Evaluation of hemostatic devices in a randomized porcine model of junctional hemorrhage and 72-hour prolonged field care.

BACKGROUND: Hemorrhage control in prolonged field care (PFC) presents unique challenges that drive the need for enhanced point of injury treatment capabilities to maintain patient stability beyond the Golden Hour. To address this, two hemostatic agents, Combat Gauze (CG) and XSTAT, were evaluated in a porcine model of uncontrolled junctional hemorrhage for speed of deployment and hemostatic efficacy over 72 hours. METHODS: The left subclavian artery and subscapular vein were isolated in anesthetized male Yorkshire swine (70-85 kg) and injured via 50% transection, followed by 30 seconds of hemorrhage. Combat Gauze (n = 6) or XSTAT (n = 6) was administered until bleeding stopped and remained within subjects for observation over 72 hours. Physiologic monitoring, hemostatic efficacy, and hematological parameters were measured throughout the protocol. Gross necropsy and histology were performed following humane euthanasia. RESULTS: Both CG and XSTAT maintained hemostasis throughout the full duration of the protocol. There were no significant differences between groups in hemorrhage volume (CG: 1021.0 ± 183.7 mL vs. XSTAT: 968.2 ± 243.3 mL), total blood loss (CG: 20.8 ± 2.7% vs. XSTAT: 20.1 ± 5.1%), or devices used (CG: 3.8 ± 1.2 vs. XSTAT: 5.3 ± 1.4). XSTAT absorbed significantly more blood than CG (CG: 199.5 ± 50.3 mL vs. XSTAT: 327.6 ± 71.4 mL) and was significantly faster to administer (CG: 3.4 ± 1.6 minutes vs. XSTAT: 1.4 ± 0.5 minutes). There were no significant changes in activated clot time, prothrombin time, or international normalized ratio between groups or compared with baseline throughout the 72-hour protocol. Histopathology revealed no evidence of microthromboemboli or disseminated coagulopathies across evaluated tissues in either group. CONCLUSION: Combat Gauze and XSTAT demonstrated equivalent hemostatic ability through 72 hours, with no overt evidence of coagulopathies from prolonged indwelling. In addition, XSTAT offered significantly faster administration and the ability to absorb more blood. Taken together, XSTAT offers logistical and efficiency advantages over CG for immediate control of junctional noncompressible hemorrhage, particularly in a tactical environment. In addition, extension of indicated timelines to 72 hours allows translation to PFC.

FOxTROT2: innovative trial design to evaluate the role of neoadjuvant chemotherapy for treating locally advanced colon cancer in older adults or those with frailty.

Treating older adults with cancer is increasingly important in modern oncology practice. However, we currently lack the high-quality evidence needed to guide optimal management of this heterogeneous group. Principally, historic under-recruitment of older adults to clinical trials limits our understanding of how existing evidence can be applied to this group. Such uncertainty is particularly prevalent in the management of colon cancer (CC). With CC being most common in older adults, many patients also suffer from frailty, which is recognised as being strongly associated with poor clinical outcomes. Conducting clinical trials in older adults presents several major challenges, many of which impact the clinical relevance of results to a real-world population. When considering this heterogeneous group, it may be difficult to define the target population, recruit participants effectively, choose an appropriate trial design, and ensure participants remain engaged with the trial during follow-up. Furthermore, after overcoming these challenges, clinical trials tend to enrol highly selected patient cohorts that comprise only the fittest older patients, which are not representative of the wider population. FOxTROT1 was the first phase III randomised controlled trial to illustrate the benefit of neoadjuvant chemotherapy (NAC) in the treatment of CC. Patients receiving NAC had greater 2-year disease-free survival compared to those proceeding straight to surgery. Outcomes for older adults in FOxTROT1 were similarly impressive when compared to their younger counterparts. Yet, this group inevitably represents a fitter subgroup of the older patient population. FOxTROT2 has been designed to investigate NAC in a full range of older adults with CC, including those with frailty. In this review, we describe the key challenges to conducting a robust clinical trial in this heterogeneous patient group, highlight our strategies for overcoming these challenges in FOxTROT2, and explain how we hope to provide clarity on the optimal treatment of CC in older adults.

Deep Learning for Radiotherapy Outcome Prediction Using Dose Data - A Review.

Artificial intelligence, and in particular deep learning using convolutional neural networks, has been used extensively for image classification and segmentation, including on medical images for diagnosis and prognosis prediction. Use in radiotherapy prognostic modelling is still limited, however, especially as applied to toxicity and tumour response prediction from radiation dose distributions. We review and summarise studies that applied deep learning to radiotherapy dose data, in particular studies that utilised full three-dimensional dose distributions. Ten papers have reported on deep learning models for outcome prediction utilising spatial dose information, whereas four studies used reduced dimensionality (dose volume histogram) information for prediction. Many of these studies suffer from the same issues that plagued early normal tissue complication probability modelling, including small, single-institutional patient cohorts, lack of external validation, poor data and model reporting, use of late toxicity data without taking time-to-event into account, and nearly exclusive focus on clinician-reported complications. They demonstrate, however, how radiation dose, imaging and clinical data may be technically integrated in convolutional neural networks-based models; and some studies explore how deep learning may help better understand spatial variation in radiosensitivity. In general, there are a number of issues specific to the intersection of radiotherapy outcome modelling and deep learning, for example translation of model developments into treatment plan optimisation, which will require further combined effort from the radiation oncology and artificial intelligence communities.

Intensity-modulated Radiotherapy for Rectal Cancer in the UK in 2020.

AIMS: Preoperative (chemo)radiotherapy followed by total mesorectal excision is the current standard of care for patients with locally advanced rectal cancer. The use of intensity-modulated radiotherapy (IMRT) for rectal cancer is increasing in the UK. However, the extent of IMRT implementation and current practice was not previously known. A national survey was commissioned to investigate the landscape of IMRT use for rectal cancer and to inform the development of national rectal cancer IMRT guidance. MATERIALS AND METHODS: A web-based survey was developed by the National Rectal Cancer IMRT Guidance working group in collaboration with the Royal College of Radiologists and disseminated to all UK radiotherapy centres. The survey enquired about the implementation of IMRT with a focus on the following aspects of the workflow: dose fractionation schedules and use of a boost; pre-treatment preparation and simulation; target volume/organ at risk definition; treatment planning and treatment verification. A descriptive statistical analysis was carried out. RESULTS: In total, 44 of 63 centres (70%) responded to the survey; 30/44 (68%) and 36/44 (82%) centres currently use IMRT to treat all patients and selected patients with rectal cancer, respectively. There was general agreement concerning several aspects of the IMRT workflow, including patient positioning, use of intravenous contrast and bladder protocols. Greater variation in practice was identified regarding rectal protocols; use of a boost to primary/nodal disease; target volume delineation; organ at risk delineation and dose constraints and treatment verification. Delineation of individual small bowel loops and daily volumetric treatment verification were considered potentially feasible by most centres. CONCLUSION: This survey identified that IMRT is already used to treat rectal cancer in many UK radiotherapy centres, but there is heterogeneity between centres in its implementation and practice. These results have been a valuable aid in framing the recommendations within the new National Rectal Cancer IMRT Guidance.

Subclinical Hyperthyroidism: Status of the Cholesterol Transfers to HDL and Other Parameters Related to Lipoprotein Metabolism in Patients Submitted to Thyroidectomy for Thyroid Cancer.

Purpose: Lipid metabolism has been poorly explored in subclinical hyperthyroidism. The aim was to examine the effects of exogenous subclinical hyperthyroidism in women under levothyroxine treatment upon plasma lipids and aspects of HDL metabolism. Methodology: Ten women were studied in euthyroidism and again in exogenous subclinical hyperthyroidism. Thyroid function tests and plasma lipids were studied. Results: HDL-cholesterol (increased 21.6%, p = 0.0004), unesterified cholesterol (increased 12.3%, p = 0.04) and Lp(a) (increased 33,3%, P = 0.02) plasma concentrations were higher in subclinical hyperthyroidism compared to euthyroidism, but total cholesterol, LDL, non-HDL cholesterol, triglycerides, apo A-I, apo B were unchanged. PON1 activity (decreased 75%, p = 0.0006) was lower in subclinical hyperthyroidism. There were no changes in HDL particle size, CETP and LCAT concentrations. The in vitro assay that estimates the lipid transfers to HDL showed that esterified cholesterol (increased 7.1%, p = 0.03), unesterified cholesterol (increased 7.8%, p = 0.02) and triglycerides (increased 6.8%, p = 0.006) transfers were higher in subclinical hyperthyroidism. There were no changes in phospholipid transfers to HDL in subclinical hyperthyroidism. Conclusions: Several alterations in the plasma lipid metabolism were observed in the subclinical hyperthyroidism state that highlight the importance of this aspect in the follow-up of those patients. The increase in HDL-C and in the transfer of unesterified and esterified cholesterol to HDL, an important anti-atherogenic HDL function are consistently protective for cardiovascular health. The increase in Lp(a) and the decrease in PON-1 activity that are important risk factors were documented here in subclinical hyperthyroidism and these results should be confirmed in larger studies due to great data variation but should not be neglected in the follow-up of those patients.

Oiling of American white pelicans, common loons, and northern gannets in the winter following the Deepwater Horizon (MC252) oil spill.

The Natural Resource Damage Assessment and Restoration Trustees for the Deepwater Horizon oil spill assessed the external oiling of migratory bird species dependent on open water in the Gulf of Mexico following the aforementioned spill. The assessment was designed to evaluate birds that use open water during the winter within 40 km of the Gulf shoreline. We focused on the American white pelican (Pelecanus erythrorhynchos), common loon (Gavia immer), and northern gannet (Morus bassanus). Point counts (pelican, loon) or strip transects (gannet) were used and each target species was assessed for oiling (unoiled, trace, light, moderate, or heavy amounts) and photographed. Due to distance at sighting and/or poor visibility, not all visible birds were assessed. The percentage of birds oiled varied by species, with the common loon being the highest (23.6%), followed by American white pelican (16.9%), and northern gannet (6.9%). Most of the American white pelicans and common loons had trace (83% and 72%, respectively) or light levels (11% and 24%, respectively) of oiling. The northern gannet had just trace levels of oiling. Some pelicans (6%) and loons (4%) had moderate amounts of oiling. Based on expert derived-mortality estimates and our estimates of oil exposure, we used Monte Carlo simulations to predict expected decreases of 2.5%, 4%, and 11% in the observed population for the northern gannet, American white pelican, and common loon, respectively. While these values are underestimates of the true values given the long time lag (10-12 months) between the oil spill and the assessment, these data represent some of the few estimates of exposure for these species and describe minimum risk estimates to these species.

UK national cohort of anal cancer treated with intensity-modulated radiotherapy: One-year oncological and patient-reported outcomes.

BACKGROUND: Concurrent chemoradiotherapy is the standard treatment for anal cancer. Following national UK implementation of intensity-modulated radiotherapy (IMRT), this prospective, national cohort evaluates the one-year oncological outcomes and patient-reported toxicity outcomes (PRO) after treatment. MATERIALS AND METHODS: A national cohort of UK cancer centers implementing IMRT was carried out between February to July 2015. Cancer centers provided data on oncological outcomes, including survival, and disease and colostomy status at one-year. EORTC-QLQ core (C30) and colorectal (CR29) questionnaires were completed at baseline and one-year followup. The PRO scores at baseline and one year were compared. RESULTS: 40 UK Cancer Centers returned data with a total of 187 patients included in the analysis. 92% received mitomycin with 5-fluorouracil or capecitabine. One-year overall survival was 94%; 84% were disease-free and 86% colostomy-free at one-year followup. At one year, PRO results found significant improvements in buttock pain, blood and mucus in stools, pain, constipation, appetite loss, and health anxiety compared to baseline. No significant deteriorations were reported in diarrhea, bowel frequency, and flatulence. Urinary symptom scores were low at one year. Moderate impotence symptoms at baseline remained at one year, and a moderate deterioration in dyspareunia reported. CONCLUSIONS: With national anal cancer IMRT implementation, at this early pre-defined time point, one-year oncological outcomes were reassuring and resulted in good disease-related symptom control. one-year symptomatic complications following CRT for anal cancer using IMRT techniques appear to be relatively mild. These PRO results provide a basis to benchmark future studies.

Time to Surgery Following Short-Course Radiotherapy in Rectal Cancer and its Impact on Postoperative Outcomes. A Population-Based Study Across the English National Health Service, 2009-2014.

AIMS: Preoperative short-course radiotherapy (SCRT) is an important treatment option for rectal cancer. The length of time between completing SCRT and surgery may influence postoperative outcomes, but the evidence available to determine the optimal interval is limited and often conflicting. MATERIALS AND METHODS: Information was extracted from a colorectal cancer data repository (CORECT-R) on all surgically treated rectal cancer patients who received SCRT in the English National Health Service between April 2009 and December 2014. The time from radiotherapy to surgery was described across the population. Thirty-day postoperative mortality, returns to theatre, length of stay and 1-year survival were investigated in relation to the interval between radiotherapy and surgery. RESULTS: Within the cohort of 3469 patients, the time to surgery was 0-7 days for 76% of patients, 8-14 days for 19% of patients and 15-27 days for 5% of patients. There was a clear variation in relation to different patient characteristics. There was, however, no evidence of differences in postoperative outcomes in relation to interval length. CONCLUSIONS: This study suggests that the time interval between SCRT and surgery does not influence postoperative outcomes up to a year after surgery. The study provides population-level, real-world evidence to complement that from clinical trials.

Prediction of outcome in anal squamous cell carcinoma using radiomic feature analysis of pre-treatment FDG PET-CT.

PURPOSE: Incidence of anal squamous cell carcinoma (ASCC) is increasing, with curative chemoradiotherapy (CRT) as the primary treatment of non-metastatic disease. A significant proportion of patients have locoregional treatment failure (LRF), but distant relapse is uncommon. Accurate prognostication of progression-free survival (PFS) would help personalisation of CRT regimens. The study aim was to evaluate novel imaging pre-treatment features, to prognosticate for PFS in ASCC. METHODS: Consecutive patients with ASCC treated with curative intent at a large tertiary referral centre who underwent pre-treatment FDG-PET/CT were included. Radiomic feature extraction was performed using LIFEx software on baseline FDG-PET/CT. Outcome data (PFS) was collated from electronic patient records. Elastic net regularisation and feature selection were used for logistic regression model generation on a randomly selected training cohort and applied to a validation cohort using TRIPOD guidelines. ROC-AUC analysis was used to compare performance of a regression model encompassing standard clinical prognostic factors (age, sex, tumour and nodal stage-model A), a radiomic feature model (model B) and a combined radiomic/clinical model (model C). RESULTS: A total of 189 patients were included in the study, with 145 in the training cohort and 44 in the validation cohort. Median follow-up was 35.1 and 37. 9 months, respectively for each cohort, with 70.3% and 68.2% reaching this time-point with PFS. GLCM entropy (a measure of randomness of distribution of co-occurring pixel grey-levels), NGLDM busyness (a measure of spatial frequency of changes in intensity between nearby voxels of different grey-level), minimum CT value (lowest HU within the lesion) and SMTV (a standardized version of MTV) were selected for inclusion in the prognostic model, alongside tumour and nodal stage. AUCs for performance of model A (clinical), B (radiomic) and C (radiomic/clinical) were 0.6355, 0.7403, 0.7412 in the training cohort and 0.6024, 0.6595, 0.7381 in the validation cohort. CONCLUSION: Radiomic features extracted from pre-treatment FDG-PET/CT in patients with ASCC may provide better PFS prognosis than conventional staging parameters. With external validation, this might be useful to help personalise CRT regimens in the future.

Effects of Short-Term Hypothyroidism on the Lipid Transfer to High-Density Lipoprotein and Other Parameters Related to Lipoprotein Metabolism in Patients Submitted to Thyroidectomy for Thyroid Cancer.

BACKGROUND: Elevation of low-density lipoprotein (LDL) cholesterol is the hallmark of the dyslipidemia observed in hypothyroidism, but alterations on high-density lipoprotein (HDL) plasma levels and metabolism are less understood. The aim of this study was to explore aspects of HDL metabolism and enzymes that act on HDL after a short period of overt hypothyroidism. METHODS: Eighteen women (age 44 ± 11 years; body mass index 27.9 ± 5.2 kg/m2) were studied before total thyroidectomy for thyroid cancer, when they were euthyroid, and after thyroidectomy, in overt hypothyroidism for three weeks, following levothyroxine withdrawal for performance of a whole-body scan. RESULTS: Thyrotropin and free thyroxine confirmed hypothyroidism; low thyroglobulin and radioiodine uptake indicated near absence of thyroid tissue. LDL cholesterol (125 ± 35 vs. 167 ± 40 mg/dL; p = 0.0002), HDL cholesterol (HDL-C; 39 ± 8 vs. 46 ± 10 mg/dL; p = 0.0025), non-HDL-C (149 ± 38 vs. 201 ± 46 mg/dL; p < 0.0001), unesterified cholesterol (53 ± 10 vs. 70 ± 16 mg/dL; p = 0.0003), apolipoprotein (apo) A-I (1.32 ± 0.19 vs. 1.44 ± 0.22 g/L; p < 0.04), and apo B (0.97 ± 0.25 vs. 1.31 ± 0.28 g/L; p < 0.0001) plasma concentrations were all higher in hypothyroidism compared to values in the euthyroid state, but triglycerides and Lp(a) were unchanged. There were no changes in HDL particle size and lipid composition, cholesteryl ester transfer protein and lecithin cholesterol acyltransferase concentrations and in paraoxonase-1 activity. Regarding the in vitro assay to estimate lipid transfer to HDL, there were no changes when comparing the euthyroid to the hypothyroid state, but when adjusted for HDL-C, the unesterified cholesterol (0.14 ± 0.03 vs. 0.11 ± 0.02; p < 0.0001), triglycerides (0.11 ± 0.02 vs. 0.09 ± 0.02; p < 0.0001), phospholipids (0.44 ± 0.09 vs. 0.40 ± 0.07; p = 0.0205), and esterified cholesterol (0.14 ± 0.03 vs. 0.13 ± 0.03; p = 0.0043) transfer to HDL were all diminished in hypothyroidism. CONCLUSIONS: In short-term hypothyroidism, HDL-C increased, but this did not increase the capacity of the HDL fraction to receive lipids or the activity of paraoxonase-1, the anti-oxidation enzyme associated to HDL.

Enhancement of coral calcification via the interplay of nickel and urease.

Corals are the main reef builders through the formation of calcium carbonate skeletons. In recent decades, coral calcification has however been impacted by many global (climate change) and local stressors (such as destructive fishing practices and changes in water quality). In this particular context, it is crucial to identify and characterize the various factors that promote coral calcification. We thus performed the first investigation of the effect of nickel and urea enrichment on the calcification rates of three coral species. These two factors may indeed interact with calcification through the activity of urease, which catalyzes the hydrolysis of urea to produce inorganic carbon and ammonia that are involved in the calcification process. Experiments were performed with the asymbiotic coral Dendrophyllia arbuscula and, to further assess if urea and/or nickel has an indirect link with calcification through photosynthesis, results were compared with those obtained with two symbiotic corals, Acropora muricata and Pocillopora damicornis, for which we also measured photosynthetic rates. Ambient and enriched nickel (0.12 and 3.50 µg L-1) combined with ambient and enriched urea concentrations (0.26 and 5.52 µmol L-1) were tested during 4 weeks in aquaria. We demonstrate in the study that a nickel enrichment alone or combined with a urea enrichment strongly stimulated urea uptake rates of the three tested species. In addition, this enhancement of urea uptake and hydrolysis significantly increased the long-term calcification rates (i.e. growth) of the three coral species investigated, inducing a 1.49-fold to 1.64-fold increase, respectively for D. arbuscula and P. damicornis. Since calcification was greatly enhanced by nickel in the asymbiotic coral species - i.e. in absence of photosynthesis - we concluded that the effect of increased urease activity on calcification was mainly direct. According to our results, it can be assumed that corals in some fringing reefs, benefiting from seawater enriched in nickel may have advantages and might be able to use urea more effectively as a carbon and nitrogen source. It can also be suggested that urea, for which hotspots are regularly measured in reef waters may alleviate the negative consequences of thermal stress on corals.

Intraperitoneal drains move.

INTRODUCTION: The use of surgical drains is the subject of much debate but they continue to be commonly used. The phenomenon of drain migration from their desired position following surgery has not been studied. The aim of this study was to evaluate the incidence of the displacement of surgical drains among patients undergoing abdominal gastrointestinal surgery. PATIENTS AND METHODS: We performed a review of all patients who underwent an early CT-scan postoperatively after abdominal gastrointestinal surgery prior to drain mobilization, between January 2013 and April 2016 in the Dijon University Hospital Center. Pre-and intra-operative data (number, type and position of drains) and postoperative data (imaging and evolution) were collected retrospectively. RESULTS: This study included 125 patients. Thirty-five (28%) were found to have a displacement of at least one drain from its original position. Forty-one (19.8%) of the 207 studied drains had moved. Postoperative morbidity was not higher in patients with displaced drains (P=0.51). None of all the studied preoperative and operative factors have been found to be a risk factor for drain displacement. CONCLUSION: Surgical drains displacement is frequently encountered in patients undergoing digestive abdominal surgery. In our experience, this phenomenon does not seem to have any clinical implications. When a benefit is expected from the use of surgical drains, intraperitoneal fixation appears to be necessary.

Humanitarianism in surgery.

PURPOSE: Humanitarianism is by definition a moral of kindness, benevolence and sympathy extended to all human beings. In our view as surgeons working in underserved countries, humanitarianism means performing the best operation in the best possible circumstances with high income country (HIC) results and training in-country surgeons to do the same. Hernia Repair for the Underserved (HRFU), a not for profit organization, is developing a long term public health initiative for hernia surgery in Western Hemisphere countries. We report the progress of HRFUs methods to render humanitarian care. METHODS: In a collaborative effort, Creighton University and the Institute for Latin American Concern developed an outpatient surgery site for hernia surgery in Santiago, Dominican Republic. Based on this experience, we developed a sustainable care model by recruiting American and European Hernia Society expert surgeons, staff members they recommended, building relationships with local and industry partners, and selecting local surgeons to be trained in mesh hernioplasty. HRFU then extended the care model to other Western Hemisphere countries. RESULTS: Between 2004 and 2015, the HRFU elective hernia morbidity and mortality rates for 2052 hernia operations were 0.7 and 0%, respectively. This is consistent with outcomes from HICs and confirms the feasibility of a public health initiative based on the principles of the Preferential Option for the Poor. CONCLUSIONS: HRFU has recorded HIC morbidity and mortality rates for hernia surgery in low and middle income countries and has initiated a new surgical training model for sustainability of effect.

Nickel and ocean warming affect scleractinian coral growth.

The sensitivity of corals and their Symbiodinium to warming has been extensively documented; however very few studies considered that anthropogenic inputs such as metal pollution have already an impact on many fringing reefs. Thus, today, nickel releases are common in coastal ecosystems. In this study, two major reef-building species Acropora muricata and Pocillopora damicornis were exposed in situ to ambient and moderate nickel concentrations on a short-term period (1h) using benthic chamber experiments. Simultaneously, we tested in laboratory conditions the combined effects of a chronic exposure (8weeks) to moderate nickel concentrations and ocean warming on A. muricata. The in situ experiment highlighted that nickel enrichment, at ambient temperature, stimulated by 27 to 47% the calcification rates of both species but not their photosynthetic performances. In contrast, an exposure to higher nickel concentration, in combination with elevated temperature simulated in aquaria, severely depressed by 30% the growth of A. muricata.

Amidation of Polyesters Is Slow in Nonaqueous Solvents: Efficient Amidation of Poly(ethylene terephthalate) with 3-Aminopropyltriethoxysilane in Water for Generating Multifunctional Surfaces.

This paper describes surface functionalization of poly(ethylene terephthalate) (PET) films by transamidation of the ester groups with primary amines. The use of water as a solvent improves tremendously the reaction rate and yield compared to conventionally used alcohols. In this study, PET films were exposed to an aqueous solution of 3-aminopropyltriethoxysilane (APTES), which resulted in ester-to-amide reactions on the surface of the film. Hydrolysis of the resulting ethoxy moieties in APTES creates hydroxyl groups that can be used as anchoring points for further modification of PET films. This scheme offers an alternative approach to modify polyesters using water as the solvent.

Meditation and vacation effects have an impact on disease-associated molecular phenotypes.

Meditation is becoming increasingly practiced, especially for stress-related medical conditions. Meditation may improve cellular health; however, studies have not separated out effects of meditation from vacation-like effects in a residential randomized controlled trial. We recruited healthy women non-meditators to live at a resort for 6 days and randomized to either meditation retreat or relaxing on-site, with both groups compared with 'regular meditators' already enrolled in the retreat. Blood drawn at baseline and post intervention was assessed for transcriptome-wide expression patterns and aging-related biomarkers. Highly significant gene expression changes were detected across all groups (the 'vacation effect') that could accurately predict (96% accuracy) between baseline and post-intervention states and were characterized by improved regulation of stress response, immune function and amyloid beta (Aß) metabolism. Although a smaller set of genes was affected, regular meditators showed post-intervention differences in a gene network characterized by lower regulation of protein synthesis and viral genome activity. Changes in well-being were assessed post intervention relative to baseline, as well as 1 and 10 months later. All groups showed equivalently large immediate post-intervention improvements in well-being, but novice meditators showed greater maintenance of lower distress over time compared with those in the vacation arm. Regular meditators showed a trend toward increased telomerase activity compared with randomized women, who showed increased plasma Aß42/Aß40 ratios and tumor necrosis factor alpha (TNF-α) levels. This highly controlled residential study showed large salutary changes in gene expression networks due to the vacation effect, common to all groups. For those already trained in the practice of meditation, a retreat appears to provide additional benefits to cellular health beyond the vacation effect.

Differential evolution of peripheral cytokine levels in symptomatic and asymptomatic responses to experimental influenza virus challenge.

Exposure to influenza virus triggers a complex cascade of events in the human host. In order to understand more clearly the evolution of this intricate response over time, human volunteers were inoculated with influenza A/Wisconsin/67/2005 (H3N2), and then had serial peripheral blood samples drawn and tested for the presence of 25 major human cytokines. Nine of 17 (53%) inoculated subjects developed symptomatic influenza infection. Individuals who will go on to become symptomatic demonstrate increased circulating levels of interleukin (IL)-6, IL-8, IL-15, monocyte chemotactic protein (MCP)-1 and interferon (IFN) gamma-induced protein (IP)-10 as early as 12-29 h post-inoculation (during the presymptomatic phase), whereas challenged patients who remain asymptomatic do not. Overall, the immunological pathways of leucocyte recruitment, Toll-like receptor (TLR)-signalling, innate anti-viral immunity and fever production are all over-represented in symptomatic individuals very early in disease, but are also dynamic and evolve continuously over time. Comparison with simultaneous peripheral blood genomics demonstrates that some inflammatory mediators (MCP-1, IP-10, IL-15) are being expressed actively in circulating cells, while others (IL-6, IL-8, IFN-α and IFN-γ) are probable effectors produced locally at the site of infection. Interestingly, asymptomatic exposed subjects are not quiescent either immunologically or genomically, but instead exhibit early and persistent down-regulation of important inflammatory mediators in the periphery. The host inflammatory response to influenza infection is variable but robust, and evolves over time. These results offer critical insight into pathways driving influenza-related symptomatology and offer the potential to contribute to early detection and differentiation of infected hosts.