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The diagnostic boundaries of social anxiety disorder (SAD) are still controversial and recent evidence suggests that the condition could be better understood as a continuum of severity, rather than a strictly circumscribed entity. Current neuroanatomical theories on SAD support the involvement of limbic structures in its pathophysiology, with an emphasis on the amygdala. Thus, the objective of this study was to investigate the hypothesis of volumetric alterations in the amygdala of subjects in different points of the social anxiety spectrum.
The sample consisted of patients with generalized SAD (n=17), subthreshold SAD (increased social anxiety without avoidance; n=13), and healthy controls (n=15). Participants underwent structural magnetic resonance scans and the volume of the bilateral amygdala was manually determined.
Significantly greater volumes of bilateral amygdala were found in socially anxious individuals. Amygdala volumes of subthreshold SAD participants fell between the values found for generalized SAD and healthy controls.
Individuals suffering from SAD have greater amygdala volumes compared to controls and this difference seems to be in agreement with the theoretical conception of SAD as a severity continuum and not as a circumscribed nosological entity.
Postgraduate medical trainees experience high rates of burnout, but evidence regarding psychiatric trainees is missing. We aim to determine burnout rates among psychiatric trainees, and identify individual, educational and work-related factors associated with severe burnout.
In an online survey psychiatric trainees from 22 countries were asked to complete the Maslach Burnout Inventory (MBI-GS) and provide information on individual, educational and work-related parameters. Linear mixed models were used to predict the MBI-GS scores, and a generalized linear mixed model to predict severe burnout.
This is the largest study on burnout and training conditions among psychiatric trainees to date. Complete data were obtained from 1980 out of 7625 approached trainees (26%; range 17.8–65.6%). Participants were 31.9 (SD 5.3) years old with 2.8 (SD 1.9) years of training. Severe burnout was found in 726 (36.7%) trainees. The risk was higher for trainees who were younger (P < 0.001), without children (P = 0.010), and had not opted for psychiatry as a first career choice (P = 0.043). After adjustment for socio-demographic characteristics, years in training and country differences in burnout, severe burnout remained associated with long working hours (P < 0.001), lack of supervision (P < 0.001), and not having regular time to rest (P = 0.001). Main findings were replicated in a sensitivity analysis with countries with response rate above 50%.
Besides previously described risk factors such as working hours and younger age, this is the first evidence of negative influence of lack of supervision and not opting for psychiatry as a first career choice on trainees’ burnout.
Recent evidences have consistently reported lower glutamate (Glu) levels in various brain regions, including the medial prefrontal cortex (mPFC), in chronic schizophrenia but findings in the early (EP) or in the prodromal phase of the disorder are equivocal. Although regular cannabis use has been associated with an increased risk of subsequent psychosis and with a perturbed Glu signalling, to date, the critical question of whether or not Glu abnormalities exist in EP and are related to cannabis use remains unanswered. Magnetic resonance spectroscopy was used to measure [GlumPFC] of 35 EP subjects (18 of whom were regular cannabis users) and 33 healthy controls (HC). For correlative analysis, neuropsychological performances were scored by a comprehensive cognitive battery. [GlumPFC] was lower in EP users comparing to both HC and EP non-users (P = 0.001 and P = 0.01, respectively), while no differences were observed between HC and EP non-users. In EP users Glu declined with age (r = −0.46; P = 0.04) but this relationship was not observed in non-users. Among neuropsychological profiles, working memory was the only domain that differentiates patients depending on their cannabis use, with users having poorer performances. In summary, our research revealed that cannabis use in EP is associated with Glu decreased levels, which are normally not seen in the early phase of the disorder. This finding is in line with previous 1H-MRS studies in cannabis users without a psychotic disorder and sheds light for the role of cannabis use in the progression of the disease.
Disclosure of interest
The authors have not supplied their declaration of competing interest.
Although the onset of bipolar disorder (BD) is usually estimated in early adulthood (Burke et al., 1990; Kessler et al., 1997), it is still not clear which age-specific triggering factors may contribute to the underlying vulnerability.
The present meta-analysis attempts to clarify the number of untreated years of BD, from first symptoms appearance, to first actions carried out by health services (first diagnosis, treatment and hospitalization).
A literature search of three databases PubMed, Web of Science and Psychology and Behavioral Sciences Collection was performed, looking for peer-reviewed publications in English, French, German and Italian language that reported the AOO of BD; the search string adopted was “bipolar and onset”. Standardized mean differences were calculated between (i) mean AOO, operationally defined as onset of first symptoms/episodes, and (ii) mean AOO, operationally defined according to four criteria: first contact with services, date of the diagnosis, first pharmacological treatment, or first hospitalization.
The searches yielded 8710 articles; 2424 of these articles met the inclusion criteria. A final set of 19 studies presenting multiple definitions of AOO has been analyzed, revealing an overall effect size of 6.96 of untreated years (Cohen's d = 0.65)
To our knowledge, this is the first meta-analysis that addresses the definition and the modulation of the AOO in bipolar disorder. Identifying the time-frame of untreated illness is very important for the best planning of timely interventions.
Disclosure of interest
The authors have not supplied their declaration of competing interest.
Intake in sugar-rich diets can be limited either via rumen fill or excessive rumen fermentation and source of non-fibre carbohydrate (NFC) in the diet can affect both factors. The aim of the current study was to quantify the effect of partially replacing ground maize (GM) with steam-rolled maize (SRM) or pelleted citrus pulp (PCP) at two concentrate levels in sugarcane-based diets on digestibility, rumen ecosystem and metabolism of Nellore steers. Six rumen-cannulated steers were assigned to a 6 × 6 Latin square, replicated in time, in a 2 × 3 factorial arrangement of treatments with two levels of concentrate (600 or 800 g concentrate/kg dry matter [DM]) and three NFC sources. Each steer within a period was considered an experimental unit. Feeding more concentrate increased total tract digestibility of organic matter and decreased fibre intake and passage rate. It also reduced rumen populations of Fibrobacter succinogenes and Streptococcus bovis and increased Ruminococcus flavefaciens. Substituting PCP for GM increased rumen pH, acetic acid and organic matter digestibility. Feeding PCP also reduced R. flavefaciens and R. amylophilus rumen populations. Substituting SRM for GM increased starch digestibility and rumen propionic acid, but decreased rumen ammonia concentration. Feeding SRM increased rumen populations of Megasphaera elsdenii with the high-concentrate diet but reduced Ruminococcus albus populations at both concentrate levels. In conclusion, partial replacement of GM by PCP decreased intake in sugar-rich diets, while increasing total tract neutral detergent fibre digestibility. Replacement of GM with SRM increases rumen fermentation and total tract digestibility of starch.
Replacing ground maize (GM) with steam-rolled maize typically increases feed efficiency in maize-silage-based diets. However, little is known about optimal carbohydrate supplementation in sugarcane silage-based diets. The objective was to quantify the effect of partially replacing GM with steam-rolled maize (SRM) or pelleted citrus pulp (PCP) at two concentrate levels (600 or 800 g/kg DM) in sugarcane-based diets on feeding behaviour, performance and blood parameters of finishing Nellore bulls. One hundred and eight young bulls were allocated to 36 pens in a randomized block design and fed for 84 d. Feeding 800 g/kg concentrate decreased time spending eating and ruminating, but improved G:F ratio, hot carcass weight and carcass dressing, compared to 600 g/kg concentrate. Bulls fed SRM and PCP diets with 600 g/kg concentrate had lower intake compared to GM. Both final weight and average daily gain decreased when bulls were fed PCP and SRM with 600 g/kg concentrate compared to GM diets, and when fed with PCP and 800 g/kg concentrate. Substituting PCP for GM decreased gain efficiency, carcass weight, rumination time and intake efficiency, indicating that the bulls consumed less feed per hour spent eating. Substituting SRM for GM increased backfat thickness and blood urea concentration. In conclusion, the replacement of GM with PCP reduces intake and enhances selection against large particles, decreasing rumination, performance and final carcass weight and dressing. Replacement of GM with SRM increases blood urea and fat deposition, with no impact on performance.
Keel bone damage (KBD) in laying hens is an important welfare problem in both conventional and organic egg production systems. We aimed to identify possible risk factors for KBD in organic hens by analysing cross-sectional data of 107 flocks assessed in eight European countries. Due to partly missing data, the final multiple regression model was based on data from 50 flocks. Keel bone damage included fractures and/or deviations, and was recorded, alongside with other animal based measures, by palpation and visual inspection of at least 50 randomly collected hens per flock between 52 and 73 weeks of age. Management and housing data were obtained by interviews, inspection and by feed analysis. Keel bone damage flock prevalences ranged from 3% to 88%. Compiled on the basis of literature and practical experience, 26 potential associative factors of KBD went into an univariable selection by Spearman correlation analysis or Mann–Whitney U test (with P<0.1 level). The resulting nine factors were presented to stepwise forward linear regression modelling. Aviary v. floor systems, absence of natural daylight in the hen house, a higher proportion of underweight birds, as well as a higher laying performance were found to be significantly associated with a higher percentage of hens with KBD. The final model explained 32% of the variation in KBD between farms. The moderate explanatory value of the model underlines the multifactorial nature of KBD. Based on the results increased attention should be paid to an adequate housing design and lighting that allows the birds easy orientation and safe manoeuvring in the system. Furthermore, feeding management should aim at sufficient bird live weights that fulfil breeder weight standards. In order to achieve a better understanding of the relationships between laying performance, feed management and KBD further investigations are needed.
The crystal structure of tlapallite has been determined using single-crystal X-ray diffraction and supported by electron probe micro-analysis, powder diffraction and Raman spectroscopy. Tlapallite is trigonal, space group P321, with a = 9.1219(17) Å, c = 11.9320(9) Å and V = 859.8(3) Å3, and was refined to R1 = 0.0296 for 786 reflections with I > 2σ(I). This study resulted from the discovery of well-crystallised tlapallite at the Wildcat prospect, Utah, USA. The chemical formula of tlapallite has been revised to (Ca,Pb)3CaCu6[Te4+3Te6+O12]2(Te4+O3)2(SO4)2·3H2O, or more simply (Ca,Pb)3CaCu6Te4+8Te6+2O30(SO4)2·3H2O, from H6(Ca,Pb)2(Cu,Zn)3(TeO3)4(TeO6)(SO4). The tlapallite structure consists of layers containing distorted Cu2+O6 octahedra, Te6+O6 octahedra and Te4+O4 disphenoids (which together form the new mixed-valence phyllotellurate anion [Te4+3Te6+O12]12−), Te4+O3 trigonal pyramids and CaO8 polyhedra. SO4 tetrahedra, Ca(H2O)3O6 polyhedra and H2O groups fill the space between the layers. Tlapallite is only the second naturally occurring compound containing tellurium in both the 4+ and 6+ oxidation states with a known crystal structure, the other being carlfriesite, CaTe4+2Te6+O8. Carlfriesite is the predominant secondary tellurium mineral at the Wildcat prospect. We also present an updated structure for carlfriesite, which has been refined to R1 = 0.0230 for 874 reflections with I > 2σ(I). This updated structural refinement improves upon the one reported previously by refining all atoms anisotropically and presenting models of bond valence and Te4+ secondary bonding.
Measles is a target for elimination in all six WHO regions by 2020, and over the last decade, there has been considerable progress towards this goal. Surveillance is recognised as a cornerstone of elimination programmes, allowing early identification of outbreaks, thus enabling control and preventing re-emergence. Fever–rash surveillance is increasingly available across WHO regions, and this symptom-based reporting is broadly used for measles surveillance. However, as measles control increases, symptom-based cases are increasingly likely to reflect infection with other diseases with similar symptoms such as rubella, which affects the same populations, and can have a similar seasonality. The WHO recommends that cases from suspected measles outbreaks be laboratory-confirmed, to identify ‘true’ cases, corresponding to measles IgM titres exceeding a threshold indicative of infection. Although serological testing for IgM has been integrated into the fever–rash surveillance systems in many countries, the logistics of sending in every suspected case are often beyond the health system's capacity. We show how age data from serologically confirmed cases can be leveraged to infer the status of non-tested samples, thus strengthening the information we can extract from symptom-based surveillance. Applying an age-specific confirmation model to data from three countries with divergent epidemiology across Africa, we identify the proportion of cases that need to be serologically tested to achieve target levels of accuracy in estimated infected numbers and discuss how this varies depending on the epidemiological context. Our analysis provides an approach to refining estimates of incidence leveraging all available data, which has the potential to improve allocation of resources, and thus contribute to rapid and efficient control of outbreaks.
Introduction: Delays in transfer to an in-patient bed of admitted patients boarded in the ED has been identified as one of the chief drivers of ED overcrowding. Our study aims to replicate findings from a previous study in identifying patient characteristics associated with increased boarding time, and the impact of increased boarding time on in-patient length of stay (IPLOS). Methods: We conducted a retrospective single-centre observational study during the period between January 1, 2015 December 31, 2015 at a very high volume community hospital (~ 75,000 ED visits/year). All patients admitted from the ED to Medicine, Pediatrics, Surgery, and Critical Care were identified. The mean time to in-patient bed (TTB), as well as patient-specific and institutional factors that were associated with prolonged boarding times ( 12 hours) were identified. Mean IP LOS was calculated for those with prolonged boarding times and compared to those without prolonged boarding times. Results: There were 8,096 unique admissions during the study period. Patients admitted to the Medicine service exhibited significantly higher boarding times than those admitted to other services, with a mean boarding time of 17.4 hrs, as compared to 4.2 hrs, 5.7 hrs, and 4.0 hrs for those admitted to Surgery, Critical Care and Pediatrics respectively. Within Medicine patients, there was a statistically significant greater odds of prolonged boarding time for patients who were older, had a greater comorbidity burden, and required more specialized in-patient care (i.e. an isolation bed or telemetry bed). Medicine patients with prolonged boarding times also experienced 0.7 days longer IP LOS, even after correcting for age and comorbidity (mean adjusted IP LOS 10.6 days versus 11.3 days). Conclusion: Within our study period, older, sicker patients and those patients requiring more resource-intensive in-patient care have the longest ED boarding times. These prolonged ‘boarding’ times are associated with significantly increased IP LOS.
Measles eradication efforts have been successful at achieving elimination in many countries worldwide. Such countries actively work to maintain this elimination by continuing to improve coverage of two routine doses of measles vaccine following measles elimination. While improving measles vaccine coverage is always beneficial, we show, using a steady-state analysis of a dynamical model, that the correlation between populations receiving the first and second routine dose also has a significant impact on the population immunity achieved by a specified combination of first and second dose coverage. If the second dose is administered to people independently of whether they had the first dose, high second-dose coverage improves the proportion of the population receiving at least one dose, and will have a large effect on population immunity. If the second dose is administered only to people who have had the first dose, high second-dose coverage reduces the rate of primary vaccine failure, but does not reach people who missed the first dose; this will therefore have a relatively small effect on population immunity. When doses are administered dependently, and assuming the first dose has higher coverage, increasing the coverage of the first dose has a larger impact on population immunity than does increasing the coverage of the second. Correlation between vaccine doses has a significant impact on the level of population immunity maintained by current vaccination coverage, potentially outweighing the effects of age structure and, in some cases, recent improvements in vaccine coverage. It is therefore important to understand the correlation between vaccine doses as such correlation may have a large impact on the effectiveness of measles vaccination strategies.
Rubella virus infection typically presents as a mild illness in children; however, infection during pregnancy may cause the birth of an infant with congenital rubella syndrome (CRS). As of February 2017, India began introducing rubella-containing vaccine (RCV) into the public-sector childhood vaccination programme. Low-level RCV coverage among children over several years can result in an increase in CRS incidence by increasing the average age of infection without sufficiently reducing rubella incidence. We evaluated the impact of RCV introduction on CRS incidence across India's heterogeneous demographic and epidemiological contexts. We used a deterministic age-structured model that reflects Indian states’ rural and urban area-specific demography and vaccination coverage levels to simulate rubella dynamics and estimate CRS incidence with and without RCV introduction to the public sector. Our analysis suggests that current low-level private-sector vaccination has already slightly increased the burden of CRS in India. We additionally found that the effect of public-sector RCV introduction depends on the basic reproductive number, R0, of rubella. If R0 is five, a value empirically estimated from an array of settings, CRS incidence post-RCV introduction will likely decrease. However, if R0 is seven or nine, some states may experience short-term or annual increases in CRS, even if a long-term total reduction in cases (30 years) is expected. Investment in population-based serological surveys and India's fever/rash surveillance system will be key to monitoring the success of the vaccination programme.
Exercise during pregnancy has beneficial effects on maternal and offspring’s health in humans and mice. The underlying mechanisms remain unclear. This comparative study aimed to determine the long-term effects of an exercise program on metabolism, weight gain, body composition and changes in hormones [insulin, leptin, brain-derived neurotrophic factor (BDNF)]. Pregnant women (n=34) and mouse dams (n=44) were subjected to an exercise program compared with matched controls (period I). Follow-up in the offspring was performed over 6 months in humans, corresponding to postnatal day (P) 21 in mice (period II). Half of the mouse offspring was challenged with a high-fat diet (HFD) for 6 weeks between P70 and P112 (period III). In period I, exercise during pregnancy led to 6% lower fat content, 40% lower leptin levels and an increase of 50% BDNF levels in humans compared with controls, which was not observed in mice. After period II in humans and mice, offspring body weight did not differ from that of the controls. Further differences were observed in period III. Offspring of exercising mouse dams had significantly lower fat mass and leptin levels compared with controls. In addition, at P112, BDNF levels in offspring were significantly higher from exercising mothers while this effect was completely blunted by HFD feeding. In this study, we found comparable effects on maternal and offspring’s weight gain in humans and mice but different effects in insulin, leptin and BDNF. The long-term potential protective effects of exercise on biomarkers should be examined in human studies.
This study aimed to examine the association between vitamin B6, folate and vitamin B12 biomarkers and plasma fatty acids in European adolescents. A subsample from the Healthy Lifestyle in Europe by Nutrition in Adolescence study with valid data on B-vitamins and fatty acid blood parameters, and all the other covariates used in the analyses such as BMI, Diet Quality Index, education of the mother and physical activity assessed by a questionnaire, was selected resulting in 674 cases (43 % males). B-vitamin biomarkers were measured by chromatography and immunoassay and fatty acids by enzymatic analyses. Linear mixed models elucidated the association between B-vitamins and fatty acid blood parameters (changes in fatty acid profiles according to change in 10 units of vitamin B biomarkers). DHA, EPA) and n-3 fatty acids showed positive associations with B-vitamin biomarkers, mainly with those corresponding to folate and vitamin B12. Contrarily, negative associations were found with n-6:n-3 ratio, trans-fatty acids and oleic:stearic ratio. With total homocysteine (tHcy), all the associations found with these parameters were opposite (for instance, an increase of 10 nmol/l in red blood cell folate or holotranscobalamin in females produces an increase of 15·85 µmol/l of EPA (P value <0·01), whereas an increase of 10 nmol/l of tHcy in males produces a decrease of 2·06 µmol/l of DHA (P value <0·05). Positive associations between B-vitamins and specific fatty acids might suggest underlying mechanisms between B-vitamins and CVD and it is worth the attention of public health policies.
Measles was eliminated in the Americas in 2002 by a combination of routine immunizations and supplementary immunization activities. Recent outbreaks underscore the importance of reconsidering vaccine policy in order to maintain elimination. We constructed an age-structured dynamical model for the distribution of immunity in a population with routine immunization and without disease, and analysed the steady state for an idealized age structure and for real age structures of countries in the Americas. We compared the level of immunity maintained by current policy in these countries to the level maintainable by an optimal policy. The optimal age target for the first routine dose of measles vaccine depends on the timing and coverage of both doses. Similarly, the optimal age target for the second dose of measles vaccine depends on the timing and coverage of the first dose. The age targets for the first and second doses of measles vaccine should be adjusted for the post-elimination era, by specifically accounting for current context, including realized coverage of both doses, and altered maternal immunity. Doing so can greatly improve the proportion immune within a population, and therefore the chances of maintaining measles elimination, without changing coverage.
Measles elimination goals have been adopted in a range of countries, sub-regions, and regions since the WHO declared an elimination goal by 2015 or 2020. All countries attempt to achieve and maintain high coverage through routine immunization programmes. This routine strategy, however, does not ensure the elimination goal of measles. Many developed countries, such as the United States, that have succeeded in interrupting measles transmission earlier, are now experiencing outbreaks with an increasing number of cases. Using a stochastic, age-structured model of measles vaccination dynamics, we explore and characterize the transient dynamics of measles susceptibility in the years following the implementation of routine vaccination at the herd immunity threshold. We demonstrate how a population could face risks of potentially large outbreaks even within few years of vaccination. We characterize different risk profiles depending on the incidence pattern in the years prior to vaccination. These results suggest that the classic critical vaccination threshold is necessary to achieve herd immunity, but not sufficient to prevent long periods of transient, super-critical dynamics. Our results suggest the need of future work for more careful monitoring of the impacts of current immunization programmes, and developing models that take into account more complicated vaccination strategies, demographic factors, and population movements.
The Evolutionary Map of the Universe (EMU) is a proposed radio continuum survey
of the Southern Hemisphere up to declination + 30°, with the Australian
Square Kilometre Array Pathfinder (ASKAP). EMU will use an automated source
identification and measurement approach that is demonstrably optimal, to
maximise the reliability and robustness of the resulting radio source
catalogues. As a step toward this goal we conducted a “Data
Challenge” to test a variety of source finders on simulated images. The
aim is to quantify the accuracy and limitations of existing automated source
finding and measurement approaches. The Challenge initiators also tested the
current ASKAPsoft source-finding tool to establish how it could benefit from
incorporating successful features of the other tools. As expected, most finders
show completeness around 100% at ≈ 10σ dropping to about 10% by
≈ 5σ. Reliability is typically close to 100% at ≈
10σ, with performance to lower sensitivities varying between finders. All
finders show the expected trade-off, where a high completeness at low
signal-to-noise gives a corresponding reduction in reliability, and vice versa.
We conclude with a series of recommendations for improving the performance of
the ASKAPsoft source-finding tool.
Lead-containing (Pb-B-X)-2H apatites encompass a number of [AF]4[AT]6[(BO4)6]X2 compounds used for waste stabilization, environmental catalysis and ion conduction, but the influence of the stereochemically active lone-pair electrons of Pb2+ on crystal chemistry and functionality is poorly understood. This article presents a compilation of existing structural data for Pb apatites that demonstrate paired electrons of Pb2+ at both the AF and AT results in substantial adjustments to the PbFO6 metaprism twist angle, φ. New structure refinements are presented for several natural varieties as a function of temperature by single-crystal X-ray diffraction (XRD) of vanadinite-2H (ideally Pb10(VO4)6Cl2), pyromorphite-2H (Pb10(PO4)6Cl2), mimetite-2H/M (Pb10(As5+O4)6Cl2) and finnemanite-2H (Pb10(As3+O3)6Cl2). A supercell for mimetite is confirmed using synchrotron single-crystal XRD. It is suggested the superstructure is necessary to accommodate displacement of the stereochemically active 6s2 lone-pair electrons on the Pb2+ that occupy a volume similar to an O2− anion. We propose that depending on the temperature and concentration of minor substitutional ions, the mimetite superstructure is a structural adaptation common to all Pb-containing apatites and by extension apatite electrolytes, where oxide ion interstitials are found at similar positions to the lonepair electrons. It is also shown that plumbous apatite framework flexes substantially through adjustments of the PbFO6 metaprism twist-angles (φ) as the temperature changes. Finally, crystalchemical  zoning observed at submicron scales will probably impact on the treatment of diffraction data and may account for certain inconsistencies in reported structures.
Despite their high prevalence, the global burden of anxiety disorders has never been calculated comprehensively. The new Global Burden of Disease (GBD) study has estimated burden due to morbidity and mortality caused by any anxiety disorder.
Prevalence was estimated using Bayesian meta-regression informed by data identified in a systematic review. Years of life lived with disability (YLDs) were calculated by multiplying prevalent cases by an average disability weight based on severity proportions (mild, moderate and severe). Disability-adjusted life years (DALYs) were then calculated and age standardized using global standard population figures. Estimates were also made for additional suicide mortality attributable to anxiety disorders. Findings are presented for YLDs, DALYs and attributable burden due to suicide for 21 world regions in 1990 and 2010.
Anxiety disorders were the sixth leading cause of disability, in terms of YLDs, in both high-income (HI) and low- and middle-income (LMI) countries. Globally, anxiety disorders accounted for 390 DALYs per 100 000 persons [95% uncertainty interval (UI) 191–371 DALYs per 100 000] in 2010, with no discernible change observed over time. Females accounted for about 65% of the DALYs caused by anxiety disorders, with the highest burden in both males and females experienced by those aged between 15 and 34 years. Although there was regional variation in prevalence, the overlap between uncertainty estimates means that substantive differences in burden between populations could not be identified.
Anxiety disorders are chronic, disabling conditions that are distributed across the globe. Future estimates of burden could be further improved by obtaining more representative data on severity state proportions.