Increases in the prevalence of type 2 diabetes will likely be greater in the Middle East and other developing countries than in most other regions during the coming two decades, placing a heavy burden on regional healthcare resources.Medline search, examination of data from major epidemiological studies in the Middle Eastern countries.The aetiology and pathophysiology of diabetes appears comparable in Middle Eastern and other populations. Lifestyle intervention is key to the management of diabetes in all type 2 diabetes patients, who should be encouraged strongly to diet and exercise. The options for pharmacologic therapy in the management of diabetes have increased recently, particularly the number of potential antidiabetic combinations. Metformin appears to be used less frequently to initiate antidiabetic therapy in the Middle East than in other countries. Available clinical evidence, supported by current guidelines, strongly favours the initiation of antidiabetic therapy with metformin in Middle Eastern type 2 diabetes patients, where no contraindications exist. This is due to its equivalent or greater efficacy relative to other oral antidiabetic treatments, its proven tolerability and safety profiles, its weight neutrality, the lack of clinically significant hypoglycaemia, the demonstration of cardiovascular protection for metformin relative to diet in the UK Prospective Diabetes Study and in observational studies, and its low cost. Additional treatments should be added to metformin and lifestyle intervention as diabetes progresses, until patients are receiving an intensive insulin regimen with or without additional oral agents.The current evidence base strongly favours the initiation of antidiabetic therapy with metformin, where no contraindications exist. However, metformin may be under-prescribed in the Middle East. The burden of diabetes is high in the Middle East.The Middle East has largely been overlooked by guideline writers.Type 2 diabetes is often sub-optimally managed in the Middle East.The pathophysiology of the disease in Middle Eastern patients resembles that in other populations, but few clinical trials recruited Middle Eastern populations.Metformin appears to be under-used in the region, and should be considered as initial pharmacologic therapy, in line with international guidelines for the management of type 2 diabetes.Evidence-based guidelines are necessary to the application of treatments for type 2 diabetes and to ensure best practice in diabetes management  1–6). T–6. T1–6)These guidelines, described in detail below, have increasingly favoured the initiation of oral antidiabetic pharmacotherapy with metformin. Although it is difficult to define the frequency of use of metformin as initial pharmacotherapy for type 2 diabetes in the Middle East, this treatment may be underused in the region. Survey evidence suggests that about four-fifths of the recently diagnosed type 2 diabetes patients in the UK start oral antidiabetic drug treatment with metformin, compared with only about one-third in the Middle East . It appeThe progression of hyperglycaemia in type 2 diabetes is driven by β-cell dysfunction occurring against a background of insulin resistance ,2. The dper se is toxic to the β-cell; thus, any treatment which reduces the severity of hyperglycaemia is likely to improve β-cell function to some extent over the short term.Most oral antidiabetic treatments target insulin resistance or β-cell dysfunction as their primary mechanisms of action . MetformThe burden of diabetes in the Middle East is high. When considering the data shown in A substantial burden of non-diabetic dysglycaemia [impaired glucose tolerance (IGT) or impaired fasting glucose (IFG)] provides a large reservoir of patients at high risk of developing type 2 diabetes in the Middle East, as elsewhere  9). A h. A h9). The cost of managing diabetes is high. The majority of the cost of managing diabetes arises from the management of diabetic complications, especially in hospital. In the main analysis of the UKPDS, treatment of complications accounted for 63% of overall within-trial costs in the group randomised to receive conventional (diet treatment) . SimilarThe clinical characteristics of diabetes have not been well studied in many countries of the region. However, it is clear that obesity , family history of diabetes and other commonly occurring cardiometabolic risk factors are associated with a significant increase in the risk of developing type 2 diabetes in this population, as has been demonstrated elsewhere ,21. A lan= 17,230, age 30–70 years)  demonstrated a prevalence of hypertension of 26%, in each case    and Egypressure) . Similarressure) .Epidemiological studies in the region may be complicated by the relatively high proportion of expatriate workers in some Middle-Eastern countries. However, another study from Saudi Arabia showed that the prevalence of individual cardiometabolic risk factors  differed little among Saudi and non-Saudi patients with type 2 diabetes .2 (46%), LDL-C < 2.6 mmol/l (100 mg/dl) (18%), or HDL-C > 1.1 mmol/l (43 mg/dl) (33%) , triglycerides < 2.3 mmol/l (200 mg/dl) (35%), body mass index < 27 kg/ml) (33%) . In the l) (33%) .Although the association between type 2 diabetes and cardiovascular risk has not been studied as intensively in the Middle East as in other populations, there is evidence that a comparable relationship exists between a diagnosis of diabetes and adverse cardiovascular outcomes. The prevalence of coronary artery disease in Emirati subjects tended to increase consistent with the severity of dysglycaemia, from prediabetes (4.7%) to undiagnosed (5.0%) or diagnosed (10.5%) diabetes . A similThe association between long-term hyperglycaemia and an increased risk of microvascular diabetic complications appears comparable for the Middle East and elsewhere. A survey in Egypt confirmed the high prevalence of microvascular complications in an Arab population with diabetes  13). El. El13). 1C values of 9.2% in patients with previously diagnosed diabetes and 8.7% in patients with previously undiagnosed diabetes (1C < 7.0% (1C 8.3%) or undiagnosed (mean HbA1C 6.7%) diabetes in the United Arab Emirates  is controversial, and previous meta analyses have provided conflicting results, especially with respect to rosiglitazone –54. PiogIncretin enhancers act via blockade of DPP-4, which is present in immune cells. Although there is currently no hard clinical evidence to support an association between DPP-4 inhibition and adverse effects on the immune system, a Cochrane analysis has called for more data , and theRandomisation to metformin in the UKPDS was associated with significant improvement in a range of cardiovascular end-points, with these benefits maintained after 10 years of posttrial monitoring during which patients returned to the usual care of their physician  58,59).,59.58,59post hoc analysis of the prevention of restenosis with tranilast and its outcomes (PRESTO) trial, involving analysis of data from 1997 patients with type 2 diabetes at baseline who received either metformin or other oral antidiabetic treatments that do not influence the action of insulin as their primary mechanism (i.e. patients receiving a thiazolidinedione were excluded)  . PatientPioglitazone improved secondary cardiovascular end-points in the PROACTIVE trial –64, althThe cost of treatment is another important issue influencing the access of many patients to healthcare. Metformin and some sulfonylureas are available as generic preparations; therefore limiting their cost. However, the quality of some of these generic preparations remains a cause for concern. Thiazolidinediones, α-glucosidase inhibitors and agents acting via the incretin system are branded preparations and are thus more expensive.The principal factors in selecting an oral antidiabetic agent are its antihyperglycaemic efficacy, together with other properties that suggest a potential long-term benefit ,3. CliniThe role of oral antidiabetic therapy in the management of gestational diabetes requires further research, not least as women with PCOS may become pregnant while receiving treatment for this condition. At present, insulin is the mainstay of the management of gestational diabetes, and oral agents are discontinued. However, a recent systematic review has shown that the use of oral antidiabetic therapy, including metformin, was not associated with an increased risk of adverse foetal outcomes, and a lower rate of neonatal hypoglycaemia, relative to insulin .1C above 7.0% who are able to receive metformin. This is followed, when required, by combination therapy with a sulfonylurea or basal insulin [i.e. neutral protamine hagedorn (NPH) insulin or newer insulin analogues], which are considered to be well-validated therapies. Where metformin-sulfonylurea combinations do not control glycaemia sufficiently, patients should receive metformin plus basal insulin. Combinations based on metformin with pioglitazone (rosiglitazone is not recommended following recent concerns over the risk:benefit profile of this agent) or an incretin mimetic (GLP-1 agonist) are included as ‘less well-validated therapy’. Eventually, all patients requiring insulin should progress to treatment with lifestyle intervention, metformin and an intensive insulin regimen.Data on the effectiveness of antidiabetic interventions in Middle-Eastern subjects are scarce. Accordingly, it is reasonable to assess individual therapies on the basis of their therapeutic profiles demonstrated in other populations, especially as the aetiology and pathogenesis of diabetes in the Middle East and other regions appear comparable (as described above). The major international guideline issued by the IDF  and an aRamadan is a religious observance of the Muslim faith that involves abstinence from food and drink between dawn and sunset for a period of one month. Fasting during Ramadan alters the delivery of antidiabetic treatment for an estimated 40–50 million Muslim patients with diabetes worldwide . GuidancRecommendations for the use of oral antidiabetic therapy in the management of type 2 diabetes are summarised in Treatment may be initiated with lifestyle intervention. Even a brief trial of lifestyle intervention, of as little as 1 month, is often useful in indicating the potential of this treatment to impact substantially on hyperglycaemia. A separate trial of lifestyle intervention also emphasises the importance of this treatment in its own right and helps to educate patients that it is not an optional extra to pharmacotherapy. It should be noted; however, that access to healthcare may represent an important barrier to treatment for many Middle-Eastern patients, and that the additional clinic visits necessary to administer a trial of lifestyle intervention may be problematic in some cases. For these patients, metformin may be co-prescribed at this time, as per the ADA/EASD guideline, according to the physician’s judgement. Basal insulin  or a sulfonylurea is the preferred next step in treatment intensification, although other agents may be more appropriate for an individual patient . Patients maintained on oral combinations then receive basal insulin, with intensive insulin regimens  as the final step.The application of evidence-based therapy for patients with type 2 diabetes is essential given the projected large increases in the prevalence of type 2 diabetes in countries of the Middle East. Although the number of treatments for type 2 diabetes has increased in recent years, metformin plus lifestyle intervention remains the preferred strategy for the initiation of oral antidiabetic pharmacotherapy.


The question of whether air pollution contributes to asthma onset remains unresolved.In this study, we assessed the association between asthma onset in children and traffic-related air pollution.We selected a sample of 217 children from participants in the Southern California Children’s Health Study, a prospective cohort designed to investigate associations between air pollution and respiratory health in children 10–18 years of age. Individual covariates and new asthma incidence (30 cases) were reported annually through questionnaires during 8 years of follow-up. Children had nitrogen dioxide monitors placed outside their home for 2 weeks in the summer and 2 weeks in the fall–winter season as a marker of traffic-related air pollution. We used multilevel Cox models to test the associations between asthma and air pollution.2. Using the total interquartile range for all measurements of 28.9 ppb increased the HR to 3.25 .In models controlling for confounders, incident asthma was positively associated with traffic pollution, with a hazard ratio (HR) of 1.29  across the average within-community interquartile range of 6.2 ppb in annual residential NOIn this cohort, markers of traffic-related air pollution were associated with the onset of asthma. The risks observed suggest that air pollution exposure contributes to new-onset asthma. Toxicologic and epidemiologic research suggests that air pollution exacerbates asthma symptoms , but fewA few prospective studies have assessed the relation between traffic pollution and asthma onset . A case–We selected a sample of 217 children from 917 eligible subjects living in 11 communities in the Southern California Children’s Health Study (CHS), a prospective cohort study of air pollution and respiratory health. Subjects were selected randomly from the larger cohort based on different levels of traffic-related exposure. Specifically, we divided subjects into two strata (above and below the median traffic exposures within each community) and then selected an equal number randomly from each of the strata. Although our study is similar to an earlier cross-sectional study from this population that focused on the effect of freeway-related traffic in 10 CHS communities , in thisCase ascertainment was as described previously . We excl2 monitors  placed in the front or back yard of their home in the year 2000 for 2 weeks in the summer (mid-August) and 2 weeks in the fall–winter season (mid-November). We deployed all monitors within 4 days to minimize temporal variation of the exposure estimates by change of season or meteorologic events. Within each community, monitors were deployed within a 4-hr period. We obtained valid readings for 209 subjects for the ambient household level of NO2 measurements during fall–winter months and 204 for summer months. We assessed exposures by season and as an average of the two measurement periods.As described previously , childreWe also derived a series of potential “contextual” confounders at the community level. Contextual characteristics of the community, particularly socioeconomic position (SEP), have been associated with respiratory health effects . For thiCharacteristics of SEP were aggregated from census blocks where study subjects lived. We used data from the U.S. 1990 census to estimate community conditions at the time of study enrollment, which began in 1993. Because we recruited subjects through schools, residential locations clustered together. To compensate for clustering of study subjects, we weighted these community-level data by the proportion of the census blocks included in a community-specific bounding rectangle that contained 95% of local study subjects . This spMeteorologic conditions, especially temperature and humidity, may also be potential risk factors for asthma . Based oWe used random-effects Cox proportional hazards models to assess the risk of asthma onset in relation to pollution exposures, while stratifying for age in years and sex in the baseline hazard. Community-level random effects allowed for clustering and assessment of residual community variation in time to asthma onset . The modhij(t) is the hazard function for the ith subject in jth community, h0s(t) is the baseline hazard function for stratum s , ηj represents the positive random effects for community j with expectation 1 and variance σ2, Xij is the air pollution exposure  for individual i in community j, and Zij represents covariates  for individual i in community j.where 2. We report results across the average within-community interquartile range of annual average NO2 exposure.We evaluated pollution exposures with other covariates such as relative humidity and medical insurance, which we treated as confounders if they had an association with asthma incidence and changed the pollution coefficient by ≥ 5% for the annual NOTo determine whether exposures could be assessed at the individual level across the entire range, we tested for significant differences in effects from community aggregated means from the individually assigned exposure deviated from those community means. The model that allows for separate between-community means and the within-community deviations had the following form:Xij is the individually assigned exposure  and Xj is the community average of the individual measurements. We then assessed the equivalence of these two pollution effects by testing the hypothesis H0: β1 = β2. If the two exposure β values were not statistically different based on the log-likelihood ratio test, we concluded that there was no need to distinguish between the within-community and between-community effects of pollution.where We examined this alternative model to determine whether the individual exposures specified in Equation 1 were appropriate or whether we needed a model specifying different within- and between-community effects for correct interpretation of results.The bivariate associations of individual and household variables as predictors of asthma were largely not statistically significant . Associa2 levels within each study community. Variation exists within communities, and a broader regional pattern is also present. Communities in the Los Angeles metropolitan area have generally higher levels than do communities to the north and south, showing a spatial pattern consistent with earlier measurements based on central monitors ].In monitors . We exam2.2 the hazard ratio (HR) was 1.29  across the average within-community interquartile range of 6.2 ppb. The fall–winter HR of 1.29  was nearly the same as the annual average, whereas the summer HR of 1.27  was slightly smaller. The sample size was 196 with 26 cases , so it is possible that influential outliers might have affected the results. However, there were no cases with exceptionally high exposure to NO2 and no noncases with notably low exposure to NO2.We tested each of the individual variables shown in 2 values are the random-effects variance estimates, which represent the residual variation in asthma incidence attributable to the community cluster after we included all other fixed predictors in the model (2 only slightly from a null model containing only baseline age and sex strata (results not shown). Models 2 and 3 show the large decline in σ2 when we included community relative humidity and pollution, respectively, indicating that both variables account for a large proportion of the residual between-community variation in asthma incidence.The σhe model . Additio2 per community). We used these variables to compare within- and between-community pollution effects. 2 point estimate was larger than the within-community estimate, but these estimates had large CI values and were not significantly different based on the likelihood ratio test. For yearly average and winter NO2, the within- and between-community effects were similar.We assessed exposures both as the deviation of the individual specific exposure metric from the corresponding community mean and as the community average .Interactions between humidity and air pollution were tested, but found not to be significant, although pollution did appear to exert larger effects in more humid areas  than did the individual-level variables included as confounders. The results for residential NO2 were sensitive to inclusion of the relative humidity variable. This variable met our criteria for confounding and increased the pollution effect . In this case, we did observe a negative bias when humidity was not included in the model. We would also expect a negative bias in the humidity effect when we exclude NO2 from the model. 2 in the model. Without NO2, the risks were attenuated in all models, and the negative bias was strongest in the summer season. Thus, the impact of humidity was negatively biased when we excluded NO2 from the model, which is consistent with the positive confounding effect observed in the NO2 models. These results imply that simultaneous consideration of meteorology and air pollution may be important in models assessing the effects of chronic air pollution exposure on respiratory disease.We further investigated the possibility of positive confounding by examining the correlation between humidity and NO2 findings is complicated because it represents a mixture of local and regionally transported pollutants in Southern California. In an earlier analysis, 2 and various measures of traffic proximity or modeled concentrations. Although some toxicologic evidence supports the potential for NO2 as a direct causative agent for respiratory health effects at high concentrations . The general conclusions, therefore, are similar even after excluding children with wheeze at baseline or with a history of early childhood illness.Notable strengths of this study are the prospective design, individually measured pollutant exposures, incident disease assessment, and the large effects. Limitations include an inability to identify the specific constituents of pollution that were responsible for the observed health effects, the relatively small sample size, and questionnaire case ascertainment. Although a potential limitation, self-reported physician diagnosis is widely used to define asthma in epidemiologic studies , is repre summer , and theThe overall asthma incidence rate per thousand person-years of 18.8 cases resulting from parent- or child-reported physician diagnosis was high but is similar to rates reported previously in the CHS cohort  and in o2. Although the specific pollutant or related mixture of constituents responsible for the effects remains the focus of future research, the large risks observed suggest that traffic-related air pollution exposure contributes to new-onset asthma.Further field studies measuring plausibly causal ultrafine particles, metals, and poly-cyclic aromatic hydrocarbons simultaneously  might id


Pegylated interferon plus ribavirin therapy for hepatitis C virus (HCV) fails in approximately half of genotype 1 patients. Treatment failure occurs either by nonresponse  or relapse . HCV is highly variable genetically. To determine if viral genetic differences contribute to the difference between response and relapse, we examined the inter-patient genetic diversity and mutation pattern in the full open reading frame HCV genotype 1a consensus sequences.Pre- and post-therapy sequences were analyzed for 10 nonresponders and 10 relapsers from the Virahep-C clinical study. Pre-therapy interpatient diversity among the relapsers was higher than in the nonresponders in the viral NS2 and NS3 genes, and post-therapy diversity was higher in the relapsers for most of HCV's ten genes. Pre-therapy diversity among the relapsers was intermediate between that of the non-responders and responders to therapy. The average mutation rate was just 0.9% at the amino acid level and similar numbers of mutations occurred in the nonresponder and relapser sequences, but the mutations in NS2 of relapsers were less conservative than in nonresponders. Finally, the number and distribution of regions under positive selection was similar between the two groups, although the nonresponders had more foci of positive selection in E2.The HCV sequences were unexpectedly stable during failed antiviral therapy, both nonresponder and relapser sequences were under selective pressure during therapy, and variation in NS2 may have contributed to the difference in response between the nonresponder and relapser groups. These data support a role for viral genetic variability in determining the outcome of anti-HCV therapy, with those sequences that are more distant from an optimal sequence being less able to resist the pressures of interferon-based therapy.NCT00038974ClinicalTrials.gov  Hepatitis C Virus (HCV) infects over 170 million people worldwide and more than 4 million in the USA Hepacivirus in the Flaviviridae family. Its genome is a ∼9600 nucleotide, positive polarity single stranded RNA which contains a single large open-reading frame. The structural proteins include the core protein, which forms the viral capsid, and two surface glycoproteins, E1 and E2. Nonstructural proteins include a putative ion channel (p7), an autoprotease (NS2), a protease/helicase (NS3/4A), a putative organizer of the replication complex (NS4B), a pleiotropic regulatory protein (NS5A), and an RNA-dependent RNA polymerase (NS5B). An eleventh protein, the alternate reading frame protein, is encoded in the +1 frame of the core gene and is of unknown function HCV is a HCV is highly genetically variable, with six different genotypes that have less than 72% homology at the nucleotide level. Each genotype is divided into multiple subtypes with 80-85% similarity. Isolates within each subtype are also extremely variable, with 8-12% divergence between isolates from independent patients There are at least two different patterns by which HCV therapy can fail. Nonresponders have only minimal declines in viral titers, while relapsers have robust declines followed by a rebound in titers either during or after therapy. These different patterns could be affected by many factors including host genetics, immune response, and viral genetic differences We previously reported that high pre-therapy inter-patient variability in NS3 and NS5A correlated strongly with early response to therapy in genotype 1a infected patients 10 IU/mL and absolute titers of ≥4.62 log10 IU/mL at nadir. Relapsers had declines in viral titers of ≥2.8 log10 and their absolute titers transiently dropped below the detection limit (2.78 log10 IU/mL)  . The basWe first determined if there were consistent genetic differences at discrete amino acid positions between the nonresponders and relapsers. To do this, we created consensus sequences of the nonresponder and relapser sequences at 60% conservation levels for both pre- and post-therapy samples. The consensus sequences for the nonresponder and relapser alignments were then compared to determine if there were positions that differed consistently between the two phenotypes. For pre-therapy sequences, nine positions differed between nonresponders and relapsers . In mostTherefore, there were only a few amino acids that differed consistently between the nonresponder and relapser sequences, and these differences were relatively conserved after therapy. However, the weak degree of conservation at these positions, the common presence of the alternate amino acid from the opposing phenotype, and the conservative nature of the alternate amino acids at these positions all argue against variation at these positions playing a major role in determining if the patient was a nonresponder or relapser during therapy.Since there were no amino acid positions at which genetic differences strongly correlated with nonresponse or relapse, we next examined the groups of sequences to determine if there were differences in inter-patient diversity between the nonresponders and relapsers that correlated with the response pattern. Diversity differences were measured by comparing the numbers of amino acid variations relative to a reference sequence and by measuring differences in the average protein distances within the two groups.First, each sample was aligned against an external genotype 1a reference sequence As a second measure of sample diversity, we compared the average pair-wise protein distance within each group. The pair-wise protein distances among the nonresponders and relapsers were determined separately, and the mean protein distance for each sample relative to the other nine nonresponder or relapser sequences was determined. We then compared the average distances among the nonresponders and relapsers and determined their statistical significance using the Mann-Whitney test. In the pre-therapy data , relapseWe next asked whether the greater differences between nonresponders and relapsers in the post-therapy analysis were due to changes in sequences from the nonresponders, relapsers, or both by comparing the pre- versus post-therapy protein distances among the nonresponders and relapsers . The proFinally, the inter-patient protein distance of pre-therapy sequences among nonresponders, relapsers, and responders was compared to the distance among sustained viral responders to antiviral therapy in the Virahep-C study If differences in viral genetic variability contribute to the ability of the virus to withstand the pressures induced by therapy, those isolates that survive therapy would be relatively resistant to the effects of the drugs whereas those that do not survive would be sensitive. Resistance could either be present initially or evolve during therapy. Therefore, we hypothesized that there would be a difference in evolution between the two groups of sequences, with relapsers evolving to become more resistant to therapy while nonresponders would evolve less because they were initially relatively resistant. To test this hypothesis, paired pre- and post-therapy sequences from each patient were aligned, and mutations at the amino acid level that occurred during therapy were identified. Contrary to our expectations, nonresponders had more mutations in the polyprotein than the relapsers , but thiTo assess the likelihood that these mutations may have altered the activity of the proteins, the BLOSUM90 scores for each mutation were evaluated. BLOSUM scores are log-odds ratios of amino acid substitutions. Substitutions which occur more often than expected have positive scores and reflect conservative changes, and substitutions which occur less often than expected have negative scores and reflect non-conservative changes. For all proteins except NS2, the scores in nonresponders and relapsers were not significantly different. In NS2, relapsers had significantly lower scores than nonresponders by the Kolmogorov-Smirnov test (p = 0.023) . We nextCrystal structures have been determined for all or part of NS2 To determine if there was a difference in the degree or pattern of positive selection between nonresponders and relapsers during therapy, we measured the nonsynonymous to synonymous substitution ratio (dN/dS) by the Nei-Gojobori method in each patient and compared the ratios between nonresponders and relapsers using the Mann-Whitney test. For the entire polyprotein, nonresponders had higher dN/dS ratios than relapsers (p = 0.008) . HoweverMany different selective pressures could be applied to the HCV genome by the pleiotropic effects of interferon and ribavirin. Negative selection maintains critical functions in many positions, and positive selection would affect specific regions of proteins associated with differences in response to the therapy. However, because all genes in the HCV genome are linked, positive selection at any given site could co-select neutral variations throughout the genome. Therefore, to determine if there were small regions of the protein that were under positive selective pressure, we examined the dN/dS ratio by the Li-Kimura method in overlapping windows of 10 codons. Seven of ten nonresponders and seven of ten relapsers had regions of positive selection (dN/dS >1), and these regions were distributed throughout the viral genome . The polHCV replicates as a quasispecies, but our analyses were performed on the consensus sequence. Therefore, to determine if there were differences in the quasispecies breadth between the nonresponder and relapser sequences, we evaluated the prevalence of mixed base positions in the sequence traces of the uncloned sequencing templates using the method developed by A. F. Poon Genetic bottlenecks decrease the genetic breadth within a population, and a decrease in the diversity of both nonresponders and relapsers was observed, consistent with both groups passing through a bottleneck. However, the decline in diversity would be expected to be greater in those populations that pass through a tighter bottleneck. Thus, we expected the proportions of mixed bases retained in the post-therapy samples relative to pre-therapy samples to be lower in relapsers than in nonresponders. When the proportions of mixed bases were compared, the relapsers had the expected greater decline in mixed bases from pre- to post-therapy samples than the nonresponders, but this difference was not statistically significant by the Mann-Whitney test (p = 0.079) .Failure of interferon plus ribavirin therapy for HCV can occur in two different patterns: nonresponse and relapse. HCV is highly diverse genetically, and this diversity could affect how the virus responds to therapy. Furthermore, HCV can evolve rapidly, and hence therapy could drive evolution of the virus by selecting relatively resistant variants. We previously found that high genetic diversity in genotype 1a pre-therapy NS3 and NS5A sequences correlated robustly with response to therapy To evaluate how the viral protein sequences changed during treatment, we examined the number and pattern of amino acid mutations that occurred in each sequence during therapy. We expected to find a relatively high mutation frequency due to HCV's high genetic plasticity, but contrary to our expectations, the 0.9% mutation frequency observed in the samples was relatively small in relation to the variability among independent HCV isolates (10–12%), and was in the range of quasispecies variability typically found in a given individual (∼1–4%). Furthermore, about one third of the mutations we observed were in E2, especially in HVR1, so the mutation rate of the HCV ORF outside E2 was just 0.59%. Thus, a primary conclusion of this study is that the HCV consensus sequence is relatively stable during failed antiviral therapy. Most previous studies of HCV evolution during therapy have focused on small regions of the genome, primarily in NS5A and E2, and especially on the highly variable regions in these genes The second major conclusion from this study was that genetic differences in NS2 correlated with the pattern of failed response to interferon-based therapy. These correlations were evident in the number of pre-therapy unique variations , the preDespite the overall stability of the HCV sequences, a substantial number of mutations did occur during failed therapy, but no significant difference was observed in the number of mutations between the nonresponders and relapsers . We had To determine which sequence motifs may have been under positive selection during therapy, we examined the dN/dS ratio in a sliding window of ten codons. Many regions of strong positive selection were observed , but theGenetic bottlenecks can cause a constriction of the genetic variability within a population. In HCV, this is reflected in the breadth of the quasispecies within an individual. We expected the difference in the strength of the bottlenecks experienced by nonresponder and relapser groups to cause a greater decline in the quasispecies breadth in the relapsers. We found that the intra-patient quasispecies breadth declined in both nonresponders and in relapsers, and that the decline in relapsers was greater than in nonresponders, but this difference did not reach statistical significance . Other gThis study was designed to assess that role of HCV genetic variation at the protein level on outcome of therapy. Variability in the RNA itself can also predicted to affect the response to therapy by altering the RNA structure or the interactions of the RNA with host proteins and/or the viral replication machinery. RNA elements associated with protein binding could occur anywhere in the viral RNA, but they are most likely to occur in the 3′ and 5′ UTRs since these areas are known to contain the promoters for viral replication and the viral internal ribosome entry site. The sequences obtained for this study include part of the UTRs, but these sequences are of varying length, and in some cases are absent. This precludes meaningful analysis of these samples outside the ORF.This study is the largest examination to date of genetic changes in the full-length viral open-reading frame during interferon-based therapy, and it is the first study comparing nonresponders to relapsers in genotype 1a. Previous studies have examined the changes in patient samples over the course of therapy. Enomoto identified the ISDR Genetic variability between HCV genotypes can lead to difference in response to therapy (e.g. genotype 1 vs. 2), and we have shown that variability differences are also associated with early response to therapy within a given viral subgenotype Virahep-C was a multi-center clinical study of peginterferon α-2a and ribavirin therapy in treatment naïve patients chronically infected with HCV genotype 1 Consensus sequences for the full HCV ORF were obtained by direct sequencing of overlapping nested RT-PCR reactions as described previously Amino acid sequences were deduced from nucleic acid sequences. Sequence alignments were done with ClustalW. The ARF gene was not analyzed due to differences in length of the protein in individual isolates. Amino acid positions that varied relative to the genotype 1a population consensus sequence The sequence, quality, and polymorphisms in trace files of the first 1064 nucleotides of E2 were compiled for all 20 samples using Phred The average genetic distance and numbers of unique variations between samples were compared using the Mann-Whitney test. BLOSUM90 scores were compared using the Kolmogorov-Smirnov test. A p-value of ≤0.05 was considered statistically significant. Statistical analyses were performed using SAS software or SPSS v. 13.0.Checklist S1CONSORT type checklist for the viral evolution study within the Virahep-C study.(0.05 MB DOC)Click here for additional data file.Figure S1CONSORT flowchart. A depiction of how patients were selected from the main Virahep-C study for this study on viral evolution.(5.63 MB DOC)Click here for additional data file.


Aim of this longitudinal study was to investigate the sensitivity to change of the Swedish Self Evaluation of Communication Experiences after Laryngeal Cancer questionnaire (the S-SECEL), addressing communication dysfunction in patients treated for laryngeal cancer. Previous studies have highlighted the need for more specific questionnaires for this purpose.U test. Magnitude of group differences was analyzed by means of effect sizes.100 patients with Tis-T4 laryngeal cancer were included prior to treatment onset. Patients answered four questionnaires at six occasions during one year; the S-SECEL, the European Organisation for Research and Treatment of Cancer (EORTC) Core Quality of Life Core Questionnaire (QLQ-C30) supplemented by the Head and Neck cancer module (QLQ-H&N35) and the Hospital Anxiety and Depression (HAD) scale. In addition, performance status was assessed. Differences within groups were tested with the Wilcoxon paired signed ranks test and between-group analyses were carried out using the Mann-Whitney The S-SECEL was well accepted with a response rate of 76%. Communication dysfunction increased at 1 month, followed by a continuous decrease throughout the year. Changes were statistically significant at most measurement, demonstrating the sensitivity of the S-SECEL to changes in communication over time. The S-SECEL and the EORTC QLQ-C30 with the QLQ-H&N35 demonstrated similar results; however the S-SECEL was more sensitive regarding communication dysfunction. The largest changes were found in the most diagnose specific items concerning voice and speech.The S-SECEL was investigated in the largest Scandinavian longitudinal study concerning health-related quality of life (HRQL) in laryngeal cancer patients. The questionnaire was responsive to change and showed convergent results when compared to established HRQL questionnaires. Our findings also indicate that the S-SECEL could be a more suitable instrument than the EORTC QLQ-C30 with QLQ-H&N35 when measuring communication experiences in patients with laryngeal cancer; it is more sensitive, shorter and can be used on an individual basis. As a routine screening instrument the S-SECEL could be a valuable tool for identifying patients at risk for psychosocial problems and to help plan rehabilitation. It is therefore recommended for clinical use in evaluation of communication dysfunction for all patients with laryngeal cancer irrespective of treatment. Patients with head and neck cancer not only have to deal with the impact of a life-threatening disease, but also with the effect of treatment on physical, psychological, and social functioning. Studies have indicated that as many as one third of cancer patients suffer from psychiatric morbidity -3. RegarTherefore, a short but comprehensive self-report instrument measuring perceived adjustment to communication experiences in laryngeal cancer patients treated with laryngectomy, the Self Evaluation of Communication Experiences after Laryngectomy (SECEL), was developed and psychometrically evaluated in the United States . The SECThe primary aim of the present study investigated whether the S-SECEL was sensitive to changes in communication and psychosocial dysfunction over time in a large cohort of laryngeal cancer patients. Secondary aim was to evaluate longitudinal score changes in relation to established and validated HRQL instruments.All patients with newly diagnosed or relapsing laryngeal cancer in the western part of Sweden are continuously admitted to a weekly tumour conference at Sahlgrenska University Hospital, where the appropriate cancer treatment for each patient is discussed. During the inclusion period, all patients with laryngeal cancer were asked to participate in the current study were excluded from the study, as well as patients with some other concurrent cancer diagnosis and patients participating in other studies.During the study period 210 patients with laryngeal cancer were admitted to the tumour conference, 100 were included in the study while 110 patients were excluded. Reasons for exclusion were poor general health (WHO performance status 3–4) or dementia diagnosed by a psychiatrist or GP (56), participation in other studies (19), poor knowledge of Swedish (10), family reasons (3), other concurrent cancer disease (3), and unknown reasons (2). Another 17 patients declined participation.Data used in this prospective longitudinal study was derived from a battery of Patient Related Outcome (PRO) questionnaires. The study was ongoing between 1998 and 2005 with a discontinuation for two years. Results from repeated measures were compared for three forms; the S-SECEL, the HAD scale and the EORTC QLQ-C30 with QLQ-H&N35.Participants answered questionnaires regarding HRQL and voice and speech on six occasions during a follow-up time of one year. Before start of treatment (baseline) questionnaires were distributed to patients at the tumour conference and mailed-back. A mail-out/mail-back procedure was used for follow-up assessments at 1, 2, 3, 6 and 12 months after start of treatment. Patients who had not returned their questionnaires within 2–3 weeks were reminded once by mail. Patients were further followed up with a visit to the outpatient clinic 12 months after treatment start, with recording of received treatment and evaluation of performance status and residual tumour.At the conference, diagnosis according to TNM (UICC) and ICD and histopathology was recorded. Performance status was rated according to the WHO performance scale. For clinical purposes, the patients were asked about previous and present diseases, present symptoms, weight loss and smoking habits. Socio-demographic data such as family situation, education level, occupation, and smoking habits were also recorded.All patients had received or were receiving radiotherapy as part of their treatment. The majority of the patients with T0-T1 disease received conventionally fractionated radiation therapy, a few received hyper fractionated radiation therapy. Patients with T2-T4 disease received either hyper fractionated radiotherapy or conventionally fractionated, in a majority the regional nodes were also irradiated as well. Chemotherapy was given to 9 patients with stage III-IV tumours. One patient was laryngectomised before inclusion in the study, 2 patients were treated with primary laryngectomy and 4 patients were treated with laryngectomy as salvage surgery during the study year.The original Self Evaluation of Communication Experiences after Laryngectomy (SECEL) was developed to assess communication dysfunction in patients with laryngectomies and has demonstrated satisfactory psychometric properties . The SweThe questionnaire consists of 35 items addressing communication experiences and dysfunction (App I). 34 of the items are aggregated into three subscales. The first subscale, General (5 items), describes general attitudes about being relaxed or calm and acknowledgement of the sickness and treatment. Examples of questions are "Do you think that your speech improves with practice?" or "Would you describe yourself as outgoing and talkative?" The second subscale, Environmental (14 items), focuses on how the patient experiences his/her voice in different environments. Questions are for example; "Do you have trouble speaking in a large room?" and "Do you have difficulty yelling or calling out to people?" The third subscale, Attitudinal (15 items), describes attitudes about speech, feelings about self-perceptions and perceptions of others, for example "Do you avoid speaking because of your voice?" and "Do you feel that people get annoyed with you because of your voice?" Each item is rated on a 4-point categorical scale ranging from 0 (never) to 3 , and addressing the last 30 days. Scoring of subscales and a total scale is carried out by simple addition. Thus, the summary scale scores range from 0–15 for General, 0–42 for Environmental, 0–45 for Attitudinal and 0–102 for Total, respectively. A higher score indicates greater perceived communication dysfunction. The 35th item "Do you talk the same amount now as before your laryngeal cancer" has three response categories, Yes/More/Less, and is not included in the scoring system.The EORTC Study Group on Quality of Life has developed a modular measurement system for evaluating quality of life in cancer patients participating in clinical trials . A 30-itCalculated scale scores range from 0–100. On the Functioning scales and Global quality of life scale a score of 100 corresponds to maximum functioning, whereas on the Symptom scales and items a score of 100 means worst possible symptoms . A changThe HAD scale is a tool detecting mood disorders in somatically ill patients  and has The statistical software SPSS 14.0 for Windows was used in the statistical analyses.U test. Level of significance was set at 5% throughout. Clinical significance has also been calculated for EORTC, i.e. a score difference of >10 points. Magnitude of group differences was further analyzed by means of effect sizes (ES). ES of within-group change was calculated as mean change between assessments divided by the standard deviation of change [Descriptive statistics with 95% confidence interval (CI) were calculated according to standard procedures. Differences within groups were tested with the Wilcoxon paired signed ranks test and between-group analyses were carried out using the Mann-Whitney f change . ES weref change . This meThe study was conducted in accordance with the Declaration of Helsinki and was approved by the ethical committee at Sahlgrenska University Hospital, Göteborg, Sweden.Socio-demographic characteristics of included and excluded patients are presented in Table The questionnaire response rate was 100% at baseline, 95% at one month, 86% at two months, 81% at three months, 75% at six months and 71% at one year. Of the 71 patients completing the study five were laryngectomised while 66 (93%) had preserved larynx. At the end of the study year five patients still had active disease or were deceased. Thus, the cumulative response rate of patients answering all six questionnaires over one year was 76 %, and the item response rate was 99.5%, i.e., only 0.5% of the questions were left unanswered The 29 drop-out patients missing at follow-up did not differ from the participants completing the study regarding gender, age, civil status or educational level but significantly more were smokers and had a supraglottic localisation (data not shown).No significant differences in S-SECEL baseline scores were found between the 29 drop-out patients and the 71 patients completing the studyThe mean S-SECEL total and subscale scores at the different measurement points are shown in Table Two items explained most of the difference in the Environmental scale: 'difficulty yelling or calling out to people' and 'trouble speaking in large groups' (Mdiff = 0.60/0.54). These questions also displayed the largest dysfunction before treatment. For the General scale one item differed more than the others: 'does your speech improve with practice' (Mdiff = 0.89) while the smallest change was noted for 'are you a calm and quiet person'. Items in the Attitudinal scale scored low both before and after treatment but the greatest change was found for 'is your private or social life limited' (Mdiff = 0.37)Data for the EORTC QLQ-C30 and QLQ-H&N35 scales and items are shown in Table For the H&N35, an increase was seen in all scales, but Sexuality, as well as all single items at one month, and most of these were both clinically and statistically significant. At the 12 month follow-up an improvement compared to baseline was reported for two of the scales and one item. However, patients still reported more problems with Senses and Sticky saliva.One month after treatment start, patients reported a small but significant decrease in mean anxiety scores compared to baseline Table , Fig 2. Results from our study proved the S-SECEL to be sensitive to changes in communication and psychosocial dysfunction longitudinally. The response pattern over time, when compared to the EORTC QLQ-C30 with H&N35 and the HAD, lent further support to the construct validity of the S-SECEL. The response rate for the used set of questionnaires was high, 76% at the last follow-up, supporting the feasibility of assessment method in clinical settings.When looking at the individual S-SECEL scales, at the 12-month follow-up the decrease in the General scale is moderate. However, it should be noted that patients report little dysfunction before as well as after treatment. The General scale displays a somewhat different pattern to the other subscales during the year. There is no decrease at one month but already at the two month follow-up a small but significant improvement is seen. This different pattern might be explained by items being somewhat disparate, covering questions about voice quality as well as personality, and therefore of differing relevance. The question "Do you think your speech improves with practice" changes the most over the study period and this is a highly relevant question since it detects the effect of voice rehabilitation measures. It should be noted, that there is no corresponding question in the EORTC. The question "Would you describe yourself as a calm and quiet person?" changes the least, probably due to this question rather measuring a trait of character then effects of illness or treatment.Both the Environmental and the Attitudinal subscales show a small but significant increased dysfunction one month after start of treatment. This is reasonable since the patients still receive treatment and therefore are suffering from various side effects, also affecting the voice. At the following measuring points scores decrease, but the decrease is not significant until the 6 month follow-up and these results are in accordance with previous studies ,32. AlthWhen reviewing the results of the EORTC QLQ-C30 and the QLQ-H&N35, we find diverging results for the different methods of significance testing. In a number of scales, at several measurement points, there are statistical but no clinical significances and effect sizes are small or even trivial. This illustrates the additional value of not using p-values alone as measure of significance.In the EORTC QLQ-C30, only two of the scales, Role and Emotional, show significant changes at 12 months. The questions that constitute these scales have their equivalence in the S-SECEL. The Role scale consists of two questions concerning how the disease affects patients' ability to function in daily activities, work and leisure. This area is more specifically covered in the subscale Environmental of the S-SECEL. The Emotional scale in the EORTC consists of four questions about feeling annoyed, depressed, tense or worried. Some of these symptoms are covered in the Attitudinal scale and there in relation to voice and speech. This is an important distinction since, for example, one can feel annoyed in a specific situation such as a conversation without feel annoyed in general.The significant changes in C30 and H&N35, statistically as well as clinically, are mainly seen in items in the head and neck module. All single items show significant changes one month after start of treatment as well as four of the scales. As with the S-SECEL, these changes probably reflect treatment effects. At one year there is only one clinically significant improvement reported, the Speech scale. It is well known that the main problems for patients with laryngeal cancer are voice related. The Speech scale in the QLQ-H&N35, however, consists of only two questions directly addressing quality of voice and speech; "Difficulties speaking to other people?" and "Problems speaking on the phone?". The scales Senses and Social contact and the single item Dry mouth show statistical significance at 12 months, but the effect sizes were only small and not clinically significant. Müller et al  argue thBaseline results of the HAD scale corresponds well to other comparable studies ,33, bothMean values of depression was low at baseline and did not change, a finding in line with previous studies, e.g. . HoweverA shortcoming of our study is that the patients excluded from the study had a more advanced disease and lower performance status than those included. This might have lead to an underestimation of the prevalence of psychiatric morbidity and communication dysfunction. On the other hand, this is to our knowledge the largest Scandinavian longitudinal study made on HRQL and communication dysfunction in patients treated for laryngeal cancer.The S-SECEL has been investigated in the largest Scandinavian longitudinal study concerning HRQL in patients with laryngeal cancer. The questionnaire is sensitive to change over time and shows convergent results when compared to established HRQL questionnaires. Our findings also indicate that the S-SECEL could be a more suitable instrument than the EORTC QLQ-C30 with QLQ-H&N35 in patients with laryngeal cancer; it is more sensitive, it is shorter and can be used on an individual basis. As a routine screening instrument, with the use of a specific cut off value, the S-SECEL could be a valuable tool for identifying patients at risk for psychosocial problems, to help to plan rehabilitation. It is therefore recommended for clinical use in evaluation of communication dysfunction for all patients with laryngeal cancer irrespective of treatment.The author(s) declare that they have no competing interests.We hereby certify our personal contribution; CF was responsible for the design and planning of the study. AR carried out the statistical analysis. MJ performed the literature search/analysis. AR and MJ were responsible for the data interpretation. All authors participated in preparation of manuscript. All authors read and approved the final manuscript.1) feel relaxed and comfortable in social settings2) describe yourself as calm and quiet3) describe yourself as outgoing, talkative4) admit having had laryngeal cancer5) your speech improves with practice1) limited in meetings due to speech2) difficulty getting peoples' attention3) difficulty yelling or calling out to people4) people having difficulty to understand5) repeat things to be understood6) trouble speaking in large groups7) trouble speaking in small groups8) trouble speaking with one person9) trouble speaking in different rooms10) trouble speaking in loud and noisy places11) trouble speaking on telephone12) trouble speaking in car or bus13) difficulty attending parties or social activities14) use telephone less often1) feel left out in group2) limited private or social life3) depressed due to speech4) frustrated when not understood5) different or peculiar6) hesitate to meet new people7) get left out of conversations8) avoid speaking9) people fill in words10) people interrupt11) people tell you they can't understand12) people get annoyed13) people avoid you14) people speak differently to you15) family and friends difficulty understanding your communication situationResponse alternatives: Always/Most of the time/Sometimes/Never1) Do you talk the same amount now as before your laryngeal cancer?Response alternatives: Yes/More/LessThe pre-publication history for this paper can be accessed here:


Accurate estimates of incidence and prevalence of the disease is a vital step toward appropriate interventions for chronic disease like diabetes. A growing body of scientific literature is now available on producing accurate information from administrative data. Advantages of use of administrative data to determine disease incidence include feasibility, accessibility and low cost, but straightforward use of administrative data can produce biased information on incident cases of chronic disease like diabetes. The present study aimed to compare criteria for the selection of diabetes incident cases in a medical administrative database.An exhaustive retrospective cohort of diabetes cases was constructed for 2002 using the Canadian National Diabetes Surveillance System case definition  with the Quebec health service database. To identify previous occurrence of diabetes in the database, a five-year observation period was evaluated using retrograde survival function and kappa agreement. The use of NDSS case definition to identify incident cases was compared to a single occurrence of an ICD-9 code 250 in the records using the McNemar test.Retrograde survival function showed that the probability of being a true incident case after a 5-year diabetes-free observation period was almost constant and near 0.14. Agreement between 10 years (maximum period) and 5 years and more diabetes-free observation periods were excellent (kappa > 0.9). Respectively 41,261 and 37,473 incident cases were identified using a 5-year diabetes-free observation period with NDSS definition and using a single ICD-9 code 250.A 5-year diabetes-free observation period was a conservative time to identify incident cases in an administrative database using one ICD-9 code 250 record. Diabetes is one of the most costly and burdensome chronic diseases of our millennium . AccordiPlanning, implementing and monitoring of appropriate intervention for this disease requires accurate estimates of incidence and prevalence of the disease. Although surveys are used for precise estimation of prevalence and incidence, they are very expensive and time consuming. Alternative methods include secondary analysis of existing data and use of administrative data ,4. AdvanHowever, there are several potential pitfalls of administrative data to estimate disease incidence . One genRégie de l'Assurance Maladie du Québec (RAMQ) and the registry Maintenance et exploitation des données pour l'étude de la clientèle hospitalière (Med-Echo). The RAMQ provides universal health insurance for Quebec inhabitants, which includes coverage for physician and hospital services, as in other Canadian provinces. For each physician service, the patient's identification, date of service, diagnosis (a four digit ICD-9 code), and service code are entered into a "physician claims" database. Similarly, after each hospital discharge, Quebec hospitals submit a discharge summary that includes the patient's identification, dates of admission and discharge, attending physicians, main reason for admission and up to 16 ICD-9 diagnoses. These hospital discharge records constitute the Med-Echo registry. The accuracy of this administrative health data has been demonstrated for a number of medical conditions [A retrospective population-based cohort was constructed using data from the nditions ,12. All The study population includes all individuals 20 years old or older living in the province of Quebec in 2002. The date of the first claim for diabetes or hospitalization in the year 2002 was defined as the index date. We excluded women with gestational diabetes mellitus. To eliminate gestational diabetes any record with an obstetrics event within 5 months of the index date was excluded.A single cohort was selected to determine incident cases of diabetes. The 2002 cohort was selected as an example of application. This cohort provided 10 years of retrospective observation to exclude previous cases. A diabetes case was defined according to the Canadian National Diabetes Surveillance System (NDSS) case definition: two physician claims with a diagnosis of diabetes (ICD-9 Code 250) on 2 different days within 2 years or one hospital discharge with a diabetes diagnosis code in any field among 16 diagnosis codes. To find the cases we started from the date of the first claim for diabetes or hospitalization in the year 2002, whichever came first. To apply the definition, the databases were observed for the 720 days before the index date. To differentiate between prevalent cases and incident cases, a minimum diabetes-free retrospective observation period (clearance period) and a definition for repeated cases were needed. Our options for identifying repeated cases were using NDSS case definition  or using a single record of ICD-9 code 250  during the retrospective observation period. In this study NDSS case definition criteria is called "NDSS method" and a single record of ICD-9 code 250 is called "one hit method ". To define the cut-off point for a clearance period for each index case in 2002, the backward time to the previous event was separately calculated using NDSS method and using the one hit method. Time was measured in days from the index point. The maximum (backward) observation period was 3650 days.The Population at risk of diabetes at the beginning of the year 2002 includes people not diagnosed with diabetes and new cases of diabetes. As it was shown in figure Descriptive statistics and McNemar matched pair chi-square test are used to compare the NDSS method and the one hit method to exclude prevalent cases.Kappa statistics is used to show the level of agreement between different lengths of observation periods and ten years as the maximum observation period. Kappa values are categorized as follows by Byrt,14 valueNext, The probability of being an incident case (being free of retrospective event) at different times (cut-points) is calculated by retrograde survival function. By this method, survival (being an incident case) at a given time is the conditional probability of surviving (not having a preceding record) to a specific time given that the individual is at risk for the event (having a preceding record) at that time. To find the cut-off point, we assumed that there is a time when all previous cases have been accounted and the patient is no longer at risk of a previous event. The cut-off point of the clearance period will be considered the point that the probability for being at risk of a previous event begins to remain constant. Statistical analyses were performed using SAS 9.1.Faculté de médecine of the Université de Sherbrooke and the Commission d'accès à l'information du Québec.This project was approved by the Ethics Review Board of the P < 0.0001).There were 5,686255 adults, 20 years old or older for the year 2002. A total of 263,213 patients met the NDSS case definition for being a diabetes case . The agreement is also excellent between a ten-year clearance period and clearance periods of four years or more (kappa > 0.90). The agreement changed to very good (kappa > 0.85), good (kappa > 0.74), and fair (kappa > 0.43) when a three, two and one-year clearance period was used, respectively. Results using the NDSS method were similar and showed that agreements between a ten-year clearance period and clearance periods of four years and more were excellent Table .The estimation using survival function by one hit method for eliminating prevalent cases at one year (365 days) was  Figure . There wPrevious studies on diabetes incidence for Canadian adults from administrative data relied on the NDSS  case definition and employed a free observation period to remove the prevalent pool effect ,6. In ouDiabetes is an insidious disease which may go undiagnosed for many years. In this retrograde method, we started with the diabetes cases who already met the criteria of NDSS in the year 2002. Canadian studies show the NDSS case definition has a sensitivity above 86%; specificity around 97%; and positive predictive values of 80% ,6. We aiIn practice, it is usual to exclude patients who received the same diagnosis several years before the beginning of the study period ,1,17. PrWe found excellent agreement (kappa > 0.90) between a 10-year clearance period and a clearance period of 4 years or more. However such a high agreement (kappa > 0.90) may be related to the high prevalence of cases in our database . For thiThe accuracy of our incidence estimation may also be affected by validity of diagnosis codes recorded in administrative databases and time. Canadian studies on administrative data showed that there is a good agreement between recorded cases in administrative databases and self-reported disease ,18. To eWe also evaluated the consistency of a five-year clearance period when different selection criteria were used. Kappa were > 0.90 between a clearance period of 10 years vs. a clearance period of 4 years or more whether one hit method or NDSS method were used.Our study has some limitations. We used medico-administrative data to find the incident cases. This may underestimate the real incidence because most people with diabetes remain asymptomatic for years after onset of the disease and because only patients who received health care services are entered in these databases ,20. In C1-People who did not need the services; 2-diabetic patients who used services for other reasons; 3-sick people who left the country.One study in Manitoba showed the probability of 0.96 for diabetic patients to have a subsequent medical contact for the diabetes within two years . A validIn our database, it was not possible to differentiate between diabetes type 1 and type 2.The results may not be representative for the younger populations with diabetes because patterns and temporal evolution of disease is different between diabetes type 1 and type 2 and incidence of the former is higher in young populations. Furthermore, we did not assess clearance periods of more than ten years. However the results of our retrograde survival function analyses showed stabilization of risk of being a previous case after a clearance period of 5 or more years.Use of recorded administrative data to estimate incidence of diabetes using either the Canadian National Diabetes Surveillance System definition or one ICD-9 code 250 produces biased estimates in part because of inclusion of prevalent cases as incident cases. A clearance period of 5 years or more is sufficient to improve performance of this convenient, accessible and inexpensive method to estimate incidence of diabetes.ACC regularly consults for many pharmaceutical companies on lipid and diabetes drugs. He is also involved in many research contracts with the pharmaceutical industry. Moreover, he received funding from GSK to create a CIHR/industry chair on diabetes.Neither the funding sources nor author contracts played a role in the study's design, conduct, or reporting or in the decision to submit the article for publication.All authors participated in the study's conception and design. AV, SA, and JC developed the methodology and analysis approach. SA drafted the manuscript. AV and JC helped draft 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/1471-2288/9/62/prepub


Early identification of patients who need post-acute care (PAC) may improve discharge planning. The purposes of the study were to develop and validate a score predicting discharge to a post-acute care (PAC) facility and to determine its best assessment time.We conducted a prospective study including 349 (derivation cohort) and 161  consecutive patients in a general internal medicine service of a teaching hospital. We developed logistic regression models predicting discharge to a PAC facility, based on patient variables measured on admission (day 1) and on day 3. The value of each model was assessed by its area under the receiver operating characteristics curve (AUC). A simple numerical score was derived from the best model, and was validated in a separate cohort.Prediction of discharge to a PAC facility was as accurate on day 1 (AUC: 0.81) as on day 3 (AUC: 0.82). The day-3 model was more parsimonious, with 5 variables: patient's partner inability to provide home help (4 pts); inability to self-manage drug regimen (4 pts); number of active medical problems on admission (1 pt per problem); dependency in bathing (4 pts) and in transfers from bed to chair (4 pts) on day 3. A score ≥ 8 points predicted discharge to a PAC facility with a sensitivity of 87% and a specificity of 63%, and was significantly associated with inappropriate hospital days due to discharge delays. Internal and external validations confirmed these results.A simple score computed on the 3rd hospital day predicted discharge to a PAC facility with good accuracy. A score > 8 points should prompt early discharge planning. Efficient discharge planning is an important component of hospital care. The goals of discharge planning are to ensure continuity in health care beyond hospital discharge and optimal use of hospital beds .Current evidence suggests that discharge delays are an important cause of inefficient hospital use. In general internal medicine wards, 30% of all hospital discharges may be delayed for non-medical reasons, and these delays represent 17% of all hospital days . At our Several studies have tried to develop screening instruments of problems linked with the discharge process in patients hospitalized for acute medical conditions -8. HowevThe purposes of this study were to determine, among patients hospitalized for an acute medical condition, which factors predicted their risk of being discharged to a PAC facility, and to identify which assessment time of the corresponding variables had the best predictive power and was the most efficient. We compared two strategies of early detection: the first used data collected within the first 24 hours of admission (day 1) and the second data collected on the 3rd hospital day (day 3). Then, we developed and validated a simple score based on our preferred model that stratified patients' risks of discharge to a PAC facility for use as a screening instrument in ordinary clinical settings.th 2003.This prospective study was divided into two parts: the development phase  from January 1st to April 30th 2001; and the prospective validation phase  from October 1st to November 30The Geneva University Hospitals is an 1100-bed urban teaching hospital with 224 medical beds, serving a large community as well as a referral population. Only medical patients with an acute condition are admitted in these medical beds. At our study site, discharge planning services are provided in accordance with the medical plan of care. Patient's physician and primary nurse manage routine or uncomplicated discharges. For complicated or non-routine discharges, we use a consultative discharge planning model in which physicians, ward nurses and social workers work together to assess, coordinate and implement the patients' discharge plan. In addition, a weekly formal multidisciplinary ward round is held for the assessment of all patients' discharge plan.Patients were recruited on admission to the general internal medicine wards. To be included in the derivation and validation cohorts, patients had to be discharged to home or to a PAC facility (skilled nursing facility or inpatient rehabilitation facility). Comatose and terminally ill patients on admission were excluded. We also excluded from further analysis patients who died in hospital after enrolment, were transferred to other acute care hospital settings, or were discharged to the nursing home in which they lived prior hospital admission. The study was part of a hospital quality improvement protocol and was approved by the institutional ethics committeeOur main outcome variable was the patient's discharge destination, i.e. whether the patient was discharge to home or was discharge to a PAC facility. In this study indeed, as the most frequent cause for discharge delays in our service was waiting for a bed in a PAC facility, we were concerned with discriminating patients unable to return home and eventually transferred to a PAC facility from those returning home with (or without) formal  help. Therefore, we did not consider referral to home care as a PAC destination.Secondary outcomes, which were not used in modeling, included: LOS, number of inappropriate hospital days, and number of inappropriate hospital days due to discharge delays, as determined by the Appropriateness Evaluation Protocol (AEP) and Delay Tool ,9. The Ard hospital day. They collected demographic, clinical, and administrative data, as well as discharge diagnoses and treatment regimens from medical charts and hospital administrative databases. The baseline patient questionnaire included information about living situation, formal or informal home help, drug regimen prior to hospitalization, the number of hospitalizations or medical visits during the prior 3 months, self-reported basic activities of daily living (ADLs) and self-reported instrumental activities of daily living (IADLs) two weeks prior to admission. The seven basic ADLs  and the five IADLs , meal preparation, housework, medication use (preparing and taking correct dose)) were dichotomously rated as dependent or independent by research nurses. Dependency was defined as partial or total need of assistance from another person. On admission, the following data were also collected: type of admission , number of active medical problems , Charlson comorbidity index [Two trained clinical nurse researchers carried out structured questionnaires with the patients and their family if necessary, the residents in charge of their care, and their primary nurses within 24 hours of admission and on the 3ty index , Mini-Mety index , sensoryInformation extracted from internal databases let us expect a transfer rate of 30% to a PAC facility. The sample size needed to estimate this proportion with a 95 percent confidence interval of 0.05 is 323. We therefore aimed at this sample size, increasing our recruitment in order to take into account ineligible patients and dropouts.Univariable analyses, using chi-square tests or student t-tests, were performed to assess the association between demographic and clinical characteristics and discharge to a PAC facility. To assess independent associations with the outcome of interest, all variables were included into 2 multivariable logistic regression models, separately for the two data collection times (day 1 vs. day 3). Two-way interaction terms were tested as well. Backward elimination, in which the least significant variable was discarded at each step, was then used, until all remaining variables in the models reached a significance level of 0.05 or less. The accuracy of both multivariable models to identify patients discharged to a PAC facility was assessed by means of their ROC curves.A simple integer score was computed from the best final parsimonious multivariable logistic regression model, assigning points in proportion to the regression coefficients. Then, a cross-validation procedure was performed in order to assess the degree of over-fitting of the prediction model to the development sample . The samrd hospital day by the research nurses who kept the ward staff blinded to its results. The score capacity to predict discharge to a PAC facility was compared between the prospective validation cohort and the initial derivation cohort by means of AUCs.The predictive score created in the derivation cohort was calculated in the prospective validation cohort on the 3Finally, the association between score's risk categories and LOS, as well as the number of inappropriate hospital days and the number of inappropriate hospital days due to awaiting for post discharge facilities were assessed in both cohorts by means of Kruskall-Wallis equality of populations rank test. Analyses were performed using Stata release 8 .During the derivation enrolment phase, we recruited 412 patients, of whom 63 (15.3%) were excluded from further analyses: the main reasons were death during hospital stay ; transfer to other acute care hospital settings, such as intensive care unit or surgical wards ; and patients' discharge to the nursing home in which they lived prior to hospital admission . Excluded patients were older than enrolled patients , were more likely to live alone, and reported a higher number of disabilities in both ADL and IADL tasks .Of the 349 patients evaluated on admission and enrolled in the study to build the day 1 model, 245 (70%) were discharged home and 104 (30%) to a PAC facility. Patients discharged to a PAC facility were older and were more likely to live alone than patients discharged home (Table Since 30% (n = 104) of the 349 enrolled patients received professional home care before their admission, we compared these patients with those not receiving such help (n = 245). Not surprisingly, these patients were older , had more disability in ADLs , IADLs , and comorbidities assessed by the Charlson comorbidity index ; they were also more likely to live alone  and less likely to be helped by a partner . In terms of sex, and active medical problems, both groups were similar. Among these 104 patients, 64 (62%) were discharged home and 40 (38%) to a PAC facility. Both groups were however similar except in terms of disability in IADLs .After admission, 50 patients left our service within 3 days: 41 (11.7%) were discharged home and 9 (2.6%) to a PAC facility. These 50 patients were significantly younger than patients who remained 3 days or more . The remaining 299 patients (85.7%) were evaluated on the 3rd hospital day and enrolled to built the day 3 model; 95 of them (31.8%) were later discharged to a PAC facility.Logistic regression modeling with backward elimination yielded slightly different models according to the time of data collection (day 1 vs. day 3) Table . In bothSince 50 out of 349 patients (14%) left the hospital before day 3, we considered that assessing the likelihood of being discharged to a PAC facility on day 1 was not an efficient strategy. Therefore, construction of the predictive score was based on the model developed from data collected in 299 patients on day 3. Table At a cut-point of 8 or more, the score correctly classified 71% of the patients discharged to a PAC facility and predicted the risk of being discharged to a PAC facility with a sensitivity of 87%, a specificity of 63%, a positive predictive value of 53% and a negative predictive value of 91%. At a cut-point of 16 or more, the score correctly classified only 42% of the patients discharged to a PAC facility and predicted this outcome with a sensitivity of 42%, a specificity of 95%, a positive predictive value of 80% and a negative predictive value of 78%. Therefore, the score was chosen as the cut-point of 8 and more in an attempt to maximize both sensitivity and specificity. Indeed, our goal was to early identify patients at risk of not returning home in order to take appropriate actions towards these patients. Consequently, we were more willing to accept a high number of false positives (i.e patients identified as candidates for transfer to a PAC facility who subsequently would not experience it) than a high number of false negatives, (i.e. patients not identified as candidates for transfer to a PAC facility who subsequently would require it).We finally analyzed misclassified patients using our algorithm. Out of the 158 patients with a score of 8 points or more, 75 subsequently return home. These patients were similar to patients discharged to PAC facility (n = 83) in terms of living situation, formal or informal home help, comorbidities and active medical problems. However, these patients were younger  and had less disabilities in ADLs  and IADLs . False negatives patients were less frequent (n = 12) and did not significantly differ from patients returning home with the same score (less than 8 points).rd hospital day .). Their 3-day scores ranged from 1 to 22. The score's capacity to predict discharge to a PAC facility was higher in the derivation cohort (AUC = 0.82) than in the prospective validation cohort (AUC = 0.77) but the difference was not statistically significant (p = 0.31)  were excluded from further analysis: 4 patients died during the hospital stay, 8 were transferred to other acute care hospital settings and 10 were discharged to the nursing home where they lived. Of the 161 remaining patients, 58 (36%) patients were discharged to a PAC facility and 103 (64%) home. Clinical characteristics of the 161 patients were similar to those of the derivation cohort except in terms of mean number of informal care providers at home , of mean Charlson comorbidity index , and of mean number of impairment in the ADL's on the 3Since death or transfer to other acute care hospital settings are not predictable on day 3, we checked whether including the 22 patients who experienced such outcomes in the validation cohort significantly modified our results. Mean 3-day score among them reached 11.2 ± 5.8 points vs. 10.7 ± 6.0 for patients discharged home or transferred to a PAC facility (p = 0.68). However, the score's capacity to predict discharge to a PAC facility was not significantly different in the validation cohort when these patients were included in the analysis . Therefore, for strict comparability purposes between the derivation and the validation cohorts, we decided to keep these 22 patients out of further analyses.We arbitrarily stratified patients of the derivation cohort into three score categories according to the proportion of patients discharged to a PAC facility: 0 to 7 points (less than 10% of patients); 8 to 15 points 40%); and 16 points and over (80%). LOS, number of inappropriate hospital days, and number of inappropriate hospital days due to discharge delays significantly increased as the score categories increased  compared with North American hospitals ,33. In aOur study provides a validated, simple, and easy-to-use prediction tool that predicts medical patients' risks of discharge to a PAC facility at the end of an acute hospital stay. Specific interventions targeted towards high-risk patients could save inappropriate hospital use.The authors declare that they have no competing interests.MLS conceived and designed the study, managed the protocol, supervised the acquisition of data, analysed and interpreted the data and wrote the manuscript. MPK conceived and designed the study, managed the protocol, supervised the acquisition of data, analysed and interpreted the data and wrote the manuscript. PC contributed to the protocol design, participated in data analysis and in the writing of the paper. PS collected the data and checked their accuracy. TVP contributed to the protocol design, gave expertise in statistical analysis, participated in data analysis and in the writing of the paper. J–MG contributed to the protocol design, analysed and interpreted the data and participated in the writing of the paper.The pre-publication history for this paper can be accessed here:


Despite CDC recommendations regarding universal catch-up vaccination against human papillomavirus (HPV), only about ten percent of young adult women in the United States have been vaccinated. The purpose of this study was to better understand reasons for non-vaccination among insured 19-26 year-old women and to evaluate future vaccination intentions.We used an administrative claims database from a large US managed care plan to identify women aged 19-26 for receipt of a mailed survey. From a sample of 1,375 women with no evidence of HPV vaccination from June 1, 2006 through April 30, 2007, 222 completed surveys were received, of which 185 were eligible for this analysis. The main outcome measures were unvaccinated women's attitudes and vaccine awareness, likelihood of future action regarding the vaccine, and reasons for inaction.Among the 185 non-vaccinees, 25.4% were married, 83.2% were white, and 89.2% had a college or higher level education. The vaccine was described as very important by 32.4% of subjects, and 30.1% had discussed the vaccine with a doctor and received a doctor's recommendation. Half or fewer of respondents were "very" or "extremely" likely to discuss the vaccine with their doctor (50.0%), do additional research on the vaccine (42.6%), ask a doctor to get the vaccine (37.5%), or make an appointment to get the vaccine (27.8%), while 48.0% were "somewhat", "very", or "extremely" likely to do nothing to get the vaccine. Among the latter, reasons for taking no action included being married or in a monogamous relationship (54.9%), belief that the vaccine is too new (35.4%), not having enough information about the vaccine (31.7%), concerns about side effects (24.4%), and uncertainty about insurance coverage (24.4%).Educational interventions may be needed to enhance HPV vaccination rates among 19-26 year-old women, particularly regarding information about vaccine safety, vaccine efficacy, insurance coverage, and the value of vaccination to women in monogamous relationships. Human papillomavirus (HPV) is the most common sexually transmitted infection in the United States . Low-risTwo vaccines have been developed for the prevention of HPV infection. One is bivalent, targeting high-risk HPV types 16 and 18 , and appDespite the ACIP recommendation, vaccination coverage rates remain low (≤36%) ,13, partA previous article by the authors using the same database as the present study compared vaccinated with non-vaccinated women and demonstrated the importance of a physician's recommendation to vaccination decisions . The prehttp://www.wma.net/en/30publications/10policies/b3/17c.pdf) and ethics approval for the study was obtained by the Copernicus Group Independent Review Board (http://www.copernicusgroup.com).Subjects were identified using medical and pharmacy claims from a large US managed care plan affiliated with i3 Innovus. The health plan provides fully insured coverage of physician, hospital, and prescription drug services to more than 15 million patients across the four major geographic regions of the United States: the Northeast, Midwest, South, and West. A self-administered survey assessed factors related to an individual's decision to receive or not receive HPV vaccine administration. One of the authors (MBG) is an employee of i3 Innovus and accessed the claims data to identify patients who qualified for this study. This research was carried out in compliance with the Declaration of Helsinki ; and were continuously enrolled in the health plan for 6 months prior to and 12 months following the index date. Women were excluded if they had a medical claim related to pregnancy, delivery, or cervical cancer during the identification period. A total of 611,955 women met the above criteria.Two samples of 1,375 women were randomly selected from among women who had: (1) a first HPV vaccine dose during the identification period, and (2) no doses of HPV vaccine during the identification period or during the 6 months before that period . The secSurvey packets were mailed beginning in April 2008. Packets contained an invitation letter, an informed consent form, a 7-page survey assessing factors related to an individual's decision to receive or not receive the HPV vaccine, and a payment of $10 as compensation for participation. Reminder post-cards were sent one week following the initial mailing, and a second survey packet was sent to non-respondents after three weeks. The total survey collection period was 8 weeks.The survey collected standard demographic and health status information  to 6 (strongly agree), with statements such as "Cervical cancer is a devastating disease," "Genital warts are an embarrassing condition," and "I am comfortable discussing sexual health issues with a doctor or nurse."To assess vaccine awareness, respondents were first asked if they had ever heard of a vaccine to help prevent cervical cancer or HPV infection. If yes, they were then asked a series of questions about their perception of the personal importance of the HPV vaccine by the question, "How important do you think the vaccine to help prevent cervical cancer is for you?" Possible answers were 'not at all important', 'not very important', 'somewhat important', and 'very important'.strongly did the doctor recommend you get the cervical cancer vaccine on a scale from 1 to 5?" A rating of 1 corresponded to the response that 'a doctor did not strongly recommend the vaccine' and a rating of 5 meant that 'a doctor strongly recommended the vaccine'.The questions that addressed discussion with and recommendation by a physician were: "Have you discussed the vaccine to help prevent cervical cancer with a doctor?" and "Did a doctor recommend that you get the vaccine to help prevent cervical cancer?" If the respondent reported that a doctor did recommend the vaccine, she was asked, "How The likelihood of taking additional action regarding the HPV vaccine was assessed via the question, "If you have not received a single dose of the cervical cancer vaccine, in the future how likely are you to" followed by 5 choices: 'Ask a doctor to get this vaccine?', 'Do additional research on this vaccine?', 'Discuss the vaccine with a doctor?', 'Make an appointment to get the vaccine?', and 'Do nothing to get the vaccine?'. The answers were measured on a 5-point Likert-type scale, ranging from 'not at all likely' (1) to 'extremely likely' (5).Respondents who were somewhat, very, or extremely likely  to 'do nothing to get the vaccine' were asked their reasons for inaction. Possible answers were 'I am not sexually active', 'The vaccine is too new', 'I am married or in an exclusive (monogamous) relationship', 'I am unsure if my insurance would cover the vaccine cost', 'I do not have enough information about this vaccine', 'I am concerned about the side effects', 'I am pregnant or trying to conceive', 'My doctor recommended against getting the vaccine', and 'I cannot afford the cost of the vaccine'. Respondents were instructed to 'check all that apply' and were given the option of articulating their own reason(s).A descriptive analysis was conducted to determine the attitudes of non-vaccinees toward the HPV vaccine, their awareness of the vaccine, their interaction with a physician relating to the vaccine, the likelihood of their taking future action regarding HPV vaccination, and their reasons for inaction.Of the 1,375 surveys sent out to non-vaccinees, 222 were returned complete, for a response rate of 16.1%. Thirty-seven non-vaccinees were subsequently determined to be ineligible due to disenrollment or vaccination after the identification period, leaving 185 surveys eligible for analysis. As reported in our earlier paper, there were no differences between respondents and non-respondents with respect to region of residence or number of comorbidities . RespondThe sociodemographic characteristics and health status of the respondents are shown in Table Most respondents agreed that cervical cancer is a devastating disease (93.5%) and that genital warts are an embarrassing condition (90.0%), and most reported being comfortable discussing sexual health issues with a doctor or nurse , to do additional research on the vaccine (75.0%), ask a doctor to vaccinate them (69.9%), or to make an appointment to be vaccinated  . In addiAlthough the majority of unvaccinated respondents in this study recognized the potential impact of cervical cancer and genital warts, only about one in three considered vaccination against HPV to be important to them. Half of respondents reported being very or extremely likely to discuss the vaccine with a doctor but almost half (48.1%) were at least somewhat likely to do nothing to pursue vaccination. The most frequent reason for inaction was being married or in a monogamous relationship, but other reasons relating to uncertainty about the vaccine and insurance/cost issues were common.These reasons for inaction echo findings of previous studies, which noted a perceived lack of need, concerns about the vaccine, and perceived barriers as factors in the decision not to be vaccinated. A perceived lack of need, usually due to sexual inactivity or low risk, was found to be a factor in previous population surveys of this age group ,15. SafeAs in the present study, a relatively small proportion of women (7%) in the National Immunization Survey (NIS) 2007 were concerned about cost or insurance issues . Cost waIn our previous paper published from this data set we found that those respondents who reported physician discussion/recommendation of HPV vaccination were significantly more likely to be in the vaccinated group . The womResponses to questions about taking additional action suggested ambivalence on the part of non-vaccinees . This inconsistency may have resulted from the choice of cutoff  in the accepted responses. There was no discrepancy if the threshold was set at "very" or "extremely" likely, when from 27.8% to 50.0% would take some action regarding the vaccine, and 27.1% would do nothing. Ambivalence about vaccination is, however, consistent with the lack of correlation between the intention to be vaccinated and actual vaccination observed in one post-vaccine study . This reThese findings suggest that educational interventions may be necessary to enhance HPV vaccination rates among young adult women. Although some of these women currently may be at low risk for infection, using assessment of risk as a basis for deciding who to vaccinate is unlikely to be an effective approach . FurtherGDZ and SLR have served as paid research consultants to Merck & Co., Inc. They are also co-principal investigators and co-investigators on two investigator-initiated research studies funded by Merck & Co., Inc.TWW and MDV are employees of Merck & Co., Inc.MBG is an employee of I3 Innovus.The research reported in this article was funded by Merck & Co., Inc.GDZ took primary responsibility for designing the study and writing the paper and contributed to statistical analyses; TWW contributed to study design, statistical analyses, and writing of the paper; SLR contributed to study design and helped write the paper; MBG was responsible for data acquisition and helped write the paper; MDV contributed to study design and helped write the paper. All authors read and approved the manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6874/10/27/prepubHPV vaccine questionnaire 18-26. This questionnaire was directed toward 18-26 year old women and assessed HPV vaccination status and reasons for vaccination/non-vaccination as well as knowledge and attitudes about HPV and HPV vaccination.Click here for file