Enhancer RNAs step forward: new insights into enhancer function.

Enhancers confer precise spatiotemporal patterns of gene expression in response to developmental and environmental stimuli. Over the last decade, the transcription of enhancer RNAs (eRNAs) - nascent RNAs transcribed from active enhancers - has emerged as a key factor regulating enhancer activity. eRNAs are relatively short-lived RNA species that are transcribed at very high rates but also quickly degraded. Nevertheless, eRNAs are deeply intertwined within enhancer regulatory networks and are implicated in a number of transcriptional control mechanisms. Enhancers show changes in function and sequence over evolutionary time, raising questions about the relationship between enhancer sequences and eRNA function. Moreover, the vast majority of single nucleotide polymorphisms associated with human complex diseases map to the non-coding genome, with causal disease variants enriched within enhancers. In this Primer, we survey the diverse roles played by eRNAs in enhancer-dependent gene expression, evaluating different models for eRNA function. We also explore questions surrounding the genetic conservation of enhancers and how this relates to eRNA function and dysfunction.

Systematic review of the diagnosis and management of necrotising otitis externa: Highlighting the need for high-quality research.

OBJECTIVES: To present a systematic review and critical analysis of clinical studies for necrotising otitis externa (NOE), with the aim of informing best practice for diagnosis and management. DESIGN: Medline, Embase, Cochrane Library and Web of Science were searched from database inception until 30 April 2021 for all clinical articles on NOE. The review was registered on PROSPERO (ID: CRD42020128957) and conducted in accordance with PRISMA guidelines. RESULTS: Seventy articles, including 2274 patients were included in the final synthesis. Seventy-three percent were retrospective case series; the remainder were of low methodological quality. Case definitions varied widely. Median patient age was 69.2 years; 68% were male, 84% had diabetes and 10% had no reported immunosuppressive risk factor. Otalgia was almost universal (96%), with granulation (69%) and oedema (76%) the commonest signs reported. Pseudomonas aeruginosa was isolated in 62%, but a range of bacterial and fungal pathogens were reported and 14% grew no organism. Optimal imaging modality for diagnosis or follow-up was unclear. Median antimicrobial therapy duration was 7.2 weeks, with no definitive evidence for optimal regimens. Twenty-one percent had surgery with widely variable timing, indication, or procedure. One-year disease-specific mortality was 2%; treatment failure and relapse rates were 22% and 7%, respectively. CONCLUSION: There is a lack of robust, high-quality data to support best practice for diagnosis and management for this neglected condition. A minimum set of reporting requirements is proposed for future studies. A consensus case definition is urgently needed to facilitate high-quality research.

Unique deficit in embodied simulation in autism: An fMRI study comparing autism and developmental coordination disorder.

A deficit in pre-cognitively mirroring other people's actions and experiences may be related to the social impairments observed in autism spectrum disorder (ASD). However, it is unclear whether such embodied simulation deficits are unique to ASD or instead are related to motor impairment, which is commonly comorbid with ASD. Here we aim to disentangle how, neurologically, motor impairments contribute to simulation deficits and identify unique neural signatures of ASD. We compare children with ASD (N = 30) to children with Developmental Coordination Disorder (DCD; N = 23) as well as a typically developing group (N = 33) during fMRI tasks in which children observe, imitate, and mentalize about other people's actions. Results indicate a unique neural signature in ASD: during action observation, only the ASD group shows hypoactivity in a region important for simulation (inferior frontal gyrus, pars opercularis, IFGop). However, during a motor production task (imitation), the IFGop is hypoactive for both ASD and DCD groups. For all tasks, we find correlations across groups with motor ability, even after controlling for age, IQ, and social impairment. Conversely, across groups, mentalizing ability is correlated with activity in the dorsomedial prefrontal cortex when controlling for motor ability. These findings help identify the unique neurobiological basis of ASD for aspects of social processing. Furthermore, as no previous fMRI studies correlated brain activity with motor impairment in ASD, these findings help explain prior conflicting reports in these simulation networks.

Sexual satisfaction with daily oral HIV pre-exposure prophylaxis (PrEP) among gay and bisexual men at two urban PrEP clinics in the United States: an observational study.

Background Pre-exposure prophylaxis (PrEP) is highly effective in preventing HIV infection among men who have sex with men (MSM). However, limited data are available on the effect of PrEP use and sexual satisfaction among MSM taking PrEP. METHODS: We conducted a one-time, cross-sectional survey of MSM receiving PrEP care at two hospital-based PrEP clinics in Providence, Rhode Island and Boston, Massachusetts, USA (April-September 2017). We oversampled Black and Hispanic/Latino individuals. Participants completed the 20-item New Sexual Satisfaction Scale (NSSS) twice, once for before and once for after starting PrEP. Participants reported sexual behaviours, PrEP adherence, PrEP attitudes, and quality of life with PrEP. RESULTS: A total of 108 gay and bisexual men (GBM) participated. Overall, 15.7% were Black (non-Hispanic/Latino) and 23.1% were Hispanic/Latino, with an average age of 36.6 years. Most participants reported private health insurance coverage (71.3%), and 88.9% identified as homosexual, gay, or same gender-loving. The mean NSSS score before PrEP initiation across all 20 items was 3.94 (maximum = 5; 95% CI: 4.22, 4.43), and increased significantly after PrEP initiation (4.33, 95% CI: 4.22, 4.43; P < 0.001). Most participants (73.2%) reported that PrEP increased quality of life. This was associated with significant change in pre- to post-PrEP NSSS scores (linear regression coefficient = 1.21; 95% CI: 0.585, 1.84). CONCLUSIONS: Initiating PrEP and reporting improved quality of life were significantly associated with an increase in sexual satisfaction. PrEP implementation efforts should consider sexual satisfaction to promote PrEP engagement and retention, and researchers and providers should adopt a sex-positive approach with PrEP patients, especially among MSM.

Stopping immunosuppressive treatment in autoimmune hepatitis (AIH): Is it justified (and in whom and when)?

BACKGROUND: Initial treatment of autoimmune hepatitis (AIH) with prednisolone ± azathioprine is based on randomised controlled trials. Many patients receive long-term immunosuppressive treatment to prevent disease relapse; this strategy has a weaker evidence base. AIM: To consider whether immunosuppressive treatment (IST) withdrawal in AIH is justified and to develop a rationale for patient selection. METHODS: We reviewed published papers between 1972 and 2018, which addressed the outcomes of IST withdrawal and/or complications of IST in AIH. RESULTS: (1) AIH relapse rates after withdrawal of IST vary between 25% and 100%. There is heterogeneity in these studies regarding relapse definition, IST duration prior to withdrawal and criteria for biochemical and histological remission prior to withdrawal. (2) Factors associated with relapse following IST withdrawal include: (a) absence of an identifiable initial disease trigger, (b) presence of other autoimmune diseases, (c) longer time to biochemical remission and (d) elevated serum transaminases on treatment withdrawal. Reports of associations between relapse and age, IST duration and failure of histological remission have been inconsistent. (3) Continued IST reduces risk of AIH relapse over at least 5 years. However, there is no evidence that routine (as opposed to selective) long-term IST improves disease outcome. (4) Patients with AIH have an increased risk of extrahepatic cancer, notably non-melanoma skin cancer, to which long-term IST may contribute. Long-term corticosteroid therapy is associated with weight gain, low-trauma fractures, diabetes and possibly vascular disease. CONCLUSIONS: While further studies are needed, evidence supports a strategy of IST withdrawal in some patients with AIH who have achieved remission.

Patients with chronic kidney disease have abnormal upper gastro-intestinal tract digestive function: A study of uremic enteropathy.

BACKGROUND AND AIM: Chronic kidney disease (CKD) affects gastrointestinal (GI) function and results in numerous adaptive and maladaptive responses. Disruption of the colonic microbiome and its attendant consequences-the loss of gut barrier integrity and increased generation of uremic toxins-has become well-recognized. However, less attention has been paid to characterizing the mechanisms behind dysfunction of the upper GI tract, largely owing to the difficulty of studying small bowel function in vivo. This present study was designed to comprehensively describe upper GI function in those with advanced renal impairment. METHODS: Thirty-five non-diabetic subjects (12 CKD stage 4/5 patients, 23 healthy controls) underwent detailed GI magnetic resonance imaging (MRI) in both fasted and fed states. Upper GI function was assessed by quantification of gastric emptying and intra-luminal small bowel water. Characterization of hydration and cardiovascular status was performed at baseline. Gut barrier integrity was assessed using serum endotoxin level. RESULTS: Chronic kidney disease was associated with dysmotility (gastric half-emptying time 96 ± 32 vs 74 ± 27 min, P = 0.04) and reduced fasting and post-prandial small bowel water (36 ± 22 mL vs 78 ± 42 mL, P < 0.001), reflecting abnormal digestive secretion, and absorption. This was related to the degree of endotoxemia (r = -0.60, P = 0.04) and poorer symptom scores, but not to disease severity, arterial stiffness or hydration status. CONCLUSION: Chronic kidney disease adversely affects digestive function. Abnormalities in digestive secretion and absorption may potentially have a broad impact in the prevention and treatment of both CKD and its complications. Further study is required to assess the factors that contribute to this dysfunction in a wider CKD population.

Liver toxicity associated with sofosbuvir, an NS5A inhibitor and ribavirin use.

Hepatitis C virus (HCV) infection is a major cause of end-stage liver disease and hepatocellular carcinoma. There have been rapid advances in HCV treatment with the development of oral direct-acting antivirals (DAAs). Studies have shown sustained virological response rates above 90% with combinations of DAAs, including patients with compensated cirrhosis. Thus far, significant drug toxicity has not been seen with these agents, but there is limited experience of using DAAs in decompensated HCV cirrhosis. This report describes the first experience of serious drug-induced hepatotoxicity with the new DAAs. The mechanism underlying these drug reactions is currently unknown. Few patients with decompensated cirrhosis have been treated with DAAs, so the exact pharmacokinetics in this population have not been characterised. In both cases presented here, patients were taking or had recently taken other drugs. It is possible that an unknown interaction or reaction to the drug combination caused the hepatotoxicity. Although the association with the DAAs is not proven these cases indicate that patients with advanced liver disease need close monitoring while on DAA therapy and if there is a significant unexplained deterioration in liver function the DAAs should be discontinued.

An Enhanced Default Approach Bias Following Amygdala Lesions in Humans.

Approach and avoidance constitute a basic dimension of all animal behavior. Although a large number of studies have investigated approach and avoidance elicited by specific sensory stimuli, comparatively little is known about default approach biases when stimulus information is absent or reduced. The amygdala is well known to contribute to approach and avoidance behaviors in response to specific sensory stimuli; we tested whether the amygdala's role might extend to situations in which stimulus information is reduced. In a novel task, 3 patients with rare bilateral amygdala lesions (and control subjects) made approach-related judgments about photos of intact faces and of the same faces with all internal facial features occluded. Direct comparisons of the judgments of these stimuli isolated a default bias. The patients showed a greater tendency than the control subjects to rate occluded faces as more approachable than whole faces. These findings suggest that the amygdala's role in approach behavior extends beyond responses to specific stimuli.

The role of Rhes, Ras homolog enriched in striatum, in neurodegenerative processes.

Rhes is a small GTPase whose expression is highly enriched in striatum. It shares homology with Ras proteins, but also contains a C-terminal extension, thus suggesting additional functions. Signaling by 7 transmembrane receptors through heterotrimeric G proteins is inhibited by Rhes. However, perhaps the most remarkable feature of this small GTPase described thus far is that it can account for the selective vulnerability of the striatum in Huntington's Disease (HD). HD is an autosomal dominant neurodegenerative disease caused by a poly-glutamine expansion in the protein huntingtin. Despite the presence of huntingtin throughout the brain and the rest of the body, the striatum is selectively degenerated. Recent work shows that Rhes acts as an E3 ligase for attachment of SUMO (small ubiquitin-like modifier). As this post-translational modification decreases the formation of huntingtin aggregates and promotes cell death, this property of Rhes offers an explanation for selective striatal vulnerability in HD. In addition, the sequestering of Rhes through its binding to mutant huntingtin may decrease the ability of Rhes to perform vital physiological functions in the neuron. Thus, as Rhes is an attractive candidate for HD therapy, a thorough understanding of its physiological functions will allow for specific targeting of its pathological functions.

Central venous oxygen saturation: a potential new marker for circulatory stress in haemodialysis patients?

BACKGROUND/AIMS: Haemodialysis causes recurrent haemodynamic stress with subsequent ischaemic end-organ dysfunction. As dialysis prescriptions/schedules can be modified to lessen this circulatory stress, an easily applicable test to allow targeted interventions in vulnerable patients is urgently required. METHODS: Intra-dialytic central venous oxygen saturation (ScvO2) and clinical markers (including ultrafiltration, blood pressure) were measured in 18 prevalent haemodialysis patients. RESULTS: Pre-dialysis ScvO2 was 63.5 ± 13% and fell significantly to 56.4 ± 8% at end dialysis (p = 0.046). Ultrafiltration volume, a key driver of dialysis-induced myocardial ischaemia, inversely correlated to ScvO2 (r = -0.680, p = 0.015). CONCLUSIONS: This initial study demonstrates ScvO2 sampling is practical, with a potential clinical utility as an indicator of circulatory stress during dialysis.

Circulating endotoxaemia and frequent haemodialysis schedules.

BACKGROUND/AIMS: Endotoxaemia, a driver of systemic inflammation, appears to be driven by dialysis-induced circulatory stress in haemodialysis (HD) patients. More frequent HD regimens are associated with lower ultrafiltration requirements, improved haemodynamic stability and lower systemic inflammation. This study investigated the hypothesis that more frequently dialysed patients, with reduced exposure to dialysis-induced haemodynamic perturbation, would have lower circulating endotoxin (ET) levels. METHODS: A cross-sectional study of 86 established HD patients compared three groups: conventional HD 3× per week (HD3, n = 56), frequent HD 5-6× per week (SDHD, n = 20), and nocturnal HD (NHD, n = 10). Data collection included ultrafiltration volume and rate, serial blood pressures and blood sampling with quantification of ET, troponin T and high-sensitivity CRP (hsCRP). RESULTS: Pre-dialysis serum ET was highest in the conventional HD group (HD3 0.66 ± 0.29 EU/ml vs. NHD 0.08 ± 0.04 EU/ml). Across the study population, severity of endotoxaemia was associated with higher ultrafiltration rates, degree of intradialytic hypotension, troponin T and hsCRP levels. NHD patients had the lowest ultrafiltration requirements, the greatest haemodynamic stability and lower ET levels. CONCLUSION: More frequent HD regimens are associated with lower levels of circulating ET compared with conventional HD. Reduced ET translocation may be related to the greater haemodynamic stability of these treatments, with superior maintenance of splanchnic perfusion.

Pharyngo-cutaneous fistula complicating laryngectomy in the chemo-radiotherapy organ-preservation epoch.

Pharyngo-cutaneous fistula is a serious complication of laryngectomy, with a significant associated morbidity and mortality. The oncologic success of organ-preservation protocols with radiotherapy or chemo-radiotherapy for laryngeal carcinoma means laryngectomy is increasingly reserved for surgical salvage in the event of persistent or recurrent disease. A retrospective review of fistula incidence after laryngectomy in 171 patients in a UK tertiary referral centre over the last decade was conducted to identify trends in this complication in the epoch of non-surgical organ preservation. The overall fistula incidence following laryngectomy is 29.2% (50/171). Fistula incidence following salvage total laryngectomy is significantly higher than after primary total laryngectomy [19/51 (37.3%) vs. 8/47 (17.0%), χ2 = 5.02, p = 0.03]. There is no significant effect of prior treatment on fistula incidence following laryngo-pharyngectomy or pharyngo-laryngo-oesophagectomy [14/39 (35.9%) vs. 9/27 (33.3%), χ2 = 0.05, p = 0.83]. Prophylactic vascularised tissue flaps to reinforce the pharyngeal suture line may reduce fistula incidence and fistula severity in salvage total laryngectomy.

Caregiver and youth inter-rater assessment agreement in autism spectrum disorder, developmental coordination disorder, and typical development.

Youth diagnosed with autism spectrum disorder (ASD) and those with developmental coordination disorder (DCD) are at heightened risk for co-occurring mental health diagnoses, especially anxiety and attention-deficit/hyperactivity disorder (ADHD). However, caregiver-child agreement on presence of related symptoms in populations with neurodevelopmental conditions is not well understood. Here, we examine the extent to which 37 ASD, 26 DCD, and 40 typically developing children and their caregivers agree on the degree of the child's symptoms of anxiety and ADHD. All caregiver-child dyads completed the Screen for Child Anxiety Related Emotional Disorders and Conners 3 ADHD Index. Across groups, intraclass correlations indicated generally poor agreement on anxiety and ADHD symptomatology. Although youth generally reported greater internalizing symptoms (i.e., anxiety), caregivers tended to report more observable externalizing behaviors (i.e., ADHD). Together, the results of this study support the need for a multi-informant approach in assessments of anxiety and ADHD in youth with neurodevelopmental disorders.

A new dimension of health care: systematic review of the uses, benefits, and limitations of social media for health communication.

BACKGROUND: There is currently a lack of information about the uses, benefits, and limitations of social media for health communication among the general public, patients, and health professionals from primary research. OBJECTIVE: To review the current published literature to identify the uses, benefits, and limitations of social media for health communication among the general public, patients, and health professionals, and identify current gaps in the literature to provide recommendations for future health communication research. METHODS: This paper is a review using a systematic approach. A systematic search of the literature was conducted using nine electronic databases and manual searches to locate peer-reviewed studies published between January 2002 and February 2012. RESULTS: The search identified 98 original research studies that included the uses, benefits, and/or limitations of social media for health communication among the general public, patients, and health professionals. The methodological quality of the studies assessed using the Downs and Black instrument was low; this was mainly due to the fact that the vast majority of the studies in this review included limited methodologies and was mainly exploratory and descriptive in nature. Seven main uses of social media for health communication were identified, including focusing on increasing interactions with others, and facilitating, sharing, and obtaining health messages. The six key overarching benefits were identified as (1) increased interactions with others, (2) more available, shared, and tailored information, (3) increased accessibility and widening access to health information, (4) peer/social/emotional support, (5) public health surveillance, and (6) potential to influence health policy. Twelve limitations were identified, primarily consisting of quality concerns and lack of reliability, confidentiality, and privacy. CONCLUSIONS: Social media brings a new dimension to health care as it offers a medium to be used by the public, patients, and health professionals to communicate about health issues with the possibility of potentially improving health outcomes. Social media is a powerful tool, which offers collaboration between users and is a social interaction mechanism for a range of individuals. Although there are several benefits to the use of social media for health communication, the information exchanged needs to be monitored for quality and reliability, and the users' confidentiality and privacy need to be maintained. Eight gaps in the literature and key recommendations for future health communication research were provided. Examples of these recommendations include the need to determine the relative effectiveness of different types of social media for health communication using randomized control trials and to explore potential mechanisms for monitoring and enhancing the quality and reliability of health communication using social media. Further robust and comprehensive evaluation and review, using a range of methodologies, are required to establish whether social media improves health communication practice both in the short and long terms.

Long-term Outcome of Autoimmune Hepatitis: Consecutive Patient Cohort and Data on the Second Twenty Years.

BACKGROUND: Mortality rates for autoimmune hepatitis (AIH) vary. Data are lacking beyond 20 years follow-up. AIMS: Analysis of a consecutively recruited large AIH cohort from a single non-transplant tertiary centre in England and an overlapping cohort, already followed for ≥ 20 years. METHODS: We assessed 330 patients presenting 1987-2016 and 65 patients presenting 1971-96 already followed for 20 years. RESULTS: Death/liver transplant rate was 51±4% (all-cause) and 21±4% (liver-related) over 20 years and was independently associated with: decompensation and lower serum ALT at diagnosis; and failure of serum ALT normalisation and higher relapse rate. There was excess mortality over the first year. Patients (n = 65) already followed for twenty years had similar subsequent rates of relapse, disease progression and mortality, to those followed from diagnosis. Azathioprine-intolerant patients (n = 23) switching to Mycophenolate did not have higher mortality over 4(1-17) years, than patients continuing Azathioprine. Following immunosuppression withdrawal (n = 26), six (23% patients) relapsed with no liver-related deaths over 2.3(0-23.1) years. CONCLUSIONS: In this consecutive autoimmune hepatitis cohort, mortality was similar to that in national registry studies, disease progression continued after 20 years, and immunosuppression withdrawal did not compromise survival.

Relationships between alexithymia, interoception, and emotional empathy in autism spectrum disorder.

LAY ABSTRACT: Empathy, the ability to understand and share the emotions of others, is a necessary skill for social functioning and can be categorized into cognitive and emotional empathy. There is evidence to suggest that individuals with autism spectrum disorder have difficulties with cognitive empathy, the ability to imagine how another person is thinking or feeling. However, it is unclear if individuals with autism spectrum disorder struggle with emotional empathy, the ability to share and feel emotions others are experiencing. Self-report and interview data were collected to explore the relationships between interoception (individuals' self-reported awareness of sensation from their body such as thirst, heartbeat, etc.), alexithymia (an individual's ability to describe and distinguish between their own emotions), and emotional empathy in 35 youth with autism spectrum disorder and 40 typically developing youth. Greater personal distress to others' emotions and greater difficulty describing and recognizing self-emotions were associated with reporting fewer physical sensations in the body when experiencing emotion in the autism spectrum disorder group. The results of this study suggest that while autism spectrum disorder youth with concomitant alexithymia may experience emotional empathy differently, it should not be characterized as an absence of a capacity for emotional empathy.

Connectivity differences between inferior frontal gyrus and mentalizing network in autism as compared to developmental coordination disorder and non-autistic youth.

Prior studies have compared neural connectivity during mentalizing tasks in autism (ASD) to non-autistic individuals and found reduced connectivity between the inferior frontal gyrus (IFG) and mentalizing regions. However, given that the IFG is involved in motor processing, and about 80% of autistic individuals have motor-related difficulties, it is necessary to explore if these differences are specific to ASD or instead similar across other developmental motor disorders, such as developmental coordination disorder (DCD). Participants (29 ASD, 20 DCD, 31 typically developing [TD]; ages 8-17) completed a mentalizing task in the fMRI scanner, where they were asked to think about why someone was performing an action. Results indicated that the ASD group, as compared to both TD and DCD groups, showed significant functional connectivity differences when mentalizing about other's actions. The left IFG seed revealed ASD connectivity differences with the: bilateral temporoparietal junction (TPJ), left insular cortex, and bilateral dorsolateral prefrontal cortex (DLPFC). Connectivity differences using the right IFG seed revealed ASD differences in the: left insula, and right DLPFC. These results indicate that connectivity differences between the IFG, mentalizing regions, emotion and motor processing regions are specific to ASD and not a result of potentially co-occurring motor differences.

Trends and Disparities in Firearm Deaths Among Children.

BACKGROUND AND OBJECTIVES: In 2020, firearm injuries became the leading cause of death among US children and adolescents. This study aimed to evaluate new 2021 data on US pediatric firearm deaths and disparities to understand trends compared with previous years. METHODS: Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research was queried for firearm mortalities in children/adolescents from 2018 to 2021. Absolute mortality, death rates, and characteristics were reported. Death rates were defined per 100 000 persons in that population per year. Death rates across states were illustrated via geographic heat maps, and correlations with state poverty levels were calculated. RESULTS: In 2021, firearms continued to be the leading cause of death among US children. From 2018 to 2021, there was a 41.6% increase in the firearm death rate. In 2021, among children who died by firearms, 84.8% were male, 49.9% were Black, 82.6% were aged 15 to 19 years, and 64.3% died by homicide. Black children accounted for 67.3% of firearm homicides, with a death rate increase of 1.8 from 2020 to 2021. White children accounted for 78.4% of firearm suicides. From 2020 to 2021, the suicide rate increased among Black and white children, yet decreased among American Indian or Alaskan Native children. Geographically, there were worsening clusters of firearm death rates in Southern states and increasing rates in Midwestern states from 2018 to 2021. Across the United States, higher poverty levels correlated with higher firearm death rates (R = 0.76, P < .001). CONCLUSIONS: US pediatric firearm deaths increased in 2021, above the spike in 2020, with worsening disparities. Implementation of prevention strategies and policies among communities at highest risk is critical.

The relationship between alexithymia, interoception, and neural functional connectivity during facial expression processing in autism spectrum disorder.

Neural processing differences of emotional facial expressions, while common in autism spectrum disorder (ASD), may be related to co-occurring alexithymia and interoceptive processing differences rather than autism per se. Here, we investigate relationships between alexithymia, interoceptive awareness of emotions, and functional connectivity during observation of facial expressions in youth (aged 8-17) with ASD (n = 28) compared to typically developing peers (TD; n = 37). Behaviorally, we found no significant differences between ASD and TD groups in interoceptive awareness of emotions, though alexithymia severity was significantly higher in the ASD group. In the ASD group, increased alexithymia was significantly correlated with lower interoceptive sensation felt during emotion. Using psycho-physiological interaction (PPI) analysis, the ASD group showed higher functional connectivity between the left ventral anterior insula and the left lateral prefrontal cortex than the TD group when viewing facial expressions. Further, alexithymia was associated with reduced left anterior insula-right precuneus connectivity and reduced right dorsal anterior insula-left ventral anterior insula connectivity when viewing facial expressions. In the ASD group, the degree of interoceptive sensation felt during emotion was positively correlated with left ventral anterior insula-right IFG connectivity when viewing facial expressions. However, across all participants, neither alexithymia nor interoceptive awareness of emotions predicted connectivity between emotion-related brain regions when viewing emotional facial expressions. To summarize, we found that in ASD compared to TD: 1) there is stronger connectivity between the insula and lateral prefrontal cortex; and 2) differences in interhemispheric and within left hemisphere connectivity between the insula and other emotion-related brain regions are related to individual differences in interoceptive processing and alexithymia. These results highlight complex relationships between alexithymia, interoception, and brain processing in ASD.