Association Between T2-related Comorbidities and Effectiveness of Biologics in Severe Asthma.

Rationale: Previous studies investigating the impact of comorbidities on the effectiveness of biologic agents have been relatively small and of short duration and have not compared classes of biologic agents. Objectives: To determine the association between type 2-related comorbidities and biologic agent effectiveness in adults with severe asthma (SA). Methods: This cohort study used International Severe Asthma Registry data from 21 countries (2017-2022) to quantify changes in four outcomes before and after biologic therapy-annual asthma exacerbation rate, FEV1% predicted, asthma control, and long-term oral corticosteroid daily dose-in patients with or without allergic rhinitis, chronic rhinosinusitis (CRS) with or without nasal polyps (NPs), NPs, or eczema/atopic dermatitis. Measurements and Main Results: Of 1,765 patients, 1,257, 421, and 87 initiated anti-IL-5/5 receptor, anti-IgE, and anti-IL-4/13 therapies, respectively. In general, pre- versus post-biologic therapy improvements were noted in all four asthma outcomes assessed, irrespective of comorbidity status. However, patients with comorbid CRS with or without NPs experienced 23% fewer exacerbations per year (95% CI, 10-35%; P < 0.001) and had 59% higher odds of better post-biologic therapy asthma control (95% CI, 26-102%; P < 0.001) than those without CRS with or without NPs. Similar estimates were noted for those with comorbid NPs: 22% fewer exacerbations and 56% higher odds of better post-biologic therapy control. Patients with SA and CRS with or without NPs had an additional FEV1% predicted improvement of 3.2% (95% CI, 1.0-5.3; P = 0.004), a trend that was also noted in those with comorbid NPs. The presence of allergic rhinitis or atopic dermatitis was not associated with post-biologic therapy effect for any outcome assessed. Conclusions: These findings highlight the importance of systematic comorbidity evaluation. The presence of CRS with or without NPs or NPs alone may be considered a predictor of the effectiveness of biologic agents in patients with SA.

Exploring Definitions and Predictors of Severe Asthma Clinical Remission Post-Biologic in Adults.

RATIONALE: There is no consensus on criteria to include in an asthma remission definition in real-life. Factors associated with achieving remission post-biologic-initiation remain poorly understood. OBJECTIVES: To quantify the proportion of adults with severe asthma achieving multi-domain-defined remission post-biologic-initiation and identify pre-biologic characteristics associated with achieving remission which may be used to predict it. METHODS: This was a longitudinal cohort study using data from 23 countries from the International Severe Asthma Registry. Four asthma outcome domains were assessed in the 1-year pre- and post-biologic-initiation. A priori-defined remission cut-offs were: 0 exacerbations/year, no long-term oral corticosteroid (LTOCS), partly/well-controlled asthma, and percent predicted forced expiratory volume in one second ≥80%. Remission was defined using 2 (exacerbations + LTOCS), 3 (+control or +lung function) and 4 of these domains. The association between pre-biologic characteristics and post-biologic remission was assessed by multivariable analysis. MEASUREMENTS AND MAIN RESULTS: 50.2%, 33.5%, 25.8% and 20.3% of patients met criteria for 2, 3 (+control), 3 (+lung function) and 4-domain-remission, respectively. The odds of achieving 4-domain remission decreased by 15% for every additional 10-years asthma duration (odds ratio: 0.85; 95% CI: 0.73, 1.00). The odds of remission increased in those with fewer exacerbations/year, lower LTOCS daily dose, better control and better lung function pre-biologic-initiation. CONCLUSIONS: One in 5 patients achieved 4-domain remission within 1-year of biologic-initiation. Patients with less severe impairment and shorter asthma duration at initiation had a greater chance of achieving remission post-biologic, indicating that biologic treatment should not be delayed if remission is the goal. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Bose-Einstein Condensation by Polarization Gradient Laser Cooling.

Attempts to create quantum degenerate gases without evaporative cooling have been pursued since the early days of laser cooling, with the consensus that polarization gradient cooling (PGC, also known as "optical molasses") alone cannot reach condensation. In the present work, we report that simple PGC can generate a small Bose-Einstein condensate (BEC) inside a corrugated micrometer-sized optical dipole trap. The experimental parameters enabling BEC creation were found by machine learning, which increased the atom number by a factor of 5 and decreased the temperature by a factor of 2.5, corresponding to almost 2 orders of magnitude gain in phase space density. When the trapping light is slightly misaligned through a microscopic objective lens, a BEC of ∼250 ^{87}Rb atoms is formed inside a local dimple within 40 ms of PGC after MOT loading.

Biologics (mepolizumab and omalizumab) induced remission in severe asthma patients.

BACKGROUND: Asthma remission has emerged as a potential treatment goal. This study evaluated the effectiveness of two biologics (mepolizumab/omalizumab) in achieving asthma remission. METHODS: This observational study included 453 severe asthma patients (41% male; mean age ± SD 55.7 ± 14.7 years) from two real-world drug registries: the Australian Mepolizumab Registry and the Australian Xolair Registry. The composite outcome clinical remission was defined as zero exacerbations and zero oral corticosteroids during the previous 6 months assessed at 12 months and 5-item Asthma Control Questionnaire (ACQ-5) ≤1 at 12 months. We also assessed clinical remission plus optimization (post-bronchodilator FEV1 ≥80%) or stabilization (post-bronchodilator FEV1 not greater than 5% decline from baseline) of lung function at 12 months. Sensitivity analyses explored various cut-offs of ACQ-5/FEV1 scores. The predictors of clinical remission were identified. RESULTS: 29.3% (73/249) of AMR and 22.8% (37/162) of AXR cohort met the criteria for clinical remission. When lung function criteria were added, the remission rates were reduced to 25.2% and 19.1%, respectively. Sensitivity analyses identified that the remission rate ranged between 18.1% and 34.9% in the AMR cohort and 10.6% and 27.2% in the AXR cohort. Better lung function, lower body mass index, mild disease and absence of comorbidities such as obesity, depression and osteoporosis predicted the odds of achieving clinical remission. CONCLUSION: Biologic treatment with mepolizumab or omalizumab for severe asthma-induced asthma remission in a subgroup of patients. Remission on treatment may be an achievable treatment target and future studies should consider remission as an outcome measure.

Real-world biologics response and super-response in the International Severe Asthma Registry cohort.

BACKGROUND: Biologic asthma therapies reduce exacerbations and long-term oral corticosteroids (LTOCS) use in randomized controlled trials (RCTs); however, there are limited data on outcomes among patients ineligible for RCTs. Hence, we investigated responsiveness to biologics in a real-world population of adults with severe asthma. METHODS: Adults in the International Severe Asthma Registry (ISAR) with ≥24 weeks of follow-up were grouped into those who did, or did not, initiate biologics (anti-IgE, anti-IL5/IL5R, anti-IL4/13). Treatment responses were examined across four domains: forced expiratory volume in 1 second (FEV1) increase by ≥100 mL, improved asthma control, annualized exacerbation rate (AER) reduction ≥50%, and any LTOCS dose reduction. Super-response criteria were: FEV1 increase by ≥500 mL, new well-controlled asthma, no exacerbations, and LTOCS cessation or tapering to ≤5 mg/day. RESULTS: 5.3% of ISAR patients met basic RCT inclusion criteria; 2116/8451 started biologics. Biologic initiators had worse baseline impairment than non-initiators, despite having similar biomarker levels. Half or more of initiators had treatment responses: 59% AER reduction, 54% FEV1 increase, 49% improved control, 49% reduced LTOCS, of which 32%, 19%, 30%, and 39%, respectively, were super-responses. Responses/super-responses were more frequent in biologic initiators than in non-initiators; nevertheless, ~40-50% of initiators did not meet response criteria. CONCLUSIONS: Most patients with severe asthma are ineligible for RCTs of biologic therapies. Biologics are initiated in patients who have worse baseline impairments than non-initiators despite similar biomarker levels. Although biologic initiators exhibited clinical responses and super-responses in all outcome domains, 40-50% did not meet the response criteria.

The glymphatic system's role in traumatic brain injury-related neurodegeneration.

In at least some individuals who suffer a traumatic brain injury (TBI), there exists a risk of future neurodegenerative illness. This review focuses on the association between the brain-based paravascular drainage pathway known as the "glymphatic system" and TBI-related neurodegeneration. The glymphatic system is composed of cerebrospinal fluid (CSF) flowing into the brain parenchyma along paravascular spaces surrounding penetrating arterioles where it mixes with interstitial fluid (ISF) before being cleared along paravenous drainage pathways. Aquaporin-4 (AQP4) water channels on astrocytic end-feet appear essential for the functioning of this system. The current literature linking glymphatic system disruption and TBI-related neurodegeneration is largely based on murine models with existing human research focused on the need for biomarkers of glymphatic system function (e.g., neuroimaging modalities). Key findings from the existing literature include evidence of glymphatic system flow disruption following TBI, mechanisms of this decreased flow (i.e., AQP4 depolarization), and evidence of protein accumulation and deposition (e.g., amyloid ß, tau). The same studies suggest that glymphatic dysfunction leads to subsequent neurodegeneration, cognitive decline, and/or behavioral change although replication in humans is needed. Identified emerging topics from the literature are as follows: link between TBI, sleep, and glymphatic system dysfunction; influence of glymphatic system disruption on TBI biomarkers; and development of novel treatments for glymphatic system disruption following TBI. Although a burgeoning field, more research is needed to elucidate the role of glymphatic system disruption in TBI-related neurodegeneration.

Analysis of comorbidities and multimorbidity in adult patients in the International Severe Asthma Registry.

BACKGROUND: Investigation for the presence of asthma comorbidities is recommended by the Global Initiative for Asthma because their presence can complicate asthma management. OBJECTIVE: To understand the prevalence and pattern of comorbidities and multimorbidity in adults with severe asthma and their association with asthma-related outcomes. METHODS: This was a cross-sectional study using data from the International Severe Asthma Registry from 22 countries. A total of 30 comorbidities were identified and categorized a priori as any of the following: (1) potentially type 2-related comorbidities, (2) potentially oral corticosteroid (OCS)-related comorbidities, or (3) comorbidities mimicking or aggravating asthma. The association between comorbidities and asthma-related outcomes was investigated using multivariable models adjusted for country, age at enrollment, and sex (ie male or female). RESULTS: Of the 11,821 patients, 69%, 67%, and 55% had at least 1 potentially type 2-related, potentially OCS-related, or mimicking or aggravating comorbidities, respectively; 57% had 3 or more comorbidities, and 33% had comorbidities in all 3 categories. Patients with allergic rhinitis, nasal polyposis, and chronic rhinosinusitis experienced 1.12 (P = .003), 1.16 (P < .001), and 1.29 times (P < .001) more exacerbations per year, respectively, than those without. Patients with nasal polyposis and chronic rhinosinusitis were 40% and 46% more likely (P < .001), respectively, to have received long-term (LT) OCS. All assessed potential OCS-related comorbidities (except obesity) were associated with a greater likelihood of LTOCS use (odds ratios [ORs]: 1.23-2.77) and, except for dyslipidemia, with a greater likelihood of uncontrolled asthma (ORs: 1.29-1.68). All mimicking or aggravating comorbidities assessed were associated with more exacerbations (1.24-1.68 times more), all (except bronchiectasis) with increased likelihood of uncontrolled asthma (ORs: 1.57-1.81), and all (except chronic obstructive pulmonary disease) with increased likelihood of LTOCS use (ORs: 1.37-1.57). A greater number of comorbidities was associated with worse outcomes. CONCLUSION: In a global study, comorbidity or multimorbidity is reported in most adults with severe asthma and is associated with poorer asthma-related outcomes. CLINICAL TRIAL REGISTRATION: The International Severe Asthma Registry database has ethical approval from the Anonymous Data Ethics Protocols and Transparency (ADEPT) committee (ADEPT0218) and is registered with the European Union Electronic Register of Post-Authorization Studies (European Network Centres for Pharmacoepidemiology and Pharmacovigilance [ENCEPP]/DSPP/23720). The study was designed, implemented, and reported in compliance with the European Network Centres for Pharmacoepidemiology and Pharmacovigilance (ENCEPP) Code of Conduct (EMA 2014; EUPAS44024) and with all applicable local and international laws and regulations, and registered with ENCEPP (https://www.encepp.eu/encepp/viewResource.htm?id=48848). Governance was provided by ADEPT (registration number: ADEPT1121).

Impact of pre-biologic impairment on meeting domain-specific biologic responder definitions in patients with severe asthma.

BACKGROUND: There is little agreement on clinically useful criteria for identifying real-world responders to biologic treatments for asthma. OBJECTIVE: To investigate the impact of pre-biologic impairment on meeting domain-specific biologic responder definitions in adults with severe asthma. METHODS: This was a longitudinal, cohort study across 22 countries participating in the International Severe Asthma Registry (https://isaregistries.org/) between May 2017 and January 2023. Change in 4 asthma domains (exacerbation rate, asthma control, long-term oral corticosteroid [LTOCS] dose, and lung function) was assessed from biologic initiation to 1 year post-treatment (minimum 24 weeks). Pre- to post-biologic changes for responders and nonresponders were described along a categorical gradient for each domain derived from pre-biologic distributions (exacerbation rate: 0 to 6+/y; asthma control: well controlled to uncontrolled; LTOCS: 0 to >30 mg/d; percent-predicted forced expiratory volume in 1 second [ppFEV1]: <50% to ≥80%). RESULTS: Percentage of biologic responders (ie, those with a category improvement pre- to post-biologic) varied by domain and increased with greater pre-biologic impairment, increasing from 70.2% to 90.0% for exacerbation rate, 46.3% to 52.3% for asthma control, 31.1% to 58.5% for LTOCS daily dose, and 35.8% to 50.6% for ppFEV1. The proportion of patients having improvement post-biologic tended to be greater for anti-IL-5/5R compared with for anti-IgE for exacerbation, asthma control, and ppFEV1 domains, irrespective of pre-biologic impairment. CONCLUSION: Our results provide realistic outcome-specific post-biologic expectations for both physicians and patients, will be foundational to inform future work on a multidimensional approach to define and assess biologic responders and response, and may enhance appropriate patient selection for biologic therapies. TRIAL REGISTRATION: The ISAR database has ethical approval from the Anonymous Data Ethics Protocols and Transparency (ADEPT) committee (ADEPT0218) and is registered with the European Union Electronic Register of Post-Authorization studies (ENCEPP/DSPP/23720). The study was designed, implemented, and reported in compliance with the European Network Centres for Pharmacoepidemiology and Pharmacovigilance (ENCEPP) Code of Conduct (EUPAS38288) and with all applicable local and international laws and regulation, and registered with ENCEPP (https://www.encepp.eu/encepp/viewResource.htm?id=38289). Governance was provided by ADEPT (registration number: ADEPT1220).

Association of Win-Loss Record With Neuropsychiatric Symptoms and Brain Health Among Professional Fighters.

OBJECTIVE: Repetitive head impacts in professional fighting commonly lead to head injuries. Increased exposure to repetitive head trauma, measured by the number of professional fights and years of fighting, has been associated with slower processing speed and smaller brain volumes. The impact of win-loss outcomes has been investigated in other sports, with several studies suggesting that individuals on losing teams experience more head injuries. Here, the authors hypothesized that fighters with a worse fight record would exhibit poorer brain health outcomes. METHODS: The Professional Fighters Brain Health Study examined changes in neuropsychiatric symptoms, regional brain volume, and cognition among professional boxers and mixed martial arts fighters. These data were used to evaluate the relationship between win-loss ratios and brain health outcomes among professional fighters (N=212) by using validated neuropsychiatric symptom and cognitive measures and MRI data. RESULTS: Retired fighters with a better record demonstrated more impulsiveness (B=0.21, df=48) and slower processing speed (B=-0.42, df=31). More successful fighters did not perform better than fighters with worse records on any neuropsychiatric or cognitive test. Retired fighters with better fight records had smaller brain volumes in the subcortical gray matter, anterior corpus callosum, left and right hippocampi, left and right amygdala, and left thalamus. More successful active fighters had a smaller left amygdala volume. CONCLUSIONS: These findings suggest that among retired fighters, a better fight record was associated with greater impulsiveness, slower processing speed, and smaller brain volume in certain regions. This study shows that even successful fighters experience adverse effects on brain health.

National Health and Medical Research Council statement on electronic cigarettes: 2022 update.

INTRODUCTION: Electronic cigarette (e-cigarette) use in Australia has rapidly increased since the 2017 National Health and Medical Research Council (NHMRC) Chief Executive Officer (CEO) statement on e-cigarettes. The type of products available and the demographic characteristics of people using these products have changed. New evidence has been published and there is growing concern among public health professionals about the increased use, particularly among young people who do not currently smoke combustible cigarettes. The combination of these issues led NHMRC to review the current evidence and provide an updated statement on e-cigarettes. In this article, we describe the comprehensive process used to review the evidence and develop the 2022 NHMRC CEO statement on electronic cigarettes. MAIN RECOMMENDATIONS: E-cigarettes can be harmful; all e-cigarette users are exposed to chemicals and toxins that have the potential to cause adverse health effects. There are no health benefits of using e-cigarettes if you do not currently smoke tobacco cigarettes. Adolescents are more likely to try e-cigarettes if they are exposed to e-cigarettes on social media. Short term e-cigarette use may help some smokers to quit who have been previously unsuccessful with other smoking cessation aids. There are other proven safe and effective options available to help smokers to quit. CHANGES IN MANAGEMENT AS A RESULT OF THIS STATEMENT: The evidence base for the harms of e-cigarette use has strengthened since the previous NHMRC statement. Significant gaps in the evidence base remain, especially about the longer term health harms of using e-cigarettes and the toxicity of many chemicals in e-cigarettes inhaled as an aerosol.

Cocaine history and impulsiveness in professional boxers and mixed martial arts fighters.

BACKGROUND/OBJECTIVES: Impulsiveness is linked to cocaine history (CH) in the general population and greater fight exposure in professional fighters. Among fighters, no previous studies have quantified CH or investigated its relationship with impulsiveness. METHODS: Adjusted multivariable regressions were utilized to examine the relationship between CH and impulsiveness in 335 fighters from the Professional Fighters Brain Health Study. RESULTS: Twenty percent of fighters reported CH. CH was significantly associated with impulsiveness overall and on three subscales. DISCUSSION/CONCLUSION: Cocaine's prevalence and significant association with impulsiveness in fighters merit further study. SCIENTIFIC SIGNIFICANCE: We quantify CH and demonstrate its significant association with impulsiveness in professional fighters for the first time.

Associations of Prior Head Injury With Mild Behavioral Impairment Domains.

OBJECTIVE: This study investigated associations of prior head injury and number of prior head injuries with mild behavioral impairment (MBI) domains. SETTING: The Atherosclerosis Risk in Communities (ARIC) Study. PARTICIPANTS: A total of 2534 community-dwelling older adults who took part in the ARIC Neurocognitive Study stage 2 examination were included. DESIGN: This was a prospective cohort study. Head injury was defined using self-reported and International Classification of Diseases, Ninth Revision ( ICD -9) code data. MBI domains were defined using the Neuropsychiatric Inventory Questionnaire (NPI-Q) via an established algorithm mapping noncognitive neuropsychiatric symptoms to the 6 domains of decreased motivation, affective dysregulation, impulse dyscontrol, social inappropriateness, and abnormal perception/thought content. MAIN MEASURES: The primary outcome was the presence of impairment in MBI domains. RESULTS: Participants were a mean age of 76 years, with a median time from first head injury to NPI-Q administration of 32 years. The age-adjusted prevalence of symptoms in any 1+ MBI domains was significantly higher among individuals with versus without prior head injury (31.3% vs 26.0%, P = .027). In adjusted models, a history of 2+ head injuries, but not 1 prior head injury, was associated with increased odds of impairment in affective dysregulation and impulse dyscontrol domains, compared with no history of head injury (odds ratio [OR] = 1.83, 95% CI = 1.13-2.98, and OR = 1.74, 95% CI = 1.08-2.78, respectively). Prior head injury was not associated with symptoms in MBI domains of decreased motivation, social inappropriateness, and abnormal perception/thought content (all P > .05). CONCLUSION: Prior head injury in older adults was associated with greater MBI domain symptoms, specifically affective dysregulation and impulse dyscontrol. Our results suggest that the construct of MBI can be used to systematically examine the noncognitive neuropsychiatric sequelae of head injury; further studies are needed to examine whether the systematic identification and rapid treatment of neuropsychiatric symptoms after head injury is associated with improved outcomes.

Asthma exacerbations are associated with a decline in lung function: a longitudinal population-based study.

RATIONALE: Progressive lung function (LF) decline in patients with asthma contributes to worse outcomes. Asthma exacerbations are thought to contribute to this decline; however, evidence is limited with mixed results. METHODS: This historical cohort study of a broad asthma patient population in the Optimum Patient Care Research Database, examined asthma patients with 3+eligible post-18th birthday peak expiratory flow rate (PEF) records (primary analysis) or records of forced expiratory flow in 1 s (FEV1) (sensitivity analysis). Adjusted linear growth models tested the association between mean annual exacerbation rate (AER) and LF trajectory. RESULTS: We studied 1 09 182 patients with follow-up ranging from 5 to 50 years, of which 75 280 had data for all variables included in the adjusted analyses. For each additional exacerbation, an estimated additional -1.34 L/min PEF per year (95% CI -1.23 to -1.50) were lost. Patients with AERs >2/year and aged 18-24 years at baseline lost an additional -5.95 L/min PEF/year (95% CI -8.63 to -3.28) compared with those with AER 0. These differences in the rate of LF decline between AER groups became progressively smaller as age at baseline increased. The results using FEV1 were consistent with the above. CONCLUSION: To our knowledge, this study is the largest nationwide cohort of its kind and demonstrates that asthma exacerbations are associated with faster LF decline. This was more prominent in younger patients but was evident in older patients when it was related to lower starting LF, suggesting a persistent deteriorating phenotype that develops in adulthood over time. Earlier intervention with appropriate management in younger patients with asthma could be of value to prevent excessive LF decline.

Comparative effectiveness of anti-IL5 and anti-IgE biologic classes in patients with severe asthma eligible for both.

BACKGROUND: Patients with severe asthma may present with characteristics representing overlapping phenotypes, making them eligible for more than one class of biologic. Our aim was to describe the profile of adult patients with severe asthma eligible for both anti-IgE and anti-IL5/5R and to compare the effectiveness of both classes of treatment in real life. METHODS: This was a prospective cohort study that included adult patients with severe asthma from 22 countries enrolled into the International Severe Asthma registry (ISAR) who were eligible for both anti-IgE and anti-IL5/5R. The effectiveness of anti-IgE and anti-IL5/5R was compared in a 1:1 matched cohort. Exacerbation rate was the primary effectiveness endpoint. Secondary endpoints included long-term-oral corticosteroid (LTOCS) use, asthma-related emergency room (ER) attendance, and hospital admissions. RESULTS: In the matched analysis (n = 350/group), the mean annualized exacerbation rate decreased by 47.1% in the anti-IL5/5R group and 38.7% in the anti-IgE group. Patients treated with anti-IL5/5R were less likely to experience a future exacerbation (adjusted IRR 0.76; 95% CI 0.64, 0.89; p < 0.001) and experienced a greater reduction in mean LTOCS dose than those treated with anti-IgE (37.44% vs. 20.55% reduction; p = 0.023). There was some evidence to suggest that patients treated with anti-IL5/5R experienced fewer asthma-related hospitalizations (IRR 0.64; 95% CI 0.38, 1.08), but not ER visits (IRR 0.94, 95% CI 0.61, 1.43). CONCLUSIONS: In real life, both anti-IgE and anti-IL5/5R improve asthma outcomes in patients eligible for both biologic classes; however, anti-IL5/5R was superior in terms of reducing asthma exacerbations and LTOCS use.

Longitudinal Trajectories of Post-Concussive Symptoms Following Mild Traumatic Brain Injury.

BACKGROUND: Individuals recovering from mild traumatic brain injury (TBI) represent a heterogenous population that requires distinct treatment approaches. Identification of recovery trajectories improves our ability to understand the natural history of mild TBI recovery and develop targeted interventions. OBJECTIVE: To utilize group-based trajectory modeling (GBTM) to identify distinct patterns of symptom recovery following mild TBI in the first 6 months after mild TBI. METHODS: This study is comprised of 253 adults who presented to the emergency department with mild TBI and completed assessments for six-months post-injury. Patients were recruited for the prospective observational cohort study, HeadSMART. The primary outcome measure was the Rivermead Postconcussion Symptom Questionnaire. GBTM was used to identify longitudinal trajectories of recovery following mild TBI using Rivermead scores at baseline, one, three, and six months following diagnosis. RESULTS: Findings identified four distinct trajectories of symptom recovery follwing mild TBI including 9% of participants who were categorized with minimal acute symptoms that decreased over time, 45% with mild acute symptoms that decreased over time, 33% with relatively higher acute symptoms that decreased over time, and 13% with relatively higher acute symptoms that increased over time. CONCLUSIONS: GBTM identified four distinct trajectories of recovery following mild TBI and GBTM may be useful for research interventions that can alter recovery trajectories.

The Impact of Orbital Volume on Post-traumatic Enophthalmos: A Systematic Review and Meta-analysis.

PURPOSE: Orbital volume increase has been previously linked with post-traumatic enophthalmos. However, this varies and some studies show no correlation. This systematic review and meta-analysis aimed to synthesize the correlation between orbital volume and enophthalmos and to determine if surgical intervention, enophthalmos measurement method, fracture location, or timing affect this correlation. METHODS: Automation tools were used to assist in this review of 6 databases. Searches were performed across all dates. Included studies quantitatively reported orbital volume and enophthalmos following traumatic orbital wall fractures in at least 5 adult subjects. Correlational data were extracted or calculated. Random-effects meta-analysis was used with subgroup analyses for each of the secondary aims. RESULTS: Twenty-five articles describing 648 patients were included. The pooled correlation between orbital volume and enophthalmos was r =0.71 ( R2 =0.50, P <0.001). Operative status, enophthalmos measurement method, and fracture location did not affect pooled correlation. The delay between trauma or surgery and enophthalmos measurement was not shown to modulate correlation for unoperated patients ( R2 =0.05, P =0.22) but showed a negative relationship for postoperative patients ( z =-0.0281, SE=0.0128, R2 =0.63, P =0.03), but this was heavily influenced by a single article. All results had high residual heterogeneity. Studies were rated as moderate, low, or very low quality with few stating explicit hypotheses or limitations. CONCLUSIONS: Bony orbital volume expansion accounts for around 50% of post-traumatic enophthalmos. The other half is probably explained by soft tissue or geometric bony, rather than volumetric, changes.

Prevalence and Correlates of Depressive Symptoms Within 6 Months After First-Time Mild Traumatic Brain Injury.

OBJECTIVE: Depressive symptoms are among the most common neuropsychiatric sequelae of mild traumatic brain injury (mTBI). Very few studies have compared correlates of depressive symptoms within the first 6 months of injury in cohorts experiencing their first TBI. The authors investigated whether the correlates of depressive symptoms (being female, older, lower education, having brain lesions, experiencing worse postconcussive symptoms, and incomplete functional recovery) that have been established in populations with moderate to severe TBI were the same for individuals with first-time mTBI within the first 6 months of recovery. METHODS: Two hundred seventeen individuals with first-time mTBI were divided into subgroups-new-onset depressive symptoms, recurrent depressive symptoms, prior depression history only, and never depressed-and compared on clinical and demographic variables and the presence of postconcussive symptoms and functional recovery at 3 and 6 months. RESULTS: New-onset depressive symptoms developed in 12% of the cohort, whereas 11% of the cohort had recurrent depressive symptoms. Both depressive symptoms groups were more likely to comprise women and persons of color and were at higher risk for clinically significant postconcussive symptoms and incomplete functional recovery for the first 6 months postinjury. CONCLUSIONS: Presence of depressive symptoms after first-time mTBI was associated with persistent postconcussive symptoms and incomplete functional recovery in the first 6 months. Adding to the existing literature, these findings identified correlates of depressive symptom development and poor outcomes after mTBI, thus providing further evidence that mTBI may produce persistent symptoms and functional limitations that warrant clinical attention.

Perceptions, attitudes, and behaviors of short-acting beta2 agonist users: an Australian cross-sectional community pharmacy-based study.

BACKGROUND: High use of short-acting beta-2-agonist (SABA) medication is a significant problem. Attitudes and perceptions toward asthma of over-the-counter (OTC) reliever users are unknown. The study aimed to describe the asthma attitudes, perceptions, medication knowledge and information gathering behavior of people with asthma with recent high SABA use (i.e. SABA use > twice a week in the last 4 weeks) and compare them to people with asthma with no recent high SABA use. METHOD: A real-world cross-sectional observational study in Australian community pharmacies was conducted; surveying patients ages ≥ 16 years requesting SABA medication OTC. Data collected included; demographics, medication usage, asthma control, asthma-related perceptions and behaviors. Data were summarized by using descriptive analyses. RESULTS: 375 participants completed the survey, 73.9% were high SABA users. Of the 375, 90.4% reported that their asthma symptoms were controlled or somewhat controlled and 56.0% felt that their asthma was not serious. However, only 17.6%, had controlled asthma according to GINA-defined criteria. High SABA users tended to be more anxious about their asthma and worried about its impact in the future (50.5% vs. 28.6%, p < 0.001). High SABA users were more likely to agree with the statements suggesting that asthma impacted on activities of daily living (46.6% vs. 16.3%, p < 0.001); were socially conscious about their asthma and more likely to feel embarrassed carrying (21.3% vs 9.2%, p = 0.007) and using (29.2% vs 18.4%, p = 0.036) their asthma inhaler. CONCLUSION: This study revealed the extent of uncontrolled asthma and uncovered an anxious and socially conscious group of OTC SABA users. There is a need to better understand patient perceptions and their relationships to high-SABA use, to ensure targeted educational interventions are developed and implemented.

The cost-effectiveness of azithromycin in reducing exacerbations in uncontrolled asthma.

Add-on azithromycin (AZM) results in a significant reduction in exacerbations among adults with persistent uncontrolled asthma. The aim of this study was to assess the cost-effectiveness of add-on AZM in terms of healthcare and societal costs.The AMAZES trial randomly assigned 420 participants to AZM or placebo. Healthcare use and asthma exacerbations were measured during the treatment period. Healthcare use included all prescribed medicine and healthcare contacts. Costs of antimicrobial resistance (AMR) were estimated based on overall consumption and published estimates of costs. The value of an avoided exacerbation was based on published references. Differences in cost between the two groups were related to differences in exacerbations in a series of net monetary benefit estimates. Societal costs included lost productivity, over the counter medicines, steroid induced morbidity and AMR costs.Add-on AZM resulted in a reduction in healthcare costs (mean (95% CI)) including nights in hospital (AUD 433.70 (AUD 48.59-818.81) or EUR 260.22 (EUR 29.15-491.29)), unplanned healthcare visits (AUD 20.25 (AUD 5.23-35.27) or EUR 12.15 (EUR 3.14-21.16)), antibiotic costs (AUD 14.88 (AUD 7.55-22.21) or EUR 8.93 (EUR 4.53-13.33)) and oral corticosteroid costs (AUD 4.73 (AUD 0.82-8.64) or EUR 2.84 (EUR 0.49-5.18)); all p<0.05. Overall healthcare and societal costs were lower (AUD 77.30 (EUR 46.38) and AUD 256.22 (EUR 153.73) respectively) albeit not statistically significant. The net monetary benefit of add-on AZM was estimated to be AUD 2072.30 (95% CI AUD 1348.55-2805.23) or (EUR 1243.38 (EUR 809.13-1683.14) assuming a willingness to pay per exacerbation avoided of AUD 2651 (EUR 1590.60). Irrespective of the sensitivity analysis applied, the net monetary benefit for total, moderate and severe exacerbations remained positive and significant.Add-on AZM therapy in poorly controlled asthma was a cost-effective therapy. Costs associated with AMR did not influence estimated cost-effectiveness.

Sputum TNF markers are increased in neutrophilic and severe asthma and are reduced by azithromycin treatment.

BACKGROUND: The AMAZES randomized controlled trial demonstrated that long-term low-dose azithromycin treatment reduces exacerbations of poorly controlled asthma, but the therapeutic mechanisms remain unclear. Dysregulation of the inflammatory tumour necrosis factor (TNF) pathway is implicated in asthma and could be suppressed by azithromycin. We aimed to determine the inflammatory and clinical associations of soluble TNF signalling proteins (TNF receptors [TNFR] 1 and 2, TNF) in sputum and serum, and to test the effect of 48 weeks of azithromycin vs placebo on TNF markers. METHODS: Sputum supernatant and serum TNFR1, TNFR2 (n = 142; 75 azithromycin-treated, 67 placebo-treated) and TNF (n = 48; 22 azithromycin-treated, 26 placebo-treated) were measured by ELISA in an AMAZES trial sub-population at baseline and end of treatment. Baseline levels were compared between sputum inflammatory phenotypes, severe/non-severe asthma and frequent/non-frequent exacerbators. Effect of azithromycin on markers was tested using linear mixed models. RESULTS: Baseline sputum TNFR1 and TNFR2 were significantly increased in neutrophilic vs non-neutrophilic asthma phenotypes, while serum markers did not differ. Sputum TNFR1 and TNFR2 were increased in severe asthma and correlated with poorer lung function, worse asthma control and increasing age. Serum TNFR1 was also increased in severe asthma. Sputum and serum TNFR2 were increased in frequent exacerbators. Azithromycin treatment significantly reduced sputum TNFR2 and TNF relative to placebo, specifically in non-eosinophilic participants. CONCLUSIONS: We demonstrate dysregulation of TNF markers, particularly in the airways, that relates to clinically important phenotypes of asthma including neutrophilic and severe asthma. Suppression of dysregulated TNF signalling by azithromycin could contribute to its therapeutic mechanism.