Association between T2-related co-morbidities and effectiveness of biologics in severe asthma

Acknowledgments The authors thank Mr. Joash Tan (BSc, Hons), of the Observational and Pragmatic Research Institute (OPRI), and Ms Andrea Lim (BSc, Hons) of the Observational Pragmatic Research Institute (OPRI) for their editorial and formatting assistance that supported the development of this publication. Funding statement: This study was conducted by the Observational and Pragmatic Research Institute (OPRI) Pte Ltd and was partially funded by Optimum Patient Care Global and AstraZeneca Ltd. AstraZeneca UK LimitedPeer reviewe

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

The Effect Of Stress On Drosophila Deficient In Werner Protein

Stress affects a wide-range of biochemical and physiological processes including metabolism, development, and aging. Environmental stressors such as chemical exposure, diet, and temperature can cause free radicals that can damage DNA and lead to mutations. Proteins such as Werner (WRN) help to maintain genomic stability due to their involvement in DNA repair and replication. In humans, mutations in WRN cause Werner syndrome (WS), an autosomal disease characterized by accelerated aging and predisposition to cancer. In Drosophila melanogaster (fruit flies), mutations in the Drosophila homolog of WRN, WRNexo, lead to similar phenotypes as Werner patients, such as shortened lifespan, high tumor incidence, and muscle degradation. Therefore we can use WRNexo mutant flies (WRNexo ) to study the link between stress, aging, and disease. Because very little is known about the impact of thermal stress on genome stability, we tested the response of WRNexo mutant flies (WRNexo ) to varying thermal environments during larval and adult developmental stages. To assess larval sensitivity, WRNexo heterozygous larvae were reared on cornmeal agar and stored in an 18°C, 25°C (control), or 29°C incubator. Thermal sensitivity was determined by the percent of WRNexo homozygotes exposed to 18 °C and 29 °C that survive to adulthood compared to the percent control WRNexo homozygotes. To assess adult sensitivity, activity of individual WRNexo and wild type adult flies was monitored at regular intervals using a Drosophila Activity Monitor. We expected to observe a decrease in larval survival and reduced active periods in adult flies exposed to 18°C and 29°C due to the inability of the mutants to cope with thermal stress. We found that WRNexo larvae were not sensitive to thermal stress as shown by their high relative survival percentages at 18°C and 29°C. Thermal stress affected adult locomotor activity in a sex-specific manner. While average locomotor activity did not differ between WRNexo and wild type for either sex at 18°C and 25°C, a significant reduction in locomotor activity was observed in female WRNexo mutants when exposed to 29°C. When we looked at diurnal activity patterns, we found that the evening activity peaks present in wild type flies were absent in WRNexo flies, although these results were only significant in females at 29°C. These results would suggest that WRNexo may have roles in protecting female adult flies against thermal stress induced by warmer temperatures. Our results contribute to a broader knowledge of the involvement of WRN in genome longevity and the molecular mechanisms involved in stress. Overall, this knowledge can be used to benefit the general public by developing new approaches to regulate aging and age-associated diseases

Evidence for premature aging in a Drosophila model of Werner syndrome

Werner syndrome (WS) is an autosomal recessive progeroid disease characterized by patients\u27 early onset of aging, increased risk of cancer and other age-related pathologies. WS is caused by mutations in WRN, a RecQ helicase that has essential roles responding to DNA damage and preventing genomic instability. While human WRN has both an exonuclease and helicase domain, Drosophila WRNexo has high genetic and functional homology to only the exonuclease domain of WRN. Like WRN-deficient human cells, Drosophila WRNexo null mutants (WRNexoΔ) are sensitive to replication stress, demonstrating mechanistic similarities between these two models. Compared to age-matched wild-type controls, WRNexoΔ flies exhibit increased physiological signs of aging, such as shorter lifespans, higher tumor incidence, muscle degeneration, reduced climbing ability, altered behavior, and reduced locomotor activity. Interestingly, these effects are more pronounced in females suggesting sex-specific differences in the role of WRNexo in aging. This and future mechanistic studies will contribute to our knowledge in linking faulty DNA repair mechanisms with the process of aging

Characterization of stress responses in a drosophila model of werner syndrome

As organisms age, their resistance to stress decreases while their risk of disease increases. This can be shown in patients with Werner syndrome (WS), which is a genetic disease characterized by accelerated aging along with increased risk of cancer and metabolic disease. WS is caused by mutations in WRN, a gene involved in DNA replication and repair. Recent research has shown that WRN mutations contribute to multiple hallmarks of aging including genomic instability, telomere attrition, and mitochondrial dysfunction. However, questions remain regarding the onset and effect of stress on early aging. We used a fly model of WS (WRNexo∆ ) to investigate stress response during different life stages and found that stress sensitivity varies according to age and stressor. While larvae and young WRNexo∆ adults are not sensitive to exogenous oxidative stress, high antioxidant activity suggests high levels of endogenous oxidative stress. WRNexo∆ adults are sensitive to stress caused by elevated temperature and starvation suggesting abnormalities in energy storage and a possible link to metabolic dysfunction in WS patients. We also observed higher levels of sleep in aged WRNexo∆ adults suggesting an additional adaptive mechanism to protect against age-related stress. We suggest that stress response in WRNexo∆ is multifaceted and evokes a systemic physiological response to protect against cellular damage. These data further validate WRNexo∆ flies as a WS model with which to study mechanisms of early aging and provide a foundation for development of treatments for WS and similar diseases

Molecular-Level Processing of Si-(B)-C Materials with Tailored Nano/Microstructures

International audienc

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

Acknowledgements In memory of Professor J. Mark Fitzgerald, the authors would like to acknowledge him for his valuable contribution to the development of the manuscript. The authors also acknowledge Ms. Daniela Morrone (MSc) of Cromsource, Verona, Italy for her contribution during the development of the manuscript and Mr. Joash Tan (BSc, Hons) of the Observational and Pragmatic Research Institute (OPRI), for editorial and formatting assistance that supported the development of this publication. Funding information This study was conducted by the Observational and Pragmatic Research Institute (OPRI) Pte Ltd and was partially funded by Optimum Patient Care Global and AstraZeneca Ltd. No funding was received by the Observational & Pragmatic Research Institute Pte Ltd (OPRI) for its contribution.Peer reviewedPublisher PD

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.publishedVersionPeer reviewe

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

Q2Q2Pacientes con Asma severaBackground: Investigation for the presence of asthma comorbidities is recommended by GINA as 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. Thirty comorbidities were identified and categorized a priori as either (1) potentially T2-related, (2) potentially oral corticosteroid (OCS)-related or (3) mimicking/aggravating asthma. The association between comorbidities and asthma-related outcomes was investigated using multivariable models adjusted for country, age at enrollment, and sex. Results: Of 11,821 patients, 69%, 67%, and 55% had ≥1 potentially T2-related, potentially OCS-related, or mimicking/aggravating comorbidities, respectively; 57% had ≥3 comorbidities, and 33% had comorbidities in all three categories. Patients with allergic rhinitis (AR), nasal polyposis (NP), and chronic rhinosinusitis (CRS) experienced 1.12- (p=0.003), 1.16- (p<0.001) and 1.29-times (p<0.001) more exacerbations/year, respectively, than those without. Patients with NP and CRS were 40% and 46% more likely (p<0.001), respectively, to have received long-term (LT) OCS. All assessed potential OCS-related comorbidities (except obesity) were associated with greater likelihood of LTOCS use (ORs: 1.23-2.77) and, except for dyslipidemia, with greater likelihood of uncontrolled asthma (ORs: 1.29-1.68). All mimicking/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 COPD) with increased likelihood of LTOCS use (ORs: 1.37-1.57). Greater number of comorbidities was associated with worse outcome. Conclusion: In a global study, comorbidity or multimorbidity is reported in most adults with severe asthma and is associated with poorer asthma-related outcomes.https://orcid.org/0000-0001-8405-4513https://orcid.org/0000-0002-0100-1940https://orcid.org/0000-0001-6461-2725Revista Internacional - IndexadaA1N