How stakeholder engagement has led us to reconsider definitions of rigour in systematic reviews

Abstract: As a methodology designed to inform policy and practice decisions, it is particularly important to ensure that systematic reviews are shaped by those who will use them. There is a broad range of approaches for engagement of the potential users of reviews that aim to elicit their priorities and needs and incorporate these into the review design. This incorporation of their priorities and needs can create a tension between their calls for locally-specific, often rapidly-produced evidence syntheses for policy needs and the production of unbiased, generalisable, globally-relevant systematic reviews. This tension raises the question of what is a ‘gold standard’ review. This commentary aims to address head on this often undiscussed key challenge with regard to stakeholder involvement in systematic reviews: that responding to stakeholders can mean reconsidering what makes a review rigorous. The commentary proposes a new model to address these tensions that combines the production of public-good reviews, with stakeholder-driven syntheses. In this, it presents the approach taken by our team in [Anonymised] to achieve two different but complementary outputs: (i) ‘public goods’, namely comprehensive and generalisable systematic reviews of the evidence available for and accessible to a global audience, and (ii) locally-focussed, stakeholder-driven, pragmatically-produced syntheses for decision-making at a policy level. The designed approach incorporates balancing the formal requirements of full, published systematic reviews with engagement of national and international decision-makers. It also accommodates space to move from stakeholder engagement to co-production, where stakeholders are engaged to such an extent that they become partners in the production of the review. These approaches are integrated into the traditional steps for producing a systematic review with implications as to what constitutes a gold standard approach to synthesising evidence

Building capacity for evidence-informed decision making: an example from South Africa

Abstract: To maximise the potential impact and acceptability of EIDM capacity building, there is a need for programmes to coordinate their remits within existing systems, playing both ‘insider’ and ‘outsider’ roles. Through a review of the South African evidence-policy landscape and analysis of a stakeholder event that brought together EIDM role players, this paper illustrates how one capacity-building programme navigated its position within the national evidence-policy interface. It identifies strategies for improving the acceptability and potential effectiveness of donor-funded EIDM capacity-building activities: understanding the evidence-policy interface, incorporating programmes into the decision-making infrastructure (being an ‘insider’), whilst retaining an element of neutrality (being an ‘outsider’)

Personal preferences of participation in fall prevention programmes: A descriptive study

Background: Participation in fall prevention programmes is associated with lower risk of injurious falls among older adults. However participation rates in fall prevention interventions are low. The limited participation in fall prevention might increase with a preference based approach. Therefore, the aims of this study are to a) determine the personal preferences of older adults regarding fall prevention and b) explore the association between personal preferences and participation. Methods: We assessed the personal preferences of older adults and the association between their preferences, chosen programme and participation level. Nine different programmes, with a focus on those best matching their personal preferences, were offered to participants. Twelve weeks after the start of the programme, participation was assessed by questionnaire. Logistic regression was performed to test the association between preferences and participation and an ANOVA was performed to assess differences between the number of preferences included in the chosen programme and participation level. Results: Of the 134 participants, 49% preferred to exercise at home versus 43% elsewhere, 46% preferred to exercise alone versus 44% in a group and 41% indicated a programme must be free of charge while 51% were willing to pay. The combination of an external location, in a group and for a fee was preferred by 27%, whereas 26% preferred at home, alone and only for free. The presence of preferences or the extent to which the programme matched earlier preferences was not associated with participation. Conclusion: Despite the fact that preferences can vary greatly among older adults, local programmes should be available for at least the two largest subgroups. This includes a programme at home, offered individually and for free. In addition, local healthcare providers should cooperate to increase the accessibility of currently available group programmes

Establishing Ghanaian adult reference intervals for hematological parameters controlling for latent anemia and inflammation

CITATION: Bawua, A. et al. 2020. Establishing Ghanaian adult reference intervals for hematological parameters controlling for latent anemia and inflammation. International journal of laboratory hematology, 42(6):705–717. doi:10.1111/ijlh.13296The original publication is available at https://onlinelibrary.wiley.com/journal/1751553xBackground: In Ghana, diagnostic laboratories rely on reference intervals (RIs) provided by manufacturers of laboratory analyzers which may not be appropriate. This study aimed to establish RIs for hematological parameters in adult Ghanaian population. Methods: This cross-sectional study recruited 501 apparently healthy adults from two major urban areas in Ghana based on the protocol by IFCC Committee for Reference Intervals and Decision Limits. Whole blood was tested for complete blood count (CBC) by Sysmex XN-1000 analyzer, sera were tested for iron and ferritin by Beckman-Coulter/AU480, for transferrin, vitamin-B12, and folate was measured by Centaur-XP/Siemen. Partitioning of reference values by sex and age was guided by “effect size” of between-subgroup differences defined as standard deviation ratio (SDR) based on ANOVA. RIs were derived using parametric method with application of latent abnormal values exclusion method (LAVE), a multifaceted method of detecting subjects with abnormal results in related parameters. Results: Using SDR ≥ 0.4 as a threshold, RIs were partitioned by sex for platelet, erythrocyte parameters except mean corpuscular constants, and iron markers. Application of LAVE had prominent effect on RIs for majority of erythrocyte and iron parameters. Global comparison of Ghanaian RIs revealed lower-side shift of RIs for leukocyte and neutrophil counts, female hemoglobin and male platelet count, especially compared to non-African countries. Conclusion: The LAVE effect on many hematological RIs indicates the need for de-liberate secondary exclusion for proper derivation of RIs. Obvious differences in Ghanaian RIs compared to other countries underscore the importance of country-specific RIs for improved clinical decision-making.https://onlinelibrary.wiley.com/doi/10.1111/ijlh.13296Publishers versio

Behavioural, brain and cardiac responses to hypobaric hypoxia in broiler chickens

A novel approach to pre-slaughter stunning of chickens has been developed in which birds are rendered unconscious by progressive hypobaric hypoxia. Termed Low Atmospheric Pressure Stunning (LAPS), this approach involves application of gradual decompression lasting 280 s according to a prescribed curve. We examined responses to LAPS by recording behaviour, electroencephalogram (EEG) and electrocardiogram (ECG) in individual male chickens, and interpreted these with regard to the welfare impact of the process. We also examined the effect of two temperature adjusted pressure curves on these responses. Broiler chickens were exposed to LAPS in 30 triplets (16 and 14 triplets assigned to each pressure curve). In each triplet, one bird was instrumented for recording of EEG and ECG while the behaviour of all three birds was observed. Birds showed a consistent sequence of behaviours during LAPS (ataxia, loss of posture, clonic convulsions and motionless) which were observed in all birds. Leg paddling, tonic convulsions, slow wing flapping, mandibulation, head shaking, open bill breathing, deep inhalation, jumping and vocalisation were observed in a proportion of birds. Spectral analysis of EEG responses at 2 s intervals throughout LAPS revealed progressive decreases in median frequency at the same time as corresponding progressive increases in total power, followed later by decreases in total power as all birds exhibited isoelectric EEG and died. There was a very pronounced increase in total power at 50–60 s into the LAPS cycle, which corresponded to dominance of the signal by high amplitude slow waves, indicating loss of consciousness. Slow wave EEG was seen early in the LAPS process, before behavioural evidence of loss of consciousness such as ataxia and loss of posture, almost certainly due to the fact that it was completely dark in the LAPS chamber. ECG recordings showed a pronounced bradycardia (starting on average 49.6 s into LAPS), often associated with arrhythmia, until around 60 s into LAPS when heart rate levelled off. There was a good correlation between behavioural, EEG and cardiac measures in relation to loss of consciousness which collectively provide a loss of consciousness estimate of around 60 s. There were some effects of temperature adjusted pressure curves on behavioural latencies and ECG responses, but in general responses were consistent and very similar to those reported in previous research on controlled atmosphere stunning with inert gases. The results suggest that the process is humane (slaughter without avoidable fear, anxiety, pain, suffering and distress). In particular, the maintenance of slow wave EEG patterns in the early part of LAPS (while birds are still conscious) is strongly suggestive that LAPS is non-aversive, since we would expect this to be interrupted by pain or discomfort

Dolutegravir twice-daily dosing in children with HIV-associated tuberculosis: a pharmacokinetic and safety study within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial

Background: Children with HIV-associated tuberculosis (TB) have few antiretroviral therapy (ART) options. We aimed to evaluate the safety and pharmacokinetics of dolutegravir twice-daily dosing in children receiving rifampicin for HIV-associated TB. Methods: We nested a two-period, fixed-order pharmacokinetic substudy within the open-label, multicentre, randomised, controlled, non-inferiority ODYSSEY trial at research centres in South Africa, Uganda, and Zimbabwe. Children (aged 4 weeks to <18 years) with HIV-associated TB who were receiving rifampicin and twice-daily dolutegravir were eligible for inclusion. We did a 12-h pharmacokinetic profile on rifampicin and twice-daily dolutegravir and a 24-h profile on once-daily dolutegravir. Geometric mean ratios for trough plasma concentration (Ctrough), area under the plasma concentration time curve from 0 h to 24 h after dosing (AUC0–24 h), and maximum plasma concentration (Cmax) were used to compare dolutegravir concentrations between substudy days. We assessed rifampicin Cmax on the first substudy day. All children within ODYSSEY with HIV-associated TB who received rifampicin and twice-daily dolutegravir were included in the safety analysis. We described adverse events reported from starting twice-daily dolutegravir to 30 days after returning to once-daily dolutegravir. This trial is registered with ClinicalTrials.gov (NCT02259127), EudraCT (2014–002632-14), and the ISRCTN registry (ISRCTN91737921). Findings: Between Sept 20, 2016, and June 28, 2021, 37 children with HIV-associated TB (median age 11·9 years [range 0·4–17·6], 19 [51%] were female and 18 [49%] were male, 36 [97%] in Africa and one [3%] in Thailand) received rifampicin with twice-daily dolutegravir and were included in the safety analysis. 20 (54%) of 37 children enrolled in the pharmacokinetic substudy, 14 of whom contributed at least one evaluable pharmacokinetic curve for dolutegravir, including 12 who had within-participant comparisons. Geometric mean ratios for rifampicin and twice-daily dolutegravir versus once-daily dolutegravir were 1·51 (90% CI 1·08–2·11) for Ctrough, 1·23 (0·99–1·53) for AUC0–24 h, and 0·94 (0·76–1·16) for Cmax. Individual dolutegravir Ctrough concentrations were higher than the 90% effective concentration (ie, 0·32 mg/L) in all children receiving rifampicin and twice-daily dolutegravir. Of 18 children with evaluable rifampicin concentrations, 15 (83%) had a Cmax of less than the optimal target concentration of 8 mg/L. Rifampicin geometric mean Cmax was 5·1 mg/L (coefficient of variation 71%). During a median follow-up of 31 weeks (IQR 30–40), 15 grade 3 or higher adverse events occurred among 11 (30%) of 37 children, ten serious adverse events occurred among eight (22%) children, including two deaths (one tuberculosis-related death, one death due to traumatic injury); no adverse events, including deaths, were considered related to dolutegravir. Interpretation: Twice-daily dolutegravir was shown to be safe and sufficient to overcome the rifampicin enzyme-inducing effect in children, and could provide a practical ART option for children with HIV-associated TB

Neuropsychiatric manifestations and sleep disturbances with dolutegravir-based antiretroviral therapy versus standard of care in children and adolescents: a secondary analysis of the ODYSSEY trial

BACKGROUND: Cohort studies in adults with HIV showed that dolutegravir was associated with neuropsychiatric adverse events and sleep problems, yet data are scarce in children and adolescents. We aimed to evaluate neuropsychiatric manifestations in children and adolescents treated with dolutegravir-based treatment versus alternative antiretroviral therapy. METHODS: This is a secondary analysis of ODYSSEY, an open-label, multicentre, randomised, non-inferiority trial, in which adolescents and children initiating first-line or second-line antiretroviral therapy were randomly assigned 1:1 to dolutegravir-based treatment or standard-of-care treatment. We assessed neuropsychiatric adverse events (reported by clinicians) and responses to the mood and sleep questionnaires (reported by the participant or their carer) in both groups. We compared the proportions of patients with neuropsychiatric adverse events (neurological, psychiatric, and total), time to first neuropsychiatric adverse event, and participant-reported responses to questionnaires capturing issues with mood, suicidal thoughts, and sleep problems. FINDINGS: Between Sept 20, 2016, and June 22, 2018, 707 participants were enrolled, of whom 345 (49%) were female and 362 (51%) were male, and 623 (88%) were Black-African. Of 707 participants, 350 (50%) were randomly assigned to dolutegravir-based antiretroviral therapy and 357 (50%) to non-dolutegravir-based standard-of-care. 311 (44%) of 707 participants started first-line antiretroviral therapy (ODYSSEY-A; 145 [92%] of 157 participants had efavirenz-based therapy in the standard-of-care group), and 396 (56%) of 707 started second-line therapy (ODYSSEY-B; 195 [98%] of 200 had protease inhibitor-based therapy in the standard-of-care group). During follow-up (median 142 weeks, IQR 124–159), 23 participants had 31 neuropsychiatric adverse events (15 in the dolutegravir group and eight in the standard-of-care group; difference in proportion of participants with ≥1 event p=0·13). 11 participants had one or more neurological events (six and five; p=0·74) and 14 participants had one or more psychiatric events (ten and four; p=0·097). Among 14 participants with psychiatric events, eight participants in the dolutegravir group and four in standard-of-care group had suicidal ideation or behaviour. More participants in the dolutegravir group than the standard-of-care group reported symptoms of self-harm (eight vs one; p=0·025), life not worth living (17 vs five; p=0·0091), or suicidal thoughts (13 vs none; p=0·0006) at one or more follow-up visits. Most reports were transient. There were no differences by treatment group in low mood or feeling sad, problems concentrating, feeling worried or feeling angry or aggressive, sleep problems, or sleep quality. INTERPRETATION: The numbers of neuropsychiatric adverse events and reported neuropsychiatric symptoms were low. However, numerically more participants had psychiatric events and reported suicidality ideation in the dolutegravir group than the standard-of-care group. These differences should be interpreted with caution in an open-label trial. Clinicians and policy makers should consider including suicidality screening of children or adolescents receiving dolutegravir

Contributions of mean and shape of blood pressure distribution to worldwide trends and variations in raised blood pressure: A pooled analysis of 1018 population-based measurement studies with 88.6 million participants

© The Author(s) 2018. Background: Change in the prevalence of raised blood pressure could be due to both shifts in the entire distribution of blood pressure (representing the combined effects of public health interventions and secular trends) and changes in its high-blood-pressure tail (representing successful clinical interventions to control blood pressure in the hypertensive population). Our aim was to quantify the contributions of these two phenomena to the worldwide trends in the prevalence of raised blood pressure. Methods: We pooled 1018 population-based studies with blood pressure measurements on 88.6 million participants from 1985 to 2016. We first calculated mean systolic blood pressure (SBP), mean diastolic blood pressure (DBP) and prevalence of raised blood pressure by sex and 10-year age group from 20-29 years to 70-79 years in each study, taking into account complex survey design and survey sample weights, where relevant. We used a linear mixed effect model to quantify the association between (probittransformed) prevalence of raised blood pressure and age-group- and sex-specific mean blood pressure. We calculated the contributions of change in mean SBP and DBP, and of change in the prevalence-mean association, to the change in prevalence of raised blood pressure. Results: In 2005-16, at the same level of population mean SBP and DBP, men and women in South Asia and in Central Asia, the Middle East and North Africa would have the highest prevalence of raised blood pressure, and men and women in the highincome Asia Pacific and high-income Western regions would have the lowest. In most region-sex-age groups where the prevalence of raised blood pressure declined, one half or more of the decline was due to the decline in mean blood pressure. Where prevalence of raised blood pressure has increased, the change was entirely driven by increasing mean blood pressure, offset partly by the change in the prevalence-mean association. Conclusions: Change in mean blood pressure is the main driver of the worldwide change in the prevalence of raised blood pressure, but change in the high-blood-pressure tail of the distribution has also contributed to the change in prevalence, especially in older age groups

Repositioning of the global epicentre of non-optimal cholesterol

High blood cholesterol is typically considered a feature of wealthy western countries(1,2). However, dietary and behavioural determinants of blood cholesterol are changing rapidly throughout the world(3) and countries are using lipid-lowering medications at varying rates. These changes can have distinct effects on the levels of high-density lipoprotein (HDL) cholesterol and non-HDL cholesterol, which have different effects on human health(4,5). However, the trends of HDL and non-HDL cholesterol levels over time have not been previously reported in a global analysis. Here we pooled 1,127 population-based studies that measured blood lipids in 102.6 million individuals aged 18 years and older to estimate trends from 1980 to 2018 in mean total, non-HDL and HDL cholesterol levels for 200 countries. Globally, there was little change in total or non-HDL cholesterol from 1980 to 2018. This was a net effect of increases in low- and middle-income countries, especially in east and southeast Asia, and decreases in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe. As a result, countries with the highest level of non-HDL cholesterol-which is a marker of cardiovascular riskchanged from those in western Europe such as Belgium, Finland, Greenland, Iceland, Norway, Sweden, Switzerland and Malta in 1980 to those in Asia and the Pacific, such as Tokelau, Malaysia, The Philippines and Thailand. In 2017, high non-HDL cholesterol was responsible for an estimated 3.9 million (95% credible interval 3.7 million-4.2 million) worldwide deaths, half of which occurred in east, southeast and south Asia. The global repositioning of lipid-related risk, with non-optimal cholesterol shifting from a distinct feature of high-income countries in northwestern Europe, north America and Australasia to one that affects countries in east and southeast Asia and Oceania should motivate the use of population-based policies and personal interventions to improve nutrition and enhance access to treatment throughout the world.Peer reviewe