Allosteric coupling asymmetry mediates paradoxical activation of BRAF by type II inhibitors.

The type II class of RAF inhibitors currently in clinical trials paradoxically activate BRAF at subsaturating concentrations. Activation is mediated by induction of BRAF dimers, but why activation rather than inhibition occurs remains unclear. Using biophysical methods tracking BRAF dimerization and conformation, we built an allosteric model of inhibitor-induced dimerization that resolves the allosteric contributions of inhibitor binding to the two active sites of the dimer, revealing key differences between type I and type II RAF inhibitors. For type II inhibitors the allosteric coupling between inhibitor binding and BRAF dimerization is distributed asymmetrically across the two dimer binding sites, with binding to the first site dominating the allostery. This asymmetry results in efficient and selective induction of dimers with one inhibited and one catalytically active subunit. Our allosteric models quantitatively account for paradoxical activation data measured for 11 RAF inhibitors. Unlike type II inhibitors, type I inhibitors lack allosteric asymmetry and do not activate BRAF homodimers. Finally, NMR data reveal that BRAF homodimers are dynamically asymmetric with only one of the subunits locked in the active αC-in state. This provides a structural mechanism for how binding of only a single αC-in inhibitor molecule can induce potent BRAF dimerization and activation.

A polygenic risk score for alcohol-associated cirrhosis among heavy drinkers with European ancestry.

BACKGROUND: Polygenic Risk Scores (PRS) based on results from genome-wide association studies offer the prospect of risk stratification for many common and complex diseases. We developed a PRS for alcohol-associated cirrhosis by comparing single-nucleotide polymorphisms among patients with alcohol-associated cirrhosis (ALC) versus drinkers who did not have evidence of liver fibrosis/cirrhosis. METHODS: Using a data-driven approach, a PRS for ALC was generated using a meta-genome-wide association study of ALC (N=4305) and an independent cohort of heavy drinkers with ALC and without significant liver disease (N=3037). It was validated in 2 additional independent cohorts from the UK Biobank with diagnosed ALC (N=467) and high-risk drinking controls (N=8981) and participants in the Indiana Biobank Liver cohort with alcohol-associated liver disease (N=121) and controls without liver disease (N=3239). RESULTS: A 20-single-nucleotide polymorphisms PRS for ALC (PRSALC) was generated that stratified risk for ALC comparing the top and bottom deciles of PRS in the 2 validation cohorts (ORs: 2.83 [95% CI: 1.82 -4.39] in UK Biobank; 4.40 [1.56 -12.44] in Indiana Biobank Liver cohort). Furthermore, PRSALC improved the prediction of ALC risk when added to the models of clinically known predictors of ALC risk. It also stratified the risk for metabolic dysfunction -associated steatotic liver disease -cirrhosis (3.94 [2.23 -6.95]) in the Indiana Biobank Liver cohort -based exploratory analysis. CONCLUSIONS: PRSALC incorporates 20 single-nucleotide polymorphisms, predicts increased risk for ALC, and improves risk stratification for ALC compared with the models that only include clinical risk factors. This new score has the potential for early detection of heavy drinking patients who are at high risk for ALC.

Memory, mood and associated neuroanatomy in individuals with steroid sulphatase deficiency (X-linked ichthyosis).

Steroid sulphatase (STS) cleaves sulphate groups from steroid hormones, and steroid (sulphate) levels correlate with mood and age-related cognitive decline. In animals, STS inhibition or deletion of the associated gene, enhances memory/neuroprotection and alters hippocampal neurochemistry. Little is known about the consequences of constitutive STS deficiency on memory-related processes in humans. We investigated self-reported memory performance (Multifactorial Memory Questionnaire), word-picture recall and recent mood (Kessler Psychological Distress Scale, K10) in adult males with STS deficiency diagnosed with the dermatological condition X-linked ichthyosis (XLI; n = 41) and in adult female carriers of XLI-associated genetic variants (n = 79); we compared results to those obtained from matched control subjects [diagnosed with ichthyosis vulgaris (IV, n = 98) or recruited from the general population (n = 250)]. Using the UK Biobank, we compared mood/memory-related neuroanatomy in carriers of genetic deletions encompassing STS (n = 28) and non-carriers (n = 34,522). We found poorer word-picture recall and lower perceived memory abilities in males with XLI and female carriers compared with control groups. XLI-associated variant carriers and individuals with IV reported more adverse mood symptoms, reduced memory contentment and greater use of memory aids, compared with general population controls. Mood and memory findings appeared largely independent. Neuroanatomical analysis only indicated a nominally-significantly larger molecular layer in the right hippocampal body of deletion carriers relative to non-carriers. In humans, constitutive STS deficiency appears associated with mood-independent impairments in memory but not with large effects on underlying brain structure; the mediating psychobiological mechanisms might be explored further in individuals with XLI and in new mammalian models lacking STS developmentally.

Exploratory and confirmatory factor analysis of emPHasis-10: The health-related quality-of-life measure in pulmonary hypertension.

The emPHasis-10 is a health-related quality of life (HRQoL) unidimensional measure developed specifically for adults with pulmonary hypertension. The tool has excellent psychometric properties and is well used in research and clinical settings. Its factor structure has not been examined, which may help to identity a complimentary approach to using the measure to examine patient functioning. We performed an exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) on a data set collected from 263 adults with PH recruited from a community setting. The EFA suggested the emPHasis-10 consists of three underlying latent variables, which based on the loading of items, were termed "fatigue" (Items 3, 4, and 5), "independence" (Items 7, 8, 9, and 10), and "breathlessness" (Items 1, 2, and 6). All factors were found to have good internal consistency. "Independence" accounted for most of the variance (29%), followed by "breathlessness" (22%) and "fatigue" (19%). The CFA looked to confirm the fit of a three-factor model. A higher-order model was found to be the best fit consisting of HRQoL as a superordinate factor, for which the association between this factor and the 10 items was mediated through the three latent factors. Further analyses were performed testing the validity of the latent variables revealing all were significantly correlated with self-reported measures of depression, anxiety, health-anxiety, and dyspnea. Our analyses support the emPHasis-10 as a measure of HRQoL, while also proposing the clinical utility of examining the three emergent factors, which could be used to glean additional insight into the respondent's functioning and inform care.

A mixed-methods evaluation of patients' views on primary care multi-disciplinary teams in Scotland.

BACKGROUND: Expanding primary care multi-disciplinary teams (MDTs) was a key component of the 2018 Scottish GP contract, with over 4,700 MDT staff appointed since then. AIM: To explore patients' views on primary care MDT expansion in Scotland. DESIGN AND METHODS: (1) Survey of patients recently consulting a GP in deprived-urban, affluent-urban and remote/rural areas, assessing awareness of five MDT roles and attitudes towards receptionist signposting; (2) 30 individual interviews exploring MDT-care experiences. RESULTS: Of 1,053 survey respondents, most were unaware of the option of MDT rather than GP consultations for three out of five roles (69% unaware of link worker appointments; 68% mental health nurse; 58% pharmacist). Reception signposting was less popular in deprived-urban areas (34% unhappy vs 29% in remote/rural vs 21% affluent-urban; P<0.001), and in patients with multimorbidity (31% unhappy vs 24% in non-multimorbid; P<0.05).Two-thirds of interviewees had multimorbidity and almost all reported positive MDT-care experiences. However, MDT-care was generally seen as a supplement rather than a substitute for GP care. Around half of patients expressed concerns about reception signposting. These patients were more likely to also express concerns about GP access in general. Both of these concerns were more common in deprived-urban areas than in remote/rural or affluent-urban areas. CONCLUSION: MDT-care has expanded in Scotland with limited patient awareness. Although patients understand its potential value, many patients are unhappy with reception signposting to first-contact MDT care, especially those in deprived-urban areas living with multimorbidity. This represents a barrier to the aims of the new GP contract.

Online compassion-based self-help for depression in people with skin conditions: a feasibility study.

BACKGROUND: There is a need to develop psychological interventions for depression in people with skin conditions. This study aimed to investigate the acceptability, feasibility, and effects of an online compassion-based self-help intervention for depression in people with skin conditions. METHODS: Adult participants (n = 34) with skin conditions and mild-moderate depressive symptoms were invited to undertake a six-week, compassion-based online intervention for depression with email support. Engagement with the intervention was monitored, along with time spent facilitating the intervention, and participant feedback was collected each week and post-intervention. Pre-post changes in depression, self-compassion and dermatological quality of life were also assessed. RESULTS: The intervention was started by 25 participants and completed by 13. Feedback scores indicated that the website was evaluated positively and that the sessions had positive impacts on participants. Participants appreciated the skin-specific aspects of the intervention but varied as to which of the compassion-based exercises they found helpful. The online intervention was feasible to provide and facilitate, and treatment completers showed improvements in depression, quality of life and self-compassion. CONCLUSIONS: The online compassion-based intervention holds promise as a treatment for depression in people with skin conditions. Recommendations are made for future research and further development of the intervention. TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov on 21 October 2019, NCT04132973.

Dynamic Opportunities for Medical Students to Assume the Roles of "Medical Teacher".

The traditional undergraduate medical education curriculum focuses on bolstering knowledge for practice and building clinical skills. However, as future clinicians, medical students will be tasked with teaching throughout their careers, first as residents and then as attendings. Here, we describe teaching opportunities for students that foster their development as future teachers and potential clinician educators. These offerings are diverse in their focus and duration and are offered across various levels of the curriculum - including course-based learning, longitudinal electives, and extra-curricular opportunities for medical students who have a passion for teaching.

Longitudinal Patterns of Multimorbidity in Gulf War Era Veterans With and Without Gulf War Illness.

Objectives: To examine whether severe Gulf War illness (SGWI) case status was associated with longitudinal multimorbidity patterns. Methods: Participants were users of the Veteran Health Administration Health Care System drawn from the Gulf War Era Cohort and Biorepository (n = 840). Longitudinal measures of multimorbidity were constructed using (1) electronic health records (Charlson Comorbidity Index; Elixhauser; and Veterans Affairs Frailty Index) from 10/1/1999 to 6/30/2023 and (2) self-reported medical conditions (Deficit Accumulation Index) since the war until the survey date. Accelerated failure time models examined SGWI case status as a predictor of time until threshold level of multimorbidity was reached, adjusted for age and sociodemographic and military characteristics. Results: Models, adjusted for covariates, revealed that (1) relative to the SWGI- group, the SGWI+ group was associated with an accelerated time for reaching each threshold and (2) the relationship between SGWI and each threshold was not moderated by age. Discussion: Findings suggest that veterans with SGWI experienced accelerated aging.

Cross-species spill-over potential of the H9N2 bat influenza A virus.

In 2017, a novel influenza A virus (IAV) was isolated from an Egyptian fruit bat. In contrast to other bat influenza viruses, the virus was related to avian A(H9N2) viruses and was probably the result of a bird-to-bat transmission event. To determine the cross-species spill-over potential, we biologically characterize features of A/bat/Egypt/381OP/2017(H9N2). The virus has a pH inactivation profile and neuraminidase activity similar to those of human-adapted IAVs. Despite the virus having an avian virus-like preference for α2,3 sialic acid receptors, it is unable to replicate in male mallard ducks; however, it readily infects ex-vivo human respiratory cell cultures and replicates in the lungs of female mice. A/bat/Egypt/381OP/2017 replicates in the upper respiratory tract of experimentally-infected male ferrets featuring direct-contact and airborne transmission. These data suggest that the bat A(H9N2) virus has features associated with increased risk to humans without a shift to a preference for α2,6 sialic acid receptors.

Does Acinetobacter calcoaceticus glucose dehydrogenase produce self-damaging H2O2?

The soluble glucose dehydrogenase (sGDH) from Acinetobacter calcoaceticus has been widely studied and is used, in biosensors, to detect the presence of glucose, taking advantage of its high turnover and insensitivity to molecular oxygen. This approach, however, presents two drawbacks: the enzyme has broad substrate specificity (leading to imprecise blood glucose measurements) and shows instability over time (inferior to other oxidizing glucose enzymes). We report the characterization of two sGDH mutants: the single mutant Y343F, and the double mutant D143E/Y343F. The mutants present enzyme selectivity and specificity of 1.2 (Y343F) and 5.7 (D143E/Y343F) times higher for glucose compared to that of the wild type. Crystallographic experiments, designed to characterise these mutants, surprisingly revealed that the prosthetic group PQQ (pyrroloquinoline quinone), essential for the enzymatic activity, is in a cleaved form for both wild-type and mutant structures. We provide evidence suggesting that the sGDH produces H2O2, the level of production depending on the mutation. In addition, spectroscopic experiments allowed us to follow the self-degradation of the prosthetic group and the disappearance of sGDH's glucose oxidation activity. These studies suggest that the enzyme is sensitive to its self-production of H2O2. We show that the premature aging of sGDH can be slowed down by adding catalase to consume the H2O2 produced, allowing the design of a more stable biosensor over time. Our research opens questions about the mechanism of H2O2 production and the physiological role of this activity by sGDH.

A chromosome-level genome assembly of Solanum chilense, a tomato wild relative associated with resistance to salinity and drought.

Introduction: Solanum chilense is a wild relative of tomato reported to exhibit resistance to biotic and abiotic stresses. There is potential to improve tomato cultivars via breeding with wild relatives, a process greatly accelerated by suitable genomic and genetic resources. Methods: In this study we generated a high-quality, chromosome-level, de novo assembly for the S. chilense accession LA1972 using a hybrid assembly strategy with ~180 Gbp of Illumina short reads and ~50 Gbp long PacBio reads. Further scaffolding was performed using Bionano optical maps and 10x Chromium reads. Results: The resulting sequences were arranged into 12 pseudomolecules using Hi-C sequencing. This resulted in a 901 Mbp assembly, with a completeness of 95%, as determined by Benchmarking with Universal Single-Copy Orthologs (BUSCO). Sequencing of RNA from multiple tissues resulting in ~219 Gbp of reads was used to annotate the genome assembly with an RNA-Seq guided gene prediction, and for a de novo transcriptome assembly. This chromosome-level, high-quality reference genome for S. chilense accession LA1972 will support future breeding efforts for more sustainable tomato production. Discussion: Gene sequences related to drought and salt resistance were compared between S. chilense and S. lycopersicum to identify amino acid variations with high potential for functional impact. These variants were subsequently analysed in 84 resequenced tomato lines across 12 different related species to explore the variant distributions. We identified a set of 7 putative impactful amino acid variants some of which may also impact on fruit development for example the ethylene-responsive transcription factor WIN1 and ethylene-insensitive protein 2. These variants could be tested for their ability to confer functional phenotypes to cultivars that have lost these variants.

21 Gy single fraction prostate HDR brachytherapy: 5-year results of a single institution prospective pilot study.

PURPOSE: To present the outcome and toxicity results of a prospective trial of 21 Gy single fraction high-dose-rate (HDR) brachytherapy for men with low- or intermediate-risk prostate cancer. METHODS AND MATERIALS: Patients were treated according to an IRB-approved prospective study of single fraction HDR brachytherapy. Eligible patients had low- or intermediate-risk prostate cancer with tumor stage ≤ T2b, PSA ≤ 15, and Gleason score ≤ 7. Patients underwent trans-rectal ultrasound-guided trans-perineal implant of the prostate followed by single fraction HDR brachytherapy to a dose of 21 Gy. The primary endpoint was grade ≥ 2 urinary/GI toxicity rates. RESULTS: Twenty-six patients were enrolled with a median follow up of 5.1 years and median age of 64 years. 88.5% of patients had T1 disease, 15.4% had Gleason score 6 (84.6% Gleason 7), and median pre-treatment PSA was 5.0 ng/mL. Acute and chronic grade ≥ 2 urinary toxicity rates were 38.5% and 38.5%, respectively. There were no grade ≥ 2 acute or chronic GI toxicities. Six (23.1%) patients experienced biochemical failure, six (23.1%) patients experienced radiographic local failure, and five (19.2%) patients had biopsy-proven local failure. No patients developed regional lymph node recurrence or distant metastasis. 5-year overall survival and cause-specific survival were 96.2% and 100%, respectively. CONCLUSIONS: 21 Gy single fraction HDR brachytherapy was associated with modestly higher-than-anticipated chronic urinary toxicity, as well as high biochemical and local failure rates. The results from this prospective pilot study do not support the use of this regimen in standard clinical practice.

Burden of Disease and Treatment Patterns Amongst Patients With Vitiligo: Findings From a National, Longitudinal Retrospective Study in the United Kingdom.

This retrospective study, using UK Clinical Practice Research Datalink and Hospital Episode Statistics databases, analysed 17,239 incident patients with vitiligo. Mean incidence of vitiligo was 0.16 (2010-2021) per 1000 person-years (range: 0.10 [2010-COVID] to 0.19 [2013/2018]); prevalence increased from 0.21% (2010) to 0.38% (2021). The most common comorbidities recorded after vitiligo diagnosis were diabetes (19.4%), eczema (8.9%), thyroid disease (7.5%), and rheumatoid arthritis (6.9%). Mental health diagnoses recorded at any time were most commonly depression and/or anxiety (24.6%), depression (18.5%), anxiety (16.0%), and sleep disturbance (12.7%); recorded after vitiligo diagnosis in 6.4%, 4.4%, 5.5%, and 3.9%, respectively. Mental health comorbidities were more common among White patients (eg, depression and/or anxiety, 29.0%) than Black (18.8%), Asian (16.1%), and other ethnicities (21.4%). In adolescents, depression and/or anxiety was most commonly diagnosed after vitiligo diagnosis (7.4% vs before, 1.8%). Healthcare resources were used most frequently in the first year after vitiligo diagnosis (incident cohort), typically dermatology-related outpatient appointments (101.9/100 person-years) and general practitioner consultations (97.9/100 person-years). In the year after diagnosis, 60.8% of incident patients did not receive vitiligo-related treatments (ie, topical corticosteroids, topical calcineurin inhibitors, oral corticosteroids, phototherapy), increasing to 82.0% the next year; median (95% CI) time from diagnosis to first treatment was 34.0 (31.6-36.4) months. Antidepressants and/or anxiolytics were recorded for 16.7% of incident patients in the year after diagnosis. In 2019, 85.0% of prevalent patients did not receive vitiligo-related treatments; 16.6% had a record of antidepressant and/or anxiolytic treatments. Most patients were not on vitiligo-related treatments within a year of diagnosis, with time to first treatment >2 years, suggesting that vitiligo may be dismissed as unimportant and not treated early, in part due to limited effectiveness of available treatments. New effective treatments, early initiation, and psychological intervention and support are needed to reduce vitiligo burden on patients.

Genes involved in auxin biosynthesis, transport and signalling underlie the extreme adventitious root phenotype of the tomato aer mutant.

The use of tomato rootstocks has helped to alleviate the soaring abiotic stresses provoked by the adverse effects of climate change. Lateral and adventitious roots can improve topsoil exploration and nutrient uptake, shoot biomass and resulting overall yield. It is essential to understand the genetic basis of root structure development and how lateral and adventitious roots are produced. Existing mutant lines with specific root phenotypes are an excellent resource to analyse and comprehend the molecular basis of root developmental traits. The tomato aerial roots (aer) mutant exhibits an extreme adventitious rooting phenotype on the primary stem. It is known that this phenotype is associated with restricted polar auxin transport from the juvenile to the more mature stem, but prior to this study, the genetic loci responsible for the aer phenotype were unknown. We used genomic approaches to define the polygenic nature of the aer phenotype and provide evidence that increased expression of specific auxin biosynthesis, transport and signalling genes in different loci causes the initiation of adventitious root primordia in tomato stems. Our results allow the selection of different levels of adventitious rooting using molecular markers, potentially contributing to rootstock breeding strategies in grafted vegetable crops, especially in tomato. In crops vegetatively propagated as cuttings, such as fruit trees and cane fruits, orthologous genes may be useful for the selection of cultivars more amenable to propagation.

The development of a novel sexual health promotion intervention for young people with mental ill-health: the PROSPEct project.

BACKGROUND: Young people with mental ill-health experience higher rates of high-risk sexual behaviour, have poorer sexual health outcomes, and lower satisfaction with their sexual wellbeing compared to their peers. Ensuring good sexual health in this cohort is a public health concern, but best practice intervention in the area remains under-researched. This study aimed to co-design a novel intervention to address the sexual health needs of young people with mental ill-health to test its effectiveness in a future trial undertaken in youth mental health services in Melbourne, Australia. METHODS: We followed the 2022 Medical Research Council (MRC) guidelines for developing and evaluating complex interventions. This involved synthesising evidence from the 'top down' (published evidence) and 'bottom up' (stakeholder views). We combined systematic review findings with data elicited from qualitative interviews and focus groups with young people, carers, and clinicians and identified critical cultural issues to inform the development of our intervention. RESULTS: Existing evidence in the field of sexual health in youth mental health was limited but suggested the need to address sexual wellbeing as a concept broader than an absence of negative health outcomes. The Information-Motivation-Belief (IMB) model was chosen as the theoretical Framework on which to base the intervention. Interviews/focus groups were conducted with 29 stakeholders (18 clinicians, three carers, and eight young people). Synthesis of the evidence gathered resulted in the co-design of a novel intervention consisting of an initial consultation and four 60-90-minute sessions delivered individually by a young 'sex-positive' clinician with additional training in sexual health. Barriers and supports to intervention success were also identified. CONCLUSIONS: Using the MRC Framework has guided the co-design of a potentially promising intervention that addresses the sexual health needs of young people with mental ill-health. The next step is to test the intervention in a one-arm feasibility trial.

Understanding the Mechanisms of Cognitive Remediation on Recovery in People With Early Psychosis: A Mediation and Moderation Analysis.

BACKGROUND: To provide precision cognitive remediation therapy (CR) for schizophrenia, we need to understand whether the mechanism for improved functioning is via cognition improvements. This mechanism has not been rigorously tested for potential moderator effects. STUDY DESIGN: We used data (n = 377) from a randomized controlled trial using CIRCuiTS, a therapist-supported CR, with participants from first-episode psychosis services. We applied structured equation modeling to test whether: (1) CR hours explain the goal attainment functional outcome (GAS) at posttreatment, (2) global cognitive improvement mediates GAS, and if (3) total symptoms moderate the CR hours to cognitive improvement pathway, and/or negative symptoms moderate the cognition to functioning pathway, testing moderator effects via the mediator or directly on CR hours to functioning path. STUDY RESULTS: CR produced significant functioning benefit for each therapy hour (Coeff = 0.203, 95% CI 0.101-0.304, P < .001). The mediated path from CR hours to cognition and cognition to functioning was small and nonsignificant (Coeff = 0.014, 95% CI = -0.010, 0.037, P = .256). Total symptoms did not moderate the path to cognition (P = .211) or the direct path to outcome (P = .896). However, negative symptoms significantly moderated the effect of cognitive improvements on functioning (P = .015) with high negative symptoms reducing the functional gains of improved cognition. CONCLUSIONS: Although cognitive improvements were correlated with functioning benefit, they did not fully explain the positive effect of increased therapy hours on functioning, suggesting additional CR factors also contribute to therapy benefit. Negative symptoms interfere with the translation of cognitive improvements into functional gains so need consideration.

Additive Impacts of Liveweight and Body Condition Score at Breeding on the Reproductive Performance of Merino and Non-Merino Ewe Lambs.

Ewe lambs that are heavier due to improved nutrition pre- and post-weaning achieve puberty at a younger age, are more fertile, and have a higher reproductive rate. Fatness is intimately linked to reproduction, and we hypothesised that higher body condition scores at breeding would have positive effects on the reproductive rate of ewe lambs over and above liveweight. We also expected that if only a proportion of ewe lambs were presented for breeding, then it would be more effective to select them based on both liveweight and body condition score. To test these hypotheses, we analysed data from over 17,000 records from Merino and non-Merino ewe lambs from 22 different flocks across Australia. Non-Merino ewe lambs were more fertile (69.4% vs. 48.7%) and achieved a higher reproductive rate than Merino ewe lambs (96.9% vs. 60.7%). There were significant curvilinear relationships between liveweight (p < 0.001) or body condition score (p < 0.001) prior to breeding and reproductive rate for both Merino and non-Merino ewe lambs. For both breeds, there was a significant (p < 0.001) quadratic effect of body condition score prior to breeding on reproductive rate, independent of the correlated changes in liveweight, and at the same liveweight, an extra 0.5 of a body condition score up to 3.3 improved reproductive rate by about 20%. Nevertheless, the results indicated that if only a proportion of ewe lambs were selected for breeding, then selection based on both liveweight and body condition scores may only improve the overall reproductive rate by 1 to 2% compared to selection based on liveweight alone. We conclude that liveweight is a more effective method than body condition score for selecting ewe lambs for breeding.

How healthcare systems are experienced by autistic adults in the United Kingdom: A meta-ethnography.

LAY ABSTRACT: Autistic adults are more likely to experience mental and physical health difficulties, and yet can find it difficult to get the support that they need. A meta-ethnographic approach was used to review the existing research on autistic adults' experiences of accessing healthcare. Four databases were searched for qualitative and mixed-method studies which looked at the experiences of autistic adults who did not also have a learning disability when using healthcare services in the United Kingdom. Fifteen papers met the criteria to be included, and seven steps were used to analyse the information and develop new themes. Three main themes were identified: Professionals' lack of knowledge can be damaging, Need to reduce processing demands and Adaptation to improve engagement. This review highlights how damaging misdiagnosis, inappropriate treatment, overwhelming environments and systems that are difficult to access can have on the well-being of autistic adults. Limited knowledge and understanding about autism knowledge among healthcare professionals along with autistic adult's own communication and sensory differences indicate that there is a need for improved training developed with autistic adults and adaptations.