Background: Fatigue is a common side effect of conventional prostate cancer radiation therapy. The increased delivery precision necessitated by the high dose per fraction of stereotactic body radiation therapy (SBRT) offers the potential of reduce target volumes and hence the exposure of normal tissues to high radiation doses. Herein, we examine the level of fatigue associated with SBRT treatment. Methods: Forty patients with localized prostate cancer treated with hypofractionated SBRT, and a minimum of 12 months follow-up were included in this analysis. Self-reported fatigue and other quality of life measures were assessed at baseline and at 1, 3, 6, 9, and 12 months post-SBRT. Results: Mean levels of fatigue were elevated at 1 month post-SBRT compared to baseline values (P = 0.02). Fatigue at the 3-month follow-up and later were higher but not statistically significantly different compared to baseline. African-American patients reported higher fatigue post-SBRT than Caucasian patients. Fatigue was correlated with hormonal symptoms as measured by the Expanded Prostate Cancer Index Composite (EPIC) quality of life questionnaire, but not with urinary, bowel, or sexual symptoms. Age, co-morbidities, smoking, prostate specific antigen (PSA) levels, testosterone levels, tumor stage, and treatment variables were not associated with fatigue. Conclusion: This is the first study to investigate fatigue as a side effect of SBRT. In contrast to standard radiation therapy, results suggest SBRT-related fatigue is short-term rather than a long-term side effect of SBRT. These results also suggest post-SBRT fatigue to be a more frequent complication in African-Americans than Caucasians. Fatigue limits a patient’s ability to care for themselves and decreases their quality of life  radiation. This demanding schedule possibly induces fatigue independent of treatment. Recently, large radiation fraction sizes have been shown to be radiobiologically favorable compared to smaller fraction sizes in prostate cancer radiotherapy Fowler, . TypicalPublished outcomes for CyberKnife delivered SBRT suggest high biochemical control rates with acceptable toxicity a few years following treatment  histologically confirmed prostate cancer; (2) age 75 or less; (3) a minimum of 12 months follow-up; and (4) completion of the Functional Assessment of Cancer Therapy (FACIT)-Fatigue survey  and testosterone levels were recorded, toxicity assessed, and fatigue and health related quality of life (HRQOL) questionnaires completed at baseline and each follow-up. Fatigue was measured using the FACIT-Fatigue survey managed and distributed by Health related quality of life (HRQOL) was measured using two instruments – the EPIC-26 survey and the AUA prostate symptom survey. The EPIC-26 is a 26-item short form version of the original EPIC survey designed to evaluate patient function and bother after prostate cancer treatment  associated with clinical benign prostatic hypertrophy. A high score indicates greater symptom bother and lower HRQOL.In addition to information on fatigue and HRQOL, data on the following covariates were also collected: age, race, co-morbidities including history of HIV and other cancers, smoking status, PSA levels, testosterone levels, AJCC/UICC TNM stage, and Gleason score.FACIT.org). Domain scores for the EPIC-26 survey were calculated using the information provided in the University of Michigan’s EPIC websiteBaseline characteristics of the study participants were summarized using frequencies and means. Fatigue scores  were calculated using guidelines provided by the FACIT Measurement System  to determine whether there was any evidence of effect modification by these variables on the fatigue scores pre- and post-SBRT. Statistical significance of the effect modification by race was determined by including a multiplicative (race × treatment) variable in the GEE model. All statistical analyses were conducted using SAS v. 9.3 .Correlations between the FACIT-Fatigue scores and the HRQOL measures were tested using non-parametric (Spearman correlation coefficient) methods. Associations of fatigue scores prior to SBRT (at baseline) with selected variables  were investigated using multiple linear regression models. Linear generalized estimating equations (GEE) models were used to determine whether post-SBRT fatigue scores  were significantly different from baseline scores. Repeat fatigue score measurements for an individual over time were accounted for using an autoregressive model of correlation that assumes a higher degree of correlation between measurements conducted closer in time than those that are farther apart. The age-adjusted fatigue scores were derived using the least square means in the GEE models that included age as a fixed effect. Forty patients with a minimum of 12 months follow-up met the eligibility criteria and are the subject of this analysis. The patient characteristics are presented in Table P = 0.05) with a higher baseline PSA level associated with a lower FACIT-Fatigue score (higher fatigue). Analysis of correlations between fatigue scores with the HRQOL measures (EPIC-26 domains and AUA symptom score) identified the EPIC hormone domain as the only HRQOL score significantly correlated with the FACIT-Fatigue score . Lower FACIT-Fatigue scores were associated with higher reported HRQOL in the EPIC hormone domain.Overall questionnaire completion compliance was greater than 95%. No association with baseline fatigue scores was found between age, race, smoking status, HIV status, history of another cancer in addition to prostate cancer, baseline testosterone levels, or tumor stage. Baseline PSA levels and fatigue scores were statistically significantly associated (Age-adjusted mean FACIT-Fatigue scores at baseline and during follow-up after CyberKnife SBRT are presented in Table P = 0.22).The impact of race on the change in FACIT-Fatigue scores post-SBRT was compared to baseline by stratifying the age-adjusted fatigue scores by race Figure . Given tAt the 1-month post-SBRT, a statistically and clinically significant increase in fatigue was observed for African-American patients but not for Caucasian patients. In addition, the 12-month post-SBRT FACIT-Fatigue score for Caucasian patients was slightly higher than the pre-treatment score but for African-Americans post-SBRT fatigue scores consistently remained low compared to the baseline.The results of the EPIC hormone domain analysis were similar to the race-stratified results for FACIT-Fatigue scores Figure . AfricanFatigue was not a major side effect for prostate cancer patients undergoing hypofractionated SBRT. Although fatigue at 1-month post-SBRT was higher than baseline, the change was not clinically significant. Additionally, levels of fatigue at 3, 6, 9, and 12-month post-SBRT were not significantly different from baseline. However, a racial disparity in fatigue following SBRT was present with African-American patients reporting increased treatment-related fatigue compared to Caucasian patients.This is the first study to measure SBRT-related fatigue using the FACIT-Fatigue scale. The level of fatigue reported at baseline by prostate cancer patients [Mean (SD): 43.8 (8.2)] is very similar to that reported for the general US population [43.6 (9.4); Cella et al., Acute increases in fatigue following radiotherapy for prostate cancer have been previously reported  on both questionnaires. While small declines in testosterone levels have been reported following hypofractionated SBRT (Oermann et al., Previous studies have also reported that fatigue is associated with and has an impact on HRQOL (Rodrigues et al., Strengths of this study include a high proportion of African-Americans in the patient population, multiple follow-up intervals after SBRT, and use of validated instruments to measure fatigue and HRQOL. The FACIT-Fatigue Scale is a brief and easy to use measure of fatigue assessing the intensity of fatigue and the impact on a patient’s daily life. It distinguishes itself psychometrically from other measures as cutoff scores have been developed to aid in clinical interpretation. Additionally, raw scores have been transformed to a 0–100 interval measure which aids in the analysis of group differences assessing change over time as in the present study.Limitations of this study include the number of participants, pre-existing co-morbidities and possible variation in patient lifestyle. Specifically, the statistical power was inadequate to analyze associations between fatigue and other baseline variables, such as PSA levels and tumor stage. In addition, almost all prostate cancer patients in our study had some co-morbidity, most frequently cardiovascular, and it is unknown whether changes in fatigue might have been associated with those co-morbidities. Nevertheless, the mean fatigue scores at baseline in our patient population were very similar to the general US population, thus it is unlikely that co-morbidities affected the reporting of fatigue levels. The multivariate analyses were adjusted for co-morbidities and none of the reported co-morbidities were associated with fatigue. Lastly, it is well known that lifestyle factors such as diet and exercise affect fatigue; however, lifestyle factors were not factored into the multivariate models.A low incidence of fatigue was observed in prostate cancer patients undergoing hypofractionated SBRT. Reported fatigue was highest at 1 month post-SBRT, primarily among African-American patients. At 12 months post-SBRT fatigue levels for both Caucasians and African-American patients returned to near baseline levels. More studies with additional patients are needed to confirm these findings and investigate whether racial disparity is a component of fatigue following SBRT for prostate cancer.Sean Collins serves as a clinical consultant to Accuray, Inc. The other authors declare no competing interests.


High-dose melphalan with autologous stem cell rescue has been regarded as the standard of care for patients with newly diagnosed myeloma up to the age of 65–70 years. The recent development of agents with potent anti-tumor activity such as thalidomide, lenalidomide and bortezomib has further improved overall survival and response rates. However, relapse is a continuous risk.graft-vs-myeloma effects. However, its role has been hotly debated. Even though molecular remissions have been reported up to 50% after high-dose myeloablative conditionings, their applications, given the high toxicity, have been for long limited to younger relapsed/refractory patients. These limitations have greatly been reduced through the introduction of non-myeloablative/reduced-intensity conditionings.Allografting is a potentially curative treatment for a subset of multiple myeloma patients for its well documented graft-vs-myeloma effects.The introduction of new drugs, characterised by low risks of early mortality, indeed requires to define role and timing of an allograft to capture the subset of patients who may most benefit from graft-versus-myeloma effects as consolidation/maintenance therapy after an allograft. However, this combination should be explored only in well-designed clinical trials.Ultimately, new drugs should not be viewed as mutually exclusive with an allograft. They may be employed to achieve profound cytoreduction before and enhance  High-dose chemotherapy and autologous transplantation with/without these newer agents has been regarded as standard treatment for newly diagnosed younger patients. Disease recurrence is, however, a continuous risk. Allografting appears the only potentially curative treatment on account of well-documented Figure 1). This clinical activity may be divided into three main periods. Up to the late 90’, intense myeloablative conditionings were employed. Given their high mortality and toxicity, their application was primarily limited to heavily pretreated patients at relapse or refractory to chemotherapies.Between 1989 and 2008, 1089 allogeneic transplants were performed in Italy through the activity of the Gruppo Italiano Trapianto di Midollo (GITMO)  and fludarabine, followed by peripheral blood stem cells and potent immunosuppression with cyclosporine and mycophenolate mofetil.172 and the graft-vs-myeloma effect with the potential of drastically reducing treatment-related toxicity and mortality.The tandem approach of an autologous transplant followed by a low dose non-myeloablative total body irradiation has become the most widely used conditioning for myeloma patients. The rationale for this tandem “autologous-allogeneic” approach was to separate in time the high-dose cytoreduction with melphalan at standard 200 mg/mTwo large series from Seattle and Italy have recently reported on more than 200 patients using the tandem auto/allo strategy. Long-term clinical outcomes of 102 patents treated with this approach, after a follow up of 6.3 years, were recently reported by Rotta et al.2, with or without fludarabine, and intermediate-dose busulfan.In recent years, several reduce-intensity regimens have been designed including melphalan, 100–140 mg/mMore recently, studies comparing allografting after reduced-intensity conditionings and autografting have been published. The concept of Mendelian or genetic randomization has been applied to the assessment of outcomes in patients with hematological disorders who were treated with allografting or other therapies.2. Sixty-five patients with HLA-identical sibling donors then received an allograft after a conditioning with busulfan, fludarabine and high-dose anti-thymocyte globulin, 12.5 mg/kg. Outcomes were compared with 219 high risk patients who were treated with a second autograft after melphalan at 220 mg/m2. Transplant-related mortality and response rates were not different. After a median follow-up of 2 years, overall and event free survivals were 35% and 25%, and 41% and 30% for the double autologous and the autologous-allogeneic cohorts, respectively. The Authors concluded that patients with high risk features may not benefit from a reduced-intensity allograft. This study was criticized for the inclusion of high dose anti thymocyte globulin, 12.5 mg/kg, in the conditioning regimen. As a matter of fact, though the incidence of chronic GvHD was 7%, the high dose of anti-thymocyte globulin may have highly prevented potentially curative graft-vs-myeloma effects. This study was also updated.The first such study was reported by the French group. The study compared two trials which included high risk myeloma patients carrying elevated serum β2-microglobulin and del(13).2, or intermediate-dose, 100 mg/m2, of melphalan. After a median follow up of 45 months, overall and event-free survivals were significantly longer in patients with donors: 80 versus 54 months and 35 versus 29 months. By multivariate analysis, having an HLA-identical sibling was an independent variable significantly associated with longer overall and event-free survivals. Overall, 58 and 46 patients completed the tandem autologous-allogeneic and the tandem autologous programs, with complete remission rates of 55% versus 26%. Transplant-related mortality was 10% and 2% respectively. Median overall survival was not reached in the tandem autologous-allogeneic cohort and was 58 months in the tandem autologous cohort. Event-free survival was 43 and 33 months, respectively. Criticisms to the study were that only 58 and 46 patients in in the tandem autologous-allogeneic cohort and in the tandem autologous cohort, respectively, completed their assigned treatments and the relatively poor outcome of the patients assigned to the tandem autograft. This study was also updated after a median follow up of 6 years. Overall survival was not reached for the 80 patients with an HLA-identical sibling and was 52 months for those without, p=0.004; event free survival remained significantly longer in patients with HLA-identical siblings: 35 versus 29 months, p=0.009. Median overall survival was not reached in the 58 patients who completed the tandem autologous-allogeneic program and was 64 months in the 46 who completed the double autologous program, p=0.04. Event-free survival was 37 and 33 months p=0.06.Another study by Bruno et al. reported on 245 consecutive newly diagnosed myeloma patients, up to the age of 65 years, diagnosed between 1998–2004 where 162 out of 199 with at least one sibling were HLA-typed with their potential sibling donors.A third biologically randomized study was reported by the Spanish PETHEMA group.Finally, 4 large prospective randomized studies, the Blood and Marrow Transplant Clinical Trials Network (BMT-CTN) 0102 trial in the U.S.A.; the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON) trial,The large BMT-CTN 0102 trial comparing double autologous transplant versus tandem autologous/non-myeloablative allogeneic transplant completed the accrual in March 2007. More than 150 patients were biologically randomized to the latter cohort. The results from this study are eagerly awaited and should be released in 2010.In the HOVON 54 study, newly diagnosed patients with an HLA-identical sibling donor included in the HOVON 50 study, a phase 3 study for the evaluation of thalidomide combined with high-dose melphalan, were allowed to proceed to a non-myeloablative allogeneic transplant from 2 and 6 months after a standard autograft, whereas patients without a suitable donor were randomized to thalidomide or interferon maintenance. By intent-to-treat analysis, no difference in progression free survival and overall survival were observed with an interim analysis that included 126 patients with a donor and 141 patients without.38In the EBMT trial, progression free survival at 60 months was 35% for the tandem auto/allo cohort as compared to 18% for double auto, and overall survival 65% and 57% respectively.Another prospective study comparing double autologous transplant versus tandem autologous/reduced-intensity allogeneic transplant, after a conditioning with fludarabine and melphalan, has been reported by the German DSMM.The potentially unique, curative role of allografting consist of the immune reaction of donor T cells against myeloma cells through the recognition of possibly disease-specific antigens. Evidence for the existence of such reactions was initially documented by the achievement of complete remissions after the discontinuation of immunosuppression or after the infusion of donor T lymphocytes in patients with recurrent disease post-transplant.48So called “new drugs” have greatly changed the treatment options for multiple myeloma. Not only do they target malignant plasma cells but also affect their cross-talk with the marrow microenvironment due to several immunomodulatory properties. Interestingly, they modulate T cell subpopulations that may play a pivotal role in graft-vs-myeloma effects. Thus, their role in combination with allografting should be extensively investigated.Thalidomide, lenalidomide and bortezomib have recently been included in a number of randomized clinical trials in both young and elderly patients.In the setting of allografting, these new drugs have first been employed in patients relapsing after allografting. The addition of thalidomide to donor lymphocyte infusions improved efficacy of salvage treatment without increasing GvHD.53Remarkable results have been obtained with lenalidomide in a cohort of patients with progressive disease after reduced-intensity allografting.Bortezomib has also been shown to be effective in patients with relapsed disease.Overall, myeloablative allografts have cured a minority of patients who obtained complete clinical remission after transplant. Reduced-intensity and non-myeloablative conditionings represent a clinical and biological breakthrough given that toxicity was greatly reduced and the existence of graft-vs-myeloma effects were indubitably shown. Long-term disease control and disabling chronic GVHD in a subset of patients represent important issues.If an allograft should be part of first-line treatment plans or of salvage therapy for refractory/relapsed patients is still hotly debated. In newly diagnosed patients with chemosensitive disease, therefore in complete or very good remissions, a non-myeloablative conditioning would safely allow for donor engraftment with a reduced risk of toxicity and would potentially add a curative graft.vs.myeloma effect in a subset of patients. To support this, many reports show that better outcome is associated with chemosensitive disease at transplant and that allografting at an earlier disease phase is associated with stronger graft-vs-myeloma effects.Other Authors underline the fact that new treatment schemas may likely translate into longer overall survival and would be more inclined to offer an allograft at relapse. In this case, however, disease reduction prior to transplant and a more intense conditioning, rather than a non-myeloablative regimen, would be required despite a higher risk of toxicity.In conclusion, future studies cannot be designed without the combination of new drugs that may enhance graft-versus-myeloma effects to allow long-term disease control and prolong survival even in patients with high risk disease. Profound cytoreduction before and enhanced graft-versus-myeloma effects after allografts through the immunomodulatory properties of lenalidomide and bortezomib may be key factors to improve clinical outcomes.Optimal timing of an allograft and dosage of new drugs remain to be determined and should be explored prospectively only in the context of clinical trials and not routinely recommended.


The relatively short durations of the initial pivotal randomized placebo-controlled trials involving atomoxetine HCl for the treatment of attention-deficit/hyperactivity disorder (ADHD) provided limited insight into the time courses of ADHD core symptom responses to this nonstimulant, selective norepinephrine reuptake inhibitor. The aim of this analysis was to evaluate time courses of treatment responses or remission, as assessed by attainment of prespecified scores on the ADHD Rating Scale-IV-Parent Version: Investigator Administered and Scored (ADHDRS-IV-PI) and the Clinical Global Impressions-ADHD-Severity (CGI-ADHD-S) scales, during up to 1 year of atomoxetine treatment in children with ADHD.Using pooled data from three Canadian open-label studies involving 338 children ages 6-11 years with ADHD who were treated with atomoxetine for 3, 6 and 12 months, and survival analysis methods for interval-censored data, we estimated the time to: 1) improvement and robust improvement defined by ≥25% and ≥40% reductions from baseline ADHDRS-IV-PI total scores, respectively; and 2) remission using two definitions: a final score of ADHDRS-IV-PI ≤18 or a final score of CGI-ADHD-S ≤2.p = .33).The median time to improvement was 3.7 weeks (~1 month), but remission of symptoms did not occur until a median of 14.3 weeks (~3.5 months) using the most stringent CGI-ADHD-S threshold. Probabilities of robust improvement were 47% at or before 4 weeks of treatment; 76% at 12 weeks; 85% at 26 weeks; and 96% at 52 weeks. Probabilities of remission at these corresponding time points were 30%, 59%, 77%, and 85%  and 8%, 47%, 67%, and 75% . The change from atomoxetine treatment month 5 to month 12 of -1.01 (1.03) was not statistically significant (Reductions in core ADHD symptoms during atomoxetine treatment are gradual. Although approximately one-half of study participants showed improvement at 1 month of atomoxetine treatment, remission criteria were not met until about 3 months. Understanding the time course of children's responses to atomoxetine treatment may inform clinical decision making and also influence the durations of trials comparing the effects of this medication with other ADHD treatments.NCT00191633, NCT00216918, NCT00191880.clinicaltrials.gov:  Both psychostimulants and the selective norepinephrine reuptake inhibitor atomoxetine HCl are recommended psychopharmacological treatment options for children diagnosed with attention-deficit/hyperactivity disorder (ADHD), which is considered to be the most common neurobehavioral disorder affecting children -3. In clOur initial understanding of the time courses of atomoxetine responses was based on randomized placebo-controlled clinical trials with relatively short durations  -8. NotabAlthough attainment of predefined thresholds on validated scales as a measure of symptom remission is a useful barometer of improvement, the time courses of responses to various treatments must be considered when this outcome measure is used to compare interventions; this may be of marked importance when comparing treatments for ADHD--both pharmacological and non-pharmacological --that have slower onsets of actions compared with stimulants. Stimulants are notable within the psychopharmacological armamentarium for the relative short time to peak clinical effects.Improvements in ADHD symptoms have been defined as ≥25% reductions (and robust improvement as ≥40% reductions) on the ADHD Rating Scale-IV-Parent Version: Investigator Administered and Scored (ADHDRS-IV-PI) total score . HoweverThe primary objective of this study was to determine times to response and remission according to predefined thresholds on the ADHDRS-IV-PI and CGI-ADHD-S scales in children treated with atomoxetine at usual clinical dosages ,12. To aIn this retrospective efficacy analysis, data were pooled from three Canadian open-label studies -15. ThesDiagnostic and Statistical Manual of Mental Disorders Text Revision (DSM-IV-TR) ) age  was 8.7 (0.08) years. Of study participants in Study S012, 54.7% were stimulant-naïve compared with 38.1% of those in Study S013 and 100% of those in Study LYCS. Mean (SE) baseline scores were 39.1 (0.43) on the ADHDRS-IV-PI and 4.8 (0.05) on the CGI-ADHD-S (Table The pooled study sample comprised 249 (73.7%) boys and 89 (26.3%) girls whose mean , followed by adverse events (6.5%). Five (1.5%) study participants were lost to follow-up.SE) and median (range) duration of follow-up (weeks) by individual study, as well as for the combined studies.The median number of weeks from baseline to the last available ADHDR-IV-PI assessment for the pooled studies was 13 weeks (~3 months). The follow-up time between the baseline and last available assessment varied according to the duration of each study. Table p = .33).Atomoxetine treatment reduced ADHD symptoms sharply during the first month and was associated with further reductions in subsequent months. Mean ADHDRS-IV-PI total scores leveled out at approximately month 5 Table . The chaAs shown in Table Longer treatment intervals were required to meet definitions of symptom remission. The median time to remission, defined as a total ADHDRS-IV-PI of ≤18, was 8.0 weeks, and the probability of remission did not reach 75% until approximately 24 weeks. To meet the most rigorous criterion for remission (achieving a CGI-ADHD-S score ≤2), the median time was 14.3 weeks. For this endpoint, the probability of remission by 26 weeks was approximately 67%  were associated with a shorter time to improvement and robust improvement; whereas lower baseline ADHDRS-IV-PI total scores were associated with a shorter time to attain remission. The baseline value of CGI-ADHD-S was also a significant predictor of time to remission, with lower values (indicative of less severe ADHD symptomatology) being associated with shorter time required to achieve remission defined as a CGI-ADHD-S score of ≤2.In this study, there was a progressive increase in the likelihood that treatment met predefined thresholds for response and remission with increasing time on atomoxetine. Of interest, children's ADHD symptoms continued to improve up to approximately 5 months. Although there was symptomatic improvement as measured by the ADHDRS-IV-PI total score beyond this time, the change was not statistically significant.The present analysis of three Canadian open-label clinical trials of atomoxetine produced clinically meaningful findings that are consistent with data from two recently reported European randomized, double-blind, placebo-controlled studies that reported increased efficacy of atomoxetine over time ,20. FirsThe gradual and progressive efficacy of atomoxetine in treating core symptoms of ADHD, which was observed in the present study, has potential implications for understanding three previously reported studies comparing the effects of atomoxetine to those of long-acting stimulants -23. The Evidence from these comparator studies, the European studies discussed above ,20, and In our study, baseline illness severity substantially influenced the time to meet predefined measures of improvement. Children initiating atomoxetine therapy with higher symptom severity scores met percentage improvement criteria in a shorter time than children starting with lower baseline symptom severity scores. In contrast, children rated as less severely symptomatic on the CGI-ADHD-S and ADHDRS-IV-PI achieved remission thresholds more rapidly. Of clinical interest, the Integrated Data Exploratory Analysis study, a retrospective analysis of randomized controlled trials having 6- to 9-week durations, did not identify potential baseline (moderator) predictors of response but did find that the only predictor (on-treatment mediator) of a much improved response at trial endpoint (≥40% decrease on the ADHDRS-IV-PI) was being at least minimally improved (≥25% but <40% decrease on the ADHDRS-IV-PI) by treatment week 4 . This fiOur findings are most generalizable to Canadian children ages 6 to 11.5 years who: 1) are of at least average intelligence and whose ADHD symptoms are well above age and gender norms for severity; 2) do not have comorbid conditions such as bipolar disorder, psychoses, pervasive developmental disorders, conduct disorder, or serious suicide risk; and/or 3) are treated with atomoxetine on an outpatient basis. Most study participants (>70%) were boys and had the combined subtype of ADHD. In addition, approximately two-thirds of enrolled children  were previously untreated with ADHD medications and therefore may have been more responsive to medication than children who had received, but failed, prior treatments. The trials were all open label, and this study design feature may have encouraged positive clinician bias in estimating improvements; in Canada, it was considered unethical to include a placebo arm in extended-duration studies of ADHD. The results of the three open-label trials included in our study may have been influenced by initial patient selection and rater drift. Given the characteristics of our sample, the designs of the studies, and the potential advantages to children of clinical trial participation, it is possible that the relatively high rates of response we report with atomoxetine treatment will not be replicated in usual clinical practice.The slow upward titration of atomoxetine and the differences in the titration schedules mandated by the study protocols may have had some impact on early response rates, but it is unlikely that the dosing of atomoxetine during the initial part of the study impacted the major finding of the study, which was that there is slow but progressive improvement over time during atomoxetine treatment long after titration is complete.Only one of the primary studies (Study SO13) analyzed herein included teachers' evaluations, precluding inclusion of teachers' important perspectives on time courses to response or remission with atomoxetine. In Study S013, baseline symptom ratings completed by the teachers were indicative of less severe symptoms than ratings completed by parents, but the progressive improvements during this 6-month study showed that symptom decrements noted by parents paralleled those of teachers . In addiNot all subjects had 12 months of follow-up; the three studies varied in length from 3-12 months and in addition approximately 30% of children did not complete their study. Therefore, we chose methods of analysis  that do not require an equal length of follow-up for each subject and that did not require that all subjects complete the study. These methods estimate response probabilities over time by using the data for each subject up to the point that they either responded or withdrew from the study. We don't know the time by which the drop-outs would have responded but each participant contributes information: for example, a child who discontinued at week 6 prior to responding provides information on the probability of achieving (or not achieving) a response by week 6.When interpreting such curves, it is essential to understand both that there are declining numbers of participants over time, and that the cumulative response probability at a given time point is based not only on those subjects still under observation, but also on the pattern of response and withdrawals at all previous time points. Thus the response probability at a certain time depends directly on those still under observation, and indirectly on those who withdrew or responded earlier.Our findings concerning time courses of response and remission with atomoxetine may inform future study design and clinical decision making. From a clinical perspective, appropriate expectations should be set with children and parents at the time of atomoxetine initiation, because reductions in symptoms are gradual but appear to progress over time. Designs of future comparison studies of medications to treat ADHD should consider differences in time of onset of efficacy (and time to peak response) between atomoxetine and stimulants and/or other treatments.ADHD: attention-deficit/hyperactivity disorder; ADHDRS-IV-PI: ADHD Rating Scale Parent Version: Investigator Administered and Scored; CGI-ADHD-S: Clinical Global Impressions-ADHD-Severity; MAS XR: mixed amphetamine salts extended-release; OROS MPH: osmotic-release oral system methylphenidate;RAD: employee of the study sponsor with stock or equity >$10,000. EM: paid consultant to the study sponsor. CG: no competing interests to disclose. SWG: paid consultant to the study sponsor and its affiliates, as well as BioBehavioral Diagnostics. MDW: advisory boards and speakers' bureaus, consultant, grant and/or other research support, study sponsor, Abbott, Janssen, Purdue Pharma, Shire, Takeda; speakers' bureau, Novartis; travel support from study sponsor to present poster at congress.All authors contributed to the conception and design of the study.MDW, AT, and other clinical investigators acquired data. EM conducted the statistical analysis. All authors interpreted the data. RAD, EM and SWG wrote the manuscript, and all authors contributed to the manuscript. All have read and approved the final manuscript except for AT. Dr. Atilla Turgay (deceased) participated in the data analysis and an early draft of the manuscript. RAD had access to all data and takes responsibility for the study and its report (study guarantor).


Patients with schizophrenia frequently switch between antipsychotics, underscoring the need to achieve and maintain important treatment outcomes such as health-related quality of life (HRQoL) following the switch. This analysis evaluated HRQoL changes among patients with schizophrenia switched from their current antipsychotic to lurasidone.Stable but symptomatic outpatients with schizophrenia were switched from their current antipsychotic to lurasidone in a six-week, open-label trial. HRQoL was assessed using two validated patient-reported measures, the Personal Evaluation of Transitions in Treatment (PETiT) scale and the Short-Form 12 (SF-12). Total and domain scores  were assessed using the PETiT scale; patients’ mental and physical component summary scores (MCS and PCS) were assessed using the SF-12. Changes in HRQoL from baseline to study endpoint were compared using ANCOVA, with baseline score, treatment, and pooled site as covariates. Changes were assessed among all patients and those switched from specific antipsychotics to lurasidone.The analysis included 235 patients with data on the PETiT and SF-12 who had received ≥1 dose of lurasidone. Statistically significant improvements were observed from baseline to study endpoint on the PETiT total (mean change [SD]: 3.2 [8.5]) and psychosocial functioning (2.5 [6.9]) and adherence-related attitude (0.7 [2.6]) domain scores . When examined by preswitch antipsychotic, significant improvements in PETiT total scores were observed in patients switched from quetiapine, risperidone, aripiprazole, and ziprasidone  but not olanzapine (p = 0.893). Improvements on the SF-12 MCS score were observed for all patients  and for those switched from quetiapine or aripiprazole (both p < 0.03). The SF-12 PCS scores remained comparable to those at baseline in all patient groups.These findings indicate that patients switching from other antipsychotics to lurasidone experienced statistically significant improvement of HRQoL, based on PETiT scores, within six weeks of treatment. Patient health status remained stable with respect to the SF-12 physical component and showed improvement on the mental component. Changes in HRQoL varied based on the antipsychotic used before switching to lurasidone.NCT01143077. Schizophrenia is a severe, chronic, and costly psychiatric disorder characterized by acute psychotic episodes. Affected individuals demonstrate a heterogeneous phenotype that includes a vast array of symptomology, variable responses to treatment, and poor health-related quality of life (HRQoL) -4. PatiePatient adherence to treatment has also been considerably variable among different antipsychotics, and a patient’s subjective response or attitude to a therapy  may impact adherence . Since tSeveral studies have shown that poor adherence and/or treatment discontinuation are associated with an increased risk of relapse and re-hospitalization, both of which may negatively affect HRQoL -23. ThusLurasidone is a second-generation atypical antipsychotic that received approval in October 2010 by the United States (US) Food and Drug administration (FDA) for the treatment of adult patients with schizophrenia . LurasidThe results of a recently published study demonstrated that switching clinically stable yet symptomatic patients with schizophrenia or schizoaffective disorder to lurasidone from other antipsychotic agents was well tolerated, with low rates of patient discontinuation . This anThe analysis was based on data from a six-week, open-label, parallel-group trial of stable but symptomatic outpatients with schizophrenia who were switched from their current antipsychotic to lurasidone . The detThe primary study outcome was time to treatment failure, defined as any occurrence of insufficient clinical response, exacerbation of underlying disease, or discontinuation due to an adverse event (AE), as determined by investigator judgement. HRQoL and general health status, including evaluation of physical functioning and mental health, were studied as secondary endpoints using the PETiT and SF-12 Patient Reported Outcomes measures. The PETiT and SF-12 assessments were administered at baseline and at six weeks.The PETiT scale is a validated, 30-item instrument designed to capture and quantify the impact of treatment on self-perceived subjective aspects of patient HRQoL . The scaQuality of life outcomes were also assessed in patients switched to lurasidone using the SF-12 survey, a multipurpose generic measure of health status . The SF-The intent-to-treat (ITT) population was used for the PETiT and SF-12 analysis. The ITT population was defined as all patients who had received at least one dose of lurasidone and had non-missing values for PETiT and SF-12 scores at baseline and ≥1 post-baseline value at study endpoint. The study endpoint was the last observation carried forward (LOCF), defined as the last non-missing value for any PETiT or SF-12 item at a scheduled or unscheduled visit post-baseline. Mean changes from baseline to LOCF in PETiT and SF-12 scores were calculated using analysis of covariance (ANCOVA) models, with treatment and pooled center as fixed factors and baseline value as a covariate.Mean changes from baseline to LOCF for the PETiT scale total score, its domains, and the SF-12 PCS and MCS scores were determined for all patients in the ITT population. The analysis further examined PETiT and SF-12 scores by the individual preswitch antipsychotic medications that were received by ≥10% of patients in the study. Scores were additionally examined by categorizing these medications into the sedating (olanzapine and quetiapine) and non-sedating  subgroups. Finally, the analysis also examined HRQoL among patients who had completed or discontinued treatment with lurasidone due to any cause at study endpoint.The study population was comprised of 240 patients with schizophrenia or schizoaffective disorder who received at least one dose of study medication. Table The mean (± standard deviation [SD]) PETiT total score for all lurasidone patients improved from 35.0 (8.8) at baseline to 38.5 9.2) at LOCF endpoint, representing a mean improvement of 3.2 (8.5) or 9.1% (p < 0.001). Improvements from baseline to LOCF endpoint in the total score, as well as in the domains of adherence-related attitude (0.7 [2.6]) and psychosocial functioning (2.5 [6.9]), were statistically significant (p ≤ 0.002) for all patients who were switched to lurasidone , risperidone (n = 51), aripiprazole (n = 44), ziprasidone (n = 27), and olanzapine (n = 24). Patients on all of these preswitch medications except olanzapine showed statistically significant improvements in total PETiT scores, as determined by mean changes from baseline to LOCF (±SD): quetiapine 4.2 (7.7), p = 0.011; risperidone 3.6 (7.9), p = 0.029; aripiprazole 3.4 (8.0), p = 0.010; ziprasidone 5.4 (7.9), p = 0.009  and those who had received a sedating antipsychotic (olanzapine or quetiapine) prior to the switch to lurasidone. In the non-sedating group, statistically significant (p < 0.001) improvements from baseline to LOCF endpoint were observed for the total PETiT score and its psychosocial functioning and adherence-related attitude domains Table . While nPatients were categorized as subjects who discontinued (37 [16%]) or subjects who completed (198 84%]) with lurasidone in the ITT population based on discontinuation due to any cause at the six-week endpoint. When analyzed by discontinuation status, the study showed that patients who completed treatment with lurasidone had significantly improved PETiT total scores versus patients who discontinued treatment (p < 0.001) (Table %) with lFor all patients, the results of the SF-12 revealed that health status remained stable following the switch to lurasidone, with small improvements observed for both the PCS and MCS scores Table . ImproveWhen analyzed by discontinuation status, a statistically significant improvement in the MCS score was observed among patients who remained on lurasidone in the all patients (p = 0.029) and sedating subgroups (p = 0.036) versus those who had discontinued treatment at the six-week endpoint Table . No diffAlong with efficacy and safety, maintenance or improvement of HRQoL is an important outcome of treatment for patients with schizophrenia. This study is the first to systematically examine the effects of switching clinically stable patients with schizophrenia from their current antipsychotic to lurasidone on HRQoL.The PETiT scale offers a specific and integrated measure of HRQoL for patients who have switched antipsychotic medications, where a patient’s well-being is conceptualized as their subjective perception of their severity of psychotic symptoms, medication side effects, and level of psychosocial performance . The SF-The majority of patients in the switch study showed improvements from baseline to LOCF on the PETiT total score and the domains of adherence-related attitude, psychosocial functioning, activity, patient perception of cognition, and dysphoria. These findings indicate that, in this study, patients switching to lurasidone perceived improvements in a broad range of measures of well-being. The finding of improved adherence-related attitude following switch to lurasidone is of particular importance, considering the role of patient perception  in the traditionally high rates of non-adherence and discontinuation associated with antipsychotic medications -17 and tWhen examined by preswitch antipsychotic, changes in HRQoL were more variable. Patients switched from quetiapine, risperidone, aripiprazole, and ziprasidone showed statistically significant improvements in PETiT total scores. However, there were no significant changes in PETiT scores among patients switched from olanzapine. It is known that drugs in the atypical antipsychotic class differ in pharmacological profiles, clinical response, and the adverse effects experienced by patients ,11. MeasThe PETiT analysis additionally showed differences in HRQoL depending on whether the pre-study medication was sedating or non-sedating. Patients switching from non-sedating medications showed statistically significant improvements in the total, adherence-related attitude, and psychosocial functioning scores of the PETiT scale; in contrast, the improvements observed in the sedating group were not statistically significant. The difficulty in switching patients from sedating to non-sedating atypical antipsychotics is a well-known challenge in the treatment of schizophrenia . SubjectFinally, the results of the more generic SF-12 assessment also support the feasibility of switching to lurasidone from other antipsychotics. Patients generally demonstrated little change or improvements in the PCS and MCS scores, indicating that their physical and mental health status was maintained or improved by switching to lurasidone. Given the clinical stability of the patient population at baseline and the short six-week duration of follow-up, it is not unexpected that no marked difference was observed in physical component using a generic instrument such as the SF-12 .Overall, it is well recognized that the HRQoL of patients with schizophrenia can be negatively impacted by the effects of atypical antipsychotic therapies -11. The This analysis is one of few published studies to examine changes in HRQoL, functioning, and health status after switching between antipsychotics. While four relatively recent investigations of patients switching to quetiapine XR , aripiprOther studies have commented on the risk of tolerability problems, symptom exacerbations, or increased use of acute care services after switching patients between antipsychotics -41. HoweThere are a few limitations of the current study. First, being an open-label evaluation with no control group, the outcomes were prone to greater bias than outcomes from a randomized controlled clinical trial. Notwithstanding this limitation, this naturalistic switch trial has potential application for clinical practice guidance on switching patients to lurasidone. Second, the six-week duration of the study may not have been long enough to fully capture changes in HRQoL and other outcomes. However, such outcomes remain a critical source of insight concerning numerous aspects of any disease, and in particular, the perception of patient well-being in psychiatric disorders such as schizophrenia. Analysis of the longer-term effect of lurasidone on HRQoL, in both the PETiT and SF-12 assessments, from the six-month extension phase of the trial is ongoing. Another limitation was the study’s small sample size for the subgroup analyses, and interpretation of the subgroup results warrants caution. Finally, as noted previously by McEvoy and colleagues , the lacDespite these limitations, the study results suggest that stable yet symptomatic patients with schizophrenia may be efficiently switched from other antipsychotics to lurasidone, with potential improvements in psychosocial functional, attitude related to adherence, and overall mental health status.In conclusion, the results of the PETiT and SF-12 assessments indicate that patients with schizophrenia who switch to lurasidone from other antipsychotics may experience improvements in HRQoL within six weeks of treatment. Further investigation of the effects of longer-term lurasidone therapy on quality of life outcomes and patient-reported perception of switching to lurasidone is warranted.AE: Adverse events; ANCOVA: Analysis of covariance; DAI: Drug attitude inventory; DSM: Diagnostic and statistical manual of mental disorders; FDA: Food and drug administration; HRQoL: Health-related quality of life; ITT: Intention to treat; LOCF: Last observation carried forward; MCS: Mental component score; PETiT: Personal evaluation of transitions in treatment; PCS: Physical component score; SF-12: Short-form 12; US: United states; SD: Standard deviation; SWN-K: Subjective well-being under neuroleptics scale – brief form.Mariam Hassan, Antony Loebel, Jay Hsu, Andrei Pikalov, and Krithika Rajagopalan are employees of Sunovion Pharmaceuticals, Inc. George Awad has no competing interests to declare.MH and KR conceptualized the post-hoc analysis. GA, MH, KR, AL, AP and JH participated in the study analysis and data interpretation. AL, AP, and JH were involved in the conceptualizing, designing and analysis of the clinical trial. GA, MH, KR, AP, and AL critically reviewed and revised the manuscript for important intellectual content. All authors have reviewed and approved this manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-244X/14/53/prepub


Rotavirus infection has been reported to be responsible for the majority of severe diarrhea in children under-5-years-old in Indonesia. Breast milk is considered to give protection against rotavirus infection. Increasing breastfeeding promotion programs could be an alternative target to reduce the incidence of rotavirus diarrhea. This study aims to investigate the effect of breastfeeding promotion interventions on cost-effectiveness of rotavirus immunization in Indonesia, focusing on breastfeeding education and support interventions.I0) reflecting the current situation for the population of under-5-years-old, (ii) with an additional breastfeeding education intervention (I1), (iii) with a support intervention on initiation and duration (I2) and (iv) with both of these two interventions combined (I3). The model applied a 5-years time horizon, with 1 month analytical cycles for children less than 1 year of age and annually thereafter. Monte Carlo simulations were used to examine the economic acceptability and affordability of rotavirus vaccination.An age-structured cohort model was developed for the 2011 Indonesia birth cohort. We compared four interventions in scenarios: (i) base-case  with an optimal breastfeeding promotion intervention. Obviously, this is much lower than the 2011 Gross Domestic Product (GDP) per capita of US$ 3,495. Affordability results showed that at the market vaccine price, rotavirus vaccination could be affordable for the Indonesian health system.Rotavirus immunization would be a highly cost-effective public health intervention for Indonesia even under various breastfeeding promotion interventions based on the WHO’s criteria for cost-effectiveness in universal immunization. Despite the common practice of breastfeeding in developing countries, exclusive breastfeeding remains uncommon . There iThe WHO estimated that optimized breastfeeding would save 1.45 million children’s lives each year in developing countries due to averting diarrhea and respiratory tract infections . TherefoIn terms of the health economic perspective, a previous study confirmed that implementation of rotavirus vaccination in Indonesia could be cost-effective . NotablyI0) reflecting the current situation for the population of under-5-years-old, (ii) with an additional breastfeeding education intervention (I1), (iii) with a support intervention on initiation and duration (I2) and (iv) with both of these two interventions combined (I3) ion I, (iii)ned I  based on breastfeeding statuses: exclusive breastfeeding (EBF), partial breastfeeding (PBF) and no breastfeeding (NBF) . We applI0) in our study.Due to lack of data on 2011 diarrhea cases for under-5-years-old in Indonesia, we estimated 2011 diarrhea cases over breastfeeding statuses by applying 2007 data on diarrhea cases and considering the WHO’s data on relative risk of diarrhea morbidity by feeding statuses . AdditioI0 as condition without breastfeeding promotion interventions in Indonesia, we compared it with three intervention scenarios as mentioned. Firstly, we assumed a breastfeeding education intervention (I1). Based on the WHO’s 2009 study in Iran [I0. We estimated the program could reduce rotavirus-diarrhea cases for under-5-years-old by 2% [Assuming  in Iran , we assu in Iran . It requ in Iran . On the  in Iran . Conside in Iran , we estild by 2% ,11,17.I2). This method has been applied among a group of low income women in the US, where they were trained and motivated on initiating and continuing to breastfeed and had to meet a lactation consultant individually to discuss breastfeeding during pregnancy [I1) and support (I2) with three outcome measures  [Secondly, we analyzed breastfeeding support intervention (regnancy . This meregnancy . Applyinregnancy  and consuration) , we estiuration) ,11,15,18I3) [I1, I2 and I3), we assumed the proportion of rotavirus-diarrhea cases in each age group to remain the same as in I0.Thirdly, we assumed a combined effect of education and support interventions I3) . We consI3) . We calc . We cI3) ,15,18. Fet al. on rotavirus vaccine efficacy in breast-fed European infants, and a comparative study on rotavirus vaccine efficacy in low, middle and high socio-economic settings by Lopman et al.[We assumed that the RotaTeq vaccine in three doses is used in our study. For formula-fed infants (NBF), we applied the rotavirus vaccine efficacies at 70%, 84% and 76.5% as initial vaccine effectiveness for mild-moderate, severe and fatal cases, respectively [an et al.. Based oan et al.. For betan et al.,21. We aan et al. as rotavan et al.. HoweverIn terms of economic perspectives, we analyzed the data both from the healthcare and societal perspectives. From the healthcare perspective, we only considered direct medical costs while from the societal perspective we considered broader cost items  . We calcFinally, we compared the reduction in rotavirus cases, QALY losses, and the cost-of-illness due to rotavirus-diarrhea. Using a market price of US$ 5 per dose , we estiI2) to the maximal intervention (I3). Furthermore, probabilistic sensitivity analysis (PSA) was performed by running 5000 Monte Carlo simulations. We evaluated the affordability related to the required budget for vaccination (vaccination costs + treatment costs) to analyze the budget impacts on the implementation of vaccination from the healthcare perspective, which is relevant for assisting decision makers in the health sector. All input parameters are shown in Table We performed univariate and probabilistic sensitivity analyses. We investigated the effects of different input parameters by varying each parameter at value of ± 25% while keeping other parameters constant in univariate sensitivity analyses. In the context of breastfeeding promotion interventions in this study, we varied from the minimal intervention , cost-effectiveness would increase to US$ 153 , although the cost-effectiveness is still far below the WHO threshold.With a market price of US$ 5 per dose , cost-efThe impacts of parameter changes on the ICERs are shown in a tornado chart , the probability for the vaccination program to be cost-effective would be 59%; 9%; 19% and 2% for I0), breastfeeding interventions would increase EBF-rate by 120%, 84% and 179% for I1, I2 and I3, respectively, as mentioned. At the market vaccine price of US$ 5 per dose, a rotavirus immunization program in Indonesia could reduce rotavirus-diarrhea by 259,390; 118,520; 129,886 and 6,000 for mild, moderate, severe and fatal cases, respectively. Assuming the base-case (I0) as a condition without breastfeeding promotion interventions in Indonesia, breastfeeding promotion interventions could reduce rotavirus-diarrhea from I0 by 1.4% - 3.1% for I1, I2 and I3. From the social perspective, the incremental cost-effectiveness ratios are US$ 149; US$ 152; US$ 151 and US$ 153 for I0, I1, I2 and I3, respectively. Notably, our assumption that breastfeeding might decrease the effectiveness of rotavirus immunization is congruent with other studies [Compared to the base case  was highly sensitive to the mortality rate and vaccine price [In our study we took uncertainties into account by using univariate and probabilistic sensitivity analyses. The sensitivity analyses showed that the mortality rate and vaccine price were the most influential parameters impacting the cost-effectiveness results. The results on this study reconfirmed the results from previous studies on cost-effectiveness of rotavirus immunization ,27. Postne price . A critiWe found a similar required funds (vaccination and treatment costs) for childhood vaccination. Considering the market vaccine price of US$ 5 per dose, rotavirus vaccination would require a budget of US$ 63,905,000 – US$ 64,080,000. Despite all interventions required the same budget for the vaccination costs, the results indicated that breastfeeding promotion could provide some potentials to decrease the treatment costs for rotavirus immunization in Indonesia due to its effect on reducing rotavirus-diarrhea cases. Thus, breastfeeding promotion interventions could potentially result in less opportunities for cost offsets of vaccination. Compared to the total Indonesian government health budget for the whole immunization program in 2011 (US$ 198 million) , the reqOur study is not the first study on the economic analysis of rotavirus vaccination in Indonesia but it could provide crucial information for the policy makers specifically on the potential introduction of breastfeeding promotion combined with the implementation rotavirus immunization in National Immunization Programmes (NIP). This combined approach would increase the EBF-rate and reduce rotavirus-diarrhea cases at potential cost-effective efforts. We extended the CoRoVa model that has been used in a previous study to calculate cost-effectiveness of rotavirus for both developed and developing countries, by taking breastfeeding into account and investigating explicitly the effect of breastfeeding promotion interventions on cost-effectiveness of rotavirus immunization in Indonesia. The relationships between breastfeeding practice, breastfeeding promotion and rotavirus-diarrhea are well-known and therefore important to be included in our modeling approach. Despite that several other interventions on breastfeeding promotion were mentioned in previous study , in thisWe noted several limitations in our study. Firstly, due to lack of data on herd immunity, we had to apply a static model instead of a dynamic model. If we were to include herd immunity in a dynamic analysis there would be greater impacts of rotavirus vaccination and its cost-effectiveness would be further improved. Secondly, we noted lack of 2011 data on rotavirus-diarrhea incidence in Indonesia and actual data on implementation of breastfeeding promotion interventions. We applied 2007 data on rotavirus-diarrhea incidence from a previous study and assumed it would be the same with 2011, while for the implementation of breastfeeding promotion interventions, we assumed that the base-case is a condition without specific breastfeeding promotion interventions in recent years. To overcome this limitation, we varied these assumptions extensively in multiple sensitivity analysis. Finally, we only obtained treatment costs for 2007 and we adjusted to 2011 values by considering the inflation rate.Due to the low uptake of EBF in Indonesia and the high prevalence of rotavirus-diarrhea in population under-5-years-old, policy makers in Indonesia should consider taking action to enhance the introduction of rotavirus vaccination and designing more intensive programs on breastfeeding promotion interventions. We showed that this approach is potentially highly cost-effective. However, as a developing country, Indonesia is faced with limited resources especially on providing required budget both for implementation of rotavirus vaccination and breastfeeding promotion interventions. Getting funds from international organizations could be realistic sollution to overcome this problem. Hopefully, this assists the Indonesian government in designing optimal policies both in increasing the EBF-rate and in reducing the incidence of rotavirus-diarrhea.Rotavirus immunization is a highly cost-effective intervention for the Indonesian healthcare system even under various breastfeeding promotion interventions based on the WHO’s criteria for cost-effectiveness in universal immunization. Yet, the implementation of rotavirus immunization in Indonesia would be unrealistic without international organization support.MJP received grants, honoraria and travel stipends from various pharmaceutical companies, inclusive those interested in the subject matter of this paper. AAS has no relevant affiliations or financial involvement with any organizations or entity with a financial interest in or financial conflict with the subject matter or material discussed in the manuscript.AAS conceived and designed this study, collected and analyzed the data, and drafted the manuscript. MJP contributed to the drafting and critical revision of the manuscript. All of the authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/13/1106/prepub


The majority of patients with multidrug-resistant tuberculosis (MDR-TB) in South Africa are co-infected with HIV, but the radiographic features of MDR-TB and their relationship with time to sputum culture conversion in the antiretroviral therapy era have not been described.We reviewed baseline chest radiographs for 56 patients with MDR-TB from a rural area of South Africa. We analyzed the association of cavities, consolidation, pleural effusion and hilar lymphadenopathy with time to sputum culture conversion, adjusting for HIV status, baseline sputum smear and CD4 count.3 (IQR 65-249). Thirty-two (57%) patients were sputum smear positive. Twenty-two (39%) patients had a cavity and 37 (66%) patients had consolidations. Cavitary disease and consolidations were each associated with longer time to culture conversion on bivariate analysis but not after adjusting for sputum smear status . Positive baseline sputum smear remained independently associated with longer time to conversion (aOR 3.45 [1.39-8.59]). We found no association between pleural effusion or hilar lymphadenopathy and time to conversion. Seventy-nine percent of patients were cured at the end of treatment.Of the 56 subjects, 49 (88%) were HIV-positive, with a median CD4 count of 136 cells/mmDespite high rates of HIV co-infection and advanced immunodeficiency, the majority of patients had severe pathology on baseline chest radiograph. Nevertheless, culture conversion rates were high and treatment outcomes were favorable. Cavitation and consolidation do not appear to have an independent association with time to culture conversion beyond that of baseline sputum smear status. Multidrug-resistant tuberculosis (MDR-TB), defined as resistance to at least isoniazid and rifampin, remains a growing threat to TB control worldwide and is associated with high mortality—especially in the setting of HIV co-infection ,2. TreatEven in resource-limited settings, most countries providing MDR-TB treatment have access to chest radiography, but the correlation of radiographic findings with clinical disease severity and its utility in predicting TB treatment outcomes remains unclear. Although previous studies have examined the relationship between chest radiograph findings and response to TB treatment, drug-resistance and HIV co-infection may complicate this relationship. Decreased time to sputum culture conversion has been an useful early predictor of successful final treatment outcome and several studies have found that cavitary disease on chest radiograph is associated with a longer time to culture conversion in drug-susceptible TB . NotablyAmong the few studies in MDR-TB, Holtz et al, found that cavitary disease on baseline chest radiograph was associated with a longer time to sputum culture conversion , but thiTugela Ferry is a resource-limited, rural area in KwaZulu-Natal (KZN) province, South Africa with a population of approximately 160,000 Zulu people. The case notification rate of TB is over 1,100 per 100,000 population and MDR-TB incidence was 118 per 100,000 in 2007 . Since 2Patients were treated with a standardized regimen of kanamycin, ofloxacin, ethionamide, ethambutol, pyrazinamide, and cycloserine (intensive phase) for 4 months following culture conversion (defined as two consecutive negative cultures at least one month apart) and a minimum of 6 months. This regimen was continued, without kanamycin, for an additional 18 months (continuation phase). Medications were dosed by weight and modified in response to severe adverse effects. Third-line TB drugs and surgical treatment were not used. Patients with resistance to either a fluoroquinolone or one of the second-line injectable medications  were transferred to the TB referral hospital in Durban and were not eligible for this study.Most patients were hospitalized briefly to initiate MDR-TB therapy and were then discharged to continue treatment on an ambulatory basis. Patients were seen monthly at the decentralized MDR-TB clinic and sputum cultures were performed monthly throughout the course of treatment.2-permeable plastic bags and incubated in 5% CO2 at 37°C. Acid-fast microscopy was done on each positive MGIT broth. Those containing acid-fast bacilli were subcultured on Middlebrook 7H10 agar. Primary Middlebrook agar plates were read weekly for 3 weeks or until growth was observed. Microscopy was done to confirm the presence of acid-fast bacilli and all positive cultures were identified as M. tuberculosis by means of niacin and nitrate reductase tests.Sputum smears were examined with auramine fluorescent microscopy. After decontamination, sputum was inoculated in one mycobacteria growth indicator tube (MGIT) broth and on one Middlebrook 7H10 agar plate. The broths were incubated at 37°C in an automated incubator. Agar plates were sealed in COBeginning in 2008, the hospital in Tugela Ferry began routinely scanning chest radiographs for all patients with TB. Using an EPSON 10000XL photographic and document scanner with transparency attachment, radiographs were scanned at a minimum of 350 dpi, in 16 bit black and white, using SilverFast EpsonIT8 software (Vers. 6.6.0r5) by Laser Soft Imaging.Patients were eligible for inclusion in the study if they (1) had culture-confirmed pulmonary MDR-TB, (2) initiated MDR-TB therapy at the regional referral center and (3) had a scanned copy of their baseline posterior-anterior or anterior–posterior chest radiograph, taken prior to the initiation of MDR-TB therapy. When patients had multiple scanned radiographs on file, we selected the one performed as close as possible to treatment initiation, up to a maximum of 90 days prior.Radiographs were interpreted by a single chest radiologist (B.Z.) who was blinded to the subjects’ clinical/demographic characteristics and treatment outcome. A standardized case report form was used to document the presence of cavities, consolidation, nodules, hilar lymph node enlargement, mediastinal lymph node enlargement, pleural effusion, pleural calcification, volume loss, and miliary disease. The location of any cavities or consolidation was specified by dividing the lungs into six zones (upper/middle/lower for each lung). If hilar lymph nodes were enlarged, the presence of unilateral or bilateral enlargement was noted. As a quality check, the primary radiologist read each film a second time, two weeks after the initial read, blinding himself to his original interpretation. All of these reads were concordant with the earlier interpretation. Any questionable findings were reviewed by a second radiologist (L.B.H.).A cavity score and a consolidation score were each generated as follows: 0 = no cavity/consolidation present; 1=cavity/consolidation present in one lung zone; 2=cavity/consolidation present in at least two lung zones . Similarly, we created a score for hilar lymphadenopathy wherein 0 = no lymphadenopathy; 1 = unilateral; 2 = bilateral.Many patients suspected of having MDR-TB are placed on first-line TB treatment while awaiting the results of sputum culture and drug-susceptibility testing. As a result, although the initial culture may demonstrate MDR-TB, some of these patients have a negative repeat culture by the time they initiate MDR-TB treatment (possibly due to activity of ethambutol and/or pyrazinamide). We hypothesized that patients who convert their culture in this manner have less severe disease than those who are still culture-positive when they start MDR-TB treatment. We therefore created an ordinal culture conversion score in which 0 = conversion before MDR-TB treatment initiation; 1 = conversion within 60 days of initiating MDR-TB treatment; 2 = conversion after 60 days of initiating MDR-TB treatment, or no conversion at all. Time to conversion was defined as the number of days from initiation of MDR-TB therapy to the first of two negative cultures taken at least one month apart. The cut-point of 60 days was chosen because this was the median time to culture conversion seen both in our prior study of MDR-TB/HIV co-infection and in the HIV-negative literature ,16.3; at the time of MDR-TB treatment initiation).We used frequency analysis and chi-square testing to identify associations between clinical characteristics and radiographic findings. We examined the association of each of four radiographic findings  and hilar lymph node score) with the outcome of culture conversion score. We used a log-linear regression model assuming a multinomial distribution with a cumulative logit link function in which the primary predictor variable was the radiographic finding  and the dependent variable was the culture conversion score. We adjusted each of the models for three clinical variables: HIV status, baseline sputum acid-fast bacilli (AFB) smear (positive/negative) and baseline CD4 count  at the time of MDR-TB treatment initiation. Of those who were HIV-positive, 40 (82%) were already receiving ART at the time of MDR-TB initiation and an additional 6 (12%) started ART during MDR-TB therapy. Thirty two (57%) patients were sputum AFB smear positive and 24 (43%) patients had been previously treated for TB  had an available, scanned copy of their baseline chest radiograph . Patientd for TB .3, all had hilar lymphadenopathy and none had cavities. Additional radiographic findings are shown in Radiographs were taken a median of 2 days (IQR 2-6) prior to initiating MDR-TB treatment and no radiographs preceded receipt of first-line TB treatment. Only one patient had a normal chest radiograph. Twenty-two (39%) patients had a cavity, of whom 6 (27%) had cavities in more than one lung zone . Of thosThirteen (23%) patients had a negative sputum culture at the time of MDR-TB treatment initiation . EighteeAfter adjusting for baseline sputum smear, HIV status, and CD4 count, neither cavity nor consolidation score were significantly associated with longer time to conversion although there remained weak evidence of an association between cavity score and culture conversion. In this multivariate model, positive baseline sputum smear remained strongly and independently associated with later culture conversion, but we found no such association for HIV or CD4 count.Final treatment outcomes were available for all 56 patients and of these, 44 (79%) were cured, four (7%) died, 3 (5%) defaulted, 1 (2%) failed therapy and 4 (7%) were transferred to the provincial TB specialty hospital in Durban . We perfThis study, which examined the relationship between baseline chest radiographic findings and time to sputum culture conversion in MDR-TB, has several important findings. Despite extensive pathology on baseline chest radiograph, and advanced immunodeficiency in the majority of patients, MDR-TB treatment outcomes were favorable in this cohort. All but three patients (5%) achieved culture conversion and 79% of patients were cured at the end of treatment. Median time to culture conversion was 66 days, which is similar to our earlier published findings as well as reports in the HIV-negative MDR-TB literature ,16.Although the presence and degree of cavitary disease on baseline chest radiograph was associated with a longer time to culture conversion in MDR-TB in bivariate analysis, this effect did not retain statistical significance after adjusting for baseline sputum smear status. In the multivariate model, smear status was the only independent predictor of culture conversion, suggesting that smear-positivity—which reflects bacillary burden in the lung—may mediate the effect of cavitation on time to culture conversion in our analysis. Other studies have examined the prognostic significance of cavitary disease and have found an inverse relationship with likelihood of culture conversion ,17. To o3 were significantly less likely to have cavities and more likely to have hilar/mediastinal lymphadenopathy. We found a similar relationship between CD4 count and radiographic findings; all of the patients with a CD4 count ≤50 cells/mm3 had hilar lymphadenopathy and none had cavities. Overall, however, a greater proportion of our patients (39%) had cavitary disease compared to those reported by Perlman. Angthong et al. also found a higher prevalence of cavitary disease among Japanese HIV-infected patients with a CD4 count >200 cells/mm3 and drug-susceptible TB, but their study population only included 5 patients with a high CD4 count [3 [Several studies have shown that radiographic findings from TB differ between patients with and without HIV ,8,18–20.D4 count . Fishmancount [3 . We founIn their study from New York in the mid-1990’s, Telzak et al. found that cavitary disease and baseline smear, but not HIV, were associated with a prolonged time to culture conversion . This coOur findings must be taken in the context of the local drug-resistant tuberculosis epidemic. In studies from several countries, the MDR-TB subjects had received multiple courses of TB, and even MDR-TB therapy ,26–28. OThis study has several limitations. First, we did not have radiographs from a control population of drug-susceptible TB patients for comparison. Nevertheless, when compared to other studies in patients with drug-susceptible TB or MDR-TB but without HIV co-infection, our findings shed further light on the interplay between TB disease, drug-resistance, HIV infection and radiographic findings. Second, our sample size was small, and the borderline significance of the association between cavitary disease and time to conversion may reflect a lack of power. With a larger sample size, this association—which was significant on bivariate analysis—may have retained significance in the adjusted model. Similarly, the number of HIV-negative subjects in our cohort was also very small, limiting our ability to examine independent effects of HIV-infection. A third limitation is that follow-up radiographs were not available for most patients, and as a result, we were unable to examine how changes in radiographic findings during treatment might correlate with, or predict clinical course and culture conversion. Fourth, because a majority of patients initiated ART several weeks prior to starting MDR-TB therapy, we were unable to exclude the possibility that some radiographic findings represented immune reconstitution inflammatory syndrome (IRIS). Finally, post-treatment surveillance results are not available, and it is possible that patients with extensive cavitary disease and longer time to culture conversion may be at higher risk of relapse after “cure.” Future studies are needed to answer this question and to determine if such patients should receive a prolonged intensive phase, prolonged continuation phase, or other modification in treatment.The results of our study suggest that the presence of cavities on baseline chest radiograph is associated with prolonged time to sputum culture conversion. This relationship is likely mediated by a high bacillary burden in the lung and positive sputum smear for AFB. The presence and degree of lymphadenopathy and pleural effusions in this cohort were not associated with time to culture conversion. Chest radiographs remain a useful clinical tool for monitoring response to therapy and diagnosing the immune reconstitution inflammatory syndrome, and a baseline radiograph should be obtained in all patients for later comparison. As a predictive tool in this South African population, however, radiographs may not have an independent association with time to sputum culture conversion beyond that of baseline sputum smear status.


To assess the incidence of and risk factors for clinical and subclinical dengue virus (DENV) infection, we prospectively studied 1,207 adult short-term travelers from the Netherlands to dengue-endemic areas. Participants donated blood samples for serologic testing before and after travel. Blood samples were tested for antibodies against DENV. Seroconversion occurred in 14 (1.2%) travelers at risk. The incidence rate was 14.6 per 1,000 person-months. The incidence rate was significantly higher for travel during the rainy months. Dengue-like illness occurred in 5 of the 14 travelers who seroconverted. Seroconversion was significantly related to fever, retro-orbital pain, myalgia, arthralgia, and skin rash. The risk for DENV infection for short-term travelers to dengue-endemic areas is substantial. The incidence rate for this study is comparable with that in 2 other serology-based prospective studies conducted in the 1990s. Aedes spp. mosquito. The disease is endemic to tropical and subtropical regions and each year affects ≈100 million persons worldwide. Most cases are reported from Southeast Asia and Central and South America  is a flavivirus transmitted through the bite of an infected ,The incubation period for DENV infection is 3–14 days. Manifestations are nonspecific and range from asymptomatic to severe  and 2–6 weeks after return, participants donated venous blood samples for serologic testing. Before departure,they completed a standard questionnaire to collect data on sociodemographic factors, including travel history, vaccination status, and the purpose of travel .Participants were given a digital thermometer and asked to take their temperature  when feeling feverish. They kept a structured travel and posttravel diary to record symptoms and signs of dengue illness , use of insect repellent containing N,N-diethyl-meta-toluamide (DEET), and use of mosquito netting. Participants were asked to report both the presence and absence of symptoms and preventive measures on a daily basis; after travel, the diary was checked by a registered nurse in the participant’s presence.To encompass the incubation period of DENV infection, we used data from the third day after arrival at the travel destination until 2 weeks after return from travel. With respect to symptomatic outcome, we used the term travel-related to refer to this period.Destinations were grouped into regions by using the classification of the United Nations Development Agency  M antibodies to DENV antigen by using an IgM-capture ELISA and for IgG antibodies to DENV antigen serotypes 1, 2, 3, and 4 by using an indirect ELISA  according to the manufacturer’s instructions. For participants whose posttravel sample yielded positive test results for anti-DENV IgM or IgG, pretravel samples were also tested for anti-DENV IgM or IgG, respectively.–,The ELISA for anti-DENV IgM has a sensitivity of 87%–100% and a specificity of 96%  anti-DENV IgG >11 Panbio units in both the pretravel and posttravel sample, with a posttravel-to-pretravel ratio of >4:1 (We defined seroconversion indicating recent DENV infection. Criteria were as follows: 1) posttravel anti-DENV IgM >11 Panbio units with pretravel anti-DENV IgM <11 Panbio units and anti-DENV IgG <11 Panbio units; and/or 2) posttravel anti-DENV IgG >11 Panbio units and pretravel anti-DENV IgG <11 Panbio units, with a posttravel-to-pretravel ratio of To calculate risk factors for previous DENV infection, we used SPSS for Windows version 17.0  to obtain prevalence rates, univariate and multivariate prevalence rate ratios, and 95% confidence intervals (CIs) by using logistic regression modeling. All variables with an overall p value <0.05 in univariate analysis were included in multivariate analysis. Statistical interactions between variables were checked for all variables. If significant (p<0.05), they were included in multivariate analysis.We calculated attack rates of recent DENV infection per 100 travelers by dividing the number of seroconversions by the total number of participants. Incidence rates (IR) per 1,000 person-months were calculated by dividing the number of seroconversions by the total number of months in which participants were at risk for DENV infection. To calculate risk factors for recent DENV infection, incidence rate ratios (IRR) were obtained as conditional maximum-likelihood estimates of the rate ratio, with mid-P exact test, 95% CIs, and p values. We quantified the application of a protective measure against mosquito bites by dividing the number of days the measure was applied by the number of travel days; it was dichotomized by using the mean of this proportion in the total study population as the cutoff.Travel during the rainy months was assessed by using the midtravel dates. The rainy months per destination were defined as months with an average total precipitation of >100 mm, based on World Weather Information Service data from the United Nations’ World Meteorological Organisation  were excluded: 33 were lost to follow-up; 23 had their travel arrangements cancelled; 7 did not supply the posttravel blood donation; 3 changed travel plans such that inclusion criteria were not met; 2 did not complete the structured diary; and for 1, the posttravel sample was lost.Most of the remaining 1,207 participants were persons of Dutch origin who were traveling for tourism and previously had traveled to dengue-endemic areas , 2. The Twenty-six percent of travelers had received yellow fever vaccination for a previous journey, and 23% received a yellow fever vaccination for the current trip, just after blood donation (not shown in >1 previous trips to such a country), and for those whose purpose was to visit friends or relatives. In multivariate analysis, previous DENV infection was not related to yellow fever vaccination for previous travel because it was confounded by previous trips to a developing country. We found no interactions indicating effect modification.Serologic results suggestive of previous DENV infection were found for 78  participants . Previou>4:1; and 2 seroconverted for both IgM and IgG  had recent DENV infection, of whom 5 seroconverted only for IgM; 7 seroconverted only for IgG, with a posttravel-to-pretravel ratio of  and IgG . Thus, t and IgG .All 14 persons with recent infection were born in non–dengue-endemic countries; 9 were male, and 11 had traveled previously to a dengue-endemic country . The medThe incidence rate was significantly higher for travel during the rainy months . Travel during the rainy months was not related to use of insect repellent containing DEET or use of a mosquito net .The incidence rate appeared to be higher for male travelers , persons who traveled for work or education , and those who used insect repellent containing DEET <45% of travel days , but differences were not significant. With regard to age, previous travel to a dengue-endemic country, yellow fever vaccination for the current trip, and use of a mosquito net, the IRRs equaled 1.0 (p>0.05).Recent DENV infection was positively correlated with fever, retro-orbital pain, myalgia, arthralgia, and skin rash . Dengue-In this prospective study, the serology-based attack rate and incidence rate for recent DENV infection in short-term travelers to areas in which dengue is endemic were substantial: 1.2% and 14.6 per 1,000 person-months, respectively. Although most seroconversions occurred in travelers to Southeast and southern Asia, 3 occurred in travelers to sub-Saharan Africa.The risk for recent infection was significantly related to travel during the rainy months, as others have reported , although the 95% CI was wide (3.4–36.5), and cross-reactions with other flaviviruses or previous yellow fever vaccination cannot be excluded. However, cross-reactions with yellow fever vaccination are unlikely because the travelers to Africa who seroconverted for anti-DENV either did not receive a yellow fever vaccination during the study period (2 travelers) or had dengue-like illness (1) . These tThe ratio of apparent to unapparent infection in our study was 1:1.8. The 2 other prospective studies reported ratios of 1:0.75 (,,Our study has some limitations. First, our sample size was too small to yield a precise estimate of disease incidence per region or per destination. For example, travelers to Southeast Asia are considered to be at higher risk than travelers to other regions (,,,<96%, >4% of positive samples actually give false-positive results. Subclinical infections with flaviviruses other than DENV may account for some of the seroconversions (A final limitation is that, although the serologic tests used are highly sensitive and specific, false-negative and false-positive test results may have occurred. For example, 7 travelers seroconverted only for anti-DENV IgG and not for anti-DENV IgM. Although this may be because of false-positive IgG or false-negative IgM test results, these results may also suggest secondary infection. Unfortunately, no test characteristics are available that apply exactly to our study design; the best available test characteristics are probably those from studies that used paired serum samples (Unfortunately, no true standard exists for confirming or ruling out DENV infections. Even a plaque-reduction neutralization test can cross-react (In conclusion, although valid data regarding the actual frequency of DENV infection in international travelers is elusive, our prospective study confirms that the incidence rate for recent DENV infection in short-term travelers to areas in which dengue is endemic is substantial. We found no differences in incidence rate compared with other serology-based prospective cohort studies performed in the 1990s. Thus, the increase in annually reported dengue cases from network studies is possibly related to the increase in international travel and the expansion of DENV and its vector to new areas rather than to an increase in DENV transmission. Until an effective and safe vaccine that provides effective, long-term immunity against all 4 serotypes of DENV has been developed, the only useful preventive measure for travelers to areas where dengue is endemic is to avoid mosquito bites, particularly during the rainy season.


There is a worldwide obesity epidemic, but lack of a simple method, applicable for research or clinical use, to identify individuals at high risk of weight gain. Therefore, the relationship of self-rated health and 10-year percent weight change was evaluated to determine if self-rated health would predict weight change.From 1990 to 2008, adults aged 30, 40, 50 and 60 years were invited to health surveys that included self-rated health and measured weight and height. ANOVA was used to evaluate the relationship of 10-year percent weight change and self-rated health.The study population consisted of 29,207 participants (46.5% men). There was no relationship between baseline self-rated health and 10-year percent weight change for middle-aged men or women.Self-rated health is not able to predict weight change over a 10-year period in this age group. The obesity epidemic is occurring in many regions and countries of the world. A dose-response relationship exists between increasing obesity and an increasing burden of health problems, mainly cardiovascular diseases, diabetes and cancers . There aSelf-rated health is known to both predict and be associated with mortality  and manyWe were interested in determining whether self-rated health would predict weight maintenance or change in a middle-aged adult population. If so, this simple question could be used quickly, easily, and inexpensively in a clinical or public health setting. Using a large population-based study, we evaluated 10-year weight change and determined if self-rated health at baseline could predict weight change.Västerbotten County is located in Northern Sweden and covers one eighth of the country. The Västerbotten Intervention Programme (VIP) has previously been described in detail . VIP wasSurveys consist of questionnaires and health examinations administered by trained district nurses and include assessment of traditional CVD risk markers and a comprehensive questionnaire regarding demographics, socioeconomic status, self-rated health and lifestyle habits. The results of the examination are individually discussed with each participant by a trained district nurse at the end of the survey using motivational interviewing principles. Health promotion activities are also suggested at that time.This report is based on participants who were aged 30, 40 or 50 years at baseline and were initially surveyed during 1990-1998. Each participant must have returned for a follow-up visit 10 years later (2000-2008) and have valid weight, height and self-rated health data. Individuals gave informed consent prior to each health screening. The study was conducted in compliance with the Helsinki Declaration and was approved by the regional Research Ethics Board in Umeå (08-131M).Self-rated health was based on the question: "How do you assess your general health during the previous year?" There were five alternatives: "very good", "pretty good", "somewhat good", "pretty bad" and "bad" . Assessm2) was calculated. Capillary glucose and total cholesterol were measured using a Reflotron® analyzer . An oral glucose tolerance test was offered to all participants not known to have diabetes and with a fasting plasma glucose <7.0 mmol/L [Examinations were done in the morning after an overnight fast. Height and weight were measured in light indoor clothing. Ten-year percent weight change was calculated as the difference between body weight at 10-year follow-up and baseline weight, divided by baseline weight, and multiplied by 100. Body mass index  was done for 10-year percent weight change and other continuous variables by self-rated health. Post hoc testing of ANOVA was done with the Scheffe test. Comparison of percent weight change to continuous variables was also done by visual assessment of graphic distributions and Pearson correlation coefficients. Comparison of self-rated health and categorical variables was done with ΧOf the 40,555 individuals who participated in VIP from 1990 through 1998, 39,723 were eligible for the 10-year follow-up. A total of 2920 individuals were ineligible for follow-up because 1854 had moved from the region, 1007 had died (2.5% during 10 years), and 59 were excluded for another reason (such as change in person number). Of those eligible, 30,168 (75.9%) participated in the follow-up survey; of these, 46.6% were men and 53.4% were women. Table Participants who were missing values for weight at baseline or the follow-up survey, baseline height, or self-rated health at either survey were excluded (n = 961), leaving 29,207 participants. Table p = 0.65) for men and r = 0.013 (p = 0.11) for women. Box plots illustrate the results . This association was not pertinent to the aim of this study and was not evaluated further.Univariate analyses of relationships between self-rated health with biologic and socioeconomic variables showed significant relationships in the expected directions for both men and women for all variables considered (Data not shown).We found that self-rated health is unrelated to change in body weight over a period of ten years. Translated self-rated health questionnaires have been used globally with consistent findings between self-rated health and a variety of health conditions and outcomes ,24-28. GUnivariate and descriptive analyses of the relationships between 10-year percent weight change and demographic, biologic and socioeconomic variables show significant relationships in the expected directions for both men and women. See Tables One special group of interest is smokers, because they tend to report worse self-rated health than non-smokers . In thisp < 0.001 for men and women), ie, those who are younger were more likely to report very good health. Cigarette smoking is also inversely correlated with better self-rated health (p < 0.001 for men and women), ie, those who smoke are less likely to report very good health. All of these relationships were in the expected directions, confirming that self-rated health assesses objective and subjective measures as previously shown in other populations.The finding that baseline demographic, socioeconomic and biologic variables are related to self-rated health is consistent with previously established observations and trends seen from other populations -14,31. FVarious cut-points have been suggested as appropriate for use in defining weight loss, weight maintenance and weight gain in population studies. We chose to illustrate our figures with less than 5% weight change (loss or gain) to assist the reader in evaluating clinically significant weight change within the population. Many studies, both intervention and observational, have found that a 5% change in weight is clinically meaningful for conditions such as hypertension and hypercholesterolemia -36. SomeOthers have examined the relationship of self-rated BMI to self-rated health in cross-sectional surveys and found that the extremes of weight are related to poorer self-rated health  or qualiConcordant with previous results , we founWe chose to use baseline self-rated health because we were interested in the ability to predict weight change rather than evaluate the influence of weight change on self-rated health. While some researchers have used change in BMI as the measure of weight change, we used measured percent weight change because total body weight is the most commonly used and clinically meaningful (to physicians and patients) measure currently in use . We wereThe VIP surveys comprise a very large, population-based study and use standardized questionnaires and measurement techniques. The setting of the local health clinic is familiar to most Swedes, ie, the survey is conducted in their own primary care centre, and this is expected to enhance participation. Despite the 10-year follow-up interval, the participation rate among eligible subjects was high (76%) and reflects the high credibility that the Swedish population holds for primary care. In addition, the small differences in demographic characteristics between participants and non-participants (Table Self-rated health did not predict 10-year weight change in a middle-aged population. We think these results are valid and stronger than those of previous studies. The population was drawn from a free-living population in Northern Sweden in which all residents aged 30-60 years were invited to participate, the number of participants is large, and both self-rated health and objective weight change were measured in a standardized way. This allows the findings to be extrapolated to other middle-aged populations with similar demographic and socioeconomic characteristics. While self-rated health remains a useful tool for predicting other outcomes, it is not able to predict weight change, whether that be weight maintenance, loss or gain over a 10-year period.BMI: body mass index; CVD: cardiovascular disease; VIP: Västerbotten Intervention Programme.The authors declare that they have no competing interests.MN made substantial contributions to conception and study design, was involved in acquisition of data, data analyses and interpretation, and drafted and revised the manuscript. KL was involved in data interpretation and provided critical review. PLJ provided biostatistical expertice for data analyses and critical review of the manuscript. ME was involved in data interpretation and provided critical review. GL was involved in data acquisition and drop-out analyses. ANN made substantial contributions to conception and study design, was involved in data analyses and interpretation, and drafted and revised the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/11/748/prepub