Search Results (60)

Background/Objectives: Patients with severe asthma (SA) commonly present with coexisting nasal polyposis (NP), often requiring treatment with intranasal corticosteroids (INC). However, adherence to INC in this population remains inadequately characterized despite its clinical significance. This study aimed to evaluate adherence to INC in patients with SA and NP and to identify clinical and pharmacological factors associated with adherence levels. Methods: We conducted a retrospective observational study including adult patients with SA and NP treated with INC and followed at a tertiary asthma unit in Madrid during 2024. Adherence was assessed via medication possession ratio (MPR) over six months, with poor adherence defined as MPR < 50%. Pharmacological, clinical and demographic variables were analyzed for associations with adherence. Results: Of the 188 patients evaluated, 86 (45.7%) were prescribed INC. Poor adherence was observed in 53.5% of these patients. Women exhibited significantly lower adherence compared to men (p < 0.05). Fluticasone was the most commonly prescribed INC (54.6%), with no significant adherence differences across corticosteroid types. Patients on maintenance systemic corticosteroids had higher adherence (85.7%, p < 0.05), whereas those receiving biologic therapies tended toward lower adherence (51% poor adherence), though this was not statistically significant. Higher adherence was associated with increased disease severity, as indicated by multiple endoscopic sinus surgeries (p < 0.05). No significant differences were observed in spirometry or Asthma Control Test scores. Conclusions: Adherence to INC in patients with SA and NP is suboptimal, particularly among women and patients on biologics. Greater disease severity correlates with improved adherence. Targeted interventions are necessary to enhance adherence and optimize disease management in this population. Full article

Background/Objectives: Due to limited current evidence, this post-marketing database surveillance study aimed to investigate the occurrence of hospitalization due to community-acquired pneumonia (CAP) among patients with chronic obstructive pulmonary disease in Japan who received single-inhaler triple therapy (fluticasone furoate/umeclidinium/vilanterol; FF/UMEC/VI) or multiple-inhaler triple therapy (MITT). Methods: This retrospective cohort study used health insurance claims data from the Medical Data Vision Co., Ltd. database (November 2017–April 2023) to identify overall and incident users of FF/UMEC/VI or MITT. Index date was the start of FF/UMEC/VI or MITT. Hazard ratios (HRs) for CAP hospitalization were assessed using inverse probability of treatment weighting based on propensity scores (PS). Incidence rates and time to occurrence of CAP hospitalization were also assessed. Adjustments were made to the PS model to address missing body mass index data. Results: In total, 8790 and 10,881 patients were included in the overall FF/UMEC/VI and MITT cohorts, and 3939 and 4017 patients were included in the incident FF/UMEC/VI and MITT cohorts, respectively. HR for CAP hospitalization among incident users ranged from 1.05 to 1.15 across all PS adjustments. Similar incidence rates of CAP hospitalization were reported among both cohorts and across all PS adjustments. The cumulative adjusted incidence rates of first CAP hospitalization at 360 days post-index among incident users was 0.060 and 0.054 in the FF/UMEC/VI and MITT cohorts, respectively. Conclusions: There was no difference in the risk of CAP between patients treated with FF/UMEC/VI and MITT. This safety information may help healthcare providers select appropriate treatments. Full article

Background/objectives: This study aimed to investigate the impact of single-inhaler triple therapy on selecting treatment for lung cancer and the perioperative period in lung cancer patients with chronic obstructive pulmonary disease (COPD) and a forced expiratory volume in 1 s (FEV₁) <1.5 L. Methods: All patients had baseline FEV₁ < 1.5 L. The therapeutic drug for COPD, fluticasone furoate/umeclidinium/vilanterol, was initiated 2 weeks preoperatively and continued until 3 months postoperatively. Radical surgery was actively recommended for patients with an FEV₁ ≥ 1.5 L after COPD treatment; otherwise, palliative surgery and postoperative complication risks were discussed. Results: Among 675 lung cancer patients, 214 (31.7%) had COPD, 41 of whom with FEV₁ < 1.5 L were enrolled. After triple-inhaler therapy, FEV₁ improved to ≥1.5 L in 63.4% of patients. Significant differences in the Brinkman index (840 vs. 1120, p = 0.0058) and radical resection (88.5% vs. 40.0%, p = 0.0030) were observed between patients with FEV₁ ≥ 1.5 L and <1.5 L post-treatment. Pneumonia and home oxygen therapy occurred in two cases (4.9%) and one case (2.4%), respectively, all of which were patients with FEV₁ < 1.5 L post-treatment. Among patients undergoing anatomical lung resection, triple-inhaler therapy significantly improved not only post-inhalation FEV₁ (1.26 vs. 1.55 L, p < 0.0001), but also FEV₁ at 3 months postoperatively compared to the value before inhalation (1.31 vs. 1.26 L, p = 0.042). Conclusions: Preoperative triple therapy in lung cancer patients with untreated COPD and FEV₁ < 1.5 L improved respiratory function and increased the feasibility of performing radical resection surgery. Furthermore, it was considered safe and effective, indicating the potential to maintain preoperative respiratory function without increasing perioperative complications. Full article

Background: Although upper and lower respiratory tract diseases coexist, studies discussing the relationship between chronic rhinitis (CR) and chronic obstructive pulmonary disease (COPD) are limited. Fluticasone nasal sprays are common treatment options for patients with rhinitis. Therefore, we aimed to investigate the effects of fluticasone nasal spray on patients with both CR and COPD. Methods: A retrospective review was performed using data from former smokers with CR and COPD at China Medical University Hospital (CMUH). Based on their medication history, patients were allocated into Group A, who had received treatment with fluticasone nasal spray, and Group B, who had never received this treatment. Pulmonary function test results, including forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC), were collected for both groups before treatment and one year after treatment. Statistical analysis was performed to evaluate the impact of fluticasone nasal spray treatment on pulmonary function. Results: A total of 123 former smokers were included, with 62 patients in Group A and 61 patients in Group B. At baseline, there was no significant difference in age, sex, and pulmonary function between the two groups. After one year of treatment, Group A showed an upward trend in pulmonary function, with the FEV1 increasing from 1.613 ± 0.554 to 1.708 ± 0.675 (p < 0.05) and the FVC increasing from 2.540 ± 0.694 to 2.670 ± 0.839 (p < 0.05). On the other hand, Group B exhibited a downward trend in pulmonary function after one year, with the FEV1 decreasing from 1.609 ± 0.554 to 1.544 ± 0.517 (p < 0.05) and the FVC decreasing from 2.586 ± 0.665 to 2.495 ± 0.679 (p < 0.05). Conclusions: This retrospective study suggests that the combined use of fluticasone nasal spray may be associated with improved pulmonary function in former smokers with both CR and COPD. This finding supports the concept of “united airway disease”. Full article

Background/Objectives: Paediatric Obstructive Sleep Apnoea (OSA) is characterised by recurrent episodes of upper airway obstruction during sleep, manifesting as snoring, intermittent oxygen desaturation, and frequent nocturnal awakenings. Standard treatments include surgical interventions, pharmacological therapies, intranasal corticosteroids, and oral montelukast. However, significant variability exists across studies regarding dosage and outcome assessment. This literature review systematically evaluated clinical evidence regarding the efficacy and safety of intranasal corticosteroids and oral montelukast for treating sleep-disordered breathing and its primary underlying condition, adenoid hypertrophy, in otherwise healthy children. Methods: The MEDLINE (PubMed), Scopus, and Web of Science databases were systematically searched up to 13 February 2025, using tailored search terms combining keywords and synonyms related to paediatric OSA, adenoidal hypertrophy, corticosteroids, montelukast, and randomised controlled trials. Owing to variability in outcome measures, Fisher’s method for p-value combination was employed to enable a comprehensive comparison of drug effects. Results: Available evidence shows that intranasal corticosteroids (mometasone, beclometasone, budesonide, fluticasone, and flunisolide), either as monotherapy or in combination with other agents, consistently lead to clinical and instrumental improvements in adenoid hypertrophy and related respiratory symptoms, with a generally favourable safety profile. Combining montelukast with intranasal corticosteroids appears to offer superior benefits compared with monotherapy. Nevertheless, the reviewed studies varied widely in dosage, treatment duration, design, and sample size. The reported side effects are mostly mild; however, long-term studies are lacking to establish the complete safety of these treatments in children. Conclusions: Intranasal corticosteroids and oral montelukast effectively and safely manage adenoid hypertrophy and mild-to-moderate OSA symptoms in children. Nonetheless, the heterogeneity of study designs necessitates larger prospective trials with standardised protocols and more extended follow-up periods to draw more robust conclusions. Future studies should aim to stratify treatment outcomes based on OSA severity and duration to tailor therapeutic approaches better. Full article

Background: Japanese guidelines recommend the addition of a long-acting muscarinic antagonist for patients with asthma uncontrolled on inhaled corticosteroid/long-acting β₂-agonist (ICS/LABA) therapy, the effectiveness of which is evaluated here. Methods: Retrospective, observational, single-arm cohort study in patients with asthma initiating fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) following ICS/LABA, using independently analyzed data from Japanese claims databases: JMDC and Medical Data Vision (MDV). The index date was that of the first FF/UMEC/VI prescription. Outcomes were assessed during a 12-month follow-up versus a 12-month pre-index period (baseline) and included asthma exacerbations, oral corticosteroid (OCS) use, and short-acting β₂-agonist (SABA) use. P-values associated with rate ratios (RRs) were estimated using Conditional Poisson regression. Results: Overall, 3229 patients in the JMDC database and 1135 in the MDV database were included. Following FF/UMEC/VI initiation, the total annualized moderate–severe asthma exacerbation rate in the JMDC database reduced from 0.50 to 0.40 per-person-per-year (PPPY) (RR [95% confidence interval]: 0.78 [0.73, 0.84]; p < 0.001), with similar reductions in the MDV database: 0.53 to 0.42 PPPY (0.79 [0.70, 0.89]; p < 0.001). In both databases, there was a 20% reduction (JMDC: 0.80 [0.73, 0.88]; p < 0.001; MDV: 0.80 [0.68, 0.94]; p = 0.005) in patients with ≥1 OCS prescription after FF/UMEC/VI initiation. The proportion of patients with ≥1 SABA canister prescription dropped by 31% 0.69 [0.57, 0.84]; p < 0.001) in the JMDC database and 23% (0.77 [0.66, 0.90]; p < 0.001) in the MDV database. Conclusions: This suggests FF/UMEC/VI is effective in improving asthma exacerbations and reducing OCS and SABA use in Japanese patients previously using ICS/LABA in real-world clinical practice. Full article

The diagnosis and monitoring of eosinophilic esophagitis (EoE), a common pediatric pathology, typically involves invasive procedures such as an upper endoscopy with biopsies, imposing a significant burden on patients and healthcare systems. We aimed to assess miR-21-5p and miR-223-3p levels in pediatric EoE patients and evaluate their as potential non-invasive biomarkers of disease activity and response to treatments. We enrolled 13 children with EoE and 8 controls. Plasma and esophageal mucosa samples from patients were collected at diagnosis and after 8–10 weeks of therapy and compared with control samples. After microRNA(miRNA) extraction, the levels of miR-21-5p and miR-223-3p and their relevant target genes were analyzed. Bioinformatic analysis was used to identify the predicted target genes and pathways that are potentially relevant for disease pathophysiology. Plasma levels of miR-21-5p and miR-223-3p were significantly higher in EoE patients than in the controls, reflecting their levels in esophageal mucosa. The target genes of these miRNAs are involved in key signaling pathways (MAPK, Ras, and FoxO), relevant for EoE pathophysiology. Among these, STAT3 (Signal Transducer and Activator of Transcription 3) and PTEN (Phosphatase and Tensin Homolog), which are significantly downregulated in patient esophageal mucosa, are implicated in eosinophilic gastroenteropathies and autoimmune diseases. Following therapy (proton pump inhibitors and/or fluticasone propionate), plasma and tissue expression of both miRNAs significantly decreased and were no longer different from the controls. These microRNAs may serve as complementary non-invasive EoE markers and reduce the need for endoscopy/biopsies. Full article

Background/Objectives: Inhaler devices have been developed for the effective delivery of inhaled medications used in the treatment of pulmonary diseases. However, differing operating procedures across the devices can lead to user errors and reduce treatment efficacy, especially when patients use multiple devices simultaneously. To address this, we developed a novel dry powder inhaler (DPI), combining fluticasone propionate (FP), salmeterol xinafoate (SX), and tiotropium bromide (TB) into a single device designed for bioequivalent delivery compared to existing commercial products in an animal model. Methods: The micronized FP/SX/TB-loaded capsule was prepared by sieving, blending, and filling capsules. Capsule suitability of the drugs was investigated from the comparison of the stability of drugs within various capsule formulations to that of commercial products. The particle size of the drugs was adjusted using spiral air jet milling, and the ratio of lactose hydrate carriers was optimized by comparing the aerodynamic particle size distribution (APSD) with that of commercial products. To investigate the bioequivalence of micronized FP/SX/TB-loaded DPI to commercial products, the dissolution profile of FP/SX/TB particles and pharmacokinetics in rats were evaluated and compared to commercial products. Results: Capsules with hydroxypropyl methylcellulose (HPMC) without a gelling agent showed superior stability of the drugs compared to commercial products. The deposition pattern was influenced by the particle size of the drugs, and fine particle mass exhibited a significant correlation with the amount of fine carrier. Micronized FP/SX/TB-loaded DPI gave a similar APSD and dissolution profile compared to the commercial products and showed dose uniformity by the DPI device. Furthermore, micronized FP/SX/TB-loaded DPI exhibited bioequivalence to commercial products, as evidenced by no significant differences in pharmacokinetic parameters following intratracheal administration in rats. Conclusions: A novel triple-combination DPI containing FP/SX/TB was successfully developed, demonstrating comparable pharmacological performance to commercial products. Optimized FP/SX/TB-loaded DPI with HPMC capsule achieved bioequivalence in rat studies, suggesting its potential for improved patient compliance and therapeutic outcomes. This novel single-device DPI offers a promising alternative for triple therapy in pulmonary diseases. Full article

Asthma is a chronic lung disease characterized by airway inflammation, hyperresponsiveness, and narrowing, with a risk of life-threatening attacks. Most current treatments primarily consist of inhalable steroids, which are not without adverse effects. Recently, there has been growing interest in alternative approaches to asthma management. In this study, we investigated the anti-asthmatic effects of the non-steroidal compound CycloZ using acute and chronic mouse models of asthma. Allergic reactions were induced with house dust mite (HDM) extract, and CycloZ or fluticasone propionate (FP) was administered orally or intranasally, respectively. CycloZ significantly ameliorated the HDM-induced robust expression of Th2 cytokines in both models. CycloZ also decreased immune cell infiltration into the lungs and reduced IL-4 and IL-13 cytokine levels in bronchoalveolar lavage fluid (BALF). Moreover, CycloZ greatly attenuated the activation of the TLR-4 pathway, which is involved in HDM recognition and signaling. The beneficial effects of CycloZ were comparable to or even superior to the current steroid treatment, FP, suggesting that CycloZ could be a promising new option for asthma therapy. Full article

Background/Objectives: Effective airway delivery of a fixed-dose combination of triple-aerosolized inhaled corticosteroid (ICS)/long-acting beta agonist (LABA)/long-acting muscarinic antagonist (LAMA) is likely to positively affect therapeutic responses predicted in patients with asthma and chronic obstructive pulmonary disease. This study aimed to conduct in vitro fluticasone furoate, vilanterol trifenatate, and umeclidinium bromide depositions in a Next Generation Impactor. The aerodynamic properties of these inhaled medications influence the spatial distribution and drug abundance, particularly in the smaller airways, to reverse or alleviate disease pathology. Methods: The Next Generation Impactor was used to demonstrate the aerodynamic particle size distributions of fluticasone furoate, vilanterol trifenatate, and umeclidinium bromide delivered from a dry powder inhaler at different flow rates across all stages of the impactors. This in vitro study analyzed the distribution pattern of individual drug components to simulate mono-component deposition and co-deposition in the official model in the United States Pharmacopeia. An Andersen cascade impactor together with scanning electron microscope–energy-dispersive X-ray was employed to observe the drug deposition on each stage of the impactor. Results: We found that the distribution pattern of each component at the same cascade level was comparable, and the aerosol particles of the three drugs reached the in vitro representation of the lower airway compartment. The specified flow rates generated the desired fine particle fraction, fine particle dose, and mass median aerodynamic diameter. Our results also demonstrated visualized deposition patterns of the delivered drugs from different stages of the cascade impactor that may predict deposition as it occurs in vivo. Conclusions: Spatial distribution and abundance of ICS/LABA/LAMA in the same cascade levels were closely comparable, and the aerosol particles were able to reach the small aerosol-sized cascades at the lower levels to some extent. Full article

Background: Patients’ compliance to inhalation therapy is usually sub-optimal in young asthmatics. Adolescents poorly compliant to regular anti-asthma treatments and those with tattoos (and the associated attitude) can share some personality traits and maladaptive behaviors. This relationship has not been investigated. Objective: To assess if “extended” tattoos can predict long-term compliance to regular therapy of adolescents with mild-to-moderate asthma. Methods: A 12-month retrospective observational investigation was conducted on non-smoker asthmatic adolescents of both genders. Patients assuming <70% of prescribed vilanterol/fluticasone furoate o.d. were defined as “non-compliant”. Tattoo surfaces were defined as “mild” or “extended” if they were < or ≥400 cm², respectively. The relationship between tattoos and compliance on the evolution of resources consumption at 6 and 12 months was assessed by generalized estimating equation (GEE) models at the first and second semester of the treatment period. Results: It was found that 13.2% of compliant adolescents had mild tattoos, while 47.2% of non-compliant adolescents had mild-to-extended tattoos (odds ratio (OR) 6.91, 95% CI 2.49 to 19.17, p < 0.001). The mean annual adherence to treatment was 57.8% ± 10.1 SD expected doses in non-compliant subjects with “mild tattoos” (54.8 cm² ± 36.9 SD), but 38.6% ± 11.4 SD expected doses in those with “extended tattoos” (568.4 cm² ± 111.6 SD, p < 0.001). Total cost proved to be a linear trend from the lowest values of compliant patients with no/mild tattoos (EUR 65.22 at 6 months and EUR 33.63 at 12 months) to the highest values of non-compliant adolescents with extended tattoos (EUR 330.75 at 6 months and EUR 297.34 at 12 months). Conclusions: Tattoo extension might be used as a reliable predictor of poor compliance and higher health care costs in adolescents with mild-to-moderate asthma. Patients characterized by poor compliance to a long-term therapeutic strategy and tattooing attitude likely share some aspects of their personality profile. Full article

(1) Background: Sleep-disordered breathing and asthma are often interrelated. Children and adults with asthma are more susceptible to sleep apnea. Inhaled corticosteroids effectively reduce inflammation and prevent structural changes in the airways. Objective: to explore the existing literature to determine whether inhaled corticosteroids play a role in sleep-disordered breathing in patients with asthma. (2) Methods: We conducted a thorough search of the PubMed, Scopus, and Web of Science databases for English-language articles published up to 12 May 2024. We utilized the ROBINS-E tool to assess the risk of bias. (4) Conclusions: 136 articles were discerned upon conducting the literature search. A total of 13 articles underwent exhaustive full-text scrutiny, resulting in 6 being considered non-relevant. The remaining seven articles, assessed for eligibility, were incorporated into the final analysis. Five studies were identified in adults and two in children. In adult patients, inhaled corticosteroids, especially at high doses, appear to increase the risk of sleep apnea in a dose-dependent manner. Moreover, the properties of inhaled corticosteroids, such as particle size, may impact the risk of developing sleep apnea. In children, the severity of asthma is a key factor affecting the prevalence of sleep apnea, whereas inhaled corticosteroids appear to be a less significant risk factor compared to adults. All of the studies reviewed were classified as having a high risk of bias or some concerns regarding bias. Each study revealed at least one type of bias that raised notable concerns. This research highlights a complex interaction between the use of inhaled corticosteroids, the severity of asthma, and the onset of sleep apnea. Additional research is necessary to investigate these relationships further. Full article

The deposition, residence time, and dissolution profile of nasal suspensions containing corticosteroids play a key role in their in vivo efficacy after administration. However, the conventional methods available to characterize nasal products appear to be unsuitable to exhaustively cover these aspects. The work aims to investigate technological aspects of Ryaltris (mometasone furoate and olopatadine hydrochloride nasal spray) compared to other commercial anti-allergic nasal products, namely, Dymista (azelastine hydrochloride and fluticasone propionate), Nasonex (mometasone furoate), and Avamys (fluticasone furoate). Innovative characterization methods were combined with more traditional approaches to investigate the anti-allergic nasal sprays. These methods applied together allowed to differentiate between the different products and provided a clear picture of the nasal product behavior in terms of drug dissolution and deposition. In particular, the dissolution tests were performed exploiting the Respicell^® apparatus, an innovative technique that allows for the investigation of inhalation products. Then, formulation viscosities were considered along with a formulation flow test on an inclined plane. Finally, the intranasal deposition profile of the commercial formulations was determined using a silicon nasal cast. The results highlight in vitro significant differences in terms of viscosity as well as dissolution rate of the nasal products, with Ryaltris showing a higher viscosity and lower flow compared to other products, which, along with a corticosteroid faster dissolution rate than Dymista, suggest a potential advantage in terms of clinical behavior. Full article

Background: Macrophages and monocytes orchestrate inflammatory processes in the lungs. However, their role in the pathogenesis of chronic obstructive pulmonary disease (COPD), an inflammatory condition, is not well known. Here, we determined the characteristics of these cells in lungs of COPD patients and identified novel therapeutic targets. Methods: We analyzed the RNA sequencing (scRNA-seq) data of explanted human lung tissue from COPD (n = 18) and control (n = 28) lungs and found 16 transcriptionally distinct groups of macrophages and monocytes. We performed pathway and gene enrichment analyses to determine the characteristics of macrophages and monocytes from COPD (versus control) lungs and to identify the therapeutic targets, which were then validated using data from a randomized controlled trial of COPD patients (DISARM). Results: In the alveolar macrophages, 176 genes were differentially expressed (83 up- and 93 downregulated; P_adj < 0.05, |log₂FC| > 0.5) and were enriched in downstream biological processes predicted to cause poor lipid uptake and impaired cell activation, movement, and angiogenesis in COPD versus control lungs. Classical monocytes from COPD lungs harbored a differential gene set predicted to cause the activation, mobilization, and recruitment of cells and a hyperinflammatory response to influenza. In silico, the corticosteroid fluticasone propionate was one of the top compounds predicted to modulate the abnormal transcriptional profiles of these cells. In vivo, a fluticasone–salmeterol combination significantly modulated the gene expression profiles of bronchoalveolar lavage cells of COPD patients (p < 0.05). Conclusions: COPD lungs harbor transcriptionally distinct lung macrophages and monocytes, reflective of a dysfunctional and hyperinflammatory state. Inhaled corticosteroids and other compounds can modulate the transcriptomic profile of these cells in patients with COPD. Full article

Bronchial asthma is characterized by variable airflow obstruction, airway inflammation, and bronchial hyperresponsiveness (BHR) to non-specific stimuli. The role of underlying airway inflammation and of related long-lasting BHR has been suboptimally investigated in teenagers with mild-to-moderate asthma, as has the corresponding economic impact over time. The aim of the present study was to calculate the cost of mild-to-moderate atopic asthma in teenagers arising from their degree of persisting BHR over a twelve-month period. Methods: Patients aged 12–18 years with mild-to-moderate symptoms treated with fluticasone fumarate/vilanterol 92/22 mcg daily were retrospectively followed for 12 months. Usual spirometric parameters, BHR to methacholine (MCh), and resource consumption (visits, hospitalizations, systemic steroids and/or antibiotics courses, school days off) were assessed at recruitment (the index date) and after 6 and 12 months. Adherence to treatment was also calculated. The cost of asthma was calculated based on Italian tariffs and published papers. The trend over time in BHR and the association between response to MCh and total cost were investigated by using regression models adjusted for repeated measures. Results: 106 teenagers (53 males, age 15.9 ± 1.6 years) were investigated. The annual cost of asthma proved significantly related to the BHR trend: every increment of a factor 10 in the response to MCh was associated with a saving of EUR 184.90 (95% CI −305.89 to −63.90). BHR was progressively optimized after 6 and 12 months in relation to the patients’ compliance to treatment (≥70% of prescribed inhalation doses). Conclusions: the usual spirometric parameters are largely insufficient to reflect the effects of underlying persistent inflammation in milder forms of asthma in teenagers. In terms of clinical governance, the periodic assessment of non-specific BHR is the appropriate procedure from this point of view. Non-specific BHR proves a reliable procedure for predicting and monitoring the economic impact of mild-to-moderate asthma in teenagers over time. Full article