Critical review of multimorbidity outcome measures suitable for low-income and middle-income country settings: perspectives from the Global Alliance for Chronic Diseases (GACD) researchers.

OBJECTIVES: There is growing recognition around the importance of multimorbidity in low-income and middle-income country (LMIC) settings, and specifically the need for pragmatic intervention studies to reduce the risk of developing multimorbidity, and of mitigating the complications and progression of multimorbidity in LMICs. One of many challenges in completing such research has been the selection of appropriate outcomes measures. A 2018 Delphi exercise to develop a core-outcome set for multimorbidity research did not specifically address the challenges of multimorbidity in LMICs where the global burden is greatest, patterns of disease often differ and health systems are frequently fragmented. We, therefore, aimed to summarise and critically review outcome measures suitable for studies investigating mitigation of multimorbidity in LMIC settings. SETTING: LMIC. PARTICIPANTS: People with multimorbidity. OUTCOME MEASURES: Identification of all outcome measures. RESULTS: We present a critical review of outcome measures across eight domains: mortality, quality of life, function, health economics, healthcare access and utilisation, treatment burden, measures of 'Healthy Living' and self-efficacy and social functioning. CONCLUSIONS: Studies in multimorbidity are necessarily diverse and thus different outcome measures will be appropriate for different study designs. Presenting the diversity of outcome measures across domains should provide a useful summary for researchers, encourage the use of multiple domains in multimorbidity research, and provoke debate and progress in the field

Demographic and Clinical Characteristics of Patients with Severe Asthma in the Asian Pacific Region : data from the International Severe Asthma Registry (ISAR)

Peer reviewe

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

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Gaps in COPD guidelines of low- and middle-income countries: a systematic scoping review

BACKGROUND: Guidelines are critical for facilitating cost-effective COPD care. Development and implementation in low-and middle-income countries (LMICs) is challenging. To guide future strategy, an overview of current global COPD guidelines is required. RESEARCH QUESTION: We systematically reviewed national COPD guidelines, focusing on worldwide availability and identification of potential development, content, context and quality gaps that may hamper effective implementation. STUDY DESIGN: & Methods: Scoping review of national COPD management guidelines. We assessed: (1) global guideline coverage, (2) guideline information (authors, target audience, dissemination plans), (3) content (prevention, diagnosis, treatments), (4) ethical, legal, socio-economic aspects and (5) compliance with the eight Institute of Medicine (IOM) guideline standards. LMICs guidelines were compared to those from high-income countries (HICs). MAIN RESULTS: Of the 61 national COPD guidelines identified, 30 were from LMICs. Guidelines did not cover 1.93 billion (30.2%) people living in LMICs, whereas only 0.02 billion (1.9%) in HICs were without national guidelines. Compared with HICs, LMIC guidelines targeted fewer healthcare professional groups and less often addressed case finding and co-morbidities. Over 90% of all guidelines included smoking cessation advice. Air pollution reduction strategies were less frequently mentioned in both LMICs (47%) and HICs (42%). LMIC guidelines fulfilled on average 3.37 (42%) of IOM standards compared to 5.29 (66%) in HICs (p<0.05). LMICs scored significantly lower compared with HICs regarding conflicts of interest management, updates, articulation of recommendations and funding transparency (all, p<0.05). INTERPRETATION: Several development, content, context and quality gaps exist in COPD guidelines from LMICs that may hamper effective implementation. Overall, COPD guidelines in LMICs should be more widely available and should be transparently developed and updated. Guidelines may be further enhanced by better inclusion of local risk-factors, case finding and co-morbidity management, preferably tailored to available financial and staff resources

Critical review of multimorbidity outcome measures suitable for low-income and middle-income country settings: perspectives from the Global Alliance for Chronic Diseases (GACD) researchers

Objectives There is growing recognition around the importance of multimorbidity in low-income and middle-income country (LMIC) settings, and specifically the need for pragmatic intervention studies to reduce the risk of developing multimorbidity, and of mitigating the complications and progression of multimorbidity in LMICs. One of many challenges in completing such research has been the selection of appropriate outcomes measures. A 2018 Delphi exercise to develop a core-outcome set for multimorbidity research did not specifically address the challenges of multimorbidity in LMICs where the global burden is greatest, patterns of disease often differ and health systems are frequently fragmented. We, therefore, aimed to summarise and critically review outcome measures suitable for studies investigating mitigation of multimorbidity in LMIC settings.Setting LMIC.Participants People with multimorbidity.Outcome measures Identification of all outcome measures.Results We present a critical review of outcome measures across eight domains: mortality, quality of life, function, health economics, healthcare access and utilisation, treatment burden, measures of ‘Healthy Living’ and self-efficacy and social functioning.Conclusions Studies in multimorbidity are necessarily diverse and thus different outcome measures will be appropriate for different study designs. Presenting the diversity of outcome measures across domains should provide a useful summary for researchers, encourage the use of multiple domains in multimorbidity research, and provoke debate and progress in the field

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

BackgroundBiologic 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.MethodsAdults 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.Results5.3% 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.ConclusionsMost 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

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

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