Maternal immune activation during pregnancy is associated with more difficulties in socio-adaptive behaviors in autism spectrum disorder.

Autism spectrum disorder (ASD) are neurodevelopmental conditions characterised by deficits in social communication and interaction and repetitive behaviours. Maternal immune activation (MIA) during the mid-pregnancy is a known risk factor for ASD. Although reported in 15% of affected individuals, little is known about the specificity of their clinical profiles. Adaptive skills represent a holistic approach to a person's competencies and reflect specifically in ASD, their strengths and difficulties. In this study, we hypothesised that ASD individual with a history of MIA (MIA+) could be more severely socio-adaptively impaired than those without MIA during pregnancy (MIA-). To answer this question, we considered two independent cohorts of individuals with ASD (PARIS study and FACE ASD) screened for pregnancy history, and used supervised and unsupervised machine learning algorithms. We included 295 mother-child dyads with 14% of them with MIA+. We found that ASD-MIA+ individuals displayed more severe maladaptive behaviors, specifically in their socialization abilities. MIA+ directly influenced individual's socio-adaptive skills, independent of other covariates, including ASD severity. Interestingly, MIA+ affect persistently the socio-adaptive behavioral trajectories of individuals with ASD. The current study has a retrospective design with possible recall bias regarding the MIA event and, even if pooled from two cohorts, has a relatively small population. In addition, we were limited by the number of covariables available potentially impacted socio-adaptive behaviors. Larger prospective study with additional dimensions related to ASD is needed to confirm our results. Specific pathophysiological pathways may explain these clinical peculiarities of ASD- MIA+ individuals, and may open the way to new perspectives in deciphering the phenotypic complexity of ASD and for the development of specific immunomodulatory strategies.

Sex-specific associations of comorbidome and pulmorbidome with mortality in chronic obstructive pulmonary disease: results from COSYCONET.

In patients with COPD, it has not been comprehensively assessed whether the predictive value of comorbidities for mortality differs between men and women. We therefore aimed to examine sex differences of COPD comorbidities in regard with prognosis by classifying comorbidities into a comorbidome related to extrapulmonary disorders and a pulmorbidome, referring to pulmonary disorders. The study population comprised 1044 women and 1531 men with the diagnosis of COPD from COSYCONET, among them 2175 of GOLD grades 1-4 and 400 at risk. Associations of comorbidities with mortality were studied using Cox regression analysis for men and women separately. During the follow-up (median 3.7 years) 59 women and 159 men died. In men, obesity, hypertension, coronary artery disease, liver cirrhosis, osteoporosis, kidney disease, anaemia and increased heart rate (HR) predict mortality, in women heart failure, hyperuricemia, mental disorders, kidney disease and increased HR (p < 0.05 each). Regarding the pulmorbidome, significant predictors in men were impairment in diffusion capacity and hyperinflation, in women asthma and hyperinflation. Similar results were obtained when repeating the analyses in GOLD 1-4 patients only. Gender differences should be considered in COPD risk assessment for a tailored approach towards the treatment of COPD.Clinical Trial Registration: ClinicalTrials.gov NCT01245933.

Activation of immune cell proteasomes in peripheral blood of smokers and COPD patients: implications for therapy.

BACKGROUND: Immune cells contain a specialised type of proteasome, i.e. the immunoproteasome, which is required for intracellular protein degradation. Immunoproteasomes are key regulators of immune cell differentiation, inflammatory activation and autoimmunity. Immunoproteasome function in peripheral immune cells might be altered by smoking and in chronic obstructive pulmonary disease (COPD), thereby affecting immune cell responses. METHODS: We analysed the expression and activity of proteasome complexes in peripheral blood mononuclear cells (PBMCs) isolated from healthy male young smokers as well as from patients with severe COPD and compared them with matching controls. RESULTS: Proteasome expression was upregulated in COPD patients as assessed by quantitative reverse transcriptase-PCR and mass spectrometry-based proteomic analysis. Proteasome activity was quantified using activity-based probes and native gel analysis. We observed distinct activation of immunoproteasomes in the peripheral blood cells of young male smokers and severely ill COPD patients. Native gel analysis and linear regression modelling confirmed robust activation and elevated assembly of 20S proteasomes, which correlated significantly with reduced lung function parameters in COPD patients. The immunoproteasome was distinctly activated in COPD patients upon inflammatory cytokine stimulation of PBMCs in vitro. Inhibition of the immunoproteasome reduced pro-inflammatory cytokine expression in COPD-derived blood immune cells. CONCLUSIONS: Given the crucial role of chronic inflammatory signalling and the emerging involvement of autoimmune responses in COPD, therapeutic targeting of the immunoproteasome might represent a novel therapeutic concept for COPD.

Biomarkers for Comorbidities Modulate the Activity of T-Cells in COPD.

In smoking-induced chronic obstructive pulmonary disease (COPD), various comorbidities are linked to systemic inflammation and infection-induced exacerbations. The underlying mechanisms are unclear but might provide therapeutic targets. T-cell activity is central in systemic inflammation and for infection-defense mechanisms and might be influenced by comorbidities. Hypothesis: Circulating biomarkers of comorbidities modulate the activity of T-cells of the T-helper type 1 (Th1) and/or T-cytotoxic type 1 (Tc1). T-cells in peripheral blood mononuclear cells (PBMCs) from non-smokers (NS), current smokers without COPD (S), and COPD subjects (total n = 34) were ex vivo activated towards Th1/Tc1 and were then stimulated with biomarkers for metabolic and/or cardiovascular comorbidities (Brain Natriuretic Peptide, BNP; chemokine (C-C motif) ligand 18, CCL18; C-X3-C motif chemokine ligand 1, CX3CL1; interleukin-18, IL-18) or for asthma- and/or cancer-related comorbidities (CCL22; epidermal growth factor, EGF; IL-17; periostin) each at 10 or 50 ng/mL. The Th1/Tc1 activation markers interferon-γ (IFNγ), tumor necrosis factor-α (TNFα), and granulocyte-macrophage colony-stimulating factor (GM-CSF) were analyzed in culture supernatants by Enzyme-Linked Immunosorbent Assay (ELISA). Ex-vivo activation induced IFNγ and TNFα without differences between the groups but GM-CSF more in S vs. NS. At 10 ng/mL, the different biomarkers increased or reduced the T-cell activation markers without a clear trend for one direction in the different categories of comorbidities or for the different T-cell activation markers. At 50 ng/mL, there was a clear shift towards suppressive effects, particularly for the asthma- and cancer-related biomarkers and in cells of S and COPD. Comorbidities might suppress T-cell immunity in COPD. This could explain the association of comorbidities with frequent exacerbations.

Real-life effectiveness of biological therapies on symptoms in severe asthma with comorbid CRSwNP.

BACKGROUND: We aimed to evaluate the effectiveness of different antibody therapies on nasal polyp symptoms in patients treated for severe asthma. METHODS: We performed a retrospective analysis of patients with severe asthma and comorbid CRSwNP who were treated with anti-IgE, anti-IL-5/R or anti-IL-4R. CRSwNP symptom burden was evaluated before and after 6 months of therapy. RESULTS: Fifty patients were included hereof treated with anti-IgE: 9, anti-IL-5/R: 26 and anti-IL-4R: 15 patients. At baseline median SNOT-20 was similar among groups (anti-IgE: 55, anti-IL-5/R: 52 and anti-IL-4R: 56, p = 0.76), median visual analogue scale (VAS) for nasal symptoms was 4, 7 and 8 (p = 0.14) and VAS for total symptoms was higher in the anti-IL-4R group (4, 5 and 8, p = 0.002). After 6 months SNOT-20 improved significantly in all patient groups with median improvement of anti-IgE: -8 (p < 0.01), anti-IL-5/R: -13 (p < 0.001) and anti-IL-4R: -18 (p < 0.001), with larger improvement in the anti-IL-4R group than in anti-IgE (p < 0.001) and anti-IL-5/R (p < 0.001) groups. VAS nasal symptoms improved by median anti-IgE: 0 (n.s.), anti-IL-5/R: -1 (p < 0.01) and anti-IL-4R: -3 (p < 0.001), VAS total symptoms by anti-IgE: -1 (n.s.), anti-IL-5/R: -2 (p < 0.001) and anti-IL-4R: -2 (p < 0.001). CONCLUSIONS: Treatment by all antibodies showed effectiveness in reducing symptoms of CRSwNP in patients with severe asthma, with the largest reduction observed in anti-IL-4R-treated patients.

Exposure to welding fumes suppresses the activity of T-helper cells.

Welders have an increased susceptibility to airway infections with non-typeable Haemophilus influenzae (NTHi), which implicates immune defects and might promote pneumonia and chronic obstructive pulmonary disease (COPD). We hypothesized that welding-fume exposure suppresses Th1-lymphocyte activity. Non-effector CD4+ T-cells from blood of 45 welders (n = 23 gas metal arc welders, GMAW; n = 16 tungsten inert gas welders, TIG; n = 6 others) and 25 non-welders were ex vivo activated towards Th1 via polyclonal T-cell receptor stimulation and IL-12 (first activation step) and then stimulated with NTHi extract or lipopolysaccharide (LPS) (second activation step). IFNγ and IL-2 were measured by ELISA. In the first activation step, IFNγ was reduced in welders compared to non-welders and in the GMAW welders with higher concentrations of respirable particles compared to the lower exposed TIG welders. IFNγ was not influenced by tobacco smoking and correlated negatively with welding-fume exposure, respirable manganese, and iron. In the second activation step, NTHi and LPS induced additional IFNγ, which was reduced in current smokers compared to never smokers in welders as well as in non-welders. Analyzing both activation steps together, IFNγ production was lowest in smoking welders and highest in never smoking non-welders. IL-2 was not associated with any of these parameters. Welding-fume exposure might suppress Th1-based immune responses due to effects of particulate matter, which mainly consists of iron and manganese. For responses to NTHi this is strongest in smoking welders because welding fume suppresses T-cell activation towards Th1 and cigarette smoke suppresses the subsequent Th1-response to NTHi via LPS. Both effects are independent from IL-2-regulated T-cell proliferation. This might explain the increased susceptibility to infections and might promote COPD development.

Incidence of early intra-cranial bleeding and ischaemia in adult veno-arterial extracorporeal membrane oxygenation and extracorporeal cardiopulmonary resuscitation patients: a retrospective analysis of risk factors.

BACKGROUND: Cerebral complications in veno-arterial extracorporeal membrane oxygenation are known to have a strong impact on mortality and morbidity. Aim of this study is to investigate the early incidence, risk factors and in-hospital mortality of intra-cranial ischaemia and haemorrhage in adults undergoing veno-arterial extracorporeal membrane oxygenation treatment. METHODS: This study is a single-centre retrospective analysis on adult patients undergoing veno-arterial extracorporeal membrane oxygenation for different indications. The inclusion criterion included patients with early routine cerebral computed tomography imaging during extracorporeal membrane oxygenation, with no clinical evidence of cerebral pathology prior to cannulation. Cerebral complications were grouped by aetiology and the territories of the brain's supplying arteries. RESULTS: One hundred eighty-seven adult patients with a total of 190 veno-arterial extracorporeal membrane oxygenation treatments were included. A total of 16.3% (n = 31) had evidence of either cerebral ischaemia (11.1%) or haemorrhage (5.8%); one patient suffered from both. Cerebral computed tomography scans were performed early in median on the first day after extracorporeal membrane oxygenation cannulation; in-hospital mortality of intra-cranial ischaemia and haemorrhage was 71.4% and 45.5%, respectively. Associated with an increased risk for ischaemic lesions were cannulation of the ascending aorta, higher age, presence of an autoimmune disease and cardiac surgery prior to veno-arterial extracorporeal membrane oxygenation. An association with haemorrhagic lesions was found for a lower blood PaCO2 at 2 hours, lower blood flow through the extracorporeal membrane oxygenation device at 2 hours, higher international normalized ratio and constantly higher activated partial thromboplastin time values as well as higher mean arterial pressures until haemorrhagic lesions were evident. CONCLUSION: Cerebral complications are frequent in patients on veno-arterial extracorporeal membrane oxygenation and may be clinically silent events. Careful monitoring with routine neuroimaging seems to be the most appropriate diagnostic approach at present. Intra-cranial ischaemia occurs more frequent than haemorrhage and is associated with cannulation of the aorta ascendens.

Multi-Modal PET and MR Imaging in the Hen's Egg Test-Chorioallantoic Membrane (HET-CAM) Model for Initial in Vivo Testing of Target-Specific Radioligands.

The validation of novel target-specific radioligands requires animal experiments mostly using mice with xenografts. A pre-selection based on a simpler in vivo model would allow to reduce the number of animal experiments, in accordance with the 3Rs principles (reduction, replacement, refinement). In this respect, the chick embryo or hen's egg test-chorioallantoic membrane (HET-CAM) model is of special interest, as it is not considered an animal until day 17. Thus, we evaluated the feasibility of quantitative analysis of target-specific radiotracer accumulation in xenografts using the HET-CAM model and combined positron emission tomography (PET) and magnetic resonance imaging (MRI). For proof-of-principle we used established prostate-specific membrane antigen (PSMA)-positive and PSMA-negative prostate cancer xenografts and the clinically widely used PSMA-specific PET-tracer [68Ga]Ga-PSMA-11. Tracer accumulation was quantified by PET and tumor volumes measured with MRI (n = 42). Moreover, gamma-counter analysis of radiotracer accumulation was done ex-vivo. A three- to five-fold higher ligand accumulation in the PSMA-positive tumors compared to the PSMA-negative tumors was demonstrated. This proof-of-principle study shows the general feasibility of the HET-CAM xenograft model for target-specific imaging with PET and MRI. The ultimate value for characterization of novel target-specific radioligands now has to be validated in comparison to mouse xenograft experiments.

LABAs and p38MAPK Inhibitors Reverse the Corticosteroid-Insensitivity of IL-8 in Airway Smooth Muscle Cells of COPD.

Airway inflammation in chronic obstructive pulmonary disease (COPD) is partially insensitive/resistant to inhaled corticosteroids (ICS). ICS plus bronchodilator therapy has been discussed for COPD phenotypes with frequent exacerbations and participation of corticosteroid-sensitive type 2/eosinophilic inflammation. Neutralization of non-type 2/IL-8-associated airway inflammation by reversion of its corticosteroid-resistance might be a future strategy for other phenotypes. Human airway smooth muscle cells (HASMCs) produce corticosteroid-insensitive IL-8 in response to TNFα or LPS in stable disease stages or bacteria-induced exacerbations, respectively. p38-mitogen-activated-protein-kinases (p38MAPKs) are alternative therapeutic targets. Hypothesis: long-acting-ß2-agonists (LABAs) reverse the corticosteroid-insensitivity of IL-8 by p38MAPK inhibition in HASMCs. Cultivated HASMCs from COPD subjects were pre-incubated with formoterol, salmeterol, fluticasone-propionate, BIRB796 (p38MAPKα, -γ, -δ inhibitor), and/or SB203580 (p38MAPKα and -ß inhibitor) before stimulation with TNFα or LPS. IL-8 and MAPK-activities were measured by ELISA. Formoterol, salmeterol, and fluticasone did not or hardly reduced TNFα- or LPS-induced IL-8. BIRB796 and SB203580 reduced TNFα-induced IL-8. SB203580 reduced LPS-induced IL-8. Fluticasone/formoterol, fluticasone/salmeterol, and fluticasone/BIRB796, but not fluticasone/SB203580 combinations, reduced TNFα-induced IL-8 stronger than single treatments. All combinations including fluticasone/SB203580 reduced LPS-induced IL-8 stronger than single treatments. TNFα induced p38MAPKα and -γ activity. LPS induced p38MAPKα activity. Formoterol reduced TNFα-induced p38MAPKγ and LPS-induced p38MAPKα activity. LABAs reverse the corticosteroid-insensitivity of IL-8 in airway smooth muscles via p38MAPKγ in stable disease and via p38MAPKα in exacerbations. Our pre-clinical data indicate a utility for also adding ICS in non-type 2 inflammatory COPD phenotypes to bronchodilator therapy. Depending on phenotype and disease stage, isoform-specific p38MAPK blockers might also reverse corticosteroid-resistance in COPD.

The monocyte-dependent immune response to bacteria is suppressed in smoking-induced COPD.

COPD patients have an increased susceptibility to bacterial airway infections that can induce exacerbations. In response to infections, circulating monocytes become recruited to the infected tissue and secrete cytokines. We hypothesized that this cytokine response is reduced in COPD. Cultured peripheral blood monocytes of never smokers (NS) and smokers without (S) and with COPD (3 study populations, n = 36-37) were stimulated with extracts of Haemophilus influenzae, Staphylococcus aureus, or Streptococcus pneumoniae or with four different pathogen-associated molecular patterns (PAMPs). Four cytokines and 9 PAMP-related signaling molecules were measured and compared between the groups. Granulocyte-macrophage-colony-stimulating-factor responses to all stimulants were reduced in S and COPD compared to NS. Tumor-necrosis-factor-α responses to all bacterial extracts, peptidoglycan, and lipopolysaccharide were reduced in S and/or COPD. Interleukin-10 responses to S. aureus and lipoteichoic acid were increased in COPD. Correlations to pack-years and lung function were found. The peptidoglycan-receptor NOD2 and the mRNA of the lipopolysaccharide-receptor TLR4 were reduced in S and COPD. Cytokine responses of monocytes to bacteria are suppressed by smoking and in COPD possibly due to NOD2 and TLR4 reduction and/or interleukin-10 increase. This might help to explain the increased susceptibility to bacterial infections. These systemic molecular pathologies might be targets for therapeutic strategies to prevent infection-induced exacerbations. KEY MESSAGES: COPD subjects have an increased susceptibility to bacterial infections. This implies defects in the immune response to bacteria and is critical for disease progression. The cytokine response of monocytes to bacteria is reduced in COPD. This might be due to a reduced NOD2 and TLR4 and an increased IL-10 expression. This can explain the increased susceptibility to infections and help to identify drug targets.

Do Inhibitory Control Demands Affect Event-Based Prospective Memory Performance in ADHD?

OBJECTIVE: Empirical evidence on prospective memory (PM) in ADHD is inconsistent. Differential findings have been related to differential executive control demands. This study aimed at exploring the impact of inhibitory control on event-based PM performance in ADHD. METHOD: Eighteen adults with ADHD and 18 controls performed a word categorization task with an embedded event-based PM task. In addition, participants performed an acoustically presented task that put either low or high loads on inhibitory control processes. RESULTS: Inhibitory load did not differentially affect PM performance: Across both inhibitory load conditions, individuals with ADHD showed reduced PM performance when compared with controls. Moreover, inhibitory load did not influence PM performance across both groups. CONCLUSION: Possibly, full inhibitory control resources are not necessary during the entire duration of an event-based PM task, but may suffice to be employed after cue detection when needing to interrupt the ongoing task. (J. of Att. Dis. 2019; 23(1) 51-56).

Psychotropic medication and psychotherapeutic treatment of adults with intellectual disabilities (PROMPT-ID): a cross-sectional, epidemiological study in Saxony, Germany.

INTRODUCTION: The psychotropic medication and psychotherapeutic treatment of adults with intellectual disabilities study is a cross-sectional, epidemiological study carried out in Saxony, Germany. The main aim of the study is, among others, to assess the prevalence and quality of psychotropic medication in adults with ID. METHODS: Inclusion criteria are mild to profound forms of ID and an age of 18 years or older. A representative sample is realised by a two-stage sampling procedure. Study participants will be recruited from sheltered workshops (SW) and sheltered housings (SH). The stratified cluster sampling is realised by a random selection of service providing institutions followed by a random selection of adults with ID. An estimated total number of n=200 study participants via SW and n=400 via SH will be contacted to obtain data of approximately n=131 study participants recruited through SW and n=232 participants through SH. Thus, based on a psychotropic medication prevalence of 30%, an estimated number of n=109 in-depth interviews about psychotropic prescription practice will be carried out. Data collection is realised through interviews with key carers in the living environment. If psychotropics are prescribed currently, basic information (eg, dosage, treatment duration) are obtained, and a newly developed interview targeting the quality of the psychotropic medication treatment is conducted both with the carers and with the prescribing physicians. In addition to the prevalence and quality of psychotropic treatment, other parameters (eg, mental healthcare utilisation, psychiatric symptomatology, problem behaviour, institutional factors and parameters of the provision area) are assessed using well-established instruments. ETHICS AND DISSEMINATION: Approval of the responsible ethics committee was obtained. Findings will be disseminated to participating institutions, published in journals and conferences and fill the lack of representative data that is urgently needed in this often criticised health service area. They shall help to improve mental health services in adults with ID prospectively. TRIAL REGISTRATION NUMBER: NCT03558815; Pre-results.

Asthma features in severe COPD: Identifying treatable traits.

AIM: Biological therapies developed for severe asthma may have a role in COPD patients with asthma features. METHOD: We carried out a prospective, consecutive, cross-sectional analysis of 80 patients with severe COPD GOLD IV/D. RESULTS: We studied 80 patients (48.8% female), aged 57.6 ±â€¯5.1 years, ex-smokers with 35.7 ±â€¯21.2 pack years, BMI 22.3 ±â€¯3.5 kg/m2, FEV1 of 0.61 ±â€¯0.2 L (21.1 ±â€¯5.6% pred), pO2 52.4 ±â€¯8.4 mmHg, and BODE 6.9 ±â€¯1.7. 68% had >2 moderate or severe exacerbations annually. 16.1% (5/31) patients showed FEV1 reversibility of >12% and >200 ml despite maximal therapy, 33% (15/45) had FENO ≥22.5 ppb, 33% (24/73) had serum IgE ≥100 I.E./ml and there was positive allergen sensitization in 51.5% (35/68). Blood eosinophilia of ≥150 cells/µl was seen in 47% (35/74). Induced sputum showed eosinophilia of ≥2% in 56% (14/24) with respiratory pathogens in 63.8% (30/47). We identified 12 (15%) patients with asthma-COPD overlap. Of these, 10 (83.3%) had frequent exacerbations and these patients had significantly more severe exacerbations requiring NIV or ICU than those without asthma features (p < 0.005). CONCLUSION: We detected asthma features in a substantial subset of stable patients with severe COPD. Asthma features were associated with more severe exacerbation despite optimal COPD therapy, representing potential candidates for targeted therapy with anti- IgE or anti-IL5.

[Cough and its Differential Diagnosis]. / Husten ­ Differenzialdiagnosen.

A thorough anamnesis and the physical examination of a patient with cough mostly lead the way to the further diagnostic and therapeutic procedure. As far as there are no obvious reasons for the cough symptoms, any case of persisting chronic cough needs a diagnostic clarification - including computed tomography of the thorax and bronchoscopy as the final step. If clinical findings make them necessary, also invasive diagnostic procedures - such as bronchoscopy, thoracoscopy and surgical biopsy of the lung - must not be avoided. According to the clinical presentation appropriate medical disciplines have to be consulted for the diagnostic clarification of chronic cough. Besides pulmonology und allergology these are ENT medicine, gastroenterology, cardiology, infectiology, neurology and possibly psychiatry. The therapy of chronic and acute cough should be aimed at a causal treatment approach.

ß-Blockers in COPD: A Cohort Study From the TONADO Research Program.

BACKGROUND: Cardiovascular disease is a frequent comorbidity in patients with COPD. Many physicians, particularly pulmonologists, are reluctant to use ß-adrenoceptor blocking agents (ß-blockers) in patients with COPD, despite their proven effectiveness in preventing cardiovascular events. METHODS: The large (5,162 patients) phase III TONADO 1 and 2 studies assessed lung function and patient-reported outcomes in patients with moderate to very severe COPD receiving long-acting bronchodilator treatment across 1 year. This post hoc analysis characterized lung-function changes, patient-reported outcomes, and safety in the subgroup of patients receiving ß-blockers in the studies. RESULTS: In total, 557 of 5,162 patients (11%) received ß-blockers at baseline. Postbronchodilator FEV1 at baseline was higher in the ß-blocker group (1.470 L) compared with that in the no ß-blocker group (1.362 L). As expected, patients receiving ß-blockers had a more frequent history of cardiovascular comorbidities and medications. Lung function improved from baseline in patients with or those without ß-blocker treatment, and no relevant between-group differences were observed in trough FEV1 or trough FVC at 24 or 52 weeks. No relevant differences were observed for St. George's Respiratory Questionnaire results and Transition Dyspnea Index in patients with ß-blockers compared with those in patients without. Safety findings were comparable between groups. CONCLUSIONS: Lung function, overall respiratory status, and safety of tiotropium/olodaterol were not influenced by baseline ß-blocker treatment in patients with moderate to very severe COPD. Results from this large patient cohort support the cautious and appropriate use of ß-blockers in patients with COPD and cardiovascular comorbidity. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01431274 and No. NCT01431287; URL: www.clinicaltrials.gov.

Self- and proxy-rated needs in adults with mild to moderate intellectual disabilities: Perspective matters.

BACKGROUND: Adults with an intellectual disability should be supported according to their individual needs. The perception of need, however, is influenced by the values and expectations of the judging person. METHOD: Using the Camberwell Assessment of Need for Adults with Developmental and Intellectual Disabilities, self- and proxy-rated needs of n = 193 adults with mild to moderate intellectual disability were compared. RESULTS: Mean total needs and met needs, but not unmet needs, differed significantly between perspectives. As concerns the assessment of specific areas of need, indices revealed a complex and multifaceted pattern of agreement and disagreement. CONCLUSION: Different viewpoints should be considered when assessing needs among adults with intellectual disability. With respect to areas other than basic, everyday areas of need, involvement of the adult with intellectual disability is strongly recommended. The assessment of mental health problems requires the involvement of clinical professionals, assessing problem behavior broad diagnostic measures beyond a standardized instrument.

Comprehensive assessment of the safety of olodaterol 5 µg in the Respimat® device for maintenance treatment of COPD: comparison with the long-acting ß2-agonist formoterol.

This analysis provides a comprehensive clinical assessment of the long-term safety of the licensed dose of olodaterol (5 µg once daily [QD] via Respimat® inhaler) in patients with chronic obstructive pulmonary disease by exploring the occurrence of acknowledged side effects of long-acting ß2-agonists as well as those included in the olodaterol and formoterol labels. We analysed pooled data from two replicate, double-blind studies of olodaterol (5 µg QD via Respimat®) compared to formoterol (12 µg twice daily [BID]) or placebo over 48 weeks (1222.13, NCT00793624; 1222.14, NCT00796653). Patients could continue their background treatment. The analysis considered adverse events (AEs) typically associated with ß2-agonists, including cardiovascular events, as well as administration-related events. Descriptive statistics were provided for the incidence of AEs and aggregated AEs. The analysis included 1379 patients: 460 placebo, 459 olodaterol and 460 formoterol; AEs were reported by 70.9, 71.7 and 69.1% of patients, respectively. Exposure-adjusted incidence rates of cardiac AEs (arrhythmia and myocardial ischaemia) and cough were numerically lower in the olodaterol group than the formoterol group, while nasopharyngitis, throat irritation, metabolism and psychiatric disorders were numerically higher in the olodaterol group. The most frequent event in the olodaterol group was nasopharyngitis (placebo 8.0%; olodaterol 12.9%; formoterol 10.0%). Except for cough (incidence rate ratio of 0.46 [95% confidence interval 0.24, 0.89] in favour of olodaterol), there were no significant differences between active groups. In conclusion, olodaterol 5 µg QD was well tolerated over 48 weeks with a typical ß2-agonist safety profile comparable to formoterol 12 µg BID.

Down for the count: The critical endpoint in ototoxicity remains the cytocochleogram.

There are three major assays that must be conducted in standard investigational new drug (IND) -enabling ototoxicity study designs: 1) functional acoustic threshold measurements (Auditory Brainstem Respsonse, ABR); 2) otohistopathology and 3) cytocochleograms. We provide evidence to demonstrate the unreliability of auditory threshold shifts (ABRs) to predict cochlear cell death and build a case for conducting full cochlea processing and cell count measurements from the complete cochlea from apex to base.