Genomics, convergent neuroscience and progress in understanding autism spectrum disorder.

More than a hundred genes have been identified that, when disrupted, impart large risk for autism spectrum disorder (ASD). Current knowledge about the encoded proteins - although incomplete - points to a very wide range of developmentally dynamic and diverse biological processes. Moreover, the core symptoms of ASD involve distinctly human characteristics, presenting challenges to interpreting evolutionarily distant model systems. Indeed, despite a decade of striking progress in gene discovery, an actionable understanding of pathobiology remains elusive. Increasingly, convergent neuroscience approaches have been recognized as an important complement to traditional uses of genetics to illuminate the biology of human disorders. These methods seek to identify intersection among molecular-level, cellular-level and circuit-level functions across multiple risk genes and have highlighted developing excitatory neurons in the human mid-gestational prefrontal cortex as an important pathobiological nexus in ASD. In addition, neurogenesis, chromatin modification and synaptic function have emerged as key potential mediators of genetic vulnerability. The continued expansion of foundational 'omics' data sets, the application of higher-throughput model systems and incorporating developmental trajectories and sex differences into future analyses will refine and extend these results. Ultimately, a systems-level understanding of ASD genetic risk holds promise for clarifying pathobiology and advancing therapeutics.

Pleiotropy of autism-associated chromatin regulators.

Gene ontology analyses of high-confidence autism spectrum disorder (ASD) risk genes highlight chromatin regulation and synaptic function as major contributors to pathobiology. Our recent functional work in vivo has additionally implicated tubulin biology and cellular proliferation. As many chromatin regulators, including the ASD risk genes ADNP and CHD3, are known to directly regulate both tubulins and histones, we studied the five chromatin regulators most strongly associated with ASD (ADNP, CHD8, CHD2, POGZ and KMT5B) specifically with respect to tubulin biology. We observe that all five localize to microtubules of the mitotic spindle in vitro in human cells and in vivo in Xenopus. Investigation of CHD2 provides evidence that mutations present in individuals with ASD cause a range of microtubule-related phenotypes, including disrupted localization of the protein at mitotic spindles, cell cycle stalling, DNA damage and cell death. Lastly, we observe that ASD genetic risk is significantly enriched among tubulin-associated proteins, suggesting broader relevance. Together, these results provide additional evidence that the role of tubulin biology and cellular proliferation in ASD warrants further investigation and highlight the pitfalls of relying solely on annotated gene functions in the search for pathological mechanisms.

Cost-effectiveness of physical activity programs and services for older adults: a scoping review.

BACKGROUND: Evidence supporting physical activity for older adults is strongly positive. Implementation and scale-up of these interventions need to consider the value for money. This scoping review aimed to assess the volume of (i) systematic review evidence regarding economic evaluations of physical activity interventions, and (ii) of cost utility analysis (CUA) studies (trial- or model-based) of physical activity interventions for older people. METHODS: We searched five databases (January 2010 to February 2022) for systematic reviews of economic evaluations, and two databases (1976 to February 2022) for CUA studies of physical activity interventions for any population of people aged 60+ years. RESULTS: We found 12 potential reviews, two of which were eligible for inclusion. The remaining 10 reviews included eligible individual studies that were included in this review. All individual studies from the 12 reviews (n = 37) investigated the cost-effectiveness of structured exercise and most showed the intervention was more costly but more effective than no intervention. We identified 27 CUA studies: two investigated a physical activity promotion program and the remainder investigated structured exercise. Most interventions (86%) were more costly but more effective, and the remaining were cost-saving compared to no intervention. CONCLUSIONS: There is a scarcity of reviews investigating the value for money of physical activity interventions for older adults. Most studies investigated structured exercise. Physical activity interventions were generally more effective than no intervention but more costly. As such an intervention could be cost-effective and therefore worthy of wider implementation, but there is a need for more frequent economic evaluation in this field.

Impact of physical activity programs and services for older adults: a rapid review.

BACKGROUND: Knowledge of which physical activity programs are most effective for older adults in different sub-populations and contexts is limited. The objectives of this rapid review were to: 1) Overview evidence evaluating physical activity programs/services for older adults; and 2) Describe impact on physical activity, falls, intrinsic capacity (physical domain), functional ability (physical, social, and cognitive/emotional domains), and quality of life. METHODS: We conducted a rapid review of primary studies from 350 systematic reviews identified in a previous scoping review (March 2021: PEDro, MEDLINE, CINAHL, Cochrane Database). For Objective 1, we included intervention studies investigating physical activity programs/services in adults ≥ 60 years. Of these, we included good quality (≥ 6/10 PEDro scale) randomised controlled trials (RCTs) with ≥ 50 participants per group in Objective 2. RESULTS: Objective 1: Of the 1421 intervention studies identified from 8267 records, 79% were RCTs, 87% were in high income countries and 39% were good quality. Objective 2: We identified 87 large, good quality RCTs (26,861 participants). Overall activity promotion, structured exercise and recreation/sport had positive impacts (≥ 50% between-group comparisons positive) across all outcome domains. For overall activity promotion (21 intervention groups), greatest impacts were on physical activity (100% positive) and social outcomes (83% positive). Structured exercise (61 intervention groups) had particularly strong impacts on falls (91% positive), intrinsic capacity (67% positive) and physical functioning (77% positive). Recreation/sport (24 intervention groups) had particularly strong impacts on cognitive/emotional functioning (88% positive). Multicomponent exercise (39 intervention groups) had strong impacts across all outcomes, particularly physical activity (95% positive), falls (90% positive) and physical functioning (81% positive). Results for different populations and settings are presented. CONCLUSION: Evidence supporting physical activity for older adults is positive. We outline which activity types are most effective in different populations and settings.

Economic evaluation of physical activity mass media campaigns across the globe: a systematic review.

BACKGROUND: Physical activity mass media campaigns can deliver physical activity messages to many people, but it remains unclear whether they offer good value for money. We aimed to investigate the cost-effectiveness, cost-utility, and costs of physical activity mass media campaigns. METHODS: A search for economic evaluations (trial- or model-based) and costing studies of physical activity mass media campaigns was performed in six electronic databases (June/2021). The authors reviewed studies independently. A GRADE style rating was used to assess the overall certainty of each modelled economic evaluation. Results were summarised via narrative synthesis. RESULTS: Twenty-five studies (five model-based economic evaluations and 20 costing studies) were included, and all were conducted in high-income countries except for one costing study that was conducted in a middle-income country. The methods and assumptions used in the model-based analyses were highly heterogeneous and the results varied, ranging from the intervention being more effective and less costly (dominant) in two models to an incremental cost of US$130,740 (2020 base year) per QALY gained. The level of certainty of the models ranged from very low (n = 2) to low (n = 3). Overall, intervention costs were poorly reported. CONCLUSIONS: There are few economic evaluations of physical activity mass media campaigns available. The level of certainty of the models was judged to be very low to low, indicating that we have very little to little confidence that the results are reliable for decision making. Therefore, it remains unclear to what extent physical activity mass media campaigns offer good value for money. Future economic evaluations should consider selecting appropriate and comprehensive measures of campaign effectiveness, clearly report the assumptions of the models and fully explore the impact of assumptions in the results. REVIEW REGISTRATION: https://bit.ly/3tKSBZ3.

Economic evaluations of fall prevention exercise programs: a systematic review.

OBJECTIVE: To investigate cost-effectiveness and costs of fall prevention exercise programmes for older adults. DESIGN: Systematic review. DATA SOURCES: Medline, Embase, Web of Science, Scopus, National Institute for Health Research Economic Evaluation Database, Health Technology Assessment database, Tufts Cost-Effectiveness Analysis Registry, Research Papers in Economics and EconLit (inception to May 2022). ELIGIBILITY CRITERIA FOR STUDY SELECTION: Economic evaluations (trial-based or model-based) and costing studies investigating fall prevention exercise programmes versus no intervention or usual care for older adults living in the community or care facilities, and reporting incremental cost-effectiveness ratio (ICER) for fall-related outcomes or quality-adjusted life years (QALY, expressed as cost/QALY) and/or intervention costs. RESULTS: 31 studies were included. For community-dwelling older adults (21 economic evaluations, 6 costing studies), results ranged from more effective and less costly (dominant) interventions up to an ICER of US$279 802/QALY gained and US$11 986/fall prevented (US$ in 2020). Assuming an arbitrary willingness-to-pay threshold (US$100 000/QALY), most results (17/24) were considered cost-effective (moderate certainty). The greatest value for money (lower ICER/QALY gained and fall prevented) appeared to accrue for older adults and those with high fall risk, but unsupervised exercise appeared to offer poor value for money (higher ICER/QALY). For care facilities (two economic evaluations, two costing studies), ICERs ranged from dominant (low certainty) to US$35/fall prevented (moderate certainty). Overall, intervention costs varied and were poorly reported. CONCLUSIONS: Most economic evaluations investigated fall prevention exercise programmes for older adults living in the community. There is moderate certainty evidence that fall prevention exercise programmes are likely to be cost-effective. The evidence for older adults living in care facilities is more limited but promising. PROSPERO REGISTRATION NUMBER: PROSPERO 2020 CRD42020178023.

HOXC8 regulates self-renewal, differentiation and transformation of breast cancer stem cells.

BACKGROUND: Homeobox genes are master regulators of cell fate during embryonic development and their expression is altered in cancer. By regulating the balance between cell proliferation and differentiation, they maintain homeostasis of normal tissues. Here, we screened the expression of homeobox genes in mammary stem cells to establish their role in stem cells transformation in breast cancer. METHODS: Using a Homeobox Genes PCR array, we screened 83 homeobox genes in normal cancer breast stem/progenitor cells isolated by flow cytometry. The candidate gene HOXC8 epigenetic regulation was studied by DNA methylation and miRNA expression analyses. Self-renewal and differentiation of HOXC8-overexpressing or knockdown cells were assessed by flow cytometry and mammosphere, 3D matrigel and soft agar assays. Clinical relevance of in vitro findings were validated by bioinformatics analysis of patient datasets from TCGA and METABRIC studies. RESULTS: In this study we demonstrate altered expression of homeobox genes in breast cancer stem/progenitor cells. HOXC8 was consistently downregulated in stem/progenitor cells of all breast molecular subtypes, thus representing an interesting tumour suppressor candidate. We show that downregulated expression of HOXC8 is associated with DNA methylation at the gene promoter and expression of miR196 family members. Functional studies demonstrated that HOXC8 gain of function induces a decrease in the CD44+/CD24-/low cancer stem cell population and proportion of chemoresistant cells, with a concomitant increase in CD24+ differentiated cells. Increased HOXC8 levels also decrease the ability of cancer cells to form mammospheres and to grow in anchorage-independent conditions. Furthermore, loss of HOXC8 in non-tumorigenic mammary epithelial cells expands the cancer stem/progenitor cells pool, increases stem cell self-renewal, prevents differentiation induced by retinoic acid and induces a transformed phenotype. CONCLUSIONS: Taken together, our study points to an important role of homeobox genes in breast cancer stem/progenitor cell function and establishes HOXC8 as a suppressor of stemness and transformation in the mammary gland lineage.

Neonatal antibody responses are attenuated by interferon-γ produced by NK and T cells during RSV infection.

Respiratory syncytial virus (RSV) infects most children in the first year of life and is a major single cause of hospitalization in infants and young children. There is no effective vaccine, and antibody generated by primary neonatal infection is poorly protective against reinfection even with antigenically homologous viral strains. Studying the immunological basis of these observations in neonatal mice, we found that antibody responses to infection were low and unaffected by CD4 depletion, in contrast with adult mice, which had stronger CD4-dependent antibody responses. Natural killer cell depletion or codepletion of CD4(+) and CD8(+) cells during neonatal RSV infection caused a striking increase in anti-RSV antibody titer. These cells are major sources of the cytokine IFN-γ, and blocking IFN-γ also enhanced RSV-specific antibody responses in neonates. In addition, infection with a recombinant RSV engineered to produce IFN-γ reduced antibody titer, confirming that IFN-γ plays a pivotal role in inhibition of antibody responses after neonatal infection. These unexpected findings show that the induction of a strong cellular immune response may limit antibody responses in early life and that vaccines that induce IFN-γ-secreting cells might, in some situations, be less protective than those that do not.

Digital Apps to Improve Mobility in Adults with Neurological Conditions: A Health App-Focused Systematic Review.

The provision of mobility exercises through a smartphone application (app) for people undertaking neurological rehabilitation may improve mobility outcomes. However, it is difficult for clinicians and consumers to select high-quality, appropriate apps. This review aimed to identify (1) which mobile health (mHealth) apps are suitable for prescribing mobility exercises for adults with neurological health conditions, (2) how well these apps incorporate telehealth strategies, and (3) how well these apps rate in terms of quality and capacity for behaviour change. The Australian Apple iTunes Store was systematically searched, by using a search code and manually, for apps suitable for training mobility in neurological rehabilitation. Additional searches were conducted in known app repositories and for web-based apps. Trained reviewers extracted data from the included apps, including population-specific characteristics; quality, by using the Mobile App Rating Scale (MARS); and behaviour change potential, by using the App Behaviour Change Scale (ABACUS). The included apps (n = 18) provided <50 to >10,000 exercises, many incurred a subscription fee (n = 13), and half included telehealth features. App quality was moderate (mean MARS score of 3.2/5 and SD of 0.5), and potential for behaviour change was poor (mean ABACUS score of 5.7/21 and SD of 2.1). A limited number of high-quality apps are available for the prescription of mobility exercises in people with neurological conditions.

Autism genes converge on microtubule biology and RNA-binding proteins during excitatory neurogenesis.

Recent studies have identified over one hundred high-confidence (hc) autism spectrum disorder (ASD) genes. Systems biological and functional analyses on smaller subsets of these genes have consistently implicated excitatory neurogenesis. However, the extent to which the broader set of hcASD genes are involved in this process has not been explored systematically nor have the biological pathways underlying this convergence been identified. Here, we leveraged CROP-Seq to repress 87 hcASD genes in a human in vitro model of cortical neurogenesis. We identified 17 hcASD genes whose repression significantly alters developmental trajectory and results in a common cellular state characterized by disruptions in proliferation, differentiation, cell cycle, microtubule biology, and RNA-binding proteins (RBPs). We also characterized over 3,000 differentially expressed genes, 286 of which had expression profiles correlated with changes in developmental trajectory. Overall, we uncovered transcriptional disruptions downstream of hcASD gene perturbations, correlated these disruptions with distinct differentiation phenotypes, and reinforced neurogenesis, microtubule biology, and RBPs as convergent points of disruption in ASD.

A foundational atlas of autism protein interactions reveals molecular convergence.

Translating high-confidence (hc) autism spectrum disorder (ASD) genes into viable treatment targets remains elusive. We constructed a foundational protein-protein interaction (PPI) network in HEK293T cells involving 100 hcASD risk genes, revealing over 1,800 PPIs (87% novel). Interactors, expressed in the human brain and enriched for ASD but not schizophrenia genetic risk, converged on protein complexes involved in neurogenesis, tubulin biology, transcriptional regulation, and chromatin modification. A PPI map of 54 patient-derived missense variants identified differential physical interactions, and we leveraged AlphaFold-Multimer predictions to prioritize direct PPIs and specific variants for interrogation in Xenopus tropicalis and human forebrain organoids. A mutation in the transcription factor FOXP1 led to reconfiguration of DNA binding sites and altered development of deep cortical layer neurons in forebrain organoids. This work offers new insights into molecular mechanisms underlying ASD and describes a powerful platform to develop and test therapeutic strategies for many genetically-defined conditions.

Preexposure to CpG protects against the delayed effects of neonatal respiratory syncytial virus infection.

Severe respiratory viral infection in early life is associated with recurrent wheeze and asthma in later childhood. Neonatal immune responses tend to be skewed toward T helper 2 (Th2) responses, which may contribute to the development of a pathogenic recall response to respiratory infection. Since neonatal Th2 skewing can be modified by stimulation with Toll-like receptor (TLR) ligands, we investigated the effect of exposure to CpG oligodeoxynucleotides (TLR9 ligands) prior to neonatal respiratory syncytial virus (RSV) infection in mice. CpG preexposure was protective against enhanced disease during secondary adult RSV challenge, with a reduction in viral load and an increase in Th1 responses. A similar Th1 switch and reduction in disease were observed if CpG was administered in the interval between neonatal infection and challenge. In neonates, CpG pretreatment led to a transient increase in expression of major histocompatibility complex class II (MHCII) and CD80 on CD11c-positive cells and gamma interferon (IFN-γ) production by NK cells after RSV infection, suggesting that the protective effects may be mediated by antigen-presenting cells (APC) and NK cells. We conclude that the adverse effects of early-life respiratory viral infection on later lung health might be mitigated by conditions that promote TLR activation in the infant lung.

A potential molecular mechanism for hypersensitivity caused by formalin-inactivated vaccines.

Heat, oxidation and exposure to aldehydes create reactive carbonyl groups on proteins, targeting antigens to scavenger receptors. Formaldehyde is widely used in making vaccines, but has been associated with atypical enhanced disease during subsequent infection with paramyxoviruses. We show that carbonyl groups on formaldehyde-treated vaccine antigens boost T helper type 2 (T(H)2) responses and enhance respiratory syncytial virus (RSV) disease in mice, an effect partially reversible by chemical reduction of carbonyl groups.

Vitamin K epoxide reductase prefers ER membrane-anchored thioredoxin-like redox partners.

Vitamin K epoxide reductase (VKOR) sustains blood coagulation by reducing vitamin K epoxide to the hydroquinone, an essential cofactor for the gamma-glutamyl carboxylation of many clotting factors. The physiological redox partner of VKOR remains uncertain, but is likely a thioredoxin-like protein. Here, we demonstrate that human VKOR has the same membrane topology as the enzyme from Synechococcus sp., whose crystal structure was recently determined. Our results suggest that, during the redox reaction, Cys43 in a luminal loop of human VKOR forms a transient disulfide bond with a thioredoxin (Trx)-like protein located in the lumen of the endoplasmic reticulum (ER). We screened for redox partners of VKOR among the large number of mammalian Trx-like ER proteins by testing a panel of these candidates for their ability to form this specific disulfide bond with human VKOR. Our results show that VKOR interacts strongly with TMX, an ER membrane-anchored Trx-like protein with a unique CPAC active site. Weaker interactions were observed with TMX4, a close relative of TMX, and ERp18, the smallest Trx-like protein of the ER. We performed a similar screen with Ero1-alpha, an ER-luminal protein that oxidizes the Trx-like protein disulfide isomerase. We found that Ero1-alpha interacts with most of the tested Trx-like proteins, although only poorly with the membrane-anchored members of the family. Taken together, our results demonstrate that human VKOR employs the same electron transfer pathway as its bacterial homologs and that VKORs generally prefer membrane-bound Trx-like redox partners.

Exercise for fall prevention in community-dwelling people aged 60+: more effective in trials with higher fall rates in control groups.

BACKGROUND AND OBJECTIVES: Exercise is beneficial for fall prevention. Targeting interventions to people who fall more may lead to greater population impacts. As trials have used varying methods to assess participant risk level, prospectively-measured control group fall rates may provide a more accurate and poolable way to understand intervention effects in different subpopulations. We aimed to explore differences in effectiveness of fall prevention exercise according to prospectively-measured fall rate. METHODS: Secondary analysis of a Cochrane review investigating exercise for fall prevention in peopled aged ≥60 years. Meta-analysis assessed the impact of exercise on fall rate. Studies were dichotomized according to the median control group fall rate (0.87, IQR 0.54-1.37 falls/person-year). Meta-regression explored the effects on falls in trials with higher and lower control group fall rates. RESULTS: Exercise reduced the rate of falls in trials with higher (rate ratio 0.68, 95% CI 0.61-0.76, 31 studies) and lower control group fall rates (rate ratio 0.88, 95% CI 0.79-0.97, 31 studies, P = 0.006 for difference in effects). CONCLUSION: Exercise prevents falls, moreso in trials with higher control group fall rates. As past falls strongly predict future falls, targeting interventions to those with more past falls may be more efficient than other falls risk screening methods.

Antiviral activity of salt-coated materials against SARS-CoV-2.

The SARS-CoV-2 pandemic demonstrated the importance of human coronaviruses and the need to develop materials to prevent the spread of emergent respiratory viruses. Coating of surfaces with antiviral materials is a major interest in controlling spread of viruses, especially in high-risk or high-traffic areas. A number of different coatings for surfaces have been proposed, each with their own advantages and disadvantages. Here we show that simple salt coating on a range of surfaces, including a novel biomass aerogel can reduce the infectivity of SARS-CoV-2 placed onto the surface. This suggests that a simple to apply coating could be applied to a range of materials and have an antiviral effect against SARS-CoV-2, as well as other potential emerging viruses.

Physical Activity Preferences of People Living with Brain Injury: Formative Qualitative Research to Develop a Discrete Choice Experiment.

BACKGROUND AND OBJECTIVE: The World Health Organization physical activity guidelines for people living with disability do not consider the needs of people living with moderate-to-severe traumatic brain injury. This paper describes the qualitative co-development of a discrete choice experiment survey to inform the adaption of these guidelines by identifying the physical activity preferences of people living with moderate-to-severe traumatic brain injury in Australia. METHODS: The research team comprised researchers, people with lived experience of traumatic brain injury and health professionals with expertise in traumatic brain injury. We followed a four-stage process: (1) identification of key constructs and initial expression of attributes, (2) critique and refinement of attributes, (3) prioritisation of attributes and refinement of levels and (4) testing and refining language, format and comprehensibility. Data collection included deliberative dialogue, focus groups and think-aloud interviews with 22 purposively sampled people living with moderate-to-severe traumatic brain injury. Strategies were used to support inclusive participation. Analysis employed qualitative description and framework methods. RESULTS: This formative process resulted in discarding, merging, renaming and reconceptualising attributes and levels. Attributes were reduced from an initial list of 17 to six: (1) Type of activity, (2) Out-of-pocket cost, (3) Travel time, (4) Who with, (5) Facilitated by and (6) Accessibility of setting. Confusing terminology and cumbersome features of the survey instrument were also revised. Challenges included purposive recruitment, reducing diverse stakeholder views to a few attributes, finding the right language and navigating the complexity of discrete choice experiment scenarios. CONCLUSIONS: This formative co-development process significantly improved the relevance and comprehensibility of the discrete choice experiment survey tool. This process may be applicable in other discrete choice experiment studies.

Rare X-linked variants carry predominantly male risk in autism, Tourette syndrome, and ADHD.

Autism spectrum disorder (ASD), Tourette syndrome (TS), and attention-deficit/hyperactivity disorder (ADHD) display strong male sex bias, due to a combination of genetic and biological factors, as well as selective ascertainment. While the hemizygous nature of chromosome X (Chr X) in males has long been postulated as a key point of "male vulnerability", rare genetic variation on this chromosome has not been systematically characterized in large-scale whole exome sequencing studies of "idiopathic" ASD, TS, and ADHD. Here, we take advantage of informative recombinations in simplex ASD families to pinpoint risk-enriched regions on Chr X, within which rare maternally-inherited damaging variants carry substantial risk in males with ASD. We then apply a modified transmission disequilibrium test to 13,052 ASD probands and identify a novel high confidence ASD risk gene at exome-wide significance (MAGEC3). Finally, we observe that rare damaging variants within these risk regions carry similar effect sizes in males with TS or ADHD, further clarifying genetic mechanisms underlying male vulnerability in multiple neurodevelopmental disorders that can be exploited for systematic gene discovery.

Genetic susceptibility to the delayed sequelae of neonatal respiratory syncytial virus infection is MHC dependent.

Respiratory syncytial virus (RSV) is a major cause of respiratory morbidity, resulting in hospitalization for bronchiolitis in some infected infants that is associated with wheeze in later life. Genetic factors are known to affect the severity of the sequelae after RSV infection, but the complexity of the temporal and genetic effects makes it difficult to analyze this response in studies in man. Therefore, we developed a murine genetic model to analyze the sequelae occurring after RSV infection in early life. Haplotype-based genetic analysis of interstrain differences in severity identified the MHC as an important genetic determinant. This was confirmed by analysis of responses in congenic mice with different MHC haplotypes. We also found that susceptible strains had high CD8 levels during secondary infection. Analysis of first filial generation, second filial generation, and back-cross progeny produced by intercrossing resistant (H-2(k), C3H/HeN) and sensitive (H-2(b), BALB/c) strains indicated that susceptibility to sequelae after RSV infection was dominantly inherited but also segregated in a non-MHC-dependent manner. Thus, MHC haplotype and its effect on CD8 cell response is an important determinant of the outcome of neonatal RSV infection.

A Systematic Review and Meta-Analysis Exploring Effects of Third-Wave Psychological Therapies on Hearing-Related Distress, Depression, Anxiety, and Quality of Life in People With Audiological Problems.

PURPOSE: There is growing evidence supporting the use of third-wave psychological therapies, such as mindfulness-based interventions (MBIs) and acceptance and commitment therapy (ACT), for people with long-term or chronic physical health conditions. We conducted a systematic review and meta-analysis to critically evaluate the effectiveness of third-wave interventions for improving hearing-related distress and psychological well-being in people with audiological problems. METHOD: We searched online bibliographic databases and assessed study quality. We conducted random-effects meta-analyses if at least two randomized controlled trials (RCTs) examined hearing-related distress, depression, anxiety, or quality of life in people with audiological problems. Findings of pre-post studies were summarized narratively. RESULTS: We identified 15 studies: six RCTs and nine pre-post studies. The methodological quality of studies was mostly poor to moderate, and sample sizes were typically small (overall n = 750). Most studies focused on tinnitus (n = 12), MBIs (n = 8), and ACT (n = 6). Statistically significant improvements in hearing-related distress were found with ACT and MBIs versus controls and other treatments at post-intervention in people with tinnitus, while improvements in depression and anxiety were only found for ACT versus controls at post-intervention. However, gains were either not maintained or not examined at follow-up, and there was no evidence for improvements in quality of life. CONCLUSIONS: At present, there is insufficient evidence to recommend the use of third-wave interventions for improving hearing-related distress or psychological well-being in people with audiological problems. There is some evidence that ACT and MBIs may be useful in addressing hearing-related distress in people with tinnitus, but only in the short term. However, findings should be interpreted with caution given the small number of studies with generally small sample sizes and mostly poor-to-moderate methodological quality. More high-quality, adequately powered, double-blind RCTs, particularly in audiological problems other than tinnitus, are needed to draw firm conclusions and meaningful clinical recommendations. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.19735975.