In 2002, vaccination with a serogroup C meningococcal conjugate vaccine (MenC) was introduced in the Netherlands for all children aged 14 months. Despite its success, herd immunity may wane over time. Recently, a serogroup A,C,W135,Y meningococcal conjugate vaccine (MenACWY) was licensed for use in subjects of 12 months of age and above.To evaluate the cost-effectiveness of meningococcal vaccination at 14 months and an additional vaccination at the age of 12 years, both with the MenACWY vaccine.A decision analysis cohort model, with 185,000 Dutch newborns, was used to evaluate the cost-effectiveness of different immunization strategies. For strategies including a vaccination at 12 years of age, an additional cohort with adolescents aged 12 years was followed. The incremental cost-effectiveness ratio (ICER) was estimated for the current disease incidence and for a scenario when herd immunity is lost.Vaccination with MenACWY at 14 months is cost-saving. Vaccinating with MenACWY at 14 months and at 12 years would prevent 7 additional cases of meningococcal serogroup A,C,W135,Y disease in the birth cohort and adolescent cohort followed for 99 years compared to the current vaccine schedule of a single vaccination with MenC at 14 months. With the current incidence, this strategy resulted in an ICER of €635,334 per quality adjusted life year. When serogroup C disease incidence returns to pre-vaccination levels due to a loss of vaccine-induced herd-immunity, vaccination with MenACWY at 14 months and at 12 years would be cost-saving.Routine vaccination with MenACWY is cost-saving. With the current epidemiology, a booster-dose with MenACWY is not likely cost-effective. When herd immunity is lost, a booster-dose has the potential of being cost-effective. A dynamic model should be developed for more precise estimation of the cost-effectiveness of the prevention of disappearance of herd immunity. Neisseria meningitidis (the meningococcus) is an important cause of bacterial meningitis and septicaemia worldwide Neisseria meningitidis decreased as seen in the United Kingdom (UK) In the Netherlands, routine vaccination at the age of 14 months with a meningococcal serogroup C conjugate (MenC) vaccine was implemented in the National Immunization Program (NIP) after a meningococcal serogroup C disease outbreak in 2000 and 2001. This implementation was accompanied by a catch-up program for all children and adolescents aged 1 to 18 years. Hereafter, the incidence of serogroup C disease decreased considerably The decreased carriage of serogroup C meningococci has led to a reduced transmission of the bacterium whereby unvaccinated individuals are protected. This herd immunity effect might be partly the reason for the decreased incidence of serogroup C disease in the Netherlands Consequently, Austria and Switzerland have recently added a booster-dose with a conjugated MenACWY or MenC vaccine for children around the age of 12 years in addition to infant immunization While the incidence of serogroup C meningococcal disease is currently still low in the Netherlands, the incidence of serogroup Y disease is increasing, especially in adolescents  [15]. ThIn this paper, we present the economic evaluation of routine vaccination with the MenACWY vaccine at 14 months and the evaluation of an additional booster-dose with MenACWY early in adolescence.Health effects, costs, savings and the incremental cost-effectiveness ratios (ICERs) of routine vaccination with the MenACWY vaccine for infants aged 14 months and of an additional booster-dose of the MenACWY vaccine at the age of 12 years were estimated. These strategies are further named ‘MenACWY’ for only vaccinating at 14 months, and ‘MenACWY+MenACWY’ for vaccinating at 14 months and 12 years. Both strategies were compared with the current situation in the Netherlands: vaccinating with MenC at 14 months (‘MenC’). The booster-dose strategy was also compared with MenACWY at 14 months.According to the Dutch guidelines for pharmacoeconomic research A decision tree analytic model was designed to simulate the different vaccination strategies . A cohorThe incidence of meningococcal serogroup A,C,W135,Y disease was determined using data from the Netherlands Reference Laboratory for Bacterial Meningitis  (appendix S1) Based on our previous study Patients with meningococcal disease can recover completely, but the disease can also result in death or sequelae like neurological sequelae, scars or amputations. We assumed that 25% of the patients with neurological sequelae  require lifetime intensive institutional care and 50% of the patients require special education QALY losses due to permanent sequelae, i.e. amputations, scars and neurological sequelae were included in the analyses Direct and indirect costs were considered at 2011 price levels . Costs nCosts for special education were calculated by determining the age-specific additional costs per child per year for special education compared to regular education Due to the lack of studies on the vaccine effectiveness (VE) of a MenACWY conjugate vaccine in the population and because the C component in MenACWY is immunologically non-inferior to that of MenC (0) is the VE half a month after vaccination (percent), w is the annual waning rate and t is the time since protective immunity started (years). Full protection was assumed half a month after vaccination. The average duration of protection (1/w) was set at 4 years for vaccination at 14 months, based on the levels of protective antibody levels against serogroup C meningococcal disease among children 5 years after being vaccinated with the MenC vaccine at the age of 14 months Where VEIn the base-case analyses we conservatively assumed that the meningococcal C disease incidence would remain stable, despite waning of the vaccine efficacy, due to herd immunity and a low force of infection. For protection against serogroup A, W and Y it was assumed that vaccination with the MenC or MenACWY vaccine at 14 months would not induce herd immunity. Consequently, herd immunity effects in unvaccinated cohorts were assumed to be the same for MenC and MenACWY in the base-case, thereby applying herd immunity effects to the MenC incidence only.For the strategy with MenACWY vaccinations at 14 months and 12 years, ICERs were calculated with and without herd-immunity.et al. did Herd-immunity was incorporated in the model in a similar way as Rozenbaum For this scenario it was assumed that vaccination at 12 years would start at the same time as vaccination with 14 months. Therefore, a birth cohort, a 12-years old cohort and a cohort with the rest of the population was followed. Herd-immunity was accounted for only during the first year of vaccination, as it was assumed that to sustain the herd-immunity at the same level each year an additional shot at 12 years was needed, while we modelled only vaccinations in the first year of the model.In scenario analysis we calculated what the extra value of MenACWY compared to MenC in euros was for vaccination at 14 months only at a threshold values of €20,000 and €50,000 per QALY.Poor antibody persistence against meningococcal serogroup C disease following vaccination at a toddler age was observed in the UK For the scenario analysis in which the disappearance of a herd-immunity effect would be prevented by vaccination at 12 years, direct and indirect vaccination effects were incorporated.There are two key assumptions that determine the cost-effectiveness of MenACWY in comparison with MenC: the price difference and the vaccine effectiveness of both vaccines. Although the C component in the MenACWY has been shown to be immunologically non-inferior to that of MenC et al. et al.In univariate sensitivity analysis, relevant parameters were varied one at a time using the upper and lower limit of the 95% confidence intervals of the mean to determine which parameters had a great influence on the ICER. The vaccine price of MenACWY and the disease incidence were varied by 25%, as the degree of uncertainty for these parameters is unclear. Also, the vaccine effectiveness and discounting rates were varied one by one to explore their impact. Additionally, we varied the decay function for the vaccine effectiveness of the booster, thereby using the function previously used by De Wals Because the incidence of meningococcal disease is naturally fluctuating To assess the uncertainty of the ICERs, a probabilistic sensitivity analysis was performed. Parameters were generated using random sampling within the specified range of the corresponding distribution of the parameters. Outcome values were generated by running the model 10,000 times.Vaccinating with MenACWY at 14 months would avoid 1 additional case of meningococcal serogroup A,W135,Y disease for the birth cohort followed for 99 years, corresponding to a gain of 2.9 QALYs (discounted), and was estimated to be cost-saving . ImplemeAssuming herd-immunity could also be invoked for serogroup AW135Y disease and lifelong protection after vaccination at 12 years or using the most recent disease incidence figures resulted in lower ICERs, but the ICERs for vaccination at 12 years of age were still too high to be considered cost-effective .With the current low meningococcal C disease in the Netherlands, a schedule with vaccinations with MenC at 14 months and 12 years of age resulted in a high ICER of €2,620,329 per QALY, when compared to the current immunization schedule with a single vaccination with MenC at 14 months.Since MenACWY at 14 months is cost-saving compared to MenC at 14 months mainly due to a lower vaccine price, we also estimated the extra value of MenACWY compared to MenC in euros for this scenario. MenACWY could cost €0.41 more than MenC for a threshold of €20,000 per QALY and €0.90 more at a threshold of €50,000 per QALY.As the meningococcal serogroup Y disease incidence is currently increasing In bivariate sensitivity analyses, when comparing MenC at 14 months with MenACWY at 14 months, the influence of a difference in the duration of protection of both vaccines and the price differential was assessed. Assuming that herd immunity is still present, MenACWY is still cost-saving when the average duration of protection for MenACWY is 1 year shorter than for MenC (3 vs. 4 year), when the vaccine price per dose is the same for both vaccines . HoweverUnivariate sensitivity analyses, for the base-case MenACWY+MenACWY compared with MenACWY at 14 months, showed that the incidence of serogroup A,C,W135,Y disease had a high impact on the ICER. Also, the vaccine price of MenACWY and the case fatality rate had quite an impact on the ICER. No discounting of costs and effects substantially lowers the ICER, while applying a discount rate of 4% for both costs and effects dramatically increases the ICER .For the base-case, it is unlikely that vaccination with MenACWY+MenACWY could be considered cost-effective compared to MenC at 14 months as well as to MenACWY at 14 months. The scenario showing the prevention of a decline in herd immunity has a high probability to be considered cost-effective. Given the uncertainty of the model, 95% of simulations comparing MenACWY+MenACWY with MenACWY at 14 months were found below €1,750 per QALY and 100% below €15,800 per QALY.Our analysis shows that vaccinating with MenACWY at 14 months is cost-saving compared with the current situation in the Netherlands. This is mainly due to the lower vaccine price of MenACWY compared with MenC. Also, the prevention of more cases of meningococcal disease with MenACWY contributes to the favourable ICER.Using our base-case assumptions, adding a booster-dose at 12 years of age with MenACWY in addition to MenACWY at 14 months seems not to be a cost-effective strategy.Serogroup Y meningococcal disease was rare in Europe but in recent years an increase in the incidence of serogroup Y meningococcal disease has been reported In addition to a further increase in the incidence of serogroup Y disease, the potential loss of herd immunity against meningococcal C disease due to an unprotected adolescent population makes a booster dose at 12 years of age more favourable. Our scenario analysis shows that when herd immunity disappeared, MenACWY+MenACWY has the potential to be cost-effective. However, this scenario may be overrating since herd immunity will most likely disappear gradually. Moreover, part of the disease incidence reduction might be contributed to natural fluctuation. To estimate the effect of herd immunity and its disappearance more precisely, a transmission dynamic model should be used For our scenario analysis, we assumed that vaccination at 14 months only would not be sufficient to maintain herd-immunity, because a dose under the age of 5 years is not likely to maintain herd immunity as little herd immunity is observed in Spain where the MenC catch-up program was till the age of 5 years Experience with the MenC vaccine showed a reduction in serogroup C disease attack rates in unimmunized individuals and a significantly lower serogroup C carriage Data on the VE was estimated by post-vaccination studies which calculated VE by the screening method. Because this method uses data on the amount of cases in the population The clinical course and outcome of serogroup A, W-135 and Y disease was assumed to be equal to that of serogroup C disease, because limited data for serogroup A, W-135 and Y disease from the Netherlands is available. Two studies with a relatively low number of sero-group A, W-135 and Y cases indicate that serogroup W-135 and Y might be associated with a higher case-fatality rate Recently, it has been shown that three years after vaccination of toddles with MenACWY, antibody persistence was high for serogroups C, W-135 and Y, but was much lower for serogroup A Serogroup replacement by capsular switching due to vaccination was not modelled, because there is no evidence that vaccination with the MenC vaccine is an important driver in capsule switching of meningococci The MenACWY conjugate vaccine does not protect against serogroup B meningococcal (MenB) disease. Recently, a broad-coverage vaccine with the capacity to protect against MenB disease  was licensed in the European Union According to the results of this cost-effectiveness analysis, MenACWY at 14 months is cost-saving compared to MenC at 14 months, mainly due to a lower vaccine price. Adding a booster-dose with MenACWY at 12 years reduces the burden of disease but is not cost-effective with the current epidemiology. However, the scenario with the disappearance of herd immunity shows that the strategy with a booster-dose with MenACWY at 12 years has the potential to be cost-effective in the future. For a more precise estimation of the cost-effectiveness for the prevention of the loss of herd immunity, a dynamic model should be developed for the Netherlands.Appendix S1Meningococcal serogroup ACWY disease incidences.(DOCX)Click here for additional data file.Appendix S2Indirect costs.(DOCX)Click here for additional data file.


Proportions derived from neoclassical canons, initially described by Renaissance sculptors and painters, are still being employed as aesthetic guidelines during the clinical assessment of the facial morphology.1. to determine the applicability of neoclassical canons for Southern Chinese faces and 2. to explore gender differences in relation to the applicability of the neoclassical canons and their variants.3-D photographs acquired from 103 young adults  without facial dysmorphology were used to test applicability of four neoclassical canons. Standard anthropometric measurements that determine the facial canons were made on these 3-D images. The validity of the canons as well as their different variants were quantified.The neoclassical cannons seldom applied to these individuals, and facial three-section and orbital canons did not apply at all. The orbitonasal canon was most frequently applicable, with a frequency of 19%. Significant sexual dimorphism was found relative to the prevalence of the variants of facial three-section and orbitonasal canons.The neoclassical canons did not appear to apply to our sample when rigorous quantitative measurements were employed. Thus, they should not be used as esthetic goals for craniofacial surgical interventions. The human sculptures produced in ancient Greece, notably in the 4et alFarkas in lieu of the facial three-section canon. Moreover, the ‘rule of fifths’ Evaluation of facial aesthetics is a crucial to the planning of orthognathic surgery, facial plastic surgery, prosthodontic or orthodontic treatment. In these disciplines, a number of clinical textbooks and journal articles recommend derivatives of neoclassical canons as valid criteria that could be used during aesthetic evaluation. For example, the formulation of ‘facial thirds’ – in which the face is divided in the vertical plane in to three regions of equivalent height – is commonly used et alHow might one test these neoclassical formularies? With the advances in technology, non-invasive measurement systems based on stereophotography has been developed . Thus, iThe applicability of the following neoclassical canons for the Southern Chinese was tested;Three-section facial canon (tr-n = n-sn = sn-gn)Orbital canon (en-en = en-ex)Orbitonasal canon Naso–oral canon A detailed description of these canons can be found in 3-D photographs were acquired from 103 young adults  from Hong Kong. All subjects that met the following inclusion criteria were used for this study.Ethnic ChineseBetween 18–35 years of ageNo obvious facial deformitiesClass I skeletal patternNo history of maxillofacial or facial plastic surgeryThis study was approved by the Institutional Review Board of The University of Hong Kong/Hospital Authority Hong Kong West Cluster (Protocol No: UW 12-066). As no experimental interventions were performed on these subjects and due to the retrospective nature of this study a waiver of consent was granted by the IRB. The subject pictured here has granted his written consent as outlined in the PLoS consent form for publishing his photographs.3dMDface stereophotography system  was used to capture the 3-D facial photographs . Anthropometric landmarks that determine the facial Canons were selected on the 3-D images according to standard definitions .p = 0.372).There were no statistically significant differences in relation to age between the male  and female  subjects .The typical facial three-section canon was not prevalent in this sample. The “forehead>upper face<lower face” type was more common among males (51.9%), the “lower face>forehead>upper face” type was more common among females (49%).(en-en = ex-en).This canon was non-existent in this patient sample. All subjects had the en-en>ex-en variant confirming that the intercanthal distance was larger than the eye fissure length..Only 8.7% of the subjects conformed to the naso–oral canon. The ch-ch <1 ½  variant was the commonest indicating that mouth width was smaller in majority of males (92.2%) and females (82.7%) than predicted by the typical naso-oral cannon..The orbitonasal canon was found in 19.4% of the combined sample and was more prevalent in males (31.4%). However, the en-en>al-al variant was common; it was more applicable in males (90.4%) than females (56.9%).“Neoclassical canons” are frequently invoked (thought not by name) in current text books on orthodontics, prosthodontics, orthognathic surgery and plastic surgery, and they recommend these measurement prescriptions for the treatment planning. Despite the prevalence of their usage, these canons do not hold, as our project and other complementary studies et al.Many differences could be observed even among ethnic Chinese groups itself in relation to the facial canons. The applicability of the orbital and naso-oral canon was much higher in the sample from Mainland China reported by Wang Further, we found significant gender differences in relation to the frequency of facial three-section and orbitonasal canon. Most of the earlier studies on neoclassical canons did not explore sexual dimorphism in relation to their occurrence as they pooled results from both males and females.A complex assortment of main effects and interactions among genetic and environmental factors may have played significant roles in the genesis of morphological differences among ethnic groups. 5 cited in the literature due to some of the inherent limitations of landmark identification via stereophotogrammetry. The facial two-section, four-section and naso-aural canons were not tested as the vertex, zygion and some of the auricular landmarks cannot be identified accurately in stereophotographic images.It was not possible to check the applicability of all the neoclassical canonsThe aesthetic guidelines employed by present-day clinicians are rooted in the canons described for Renaissance art and sculptures, though to some extent they have been modified from the original. The anthropometric neo-classical canons for the most part did not apply to the Southern Chinese sample in this study. Thus, these canons do not provide useful formularies for planning surgical or non-surgical treatments for craniofacial dysmorphology.


Colin Crooks and colleagues studied patient outcomes in the 5 years after a non-variceal bleed and found an increased risk of all causes of death, over half of which were due to non-gastrointestinal causes. It is unclear whether an upper gastrointestinal bleed is an isolated gastrointestinal event or an indicator of a deterioration in a patient's overall health status. Therefore, we investigated the excess causes of death in individuals after a non-variceal bleed compared with deaths in a matched sample of the general population.Linked longitudinal data from the English Hospital Episodes Statistics (HES) data, General Practice Research Database (GPRD), and Office of National Statistics death register were used to define a cohort of non-variceal bleeds between 1997 and 2010. Controls were matched at the start of the study by age, sex, practice, and year. The excess risk of each cause of death in the 5 years subsequent to a bleed was then calculated whilst adjusting for competing risks using cumulative incidence functions.16,355 patients with a non-variceal upper gastrointestinal bleed were matched to 81,523 controls. The total 5-year risk of death due to gastrointestinal causes  ranged from 3.6%  to 15.2% , representing an excess over controls of between 3.6% (3.0%–4.2%) and 13.4% (12.4%–14.5%), respectively. In contrast the total 5-year risk of death due to non-gastrointestinal causes ranged from 4.1%  to 46.6% , representing an excess over controls of between 3.8% (3.1%–4.5%) and 19.0% (17.5%–20.6%), respectively. The main limitation of this study was potential misclassification of the exposure and outcome; however, we sought to minimise this by using information derived across multiple linked datasets.Deaths from all causes were increased following an upper gastrointestinal bleed compared to matched controls, and over half the excess risk of death was due to seemingly unrelated co-morbidity. A non-variceal bleed may therefore warrant a careful assessment of co-morbid illness seemingly unrelated to the bleed.Please see later in the article for the Editors' Summary Acute gastrointestinal bleeding is a potentially life-threatening abdominal emergency that remains a common cause of admission to hospital. Upper gastrointestinal bleeding  is roughly four times as common as bleeding from the lower gastrointestinal tract and is a major cause of morbidity and mortality. Upper gastrointestinal bleeding is also relatively common—every year in the United States, roughly, 100,000 people are admitted to hospital for treatment for this acute medical emergency—and the most common cause is peptic ulcer disease. Inflammation and tears in the mucosa are also common causes.In some acute emergencies, such as heart attacks , the most common cause of death relates to the associated cardiovascular disease but in other emergencies, such as stroke, death is commonly associated with other causes, such as cardiovascular disease and respiratory infections. However, despite upper gastrointestinal bleeding being the most common gastroenterology reason for admission to acute medicine, the long term outcomes of patients who have experienced a non-variceal upper gastrointestinal bleed are poorly understood . So in this study, in order to identify whether interventions might reduce mortality following a non-variceal upper gastrointestinal bleed , the researchers used information from an English database to investigate the causes of death by age and time in the 5 years following such a bleed, and compared these results with deaths in a matched sample of the general population.The researchers used longitudinal data from the English Hospital Episodes Statistics and General Practice Research Database to identify all patients who were admitted to the hospital for treatment of their first upper gastrointestinal bleed between April 1997 and August 2010. The researchers matched each case with a control of a similar age from the same General Practice and recorded causes of death from the whole cohort through the linked Office of National Statistics death register. The researchers then used a statistical method (cumulative incidence functions) to calculate the excess risk of death for those experiencing an upper gastrointestinal bleed compared to controls.-years. The rates and risk of death were 10%–15% lower for women than men. In the first month after a bleed, the mortality rate was increased for all causes of death, but the highest mortality rate was from non-malignant digestive disease (48 per 100 person-years), mostly linked to causes related to the upper gastrointestinal tract (35 per 100 person-years). For the remainder of the first year, the highest mortality rates were from malignant tumors (8.4 per 100 person-years), half of which were from sites outside the gastrointestinal tract. The researchers also found that circulatory and respiratory mortality rates were also increased over the first year but by 5 years, circulatory disease accounted for the highest mortality rate (2.5 per 100 person-years). In their analysis, the researchers calculated that the total 5-year risk of death due to gastrointestinal causes ranged from 3.6% in people ≤50 years to 15.2% in people ≥80 years, representing an excess risk of death of between 3.6% and 13.4%, respectively. The total 5-year risk of death due to non-gastrointestinal causes ranged from 4.1% in people ≤50 years to 46.6% in people ≥80 years, representing an excess risk of death of between 3.8% and 19.0%, respectively.Using these methods, the researchers identified 16,355 people who had an upper gastrointestinal bleed, of whom 6,242 subsequently died, and 81,523 matched controls. The researchers found that the crude mortality rate in the first 5 years following an upper gastrointestinal bleed was 16.0 per 100 personThese findings suggest that following an upper gastrointestinal bleed patients experienced excess risk of all causes of death, over half of which was due to non-gastrointestinal causes, particularly malignant tumors and cardiovascular disease. This excess in deaths was not explained by other simultaneous causes (co-morbidity) such as cancer or cardiovascular disease diagnosed before admission for the upper gastrointestinal bleed. An upper gastrointestinal bleed may be a marker of disease or an indicator of deterioration in non-gastrointestinal co-morbidity. A reassessment of non-gastrointestinal illnesses may be warranted in patients who have upper gastrointestinal bleeding.http://dx.doi.org/10.1371/journal.pmed.1001437.Please access these Web sites via the online version of this summary at upper gastrointestinal bleeding Wikipedia provides information on gastrointestinal bleedingMedlinePlus also provides useful information for patients on guidelines on managing acute gastrointestinal bleedingThe UK's NHS provides international consensus guidelines on managing non-variceal bleedingThe Annals of Internal Medicine has published Asia-Pacific consensus on managing non-variceal upper gastrointestinal bleedingThe journal Gut has published the  The causes of excess deaths following an acute medical event can demonstrate areas where mortality can be reduced. For example three-quarters of deaths following a myocardial infarction were found to be due to the cardiovascular disease itself, but after a stroke two-fifths of deaths were found to be due to related respiratory infections and cardiovascular disease Therefore, to identify whether interventions might reduce mortality following an upper gastrointestinal non-variceal bleed we investigated the causes of death by age and time in the 5 y following a non-variceal bleed, and compared them with deaths in a matched sample of the general population.A cohort study was designed using linked longitudinal data from the linked English Hospital Episodes Statistics (HES) data, General Practice Research Database (GPRD), and Office of National Statistics death register. This data linkage records all primary care events, hospital admissions, and causes of death between 1st April 1997 to 31st August 2010 for 3% of the English population. Because of the comprehensive English primary care system the population registered to the GPRD is representative of the general English population We selected as exposed all patients with a first non-variceal upper gastrointestinal bleed. A bleed was defined by a specific code for an upper gastrointestinal non-variceal bleed in either primary or secondary care who had a supporting code in the linked dataset. We previously described and published this methodology Patients who had a bleed recorded prior to the observed up to standard time period of our database, either in the hospital admissions database or in the longitudinal primary care record, were excluded. Bleeds prior to the observed up to research standard time period should be captured by the longitudinal primary care record, as historical records would be transferred with a patient when they change their primary care provider. Patients were required to be registered with a new primary care practice for at least 3 mo prior to any upper gastrointestinal bleed event to avoid including prevalent cases that might have been coded at the initial registration consultation. Follow-up started on the day of the first bleed.For each case five age- (±5 y) and sex-matched controls were selected who were alive at the time of the bleed and registered to the same general practice. Controls were required to have been registered with the primary care practice for at least 3 mo prior to the match date to be consistent with the definition for cases.Dates of death for the whole cohort were extracted from the linked data using the Office of National Statistics death register. All deaths in England are coded and recorded in the Office of National Statistics Death register from death certificates using the World Health Organization (WHO) guidelines Patients were followed up from the date of gastrointestinal bleed or matching until either death or censoring of the patient record (defined as the end of the observed up to research standard time period). Follow-up did not stop if a subsequent bleed occurred but continued until death or censoring of the patient record.-years following upper gastrointestinal bleed were calculated overall and by the most frequent ICD 10 chapter headings. These rates were then stratified by age group and year post bleed. Age was grouped into <50, 50–59, 60–69, 70–79, and ≥80-y-old. The time post bleed was stratified into the first 30 d, 1 mo to 1 y, and 1 y to 5 y.Crude numbers of deaths and rates per 1,000 personCrude mortality rates were calculated for those still alive and at risk at each time point. However, when studying specific causes of death this group of survivors might not be representative of the initial cohort, since deaths from other causes can select out those with relevant risk factors. One method to adjust for this bias uses cumulative incidence functions (CIFs) that calculate the probability of overall survival from all causes, combined with the instantaneous hazard of death for each specific cause We assessed whether the excess mortality associated with a bleed for each cause of death was confounded by pre-existing co-morbidity, excess alcohol, or smoking status, and whether it varied by the site of bleed. Pre-existing co-morbidity was measured by the Charlson index  could not be matched to controls and were therefore excluded from the study. Baseline demographics are shown for the bleed cases and the matched controls in n = 133), chronic duodenal ulcer with haemorrhage K264 (n = 92), chronic gastric ulcer with haemorrhage K254 (n = 44), and chronic peptic ulcer with haemorrhage K274 (n = 27). The combined codes of chronic duodenal ulcer with haemorrhage and perforation K266, acute duodenal ulcer with haemorrhage K260, oesophageal haemorrhage K228, acute gastric ulcer with haemorrhage K250, and chronic gastric ulcer with haemorrhage and perforation K256 were the underlying cause in a further ten deaths.Out of a total of 1,536 deaths within 30 d of a bleed, 306 (17%) had an underlying cause coded as an upper gastrointestinal bleed determined by the following ICD 10 codes: gastrointestinal haemorrhage K922  in the first year to 7.3 deaths per 100 person-years (95% CI 7.0–7.7) over the subsequent 4 y. The rates and risk of death were 10%–15% lower for women than men, but the relative differences between causes of death were similar. Therefore -years), and this was mostly due to causes related to the upper gastrointestinal tract (35 per 100 person-years). For the remainder of the first year the highest mortality rates were from neoplasms (8.4 per 100 person-years), half of which were from sites outside the gastrointestinal tract. Circulatory and respiratory mortality rates were also increased over the first year, but to a lesser extent than for digestive disease and neoplasms. However, by 5 y the category with the highest mortality rate was circulatory disease (2.5 per 100 person-years). The mortality rates for each cause of death remained slightly higher at 5 y following an upper gastrointestinal bleed than in the matched controls . Our findings contrast with those for other acute life-limiting medical events. For example, three-quarters of the excess death following a myocardial infarction were shown to be due to the cardiovascular disease, and two-thirds of the excess death following a stroke were shown to be due to related respiratory infections, cardiovascular disease, or the cerebrovascular disease itself The main strengths of this study compared to previous studies are its larger size, follow-up, competing risk adjustment, and general population setting. These factors allowed us to calculate accurate, unbiased, and more detailed mortality rates for different causes of death than has previously been done to our knowledge. We used linked electronic primary and secondary health care records in which the definition of bleeding was previously found to be accurate. In HES the incidence of peptic ulcer haemorrhage (1992–1995) was comparable to the 1993 regional BSG audit  A possible weakness of our study is the potentially imperfect data on some recognised risk factors for the excess mortality. These data may have caused us to overestimate the excess mortality associated with upper gastrointestinal bleeding. However, the GPRD contains comprehensive recording of all available diagnoses and prescriptions, and with the addition of information from hospital records, any bias from underreporting of co-morbidities will have been minimised. Underreporting might have occurred for alcohol and smoking; however, these risk factors did not show any important confounding of the association between upper gastrointestinal bleeding and excess mortality at their current level of ascertainment, so it is unlikely any increased reporting would account for the magnitude of the association we identified.The information on the fact and cause of death in our study is from the Office of National Statistics death registry, which uses standardised WHO guidelines to extract information from death certificates. Although death certificates can sometimes be imprecise, they are the official legal requirement for ascertaining the cause of death. As a consequence, death certificates are the only standardised method to extract cause of death information across a large population. Here, the underlying cause of death information was used to avoid the effect of changes in coding requirements over time Although the Charlson index was not directly developed for routine records, longer term follow-up, or cause specific mortality, we believe its original purpose in predicting all cause mortality using diagnosed co-morbidity was suitably similar to our study to be useful Previous studies of cause of death following upper gastrointestinal bleeding were identified by a PubMed search  across all years up to September 2012) and by examining the references of selected papers from the search results. There were a number of studies of cause of death during the first 30 d following an upper gastrointestinal bleed Helicobacter pylori eradication n = 487, deaths = 142). This methodology limits the study's generalisability to a contemporary population and introduces a selection bias towards those deemed suitable for an endoscopy In contrast, there have been only a few studies examining causes of death in the long term following a bleed. Studies in the 1980s and 1990s followed up peptic ulcer cohorts post surgical treatment rather than upper gastrointestinal bleeds shown in . These sWe found a considerable excess of all causes of death in individuals following a non-variceal upper gastrointestinal bleed, and over half of these deaths were due to non-gastrointestinal co-morbidity, particularly neoplastic and cardiovascular disease. This excess in deaths was not explained by co-morbidity such as cancer or cardiovascular disease diagnosed prior to the admission. Therefore, an upper gastrointestinal bleed may be a marker of disease or an indicator of a deterioration in non-gastrointestinal co-morbidity. Consequently, this analysis suggests that for patients who have a non-variceal upper gastrointestinal bleed, re-assessment of co-morbidity should be considered in the follow-up period.Table S1Mortality rate per 100 person-years in patients with no upper gastrointestinal bleeding, stratified by cause of death by ICD 10 headings in the 5 y post matching to a bleed case.(DOC)Click here for additional data file.Table S2Mortality rate per 100 person-years in patients following an upper gastrointestinal bleed, stratified by cause of death by ICD 10 headings and age group in the 5 y post bleed.(DOC)Click here for additional data file.Table S3Mortality rate per 100 person-years in patients with no upper gastrointestinal bleeding, stratified by cause of death by ICD 10 headings and age group in the 5 y post matching to a bleed case.(DOC)Click here for additional data file.Table S4Excess cumulative incidence function 5 y post upper gastrointestinal bleed by age group and recorded site of bleeding. 95% CIs obtained by bootstrapping (500 iterations).(DOC)Click here for additional data file.


Data on right ventricular pressure and volume, and systemic arterial pressure obtained before, during, and after inferior vena cava occlusion were analyzed using a mathematical model of realistic ventricular mechanics coupled with a simple model of the pulmonary and systemic vascular systems. The model invokes a total of 26 adjustable parameters, which were estimated based on least-squares fitting of the data. Of the 26 adjustable parameters, 14 were set to globally constant values for the entire data set. It was necessary to adjust the remaining 12 parameters to match data from all experimental groups. Of these 12 individually adjusted parameters, three parameters representing pulmonary vascular resistance, pulmonary arterial elastance, and pulmonary arterial narrowing were found to significantly change in HySu-induced remodeling. Model analysis shows a monotonic change in these parameters as disease progressed, with approximately 130% increase in pulmonary resistance, 70% decrease in unstressed pulmonary arterial volume, and 110% increase in pulmonary arterial elastance in the 28-day group compared to the control group. These changes are consistent with prior experimental measurements. Furthermore, the 28-day data could be explained only after increasing the passive elastance of the right free wall compared to the value used for the other data sets, which is likely a consequence of the increased RV collagen accumulation found experimentally. These findings may indicate a compensatory remodeling followed by pathological remodeling of the right ventricle in HySu-induced pulmonary hypertension.A computer model was used to analyze data on cardiac and vascular mechanics from C57BL6/J mice exposed to 0 ( Pulmonary arterial hypertension (PAH) is a pathophysiological condition of sustained mean pulmonary arterial pressure greater than 25 mmHg at rest with a pulmonary capillary wedge pressure lower than 15 mmHg  from compartment 1 to 2 is calculated from pressure in compartment 1 (P1) and compartment 2 (P2) and the resistance between the two compartments (R). The rate at which volume of a compartment changes is given by:where the flow rate . When the occlusion is released, the resistance is returned to the non-occlusion value.The VCO perturbation is captured in the model by increasing the resistance The set of parameter values, δ, representing the control (0-day) group, is obtained using simultaneous least squares fitting of the pressure and volume recordings of all data from this group:X represents the variables RV pressure, RV volume, and aortic pressure. The minimization of the mean residual error (objection function) E(δ) for optimal estimation of the model parameter set is carried out using MATLAB  based code of FORTRAN package called PIKAIA implementing Genetic Algorithm  includes 4 parameters associated with the heart model and 8 associated with the circulatory model. Three members of this set are associated with the pulmonary circulation: RPVB, EPA, VdPA.The individually estimated set of parameters . All results are represented as mean ± standard deviation  set is estimated from 4 independent control mouse recordings of RV pressure, volume, and aortic pressure. Heart rate is calculated from the aortic pressure time series to drive the sarcomere mechanics model (see section IVC) and downstream (CVC) of the point of occlusion . Heart rate remains with ±0.7% of the mean value for the time course illustrated in Figure Figure Figure Figures Following VCO release, the RV pressure and volume return to their baseline values within a few heart beats for 0, 14, and 21-day hypoxic mice , pulmonary arterial elastance (EPA), and pulmonary arterial narrowing (VdPA) were estimated as functions of PAH progression . The predicted increase in RPVB is consistent with the experimental measurement on total PVR by Wang et al. , suggesting significant pulmonary vascular remodeling at this stage in response to HySu.Abe et al.  reportedIt has been reported that the increased afterload associated with chronic hypoxia exposure alone will lead to RV functional adaptation to maintain ventricular-vascular coupling  was calculated. Stroke work density is computed as the area enclosed by the myofiber stress-natural strain loop (Kroon et al., f is Cauchy myofiber stress, εf is natural myofiber strain, and wf is RW stroke work density. Calculated mean stroke work densities for the four groups are shown in Figure where σWang et al.  report RIn sum, the major findings to emerge from this study are:Observed increases in pulmonary vascular resistance associated with PAH are accompanied by commensurate increases in pulmonary arterial stiffness. Predicted changes in vascular resistance and elastance with chronic hypoxia and SUGEN treatment are illustrated in Figure PA, defining the volume of PA compartment at zero pressure. Thus the model prediction is that the volume of the PA compartment is significantly reduced in late stage PAH.Model analysis predicts a significant inward remodeling of the pulmonary arteries that becomes apparent only in the later stage of PAH, i.e., 28-day group. Inward remodeling of the PA is captured by the parameter VdModel analysis predicts substantial stiffening of RV in the 28-day group, suggesting a degree of maladaptive remodeling in this group. While the fact that it was not necessary to increase the passive stiffness of the RV compared to the baseline to represent the 14- and 21-day groups does not necessarily mean changes in the passive mechanical properties of the myocardium have not occurred in these groups, it does demonstrate that any changes that did occur become apparent only in the 28-day group. This substantial increase in passive stiffness in the 28-day group is associated with a predicted drop in the mean of RV free wall stroke work density per beat, as illustrated in Figure The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Most Western health systems remain single illness orientated despite the growing prevalence of multi-morbidity. Identifying how much time people with multiple chronic conditions spend managing their health will help policy makers and health service providers make decisions about areas of patient need for support. This article presents findings from an Australian study concerning the time spent on health related activity by older adults (aged 50 years and over), most of whom had multiple chronic conditions. A recall questionnaire was developed, piloted, and adjusted. Sampling was undertaken through three bodies; the Lung Foundation Australia (COPD sub-sample), National Diabetes Services Scheme (Diabetes sub-sample) and National Seniors Australia (Seniors sub-sample). Questionnaires were mailed out during 2011 to 10,600 older adults living in Australia. 2540 survey responses were received and analysed. Descriptive analyses were completed to obtain median values for the hours spent on each activity per month. The mean number of chronic conditions was 3.7 in the COPD sub-sample, 3.4 in the Diabetes sub-sample and 2.0 in the NSA sub-sample. The study identified a clear trend of increased time use associated with increased number of chronic conditions. Median monthly time use was 5–16 hours per month overall for our three sub-samples. For respondents in the top decile with five or more chronic conditions the median time use was equivalent to two to three hours per day, and if exercise is included in the calculations, respondents spent from between five and eight hours per day: an amount similar to full-time work. Multi-morbidity imposes considerable time burdens on patients. Ageing is associated with increasing rates of multi-morbidity. Many older adults are facing high demands on their time to manage their health in the face of decreasing energy and mobility. Their time use must be considered in health service delivery and health system reform. Research on multi-morbidity  use time when undertaking health related activity (HRA). Recently Krueger noted that “Failing to take account of patient time leads us to exaggerate the productivity of the health care sector, and to underestimate the cost of health care” Management of chronic conditions includes self-management as well as interactions with health services, which together comprise HRA. Knowledge of the self-management tasks people perform and their duration has the potential to inform the planning and design of services to support efficient self-management and optimal health outcomes Self-management encompasses a range of tasks including managing the medical aspects of the condition , maintaining or changing the ways that necessary or meaningful tasks are completed , and coping with the emotions experienced Patients self-manage because they live with their condition on a daily basis and need to develop strategies to care for themselves In Australia’s health system clinical guidelines, health policies and care pathways have been developed largely in relation to single illnesses and are focussed on achieving optimum medical outcomes for single conditions. The efficient use of patient time may be taken into account, for example, in cycles of care guidelines for people with diabetes that optimise the time period between various tests . However, when multiple care pathways are brought into play because a patient has multi-morbidity, the impact on patient time will be quantitatively and perhaps qualitatively different.The social value of time has been addressed by other research The survey built on an earlier qualitative study of 61 patients and 17 informal carers, living with chronic illness in the western suburbs of Sydney and the Australian Capital Territory The sample drawn from NSA members was stratified by State and age (50–64.65–74.75 years and over), with an oversampling of older members to increase the proportions with chronic illness. The sample of registrants aged 50 years or over from the NDSS register, was stratified by State, age  and gender with no oversampling as the scheme operates specifically to subsidise costs for persons with diabetes. Samples were selected using simple random sampling within each stratum. All 3,062 members of Lung Foundation Australia with COPD were surveyed. Estimates are weighted by stratum response rates, and analyses undertaken separately for each sub-sample.The rationale behind this complex sampling framework was that NSA respondents may provide an overview of the problem in the elderly, whereas NDSS targets patients with diabetes, a condition usually associated with co-morbidity Ethics approval for the survey was obtained from the Australian National University Human Research Ethics Committee (Protocol number: 2010/468) in 2010. All respondents provided informed consent to participate by returning completed questionnaires. As well as taking care over the issues of confidentiality and consent, we were at pains to avoid any additional time burden on the respondents. We therefore tested the length of the questionnaire in the pilot.A questionnaire collected data on time use see . Recall Activities related to use of medical and allied health services in the previous month; such as making appointments, travelling to health services, waiting in waiting rooms, attending appointments and having medical treatments. These activities are referred to as ‘clinic activities’.Activities related to obtaining information, support or products in the previous month; including attending rehabilitation programs, education programs and support groups, shopping for special foods and looking for/reading health information. These activities are referred to as ‘other activities’.Activities undertaken in domestic spaces on most days . These activities are referred to as ‘home activities’.The questionnaire also collected data on a range of demographic and other variables including whether people lived in major cities, regional or remote areas, and self-reported use of health services. Australia is a large country where most people live in major cities. The number of chronic conditions was also self-reported, a well-established method for the measurement of multi-morbidity Results are presented in terms of hours per month on each grouped activity. As the distribution of time use is highly skewed, results are presented using medians. In order to examine the groups with the highest time use we also examined the time spent by individuals in the top decile of time use. The measure of total time used here excludes exercise unless otherwise stated. While the majority of respondents spent some time on HRA, many people did not spend time on every specific HRA included in the survey . When reporting on more detailed components of time use, we therefore report on both the proportion of people undertaking these tasks, and time spent by those undertaking them. Standard errors and confidence intervals were derived using bootstrapping techniques within Stata11 Overall 2,540 responses were received reflecting an overall response rate of 24.0%, with 427 respondents in the Diabetes sub-sample (16.8% response), 681 in the COPD sub-sample (22.0% response), and 1,432 in the NSA sub-sample (28.4% response). More details of the response rates are shown in The time spent on HRA by people in the different demographic and health categories is shown in Table B in There are few significant differences in time use between age, region, qualifications and income categories although some weak patterns are apparent. The one really clear set of statistically significant time relationships across all three sub-samples is with number of conditions. The number of conditions is related to time use in all sub-samples and is highly significant in all sub-samples  on HRA including exercise were 25.8 (22.0–29.5–) hours per month for the Diabetes sub-sample, 31.2 (29.1–33.2) hours for the COPD sub-sample, and 21.7 (20.3–23.0) hours for the NSA sub-sample. Therefore, exercise on average added 14–16 hours per month to median activity, or around half an hour per day. It roughly doubled the estimated median time spent on HRA for the targeted samples and quadrupled it for the NSA sub-sample. Sixteen percent of the NSA sub-sample undertook exercise but no other daily HRA, while there were very few such people in the other samples as nearly all were engaged in some other daily HRA.th percentile times showing the total time used (excluding exercise) by the top 10% of the population in each of these categories. The top 10% of time users spent over 51.4 (43.0–59.8) hours per month in the Diabetes sub-sample, over 62.6 (53.5–71.7) hours per month in the COPD sub-sample, and over 34.1 (30.7–37.5) hours per month in the NSA sub-sample on HRA. However, those people with five or more conditions spent 30 to 40 hours per month more than that, with those in the top quintile of the COPD sample who had five or more conditions spending more than 109.5 (85.7–133.3) hours per month which is equivalent to 3.5 hours per day on managing their conditions.To provide an alternate perspective, Table D in This study has been the first to quantify the time spent on HRA by older Australians with multi-morbidity. The study found that the more chronic illnesses a person had the more time they spent managing their health . Median total time spent in the past month on HRA (excluding exercise) was 16.5 hours for people in the COPD sub-sample, 11.1 hours for people in the Diabetes sub-sample, and 5.2 hours for people in the NSA sub-sample. People in the top 10% of time use from the COPD sub-sample spent 62.6 hours per month or more on HRA, the top 10% of the Diabetes sub-sample spent 51.4 hours per month or more, and the top 10% of the NSA sub-sample spent 34.1 hours per month. Within all sub-samples the time increased with increasing co-morbidity, with estimates of 109.5, 80.1 and 71.5 hours per month for people with five or more conditions in the COPD, Diabetes and NSA sub-samples respectively.The significantly higher total time for the COPD sub-sample is likely to be due to two factors; 1) that people in this sub-sample had on average more conditions than those in the other sub-samples, and 2) the time demands associated with COPD are higher than many other conditions.The number of prescribed medications a person takes is also a major and significant determinant of time use, and while numbers of conditions and numbers of medications are clearly correlated they potentially have independent effects on time use. These findings are consistent with our previous qualitative research showing the constraints that multi-morbidity place on the way people spend their time th percentile for people with 5 or more conditions is another 30–40 hours per month –110.1 hours, 147.5 hours and 118.5 hours for the Diabetes, COPD and NSA sub-samples respectively. These times are equivalent to between 3.5 and almost five hours per day on average. This means that people with the highest number of conditions in the 90th percentile were spending between 5.5 and eight hours each day on HRA.While the study shows median monthly time use of 5–16 hours per month overall for our three sub-samples, which are not excessive time demands, the demands on those with multi-morbidity become much larger, and people in the top decile of those with five or more conditions face time demands (at the median) equivalent to two to three hours per day. For people with five or more conditions it may be reasonable to assume that exercise is undertaken as part of self-management with a view to optimising health, as many of these people will be restricted by their multiple conditions. Under this assumption, with exercise added the 90The study described the median times spent on HRA either with health services or at home. A gradation of time use for HRA was found with most of the time spent on home activities, followed by time spent on clinic activities and the least time spent on ‘other’ health activities such as shopping for medicines or attending rehabilitation.While it is not surprising that the study shows that the factors determining time use relate to health it is interesting that other factors do not seem to be material .This first study into time use on HRA undertaken by Australians with chronic conditions has shown that illness management occupies considerable time for those with multi-morbidity. These data cannot identify how much of this time is spent on activities which are unnecessary or inefficient (perhaps due to lack of co-ordination). It is clear, however, that clinicians assisting patients with multi-morbidity need to be aware of the time demands made of patients. Options for reducing this demand may include instigating better co-ordination for booking consultations, identifying methods for reducing waiting times, improving support for self-management activities On a larger scale, under the current Australian health system reform, strategies are underway to improve team care and care co-ordination Finally, for a given level of multi-morbidity, some combinations of illnesses are likely to be associated with higher levels of HRA than others, depending on the concordance or discordance of the illnesses This study had a relatively low response rate, and because of its tripartite structure had relatively small samples in each group. It is possible that people with poor health may have been deterred from responding to the survey and if this is the case then the reported time use may under-estimate the real costs. The Diabetes and COPD sub-samples had lower response rates than the NSA sub-sample. However, as shown in The study used a recall questionnaire rather than a time use diary to minimize inconvenience to respondents and to extend the period over which the time use could be explored. While there is a known risk of inaccurate recall associated with questionnaires This study has demonstrated that the time people spend on HRA is substantial and identified a strong gradient in time demands and levels of illness. However, many questions remain unanswered. An important question is how people prioritise their health activities against other activities within the fixed amount of time available each day. Deciding how much time to spend on their health may depend on time scarcity, practical issues and issues of personal prioritisation The study has not captured fluctuations of time use associated with the trajectory of particular conditions. Nor, as also noted above, did the study capture the opportunity costs; the social time costs that are incurred through the chronic illness time costs Increasing numbers of chronic conditions are significantly associated with increasing time spent on HRA. On average, people in this study who only had one chronic condition spent between three and 13 hours each month on HRA, depending on the sub-sample. However, people with five or more chronic conditions spent on average between 16 and 27 hours each month on HRA, depending on the sub-sample. For those in the top decile of people with five or more chronic conditions in the COPD sub-sample the time spent on HRA was as high as 110 hours per month. Increasing numbers of prescribed medications is also significantly associated with increasing time spent on HRA. We suggest that in planning future self-management programs, health care services and health policies, considerations be made in terms of patient time use; the costs and benefits to people with multi-morbidity, who may be experiencing significant constraints on their time and changes to the way they use and experience that time.Attachment S1Final survey.(PDF)Click here for additional data file.Attachment S2Response rates.(DOCX)Click here for additional data file.File S1Tables (A–E).(DOCX)Click here for additional data file.


To examine herpes simplex virus 2 (HSV-2)/HIV co-infection as a contributing factor in the increase in HIV infection among non-injecting heroin and cocaine users in New York City.Subjects were recruited from the Beth Israel Medical Center drug detoxification and methadone maintenance programs in New York City in 1995–1999 and 2005–2011. All reported current heroin and/or cocaine use and no injection drug use. A structured questionnaire was administered and serum samples collected for HIV and HSV-2 testing. Population-attributable risk percentages (PAR%s) were estimated for associations between HSV-2 and increased susceptibility to and increased transmissibility of HIV among female NIDUs.785 subjects were recruited from 1995–1999, and 1764 subjects from 2005–2011. HIV prevalence increased from 7% to 13%, with nearly uniform increases among all demographic subgroups. HSV-2/HIV co-infection was common in both time periods, with an average (over the two time periods) of 80% of HIV negative females infected with HSV-2, an average of 43% of HIV negative males infected with HSV-2; an average of 97% of HIV positive females also infected with HSV-2 and an average of 67% of HIV positive males also infected with HSV-2. The increase in HIV prevalence was predominantly an increase in HSV-2/HIV co-infection, with relatively little HIV mono-infection in either time period. The estimated PAR%s indicate that approximately half of HIV acquisition among females was caused by HSV-2 infection and approximately 60% of HIV transmission from females was due to HSV-2 co-infection.The increase in HIV infection among these non-injecting drug users is better considered as an increase in HSV-2/HIV co-infection rather than simply an increase in HIV prevalence. Additional interventions (such as treatment as prevention and suppressing the effects of HSV-2 on HIV transmission) are needed to reduce further HIV transmission from HSV-2/HIV co-infected non-injecting drug users. While injecting drug use is strongly associated with HIV in many parts of the world. In this report, we examine the relationships between HSV-2 and HIV infection over a time period in which HIV prevalence doubled among non-injecting drug users in New York City. HSV-2 increases susceptibility to HIV infection through physical disruption of the epithelial surface by HSV-2, and recruitment and persistence of inflammatory cells in the genital tract during HSV-2 reactivation at mucosal surfaces, The data reported here are derived from ongoing analyses of data collected from drug users entering the Beth Israel Medical Center drug detoxification and methadone maintenance programs in New York City. The methods for this “Risk Factors” study have been previously described in detail Both injecting and non-injecting drug users entering the detoxification and methadone maintenance programs are eligible to participate in the study. The present analyses include only persons who reported that they have never injected illicit drugs (never-injecting drug users or NIDUs). Hospital records and the questionnaire results are checked for consistency on route of drug administration and subjects are examined for physical evidence of injecting. The data presented here are from subjects who participated in the study from 1995 to 1999 and from 2005 to 2011. Changes in the aims of the study did not allow for sampling of never-injecting drug users between 2000 and 2004.In the detoxification program, research staff visited the general admission wards of the program in a preset order and examined all intake records of a specific ward to construct lists of patients admitted within the prior 3 days. All of the patients on the list for the specific ward were then asked to participate in the study. Among patients approached by our interviewers, willingness to participate has been greater than 95%. After all of the patients admitted to a specific ward in the 3-day period have been asked to participate and interviews have been conducted among those who agreed to participate, the interviewer moved to the next ward in the preset order. As there was no relationship between the assignment of patients to wards and the order that the staff rotated through the wards, these procedures should produce an unbiased sample of persons entering the detoxification program. In the methadone program, newly admitted patients (admitted within the previous month) were asked to participate in the research during their intake process. In both programs, willingness to participate has been high, with approximately 95% of those asked agreeing to participate.never having injected illicit drugs. Most HIV risk behavior questions referred to the 6 months prior to the interview, and thus would cover the time prior to entry into drug treatment. A modest percentage of the male subjects  reported engaging in male-with-male sex. As we were particularly interested in HIV infection due to heterosexual transmission, subjects reporting MSM behavior were not included in the analyses presented here. (A separate report on HSV-2 and HIV among subjects reporting MSM behavior is in preparation.)Written informed consent was obtained and a structured questionnaire covering demographics, drug use, sexual risk behavior, and use of HIV prevention services was administered by a trained interviewer. Both persons who used drugs through injecting and non-injecting routes of administration were recruited into the study, but the data presented here include only persons who reported After completing the interview, each participant was seen by an HIV counselor for pretest counseling and serum collection. The informed consent specifically included permission to store serum samples for future testing. HIV testing was conducted at the New York City Department of Health Laboratory using a commercial, enzyme-linked, immunosorbent assays (EIA) test with Western blot confirmation . HSV-2 testing was conducted for all subjects beginning in 2005 and was performed by BioReference Laboratories using the Focus HerpeSelect 1 and 2 ELISA. We used an optical density value of 1.1 or greater for classifying a subject as HSV-2-seropostive on the HerpeSelect assay. Samples positive on HerpeSelect were confirmed using the BioPlex 2200 Multiplex System  We did not test participants surveyed between 1995 and 1999 for HSV-2 at the time of the interview. We were, however, able to assess HSV-2 status by analyzing leftover serum from these participants. Leftover serum was aliquotted into 0.5 ml aliquots, frozen and stored at −70 degrees Celsius. In order to compare relationships between HSV-2 and HIV among NIDUs prior to beginning regular HSV-2 testing in 2005, we selected a stratified sample of 200 NIDUs who participated in the study between 1995 and 1999. Serum samples from these NIDUs were thawed and tested for HSV-1 and HSV-2 as described above. We stratified the sample of NIDUs according to gender and HIV serostatus, such that 100 NIDUs were selected for each gender, with 80 HIV seronegative males, 80 HIV seronegative females, 20 HIV seropositive males and 20 HIV seropositive females. Sampling was random within these strata.We estimate “population attributable risk percentages” (PAR%s) Stata statistical programs HSV-2 was significantly associated with HIV in both time periods, odds ratio (OR) = 3.2 (95% CI 1.4 to 7.6) for 1995–1999 and OR = 3.2 (95% CI 2.3 to 4.4) for 2005–2011.The extremely high HSV-2 prevalence among the HIV seropositive females, however, suggests that an odds ratio may not accurately capture the relationship between infection with the two viruses. There was a similar pattern among males, though the pattern was less extreme. A plurality of male subjects were not infected with either virus (59% in 1995–1999 and 46% in 2005–2011). There were very modest percentages of the males who were HIV seropositive but HSV-2 seronegative .Among both males and females the major changes over the two time periods were 1) the decreases in the percentage of subjects with no infections and 2) the increases in the percentage of subjects infected with both HSV-2 and HIV . Population attributable risk percentages (PAR%s) are a standard method for assessing the importance of a casual risk factor (HSV-2 infection) in the incidence of a disease (HIV infection) in a population. To directly calculate the PAR%s for HSV-2 infection causing increased susceptibility to HIV infection and HSV-2 infection causing increased transmissibility of HIV infection in our population of NIDUs, we would need to know: a) the frequencies of risk behavior (unsafe sex) between HIV seropositive and HIV seronegatives NIDUs so that we could control for risk behavior in assessing the effects of HSV-2 on HIV transmission, b) the HSV-2 status of the NIDUs acquiring HIV when new HIV transmissions occurred, and c) the HSV-2 status of the NIDUs transmitting HIV when new HIV transmissions occurred.We do not have this information for our population of NIDUs. However, the very high rates and narrow ranges of HSV-2 among female NIDUs permit us to make some reasonable assumptions in order to quantitatively estimate the importance of HSV-2 infection for heterosexual transmission of HIV among the NIDUs. We used the following two assumptions:Since HSV-2 among HIV seronegative female NIDUs was 76% in 1995–1999 and 83% among female NIDUs in 2005–2011, we assumed an average of 80% HSV-2 seroprevalence among female NIDUs when they acquired HIV from male NIDUs.Since HSV-2 among HIV seropositive female NIDUs was 95% in 1995–1999 and 98% among female NIDUs in 2005–2011, we assumed an average of 97% HSV-2 seroprevalence among female NIDUs when they transmitted HIV to male NIDUs.Freeman et al. conducted a meta-analysis of studies of the effects of HSV-2 on HIV transmission and found that HSV-2 infection creates a relative risk of 2 to 3 for acquisition HIV In this report, we compared two samples of non-injecting drug users entering the Beth Israel Medical Center detoxification and methadone maintenance programs in New York City. There were multiple differences across the two samples; compared to the 1995–1999 subjects, the 2005–2011subjects were older, more likely to be African-American and more likely to smoke crack cocaine. The most dramatic difference, however, was that the 2005–2011 subjects were twice as likely to be HIV seropositive (13%) compared to the 1995–1999 subjects (7%). The doubling in HIV prevalence was quite consistent across demographic and behavioral subgroups, indicating that the increase in HIV prevalence was not a function of differences in the composition of the two samples. The increase in HIV prevalence (6% over a 10 year period) corresponds to an incidence of approximately 1 to 2/100 person-years, which is an unusually high HIV incidence for a heterosexual population in a high income country.There are undoubtedly multiple factors that contributed to the increase in HIV prevalence over time among these non-injecting drug users. Heterosexual risk behavior is the predominant mode of HIV transmission in this population, , and thus continuing heterosexual risk behavior would be necessary for any increase in HIV prevalence. There was, however, only a very modest increase in sexual risk behavior from 1995–1999 to 2005–2011, so that increased sexual risk behavior is not a likely explanation for the increase in HIV prevalence.HSV-2 increases both susceptibility to and transmissibility of HIV infection, and the high levels of HSV-2 in the population in both time periods undoubtedly contributed to further spread of HIV among these NIDUs. The estimated PAR%s for increased susceptibility to HIV and increased transmissibility of HIV due to HSV-2 infection among females indicate a major causal role for HSV-2 in HIV infection among these NIDUs. The HSV-2 increases in susceptibility to HIV and increase in transmissibility of HIV for the female NIDUs would be relatively uniform across the racial/ethnic, age and behavior groups in our samples, thus these biological factors could be driving the relatively uniform increases in HIV seen in HSV-2 prevalence was already high in the 1995–1999 sample, and the increase in HIV prevalence over the two time periods is best seen as a continuation of the effect of HSV-2 infection on HIV transmission that began before 1995 rather than a new development that started in 1995. Indeed, it would be an oversimplification to think of HIV among these NIDUs as only an HIV epidemic. Rather, as shown in Several limitations of the present study need to be considered. First, the data presented here are from subjects recruited at a single set of drug treatment programs. However, the treatment programs are very large, serve the city as a whole, and the 2005–2011 data are consistent with HIV prevalence among NIDUs recruited from community settings in New York City in 2004 Second, the research design used in this study was multiple cross sectional surveys, so it was not possible to observe new HSV-2 and new HIV infections in individual subjects. This meant that we were not able to identify the risk behaviors or HSV-2 status of the person acquiring HIV or the risk behaviors or HSV-2 status of the person transmitting HIV at the time of transmission. We thus could not estimate relative risks for the biological effects of HSV-2 infection on susceptibility and transmissibility specific to our population but had to use relative risks taken from the literature. If the biology of HSV-2 infection among our NIDU subjects is greatly different from the biology of HSV-2 infection among females in sub-Saharan Africa, where most of the research on HSV-2 and HIV has been conducted, then our estimates of the PAR%s for female NIDUs would be in error. The very strong relationship between HSV-2 and HIV infection we observed, however, does suggest that HSV-2 does create substantially increased susceptibility to HIV among our female NIDUs.We would note that conducting a prospective cohort study over decades, with an estimated HIV incidence of 1–2/100 person-years, measuring HSV-2 prevalence in both persons acquiring and transmitting HIV, to determine a statically reliable estimate of the numbers of persons who became infected with HIV, transmitted HIV to others, and then became infected with HSV-2, would be prohibitively expensive.underestimate the contribution of HSV-2 to HIV transmission among these NIDUs.Because of a substantial minority (one third) of the HIV infected male NIDUs were not infected with HSV-2, we did not estimate PAR%s for the male NIDUs. The very high HSV-2 prevalence among HIV seropositive females  which is clearly consistent with trend reported here from subjects in this study.Finally, we were not able to assess sexual mixing between NIDUs and other groups in the city. It is quite likely that some of the HSV-2 and HIV transmission occurred between NIDUs and persons who injected drugs (PWID) and between NIDUs and persons who did not use heroin, cocaine and methamphetamines. However, it does not seem that transmission from other groups was sufficiently common to alter the patterns of HSV-2 and HIV infection seen in both NIDU samples.These limitations are important, but it is very difficult to imagine how they would have created the strong patterns in HSV-2 and HIV infection and the increase in HIV prevalence over time that we observed. Rather it is much more likely that these patterns are sufficiently strong that we observed them despite the limitations.HIV infection among non-injecting drug users in New York City doubled from the late 1990s to the 2000s. While there were undoubtedly multiple causes for this increase, the high prevalence of HSV-2 infection among the male NIDUs and the very high HSV-2 prevalence among female NIDUs indicate that HSV-2 was clearly a major factor. The change in HIV prevalence is best described as a continuation of an epidemic of HSV-2/HIV co-infection that was already underway by 1995.There is a clear need to implement interventions to reduce HSV-2 related HIV transmission among non-injecting drug users and their sexual partners. There are a number of psychosocial/behavioral interventions to reduce unsafe sexual behavior among injecting and non-injecting drug users, but these have typically demonstrated only modest effect sizes HIV/HSV-2 co-infected persons would appear to be high priority for “Treatment as Prevention,” providing anti-retroviral therapy (ART) to HIV-infected persons at all CD4 cell counts in order to reduce HIV transmission to their sexual partners


Chronic and inflammatory diseases are major causes of mortality. Although the anti-inflammatory effects of exercise have been confirmed, but the effect of different types of exercise on inflammatory markers is different. The aim of this study is comparing the effects of two types of sprint interval (SIT) and continuous endurance (CET) training on inflammatory markers. Sixteen students who had recreational activities participated in this study and were randomly assigned to one of the two protocols. The SIT protocol consisted of four to six 30-s “all-out” Wingate tests separated by 4 minutes of recovery and The CET protocol included 90–120 minutes of cycling at 65% Vo2max. The two protocols were performed 3 days per week and for two weeks. In each group, two blood samples were collected before and 2 days (24 and 48 hrs) after the training. Results showed that there was no significant difference between the two training protocols on all measured parameters (p>0.05). The results of present study showed that the SIT and CET have identical effects on inflammatory markers. Chronic and inflammatory diseases are major causes of mortality . On the In this randomized trial, 16 students  who had regular recreational activities participated. All subjects took some form of recreational exercise two to three times per week . Subjects' completed two questionnaires before starting the training program: one about baseline information and the other about the type and intensity of their physical activity. Subjects were randomly assigned to either the SIT or the CET training program. Following routine medical screening, the purpose of the study and associated risks were explained for all subjects and written informed consent was obtained from them. The study was approved by the Research Ethics Committee of Shahid Beheshti University.2max. Following a 5-minute warm-up, the test began at 50W with the workload increasing by 25Wevery 2 minutes until volitional exhaustion. The value recorded for Vo2maxcorresponded to the highest value achieved over a 30-second collection period [2max was confirmed using established physiological criteria defined by the British Association of Sport and Exercise Science (BASES), and included a respiratory exchange ratio (RER) above 1.15, oxygen uptake reaching a plateau with increasing work rate, and a heart rate close to age predicated maximal values [Prior to baseline measurements, subjects were make several familiarization visited the laboratory in order to get informed of the testing procedures and training devices. During one of these visits, subjects performed an incremental test to exhaustion on an electronically braked cycle ergometer using an online gas collection system to determine Von period . All exel values .Subjects in the SIT group completed a 30second maximal effort on an electronically braked cycle ergometer at a resistance equivalent to 7.5% of their body mass.2max. Subjects did exercise training in the first two sessions for90 minutes, in the second and third sessions for 105 minutes, and in the last two sessions for 120 minutes. The numbers of Wingate tests performed during each training session were increased from four in sessions 1 and 2 to five in sessions 3 and 4, and finally to six in sessions 5 and 6. For all training sessions, the recovery interval between Wingate tests was fixed at 4 minutes during which, subjects rested[CET consisted of continuous cycling on an ergometer, 3 days per week for2 weeks, at a power output corresponding to 65% Voa within 24 hours preceding blood sampling. To be included in the study, subjects ought to have had no infection within one week before sampling. Blood samples were taken after 15 minutes of rest in sitting position. The first samples were taken 24 h before the first session and the second samples were taken 48 h after the last session (after 2 weeks). Blood samples (10 ml) were obtained from antecubital vein. Two ml of the blood sample was poured into EDTA tubes for WBC measurement and the rest was centrifuged at 4C for 5 minutes at 3000 g. After centrifugation, serum was stored at –70C for subsequent analyses.CRP, IL-10, IL-6were measured by ELISA kitand insulin resistance was calculated as HOMA-IR.Venous blood samples were obtained at 8–10 am in the Obesity Research Center, Research Institute for Endocrine Sciences of Shahid Beheshti University of Medical Sciences. Subjects had slept and had fasted for 8–9 hours preceding blood sampling, eat food before 2 blood sampling as same as possible, and were asked not to do heavy exercise, take medications, or get exposed to sensitizersThe distribution of variables was assessed by kolmogorov-Smirnov test. To compare groups, we calculated the difference (after- before) for each group and tested it by T test if the distribution was normal and by Mann- Whitney U test if the distribution was not normal. The before and after mean in each group was tested by Paired T test if the distribution was normal and by Wilcoxon test if the distribution was not normal. P-values less than 0.05 were considered statistically significant. Analysis was done with SPSS, PC program, version 16. .All variables with the exception of CRP had normal distribution. The baseline characteristics of subject were not statistically different between two groups Table . ResultsThe major finding of the present study was that neither CET nor SIT has any significant effect on serum levels of I-6, IL-10, CRP, WBC, and insulin resistance index. To the best of our knowledge, this is the first study on the effects of two types of interval and continuous training with identical format (cycling), frequency (3 days in the week), and duration (2 weeks) but different volume. Previous studies have investigated effects of either interval or continuous training on these markers ,17-22 buOur results are consistent with results reported by Rakobowchuk et al. 2008) and Gibala et al. (2006) that showed no difference between these two training types,15. Howe and GibaOur results shows that SIT with high intensity and low volume, and CET with moderate intensity and high volume have identical effects on the body. There were no significant improvements in inflammatory biomarkers, but the decrease in insulin resistance index was marginally significant.aAny substance to which subjects were sensitive and had mentioned it in the questionnaire.The authors declared that they have no competing interests.FH participated in study designed and drafted the manuscript. TA participated in study designed performing laboratory tests, data acquisition and drafted the manuscript. SA participated in study designed and statistical analysis. All authors read and approved the final manuscript.


Early reports of the 2009 A/H1N1 influenza pandemic (pH1N1) indicated that a disproportionate burden of illness fell on First Nations reserve communities. In addition, the impact of the pandemic on different communities may have been influenced by differing provincial policies. We compared hospitalization rates for pneumonia and influenza (P&I) attributable to pH1N1 influenza between residents of First Nations reserve communities and the general population in three Canadian provinces.Hospital admissions were geocoded using administrative claims data from three Canadian provincial data centres to identify residents of First Nations communities. Hospitalizations for P&I during both waves of pH1N1 were compared to the same time periods for the four previous years to establish pH1N1-attributable rates.Residents of First Nations communities were more likely than other residents to have a pH1N1-attributable P&I hospitalization (rate ratio [RR] 2.8-9.1). Hospitalization rates for P&I were also elevated during the baseline period (RR 1.5-2.1) compared to the general population. There was an average increase of 45% over the baseline in P&I admissions for First Nations in all 3 provinces. In contrast, admissions overall increased by approximately 10% or less in British Columbia and Manitoba and by 33% in Ontario. Subgroup analysis showed no additional risk for remote or isolated First Nations compared to other First Nations communities in Ontario or Manitoba, with similar rates noted in Manitoba and a reduction in P&I admissions during the pandemic period in remote and isolated First Nations communities in Ontario.We found an increased risk for pH1N1-related hospital admissions for First Nations communities in all 3 provinces. Interprovincial differences may be partly explained by differences in age structure and socioeconomic status. We were unable to confirm the assumption that remote communities were at higher risk for pH1N1-associated hospitalizations. The aggressive approach to influenza control in remote and isolated First Nations communities in Ontario may have played a role in limiting the impact of pH1N1 on residents of those communities. The first Canadian cases were reported in April of that year. Early descriptive studies focused on risk factors for severe disease and identified key patterns such as the increased risk for children and pregnant women and younger adults as well as those with chronic conditions . It was  studies -8. As a Prior studies in Canada have examined primarily laboratory-confirmed cases -11 and hThe potential for health and health care disparities among those living on a reserve compared to residents of other communities is higher. A reserve is a small portion of what might have previously been part of a nation’s traditional territory, which is protected by legislation for the use and benefit of a First Nation . AlthougThis study was undertaken to assess whether there were observed differences in the rates of hospitalizations attributable to pH1N1 in British Columbia, Manitoba, and Ontario between residents of First Nations communities and other residents, and between First Nations in each province.We used administrative data to examine rates of hospitalizations attributed to pH1N1 for those living on First Nations reserves and the rest of the population in British Columbia, Manitoba, and Ontario. Results were aggregated for all First Nations reserve communities in each province. We did not merge the British Columbia, Manitoba, or Ontario datasets because of documented data coding variability.The data included files held at Population Health Data British Columbia, the Manitoba Centre for Health Policy, and the Institute for Clinical Evaluative Sciences (ICES) in Ontario. Standardized data, based on every hospital contact, are submitted  as part of a system maintained and controlled by all provincial ministries of health. We used the hospitalization data available through each province’s Discharge Abstract Database (DAD) files and the demographic data available through province-specific datasets  in order to determine sex, age, and location of residence. Socioeconomic quintiles were identified using standard protocols in each province that utilize a combination of census data and location of residence. We also utilized the laboratory influenza testing result files from each province to identify the time periods of interest for waves 1 and 2 of pH1N1 in each province.In most provinces, current databases are unable to reliably report First Nations identification. Therefore, we created an ecological sample that was assumed to include all British Columbia, Manitoba, and Ontario First Nations living on a reserve. Our unit of interest was residents of First Nations reserve communities. Based on previous work by Lavoie and colleagues we used a combination of 6-digit postal code and First Nations reserve numbers (from Indians and Northern Affairs Canada) to identify all BC, Manitoba, or Ontario residents living on a First Nations reserve . In all Geographic mismatching can be a concern in any rural area, where many small communities may exist within a single postal code. In British Columbia this is of particular concern as postal codes tend to cover larger areas, and First Nations reserves are small. In the case of First Nations, the payer of British Columbia provincial health premiums is the First Nation Inuit Health Branch of Health Canada. Therefore, we were able to use both a proxy for First Nations identification (premium payer) and postal codes where reserves are located to track British Columbia First Nations individuals living on reserve.Since influenza is infrequently confirmed by laboratory tests and the criteria for testing for pH1N1 varied over the study period, and between provinces, we estimated pH1N1-attributable outcomes by applying statistical methods to administrative data. Pneumonia and influenza (P&I) hospitalization  in any diagnostic field was the primary outcome. We examined as secondary outcomes: i) hospitalizations due to pneumonia and influenza as the primary diagnosis; and ii) any respiratory condition (ICD-10 J00-J99) in any diagnostic field. To confirm the specificity of any observed differences, we examined motor vehicle collisions (ICD-10 V01-V79) as a condition where pH1N1 was not expected to have an impact.Data analyses were conducted within each province. Frequent communication during the analysis stage ensured consistency in analyses despite slight variations inherent in the health administrative data. To estimate pH1N1-attributable outcomes, we first defined periods of pH1N1 activity  using provincial laboratory data. We then determined event rates during these periods in 2009 and compared them to event rates during the same periods in the previous five years (2004 to 2008). The rate during the previous years served as the expected baseline for these outcomes, controlling for inherent differences between provinces and between First Nations communities and the general population in terms of health services utilization, public health prevention and control strategies, and influenza disease rates. pH1N1-attributable event rates were calculated as the difference between the pH1N1 waves in 2009 and the baseline periods in previous years.We conducted analyses that included crude and age standardized rates and rate ratios. Rates of admission were first determined for each week then aggregated to generate average weekly rates for the time periods of interest. For Ontario and Manitoba we also used the First Nations and Inuit Health rurality designation to determine if there were differences between Remote and Isolated First Nations reserve communities and those rated as Semi-Isolated and Non-Isolated. In Ontario, the locations and categories of each community in our dataset were compared to the information in the First Nations Community Profiles on the Aboriginal Affairs and Northern Development Canada website to ensure they were accurate. One of the investigators (MG) has content expertise in this area and was able to resolve any conflicts identified during this processes. In Manitoba this information was already available and verified from previous work by one of the investigators(JL). This was not possible in British Columbia due to the nature of the dataset obtained from Population Health Data British Columbia, where aggregation beyond the community level had already been completed prior to release of the data set, making it impossible to use this approach. We used a rate ratio approach as the relatively low event counts in the First Nations communities precluded the meaningful use of regression models to adjust for confounding variables. We used SAS 8.0/9.2 for data analysis depending on the version in use at each data centre .This project was conducted in keeping with the Tri-Council Policy Statement on Research involving Aboriginal Peoples . As we wThere were key demographic differences between First Nations reserve communities and other residents in each of the three provinces Table . ResidenFigure The remainder of the results are limited to the pandemic periods noted in Figure Our additional sensitivity analyses showed that when P&I was used as the primary diagnosis, we found similar results to our primary outcome (data not shown). For all respiratory hospitalizations an increase was also noted, but with the degree of this somewhat tempered (increases of approximately 15% rather than 44% in Ontario for example) as would be expected by the inclusion of other non-infectious respiratory admissions in this outcome (data not shown). Sensitivity analyses also showed that there was no temporal relationship noted between motor vehicle collision rates and pH1N1, although motor vehicle collision rates for residents of First Nations reserve communities were also noted to be twice that of the general population (data not shown).For Manitoba and Ontario, we were also able to compare remote and isolated First Nations reserve communities to those that are not remote or isolated Table . In ManiThis study confirms that at a population level, there was a greater risk of pH1N1-attributable hospitalization (RR = 2.8-9.1) for First Nations reserve communities than the remainder of the population. These health disparities are consistent across BC, Manitoba, and Ontario, and consistent with other studies of hospitalized or laboratory-confirmed cases in North America, Australia, and New Zealand -11,21. FWe also found elevated baseline risks of P&I hospitalization (RR = 1.5-2.1) variability in both the baseline and pH1N1-attributable hospitalization rates between provinces. Some of this variability may be explained by demographic differences between FNs reserve communities in each province. Manitoba, which had the highest rates, also has the youngest and poorest First Nations reserve population. This would be in keeping with other studies, which have shown a convincing association between lower SES and increased risk of adverse outcomes from H1N1 influenza ,23. OnceGuidelines identified remote or isolated First Nations as being at particularly increased potential risk and in some provinces such as Ontario, more aggressive pandemic control strategies  were implemented -27. Our A number of limitations to the study should be taken into consideration. The first is that we are using pH1N1-attributable rather than laboratory-confirmed hospitalizations as an outcome. We feel this is reasonable because not all patients would necessarily have been tested, but this does potentially lead to incorrect attribution of cases. We did not adjust for a number of known risk factors such chronic diseases, pregnancy, or age group. Moreover, there are other risk factors that are not measurable in administrative data  . HoweverThe findings reported here are unique in that analyses were carried out across three provinces using their health administrative data to shed light on the impact of pH1N1 among First Nations reserve communities. Findings provide empirical population level evidence of both an absolute and relative increase in risk for pH1N1-attributable hospitalizations for First Nations reserves relative to the general population. The increased baseline risk suggests that this risk is elevated in general and not specific to pH1N1.The interprovincial variations could indicate that SES, age, and other differences for which we do not have regular sources of data  are important mediators of these differences. Unlike what is generally assumed, increasing remoteness of the community was not an important risk factor. Outcomes were not related to where the communities are situated, but rather to the care provided. Future studies should examine more closely the influence of the types of health services delivered locally. Still, the aggressive use of antiviral medications in remote and isolated communities in Ontario may have contributed to the reduced impact of the pandemic in those areas.aThroughout this paper, the term Aboriginal will be used when statements apply to First Nations living on- and off-reserve, Inuit, and Métis. Elsewhere, the terms First Nations, Inuit, and Métis will be used when specific to each of these populations. Finally, the term Indigenous will only be used when speaking in international terms.MG serves as a medical officer for First Nations and Inuit Health Branch, Ontario Region and participated in the management of the H1N1 pandemic on First Nations reserves in Ontario.MG, SW, AK, JL and JK designed the study and contributed to all aspects including the development of partnerships, acquisition of data, analysis and interpretation of results. LM, SP and GL worked directly on the analysis of the administrative data. All authors contributed to the discussion and review of the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/13/1029/prepub