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

Imaging biomarker roadmap for cancer studies.

Imaging biomarkers (IBs) are integral to the routine management of patients with cancer. IBs used daily in oncology include clinical TNM stage, objective response and left ventricular ejection fraction. Other CT, MRI, PET and ultrasonography biomarkers are used extensively in cancer research and drug development. New IBs need to be established either as useful tools for testing research hypotheses in clinical trials and research studies, or as clinical decision-making tools for use in healthcare, by crossing 'translational gaps' through validation and qualification. Important differences exist between IBs and biospecimen-derived biomarkers and, therefore, the development of IBs requires a tailored 'roadmap'. Recognizing this need, Cancer Research UK (CRUK) and the European Organisation for Research and Treatment of Cancer (EORTC) assembled experts to review, debate and summarize the challenges of IB validation and qualification. This consensus group has produced 14 key recommendations for accelerating the clinical translation of IBs, which highlight the role of parallel (rather than sequential) tracks of technical (assay) validation, biological/clinical validation and assessment of cost-effectiveness; the need for IB standardization and accreditation systems; the need to continually revisit IB precision; an alternative framework for biological/clinical validation of IBs; and the essential requirements for multicentre studies to qualify IBs for clinical use.Development of this roadmap received support from Cancer Research UK and the Engineering and Physical Sciences Research Council (grant references A/15267, A/16463, A/16464, A/16465, A/16466 and A/18097), the EORTC Cancer Research Fund, and the Innovative Medicines Initiative Joint Undertaking (grant agreement number 115151), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and European Federation of Pharmaceutical Industries and Associations (EFPIA) companies' in kind contribution

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

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

Making salient messages for Indigenous tobacco control

Objectives:\ud \ud The aim of this thesis is to explore how anti-tobacco messages can be made more salient for Indigenous smokers. The research has a focus on Australian Indigenous smokers, in particular pregnant smokers and those of reproductive age. These specific groups were chosen as a focus due to their continued high levels and slow decline of smoking prevalence. Consequently there is a public health imperative for new knowledge in these areas to inform practice and policy. The overarching research questions are: are anti-tobacco messages having an impact on Indigenous Australians; can we do better; if so how?\ud \ud Methods:\ud \ud The thesis uses multiple methodologies dependent on the specific research questions. Five studies are presented that inform two main streams of inquiry: mass media anti-tobacco message development and maternal smoking, with a multi-phase design coming together in an integrated discussion of findings. The methods range from systematic reviews of the literature, interviews and focus groups, community based participatory research, cross-sectional surveys (regional and national), and the validation of psychometric instruments. The qualitative analysis draws from grounded theory, phenomenology and the constant comparative method. Factor and multivariate analyses are employed for the quantitative studies. The Risk Behaviour Diagnosis (RBD) Scale based on the Extended Parallel Process Model (EPPM) informs this work. The RBD Scale comprises measures of perceived efficacy (response and self-efficacy) and perceived threat (susceptibly and severity of threat). Regional studies were conducted in an Indigenous community in New South Wales (NSW), and organisations in most States and Territories in Australia were interviewed in a national study.\ud \ud Results:\ud \ud Study 1: A systematic review of 21 peer-reviewed publications on mass media interventions for smoking cessation among Indigenous peoples in Australia, Canada, New Zealand and the United States revealed that Indigenous peoples in the included populations preferred culturally targeted messages. Some generic anti-tobacco messages were considered by Maori women to be inappropriate for Indigenous peoples. Collectively, the studies included in the review demonstrated that perceived effectiveness and recall of generic messages among Indigenous populations were high but did not translate into increased cessation in Indigenous Australians, American Indians and Alaska Natives. In contrast, studies conducted in New Zealand showed that culturally targeted messages for Maori were as effective in the short-term as generic messages for the general population. Targeted internet-based messages had a positive impact on American Indian smokers. However, fear-based generic messages provoked more calls to the New Zealand Quitline by Maori smokers, compared with a holistic targeted campaign.\ud Study 2: A systematic review of seven Australian studies on knowledge and views about maternal tobacco smoking and barriers for cessation in Aboriginal and Torres Strait Islanders revealed eleven third-order constructs (themes) about maternal Indigenous smoking and cessation, at individual, family and community levels. The review identified pregnancy as an opportunity to encourage positive change where a strong “protector role” is expressed. However, studies included in the review demonstrate that tobacco use in the Indigenous population may be perpetuated by social norms and stressors within the Aboriginal community, insufficient knowledge of smoking harms, and lack of salience of anti-tobacco messages. Overall, the review indicated a lack of awareness among Indigenous people regarding the use of pharmacotherapy.\ud \ud Study 3: Pregnant women, partners and family members in regional NSW participated in focus groups to investigate social and family influences and responses to health messages. The results of this study showed that families were proactively managing smoke-free homes to reduce harm to babies and children, but there were some misconceptions about the age of vulnerability of children to passive smoking. Nicotine cravings were often interpreted as 'stress'. Focus group participants identified that anti-tobacco messages and cessation advice were more salient when they related to women's experiences. As a result of this study, community recommendations were made to improve approaches to maternal smoking.\ud \ud Study 4: In a national survey that targeted health organisations involved in the development of anti-tobacco messages for Indigenous Australians, a two-dimensional non-linear principal component analysis extracted components interpreted as 'cultural understanding' (bottom-up, community-based approaches, deep structures) and 'rigour' (theoretical frameworks, and planned/completed evaluations). Aboriginal Medical Services demonstrated strength in using processes of 'cultural understanding' in their anti-tobacco messages. Organisations orientated to the general population were more likely to evaluate their programs.\ud \ud Study 5: Through a community-based regional study of Aboriginal smokers of reproductive age, the RBD Scale and associated measures were found to be reliable and valid in this population. The majority of participants had high-perceived threat regarding smoking cessation. Participants with high-perceived threat and high-perceived efficacy demonstrated danger control responses. These participants had a high intention to quit and were more likely to keep smoke-free homes. However, those with low-perceived threat and low-perceived efficacy demonstrated fear control responses about the harms of smoking, which included denial and avoidance. Logistical regression indicated that independent predictors of intention to quit smoking within the next three months were high-perceived efficacy and having consulted a health professional in the past.\ud \ud Discussion:\ud \ud Anti-tobacco messages appear to be making an impact internationally for Indigenous peoples in terms or raising awareness, but there is conflicting evidence about whether they translate into quitting behaviour. Culturally targeted messages were preferred by the Indigenous populations in these studies and showed potential for future interventions. In pregnancy, messages appear to lack salience for Indigenous Australians and do not relate to women's lived experiences. Regional Aboriginal smokers in NSW had high-perceived threat levels regarding smoking, but high-perceived efficacy was an independent predictor of intention to quit smoking. Protective attitudes to children and babies were demonstrated by the reported management of smoke-free homes.\ud \ud Anti-tobacco messages could be made more salient, particularly for pregnant smokers. Attention to the twin aspects of 'cultural understanding' and rigour could have importance for the development of culturally targeted anti-tobacco messages, via health promotion campaigns and in clinical encounters. Increased awareness is required regarding Aboriginal community perceptions about the age of susceptibility of children to environmental tobacco smoke, the health risks after cessation, and the use of pharmacotherapy for quitting. Community perceptions could be addressed through culturally appropriate educational approaches.\ud \ud There has been no published peer-reviewed research directly comparing targeted versus generic messages in Indigenous peoples. More exploratory research is needed into attitudes about pharmacotherapy and to determine how evidence-based therapy can be promoted. Tobacco control and cessation messages could potentially improve the quality of quit attempts. Health professional training is warranted to support these endeavours.\ud \ud Conclusion:\ud \ud Indigenous Australian smokers of reproductive age, and Indigenous Australian pregnant smokers are urgently in need of more consistent approaches to motivating and supporting cessation attempts. The thesis has explored new approaches to developing targeted tobacco control messages with higher salience that have the potential to be translated into practice and policy. Further research is required to confirm the use of the RBD Scale in a larger sample, and its practical use to guide the tailoring and targeting of messages. The research significantly aligns with key policies in Australia for Closing the Gap on Indigenous heath, such as the NHMRC Road Map and the Aboriginal and Torres Strait Islander Health Plan. These policies outline the need to evaluate risk factors implicated in chronic conditions that impact on Indigenous health status, build resilience against tobacco in Indigenous communities, foster wellbeing for pregnant women and children, and investigate optimum means of delivering preventive health messages utilising community-based approaches. \ud  \u

Barriers and Facilitators of Adherence to Nicotine Replacement Therapy: A Systematic Review and Analysis Using the Capability, Opportunity, Motivation, and Behaviour (COM-B) Model

Background: Poor adherence to nicotine replacement therapy (NRT) is associated with low rates of smoking cessation. Hence, this study aims to identify and map patient-related factors associated with adherence to NRT using the capability, opportunity, motivation, and behaviour (COM-B) model. Methods: A systematic review was conducted by searching five databases (MEDLINE, Scopus, EMBASE, CINAHL, and PsycINFO) and grey literature on 30 August 2020. Data were extracted, thematically analysed, and mapped to the COM-B model. The Joanna Briggs Institute (JBI) critical appraisal tool was utilised to assess the quality of studies. Results: A total of 2929 citations were screened, and 26 articles with a total of 13,429 participants included. Thirty-one factors were identified and mapped to COM-B model: psychological capability (forgetfulness, education), physical capability (level of nicotine dependence, withdrawal symptoms), reflective motivation (perception about NRT and quitting), automatic motivation (alcohol use, stress, depression), physical opportunity (cost), and social opportunity (social support). The most prominent element associated with adherence was reflective motivation followed by physical capability and automatic motivation. Conclusions: Multiple personal, social, and environmental factors affect NRT adherence. Hence, it is recommended to implement a multifaceted behavioural intervention incorporating factors categorised under the COM-B model, which is the hub of the behaviour change wheel (BCW) to improve adherence and quitting

Using the risk behaviour diagnosis scale to understand Australian Aboriginal smoking — a cross-sectional validation survey in regional New South Wales

Objective\ud \ud To validate, for the first time, the Risk Behaviour Diagnosis (RBD) Scale for Aboriginal Australian tobacco smokers, based on the Extended Parallel Process Model (EPPM). Despite high smoking prevalence, little is known about how Indigenous peoples assess their smoking risks.\ud \ud Methods\ud \ud In a cross-sectional study of 121 aboriginal smokers aged 18–45 in regional New South Wales, in 2014, RBD subscales were assessed for internal consistency. Scales included measures of perceived threat (susceptibility to and severity of smoking risks) and perceived efficacy (response efficacy and self-efficacy for quitting). An Aboriginal community panel appraised face and content validity. EPPM constructs of danger control (protective motivation) and fear control (defensive motivation) were assessed for cogency.\ud \ud Results\ud \ud Scales had acceptable to good internal consistency (Cronbach's alpha = 0.65–1.0). Most participants demonstrated high-perceived threat (77%, n = 93); and half had high-perceived efficacy (52%, n = 63). High-perceived efficacy with high-threat appeared consistent with danger control dominance; low-perceived efficacy with high-threat was consistent with fear control dominance.\ud \ud Conclusions\ud \ud In these Aboriginal smokers of reproductive age, the RBD Scale appeared valid and reliable. Further research is required to assess whether the RBD Scale and EPPM can predict quit attempts and assist with tailored approaches to counselling and targeted health promotion campaigns

Knowledge and views about maternal tobacco smoking and barriers for cessation in Aboriginal and Torres Strait islanders: a systematic review and meta-ethnography

Maternal smoking rates in Australian Aboriginal women are triple that of the general population, with little evidence for successful interventions. We reviewed the literature to understand smoking and cessation in Aboriginal and Torres Strait Islander women and provide recommendations for targeted interventions. METHODS Six databases were searched using terms related to smoking, pregnancy, and Aboriginal Australians. Two reviewers independently assessed papers for inclusion and quality. Meta-ethnography synthesized first- and second-order constructs from included studies and constructed a line of argument. RESULTS Seven relevant studies were analyzed. The synthesis illustrates 11 third-order constructs operating on the levels of self, family, and social networks, the wider Aboriginal community, and broader external influences. Highlighted are social norms and stressors within the Aboriginal community perpetuating tobacco use; insufficient knowledge of smoking harms; inadequate saliency of antismoking messages; and lack of awareness and use of pharmacotherapy. Indigenous Health Workers have a challenging role, not yet fulfilling its potential. Pregnancy is an opportunity to encourage positive change where a sense of a protector role is expressed. CONCLUSIONS This review gives strength to evidence from individual studies across diverse Indigenous cultures. Pregnant Aboriginal and Torres Strait Islander smokers require comprehensive approaches, which consider the environmental context, increase knowledge of smoking harms and cessation methods, and provide culturally targeted support. Long term, broad strategies should de-normalize smoking in Aboriginal and Torres Strait Islander communities. Further research needs to examine causes of resistance to antitobacco messages, clarify contributing roles of stress and depression, and attitudes to pharmacotherapy

Evaluating level of adherence to nicotine replacement therapy and its impact on smoking cessation: a protocol for systematic review and meta-analysis

Introduction Nicotine replacement therapy (NRT) has proven effective for smoking cessation in clinical trials, however it was found less effective in population-based studies, potentially due to inconsistent or incorrect use of NRT. The aim of this paper is to describe a systematic review protocol to evaluate level of adherence to NRT; the discrepancy of adherence to NRT in clinical and population-based studies and degree of association between level of adherence and success of smoking cessation.Methods and analysis Literature search will use five databases (Medline, Scopus, Embase, CINAHL and PsycINFO). Studies will be appraised for methodological quality using National Institutes of Health Quality Assessment Tool. To reduce heterogeneity, we will analyse clinical trials and population-based studies separately; pooled analyses will be done among studies that used similar measurements. Heterogeneity of studies will be assessed by Higgins’ I2 statistical test. When studies are adequately homogeneous, results will be pooled using random-effects model with proportion and ORs with 95% CIs and p values for each outcome. We will explain sources of heterogeneity by subgroup analysis or sensitivity analysis. Funnel plots and Egger’s regression asymmetry test with p<0.05 will be used as a cut-off point to affirm presence of statistically significant publication bias. Statistical analyses will be carried out using Stata V.16 software. Only studies reporting a valid strategy to control for reverse causality will be included.Discussion This review will provide evidence to support the importance of adherence on rate of smoking cessation and level of adherence to NRT. The findings will be used to inform smoking cessation interventions, researchers and policymakers.Ethics and dissemination As a systematic literature review, this protocol does not require ethics approval. Research outcomes will be presented at relevant conferences and findings will be published in a relevant peer-reviewed journal.PROSPERO registration number CRD42020176749

Can smoking initiation contexts predict how adult Aboriginal smokers assess their smoking risks? A cross-sectional study using the 'Smoking Risk Assessment Target'

Objectives: Smoking prevalence is slow to reduce among Indigenous Australians of reproductive age. We analysed the relationships between age of smoking initiation, recalled initiation influences and self-assessment of smoking risks in Aboriginal smokers.\ud \ud Design, setting and participants: A community-based cross-sectional survey of Aboriginal smokers aged 18–45 years (N=121; 58 men) was undertaken, using single-item measures. The Smoking Risk Assessment Target (SRAT) as the primary outcome measure enabled self-assessment of smoking risks from 12 options, recategorised into 3 groups. Participants recalled influences on their smoking initiation. Multinomial logistic regression modelling included age, gender, strength of urges to smoke, age at initiation (regular uptake) and statistically significant initiation influences on χ2 tests ('to be cool’, alcohol and cannabis).\ud \ud Results: Frequent initiation influences included friends (74%; SD 0.44), family (57%; SD 0.5) and alcohol (40%; SD 0.49). 54% (n=65) of smokers had the highest risk perception on the SRAT, selected by those who cared about the smoking risks and intended to quit soon. On multivariate analyses, compared with the highest level of SRAT, male gender, lower age of uptake and strong urges to smoke were significantly associated with the lowest level of SRAT, selected by those who refuted risks or thought they could not quit. Lower age of uptake and alcohol were associated with mid-level of SRAT, selected by those who cared about smoking risks, but did not consider quitting as a priority.\ud \ud Conclusions: Characteristics of smoking initiation in youth may have far-reaching associations with how smoking risks are assessed by adults of reproductive age, and their intentions to quit smoking. Becoming a regular smoker at under the age of 16 years, and influences of alcohol on smoking uptake, were inversely associated with high-level assessment of smoking risks and intention to quit in regional Aboriginal smokers. The SRAT may help tailor approaches to Indigenous smoking cessation