Feasibility of low-intensity psychological interventions for emotional and behavioural difficulties in children and young people with genetic conditions: a case series

Background: Children with genetic conditions may experience significant mental health difficulties such as anxiety and challenging behaviour. However, understanding of the feasibility and effectiveness of psychological interventions for emotional and behavioural problems in the context of genetic conditions is limited. Low-intensity psychological interventions have demonstrated promise in paediatric populations and may be able to address their mental health difficulties. / Method: A case series design was used to assess the feasibility of low-intensity interventions for emotional and behavioural difficulties in children and young people with genetic conditions recruited from a mental health drop-in centre at a tertiary hospital. Participants received seven weekly sessions with a trained practitioner. The intervention was based on existing modular treatments and evidence-based self-help materials. Feasibility and treatment satisfaction were assessed, as well as measures of symptoms of anxiety and challenging behaviour, treatment goals, and quality of life, at baseline, during treatment, and six-month follow-up. / Results: Five participants received treatment for challenging behaviour, one for anxiety, and one for obsessive compulsive disorder. All participants completed treatment. Clinically significant change in the SDQ Total score was found in three participants. All participants demonstrated progress in goals and symptoms of emotional and behavioural difficulties over the course of treatment. / Conclusions: Low-intensity psychological interventions for emotional and behavioural difficulties in children and young people with genetic conditions is feasible, acceptable, and potentially beneficial. Further research is warranted to examine the effectiveness of the intervention and its use in clinical paediatric settings

Juvenile Idiopathic Arthritis Subtype- and Sex-specific Associations with Genetic Variants in the PSMA6/PSMC6/PSMA3 Gene Cluster

BackgroundThe ubiquitin proteasome system plays an exceptional biological role in the antigen processing and immune response and it could potentially be involved in pathogenesis of many immunity-related diseases, including juvenile idiopathic arthritis (JIA).MethodsThe PSMB5 (rs11543947), PSMA6 (rs2277460, rs1048990), PSMC6 (rs2295826, rs2295827), and PSMA3 (rs2348071) proteasomal genes were genotyped on JIA subtype- and sex-specific association; plasma proteasome levels was measured in patients having risk and protective four-locus genotypes and eventual functional significance of allele substitutions was evaluated in silico.ResultsLoci rs11543947 and rs1048990 were identified as disease neutral and other loci as disease susceptible (p < 0.05). The rs2277460, rs2295826, and rs2295827 loci had the strongest association with oligoarthritis [odds ratio (OR) = 2.024, 95% confidence interval (CI) 1.101–3.722; OR = 2.371, 95% CI 1.390–4.044; OR = 2.183, 95% CI 1.272–2.737, respectively), but the rs2348071 locus was associated with polyarthritis in females (OR = 3.438, 95% CI 1.626–7.265). A strong (p < 0.001) association was detected between the rs2277460/rs2295826/rs2295827/rs2348071 four-locus genotypes and the healthy phenotype when all loci were homozygous on common alleles (OR 0.439, 95% CI 0.283–0.681) and with the disease phenotype when the rs2348071 and the rs2295826 and/or rs2295827 loci were represented by risk genotypes simultaneously (OR 4.674, 95% CI 2.096–10.425). Rarely observed in controls, the double rs2277460/rs2348071 heterozygotes were rather frequent in affected males and more strongly associated with polyarthritis (p < 0.05). Haplotypes carrying the rare rs2295826/rs2295827 and rs2277460 alleles showed a strong (p < 0.001) association with oligo- and polyarthritis, respectively. The plasma proteasome level was found to be significantly higher in females having four-locus risk genotypes compared with protective genotypes (p < 0.001). Sequence affinity to transcription factors and similarity to splicing signals, microRNAs and/or hairpin precursors potentially depend on allele substitutions in disease susceptible loci.ConclusionWe demonstrate for the first time evidence of a sex-specific association of PSMA6/PSMC6/PSMA3 genetic variants with subtypes of JIA and plasma proteasome concentrations. Theoretical models of the functional significance of allele substitutions are discussed

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Health-related quality of life and symptoms in patients with IPF treated with nintedanib: analyses of patient-reported outcomes from the INPULSIS (R) trials

BACKGROUND: In the Phase III INPULSIS® trials, treatment of patients with idiopathic pulmonary fibrosis (IPF) with nintedanib significantly reduced the annual rate of decline in forced vital capacity (FVC) versus placebo, consistent with slowing disease progression. However, nintedanib was not associated with a benefit in health-related quality of life (HRQoL) assessed using the St George's respiratory questionnaire (SGRQ). We aimed to further examine the impact of IPF progression on HRQoL and symptoms, and to explore the effect of nintedanib on HRQoL in patients from the INPULSIS® trials stratified by clinical factors associated with disease progression. METHODS: Patient-reported outcome (PRO) data from the INPULSIS® trials were included in three post hoc analyses. Two analyses used the pooled data set to examine PRO changes from baseline to week 52 according to 1) decline in FVC and 2) occurrence of acute exacerbations. In the third analysis, patients were stratified based on clinical indicators of disease progression (gender, age and physiology [GAP] stage; FVC % predicted; diffusing capacity of the lung for carbon monoxide [DLCO] % predicted; composite physiologic index [CPI]; and SGRQ total score) at baseline; median change from baseline was measured at 52 weeks and treatment groups were compared using the Wilcoxon two-sample test. RESULTS: Data from 1061 patients (638 nintedanib, 423 placebo) were analyzed. Greater categorical decline from baseline in FVC % predicted over 52 weeks was associated with significant worsening of HRQoL and symptoms across all PRO measures. Acute exacerbations were associated with deterioration in HRQoL and worsened symptoms. In general, patients with advanced disease at baseline (defined as GAP II/III, FVC ≤ 80%, DLCO ≤ 40%, CPI >  45, or SGRQ > 40) experienced greater deterioration in PROs than patients with less-advanced disease. Among patients with advanced disease, compared with placebo, nintedanib slowed deterioration in several PROs; benefit was most apparent on the SGRQ (total and activity scores). CONCLUSIONS: In patients with advanced IPF, compared with placebo, nintedanib slowed deterioration in HRQoL and symptoms as assessed by several PROs. HRQoL measures have a higher responsiveness to change in advanced disease and may lack sensitivity to capture change in patients with less-advanced IPF.status: publishe

Health-related quality of life and symptoms in patients with IPF treated with nintedanib: analyses of patient-reported outcomes from the INPULSIS® trials

BACKGROUND: In the Phase III INPULSIS® trials, treatment of patients with idiopathic pulmonary fibrosis (IPF) with nintedanib significantly reduced the annual rate of decline in forced vital capacity (FVC) versus placebo, consistent with slowing disease progression. However, nintedanib was not associated with a benefit in health-related quality of life (HRQoL) assessed using the St George's respiratory questionnaire (SGRQ). We aimed to further examine the impact of IPF progression on HRQoL and symptoms, and to explore the effect of nintedanib on HRQoL in patients from the INPULSIS® trials stratified by clinical factors associated with disease progression. METHODS: Patient-reported outcome (PRO) data from the INPULSIS® trials were included in three post hoc analyses. Two analyses used the pooled data set to examine PRO changes from baseline to week 52 according to 1) decline in FVC and 2) occurrence of acute exacerbations. In the third analysis, patients were stratified based on clinical indicators of disease progression (gender, age and physiology [GAP] stage; FVC % predicted; diffusing capacity of the lung for carbon monoxide [DLCO] % predicted; composite physiologic index [CPI]; and SGRQ total score) at baseline; median change from baseline was measured at 52 weeks and treatment groups were compared using the Wilcoxon two-sample test. RESULTS: Data from 1061 patients (638 nintedanib, 423 placebo) were analyzed. Greater categorical decline from baseline in FVC % predicted over 52 weeks was associated with significant worsening of HRQoL and symptoms across all PRO measures. Acute exacerbations were associated with deterioration in HRQoL and worsened symptoms. In general, patients with advanced disease at baseline (defined as GAP II/III, FVC ≤ 80%, DLCO ≤ 40%, CPI >  45, or SGRQ > 40) experienced greater deterioration in PROs than patients with less-advanced disease. Among patients with advanced disease, compared with placebo, nintedanib slowed deterioration in several PROs; benefit was most apparent on the SGRQ (total and activity scores). CONCLUSIONS: In patients with advanced IPF, compared with placebo, nintedanib slowed deterioration in HRQoL and symptoms as assessed by several PROs. HRQoL measures have a higher responsiveness to change in advanced disease and may lack sensitivity to capture change in patients with less-advanced IPF

Developing a conceptual model of symptoms and impacts in progressive fibrosing interstitial lung disease to evaluate patient-reported outcome measures

Background An understanding of the experience of patients with progressive fibrosing interstitial lung disease (PF-ILD) is needed to select appropriate patient-reported outcome measures (PROMs) to evaluate treatment effect in clinical trials. Methods A systematic literature review was conducted to develop a preliminary conceptual model of the symptoms experienced by patients with PF-ILD and the impacts the disease has on them. An online survey and consensus meetings were then conducted with 12-14 stakeholders (patients, clinicians, regulatory and payer advisors) to refine the conceptual model and critically appraise how key concepts should be measured by PROMs. PROMs assessed included Living with Idiopathic Pulmonary Fibrosis, Living with Pulmonary Fibrosis, the King's Brief Interstitial Lung Disease questionnaire, Cough and Sputum Assessment Questionnaire, Evaluating Respiratory Symptoms, Leicester Cough Questionnaire, Functional Assessment of Chronic Illness Therapy (Dyspnoea/Fatigue) and St George's Respiratory Questionnaire for Idiopathic Pulmonary Fibrosis. Results The literature review identified 36 signs/symptoms and 43 impacts directly or indirectly related to pulmonary aspects of PF-ILD. The most relevant symptoms identified by participants included shortness of breath on exertion, fatigue and cough; relevant impacts included effects on physical functioning, activities of daily living and emotional wellbeing. These are presented in a conceptual model. Consensus opinion was that existing PROMs need further modification and validation before use in clinical trials. Conclusions The conceptual model improves understanding of the symptoms and impacts that living with PF-ILD has on patients' wellbeing. It can help to inform the choice of PROMs in clinical trials and highlight aspects to assess in the clinical care of patients with PF-ILD

Health-related quality of life and symptoms in patients with IPF treated with nintedanib: analyses of patient-reported outcomes from the INPULSIS® trials

Abstract Background In the Phase III INPULSIS® trials, treatment of patients with idiopathic pulmonary fibrosis (IPF) with nintedanib significantly reduced the annual rate of decline in forced vital capacity (FVC) versus placebo, consistent with slowing disease progression. However, nintedanib was not associated with a benefit in health-related quality of life (HRQoL) assessed using the St George’s respiratory questionnaire (SGRQ). We aimed to further examine the impact of IPF progression on HRQoL and symptoms, and to explore the effect of nintedanib on HRQoL in patients from the INPULSIS® trials stratified by clinical factors associated with disease progression. Methods Patient-reported outcome (PRO) data from the INPULSIS® trials were included in three post hoc analyses. Two analyses used the pooled data set to examine PRO changes from baseline to week 52 according to 1) decline in FVC and 2) occurrence of acute exacerbations. In the third analysis, patients were stratified based on clinical indicators of disease progression (gender, age and physiology [GAP] stage; FVC % predicted; diffusing capacity of the lung for carbon monoxide [DLCO] % predicted; composite physiologic index [CPI]; and SGRQ total score) at baseline; median change from baseline was measured at 52 weeks and treatment groups were compared using the Wilcoxon two-sample test. Results Data from 1061 patients (638 nintedanib, 423 placebo) were analyzed. Greater categorical decline from baseline in FVC % predicted over 52 weeks was associated with significant worsening of HRQoL and symptoms across all PRO measures. Acute exacerbations were associated with deterioration in HRQoL and worsened symptoms. In general, patients with advanced disease at baseline (defined as GAP II/III, FVC ≤ 80%, DLCO ≤ 40%, CPI &gt; 45, or SGRQ &gt; 40) experienced greater deterioration in PROs than patients with less-advanced disease. Among patients with advanced disease, compared with placebo, nintedanib slowed deterioration in several PROs; benefit was most apparent on the SGRQ (total and activity scores). Conclusions In patients with advanced IPF, compared with placebo, nintedanib slowed deterioration in HRQoL and symptoms as assessed by several PROs. HRQoL measures have a higher responsiveness to change in advanced disease and may lack sensitivity to capture change in patients with less-advanced IPF