A high burden of tuberculosis (TB) occurs in sub-Saharan African countries and many cases of active TB and drug-resistant TB remain undiagnosed. Tertiary care hospitals provide an opportunity to study TB co-morbidity with non-communicable and other communicable diseases (NCDs/CDs). We evaluated the burden of undiagnosed pulmonary TB and multi-drug resistant TB in adult inpatients, regardless of their primary admission diagnosis, in a tertiary referral centre.In this prospective study, newly admitted adult inpatients able to produce sputum at the University Teaching Hospital, Lusaka, Zambia, were screened for pulmonary TB using fluorescent smear microscopy and automated liquid culture. The burden of pulmonary TB, unsuspected TB, TB co-morbidity with NCDs and CDs was determined. Sputum was analysed from 900 inpatients (70.6% HIV infected) 277 (30.8%) non-TB suspects, 286 (31.8%) TB suspects and 337 (37.4%) were already receiving TB treatment. 202/900 (22.4%) of patients had culture confirmed TB. TB co-morbidity was detected in 20/275 (7.3%) NCD patients, significantly associated with diabetes . 27/202 (13.4%) TB cases were unsuspected. There were 18 confirmed cases of MDR-TB, 5 of which were unsuspected.A large burden of unsuspected pulmonary TB co-morbidity exists in inpatients with NCDs and other CDs. Pro-active sputum screening of all inpatients in tertiary referral centres in high TB endemic countries is recommended. The scale of the problem of undiagnosed MDR-TB in inpatients requires further study. The WHO estimates that In 2010, there were 1.45 million TB-related deaths, with the highest burden of tuberculosis (TB) in sub-Saharan Africa (SSA), where many cases of active TB and drug-resistant TB remain undiagnosed Subclinical TB has been defined as ‘asymptomatic disease in immunocompromised hosts largely associated with loss of containment’ Zambia has a high TB incidence  This study was approved by the research ethics review committee of the University of Zambia School of Medicine, Lusaka, Zambia. All study participants gave written informed consent and the study was conducted in accordance with ethics committee guidelines.A prospective study to assess the burden of pulmonary TB, MDR-TB, unsuspected TB and co-morbidity with NCDs and CDs other than TB, irrespective of admission diagnosis and HIV status, in adult inpatients presenting to UTH, Lusaka, Zambia - a tertiary referral centre.Pulmonary tuberculosis.Mycobacterium tuberculosis (M.tb) strains resistant to at least isoniazid and rifampicin.TB caused by Patient with presence of cough on admission, of at least 2 weeks’ duration  Any patient who is not a TB suspect in accordance with the above definition.Patient currently on TB therapy, initiated prior to admission.Culture confirmed TB in a non-TB suspect. As our cohort contains a broad range of patients, including HIV negative, HIV positive (at different stages of immunosuppression) and NCD patients, we use the term ‘unsuspected TB’ to define all culture confirmed TB in patients in whom TB was not suspected. These may include subclinical, asymptomatic, incipient and intermittent cases, as well as symptomatic cases missed due to co-morbidities.Infectious diseases that can be transmitted between people.Diseases that cannot be transmitted between people.Presence of culture confirmed TB, presenting with a different disease.New adult inpatient admissions to UTH were approached irrespective of admission diagnosis, including TB suspects, non-TB suspects and current TB patients, and informed consent was obtained from those willing to participate. The sole inclusion criterion was that they could produce at least one sputum specimen for analysis. Clinical details including the admission diagnosis which necessitated hospital admission were recorded. Sputum samples were collected. Due to the very high HIV prevalence in the population, the hospital has in place a Diagnostic Counselling and Testing (DCT) scheme. The majority of patients enrolled in the study were tested for HIV, as part of routine practise on admission. To assess to what degree our cohort of sputum producers was representative of the general hospital population, we compared our cohort with a set of 960 hospital records accounting for all adult admissions over a 2 month period.In accordance with routine hospital protocols, clinical staff supervised the collection of spot sputum from patients, and then left containers to collect up to two other specimens over the next 24 hours. Sputum induction is not routine at the hospital and was not performed.M.tb complex with no growth on blood agar plates and a positive TBcID (BD) culture confirmation test. Contaminated samples were retreated and re-cultured and excluded if still contaminated. Phenotypic DST was performed on M.tb positive cultures using the BACTEC MGIT 960 SIRE kit  according to the manufacturer’s instructions.Fluorescent smear microscopy was performed directly on sputum specimens as described previously Clinical and laboratory data were compiled in databases using double data entry and Epidata software During the 15 month period from Sept 2010 to Dec 2011, we conducted 218 days of recruitment with a median of 4 recruits per day. A total of 964 patients were enrolled, from whom smear and culture results were obtained for 900 patients and analysed . A total22.4% (202/900) of patients recruited had culture confirmed TB . Univari275 patients showed clear evidence of admission diagnosis of co-morbidity with a non-communicable disease. Likewise, 306 patients presented with communicable diseases (excluding TB and HIV) . AdmissiCulture DST results were available for 111 cases, of which 18 (16.2%) were MDR-TB. 33 sub-cultures were contaminated and 58 were not performed as DST was not available at the beginning of the study. All 18 MDR-TB cases detected were in current or suspected TB patients. Of the 18 MDR-TB cases, 12 were on or about to start relapse treatment. The remaining 6 MDR-TB cases were on their first course of treatment and 5 of these were not suspected by the attending physician.This study found a large burden of pulmonary TB in sputum producing inpatients at a high HIV burden tertiary referral centre in Zambia. The high TB case load (22.4%: 202/900) among patients able to expectorate was anticipated in a patient cohort with an HIV prevalence of 70.6%, where over 80% of all culture confirmed TB cases were associated with HIV. Despite moderate reductions in both HIV and TB prevalence in Zambia This study was uniquely designed to focus not only on screening of inpatients who were suspected of having active pulmonary TB on admission by the admitting physician, but also to determine the extent to which TB cases were being missed, and the burden of TB co-morbidity with NCDs and CDs. We recruited roughly equal numbers of TB suspects, non-TB suspects and current TB patients on treatment. The relative proportions of these three groups to be recruited were not pre-determined, with study clinical officers instructed to approach all admissions. That roughly one third of the cohort were not suspected of TB, yet able to expectorate and recruited onto the study was surprising, and shows that a broader range of patients than you might expect, can expectorate and could be readily screened for TB. Across the cohort as a whole, a broad range of patients were recruited, with 75.3% (678/900) of patients having an admission diagnosis other than TB, including NCDs and CDs.Several African studies have reported HIV-associated subclinical TB infections in which patients do not present with any symptoms of active TB We showed, as seen in other SSA countries, that HIV positive patients are twice as likely to have active pulmonary TB, with two thirds of TB patients co-infected with HIV The growing problem of NCDs in SSA is well documented Our data show that MDR-TB and unsuspected MDR-TB are significant problems in inpatients at UTH. In our study, of those culture positive cases analysed by culture DST, 18 out of 111 (16.2%) had MDR-TB and 5 were undiagnosed, on inappropriate therapy with first line TB treatment, and were not suspected of MDR-TB by the attending physician. This represents a significant failure to adequately diagnose and treat MDR-TB, putting other patients and staff at unnecessary risk. A more pro-active routine screening program for TB and MDR-TB is required. This finding is confluent with the fact that MDR-TB surveillance in Zambia is poor, with MDR-TB data not being routinely collected in hospitals or primary health care facilities, due to under-funding and inadequate laboratory services As this was a prospective descriptive study to evaluate the burden of TB in sputum producing new inpatient admissions using diagnostics that require disease-associated specimens, our patient cohort is not representative of the broader hospital population. Through comparison with hospital admissions data, we confirmed that patients with respiratory illnesses and TB patients were over represented and so we make no claim about the prevalence of TB within the general inpatient population. There were also factors which could have contributed to missing some TB cases. Performing culture on multiple specimens, using sputum induction and extensive investigations for extrapulmonary TB would have likely yielded more cases. Despite these limitations, the high TB burden (diagnosed and undiagnosed); co-morbidity with NCDs; and the identification of MDR-TB in inpatients able to produce sputum, calls for more pro-active screening for TB in medical inpatients using routine diagnostic protocols already in place.Most countries in SSA are now moving away from vertical programmes for TB and HIV services and more emphasis is on merging TB/HIV services for delivery of joint care


Burkholderia pseudomallei, is difficult to cure. Antimicrobial treatment comprises intravenous drugs for at least 10 days, followed by oral drugs for at least 12 weeks. The standard oral regimen based on trial evidence is trimethoprim-sulfamethoxaxole (TMP-SMX) plus doxycycline. This regimen is used in Thailand but is associated with side-effects and poor adherence by patients, and TMP-SMX alone is recommended in Australia. We compared the efficacy and side-effects of TMP-SMX with TMP-SMX plus doxycycline for the oral phase of melioidosis treatment.Melioidosis, an infectious disease caused by the Gram-negative bacillus www.controlled-trials.com, number ISRCTN86140460.For this multi-centre, double-blind, non-inferiority, randomised placebo-controlled trial, we enrolled patients (aged ≥15 years) from five centres in northeast Thailand with culture-confirmed melioidosis who had received a course of parenteral antimicrobial drugs. Using a computer-generated sequence, we randomly assigned patients to receive TMP-SMX plus placebo or TMP-SMX plus doxycycline for 20 weeks . We followed patients up every 4 months for 1 year and annually thereafter to the end of the study. The primary endpoint was culture-confirmed recurrent melioidosis, and the non-inferiority margin was a hazard ratio (HR) of 1·7. This study is registered with vs 167 [53%]).We enrolled and randomly assigned 626 patients: 311 to TMP-SMX plus placebo and 315 to TMP-SMX plus doxycycline. 16 patients (5%) in the TMP-SMX plus placebo group and 21 patients (7%) in the TMP-SMX plus doxycycline group developed culture-confirmed recurrent melioidosis . The criterion for non-inferiority was met (p=0.01). Adverse drug reactions were less common in the TMP-SMX plus placebo group than in the TMP-SMX plus doxycycline group (122 [39%] Our findings suggest that TMP-SMX is not inferior to TMP-SMX plus doxycycline for the oral phase of melioidosis treatment, and is preferable on the basis of safety and tolerance by patients.Thailand Research Fund, the Melioidosis Research Center, the Center of Excellence in Specific Health Problems in Greater Mekong Sub-region cluster, and the Wellcome Trust. Burkholderia pseudomallei, found in soil and water.Melioidosis is a serious infection caused by the Gram-negative bacillus The recommended oral antimicrobial regimen for melioidosis in Thailand is trimethoprim-sulfamethoxazole (TMP-SMX) plus doxycycline. This recommendation is based on findings that this regimen is as effective as, and better tolerated than, the previously recommended regimen of TMP-SMX plus doxycycline and chloramphenicol.B pseudomallei that was resistant to TMP-SMX or doxycycline, if their melioidosis infection was recurrent (defined as having a previous episode of culture-confirmed melioidosis within the past 2 years), or if they had a contraindication to either TMP-SMX or doxycycline . Resistance to doxycycline was determined by disc diffusion as an inhibition zone diameter ≤12 mm, which was modified from the Clinical and Laboratory Standards Institute (CLSI) breakpoint recommended for Enterobacteriaceae.B pseudomallei determined by broth dilution method.12We did this multicentre, double-blind, non-inferiority, randomised placebo-controlled trial in five hospitals in northeast Thailand: Sappasithiprasong Hospital (Ubon Ratchathani), Srinagarind Hospital (Khon Kaen), Udon Thani Hospital (Udon Thani), Mahasarakam Hospital (Mahasarakam), and Khon Kaen Hospital (Khon Kaen). We enrolled adult patients (aged ≥15 years) with culture-confirmed melioidosis who had been satisfactorily treated with parenteral antimicrobials, or who had mild localised disease that was not considered to need intravenous antimicrobial treatment by the attending physicians. We defined satisfactory clinical improvement from parenteral treatment as cessation of fever for at least 48 h and the ability to take oral drugs. We excluded patients if they were infected by www.controlled-trials.com, number IRSCTN86140460.The trial was done in accordance with the principles of good clinical practice, and the ethical principles in the Declaration of Helsinki. The study protocol was approved by the local ethical committees and the institutional review boards of all participating hospitals. The study was reviewed by an independent data safety and monitoring board. All patients gave signed or fingerprinted informed consent before randomisation. This trial is registered with We randomly allocated patients in a 1:1 ratio to receive TMP-SMX with either placebo doxycycline (hereafter referred to as placebo) or doxycycline, which were identical in appearance. Randomisation and masking was done at the coordinating centre at the Mahidol-Oxford Tropical Medicine Research Unit . The allocation sequence was computer generated with a block size of ten and was stratified by study site. To achieve treatment concealment, TMP-SMX and either placebo or doxycycline were dispensed into sequential, identical, tamper-proof bottles for each participant for 20 weeks. The study drug bottles were labelled with sequential code numbers and distributed to the study sites. TMP-SMX, placebo, and doxycycline were manufactured and provided by the Siam Pharmaceutical Company . All patients and study investigators were unaware of the drug allocation throughout the study. The randomisation codes remained sealed until after data collection, data cleaning, and completion of a masked analysis.All patients received TMP-SMX plus placebo or TMP-SMX plus doxycycline for a minimum of 20 weeks. TMP-SMX (80 mg TMP and 400 mg SMX) tablets were prescribed using a weight-based dosage, as follows: bodyweight less than 40 kg or estimated glomerular filtration rate 15–29 mL/min, 160 mg TMP and 800 mg SMX twice daily; bodyweight of 40 kg to 60 kg, 240 mg TMP and 1200 mg SMX twice daily; and bodyweight greater than 60 kg, 320 mg TMP and 1600 mg SMX twice daily.After enrolment, we followed patients up at weeks 4, 12, and 20 of oral treatment, every 4 months for 1 year after completion of treatment, and annually thereafter to the end of the study. Patients who did not attend scheduled appointments were contacted by telephone. The trial was designed to stop 1 year after the last participant was enrolled. At each clinical visit, we undertook a clinical examination and laboratory analyses, including complete blood count, blood sugar, blood urea nitrogen, creatinine, electrolyte, and liver function tests. Chest radiography and abdominal ultrasonography were done at enrolment, and repeated at weeks 12 and 20 if an abnormality was detected on the first test. We asked patients to bring the study drug bottles to follow-up visits, at which drug compliance was checked by pill counts. Treatment with the randomised drugs was extended beyond 20 weeks if clinically indicated because of evidence of residual infection, as decided by the treating physician. Concealed study drug bottles labelled with unique spare sequential code numbers were separately prepared for patients who needed treatment for more than 20 weeks. As needed, the site investigator contacted the coordinating centre by telephone to receive the code number of the extended study drug bottles for a specific study participant.Study treatment was stopped immediately if a patient developed symptoms or signs of a severe allergic reaction (grade 4),B pseudomallei at any time between enrolment and study completion. Secondary endpoints were overall recurrent melioidosis , mortality, treatment failure, extension of treatment, and adverse drug reactions. The published protocol contains an error and states that mortality was a primary rather than a secondary outcome measure . Continuous variables are presented as median (IQR). IQRs are presented in terms of 25th and 75th percentiles. Categorical data are presented as number (%). We did survival analyses using the Kaplan-Meier method and Cox proportional hazard models. Time was measured from the day of study enrolment. For the primary analysis  with culture-confirmed recurrent melioidosis as the failure outcome, participants were censored on the day of last follow-up or death due to other causes. We tested non-inferiority of the TMP-SMX plus placebo group by calculating the HR for the efficacy of TMP-SMX plus placebo over the TMP-SMX plus doxycycline, and compared the upper limit of the 95% CI to the non-inferiority margin. To accept the non-inferiority of TMP-SMX plus placebo to TMP-SMX plus doxycycline, the upper limit of the 95% CI needed to be equal to or less than 1·7. A one sided-test at an alpha error of 5% was also calculated for the non-inferiority margin. For the secondary analyses with treatment changes and treatment failure as the outcomes, participants were censored on the day of recurrent melioidosis or death due to other causes. We calculated the probabilities of event outcomes at each timepoint using the Kaplan-Meier method. For the Cox Proportional Hazard model, we assessed whether the hazard ratio was constant over time using Schoenfeld residuals. The analysis was repeated for the primary outcome in the per-protocol population, in which those who did not complete 20 weeks of study drug were excluded.As recurrent melioidosis can be caused by either relapse or re-infection, we also assessed the efficacy of TMP-SMX for culture-confirmed relapse in a sensitivity analysis on the basis that we would not expect antimicrobial treatment to prevent re-infection after treatment has been completed. We did this using culture-confirmed relapse as a failure outcome and excluding patients who had no paired bacterial isolates available for genotyping from the first and recurrent episode and those with paired isolates and genotyping results that confirmed re-infection.For safety analyses, we assessed the proportion of patients who had adverse drug reactions by treatment group. We compared proportions using the Fisher's exact test and continuous variables using the Mann-Whitney test. We used STATA (version 12.1) for all statistical analyses.The sponsors had no role in data collection, data analyses, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study. All authors participated in the final discussion and approved the submission for publication.Between Oct 24, 2005, and Feb 1, 2010, we randomly assigned 626 patients with culture-confirmed melioidosis to receive either oral TMP-SMX plus placebo (n=311), or oral TMP-SMX plus doxycycline n=315; . BaselinFollow-up was completed in Feb 21, 2011, 1 year after we enrolled the last patient. 618 patients (99%) had at least one follow-up assessment. Median follow-up duration was 17 months (IQR 13–28) in the TMP-SMX plus placebo group and 19 months (16–31) in the TMP-SMX plus doxycycline group (p=0·06). Total duration of follow-up was 536 person-years in the TMP-SMX plus placebo group and 583 person-years in the TMP-SMX plus doxycycline group.We recorded no between-group difference in our primary analysis for culture-confirmed recurrent melioidosis p=0·64; . Non-infComparison of secondary endpoints in the two treatment groups is shown in Overall, 516 (82%) patients received oral treatment for at least 12 weeks (including amoxicillin-clavulanic acid if patients needed switching) and 445 (71%) patients received oral treatment for at least 20 weeks. 37 (12%) of 311 patients given TMP-SMX plus placebo and 59 (19%) of 315 patients given TMP-SMX plus doxycycline switched treatment to amoxicillin-clavulanic acid because of adverse drug reactions. Patients given TMP-SMX plus placebo had about a 40% lower chance of switching to the second-line regimen due to adverse drug reactions than those given TMP-SMX plus doxycycline . Six patients (2%) given TMP-SMX plus placebo and six patients (2%) given TMP-SMX plus doxycycline switched due to treatment failure . Analysis of Schoenfeld residuals showed that the HR for all outcomes were not variable over time with the exception of switching due to treatment failure . Of all patients who completed 20 weeks of the study drug, nine (4%) of 226 patients in the TMP-SMX plus placebo group and 12 (6%) of 218 patients in the TMP-SMX plus doxycycline group needed an extension of treatment beyond 20 weeks (p=0·51).The proportion of patients reporting adverse drug reactions was lower in the TMP-SMX plus placebo group than in the TMP-SMX plus doxycycline group . Common We analysed 226 patients in the TMP-SMX plus placebo group and 218 patients in the TMP-SMX plus doxycycline group who completed 20 weeks of the study drug in a per-protocol analysis. Non-inferiority of TMP-SMX plus placebo for culture-confirmed recurrent melioidosis was also shown .We did bacterial genotyping for 29 (78%) of 37 patients with culture-confirmed recurrent melioidosis for whom paired isolates (from the primary and recurrent episode) were available. 14 recurrent cases (48%) were defined as relapse, and 15 recurrent cases (52%) were defined as re-infection. Median time to relapse  was shorter than median time to re-infection .vs 1·70). In this analysis, 14 patients (5%) given TMP-SMX plus placebo and 24 patients (8%) given TMP-SMX plus doxycycline died during the study period , we excluded 15 patients who developed genotype confirmed re-infection and eight patients who did not have paired isolates for genotyping . These rOur findings suggest that TMP-SMX is not inferior to TMP-SMX plus doxycycline as an oral treatment for melioidosis. Fewer patients given TMP-SMX plus placebo had adverse drug reactions or switched to the second-line regimen compared with those given TMP-SMX plus doxycycline. These findings provide the evidence for a change to the recommended oral regimen for melioidosis to TMP-SMX alone.vs 25%).The probability of having culture-confirmed recurrent melioidosis within 1 year of enrolment into the study (3%) was lower than that seen in another trial (6%),B pseudomallei that belongs to the same genotype as that causing the primary infection is low because the genetic diversity of B pseudomallei strains in soil and water is high.Findings from our bacterial genotyping analysis showed that half of recurrent infection was due to relapse, with the remainder being due to re-infection. This finding contrasts with the findings of a retrospective study of 921 patients with melioidosis over an 8 year period, in which 74% of recurrent infections 80 of 116) were due to relapse and 26% (30 of 116) were due to re-infection. were dueB pseudomallei isolates were not available for genotyping, and that non-inferiority was not shown in a sensitivity analysis. We also acknowledge that CLSI do not provide criteria for the interpretation of disc diffusion and Etest assays for B pseudomallei,Although our study, to the best of our knowledge, is the largest randomised controlled trial to compare two drug regimens for the oral treatment of melioidosis and the first to use a non-inferiority design, it has several potential limitations. The first relates to the non-inferiority margin (HR 1·7), which was selected by the scientific committee on the basis of a balance between trial feasibility (completion within 4 years) and statistical robustness. Some investigators have suggested the adoption of a larger non-inferiority margin (HR 2·0), but we considered it unacceptable to adopt a new regimen that could actually have two times the risk of recurrent culture-confirmed melioidosis than the current standard. Some investigators have also suggested the adoption of a smaller non-inferiority margin (HR 1·5), but this would have required an 8 year study period with a sample size of 1200 patients, which we thought to be unfeasible. The scientific committee agreed that an upper boundary of the 95% CI of a HR that was equal to or less than 1·7 would be sufficient to change clinical practice to the use of TMP-SMX alone for oral treatment of melioidosis. Additional limitations were that 11 patients who died at home of unknown cause might have died from recurrent melioidosis, that eight (21%) of 37 paired In this study, we also assessed the efficacy of TMP-SMX over TMP-SMX plus doxycycline for culture-confirmed relapse. The results from a sensitivity analysis were very similar to the main analysis, except that the lower bound of the 95% CI for the HR for culture-confirmed relapse was slightly greater than the non-inferiority margin. This finding is mainly because the study was not powered to assess the non-inferiority based on this outcome in the sensitivity analysis. Therefore, we would suggest that these potential limitations are unlikely to have affected the conclusions of the study.PanelSystematic reviewWe searched PubMed for randomised controlled trials that assessed oral antimicrobial treatment for melioidosis published in English between Jan 1, 1921, and Dec 31, 2012, using the following MeSH terms  AND “trial”. We searched bibliographies from selected studies for secondary references. We identified four randomised controlled trials  are used in clinical practice. Our trial shows that TMP-SMX alone is not inferior to TMP-SMX plus doxycycline, and we propose that TMP-SMX alone should be used on the basis of safety and patient tolerance.Having established that TMP-SMX is preferable to TMP-SMX and doxycycline for the oral phase of melioidosis treatment , the nex


We describe seven children with somatotropinoma with a special focus on the differences between genetic and sporadic forms.Somatotropinoma, a pituitary adenoma characterised by excessive production of growth hormone (GH), is extremely rare in childhood. A genetic defect is evident in some cases; known genetic changes include: multiple endocrine neoplasia type 1  analogues or transsphenoidal surgery. Control was defined as when insulin-like growth factor-1 (IGF-1) levels were within the normal range for the patient's age at 6 months after therapy, associated with decreasing tumour volume.Patients were aged 5-17 years and the majority (n = 6) were male. Four patients had an identified genetic mutation ; the remaining three cases were sporadic. Accelerated growth rate was reported as the first clinical sign in four patients. Five patients presented with macroadenoma; invasion was noted in four of them . Six patients were treated with SMS analogues; normalisation of IGF-1 occurred in one patient who had a sporadic intrasellar macroadenoma. Multiple types of therapy were necessary in all patients with an identified genetic mutation , whereas two of the three patients with sporadic somatotropinoma required only one type of therapy.This is the first series that analyzes the therapeutic response of somatotropinoma in paediatric patients with identified genetic defects. We found that, in children, genetic somatotropinomas are more invasive than sporadic somatotropinomas. Furthermore, SMS analogues appear to be less effective for treating genetic somatotropinoma than sporadic somatotropinoma. Somatotropinoma is a pituitary adenoma characterised by excessive production of growth hormone (GH) from the pituitary gland . In adulGenetic defects have been recently identified in some somatotropinoma cases. These defects include multiple neoplasia syndromes, including the multiple endocrine neoplasia type 1 (MEN1) ,5, the CAll children (n = 7) with a GH-secreting pituitary adenoma that was diagnosed before 18 years of age in three hospitals in France  were included in this analysis. One case was diagnosed in 1992 (when the patient was six years of age), and the other six cases were diagnosed between 2005 and 2008. We excluded patients with GH-independent gigantism, such as Beckwith-Wiedemann syndrome or Sotos syndrome, and patients with GH-releasing hormone secreting tumours.A diagnosis of excessive production of GH was established by a high level of serum GH over 24 hours, not suppressible to <1 μg/L, 180 minutes after a 75 g oral glucose tolerance test, or a high insulin-like growth factor-1 (IGF-1) level for the patient's age.Magnetic resonance imaging (MRI) was performed in six cases; images were analysed by the same radiologists. Invasiveness on MRI was assessed using the Hardy-Vezina classification . TumoursSerum GH levels were measured by radioimmunometric assay calibrated to the WHO 98/574 standard. Before 1995, the GH assay (for one patient) was performed using a polyclonal antibody kit.Serum IGF-1 levels were measured using the IGF-1 RIACT kit . Results were presented as standard deviation (SD), adjusted for sex, age and pubertal stage. Prolactin was measured by radioimmunometric assay calibrated on 84/500 standard. Other hormones of the pituitary axis were also studied.Somatostatin (SMS) analogues or transsphenoidal surgery were the first-type treatment, depending on each patient's clinical evolution and criteria. Patients received long-acting octreotide (10-30 mg) or lanreotide (30-120 mg), managed by the patient's clinician, according to IGF-1 level and growth curve. Patients also received cabergoline at a dose of 0.5 mg once to three times weekly.Control was defined as when IGF-1 was within the normal range for the patient's age at six months after therapy, associated with a decreasing tumour volume of more than 30%. SMS analogue resistance was defined in the present study as an IGF-1 level of more than +2 SD at six months when receiving the maximum dose of octreotide or lanreotide.Baseline clinical characteristics for the seven patients are presented in Table Four patients  presented for a clinical consultation because of accelerated growth.  and patient 7 (presenting with a sporadic microadenoma). Patient 7 was cured but patient 2, with MEN1 and an invasive macroadenoma, remained uncontrolled despite multiple types of treatment  as second-type therapy in combination with SMS analogues. One of these patients required no further therapy, while the other (who had McCune-Albright syndrome) was switched to pegvisomant, which successfully reduced IGF-1 levels to -1 SD, consistent with the literature ,29.In adults, genetic forms of somatotropinoma are more difficult to control than sporadic forms. In a study of adult patients with pituitary adenomas, Verges et al. observed a normalization of pituitary hypersecretion in 90% of patients with sporadic adenomas and 42% of patients with MEN1 genetic alterations ; in thatSomatotropinomas in children and adolescents are rare and more aggressive than those seen in adults. In this small series of patients, genetic somatotropinomas were more invasive than sporadic somatotropinomas. Our data suggest that SMS analogues, while effective in sporadic somatotropinoma, are less effective in genetic somatotropinoma. Further research on the incidence and types of genetic mutations in children and adolescents with somatotropinoma is necessary to increase our understanding of the disease. In addition, studies of different therapeutic options in genetic somatotropinoma would provide more information about why SMS analogues are less effective in these patients, and allow for the development of new treatment strategies in this setting.The authors declare that they have no competing interests.inScience Communications (a Wolters Kluwer business). All authors read and approved the final manuscript.CR-R, CD, PB: each of them provided data from a patient. YM measured and analyzed IGF-1 and prolactin levels. FB-C provided data from three patients and managed this work. MN provided data from a patient and managed this work. CN collected and analyzed all data and wrote this paper with the assistance of Claire Byrne of


Despite their limited licensed indications, anti-IL1 agents are often used in real-life practice for an increasing number of diseases. A national survey to record their off-label use in France was started in January 2011. The survey is coordinated by the French National Reference Centre for Auto-Inflammatory Diseases, under the aegis of the “Club Rhumatisme et Inflammation” (CRI).The survey aims at gathering information concerning: the number of patients treated with anti-IL1 agents in France, the treated disease, the kind and the indication of the used anti-IL1 agents, their efficacy and safety.We set up a physician-directed questionnaire available on the website of CRI since January 2011 to December 2012, covering the following areas: patient data, disease data, anti-IL1 agent, its efficacy, adverse events.We advertised the study on the occasion of French rheumatology congresses and by email to French physicians that could be interested.Any adult or paediatric patient who had received an anti-IL1 agent before January 2005 in France could be included.At present 94 patients from 19 centres have been included. Main diseases were: anakinra-treated CAPS (18), SoJIA (17), AoSD (15), gout (10), MKD (9), FMF (6), Schnitzler’s syndrome (5).The main off-label used agent (data known for 72 patients) was anakinra, used at least once in 66 patients. Canakinumab was used in 15 patients. Rilonacept is not yet available in France.Data gathering on off-label use of anti-IL1 agents is ongoing in France, with a good response from physicians providing information from everyday practice.The survey results might justify controlled clinical trials leading to widen the licensed indications for this class of therapeutics.


Drosophila X chromosome is a well-established phenomenon, thought to be specifically linked to the role of these genes in reproduction and/or their expression in the meiotic male germline. In particular, meiotic sex chromosome inactivation (MSCI) has been widely considered a driving force behind depletion of spermatocyte-biased X-linked genes in Drosophila by analogy with mammals, even though the existence of global MCSI in Drosophila has not been proven.Paucity of male-biased genes on the X-linked and autosomal genes, with both showing transcriptional activation concomitant with meiosis. However, the genes showing at least ten-fold expression bias toward testis are significantly underrepresented on the X chromosome. Intriguingly, the genes with similar expression bias toward tissues other than testis, even those not apparently associated with reproduction, are also strongly underrepresented on the X. Bioinformatics analysis shows that while tissue-specific genes often bind silencing-associated factors in embryonic and cultured cells, this trend is less prominent for the X-linked genes.Microarray-based study and qRT-PCR analyses show that the dynamics of gene expression during testis development are very similar between X chromosome does not occur in Drosophila. Paucity of testis-biased genes on the X appears not to be linked to reproduction or germline-specific events, but rather reflects a general underrepresentation of tissue-biased genes on this chromosome. Our analyses suggest that the activation/repression switch mechanisms that probably orchestrate the highly-biased expression of tissue-specific genes are generally not efficient on the X chromosome. This effect, probably caused by dosage compensation counteracting repression of the X-linked genes, may be the cause of the exodus of highly tissue-biased genes to the autosomes.Our data show that the global meiotic inactivation of the  X chromosome to autosomes via retroposition is a major trend conserved between different taxa [X-linked genes in the male germline [X-linked genes that function specifically in the MSCI-affected male germline cells, namely spermatocytes. Indeed, spermatocyte-specific genes are severely underrepresented on the X chromosome in mice, illustrating the proposed role of MSCI in genome evolution. In contrast, the male-specific genes expressed at either earlier or later stages of spermatogenesis (that is in spermatogonia or in round spermatids) are over-represented on the mouse X chromosome [X-linked genes proposed previously [Traffic of the newly-created testis-specific genes from the ent taxa -3. In magermline . This prromosome ,6, consieviously .X-linked genes in spermatocytes of Drosophila are not conclusive. In flies, similar to mammals, spermatocytes rapidly proceed through the S-phase and enter extended prophase I of meiosis, which lasts several days . The prosophila . The ove of MSCI ,10-14. Hferences . The finpression  further l stages . Howevergermline . Howevergermline  present X-linked genes in flies is due to MSCI or other novel, yet unknown mechanism(s). To determine whether the expression of X-linked genes changes concomitant with meiosis, we performed a study of the testis transcriptome in larval development, tracing the maturation of the first wave of spermatocytes through the third instar and up to the meiotic divisions at the beginning of pupation [X-linked genes steadily increased during spermatocyte maturation as expected, global gene expression on the X chromosome did not significantly differ from the autosomes throughout the entire period - both results being consistent with the lack of global MSCI. Further, we found that the paucity of testis-biased genes is not a unique example and that other tissue-biased genes are also underrepresented on the X chromosome, indicative of this trend not being limited to the reproduction-related genes. Our analyses suggest that the paucity of X-linked tissue-specific genes may be driven by the general inefficiency of stringent tissue-specific gene regulation on the X chromosome.In order to understand better the genome evolution and structure, and to obtain further insight into the tissue-specific gene expression, it is important to determine whether the paucity of male-biased pupation . In thisX chromosome, as has been shown in mammals [Drosophila, the vast majority of the testis-specific genes analyzed to date are activated in primary spermatocytes, that is in the meiotic prophase I [X-linked genes deviate from this trend, we quantitatively analyzed the transcription of eight previously characterized testis-biased X-linked genes in larval testis development, using real-time RT-PCR. In parallel, 18 autosomal testis-biased genes were analyzed as a reference group  through day seven Figure , dL, at s Figure . We furted genes  and founromosome , given tansgenes  do not aX-linked genes, we analyzed the global trends of X-linked gene expression during testis development using gene microarrays. To improve the resolution of the analysis, we cultured larvae at a lower temperature (18°C) and collected testes from feeding larvae at fourth, fifth, sixth and seventh days of development , and from wandering larvae at days seven and ten, just before the onset of pupation at days 11 to 12 . Throughout larval testis development, we did not find appreciable differences in expression between the X chromosome and autosomes  or any substantial reduction in X-linked gene expression   served as the reference. Chromatin protein binding was assessed as the fold enrichment in chromatin immunoprecipitation or in DNA adenine methyltransferase identification experiments [o, D1, and Polycomb (Pc) and Pc group proteins esc and Sce [Based on our analyses, we suggest that the eriments ,31. We h and Sce ,32-38. I and Sce -41. ThesX chromosome and autosomes. For this analysis, we calculated the relative enrichment with chromatin proteins for the genes that show more than two-fold expression bias toward testis, midgut, accessory gland, salivary gland, malpigian tubule, and ovary. The tissue expression bias was determined using the same approach as described above for the analysis of tissue-biased gene frequencies on chromosomes. Using arbitrarily-set thresholds to define the categories of bound versus non-bound genes for each of the analyzed chromatin proteins [X chromosome and autosomes and normalized them to the frequencies of bound genes in the entire genome. The study included nine repressor proteins and eight activators that showed the strongest 'inverse' correlations in previous analysis. The resulting graphs  or autosomal (blue bars) genes bind repressors or activators in embryos and cultured cells with a frequency different from the genome average (defined as 1.0).We inquired whether the tissue-biased gene activation generally correlates with binding of repressor proteins in the 'non-target' embryonic and cultured cells, and whether such correlation differs between the proteins ,31, we ds Figure  show wheX-linked genes this trend is reduced for the vast majority of the analyzed proteins and even reversed for three repressors and five activators  model [X chromosome causing its inactivation in meiotic cells, with the one exception that no true global X inactivation is seen, just the lack of testis-biased genes on the X. However, a recent study indicates that retroposing genes with diverse expression biases all show an affinity toward autosomes [X, previously considered as the major indirect evidence for MSCI in flies [X [X chromosome. Taking into account the recent report that somatic gene expression may be regulated by gonads [X chromosome, involves genes that have no apparent specific role in reproduction.Our findings could be consistent with the sexual antagonism driving I) model , in whicutosomes ; therefoin flies , is not flies [X , but they gonads , we inquy gonads  was founX is provided by the finding that the genes with the highest bias are affected much more than the genes with modest expression differences , and could result in a strong selective pressure toward relocation of the highly tissue-biased genes to the autosomes.Of the two components of the activation/repression switch, the repression may be vulnerable to the ic cells . To testic cells ,46 expecic cells  and a reic cells . We propWild type (Oregon) larvae were grown on yeast-molasses media at 18°C. At the specified time points larvae were collected, and testes harvested using manual dissection. Further analyses utilized samples pooled from at least 30 larvae.rp49 transcripts served as template loading reference.Total RNA was isolated from dissected testes with Trizol reagent , and cDNA synthesized from 1 μg RNA samples using oligo(dT) primer and SuperScript II reverse transcriptase (Invitrogen). Real-time PCR was performed in the iCycler iQ5 instrument  using SYBR Green chemistry; Total RNA was isolated from testes with Trizol reagent (Invitrogen), and further purified with the RNeasy kit . Poly(A)+ RNA was selectively amplified from 0.5 to 1 μg total RNA samples with the BD SMART cDNA Synthesis kit and the BD Advantage 2 PCR Enzyme System . Amplified cDNAs were cleaned with the Wizard SV Gel kit . cDNA samples of 3.5 to 4.5 μg were labeled with the ULYSIS Alexa Fluor 546 or Alexa Fluor 647  dyes according to the manufacturer's protocol, and used for competitive hybridization with microarrays.Drosophila oligonucleotide microarray set (Qiagen-Operon) was printed on aminosilane-coated slides at Tufts-New England Medical Center Expression Array Core facility (TEAC). The set contains 14,593 70-mer oligonucleotides representing 13,664 genes which cover most of genes in release 3.2 of the Drosophila genome . The probe sequences from the Operon set were re-mapped to Drosophila genome release 5.1 using BLAST, and probes with multiple hits or ambiguous mapping were excluded from subsequent analysis. Additional information on the Drosophila oligonucleotide set can be found at the manufacturer's website http://www.operon.com. Details of the array design can be found at ArrayExpress (array design Operon AROS D. melanogaster v.1.1). Labeled pairs of samples were hybridized in 1 × hybridization buffer , 20% formamide, and 0.025% each of Ficoll, polyvinylpyrrolidone, Na pyrophosphate, and heparin. Samples were incubated with microarrays for 44 hours at 37°C. After hybridization slides were washed, dried by centrifugation, and scanned on the ScanArray 4000 scanner .The limma [Fluorescence intensities of individual spots were acquired from the array images with ImaGene software (BioDiscovery). Subsequent normalization and statistical analysis were performed with package limma ,50, partlimma . Normalilimma . q < 0.1Drosophila chromosomes was performed with the web-based tool GeneMerge . Signif.umd.edu/. The sigMSCI: meiotic sex chromosome inactivation; qRT-PCR: reverse transcription followed with quantitative polymerase chain reaction analysis; FDR: false discovery rate.DIN designed research; LMM performed research; LMM and DIN analyzed data; and DIN wrote the paper. All authors read and approved the final manuscript.


Human cerebral spinal fluid (CSF) is known to be a rich source of small molecule biomarkers for neurological and neurodegenerative diseases. In 2007, we conducted a comprehensive metabolomic study and performed a detailed literature review on metabolites that could be detected (via metabolomics or other techniques) in CSF. A total of 308 detectable metabolites were identified, of which only 23% were shown to be routinely identifiable or quantifiable with the metabolomics technologies available at that time. The continuing advancement in analytical technologies along with the growing interest in CSF metabolomics has led us to re-visit the human CSF metabolome and to re-assess both its size and the level of coverage than can be achieved with today's technologies.We used five analytical platforms, including nuclear magnetic resonance (NMR), gas chromatography-mass spectrometry (GC-MS), liquid chromatography-mass spectrometry (LC-MS), direct flow injection-mass spectrometry (DFI-MS/MS) and inductively coupled plasma-mass spectrometry (ICP-MS) to perform quantitative metabolomics on multiple human CSF samples. This experimental work was complemented with an extensive literature review to acquire additional information on reported CSF compounds, their concentrations and their disease associations.NMR, GC-MS and LC-MS methods allowed the identification and quantification of 70 CSF metabolites (as previously reported). DFI-MS/MS allowed the quantification of 78 metabolites , while ICP-MS provided quantitative results for 33 metal ions in CSF. Literature analysis led to the identification of 57 more metabolites. In total, 476 compounds have now been confirmed to exist in human CSF.The use of improved metabolomic and other analytical techniques has led to a 54% increase in the known size of the human CSF metabolome over the past 5 years. Commonly available metabolomic methods, when combined, can now routinely identify and quantify 36% of the 'detectable' human CSF metabolome. Our experimental works measured 78 new metabolites that, as per our knowledge, have not been reported to be present in human CSF. An updated CSF metabolome database containing the complete set of 476 human CSF compounds, their concentrations, related literature references and links to their known disease associations is freely available at the CSF metabolome database. There is a growing need among the metabolomics and clinical communities to develop comprehensive, centralized reference resources for clinically important biofluids such as cerebrospinal fluid, blood, urine and saliva. In this regard, we have undertaken the task to systematically characterize each of these biofluids as part of the human metabolome project . The firAt the time it was first published, the CSF metabolome database consisted of a total of 308 detectable metabolites, with extensive information on compound names, structures, identifiers, concentrations, related literature references and links to known disease associations. In that CSF study , we alsoHere we wish to report the results of this work, including the use of five different metabolomic platforms (nuclear magnetic resonance (NMR), gas chromatography-mass spectrometry (GC-MS), liquid chromatography-mass spectrometry (LC-MS), direct flow injection-mass spectrometry (DFI-MS/MS) and inductively coupled plasma-mass spectrometry (ICP-MS)) to characterize multiple CSF samples as well as an extensive literature review (covering the period from 2008 to 2011) aimed at identifying and tabulating new (or previously unidentified) CSF metabolites along with new or updated CSF metabolite biomarkers. All of these data, along with their concentrations, related literature references and links to their known disease associations are freely available at the CSF metabolome database [Lumbar CSF samples were collected from patients screened for meningitis in accordance with guidelines and consent protocols established by the University of Alberta Research Ethics Board  and confA more detailed list describing the patient population is shown in Table 1H-NMR spectra were collected on 500 μl CSF samples at 25°C (via the first transient of the tnnoesy-presaturation pulse sequence) using a 500 MHz Inova  spectrometer equipped with a 5 mm Z-gradient PFG Varian cold-probe. All 1H-NMR spectra were baseline corrected and analyzed using the Chenomx NMR Suite Professional software package version 6.1 . All GC-MS data were acquired on an HP 6890/5975 GC/MS equipped with a DB-5 column. N-methyl-N-(trimethylsilyl) trifluoroacetamide (MSTFA) derivatized extracts were prepared from 200 μl of CSF using standard methods [Identical procedures using identical instruments, as described in , were em methods  in conju methods , and qua methods .IDQ™ kit). The kit is a commercially available assay from Biocrates Life Sciences AG , and it was originally validated for plasma samples. Recently, the kit has been optimized for the analysis of human CSF [In addition to characterizing CSF using NMR, GC-MS and LC-FTMS, we also employed a targeted quantitative metabolomics approach using direct flow injection mass spectrometry  mass spectrometer. A standard flow injection protocol consisting of two 20 μl injections (one for the positive and one for the negative ion detection mode) was applied for all measurements. MRM detection was used for quantification. MetIQ software, which is proprietary to Biocrates and included in the kit, was used to control the entire assay workflow. This included sample registration to automated calculation of metabolite concentrations to the export of data into other data analysis programs.The Absolute3. Elemental concentrations were determined on a Perkin-Elmer Sciex Elan 6000 quadrupole ICP-MS operating in a dual detector mode . Blank subtraction was applied after internal standard correction. A four point calibration curve was used to quantify compounds . The sample uptake rate was approximately 1 ml/minute with 35 sweeps per reading using one reading per replicate and three replicates. Dwell times were 10 to 20 ms for all elements with the exception of As (which was 100 ms). The relative standard deviation (2σ level) for As, Ni, Pb, and Zn was between 5 and 10%. The accuracy of the ICP-MS analytical protocol was periodically evaluated via the analysis of certified reference standard materials (whole rock powders) BE-N and DR-N available from the SARM laboratory at the CRPG (Centre de Recherches Pétrographiques et Géologiques).For elemental  analysis by ICP-MS, seven CSF samples were processed as described previously . In partIn addition to the experimental analysis of the CSF metabolome described above, a comprehensive literature review, covering the past 4 years (2008 to 2011) was performed to look at known or newly discovered CSF metabolites and metabolite concentrations. An in-house text-mining tool, which was originally developed for the Human Metabolome Database , was use1H-NMR spectrum and high resolution GC-MS total ion chromatogram are shown in Figures A total of 53 metabolites were identified (47 quantified) by NMR, 41 metabolites were identified (15 quantified) by GC-MS, and LC-MS permitted the identification of 17 metabolites. A total of 70 non-redundant CSF metabolites were identified (62 quantified) using these three platforms. No additional metabolites beyond those originally reported in [IDQ™ kit permits the measurement of 162 metabolites , 15 lyso-phosphatidylcholines and 15 sphingolipids). From these 162 potentially detectable metabolites, quantitative results were obtained for 78 metabolites . These results are summarized in Table The Biocrates AbsoluteOf the 78 metabolites quantified by DFI-MS/MS, 11 compounds (10 amino acids and hexose/glucose) were also measurable using NMR and/or GC-MS. The measured concentrations for these common compounds on all three platforms showed very good agreement (within 15 to 30% of each other). More importantly, the DFI-MS/MS method provided quantitative data on 67 unique compounds that GC-MS, LC-MS and NMR methods could not detect. It is important to note, however, that DFI-MS/MS generates phospholipid data (PCs) that only identifies PCs by their total acyl/alkyl chain content  rather than their precise chemical structure. These 42 PC 'species' along with their concentrations are entered in our CSF metabolome database. In addition, each PC species is linked to a list of the most probable PC structures  based on the known fatty acid compositions in humans.Trace metals are known to play an important role in enzyme function and a wide number of neurodegenerative diseases like Alzheimer's disease, Parkinson's disease and other related diseases . A new tIn the present paper, the metal ion composition of seven CSF samples was measured by using ICP-MS. ICP-MS is widely regarded as one of the best techniques for the characterization of the elemental composition of biological samples. This method was able to provide quantitative results for 33 metals or trace elements, as shown in Table Our literature review allowed us to identify another 57 metabolites that had not been previously archived in the human CSF metabolome database. Furthermore, the literature review also allowed us to update, correct and add more than 500 new concentration ranges or averages. Additionally, dozens of new disease-metabolite associations were also identified and many older disease-metabolite associations were also updated. A total of 229 disease-metabolite associations are listed in the CSF database. In many cases, multiple concentration values are given for 'normal' conditions, in order to provide the users/readers with a better estimate of the potential concentration variations obtained by different technologies or laboratories. In general, there is good agreement between most laboratories and methods.The 2008 version of the human CSF metabolome contained 308 fully identified and quantified metabolites [The main objective of this study was to advance the fields of quantitative metabolomics and global metabolic profiling to facilitate future CSF research. The updated CSF metabolome database currently contains 476 detectable metabolites. Our experimental works measured 78 new metabolites that, as per our knowledge, have not been reported to be present in human CSF. This is not a number that will remain unchanged. As technology improves, it is most likely that this number will continue to increase. However, this current set of 476 metabolites appears to provide a reasonably complete listing of the compounds that can be detected and quantified (with today's technology) in the human CSF metabolome.CSF: cerebral spinal fluid; DFI-MS/MS: direct flow injection-mass spectrometry; FTMS: Fourier transform mass spectrometry; GC-MS: gas chromatography-mass spectrometry; ICP-MS: inductively coupled plasma-mass spectrometry; LC-MS: liquid chromatography-mass spectrometry; PC: phosphatidylcholine; MRM: multiple reaction monitoring; NMR: nuclear magnetic resonance; UPLC: ultra performance liquid chromatography.The authors declare that they have no competing interests.DSW conceived the project, designed the study and wrote/revised the manuscript; RM designed the experiments, contributed to experiments and data analysis, and wrote/revised the manuscript; ACG constructed the CSF metabolome database and revised the manuscript; KKC, PL, FSY, ED and FA assisted in laboratory experiments and in the CSF metabolome database construction. All authors have read and approved this manuscript for publication.


Non-adherence to anti tuberculosis treatment is one of the crucial challenges in improving tuberculosis cure-rates and reducing further healthcare costs. The poor adherence to anti-tuberculosis treatment among patients with tuberculosis is a major problem in Ethiopia. Hence, this study assessed level of non-adherence to anti-tuberculosis therapy and associated factors among patients with tuberculosis in northwest Ethiopia.An institution based cross-sectional survey was conducted among tuberculosis patients who were following anti-tuberculosis treatment in North Gondar zone from February 20 – March 30, 2013. Data were collected by trained data collectors using a structured and pre-tested questionnaire. Data were entered to EPI INFO version 3.5.3 and analyzed using statistical package for social sciences (SPSS) version 20. Multiple logistic regressions were fitted to identify associations and to control potential confounding variables. Odds ratio (OR) with 95% confidence interval was calculated and p-values<0.05 were considered statistically significant.), is on the continuation phase of chemotherapy , had symptoms of tuberculosis during the interview , and had co-infection with HIV .A total of 280 tuberculosis patients were interviewed; 55.7% were males and nearly three quarters (72.5%) were urban dwellers. The overall non-adherence for the last one month and the last four days before the survey were 10% and 13.6% respectively. Non-adherence was high if the patients had forgetfulness (AOR 7.04, 95% CI 1.40–35.13Non-adherence to anti-tuberculosis treatment was high. Forgetfulness, being in the continuation phases of chemotherapy, having symptoms of tuberculosis during the interview, and co-infected with HIV were significantly associated with non-adherence to anti-tuberculosis therapy. Special attention on adherence counseling should be given to symptomatic patients, TB/HIV co-infected patients, and those in the continuation phase of the tuberculosis therapy. Tuberculosis (TB), one of the oldest diseases known to affect humans, is a major cause of death worldwide. It usually affects the lungs, although other organs are involved in up to one-third of the cases. If left untreated, 50–65% of TB cases will die within 5 years th in the list of high TB burden countries. In Ethiopia, TB is the leading cause of morbidity, the third cause of hospital admission, and the second cause of death. The estimated TB incidence in Ethiopia was 261/ 100,000 inhabitants in 2011. The lifetime risk of developing TB in Ethiopia is estimated to be 50–60% for HIV-infected people, only 10% for HIV-negative counterparts According to recent estimates, Ethiopia stands 7Poor adherence to treatment of chronic diseases including TB is a worldwide problem of striking magnitude The study was conducted in the North Gondar zone, northwest Ethiopia. The zone has 22 districts with a total population of 2,921,470. All health facilities providing anti-TB services in three major towns of north Gondar  were included. Newly diagnosed TB patients receive six months of standard TB chemotherapy in two phases- an intensive phase for two months and a continuation phase of four months. A fixed dose combination of RHZE  is given in the intensive phase of anti-TB therapy while only RH during the continuation phase. Patients collect anti-TB drugs daily during the intensive phase except weekends while weekly or monthly during the continuation phase. Provider initiated voluntary counseling and testing for HIV infection was also offered currently to all TB patients.An institution based cross-sectional survey was conducted from February 20 – March 30, 2013. Eligible patients were new TB patients aged at least 15 years regardless of the site or the smear status of their TB. To be eligible for this study, patients must have also taken anti-TB at least for a month.The sample size was calculated using a single population proportion formula; considering 21% proportion of non- adherence level according to previous similar study from southwest Ethiopia (16), a 5% margin of error, and 10% possible non-response rate. The sample size was estimated to be 281. All adult TB patients (≥15 years old) on anti-TB at tuberculosis follow up clinics in the three  towns within the study period were interviewed.Data were collected using an interviewer-administered questionnaire. The questionnaire was composed of socio-demographic characteristics, patient related; therapy or drug related information, social and health system /health provider related variables and pre-tested before the actual data collection. Data were collected after verbal informed consent was obtained. Six nurses who were trained for this purpose collected the data. Data collectors were also not part of the health facilities where TB patients interviewed.Recent non- adherence (last 4 days) and non-adherence during the last one month before the survey were assessed. Patients were asked to report the total number of anti-TB pills they missed 4 days before the survey. These numbers of pills were compared to the number of pills prescribed to the patient. Adherence to TB medication in the last 4 days was classified as non-adherent (missed at least 1 (25%) of the pills prescribed over 4 days) and completely adherent (no missed pill in the last 4 days before the survey). Similarly, the last one month non-adherence was calculated as total reported missed pills over the total prescribed pills within that month and classified as adherent (no more than 10% of pills missed) and otherwise non- adherent. Patients were also asked to report why they missed anti-TB drugs. A patient who scores three or more than three from a six item questions asked to measure TB knowledge were considered to have good knowledge about TB. These questions were obtained from information routinely provided to patients as part of the national TB program.Data were entered to EPI INFO version 3.5.3 and analysis was conducted using statistical package for social sciences (SPSS) version 20. Descriptive statistics like frequencies and cross tabulation were made for most selected variables. Multiple logistic regression analysis was used to assess the association between the dependent variable and each independent variable. Variables with p-values ≤0.2 in bivariate analysis were fitted in the final multiple logistic regression model to assess the strength of association and control confounding effects. Both Crude Odds Ratio (COR) and Adjusted Odds Ratio (AOR) with 95% confidence interval (CI) were used to show an association between selected variables. Variables having p-value ≤0.05 in the final model were taken as significant determinants.The ethical clearance was obtained from the Institutional Review Board of the University of Gondar. The Institutional Review Board approved the oral informed consent since it was anticipated that many of the study subjects could not read and write. In addition to this, the Institutional Review Board approved all ethical procedures, based on the awareness about the type of study (that it was harmless to study subjects) and the education level of study subjects. An official permission letter was obtained from each health facility administration office. During data collection, oral informed consent was obtained from all participants after they were introduced to the purpose of the study and informed about their rights to interrupt the interview at any time. To ensure confidentiality, names were avoided in the questionnaire and reporting the results of the study. In addition, the collected information was locked with a key (hard copies) and by passwords (soft copies). Informed oral consent was also obtained from parents or guardians for subjects under 18 years old.A total of 280 TB patients (with a response rate of 99.6%) were interviewed. Nearly three quarters (72.5%) were urban dwellers and had a mean age of 32.9 (±14.8 SD) years. About half of them (50.4%) did not attend any formal education and nearly one fifth of them were farmers. Amhara (98.2%) and Orthodox Christianity (89.6%) were the most common ethnicity and religion respectively .The overall calculated non-adherence over one month and the last four days before the survey were 10% and 13.6% respectively. Forgetfulness (34%), vomiting (24%) and traveling to other places (17%) were the most frequent reasons for missing the anti-TB pills .About 6% of TB patients reported that they had a problem of forgetfulness. Almost all (98.9%) participants had good knowledge about TB but 3.6% of participants reported they had stopped taking their medication without telling their health care provider because they felt worse when they took it. Similarly, 3.6% of participants reported that they stopped taking their anti-TB medication when they felt better. About 6% of participants were substance users.Ninety five percent of TB patients walked to and from the health facilities and 26.8% of participants reported that it took them more than half an hour to reach the nearby health facility providing them the anti-TB drugs. Nearly half of participants (54.3%) reported that the health workers were very friendly to them.Most of TB patients (97.1%) in the current study disclosed their illness to their relatives and most (75%) of those who had not disclosed were due to fear of stigma. The rest had no relatives with whom to share their problem. About one in eight (12.9%) participants visited quacks  while they were taking their chemotherapy .A significant proportion of TB patients (38.9%) reported some kind of anti-TB medication adverse effects. Three quarters (75.2%) and 37% of participants complained of minor adverse effects such as urine discolorations and headache or dizziness, respectively. Most patients (87.5%) were naive for anti-TB medication. Almost all (97.5%) of the TB patients were screened for HIV and nearly one quarter (23.4%) of them were positive .In the bivariate analysis, forgetfulness, phases of chemotherapy, symptoms of TB during the interview, HIV co-infection, experience of drug side-effects, visiting quacks, and taking additional drugs other than anti-TB were significantly associated with anti-TB treatment non-adherence.However, in the adjusted analysis, forgetfulness, phases of chemotherapy, symptoms of TB during the interview and HIV co-infection were remained significantly and independently associated with anti-TB medication non-adherence. Those patients who had a problem of forgetfulness were seven times more likely to be non-adherent than their counterparts . TB patients who were in the continuation phases of chemotherapy were seven times  more likely to be non-adherent to anti-TB medications. In addition to this, patients who had symptoms of TB during the interview  and had co-infection with HIV  were also at higher risk of non-adherence than those who were non-symptomatic during the interview and HIV sero-negatives respectively .Adherence to anti-TB treatment is a major determinant of treatment outcome. In developing countries where inequities in access to health care are high and health resources are scarce the magnitude and impact of poor adherence is assumed to be higher. It is undeniable that many patients experience difficulties in following treatment recommendations Though a self-reported level of non-adherence is assumed to be under-estimated, a high proportion (10%) of non-adherence in the last one month before the survey was found in this study. Similarly, a higher proportion of non-adherence (13.6%) in the four days prior to the survey was reported. This finding is more than twice that reported from Kenya (4.8%).However, the present non-adherence over one month was lower than the previous reports from Southern Ethiopia (20.8%), Uganda (25%), Kolkata, India (40.5%), and the Jiangsu Province of China (12.2%) In the adjusted analysis; forgetfulness, being in continuation phases of chemotherapy, having symptoms of TB during the interview, and HIV co-infection were significantly associated with anti-TB medication non-adherence. Those TB patients who were in the continuation phase of the chemotherapy were about seven times more likely to be non-adherent than those who were in the intensive/directly observed treatment short-course strategy (DOTS). However, it is believed that DOTS with daily supervision is a difficult task for most patients and in particular HIV co-infected patients who needed to attend the clinics for ART. It is also believed that DOTS is too rigid a strategy TB patients who were symptomatic during the interview were much more likely to be non-adherent than those who did not have symptoms of TB during the interview. Under normal circumstances patients whose TB symptoms were resolved quickly may be urged to leave treatment once they started feeling better. However, in this study the opposite was true. Patients may remain symptomatic as a result of their poor adherence. On the other hand, patients who remain symptomatic while sticking to treatment may be disappointed and intentionally miss their pills. However, a study conducted in Kolkata, India declared that the urge to leave treatment once patient started feeling better was a significant determinant of non-adherence to anti-TB medication The proportion of HIV co-infection among TB patients was 23.4%. About 69% of these patients were on ART. In this study, HIV co-infected TB patients were less likely to be adherent to their anti-TB medications. HIV/AIDS co-infected patients have many pills to take and the adverse effects of anti-TB medication are more common for HIV co-infected patients As previously reported from other studies However, previously confirmed factors like distance from a health facility, transportation cost, relationship with health worker, and proper counseling were not associated with non-adherence in this study. Currently, in Ethiopia, TB treatment is being provided freely at the community, grass root level. However, some patients still questioned the accessibility of TB related services. Furthermore, most TB patients had good relationship with their health care provider (99.3%). In general adherence is a dynamic issue and barriers are also liable to change over time, which necessitates continuation of multi-disciplinary collaborative researches. Finally, this study shares the limitations of cross-sectional studies and hence it might suffer from temporal relationship establishment with some variables and might not provide much stronger evidence of causality. In addition to this, this study only addressed a self-reported level of non-adherence and it might be under-estimated.Non-adherence among TB patients was high. Forgetfulness, being in continuation phases of chemotherapy, having symptoms of TB during the interview, and HIV co-infection were significantly associated with anti-TB medication non-adherence. Thus, special attention and adherence counseling should be given for those who remained symptomatic, those who are co-infected with HIV, and those in the continuation phase of the chemotherapy. Further research is also recommended since the issue of adherence is dynamic.


Socio-economically disadvantaged women are at a greater risk of spending excess time engaged in television viewing, a behavior linked to several adverse health outcomes. However, the factors which explain socio-economic differences in television viewing are unknown. This study aimed to investigate the contribution of intrapersonal, social and environmental factors to mediating socio-economic  inequalities in women's television viewing.Cross-sectional data were provided by 1,554 women (aged 18-65) who participated in the 'Socio-economic Status and Activity in Women study' of 2004. Based on an ecological framework, women self-reported their socio-economic position (highest education level), television viewing, as well as a number of potential intrapersonal , social  and physical activity environmental factors .Multiple mediating analyses showed that two intrapersonal factors (enjoyment of television viewing and weight status) and two social factors  partly explained the educational inequalities in women's television viewing. No physical activity environmental factors mediated educational variations in television viewing.Acknowledging the cross-sectional nature of this study, these findings suggest that health promotion interventions aimed at reducing educational inequalities in television viewing should focus on intrapersonal and social strategies, particularly providing enjoyable alternatives to television viewing, weight-loss/management information, increasing social cohesion in the neighborhood and promoting friend support for activity. Sedentary behavior, defined as sitting behaviors that are performed at or slightly above the resting metabolic rate 1-1.5 METS) -1.5 METS, with teNo previous studies have investigated mediators of socio-economic inequalities in television viewing among adults. Although research is limited, influences on adults' sedentary behavior, in particular television viewing, can be described in terms of intra-personal, social, and physical environmental factors, following the socio-ecological framework of human behavior . Intra-pGiven that the extent to which these intrapersonal, social and physical environmental factors vary across socio-economic groups, and whether these variations explain socio-economic differences in television viewing, are unknown, the aim of this study was to examine the role of several intra-personal, social and physical environmental factors in mediating socio-economic  inequalities in women's television viewing.The present analyses were based on cross-sectional survey data collected from 1,554 women (aged 18-65) in 2004. Details of methods and recruitment are described in detail elsewhere ,23 and sParticipants were recruited from 45 Melbourne suburbs with varying levels of socio-economic disadvantage, based on the Australian Bureau of Statistics SEIFA - Socio-economic Index for Areas . FifteenThe study was approved by the Deakin University Human Research Committee. Surveys were posted out to the selected women. Following the Dilman protocol , non-resHighest educational level was used as an indicator of individual socio-economic position. This was categorised as either 'no formal qualifications/up to year 10', 'year 12/trade/apprenticeship/certificate/diploma', or 'university degree/higher degree'. Education level has been argued as being a suitable proxy for socioeconomic position for women, since it overcomes issues relating to the instability of markers such as occupation and income that typically fluctuate for women who move in and out of the workforce during childrearing years .Participants were asked to estimate the number of hours and minutes they spent sitting watching television on a usual weekday, as well as a weekend day (in the past seven days). This measure has been found to have typical validity for similar self-report measures   and has Five potential intra-personal mediators were assessed. Enjoyment of television viewing was assessed using a modified scale   were within walking distance from home . Perceived distance to physical activity facilities  was assessed using a 10-item measure in which participants were asked to indicate whether a variety of places to be active were walking distance from home . The number of 'yes' responses for both the perceived distance to places of interest (ICC = 0.97) and perceived distance to physical activity facilities (ICC = 0.83) were summed and analyzed as two continuous variables.Marital status and children living at home were included in single and multiple mediating analyses as potentially confounding factors, since these were bivariately associated with television viewing (i.e. being married and having children living at home were associated with lower levels of television viewing). Other variables that were tested but found not to be associated with the outcome variable included long-term illness/injury, age, employment status and country of birth.Cases were excluded where they did not contain complete independent or dependent variables for the specific analyses of interest. Variables with missing data included; Television viewing (1.2%), education (1.7%), enjoyment of television viewing (12%), stress (1.7%), preference for leisure-time sedentary behavior (2.5%), weight status (6.4%), depressive symptoms (7.9%), social cohesion (2.4%), interpersonal trust (2.1%), social participation (4.9%), family support (11.8%), friend support (9.4%), safety (3.2%), aesthetics (2.3%), distance to places of interest (2.9%), distance to physical activity facilities (39.2%), marital status (1.4%), children (0.0%).Analyses were performed using STATA version 11.0. Descriptive and unilevel analyses were used to examine the distributions of, and bivariate associations between, television viewing, demographic, education and mediator variables. MacKinnon's product of coefficients test of statistical mediation was used since it has been suggested that this method has greater statistical power than other commonly-used mediating methods . The disTable The mean duration per week of time spent sitting watching television was just under 21 hours . Education was inversely associated with women's television viewing (regression coefficient (τ) = -0.48; 95% CI = -0.62, -0.33). Table Social cohesion, social participation and social support from friends to be physically active were significant mediators of educational variations in television viewing. Interpersonal trust and social support from family to be physically active were not significant mediators of educational variations in television viewing. Furthermore, no physical environmental factors were found to be significant mediators of educational variations in television viewing.Table To our knowledge, this is the first study to examine the role of intra-personal, social and physical environmental factors in explaining socio-economic differences in sedentary behavior (i.e. television viewing) amongst women. Consistent with previous literature, education was inversely associated with television viewing in women ,41, emphThe current study suggested that less educated women were more likely to enjoy sedentary behavior in leisure-time, and this may explain their greater engagement in television viewing. Although the relationship between education and enjoyment of television viewing has not been assessed previously, similar trends have been found in the physical activity literature . For exaThe relationship between education and television viewing was also partly mediated by women's weight status. Consistent with a substantial body of research, it was found that less educated women were more likely to be overweight or obese than women with higher levels of education ,42 and tThe current study provides support for the inverse association between social cohesion and television viewing -46, indiSocial support provided by friends for physical activity was found to partly mediate the relationship between education and women's television viewing. Consistent with previous research , women tLimitations of the current study include the cross-sectional design, which does not allow for causality or the direction of relationships to be determined. Self-report measures were used to assess television viewing as well as potential mediating factors. Although valid and reliable measures were used where possible, recall difficulties, error in judgment and socially desirable responses potentially limit the results. Further, the sample only included women and therefore it is not known as to whether the results of this study are generalizable to men. However, a major strength of this study is the consideration of multiple intra-personal, social and physical environmental mediators, which encompassed the constructs of the social ecological model . MoreoveSince there is already a large pool of evidence relating to the relationship between education and physical activity, this study was novel as it focussed on the relationship between education and sedentary behaviour (i.e. television viewing), a group of behaviours recognised as being distinct from physical activity. The current study provided findings that suggest that focussing on intra-personal and social factors may be important in reducing the educational inequalities in women's television viewing. However, further studies including additional mediators are required to confirm these findings and to understand the reasons behind these educational differences. Providing enjoyable alternatives to television viewing, weight-loss/management information, increasing social cohesion in the neighborhood as well as friend support for activity amongst less educated women may be important strategies to reduce the educational inequalities in women's television viewing.The authors declare that they have no competing interests.MT performed the analyses and led the writing of the manuscript. KB conceived of the study, participated in the design, the survey development and helped to draft the manuscript. JS contributed to the survey questionnaire and helped to draft the manuscript. All authors read and approved the final manuscript.


We analyzed our long-term experience with fractionated stereotactic radiotherapy (FSRT) in patients with meningioma of the optic nerve sheath (ONSM).Between January 1991 and January 2010, 40 patients with ONSM were treated using FSRT. Of these, 19 patients received radiotherapy as primary treatment, and 21 patients were treated after surgical resection. The median target volume was 9.2 ml, median total dose was 54 Gy in median single fractions of 1,8 Gy.Local progression-free survival was 100%. Median survival after FSRT was 60 months (range 4-228 months). In all patients overall toleration of FSRT was very good. Acute toxicity was mild. Prior to RT, 29 patients complained about any kind of visual impairment including visual field deficits, diplopia or amaurosis. Prior surgical resection was identified as a negative prognostic factor for visual outcome, whereas patients with larger tumor volumes demonstrated a higher number of patients with improvement of pre-existing visual deficits.Long-term outcome after FSRT for ONSM shows improved vision in patients not treated surgically prior to RT; moreover, the best improvement of visual deficits are observed in patients with larger target volumes. The absence of tumor recurrences supports that FSRT is a strong alternative to surgical resection especially in small tumors without extensive compression of normal tissue structures Treatment of primary optic nerve sheath meningiomas (ONSM) remains a challenge in the interdisciplinary team of surgeons, opthalmologists and radiation oncologists. They are located directly adjacent to the optic nerve which is sensitive to any treatment damage, including radiation or surgical procedures. They arise from meningothelial cap cells of arachniod villi which surround the optical nerve within the orbit or within the intracanalicular part of the optic nerve.In general, menigiomas are slow growing tumors with an annual incidence of 6 per 100,000; most patients remain without any clinical symptoms over very long periods of time. ONSM are a rare subtype accounting for 2% of all meningiomas, but they represent the second most frequent optic nerve tumors . InitialFor treatment of ONSM, surgical resection can be of choice for certain cases, especially for large tumors leading to intraorbital pressure and compression; for asymptomatic patients, however, also a wait-and-see strategy might be followed, and patients with remaining useful vision and no tumor progression have been observed in the past .One main risk associated with surgery is the often inevitable dissection of the vascular supply of the nerve, which leads to severe visual impairment in about 95% of the patients . There hModern photon radiation techniques such Fractionated Stereotactic Radiotherapy (FSRT) have been established in clinical routine enabling the delivery of highly conformal doses with steep dose gradients to normal tissue. With these techniques, precise treatment of malignant and non-malignant target lesions in close vicinity to organs at risk is possible. For ONSM, several groups have reported excellent clinical outcome with low rates of side effects, however, in small series with only short or mid-term follow-up ,9-12,16.In the present analysis we report our long-term results a large patient group with ONSM treated with FSRT. Special focus is set on the evaluation of prognostic factors as well as long-term preservation of quality of life.Forty consecutive patients with ONSM treated with FSRT between January 1991 and January 2010 at the Department of Radiation Oncology and the Germany Cancer Research Center (dkfz) in Heidelberg, Germany, were included into this analysis.Patients were followed prospectively. Additionally, we sent out a detailed questionnaire to all patients asking about recent neurological status including cranial nerve deficits, side effects after treatment during follow-up, additional treatments for ONSM, quality of life prior to and after FSRT as well as any improvement in pre-existing sequelae. This questionnaire was returned in 32 out of the 40 patients (80%).The median age at the time of radiotherapy was 44 years (range 17-83 years). The tumor manifestation was on the right eye in 16 patients and on the left eye in 23 patients. In one patient both eyes were affected. The female to male ratio was about 2:1 . Patients' characteristics are summarized in table For 19 patients treatment was recommended as primary treatment, and 21 were treated after surgical resection. Of these, 12 were treated for tumor progression of progressive clinical symptoms during follow up. In 9 patients, RT had been conducted immediately postoperatively. From those who underwent previous surgery all had been initially diagnosed with benign WHO Grade I meningiomas.The median time between surgical resection and radiation therapy was 43 months.The median period between surgery and RT was 3 months (range 1-7 months) for those treated immediately postoperatively, and a median of 56 months (range 2-132 months) for those treated for progression of ONSM after surgical resection.® mask; this mask allows an overall positioning accuracy of 1-2 mm. With the mask fixed to the stereotactic base frame, contrast-enhanced CT and MRI scans were performed for treatment planning. For patients without prior histological confirmation, an additional PET using 68Ga-DOTATOC was performed as reported previously [All patients were treated with FSRT. For treatment planning, patients were fixed with a custom-made Scotch casteviously ,18 to su® software developed at the German Cancer Research Center (dkfz) or the STP software . Three to four non-coplanar isocentric fields irregularly shaped with a micro-multileaf collimator were used. The median dose to the PTV was 54 Gy (range 25-66 Gy) in fractions of 1.8 - 5 Gy. None of the patients received concomitant chemotherapy.We defined the macroscopic lesion visible on contrast-enhanced MRI as the gross tumor volume (GTV), adding 1-2 mm safety margin for the planning target volume (PTV). The median PTV was 9.2 ml. Radiotherapy planning for FSRT was performed using the VoxelplanAll photon plans were delivered using a 6 MeV linear accelerator The median follow-up time was 60 months (range from 4 - 228 months). All patients were seen on regular intervals for clinical follow-up, as well as for MR-imaging. The first follow-up examination was scheduled 6 weeks after completion of RT, then in three months intervals for the first year. Thereafter, yearly follow-up visits were scheduled. Clinical examination included thorough neurological assessment and visual assessment through fomal opthalmologis assessment by the opthalmologist. Other examinations, such as endocrinological evaluation, were scheduled depending on the dose distribution of the treatment plan as well as on a clinical basis. Progression-free survival was determined based on the RECIST criteria evaluating two orthogonal diameters of the lesion. Tumor progression was determined by an increase in tumor size of more than 35%  or any increase in tumor size on subsequent imaging examinations. Overall survival was calculated from the date of the first diagnosis to the last follow-up or death (by any cause). Survival after irradiation was calculated from initiation of irradiation. Progression-free survival was calculated from the first day of irradiation until tumor progression or death , whichever occurred first, using the Kaplan-Meier method. Influence on prognostic factors on outcome was assessed using the univariate Cox proportional regression model. Statistical analyses were performed with the software program Statistica 6.1 .During follow-up, no patient developed imaging-defined progression of the ONSM after FSRT. Therefore, local progression-free survival was 100% at a median follow-up time of 60 months (range 4-228 months).Survival was 93% at 5 years after FSRT, all deaths were non-related to the ONSM.In all patients overall toleration of FSRT was very good. Acute toxicity was mild. Most patients experienced local alopecia restricted to small regions. Fatigue was a common complaint of one fifth of the 40 patients. Two patients presented with xerophthalmia, and on patient developed acute conjunctivitis during treatment. During short-term follow up, one patient complained of new headaches, and three of recurrent hyperlacrimation of the irradiated eye, one with change of taste perception. None of the patients developed dysfunctions of the pituitary gland, neuropathy, retinopathy or brain necrosis. One patient complained of scotoma and visual disorder during FSRT, which receded completely after application of steroids. However, after termination of steroid medication, symptoms returned; the ONSM was removed surgically 6 months after completion of FSRT. In this patient, a dose of 52.2 Gy had been applied, in single doses of 1.8 Gy.Prior to RT, 29 patients complained about any kind of visual impairment including visual field deficits, diplopia or amaurosis . In the surgery group, 3 patients showed improvement (20%), whereas in the RT-only group 9 patients showed symptom improvement during follow up  may lead to a major decompression , improvement in visual impairment caused by tumor compression or more likely after FSRT.This can be supported by the effect of tumor size on visual outcome: Additionally, our study revealed that patients with larger tumor volumes and thus larger treatment volumes for radiation demonstrate higher rates of improvement with respect to visual function, most likely since these symptoms originate from tumor mass effect declining after FSRT. However, in total, results are based on a limited number of patients, and no formal randomized clincial trial was performed to compare different treatment modalities.In conclusion, FSRT can achieve long-term control of ONSM without high-rates of treatment related side effects. Patients treated with prior surgical resection show reduced improvement of visual function, supporting the idea that surgery might be better reserved for large tumors with major compression and subsequent clinical symptoms, such as exophthalmia. For tumors with compression and acute symptomas surgery must be evaluated. Doses of 50-55 Gy in normofractionated regimens show safety even after long-term follow-up. Novel concepts evaluating hypofractionated regimens are currently under investigation, but should be applied cauteously within clinical trials to safely assess toxicity.The authors declare that they have no competing interests.SC, JD and SR treated the patients. SA, SR and SC collected the data. SC and SA evaluated the dataset and performed statistical analysis. SC, SA, SR, TW and JD wrote and edited the manuscript. All authors read and approved the manuscript.