited burden of disease. In patients with limited disease, defined as a gas transfer of greater than 40% predicted (2), mortality as an endpoint has a very low frequency. In contrast, mortality as an endpoint is more common in patients with advanced disease, defined as a gas transfer less than 40%. Therefore the relative endpoints are dependent on the stage of the disease. This burden/stage of disease can be defined on the basis of simple lung function testing. We would encourage the debate to consider that the appropriate endpoints should be defined on the basis of the burden or stage of disease, and that the discussions highlight the need for a simple reproducible staging system for IPF in a manner comparable to the Global Initiative for Chronic Obstructive Lung Disease classification for chronic obstructive pulmonary disease.

Assessing Feasibility of Real-Time Ultrasound Monitoring in Stereotactic Body Radiotherapy of Liver Tumors

To monitor tumor motion during stereotactic body radiotherapy (SBRT) for patients with liver cancer, an integrated ultrasound and kilo-voltage cone-beam computed tomography (KV-CBCT) system has been proposed. The presence of an ultrasound probe may interfere with the radiation beams. The purpose of this study is to minimize this interference by altering orientations of the ultrasound probe and directions of radiation beams while not compromising the quality of SBRT plans. Ten patients, who received SBRT of liver cancer, were randomly selected for this study. To simulate the presence of an ultrasound probe, a virtual probe was oriented either parallel or vertical to the longitudinal axis of the patient's body and was added on the surface of the patient's body at the nearest location to the tumor. For both the parallel and vertical probe orientations, 2 new SBRT (Probe-Para and Probe-Vert) plans that minimize the interference between the probe and radiation beams were created for each patient. These SBRT plans were compared to the original clinically accepted SBRT plans, with a treatment goal of 37.5 Gy to the planning target volume (PTV) in 3 fractions. Specific dosimetric endpoints were evaluated, including doses to 95% (D95), of the PTV plan conformal index (CI), homogeneity index (HI), and relevant endpoint doses to organs at risk. For 2 patients with superficially located tumors, no clinically acceptable SBRT plans could be produced without the interference between the probe and radiation beams. For the remaining 8 patients, the Probe-Para plans allowed 7 patients to be treated with coplanar radiation beams (without moving the treatment couch during treatment) and 1 patient to be treated with non-coplanar beams (by moving the treatment couch during treatment). The Probe-Vert plans allowed 2 patients to be treated with coplanar beams and 6 patients to be treated with non-coplanar beams. The average D95 of the PTV were 38.63 Gy ± 0.14 (р = 0.65) for Probe-Para plans, 38.48 Gy ± 0.31 (р = 0.33) for Probe-Vert plans, and 38.72 Gy ± 0.14 for clinical SBRT plans. There were no significant differences (p > 0.05) in CI and HI of all SBRT plans. The endpoint doses to the liver, heart, esophagus, right kidney, and stomach also had no significant differences (p > 0.05). Except for superficial lesions, real-time ultrasound monitoring during liver SBRT is clinically feasible. Placing the ultrasound probe parallel to the longitudinal axis of the patient allows a greater probability of utilizing preferred coplanar beams.