Evaluating Patterns and Factors Related to Sleep Disturbances in Prostate Cancer Patients.

Prostate cancer patients may experience disturbed sleep as a result of their diagnosis or treatment. This study sought to evaluate disturbed sleep and excessive daytime sleepiness in newly diagnosed patients and those receiving androgen deprivation therapy (ADT). This study was conducted with 74 patients. Subjective data using the Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS) and actigraphy data on ADT/ADT-naïve patients were collected. The prevalence of poor sleep quality, determined from PSQI and ESS scores, was 50% and 16.7% respectively. Those on ADT (n = 20) had poorer sleep quality as determined by significantly higher PSQI scores (70 vs. 40% scoring > 5) and were more likely to have poor sleep quality, sleep latency, and sleep efficiency than ADT-naïve patients (n = 40). Actigraphy data showed that ADT patients slept significantly longer (7.7 vs. 6.8 h), experienced a higher Fragmentation Index (48.3 vs. 37.4%), and had longer daytime nap duration (64.1 vs. 45.2 min) than ADT-naïve patients. The use of objective measures such as actigraphy in the clinical arena is recommended and may be used as a valuable tool for research into sleep assessment in prostate cancer patients.

COVID-19 through Adverse Outcome Pathways: Building networks to better understand the disease - 3rd CIAO AOP Design Workshop.

On April 28-29, 2021, 50 scientists from different fields of expertise met for the 3rd online CIAO workshop. The CIAO project "Modelling the Pathogenesis of COVID-19 using the Adverse Outcome Pathway (AOP) framework" aims at building a holistic assembly of the available scientific knowledge on COVID-19 using the AOP framework. An individual AOP depicts the disease progression from the initial contact with the SARS-CoV-2 virus through biological key events (KE) toward an adverse outcome such as respiratory distress, anosmia or multiorgan failure. Assembling the individual AOPs into a network highlights shared KEs as central biological nodes involved in multiple outcomes observed in COVID-19 patients. During the workshop, the KEs and AOPs established so far by the CIAO members were presented and posi­tioned on a timeline of the disease course. Modulating factors influencing the progression and severity of the disease were also addressed as well as factors beyond purely biological phenomena. CIAO relies on an interdisciplinary crowd­sourcing effort, therefore, approaches to expand the CIAO network by widening the crowd and reaching stakeholders were also discussed. To conclude the workshop, it was decided that the AOPs/KEs will be further consolidated, inte­grating virus variants and long COVID when relevant, while an outreach campaign will be launched to broaden the CIAO scientific crowd.

A structured reflective process supports student awareness of employability skills development in a science placement module.

Placements are often an extra-curricular activity of a science degree. This study reports on the outcomes of a final-year credit-bearing 6-week placement module that was specifically designed to develop and enhance students' employability skills. A key element of this module was that the student placements were not only evaluated from a science perspective, but also evaluated with an emphasis on meaningful reflection and evaluation of employability skills development. Students recorded their levels of confidence in skills before, during and after the placement via an Online Reflective Log, as part of a module's summative assessment. The results showed that taking part in the placement and conducting their own independent research helped students to make connections between their scientific knowledge, otherwise constrained within the walls of the undergraduate science laboratory, and the wider impact of their research on society. Another theme that emerged concerned career choices and aspirations, and the placement experiences either confirmed prior choices or opened new horizons. The Online Reflective Log helped students to feel supported by their university supervisor who were at a distance. Feedback on their tasks prompted students to reflect on the scientific and personal skills while being engaged in scientific activities during placement. Students agreed that they had further developed their employability skills during the placement and acknowledged that it was challenging to acquire evidence of skill development. However, students appreciated the usefulness of this reflection in relation to their future career development.

Techniques and Tips for Freehand Placement of C7 Pedicle Screws With Respect to Cervicothoracic Constructs: 2-Dimensional Operative Video.

We present a surgical video highlighting the technical pearls for C7 pedicle screw placement with respect to cervicothoracic constructs. Pedicle screw placement into C7 has been shown to enhance the biomechanical stability of both cervical and cervicothoracic constructs and is safe for patient related outcomes.1,2 Rod placement across the cervicothoracic junction is known to be difficult because of the variable starting point of the C7 pedicle screw, which may cause misalignment of the polyaxial heads with respect to the C7 and C6 screw heads. Using our step-wise method of anatomic screw placement, this potential pitfall is minimized. The T1 pedicle screw is placed first. The C6 lateral mass screw starting point is displaced slightly superiorly from the midpoint of the lateral mass in order to make room for the polyaxial head of the C7 pedicle screw. A small laminotomy is performed in order to find the medial border of the C7 pedicle. Palpation of the medial border allows for an approximation of the pedicle limits. The cranial-caudal angle of drilling is perpendicular to the C7 superior facet, and the medial-lateral trajectory typically falls between 15 and 20 degrees medial. Once the pedicle is cannulated, a ball-tipped probe is used to confirm intraosseous position. A rod is cut and contoured to the appropriate length of the construct. The C7 pedicle screw should capture the rod easily with slight displacement of the polyaxial head. Postinstrumentation anteroposterior and lateral fluoroscopy are performed to confirm good position of the lateral mass and pedicle screws. Patient consent was not required for this cadaveric surgical video.

Finding the "Sweet Spot" for C2 Root Transection in C1 Lateral Mass Exposure.

BACKGROUND: Atlantoaxial fusion often requires C2 nerve transection for complete C1 lateral mass exposure. Nerve transection is made ideally at the preganglionic segment proximal to the dorsal root ganglion to minimize the risk of postoperative dysesthesias. If the nerve is transected too proximally, cerebrospinal fluid leak may be encountered by violation of the dura and arachnoid where the sensory and motor nerve rootlets exit the subarachnoid space. In this study we aimed to quantify the length of the C2 nerve preganglionic segment using cadaveric specimens and develop a method for reliable intraoperative localization for sectioning during C1-2 arthrodesis. METHODS: Using microsurgical techniques, 16 C2 nerves from 8 frozen and injected cadaveric cervical spine specimens were dissected. Two key measurements were taken to establish a reliable method of preganglionic segment identification. The "sweet spot" for nerve transection was based on the approximate location of the midpoint of the preganglionic segment. RESULTS: The final determination of the ideal spot for C2 nerve transection using these calculations was 3 mm lateral to the medial border of the lateral mass. CONCLUSIONS: This anatomic study found remarkable consistency in the preganglionic segment length. The medial border of the lateral mass appeared to be a consistently reliable landmark for identification of the preganglionic segment of the C2 nerve root. By using relationships between known anatomic structures intraoperatively, safety of atlantoaxial fixation can be optimized to maximize complication avoidance and satisfactory patient outcomes.

Analysis of coumarin and angelica lactones in smokeless tobacco products.

Differences in health risks between different styles of smokeless tobacco products (STPs) have prompted interest in their relative levels of toxic chemicals. We report here the development of methods for the analysis of STPs for coumarin and for α-angelica lactone (α-AL), both of which have been included in various published lists of tobacco toxicants. We have also determined the concentrations of these lactones in commercial STPs from the US and Sweden, representing 80-90% of the 2010 market share for all the major STP categories in these two countries: 65 products (plus two reference products) for coumarin and 66 commercial products for α-AL. For coumarin, methanol extracts of the STPs were analysed by HPLC/MS/MS. The lower limit of quantification (LOQ) and limit of detection (LOD) were, respectively, 100 and 30 ng coumarin/g of STP on a wet weight basis (WWB). Alpha-AL was determined via direct headspace GC/MS. The LOQ and LOD were 65 and 30 ng/g WWB respectively. Coumarin was detected In 3/33 Swedish snus, 5/13 US chewing tobaccos, 16/16 moist snuffs and 5/6 dry snuffs. Concentrations in those samples with quantifiable coumarin contents ranged from 186 to 1656 ng/g WWB. Concentrations of coumarin measured in this study were consistent with levels naturally found in tobacco. None of the STPs analysed would significantly contribute to coumarin exposure in consumers compared with dietary sources, and estimated exposure levels were 1000× lower than the European Food Safety Authority Tolerable Daily Intake. Hence the relevance of coumarin to the toxicity of STPs and its inclusion in the FDA's list of harmful and potentially harmful compounds list is questionable. Measurements of α-AL in these STPs found that the majority did not have quantifiable contents, however, for three STPs concentrations of α-AL were above the LOQ (116-140 ng/g WWB) and for four other STPs concentrations of α-AL could be estimated between the LOD and LOQ. Beta-angelica lactone was tentatively identified in three of the STPs but the levels could not be reliably quantified. The levels of α-AL in tobacco products are reported here for the first time, but the relevance of α-AL to the toxicity of STPs is also highly questionable given that it has GRAS status as a permitted food additive.

Evaluating the prevalence and predictive factors of vasomotor and psychological symptoms in prostate cancer patients receiving hormonal therapy: Results from a single institution experience.

BACKGROUND & PURPOSE: The impact of vasomotor symptoms (VMS) occurring in prostate cancer (PC) patients whilst on androgen deprivation therapy (ADT) has not been extensively researched. This longitudinal study sought to assess the VMS and identify any predictive factors. MATERIAL & METHODS: Data from 250 PC patients on ADT were prospectively evaluated between January 10 and August 13 using a physician-directed questionnaire, to assess the impact of VMS. Parameters including height, weight, body surface area (BSA), body mass index (BMI), duration/type of ADT, co-morbidities and ethnicity were recorded. RESULTS: Fifty (20%) men reported no toxicity, whilst 171 (68.4%), and 29 (11.6%) reported mild to moderate and severe symptoms, respectively. Drenching sweats and hot flashes were common, and coexisted with sleep disturbances and fatigue. Patients with severe toxicity were younger (73 vs. 77 yrs; p = 0.04), had higher BMI (28 vs. 26; p = 0.02), and higher BSA (1.99 vs. 1.90; p = 0.04), when compared with those experiencing no toxicity. On multivariate analysis, younger age was predictive of sweats and hot flushes, whilst Afro-Caribbean men were twice as likely to experience sweats (OR 2.03, p = 0.05). CONCLUSIONS: The short-term side-effect profile of ADT for prostate cancer was favourable, though debilitating VMS can occur in a significant minority of cases. Younger age and higher BMI predicted for severe toxicity but not the duration of ADT.

Axitinib, cabozantinib, everolimus, nivolumab, sunitinib and best supportive care in previously treated renal cell carcinoma: a systematic review and economic evaluation.

BACKGROUND: Several therapies have recently been approved for use in the NHS for pretreated advanced or metastatic renal cell carcinoma (amRCC), but there is a lack of comparative evidence to guide decisions between them. OBJECTIVE: To evaluate the clinical effectiveness and cost-effectiveness of axitinib (Inlyta®, Pfizer Inc., NY, USA), cabozantinib (Cabometyx®, Ipsen, Slough, UK), everolimus (Afinitor®, Novartis, Basel, Switzerland), nivolumab (Opdivo®, Bristol-Myers Squibb, NY, USA), sunitinib (Sutent®, Pfizer, Inc., NY, USA) and best supportive care (BSC) for people with amRCC who were previously treated with vascular endothelial growth factor (VEGF)-targeted therapy. DATA SOURCES: A systematic review and mixed-treatment comparison (MTC) of randomised controlled trials (RCTs) and non-RCTs. Primary outcomes were overall survival (OS) and progression-free survival (PFS). Secondary outcomes were objective response rates (ORRs), adverse events (AEs) and health-related quality of life (HRQoL). MEDLINE, EMBASE and The Cochrane Library were searched from inception to January and June 2016 for RCTs and non-RCTs, respectively. Two reviewers abstracted data and performed critical appraisals. REVIEW METHODS: A fixed-effects MTC was conducted for OS, PFS [hazard ratios (HRs)] and ORR (odds ratios), and all were presented with 95% credible intervals (CrIs). The RCT data formed the primary analyses, with non-RCTs and studies rated as being at a high risk of bias included in sensitivity analyses (SAs). HRQoL and AE data were summarised narratively. A partitioned survival model with health states for pre progression, post progression and death was developed to perform a cost-utility analysis. Survival curves were fitted to the PFS and OS results from the MTC. A systematic review of HRQoL was undertaken to identify sources of health state utility values. RESULTS: Four RCTs (n = 2618) and eight non-RCTs (n = 1526) were included. The results show that cabozantinib has longer PFS than everolimus (HR 0.51, 95% CrI 0.41 to 0.63) and both treatments are better than BSC. Both cabozantinib (HR 0.66, 95% CrI 0.53 to 0.82) and nivolumab (HR 0.73, 95% CrI 0.60 to 0.89) have longer OS than everolimus. SAs were consistent with the primary analyses. The economic analysis, using drug list prices, shows that everolimus may be more cost-effective than BSC with an incremental cost-effectiveness ratio (ICER) of £45,000 per quality-adjusted life-year (QALY), as it is likely to be considered an end-of-life treatment. Cabozantinib has an ICER of £126,000 per QALY compared with everolimus and is unlikely to be cost-effective. Nivolumab was dominated by cabozantinib (i.e. more costly and less effective) and axitinib was dominated by everolimus. LIMITATIONS: Treatment comparisons were limited by the small number of RCTs. However, the key limitation of the analysis is the absence of the drug prices paid by the NHS, which was a limitation that could not be avoided owing to the confidentiality of discounts given to the NHS. CONCLUSIONS: The RCT evidence suggests that cabozantinib is likely to be the most effective for PFS and OS, closely followed by nivolumab. All treatments appear to delay disease progression and prolong survival compared with BSC, although the results are heterogeneous. The economic analysis shows that at list price everolimus could be recommended as the other drugs are much more expensive with insufficient incremental benefit. The applicability of these findings to the NHS is somewhat limited because existing confidential patient access schemes could not be used in the analysis. Future work using the discounted prices at which these drugs are provided to the NHS would better inform estimates of their relative cost-effectiveness. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016042384. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Complex problems and unchallenged solutions: Bringing ecosystem governance to the forefront of the UN sustainable development goals.

Sustainable development aims at addressing economic, social, and environmental concerns, but the current lack of responsive environmental governance hinders progress. Short-term economic development has led to limited actions, unsustainable resource management, and degraded ecosystems. The UN Sustainable Development Goals (SDGs) may continue to fall short of achieving significant progress without a better understanding of how ecosystems contribute to achieving sustainability for all people. Ecosystem governance is an approach that integrates the social and ecological components for improved sustainability and includes principles such as adaptive ecosystem co-management, subsidiarity, and telecoupling framework, as well as principles of democracy and accountability. We explain the importance of ecosystem governance in achieving the SDGs, and suggest some ways to ensure that ecosystem services are meaningfully considered. This paper reflects on how integration of these approaches into policies can enhance the current agenda of sustainability.

Interventions for treating hyperemesis gravidarum.

BACKGROUND: Hyperemesis gravidarum is a severe form of nausea and vomiting in pregnancy affecting 0.3% to 1.0% of pregnancies, and is one of the most common indications for hospitalization during pregnancy. While a previous Cochrane review examined interventions for nausea and vomiting in pregnancy, there has not yet been a review examining the interventions for the more severe condition of hyperemesis gravidarum. OBJECTIVES: To assess the effectiveness and safety, of all interventions for hyperemesis gravidarum in pregnancy up to 20 weeks' gestation. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register and the Cochrane Complementary Medicine Field's Trials Register (20 December 2015) and reference lists of retrieved studies. SELECTION CRITERIA: Randomized controlled trials of any intervention for hyperemesis gravidarum. Quasi-randomized trials and trials using a cross-over design were not eligible for inclusion.We excluded trials on nausea and vomiting of pregnancy that were not specifically studying the more severe condition of hyperemesis gravidarum. DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed the eligibility of trials, extracted data and evaluated the risk of bias. Data were checked for accuracy. MAIN RESULTS: Twenty-five trials (involving 2052 women) met the inclusion criteria but the majority of 18 different comparisons described in the review include data from single studies with small numbers of participants. The comparisons covered a range of interventions including acupressure/acupuncture, outpatient care, intravenous fluids, and various pharmaceutical interventions. The methodological quality of included studies was mixed. For selected important comparisons and outcomes, we graded the quality of the evidence and created 'Summary of findings' tables. For most outcomes the evidence was graded as low or very low quality mainly due to the imprecision of effect estimates. Comparisons included in the 'Summary of findings' tables are described below, the remaining comparisons are described in detail in the main text.No primary outcome data were available when acupuncture was compared with placebo, There was no clear evidence of differences between groups for anxiodepressive symptoms (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.73 to 1.40; one study, 36 women, very low-quality evidence), spontaneous abortion (RR 0.48, 95% CI 0.05 to 5.03; one study, 57 women, low-quality evidence), preterm birth (RR 0.12, 95% CI 0.01 to 2.26; one study, 36 women, low-quality evidence), or perinatal death (RR 0.57, 95% CI 0.04 to 8.30; one study, 36 women, low-quality evidence).There was insufficient evidence to identify clear differences between acupuncture and metoclopramide in a study with 81 participants regarding reduction/cessation in nausea or vomiting (RR 1.40, 95% CI 0.79 to 2.49 and RR 1.51, 95% CI 0.92 to 2.48, respectively; very low-quality evidence).In a study with 92 participants, women taking vitamin B6 had a slightly longer hospital stay compared with placebo (mean difference (MD) 0.80 days, 95% CI 0.08 to 1.52, moderate-quality evidence). There was insufficient evidence to demonstrate a difference in other outcomes including mean number of episodes of emesis (MD 0.50, 95% CI -0.40 to 1.40, low-quality evidence) or side effects.A comparison between metoclopramide and ondansetron identified no clear difference in the severity of nausea or vomiting (MD 1.70, 95% CI -0.15 to 3.55, and MD -0.10, 95% CI -1.63 to 1.43; one study, 83 women, respectively, very low-quality evidence). However, more women taking metoclopramide complained of drowsiness and dry mouth (RR 2.40, 95% CI 1.23 to 4.69, and RR 2.38, 95% CI 1.10 to 5.11, respectively; moderate-quality evidence). There were no clear differences between groups for other side effects.In a single study with 146 participants comparing metoclopramide with promethazine, more women taking promethazine reported drowsiness, dizziness, and dystonia (RR 0.70, 95% CI 0.56 to 0.87, RR 0.48, 95% CI 0.34 to 0.69, and RR 0.31, 95% CI 0.11 to 0.90, respectively, moderate-quality evidence). There were no clear differences between groups for other important outcomes including quality of life and other side effects.In a single trial with 30 women, those receiving ondansetron had no difference in duration of hospital admission compared to those receiving promethazine (MD 0.00, 95% CI -1.39 to 1.39, very low-quality evidence), although there was increased sedation with promethazine (RR 0.06, 95% CI 0.00 to 0.94, low-quality evidence) .Regarding corticosteroids, in a study with 110 participants there was no difference in days of hospital admission compared to placebo (MD -0.30, 95% CI -0.70 to 0.10; very low-quality evidence), but there was a decreased readmission rate (RR 0.69, 95% CI 0.50 to 0.94; four studies, 269 women). For other important outcomes including pregnancy complications, spontaneous abortion, stillbirth and congenital abnormalities, there was insufficient evidence to identify differences between groups (very low-quality evidence for all outcomes). In other single studies there were no clear differences between groups for preterm birth or side effects (very low-quality evidence).For hydrocortisone compared with metoclopramide, no data were available for primary outcomes and there was no difference in the readmission rate (RR 0.08, 95% CI 0.00 to 1.28;one study, 40 women).In a study with 80 women, compared to promethazine, those receiving prednisolone had increased nausea at 48 hours (RR 2.00, 95% CI 1.08 to 3.72; low-quality evidence), but not at 17 days (RR 0.81, 95% CI 0.58 to 1.15, very low-quality evidence). There was no clear difference in the number of episodes of emesis or subjective improvement in nausea/vomiting. There was insufficient evidence to identify differences between groups for stillbirth and neonatal death and preterm birth. AUTHORS' CONCLUSIONS: On the basis of this review, there is little high-quality and consistent evidence supporting any one intervention, which should be taken into account when making management decisions. There was also very limited reporting on the economic impact of hyperemesis gravidarum and the impact that interventions may have.The limitations in interpreting the results of the included studies highlights the importance of consistency in the definition of hyperemesis gravidarum, the use of validated outcome measures, and the need for larger placebo-controlled trials.

Contemporary hormone therapy with LHRH agonists for prostate cancer: avoiding osteoporosis and fracture.

INTRODUCTION: Prostate cancer is a large clinical burden across Europe. It is, in fact, the most common cancer in males, accounting for more than 92,300 deaths annually throughout the continent. Prostate cancer is androgen-sensitive; thus an androgen deprivation therapy (ADT) is often used for treatment by reducing androgen to castrate levels. Several ADT agents have achieved benefits with effective palliation, but, unfortunately, severe adverse events are frequent. Contemporary ADT (Luteinising Hormone Releasing Hormone agonist - LHRHa injections) can result in side effects that include osteoporosis and fractures, compromising quality of life and survival. METHODS: In this review we analysed the associated bone toxicity consequent upon contemporary ADT and based on the literature and our own experience we present future perspectives that seek to mitigate this associated toxicity both by development of novel therapies and by better identification and prediction of fracture risk. RESULTS: Preliminary results indicate that parenteral oestrogen can mitigate associated osteoporotic risk and that CT scans could provide a more accurate indicator of overall bone quality and hence fracture risk. CONCLUSIONS: As healthcare costs increase globally, cheap and effective alternatives that achieve ADT, but mitigate or avoid such bone toxicities, will be needed. More so, innovative techniques to improve both the measurement and the extent of this toxicity, by assessing bone health and prediction of fracture risk, are also required.

A longitudinal study of patients' experiences of chronic low back pain using interpretative phenomenological analysis: changes and consistencies.

This paper present data from the second and third rounds of a three-phase longitudinal research project exploring the 'lived experiences' of patients with chronic low-back pain (CLBP) in the United Kingdom. Qualitative, semi-structured interviews were conducted with eight participants 1 and 2 years after the first interviews and after attendance at a medically staffed chronic pain clinic. The transcribed accounts were analysed using interpretative phenomenological analysis and results compared with the data from time one. A main challenge for participants was managing constant unchanging pain experiences and loss across all areas of their lives. Some participants held consistent biomedical understandings of CLBP, continued to focus on the physicality of their pain and adopt a narrow range of behavioural-focused coping strategies and maintained a strong loss orientation. It is proposed that these elements demonstrated embodied experiences and contributed to comprehensive enmeshment of self and pain with little re-establishment of any behavioural activity. In comparison, participants who had experienced pain relief due to physical treatments showed increased use of mind-body strategies, a future orientation and were considered to be less enmeshed in their experiences. These changes were discussed in relation to the relationship between pain remission and illness beliefs.

Analysis of Xq27-28 linkage in the international consortium for prostate cancer genetics (ICPCG) families.

BACKGROUND: Genetic variants are likely to contribute to a portion of prostate cancer risk. Full elucidation of the genetic etiology of prostate cancer is difficult because of incomplete penetrance and genetic and phenotypic heterogeneity. Current evidence suggests that genetic linkage to prostate cancer has been found on several chromosomes including the X; however, identification of causative genes has been elusive. METHODS: Parametric and non-parametric linkage analyses were performed using 26 microsatellite markers in each of 11 groups of multiple-case prostate cancer families from the International Consortium for Prostate Cancer Genetics (ICPCG). Meta-analyses of the resultant family-specific linkage statistics across the entire 1,323 families and in several predefined subsets were then performed. RESULTS: Meta-analyses of linkage statistics resulted in a maximum parametric heterogeneity lod score (HLOD) of 1.28, and an allele-sharing lod score (LOD) of 2.0 in favor of linkage to Xq27-q28 at 138 cM. In subset analyses, families with average age at onset less than 65 years exhibited a maximum HLOD of 1.8 (at 138 cM) versus a maximum regional HLOD of only 0.32 in families with average age at onset of 65 years or older. Surprisingly, the subset of families with only 2-3 affected men and some evidence of male-to-male transmission of prostate cancer gave the strongest evidence of linkage to the region (HLOD = 3.24, 134 cM). For this subset, the HLOD was slightly increased (HLOD = 3.47 at 134 cM) when families used in the original published report of linkage to Xq27-28 were excluded. CONCLUSIONS: Although there was not strong support for linkage to the Xq27-28 region in the complete set of families, the subset of families with earlier age at onset exhibited more evidence of linkage than families with later onset of disease. A subset of families with 2-3 affected individuals and with some evidence of male to male disease transmission showed stronger linkage signals. Our results suggest that the genetic basis for prostate cancer in our families is much more complex than a single susceptibility locus on the X chromosome, and that future explorations of the Xq27-28 region should focus on the subset of families identified here with the strongest evidence of linkage to this region.

Main achievements of the World Organisation for Animal Health/United Nations Food and Agriculture Organization network on animal influenza.

The World Organisation for Animal Health (OIE)/United Nations Food and Agriculture Organization (FAO) joint network of expertise on animal influenza (OFFLU) includes all ten OIE/FAO reference laboratories and collaborating centers for avian influenza, other diagnostic laboratories, research and academic institutions, and experts in the fields of virology, epidemiology, vaccinology, and molecular biology. OFFLU has made significant progress in improving its infrastructure, in identifying and addressing technical gaps, and in establishing associations among leading veterinary institutions. Interaction with the World Health Organization (WHO) Global Influenza Program is also critical, and mechanisms for permanent interaction are being developed. OFFLU played a key role in the WHO/OIE/FAO Joint Technical Consultation held in Verona (October 7-9, 2008), which provided an opportunity to highlight and share knowledge and identify potential gaps regarding issues at the human-animal interface for avian influenza. OFFLU experts also contributed to the working group for the Unified Nomenclature System for H5N1 influenza viruses based on hemagglutinin gene phylogeny (WHO/OIE/FAO, H5N1 Evolution Working Group, Towards a unified nomenclature system for highly pathogenic avian influenza virus (H5N1) in Emerging Infectious Diseases 14:el, 2008). OFFLU technical activities, led by expert scientists from OIE/FAO reference institutions and coordinated by OIE and FAO focal points, have been prioritized to include commercial diagnostic kit evaluation, applied epidemiology, biosafety, vaccination, proficiency testing, development of standardized reference materials for sera and RNA, and issues at the human-animal interface. The progress to date and future plans for these groups will be presented. OFFLU is also involved in two national projects implemented by FAO in Indonesia and Egypt that seek to establish sustainable mechanisms for monitoring virus circulation, including viral characterization, and for streamlining the process to update poultry vaccines for avian influenza.

Advancing exposure characterization for chemical evaluation and risk assessment.

A new generation of scientific tools has emerged to rapidly measure signals from cells, tissues, and organisms following exposure to chemicals. High-visibility efforts to apply these tools for efficient toxicity testing raise important research questions in exposure science. As vast quantities of data from high-throughput screening (HTS) in vitro toxicity assays become available, this new toxicity information must be translated to assess potential risks to human health from environmental exposures. Exposure information is required to link information on potential toxicity of environmental contaminants to real-world health outcomes. In the immediate term, tools are required to characterize and classify thousands of environmental chemicals in a rapid and efficient manner to prioritize testing and assess potential for risk to human health. Rapid risk assessment requires prioritization based on both hazard and exposure dimensions of the problem. To address these immediate needs within the context of longer term objectives for chemical evaluation and risk management, a translation framework is presented for incorporating toxicity and exposure information to inform public health decisions at both the individual and population levels. Examples of required exposure science contributions are presented with a focus on early advances in tools for modeling important links across the source-to-outcome paradigm. ExpoCast, a new U.S. Environmental Protection Agency (EPA) program aimed at developing novel approaches and metrics to screen and evaluate chemicals based on the potential for biologically relevant human exposures is introduced. The goal of ExpoCast is to advance characterization of exposure required to translate findings in computational toxicology to information that can be directly used to support exposure and risk assessment for decision making and improved public health.

A gene expression network model of type 2 diabetes links cell cycle regulation in islets with diabetes susceptibility.

Insulin resistance is necessary but not sufficient for the development of type 2 diabetes. Diabetes results when pancreatic beta-cells fail to compensate for insulin resistance by increasing insulin production through an expansion of beta-cell mass or increased insulin secretion. Communication between insulin target tissues and beta-cells may initiate this compensatory response. Correlated changes in gene expression between tissues can provide evidence for such intercellular communication. We profiled gene expression in six tissues of mice from an obesity-induced diabetes-resistant and a diabetes-susceptible strain before and after the onset of diabetes. We studied the correlation structure of mRNA abundance and identified 105 co-expression gene modules. We provide an interactive gene network model showing the correlation structure between the expression modules within and among the six tissues. This resource also provides a searchable database of gene expression profiles for all genes in six tissues in lean and obese diabetes-resistant and diabetes-susceptible mice, at 4 and 10 wk of age. A cell cycle regulatory module in islets predicts diabetes susceptibility. The module predicts islet replication; we found a strong correlation between (2)H(2)O incorporation into islet DNA in vivo and the expression pattern of the cell cycle module. This pattern is highly correlated with that of several individual genes in insulin target tissues, including Igf2, which has been shown to promote beta-cell proliferation, suggesting that these genes may provide a link between insulin resistance and beta-cell proliferation.

Replication of Colonic Crohn's Disease Mucosal Escherichia coli Isolates within Macrophages and Their Susceptibility to Antibiotics.

There is increasing evidence that Escherichia coli organisms are important in Crohn's disease (CD) pathogenesis. In CD tissue they are found within macrophages, and the adherent-invasive CD ileal E. coli isolate LF82 can replicate inside macrophage phagolysosomes. This study investigates replication and antibiotic susceptibility of CD colonic E. coli isolates inside macrophages. Replication of CD colonic E. coli within J774-A1 murine macrophages and human monocyte-derived macrophages (HMDM) was assessed by culture and lysis after gentamicin killing of noninternalized bacteria and verified by electron microscopy (EM). All seven CD colonic isolates tested replicated within J774-A1 macrophages by 3 h (6.36-fold +/- 0.7-fold increase; n = 7 isolates) to a similar extent to CD ileal E. coli LF82 (6.8-fold +/- 0.8-fold) but significantly more than control patient isolates (5.2-fold +/- 0.25-fold; n = 6; P = 0.006) and E. coli K-12 (1.0-fold +/- 0.1-fold; P < 0.0001). Replication of CD E. coli HM605 within HMDM (3.9-fold +/- 0.7-fold) exceeded that for K-12 (1.4-fold +/- 0.2-fold; P = 0.03). EM showed replicating E. coli within macrophage vacuoles. Killing of HM605 within J774-A1 macrophages following a 3-h incubation with antibiotics at published peak serum concentrations (C(max)) was as follows: for ciprofloxacin, 99.5% +/- 0.2%; rifampin, 85.1% +/- 6.6%; tetracycline, 62.8% +/- 6.1%; clarithromycin, 62.1% +/- 5.6% (all P < 0.0001); sulfamethoxazole, 61.3% +/- 7.0% (P = 0.0007); trimethoprim, 56.3% +/- 3.4% (P < 0.0001); and azithromycin, 41.0% +/- 10.5% (P = 0.03). Ampicillin was not effective against intracellular E. coli. Triple antibiotic combinations were assessed at 10% C(max), with ciprofloxacin, tetracycline, and trimethoprim causing 97% +/- 0.0% killing versus 86% +/- 2.0% for ciprofloxacin alone. Colonic mucosa-associated E. coli, particularly CD isolates, replicate within macrophages. Clinical trials are indicated to assess the efficacy of a combination antibiotic therapy targeting intramacrophage E. coli.