Viral Symbiosis in the Origins and Evolution of Life with a Particular Focus on the Placental Mammals.

Advances in understanding over the last decade or so highlight the need for a reappraisal of the role of viruses in relation to the origins and evolution of cellular life, as well as in the homeostasis of the biosphere on which all of life depends. The relevant advances have, in particular, revealed an important contribution of viruses to the evolution of the placental mammals, while also contributing key roles to mammalian embryogenesis, genomic evolution, and physiology. Part of this reappraisal will include the origins of viruses, a redefinition of their quintessential nature, and a suggestion as to how we might view viruses in relation to the tree of life.

Use of contingency management incentives to improve completion of hepatitis B vaccination in people undergoing treatment for heroin dependence: a cluster randomised trial.

BACKGROUND: Poor adherence to treatment diminishes its individual and public health benefit. Financial incentives, provided on the condition of treatment attendance, could address this problem. Injecting drug users are a high-risk group for hepatitis B virus (HBV) infection and transmission, but adherence to vaccination programmes is poor. We aimed to assess whether contingency management delivered in routine clinical practice increased the completion of HBV vaccination in individuals receiving opioid substitution therapy. METHODS: In our cluster randomised controlled trial, we enrolled participants at 12 National Health Service drug treatment services in the UK that provided opioid substitution therapy and nurse-led HBV vaccination with a super-accelerated schedule (vaccination days 0, 7, and 21). Clusters were randomly allocated 1:1:1 to provide vaccination without incentive (treatment as usual), with fixed value contingency management (three £10 vouchers), or escalating value contingency management (£5, £10, and £15 vouchers). Both contingency management schedules rewarded on-time attendance at appointments. The primary outcome was completion of clinically appropriate HBV vaccination within 28 days. We also did sensitivity analyses that examined vaccination completion with full adherence to appointment times and within a 3 month window. The trial is registered with Current Controlled Trials, number ISRCTN72794493. FINDINGS: Between March 16, 2011, and April 26, 2012, we enrolled 210 eligible participants. Compared with six (9%) of 67 participants treated as usual, 35 (45%) of 78 participants in the fixed value contingency management group met the primary outcome measure (odds ratio 12·1, 95% CI 3·7-39·9; p<0·0001), as did 32 (49%) of 65 participants in the escalating value contingency management group (14·0, 4·2-46·2; p<0·0001). These differences remained significant with sensitivity analyses. INTERPRETATION: Modest financial incentives delivered in routine clinical practice significantly improve adherence to, and completion of, HBV vaccination programmes in patients receiving opioid substitution therapy. Achievement of this improvement in routine clinical practice should now prompt actual implementation. Drug treatment providers should employ contingency management to promote adherence to vaccination programmes. The effectiveness of routine use of contingency management to achieve long-term behaviour change remains unknown. FUNDING: National Institute for Health Research (RP-PG-0707-10149).

Detection of the human endogenous retrovirus ERV3-encoded Env-protein in human tissues using antibody-based proteomics.

OBJECTIVES: There is growing evidence to suggest that human endogenous retroviruses (HERVs) have contributed to human evolution, being expressed in development, normal physiology and disease. A key difficulty in the scientific evaluation of this potential viral contribution is the accurate demonstration of virally expressed protein in specific human cells and tissues. In this study, we have adopted the endogenous retrovirus, ERV3, as our test model in developing a reliable high-capacity methodology for the expression of such endogenous retrovirus-coded protein. DESIGN: Two affinity-purified polyclonal antibodies to ERV3 Env-encoded protein were generated to detect the corresponding protein expression pattern in specific human cells, tissues and organs. PARTICIPANTS: Sampling included normal tissues from 144 individuals ranging from childhood to old age. This included more than forty different tissues and organs and some 216 different cancer tissues representing the twenty commonest forms of human cancer. SETTING: The Rudbeck Laboratory, Uppsala University and Uppsala University Hospital, Uppsala, Sweden. MAIN OUTCOME MEASURES: The potential expression at likely physiological level of the ERV3Env encoded protein in a wide range of human cells, tissues and organs. RESULTS: We found that ERV3 encoded Env protein is expressed at substantive levels in placenta, testis, adrenal gland, corpus luteum, Fallopian tubes, sebaceous glands, astrocytes, bronchial epithelium and the ducts of the salivary glands. Substantive expression was also seen in a variety of epithelial cells as well as cells known to undergo fusion in inflammation and in normal physiology, including fused macrophages, myocardium and striated muscle. This contrasted strongly with the low levels expressed in other tissues types. These findings suggest that this virus plays a significant role in human physiology and may also play a possible role in disease. CONCLUSION: This technique can now be extended to the study of other HERV genomes within the human chromosomes that may have contributed to human evolution, physiology and disease.

Application of a microsystem-based project to improve the inpatient care of adults with cystic fibrosis.

BACKGROUND: Patients with cystic fibrosis (CF) hospitalized for pulmonary exacerbations complained of delayed and missed treatments. We analyzed the complaints and implemented two microsystem-based quality initiatives to improve care. METHODS: A prospective, observational study using quantitative and qualitative data collection strategies was conducted. Two interventions were implemented: a CF order set followed 9 months later by a self-administration program. MEASUREMENTS AND MAIN RESULTS: Thirty-six of 40 patients with CF received initial respiratory therapy within 2 hours of admission compared with 1 of 17 before intervention. Initial antibiotic administration time was reduced from a mean of 18 hours to within 4 hours in the majority of admissions after implementation of quality initiatives. The interventions led to improved medication delivery and increased satisfaction. Hospital length of stay for patients with CF decreased from a mean of 9.5 to 7.8 days. CONCLUSION: Application of a microsystem-based strategy that engaged patients and families as well as caregivers brought about substantial changes in CF care delivery, increased satisfaction among staff and patients, and decreased hospital length of stay.

Canadian Thoracic Society 2011 guideline update: diagnosis and treatment of sleep disordered breathing.

The Canadian Thoracic Society (CTS) published an executive summary of guidelines for the diagnosis and treatment of sleep disordered breathing in 2006/2007. These guidelines were developed during several meetings by a group of experts with evidence grading based on committee consensus. These guidelines were well received and the majority of the recommendations remain unchanged. The CTS embarked on a more rigorous process for the 2011 guideline update, and addressed eight areas that were believed to be controversial or in which new data emerged. The CTS Sleep Disordered Breathing Committee posed specific questions for each area. The recommendations regarding maximum assessment wait times, portable monitoring, treatment of asymptomatic adult obstructive sleep apnea patients, treatment with conventional continuous positive airway pressure compared with automatic continuous positive airway pressure, and treatment of central sleep apnea syndrome in heart failure patients replace the recommendations in the 2006/2007 guidelines. The recommendations on bariatric surgery, complex sleep apnea and optimum positive airway pressure technologies are new topics, which were not covered in the 2006/2007 guidelines.

Canadian Sleep Society/Canadian Thoracic Society position paper on the use of portable monitoring for the diagnosis of obstructive sleep apnea/hypopnea in adults.

The present position paper on the use of portable monitoring (PM) as a diagnostic tool for obstructive sleep apnea/hypopnea (OSAH) in adults was based on consensus and expert opinion regarding best practice standards from stakeholders across Canada. These recommendations were prepared to guide appropriate clinical use of this new technology and to ensure that quality assurance standards are adhered to. Clinical guidelines for the use of PM for the diagnosis and management of OSAH as an alternative to in-laboratory polysomnography published by the American Academy of Sleep Medicine Portable Monitoring Task Force were used to tailor our recommendations to address the following: indications; methodology including physician involvement, physician and technical staff qualifications, and follow-up requirements; technical considerations; quality assurance; and conflict of interest guidelines. When used appropriately under the supervision of a physician with training in sleep medicine, and in conjunction with a comprehensive sleep evaluation, PM may expedite treatment when there is a high clinical suspicion of OSAH.

Acidosis and catecholamine evaluation following simulated law enforcement "use of force" encounters.

OBJECTIVES: Law enforcement authorities are often charged with controlling resisting suspects. These encounters sometimes result in the sudden and unexpected death of the suspect. Drug intoxication, excited delirium syndrome, or excessive uses of force are factors that are often blamed, but sometimes the mechanism of these deaths is not fully understood. It is possible that worsening acidosis or excessive catecholamine release play a part. The objective of this study was to determine the effect on markers of acidosis and catecholamines of various tasks intended to simulate common arrest-related situations. METHODS: Subjects were assigned to one of five task groups: 1) a 150-meter sprint and wall hurdle (simulated flight from arrest); 2) 45 seconds of striking a heavy bag (simulated physical resistance); 3) a 10-second TASER X26 electronic control device exposure; 4) a fleeing and resistance exercise involving a law enforcement dog (K-9); or 5) an oleoresin capsicum (OC) exposure to the face and neck. Baseline serum pH, lactate, potassium, troponin I, catecholamines, and creatine kinase (CK) were evaluated. Serum catecholamines, pH, lactate, and potassium were sampled immediately after the task and every 2 minutes for 10 minutes posttask. Vital signs were repeated immediately after the task. Serum CK and troponin I were evaluated again at 24 hours posttask. RESULTS: Sixty-six subjects were enrolled; four did not complete their assigned task. One subject lost the intravenous (IV) access after completing the task and did not have data collected, and one subject only received a 5-second TASER device exposure and was excluded from the study, leaving 12 subjects in each task group. The greatest changes in acidosis markers occurred in the sprint and heavy bag groups. Catecholamines increased the most in the heavy bag group and the sprint group and increased to a lesser degree in the TASER, OC, and K-9 groups. Only the sprint group showed an increase in CK at 24 hours. There were no elevations in troponin I in any group, nor any clinically important changes in potassium. CONCLUSIONS: The simulations of physical resistance and fleeing on foot led to the greatest changes in markers of acidosis and catecholamines. These changes may be contributing or causal mechanisms in sudden custodial arrest-related deaths (ARDs). This initial work may have implications in guiding applications of force for law enforcement authorities (LEAs) when apprehending resisting subjects.

Financing American Indian health care: impacts and options for improving access and quality.

(1) Indian Health Service (HIS) per patient funding is less than half of national per capita health spending, and declined further between 2003 and 2006. (2) Under-funding of the IHS system has led to explicit rationing of services to American Indian and Alaska Native patients, with many specialized services provided only for "life or limb threatening" conditions. (3) IHS patients report experiencing access barriers and rate the quality of care process substantially lower than do Medicaid beneficiaries, but most indicate they prefer to use IHS for their health care. (4) Options to increase the funding for American Indian and Alaska Native health care exist, but would impose higher costs on federal and state budgets and are unlikely to be feasible in the current economic environment. However, IHS might be able to make certain organizational changes that would increase efficiency and its ability to extend existing funding to cover more services.

Pro-atherogenic cytokine profile of patients with suspected obstructive sleep apnea.

PURPOSE: Systemic inflammation is important in the pathogenesis of cardiovascular disease (CVD). We sought to characterize the systemic inflammatory profile associated with obstructive sleep apnea (OSA). METHODS: Adult patients referred for suspected OSA at the University of British Columbia Hospital Sleep Disorders Program were recruited for our study. Patients using HMG CoA inhibitors or a history of CVD were excluded. Fasting serum samples were obtained the morning after their diagnostic polysomnograms. Samples were tested for the following circulating inflammatory mediators: interferon gamma; interleukins 1B, 6, and 8; intercellular and vascular cell adhesion molecules (sICAM-1 and sVCAM-1); and leptin using a multiplex Luminex System. RESULTS: There were 176 patients; 68% were male, mean age = 50 +/- (SD) 11 years, mean apnea/hyponea index (AHI) = 22.9 +/- 22/h, mean desaturation (i.e. % of sleep time spent below an oxyhemoglobin saturation of 90%) = 5.4% +/- 15, and mean body mass index (BMI) = 32.2 +/- 8 kg/m(2). In univariate analyses, only leptin, sVCAM-1, and sICAM-1 were significantly associated with indices of OSA severity (i.e. AHI and/or desaturation). In multivariate linear regression analyses that controlled for BMI, gender, age, and current smoking; desaturation persisted as a significant independent predictor for elevated sVCAM-1 and leptin. CONCLUSIONS: We did not find significant associations between OSA and markers of activated innate immunity (IL-1B, 6, and 8). However, OSA severity was independently associated with serum levels of sVCAM-1 and leptin; these may represent mechanisms involved in the pathogenesis of OSA-related CVD.

Nasal pressure recordings to detect obstructive sleep apnea.

Obstructive sleep apnea (OSA) is a common disease. Given the costs of in-laboratory polysomnography (PSG), alternative ambulatory methods for accurate diagnosis are desirable. The objective of this study was to evaluate the performance of a simple device (SleepCheck) to identify patients with sleep apnea. A total of 30 consecutive patients with suspected OSA syndrome referred to the sleep clinic were prospectively evaluated with standard PSG and SleepCheck simultaneously during an in-laboratory, supervised full-night diagnostic study. The PSG apnea and hypopnea index (AHI) was evaluated according to standard criteria, and SleepCheck assessed the respiratory disturbance index (RDI) based on nasal cannula pressure fluctuations. Compared to the full-night PSG, SleepCheck systematically overscored respiratory events (the mean difference between SleepCheck RDI and PSG AHI was 27.4+/-13.3 events per hour). This overscoring was in part related to normal physiologic decreases in flow during rapid eye movement sleep or after an arousal. However, there was reasonable correlation between AHI and RDI (r=0.805). Receiver operating characteristic curves with threshold values of AHI of 10 and 20/h demonstrated areas under the curves (AUCs) of 0.915 and 0.910, respectively. Optimum combinations of sensitivity and specificity for these thresholds were calculated as 86.4/75.0 and 88.9/81.0, respectively. Overall, the SleepCheck substantially overscored apneas and hypopneas in patients with suspected OSA. However, after correction of the bias, the SleepCheck had reasonable accuracy with an AUC, sensitivity, and specificity similar to other ambulatory type 4 devices currently available.

A comparison of responders and nonresponders to oral appliance therapy for the treatment of obstructive sleep apnea.

INTRODUCTION: This retrospective study compared cephalometric variables between responders and nonresponders to a titratable oral appliance (OA) in a group of subjects matched for sex, pretreatment age, and body mass index (BMI). METHODS: Nine nonresponders as defined by an improvement in the apnea hypopnea index (AHI; <20%) and their individually matched responders were selected for this study. The difference in age for each matched pair was +/-5 years, and, for BMI, the difference was +/-15%. The pretreatment AHI was matched to the same category (moderate, >15 to < or =30; severe I, >30 to < or =45; and severe II, >45 AHI). RESULTS: Middle and inferior airway space and oropharyngeal airway cross-sectional area were significantly larger in the nonresponders. Position of the mandible relative to the cervical spine was the only significant skeletal variable and was larger in nonresponders. Changes in BMI between the groups were statistically significant; the averages were a 2.9% increase in the nonresponders and a 0.5% decrease in responders. The wider airway in nonresponders might reflect an enhanced neuromuscular compensation while awake. The weight gain in nonresponders was relatively small, but it might have reduced the effectiveness of the OA. CONCLUSION: When treating OSA patients with OA therapy, clinicians should pay particular attention to airway size and weight changes.

The effect of oral appliance therapy on blood pressure in patients with obstructive sleep apnea.

The objective of the study was to investigate the effects of oral appliance (OA) therapy on ambulatory blood pressure in patients with obstructive sleep apnea (OSA). Eleven OSA patients who received OA therapy were prospectively investigated. Ambulatory blood pressure was measured for 20 h from 4:00 P.M.: to 12:00 noon the next day using an ambulatory blood pressure monitor. The Respiratory Disturbance Index (RDI) was measured in the pretreatment and posttitration periods. The OA was titrated to reach a therapeutic jaw position over 2 to 8 months, and posttitration measurements were repeated. At posttitration, the RDI was significantly decreased from a mean (SD) of 24.7 (20.1) to 6.1 (4.5). Significant reductions in diastolic blood pressure (DBP) and mean arterial pressure (MAP) were found for the 20-h periods, and systolic blood pressure (SBP), DBP, and MAP while asleep. The mean values were 79.5 (5.5) to 74.6 (6.0) for DBP and 95.9 (5.4) to 91.2 (5.9) for MAP, for over a 20-h period, and 118.4 (10.0) to 113.7 (9.1) for SBP, 71.6 (8.0) to 67.2 (7.9) for DBP, and 88.4 (8.0) to 83.9 (7.5) for MAP, while asleep. This study suggests that successful OSA treatment with an OA may also be beneficial to lower blood pressure in OSA patients, as previously suggested for nasal continuous positive airway pressure therapy.