The case for a national survey of eating disorders in Australia.

In this Commentary we outline the case for a national survey of eating disorders in Australia. Given the recent focus of the federal government to provide further funding for mental health research, we call for a national survey to be made a key priority. Such high-quality, nationally representative data are critically important to informing all other domains of eating disorders research in the Australian context, and to informing the research agenda internationally.

Fear of Negative Evaluation and Weight/Shape Concerns among Adolescents: The Moderating Effects of Gender and Weight Status.

Fear of negative evaluation has been linked with weight/shape concerns among adults, however, similar research among adolescents is lacking. We investigated the relationship between fear of negative evaluation and weight/shape concerns, including the moderating roles of gender and body mass index (BMI) in adolescents. Participant were 4045 Australian adolescents (53.7% girls) aged 11-19 years (Mage = 14 years 11 months), who completed a self-report questionnaire about weight/shape concerns, fear of negative evaluation, and weight and height. Results showed a positive association between fear of negative evaluation and weight/shape concerns, with the association being stronger among girls. Furthermore, the association between fear of negative evaluation and weight/shape concerns was stronger among adolescents with higher BMIs, especially so for boys. These results highlight the role of fear of negative evaluation in weight/shape concerns and suggest potential avenues for prevention programs.

How abnormal is binge eating? 18-Year time trends in population prevalence and burden.

OBJECTIVE: Although findings suggest that binge eating is becoming increasingly normative, the 'clinical significance' of this behaviour at a population level remains uncertain. We aimed to assess the time trends in binge-eating prevalence and burden over 18 years. METHOD: Six cross-sectional face-to-face surveys of the Australian adult population were conducted in 1998, 2005, 2008, 2009, 2014, and 2015 (Ntotal = 15 126). Data were collected on demographics, 3-month prevalence of objective binge eating (OBE), health-related quality of life, days out of role, and distress related to OBE. RESULTS: The prevalence of OBE increased six-fold from 1998 (2.7%) to 2015 (13.0%). Health-related quality of life associated with OBE improved from 1998 to 2015, where it more closely approximated population norms. Days out of role remained higher among participants who reported OBE, although decreased over time. Half of participants who reported weekly (56.6%) and twice-weekly (47.1%) OBE reported that they were not distressed by this behaviour. However, the presence of distress related to OBE in 2015 was associated with greater health-related quality-of-life impairment. CONCLUSION: As the prevalence of binge eating increases over time, associated disability has been decreasing. Implications for the diagnosis of disorders associated with binge eating are discussed.

Prevalence of obesity and comorbid eating disorder behaviors in South Australia from 1995 to 2015.

BACKGROUND: Obesity and eating disorders are often studied and treated separately. While the increases in obesity prevalence are well known, examination of its co-occurrence with eating disorders, a problem also of public health concern, is important because eating disorder behaviors are known to contribute to obesity onset and maintenance, and vice versa. METHODS: Data from large cross-sectional representative statewide community samples of people in the years of 1995 (n=3001), 2005 (n=3047) and 2015 (n=3005) were analyzed. Data were collected using a structured, self-report interview that included demographic, health-related, weight, height and eating disorder behavior questions. Eating behavior questions assessed binge eating, very strict dieting/fasting and purging, and were derived from the Eating Disorder Examination. Logistic regression analyses were conducted comparing prevalence of obesity, eating disorder behaviors and their co-occurrence. RESULTS: The prevalence of obesity or binge eating, or obesity with comorbid binge eating, each increased significantly from 1995 to 2005 (P<0.001 for each comparison) and continued to increase significantly from 2005 to 2015 (P<0.001 for each comparison). The highest increases from 1995 to 2015 were in the prevalence of obesity with comorbid binge eating (7.3-fold), or obesity with comorbid very strict dieting/fasting (11.5-fold). The prevalence of very strict dieting/fasting also increased significantly from 1995 to 2015 (3.8-fold). The prevalence of purging, or obesity with comorbid purging, did not change significantly from 1995 to 2015. CONCLUSION: There were statewide increases during the 20 years from 1995 to 2015 in the independent prevalence of obesity, binge eating and very strict dieting/fasting, and even higher increases in the prevalence of obesity with comorbid binge eating, and obesity with comorbid very strict dieting/fasting. These findings support the need for more integrated approaches to both the prevention and treatment of obesity and eating disorder behaviors, namely binge eating and very strict dieting/fasting.

A randomised Phase II trial to evaluate the toxicity of high-dose rifampicin to treat pulmonary tuberculosis.

SETTING: Randomised Phase IIB clinical trial. OBJECTIVES: To assess whether increasing the dose of rifampicin (RMP) from 10 mg/kg to 15 or 20 mg/kg results in an increase in grade 3 or 4 hepatic adverse events and/or serious adverse events (SAE). METHODS: Three hundred human immunodeficiency virus negative patients with newly diagnosed microscopy-positive pulmonary tuberculosis (TB) were randomly assigned to one of three regimens: 1) the control regimen (R10), comprising daily ethambutol (EMB), isoniazid (INH), RMP and pyrazinamide for 8 weeks, followed by INH and RMP daily for 18 weeks; 2) Study Regimen 1 (R15), as above, with the RMP dose increased to 15 mg/kg body weight daily for the first 16 weeks; and 3) Study Regimen 2 (R20), as above, with RMP increased to 20 mg/kg. Serum alanine transferase (ALT) levels were measured at regular intervals. RESULTS: There were seven grade 3 increases in ALT levels, 1/100 (1%) among R10 arm patients, 2/100 (2%) in the R15 arm and 4/100 (4%) in the R20 arm (trend test P = 0.15). One (R15) patient developed jaundice, requiring treatment modification. There were no grade 4 ALT increases. There was a non-significant increase in culture negativity at 8 weeks with increasing RMP dosage: 75% (69/92) in R10, 82.5% (66/80) in R15 and 83.1% (76/91) R20 patients (P = 0.16). CONCLUSIONS: No significant increase in adverse events occurred when the RMP dose was increased from 10 mg/kg to 15 mg/kg or 20 mg/kg.

Spray Dried Aerosol Particles of Pyrazinoic Acid Salts for Tuberculosis Therapy. [Corrected].

Tuberculosis is the most serious infectious disease caused by a single organism, Mycobacterium tuberculosis (Mtb). The standard of care is a protracted and complex drug treatment regimen made more complicated and of longer duration by the incidence of multiple and extensively drug resistant disease. Pulmonary delivery of aerosols as a supplement to the existing regimen offers the advantage of delivering high local drug doses to the initial site of infection and most prominent organ system involved in disease. Pyrazinamide is used in combination with other drugs to treat tuberculosis. It is postulated that the action of pyrazinoic acid (POA), the active moiety of pyrazinamide, may be enhanced by local pH adjustment, when presented as a salt form. POA was prepared as leucine (POA-leu) and ammonium salts (POA-NH4), spray dried, and characterized in terms of physicochemical properties (melting point, crystallinity, moisture content), aerodynamic performance (aerodynamic particle size distribution, emitted dose), and in vitro inhibitory effect on two mycobacteria (Mtb and Mycobacterium bovis). Particles were prepared in sizes suitable for inhalation (3.3 and 5.4 µm mass median aerodynamic diameter and 61 and 40% of the aerodynamic particle size distribution less than 4.46 µm, as measured by inertial impaction, for POA-leu and POA-NH4, respectively) and with properties (stoichiometric 1:1 ratio of salt to drug, melting points at ∼180 °C, with water content of <1%) that would support further development as an inhaled dosage form. In addition, POA salts demonstrated greater potency in inhibiting mycobacterial growth compared with POA alone, which is promising for therapy.

Self-reported history of anorexia nervosa and current quality of life: findings from a community-based study.

PURPOSE: To evaluate the impact of a lifetime history of anorexia nervosa (AN) on current quality of life (QoL) and eating disorder (ED) symptomatology. METHOD: 3,034 participants from a randomly selected sample of households in the Australian population were interviewed for current ED symptoms and QoL (SF-36). RESULTS: 89 participants (2.9 %) reported a history of AN, 73 of whom were female. These participants scored lower on six of the eight subscales on the SF-36, including all of the mental health subscales, and were more likely to report binge eating and extreme weight or shape concerns than participants who did not report a history of AN. On the other hand, participants who reported a history of AN were less likely to be overweight. None of the participants who reported a history of AN met current criteria for AN; however, one met criteria for bulimia nervosa non-purging subtype and four met criteria for binge eating disorder. The endorsement of current ED symptoms was found to moderate the impact of a history of AN on scores of the social functioning and role limitations due to emotional health SF-36 subscales, such that participants who reported a history of AN scored lower on these subscales if they also reported current ED symptoms. CONCLUSIONS: A history of AN has a deleterious impact on current QoL, despite remittance from the disorder. This may be explained in part by the presence of certain ED symptoms, including objective binge eating and the persistence of extreme weight and shape concerns.

Pharmacokinetic/pharmacodynamic parameters and the choice of high-dosage rifamycins.

SETTING: Clinical trials and the behaviour of bacterial persisters. OBJECTIVE: To explain why the efficacies of isoniazid (INH) and rifamycins during the treatment of tuberculosis (TB) are related not to the area under the curve (AUC)/minimum inhibitory concentration (MIC), but to peak drug concentrations. DESIGN: We examined the response in clinical trials with patients treated with INH alone and divided into slow and rapid acetylators of INH. RESULTS: The efficacy of INH is best related to peak concentrations, as repeated peaks can kill low-degree resistant mutants. A similar process might result in repeated peak concentrations of rifamycins killing low-tolerance persisters. CONCLUSIONS: If the efficacy of rifamycins is best related to peak concentrations, we can explain the discrepancy between mouse studies on daily rifapentine (RPT) and the failure to accelerate elimination of TB from sputum in the TBTC Study 29A, as daily RPT greatly increases the AUC but not the peak concentrations. High dosage rifampicin may be better able than RPT to cause high peaks.

The chemotherapy of tuberculosis: past, present and future.

The history of the development of modern chemotherapy for tuberculosis (TB), largely due to the British Medical Research Council, is first described. There is a current need to shorten the duration of treatment and to prevent and cure drug-resistant disease. These aims will only be achieved if the way in which multidrug treatment prevents resistance from emerging and the reasons for the very slow response to chemotherapy are understood. Consideration of mutation rates to resistance and the size of bacterial populations in lesions makes it very unlikely that resistance would emerge spontaneously, leaving irregularity in drug taking and inadequate dosage as the main reasons for its occurrence. Slow response to treatment seems due to the presence of persister populations whose natural history is only partly known. In the future, we need to explore the persister state in patients and in experimental murine TB, and to take it into account in the design of future mouse experiments. The activity of rifamycins and pyrazinamide is being increased by a rise in rifamycin dosage and the inhalation of pyrazinoic acid. New drugs are gradually being brought into use, initially TMC207 and the nitroimadazoles, PA824 and OPC67683. They will need to be tested in new combination regimens for drug-susceptible and multi- and extensively drug-resistant disease.

Prognostic communication preferences of migrant patients and their relatives.

OBJECTIVES: Migrant patients comprise a significant proportion of Western oncologists' clientele. Although previous research has found that barriers exist in the communication between ethnically diverse patients and health professionals, little is known about their personal preferences for communication and information, or the concordance of views held between patients and family members. METHODS: Seventy-three patients (31 Anglo-Australians, and 20 Chinese, 11 Arabic and 11 Greek migrants) and 65 relatives (25 Anglo-Australians, and 23 Chinese, 11 Arabic and 7 Greek migrants) were recruited through nine Sydney oncology clinics. Following prognostic consultations, participants were interviewed in their preferred language about their experiences and ideals regarding information and communication with oncologists. Interviews were audio-taped, translated and transcribed, and then thematically analysed using N-Vivo software. RESULTS: Consistency was found in patient preferences, regardless of ethnicity, in that almost all patients preferred prognostic information to be delivered in a caring and personalised manner from an authoritative oncologist. Contrary to previous research, migrant patients often expressed a desire for prognostic disclosure. Discordance was found between migrant patients and their families. These families displayed traditional non-Western preferences of non-disclosure of prognosis and wanted to actively influence consultations by meeting with oncologists separately beforehand and directing the oncologists on what and how information should be conveyed to patients. CONCLUSIONS: Many of the communication issues facing patients in the metastatic cancer setting are shared amongst Anglo-Australian and migrant patients alike. Understanding the dynamics within migrant families is also an important component in providing culturally sensitive communication. Future directions for research are provided.

Moxifloxacin and pyrazinamide susceptibility testing in a complex case of multidrug-resistant tuberculosis.

Multidrug-resistant tuberculosis (MDR-TB) is a public health problem of global concern. It is critical that drug susceptibility testing (DST) methods accurately predict clinical response. We present a patient with a challenging case of MDR-TB with additional resistance to quinolones and pyrazinamide. Treatment with a regimen including high-dosage moxifloxacin, based on additional genotypic and phenotypic DST, produced excellent results. This case highlights the possibility of treatment with high-dose fluoroquinolones despite apparent bacterial resistance to these agents. Improved DST methods are necessary for both agents. Development of genotypic approaches may offer a susceptibility profile rapidly, enabling early introduction of individualised treatments.

The near future: improving the activity of rifamycins and pyrazinamide.

While we wait for improved new anti-tuberculosis drugs, the main aim for improving current treatment should be to optimize the use of the two current drugs, rifampicin and the pro-drug pyrazinamide, which are responsible to a similar extent for the entire sterilizing activity of current therapy. The rifamycin activity could be improved by increasing the dose size of rifampicin or by daily dosing with long acting rifapentine. Increasing the dose size of pyrazinamide is limited by toxicity but an alternative approach is to use inhalation with pyrazinoic acid, as an adjunct to standard oral therapy. This would acidify pulmonary lesions, thus increasing the bactericidal activity of the orally administered pyrazinamide. Because pyrazinoic acid is the active moiety, it should also increase overall pyrazinamide activity and, because most resistance arises in the pncA gene that converts pyrazinamide to pyrazinoic acid, it should act on most pyrazinamide resistant strains. Inhalation technology allows delivery of drug to lesions rapidly and without first pass toxicity. The properties of drug containing microparticles and nanoparticles during inhalation and storage are reviewed. Spray-dried larger Trojan particles in which the smaller encapsulated particles can reside should be able to improve localisation within alveoli and avoid some storage problems.

Timing of relapse in short-course chemotherapy trials for tuberculosis.

We have reviewed the results from 15 tuberculosis treatment trials initiated by the British Medical Research Council between 1970 and 1983 in Africa and East Asia. Of 574 relapses, 447 (78%) occurred within 6 months of stopping treatment and 525 (91%) within 12 months. We suggest that investigators should consider terminating follow-up after the last enrolled patient completes 6 months following treatment, while continuing to follow patients enrolled earlier until that time. Compared to following all patients to 24 months, the total trial duration could be reduced by 18 months, with no increase in patient numbers in a non-inferiority design.

Bactericidal activity of moxifloxacin on exponential and stationary phase cultures of Mycobacterium tuberculosis.

The bactericidal activity of moxifloxacin, alone and in combination with isoniazid and rifampin, was studied on exponential and stationary phase cultures of Mycobacterium tuberculosis H37 Rv strain, the standard strain which is a wild type of M. tuberculosis strain, not exposed to any environment, susceptible to all anti-tuberculosis drugs. Moxifloxacin alone was highly bactericidal, being intermediate in activity between isoniazid and rifampin on both types of culture. The speed of activity was slow with the stationary phase culture, causing a reduction from 6.41 log(10)cfu/ml to 2.70 log(10)cfu/ml on day 6 with the higher moxifloxacin concentration of 4 microg/ml and to 4.08 log(10)cfu/ml with the lower concentration of 0.25 microg/ml. When added to isoniazid, its activity against both exponential and stationary phase cultures was increased. However, when it was added to rifampin, no increase in activity was found with either type of culture. Addition of moxifloxacin to isoniazid and rifampin resulted in a slight increase in activity against the exponential culture but a considerable increase against the stationary culture with counts below the limit of detection at 4 and 6 days with both moxifloxacin concentrations. The synergism found with isoniazid, but not with rifampin, supports the view that isoniazid should be included in combinations with moxifloxacin during the therapy of pulmonary tuberculosis.

A Phase II study of the sterilising activities of ofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis.

SETTING: Current treatment for pulmonary tuberculosis (TB) might be shortened by the incorporation of fluoroquinolones (FQs). OBJECTIVES: A Phase II study aimed to assess the sterilising activities of three novel regimens containing FQs before a Phase III trial of a 4-month regimen containing gatifloxacin (GFX). DESIGN: A total of 217 newly diagnosed smear-positive patients were randomly allocated to one of four regimens: isoniazid (INH), pyrazinamide and rifampicin (RMP) with either ethambutol, GFX, moxifloxacin (MFX) or ofloxacin (OFX) for 2 months. At the end of the study, RMP and INH were given for 4 months. The rates of elimination of Mycobacterium tuberculosis were compared in the regimens using non-linear mixed effects modelling of the serial sputum colony counts (SSCC) during the first 8 weeks. RESULTS: After adjustment for covariates, MFX substitution appeared superior during the early phase of a bi-exponential fall in colony counts, but significant and similar acceleration of bacillary elimination during the late phase occurred with both GFX and MFX (P = 0.002). Substitution of OFX had no effect. These findings were supported by estimates of time to conversion, using Cox regression, but there were no significant differences in proportions culture-negative at 8 weeks. CONCLUSIONS: GFX and MFX improve the sterilising activity of regimens and might shorten treatment; their progression into Phase III trials therefore seems warranted.

Comparison of the sterilising activities of the nitroimidazopyran PA-824 and moxifloxacin against persisting Mycobacterium tuberculosis.

OBJECTIVES: To measure the bactericidal activity of the nitroimidazopyran PA-824 against Mycobacterium tuberculosis, strain H37Rv, in the three Hu/Coates models of bacterial persistence, in comparison with the activity of moxifloxacin (MXF), a drug shown to be likely to shorten treatment in current clinical trials. METHODS: The bactericidal activity of a wide range of PA-824 and MXF concentrations was tested against a 100-day static, starved, anaerobically-adapted culture in Model 1. In Models 2 and 3, rifampicin (RMP) 100 mg/ml was added to the 100-day culture for 5-7 days and bactericidal activities against surviving tolerant bacilli were tested by addition of the test drugs after removal of RMP in Model 2, and during exposure to RMP in Model 3. RESULTS AND DISCUSSION: PA-824 exhibited little bactericidal activity at low concentrations up to 1.25 microg/ml in each of these models, but high concentrations of >or=10 microg/ml showed considerable bactericidal activity, sufficient to kill all bacilli in Model 3, and appreciably greater than with MXF. However, as PA-824 is 94% plasma bound, concentrations of free drug sufficient to reach the zone of high bactericidal activity may not be obtained in cavities of pulmonary tuberculosis.

Clinical development of anti-tuberculosis drugs.

In the clinical development of new anti-tuberculosis drugs, the most important step is efficient Phase II studies to show whether the drug is likely to be able to shorten treatment and with what other drugs it has the greatest sterilizing activity. The use of non-linear mixed effects modelling applied to serial sputum cfu counts appears to be the most effective technique, but we know little about the optimal design of such novel studies. A paper in the current journal reports on the relative efficiencies of various timing patterns in sampling sputum.