Supporting active engagement of adults with intellectual disabilities in lifestyle modification interventions: a realist evidence synthesis of what works, for whom, in what context and why.

BACKGROUND: Lifestyle modification interventions for adults with intellectual disabilities have had, to date, mixed effectiveness. This study aimed to understand how lifestyle modification interventions for adults with intellectual disabilities work, for whom they work and in what circumstances. METHODS: A realist evidence synthesis was conducted that incorporated input from adults with intellectual disabilities and expert researchers. Following the development of an initial programme theory based on key literature and input from people with lived experience and academics working in this field, five major databases (MEDLINE, EMBASE, CINAHL, PsycINFO and ASSIA) and clinical trial repositories were systematically searched. Data from 79 studies were synthesised to develop context, mechanism and outcome configurations (CMOCs). RESULTS: The contexts and mechanisms identified related to the ability of adults with intellectual disabilities to actively take part in the intervention, which in turn contributes to what works, for whom and in what circumstances. The included CMOCs related to support involvement, negotiating the balance between autonomy and behaviour change, fostering social connectedness and fun, accessibility and suitability of intervention strategies and delivery and broader behavioural pathways to lifestyle change. It is also essential to work with people with lived experiences when developing and evaluating interventions. CONCLUSIONS: Future lifestyle interventions research should be participatory in nature, and accessible data collection methods should also be explored as a way of including people with severe and profound intellectual disabilities in research. More emphasis should be given to the broader benefits of lifestyle change, such as opportunities for social interaction and connectedness.

Lifestyle modification interventions for adults with intellectual disabilities: systematic review and meta-analysis at intervention and component levels.

BACKGROUND: Adults with intellectual disabilities (IDs) are susceptible to multiple health risk behaviours such as alcohol consumption, smoking, low physical activity, sedentary behaviour and poor diet. Lifestyle modification interventions can prevent or reduce negative health consequences caused by these behaviours. We aim to determine the effectiveness of lifestyle modification interventions and their components in targeting health risk behaviours in adults with IDs. METHODS: A systematic review and meta-analysis were conducted. Electronic databases, clinical trial registries, grey literature and citations of systematic reviews and included studies were searched in January 2021 (updated February 2022). Randomised controlled trials and non-randomised controlled trials targeting alcohol consumption, smoking, low physical activity, sedentary behaviours and poor diet in adults (aged ≥ 18 years) with ID were included. Meta-analysis was conducted at the intervention level (pairwise and network meta-analysis) and the component-level (component network meta-analysis). Studies were coded using Michie's 19-item theory coding scheme and 94-item behaviour change taxonomies. Risk of bias was assessed using the Cochrane Risk of Bias (ROB) Version 2 and Risk of Bias in Non-randomised Studies of Interventions (ROBINS-I). The study involved a patient and public involvement (PPI) group, including people with lived experience, who contributed extensively by shaping the methodology, providing valuable insights in interpreting results and organising of dissemination events. RESULTS: Our literature search identified 12 180 articles, of which 80 studies with 4805 participants were included in the review. The complexity of lifestyle modification intervention was dismantled by identifying six core components that influenced outcomes. Interventions targeting single or multiple health risk behaviours could have a single or combination of multiple core-components. Interventions (2 RCTS; 4 non-RCTs; 228 participants) targeting alcohol consumption and smoking behaviour were effective but based on limited evidence. Similarly, interventions targeting low physical activity only (16 RCTs; 17 non-RCTs; 1413 participants) or multiple behaviours (low physical activity only, sedentary behaviours and poor diet) (17 RCTs; 24 non-RCTs; 3164 participants) yielded mixed effectiveness in outcomes. Most interventions targeting low physical activity only or multiple behaviours generated positive effects on various outcomes while some interventions led to no change or worsened outcomes, which could be attributed to the presence of a single core-component or a combination of similar core components in interventions. The intervention-level meta-analysis for weight management outcomes showed that none of the interventions were associated with a statistically significant change in outcomes when compared with treatment-as-usual and each other. Interventions with core-components combination of energy deficit diet, aerobic exercise and behaviour change techniques showed the highest weight loss [mean difference (MD) = -3.61, 95% credible interval (CrI) -9.68 to 1.95] and those with core-components combination dietary advice and aerobic exercise showed a weight gain (MD 0.94, 95% CrI -3.93 to 4.91). Similar findings were found with the component network meta-analysis for which additional components were identified. Most studies had a high and moderate risk of bias. Various theories and behaviour change techniques were used in intervention development and adaptation. CONCLUSION: Our systematic review is the first to comprehensively explore lifestyle modification interventions targeting a range of single and multiple health risk behaviours in adults with ID, co-produced with people with lived experience. It has practical implications for future research as it highlights the importance of mixed-methods research in understanding lifestyle modification interventions and the need for population-specific improvements in the field (e.g., tailored interventions, development of evaluation instruments or tools, use of rigorous research methodologies and comprehensive reporting frameworks). Wide dissemination of related knowledge and the involvement of PPI groups, including people with lived experience, will help future researchers design interventions that consider the unique needs, desires and abilities of people with ID.

Dysregulated immunophenotypic attributes of plasmacytoid but not myeloid dendritic cells in HIV-1 infected individuals in the absence of highly active anti-retroviral therapy.

Dendritic cells (DC) in HIV-1-infected individuals are decreased and their dysfunction has been implicated in HIV-1 immunopathogenesis. The mechanism of their dysfunction remains unclear, thus we analysed the expression of membrane molecules associated with immune regulation and DC activation in myeloid (mDC) and plasmacytoid DC (pDC) in therapy-naive and highly active anti-retroviral therapy (HAART)-treated HIV-1(+) patients. DC from healthy controls, untreated HIV-1(+) and HAART-treated patients were assessed by flow cytometry for expression of: anergy and apoptosis inducing molecules [programmed death (PD)-1 and its ligands PD-L1 and PD-L2], inhibitory and regulatory T cell-inducing molecules [immunoglobulin-like transcript (ILT)-3 and ILT-4], interferon (IFN)-α inhibitory receptor (ILT-7) and co-stimulatory molecules (CD80, CD83, and CD86). pDC from untreated HIV-1(+) patients expressed significantly lower levels of ILT-7 compared to healthy controls, while HAART-treated patients showed normal expression. pDC were also found to express moderately higher levels of PD-L1 and ILT-3 and lower levels of PD-L2 receptors in untreated patients compared to controls and HAART-treated patients. No significant changes were observed in mDC. There were no associations between the percentages and levels of expression of these molecules by pDC and viral load or CD4 T cell count. In conclusion, pDC but not mDC from HIV-1(+) patients with active viraemia display higher levels of apoptosis and T regulatory-inducing molecules and may be predisposed to chronically produce IFN-α through down-regulation of ILT-7. HAART restored normal expression levels of these receptors.

Single-nucleotide polymorphism-defined class I and class III major histocompatibility complex genetic subregions contribute to natural long-term nonprogression in HIV infection.

We performed a genome-wide association study comparing a cohort of 144 human immunodeficiency virus (HIV type 1-infected, untreated white long-term nonprogressors (LTNPs) with a cohort of 605 HIV-1-infected white seroconverters. Forty-seven single-nucleotide polymorphisms (SNPs), located from class I to class III major histocompatibility complex (MHC) subregions, show statistical association (false discovery rate, <0.05) with the LTNP condition, among which 5 reached genome-wide significance after Bonferonni correction. The MHC LTNP-associated SNPs are ordered in ≥4 linkage disequilibrium blocks; interestingly, an MHC class III linkage disequilibrium block (defined by the rs9368699 SNP) seems specific to the LTNP phenotype.

HIV-1 clade A infection and viral control: an immunological perspective on a case of underquantification.

Although a vast majority of HIV-1-positive patients in the UK are infected with clade B virus, a large number of newly diagnosed cases of heterosexually transmitted HIV-1 are acquired abroad, in countries where non-B clade HIV-1 predominates. Since the development of the viral load assay in 1988, assessment of HIV-1 plasma viraemia has become an integral part of HIV clinical care; however, the contemporary viral load assay was developed and optimized for clade B HIV-1. Here we report the underquantification of viraemia in an individual infected with clade A virus, and the consequent initial classification of the patient as an HIV controller (HIC). Immunological investigations of interferon (IFN)-γ and lymphoproliferative responses to HIV-1 clade B antigens and peptides, in parallel with mitogenic stimulation, were performed. Subsequent comparison with responses observed within clade B-infected HIC led to viral sequencing, confirmation of infecting clade and recommendation of antiretroviral therapy initiation. We emphasize the growing need for awareness of possible limitations of the commonly used viral load assays, which cannot be relied upon unreservedly in a clinical setting. Furthermore, this case highlights the increasing need for more detailed investigation into both viral genetics and fitness when defining patients as HIC.

Altered phenotype of regulatory T cells associated with lack of human immunodeficiency virus (HIV)-1-specific suppressive function.

Mechanisms by which CD4+ regulatory T cells (T(regs)) mediate suppression of virus-specific responses remain poorly defined. Adenosine, mediated via CD39 and CD73, has been shown to play a role in the action of murine T(regs) . In this study we investigate the phenotype of T(regs) in the context of human immunodeficiency virus (HIV)-1 infection, and the function of these cells in response to HIV-1-Gag and cytomegalovirus (CMV) peptides. Phenotypic data demonstrate a decrease in forkhead box transcription factor 3 (FoxP3+) T(reg) numbers in the peripheral blood of HIV-1+ individuals compared to healthy controls, which is most pronounced in those with high HIV-1 RNA plasma load. Due to aberrant expression of CD27 and CD127 during HIV-1 disease, these markers are unreliable for T(reg) identification. The CD3+ CD4+ CD25(hi) CD45RO+ phenotype correlated well with FoxP3 expression in both the HIV-1+ and seronegative control cohorts. We observed expression of CD39 but not CD73 on T(regs) from HIV-1+ and healthy control cohorts. We demonstrate, through T(reg) depletion, the suppressive potential of T(regs) over anti-CMV responses in the context of HIV-1 infection; however, no recovery of the HIV-1-specific T cell response was observed indicating a preferential loss of HIV-1-specific T(reg) function. We propose that before immunotherapeutic manipulation of T(regs) is considered, the immunoregulatory profile and distribution kinetics of this population in chronic HIV-1 infection must be elucidated fully.

Immune modulation and reconstitution of HIV-1-specific responses: novel approaches and strategies.

Efficacious protection for future generations from HIV-1 infection through the development of prophylactic vaccines is the best hope for the millions of individuals living with the threat of HIV-1 infection. Advances in the development of non-curative chemotherapy for those already infected have changed the course of the epidemic for those with access to the drugs. However in the ten years since the advent of highly active anti-retroviral therapy, the expectancy of curative chemotherapy has been quashed, and the constant need for a next generation of drugs is evident. As our understanding of HIV-1 pathogenesis increases, it is becoming apparent that novel approaches and strategies will be required to halt the global progression of HIV-1. Immune-based therapies are being considered in the context of effective antiretroviral therapy. Such immune-based therapy must allow the induction or regeneration of HIV-1-specific T-cell responses with the potential to control viremia and purge viral reservoirs. Studies of therapy substitution, treatment interruption, therapeutic vaccines and/or cytokines and/or hormones have been carried out and are briefly summarised in this review.

An empirical assessment of taxic paleobiology.

The analysis of major changes in faunal diversity through time is a central theme of analytical paleobiology. The most important sources of data are literature-based compilations of stratigraphic ranges of fossil taxa. The levels of error in these compilations and the possible effects of such error have often been discussed but never directly assessed. We compared our comprehensive database of trilobites to the equivalent portion of J. J. Sepkoski Jr.'s widely used global genus database. More than 70% of entries in the global database are inaccurate; however, as predicted, the error is randomly distributed and does not introduce bias.