Proteomic and metabolomic profiles of plasma-derived Extracellular Vesicles differentiate melanoma patients from healthy controls.

BACKGROUND: Plasma-derived Extracellular Vesicles (EVs) have been suggested as novel biomarkers in melanoma, due to their ability to reflect the cell of origin and ease of collection. This study aimed to identify novel EV biomarkers that can discriminate between disease stages. This was achieved by characterising the plasma-derived EVs of patients with melanoma, and comparing their proteomic and metabolomic profile to those from healthy controls. METHODS: EVs were isolated from the plasma of 36 patients with melanoma and 13 healthy controls using Size Exclusion Chromatography. Proteomic and Metabolomic Analyses were performed, and machine learning algorithms were used to identify potential proteins and metabolites to differentiate the plasma-derived EVs from melanoma patients of different disease stages. RESULTS: The concentration and size of the EV population isolated was similar between groups. Proteins (APOC4, PRG4, PLG, TNC, VWF and SERPIND1) and metabolites (lyso PC a C18:2, PC ae C44:3) previously associated with melanoma pathogenesis were identified as relevant in differentiating between disease stages. CONCLUSION: The results further support the continued investigation of circulating plasma-derived EVs as biomarkers in melanoma. Furthermore, the potential of combined proteo-metabolomic signatures for differentiation between disease stages may provide valuable insights into early detection, prognosis, and personalised treatment strategies.

Variation in the mu-opioid receptor gene (OPRM1) moderates the influence of maternal sensitivity on child attachment.

The endogenous opioid system is thought to play an important role in mother-infant attachment. In infant rhesus macaques, variation in the µ-opioid receptor gene (OPRM1) is related to differences in attachment behavior that emerges following repeated separation from the mother; specifically, infants carrying at least one copy of the minor G allele of the OPRM1 C77G polymorphism show heightened and more persistent separation distress, as well as a pattern of increased contact-seeking behavior directed towards the mother during reunions (at the expense of affiliation with other group members). Research in adult humans has also linked the minor G allele of the analogous OPRM1 A118G polymorphism with greater interpersonal sensitivity. Adopting an interactionist approach, we examined whether OPRM1 A118G genotype and maternal (in)sensitivity are associated with child attachment style, predicting that children carrying the G allele may be more likely to develop an ambivalent attachment pattern in response to less sensitive maternal care. The sample consisted of 191 mothers participating with their children (n = 223) in the Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN) project, a community-based, birth cohort study of Canadian mothers and their children assessed longitudinally across the child's development. Maternal sensitivity was coded from at-home mother-child interactions videotaped when the child was 18 months of age. Child attachment was assessed at 36 months using the Strange Situation paradigm. As predicted, G allele carriers, but not AA homozygotes, showed increasing odds of being classified as ambivalently attached with decreasing levels of maternal sensitivity. Paralleling earlier non-human animal research, this work provides support for the theory that endogenous opioids contribute to the expression of attachment behaviors in humans.

Establishment of a clinical network for children with amelogenesis imperfecta and dentinogenesis imperfecta in the UK: 4-year experience.

BACKGROUND: Amelogenesis imperfecta (AI) and dentinogenesis imperfecta (DI) are two groups of genetically inherited conditions resulting in abnormal enamel and dentin formation, respectively. Children and young people may be adversely affected by these conditions, with significant reduction in oral health related quality of life. Dental management of children with AI and DI is often complex, which is exacerbated by the absence of clear referral pathways and scarce evidence-based guidelines. METHOD: The need for increased knowledge and peer support led to the development of a group of UK paediatric dentists with a special clinical interest in the management of children with AI and DI. PURPOSE: The aims of this paper are to describe the establishment of an AI/DI Clinical Excellence Network (AI/DI CEN) in paediatric dentistry including outputs and future plans, and to share our collective learning to help support others anywhere in the world advance the care of people with AI or DI.

To what extent do social support and mastery mediate the association between childhood maltreatment and depression? A sequential causal mediation analysis.

AIMS: This study aimed to examine the independent roles of various childhood maltreatment (CM) subtypes in the development of depression; quantify the joint mediation effect of social support and mastery in the association between subtypes of CM and depression and examine the additional contribution of mastery beyond the effect that is operating through social support to this relationship. METHODS: Data analysed were from the Zone d'Épidémiologie Psychiatrique du Sud-Ouest de Montréal, an ongoing longitudinal population-based study. In total, 1351 participants with complete information on the studied variables were included. The propensity score matching and inverse-probability weighted regression adjustment estimation methods were used to minimise the potential confounding in the relationship between CM and major depression. We then used inverse odds ratio-weighted estimation to estimate the direct effects of maltreatment and indirect effects of social support and mastery. RESULTS: We found that exposures to all maltreatment subtypes increased the risk of subsequent depression. The joint mediating effect of social support and mastery explained 37.63-46.97% of the association between different maltreatment subtypes and depression. The contribution of these two mediators differed by maltreatment subtypes, with social support being the major contributor to the mediating effect. CONCLUSIONS: The findings of the study not only provide scientific evidence on the importance of psychosocial attributes in the development of major depression but also suggest that prevention and invention strategies should focus on these psychosocial attributes to effectively break the vicious cycle of CM on major depression.

Unexpected intraoperative hypotension in a chronic cocaine user.

It is not uncommon for patients to present for procedures under anaesthesia with a history of recent cocaine use. The acute effects of cocaine toxicity are well documented, but the pathophysiological changes caused by chronic use are complex and can result in unexpected cardiovascular responses and interactions with anaesthetic agents. In this case report, we describe an episode of hypotension under general anaesthesia, likely due to catecholamine depletion, an unusual but significant consequence of chronic cocaine use. It should be treated with intravenous fluids and direct-acting vasopressors such as phenylephrine or noradrenaline, as they are likely to be more effective than indirect acting agents. As the prevalence of cocaine use continues to increase, anaesthesia providers need to not only be familiar with the treatment of acute cocaine toxicity, but also to anticipate and manage the cardiovascular changes associated with chronic use of this drug.

Patient-reported outcome measures for children and adolescents having dental bleaching in the UK.

PURPOSE: Dental bleaching in paediatric patients can be used to address discolouration of teeth due to trauma, endodontic treatment, or enamel and dentine defects. Despite being a minimally invasive and successful treatment, the use of bleaching products in children and young people remains controversial. This evaluation was designed to provide insight into the child's perspective on dental bleaching and the influence that this treatment has upon their life. METHOD: A dental bleaching patient reported outcome measure (PROM) was developed and piloted in 2019. Data were collected from 3 UK units (January-March 2020). Children attending these units for bleaching reviews were invited to complete the PROM. RESULTS: Twenty seven PROM questionnaires were completed including 19 courses of external bleaching and 8 courses of internal/external bleaching. The average age was 14 years old (9-17 years). The common indications for bleaching were Amelogenesis Imperfecta, dental trauma and Molar Incisor Hypomineralisation. Patients reported improvements in their appearance (89%) and self-confidence (81%). Sensitivity was the most common side effect, reported in 63% of cases. CONCLUSION: This PROM supports the use of dental bleaching in children and young people when treating dental disease that causes discolouration. Bleaching not only improved the appearance of teeth, but also patients' self-confidence. Sensitivity is a common side effect and clinicians should discuss this common risk and its management with patients and their families.

Specific and cumulative lifetime stressors in the aetiology of major depression: A longitudinal community-based population study.

AIMS: Early-life stressful circumstances (i.e. childhood maltreatment) coupled with stressful events later in life increase the likelihood of subsequent depression. However, very few studies have been conducted to examine the specific and cumulative effects of these stressors in the development of depression. There is also a paucity of research that simultaneously considers the role of biological factors combined with psychosocial stressors in the aetiology of depression. Guided by the biopsychosocial model proposed by Engel, the present study aims to examine to what extent the experience of stressors across the lifespan is associated with depression while taking into account the role of genetic predispositions. METHODS: Data analysed were from the Social and Psychiatric Epidemiology Catchment Area of the Southwest of Montreal (ZEPSOM), a large-scale, longitudinal community-based cohort study. A total of 1351 participants with complete information on the lifetime diagnoses of depression over a 10-year follow-up period were included in the study. Stressful events across the lifespan were operationalised as specific, cumulative and latent profiles of stressful experiences. Latent profile analysis (LPA) was used to explore the clustering of studied stressors including childhood maltreatment, poor parent-child relationship, and stressful life events. A polygenetic risk score was calculated for each participant to provide information on genetic liability. Multivariate logistic regression was used to examine the association between specific, cumulative and latent profiles of stressors and subsequent depression. RESULTS: We found that different subtypes of childhood maltreatment, child-parent bonding and stressful life events predicted subsequent depression. Furthermore, a significant association between combined effects of cumulative stressful experiences and depression was found [odds ratio (OR) = 1.20, 95% confidence interval (CI): 1.12-1.28]. Three latent profiles of lifetime stressors were identified in the present study and named as 'low-level of stress' (75.1%), 'moderate-level of stress' (6.8%) and 'high-level of stress' (18.1%). Individuals with a 'high-level of stress' had a substantially higher risk of depression (OR = 1.80, 95% CI: 1.08-3.00) than the other two profiles after adjusting for genetic predispositions, socio-demographic characteristics, and health-related factors. CONCLUSIONS: While controlling for genetic predispositions, the present study provides robust evidence to support the independent and cumulative as well as compositional effects of early- and later-on lifetime psychosocial stressors in the subsequent development of depression. Consequently, mental illness prevention and mental health promotion should target the occurrence of stressful events as well as build resilience in people so they can better cope with stress when it inevitably occurs.

Associations between epigenetic aging and childhood peer victimization, depression, and suicidal ideation in adolescence and adulthood: A study of two population-based samples.

Background: Prior studies indicate that peer victimization (including bullying) is associated with higher risk for depression and suicidal ideation across the life course. However, molecular mechanisms underlying these associations remain unclear. This two-cohort study proposes to test whether epigenetic aging and pace of aging, as well as a DNA methylation marker of responsive to glucocorticoids, are associated to childhood peer victimization and later depressive symptoms, or suicidal ideation. Methods: Cohort 1: Epigenome-wide DNA methylation (EPIC array) was measured in saliva collected when participants were 10.47 years (standard deviation = 0.35) in a subsample of the Quebec Longitudinal Study of Child Development (QLSCD, n = 149 participants), with self-reported peer victimization at 6-8 years, depressive symptoms (mean symptoms, and dichotomized top 30% symptoms) and suicidal ideation at 15-17 years. Cohort 2: Epigenome-wide DNA methylation (EPIC array) was measured in blood collected from participants aged 45.13 years (standard deviation = 0.37) in a subsample of the 1958 British Birth cohort (1958BBC, n = 238 participants) with information on mother-reported peer victimization at 7-11 years, self-reported depressive symptoms at 50 years, and suicidal ideation at 45 years. Five epigenetic indices were derived: three indicators of epigenetic aging [Horvath's pan-tissue (Horvath1), Horvath's Skin-and-Blood (Horvath2), Pediatric-Buccal-Epigenetic age (PedBE)], pace of aging (DunedinPACE), and stress response reactivity (Epistress). Results: Peer victimization was not associated with the epigenetic indices in either cohort. In the QLSCD, higher PedBE epigenetic aging and a slower pace of aging as measured by DunedinPACE predicted higher depressive symptoms scores. In contrast, neither the Horvath1, or Horvath2 epigenetic age estimates, nor the Epistress score were associated with depressive symptoms in either cohort, and none of the epigenetic indices predicted suicidal ideation. Conclusion: The findings are consistent with epigenome-wide and candidate gene studies suggesting that these epigenetic indices did not relate to peer victimization, challenging the hypothesis that cumulative epigenetic aging indices could translate vulnerability to depressive symptoms and suicidal ideation following peer victimization. Since some indices of epigenetic aging and pace of aging signaled higher risk for depressive symptoms, future studies should pursue this investigation to further evaluate the robustness and generalization of these preliminary findings.

O 089 - A soft robotic exosuit assisting the paretic ankle in patients post-stroke: Effect on muscle activation during overground walking.

This study compared overground walking with and without exosuit assistance in post-stroke patients. Exosuit-assisted walking was found to improve paretic propulsion and ground clearance during swing, two common gait deviations in stroke patients. No changes in leg muscle activity was found, motivating further study of the exosuit as a tool for gait training during stroke rehabilitation.

Species diversity and mycotoxin production by members of the Fusarium tricinctum species complex associated with Fusarium head blight of wheat and barley in Italy.

Fusarium head blight (FHB) is a global cereal disease caused by a complex of Fusarium species. In Europe, the main species responsible for FHB are F. graminearum, F. culmorum and F. poae. However, members of the F. tricinctum species complex (FTSC) have become increasingly important. FTSC fusaria can synthesize mycotoxins such as moniliformin (MON), enniatins (ENNs) and several other biologically active secondary metabolites that could compromise food quality. In this study, FTSC isolates primarily from Italian durum wheat and barley, together with individual strains from four non-graminaceous hosts, were collected to assess their genetic diversity and determine their potential to produce mycotoxins in vitro on rice cultures. A multilocus DNA sequence dataset (TEF1, RPB1 and RPB2) was constructed for 117 isolates from Italy and 6 from Iran to evaluate FTSC species diversity and their evolutionary relationships. Phylogenetic analyses revealed wide genetic diversity among Italian FTSC isolates. Among previously described FTSC species, F. avenaceum (FTSC 4) was the most common species in Italy (56/117 = 47.9%) while F. tricinctum (FTSC 3), and F. acuminatum (FTSC 2) accounted for 11.1% (13/117) and the 8.5% (10/117), respectively. The second most detected species was a new and unnamed Fusarium sp. (FTSC 12; 32/117 = 19%) resolved as the sister group of F. tricinctum. Collectively, these four phylospecies accounted for 111/117 = 94.9% of the Italian FTSC collection. However, we identified five other FTSC species at low frequencies, including F. iranicum (FTSC 6) and three newly discovered species (Fusarium spp. FTSC 13, 14, 15). Of the 59 FTSC isolates tested for mycotoxin production on rice cultures, 54 and 55 strains, respectively, were able to produce detectable levels of ENNs and MON. In addition, we confirmed that the ability to produce bioactive secondary metabolites such as chlamydosporol, acuminatopyrone, longiborneol, fungerin and butanolide is widespread across the FTSC.

Absence of known feline MYH7 and MYBPC3 variants in a diverse cohort of cats with hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common cause of heart disease in the domestic cat with a genetic predisposition in a few breeds. In the Maine Coon and Ragdoll breeds, two variants associated with the HCM phenotype have been identified in the cardiac myosin binding protein C gene (MYBPC3; p.Ala31Pro and p.Arg820Trp respectively), and a single variant has been identified in the myosin heavy chain gene (MYH7; p.Glu1883Lys) in one domestic cat with HCM. It is not known if these variants influence the development of HCM in other cohorts of the feline population. The objective of this study was to evaluate the presence of the known MYBPC3 and MYH7 variants in a population of cats with HCM. DNA was isolated from samples collected from non-Ragdoll and non-Maine Coon domestic cats diagnosed with HCM through the North Carolina State University College of Veterinary Medicine and genotyped for the three variants. One-hundred and three DNA samples from cats with HCM were evaluated from domestic shorthair, domestic longhair and purebred cats. All samples were wt for the MYBPC3 and MYH7 variants. Although this study was limited by its inclusion of cats from one tertiary hospital, the lack of these MYBPC3 and MYH7 variants in this feline HCM population indicates that the clinical utility of genetic testing for these variants may be isolated to the two cat breeds in which these variants have been identified. Further studies to identify the causative variants for the feline HCM population are warranted.

Myxomatous mitral valve disease in the miniature poodle: A retrospective study.

Myxomatous mitral valve disease (MMVD) is the most common cardiovascular disease in the dog. The natural history of the disease is wide ranging and includes patients without clinical signs as well as those with significant clinical consequences from cardiac arrhythmias, pulmonary hypertension and/or congestive heart failure. The factors that determine which dogs remain asymptomatic and which develop clinical disease are not known. Disease characteristics could be breed or family related; some breeds of dogs, particularly the Cavalier King Charles spaniels, develop MMVD at an early age. The purpose of this study was to retrospectively characterize MMVD in the miniature poodle, a commonly affected breed in which MMVD has not been well characterized. Thirty-two miniature poodles met the inclusion criteria. Mean age was 11±three years. Clinical signs included exercise intolerance, syncope and coughing. Eighteen dogs were classified as ACVIM Stage B1, 12 as stage B2, and two as stage C. Mean vertebral heart scale (VHS) was 10.2 (±standard deviation of 0.9); 15 of 28 dogs had a VHS <10.3. One dog had radiographic evidence of congestive heart failure. Mean diastolic left ventricle dimension normalized to body weight was 1.6 (±0.4) and mean systolic was 0.8 (±0.3). Mitral valve prolapse was subjectively classified as mild or moderate in 19 dogs and severe in two. In the miniature poodles reported here, MMVD appears to be a fairly late onset disease and often is a mild phenotype.

Integration of a recent infection testing algorithm into HIV surveillance in Ireland: improving HIV knowledge to target prevention.

Recent infection testing algorithms (RITA) for HIV combine serological assays with epidemiological data to determine likely recent infections, indicators of ongoing transmission. In 2016, we integrated RITA into national HIV surveillance in Ireland to better inform HIV prevention interventions. We determined the avidity index (AI) of new HIV diagnoses and linked the results with data captured in the national infectious disease reporting system. RITA classified a diagnosis as recent based on an AI < 1.5, unless epidemiological criteria (CD4 count <200 cells/mm3; viral load <400 copies/ml; the presence of AIDS-defining illness; prior antiretroviral therapy use) indicated a potential false-recent result. Of 508 diagnoses in 2016, we linked 448 (88.1%) to an avidity test result. RITA classified 12.5% of diagnoses as recent, with the highest proportion (26.3%) amongst people who inject drugs. On multivariable logistic regression recent infection was more likely with a concurrent sexually transmitted infection (aOR 2.59; 95% CI 1.04-6.45). Data were incomplete for at least one RITA criterion in 48% of cases. The study demonstrated the feasibility of integrating RITA into routine surveillance and showed some ongoing HIV transmission. To improve the interpretation of RITA, further efforts are required to improve completeness of the required epidemiological data.

Maternal antenatal mood and child development: an exploratory study of treatment effects on child outcomes up to 5 years.

Effective treatment of maternal antenatal depression may ameliorate adverse neurodevelopmental outcomes in offspring. We performed two follow-up rounds of children at age 2 and age 5 whose mothers had received either specialized cognitive-behavioural therapy or routine care for depression while pregnant. Of the original cohort of 54 women, renewed consent was given by 28 women for 2-year follow-up and by 24 women for 5-year follow-up. Child assessments at the 2-year follow-up included the Parenting Stress Index (PSI), Bayley Scales of Infant Development (BSID-III) and the Child Behaviour Checklist (CBCL). The 5-year follow-up included the Wechsler Preschool and Primary Scales of Intelligence (WPPSI-III) and again the CBCL. Treatment during pregnancy showed significant benefits for children's development at age 2, but not at age 5. At 2 years, intervention effects were found with lower scores on the PSI Total score, Parent Domain and Child domain (d=1.44, 1.47, 0.96 respectively). A non-significant trend favoured the intervention group on most subscales of the CBCL and the BSID-III (most notably motor development: d =0.52). In contrast, at 5-year follow-up, no intervention effects were found. Also, irrespective of treatment allocation, higher depression or anxiety during pregnancy was associated with higher CBCL and lower WPPSI-III scores at 5 years. This is one of the first controlled studies to evaluate the long-term effect of antenatal depression treatment on infant neurodevelopmental outcomes, showing some benefit. Nevertheless, caution should be taken interpreting the results because of a small sample size, and larger studies are warranted.

Inequalities in HIV testing uptake and needs among men who have sex with men living in Ireland: findings from an internet survey.

OBJECTIVES: HIV disproportionately affects men who have sex with men (MSM) in Ireland. The aim of this study was to improve understanding of HIV testing among MSM living in Ireland to inform prevention and testing initiatives. METHODS: We used data from the MSM Internet Survey Ireland 2015 (MISI 2015), a cross-sectional survey of MSM living in Ireland. We identified factors associated with never having tested for HIV using univariable and multivariable logistic regression. We identified preferred sites for future tests and examined the relationships between unmet HIV testing needs and socio-demographic groups. RESULTS: More than one-third (n = 1006; 36%) of MSM had never tested for HIV. Multivariable logistic regression showed that untested men were more likely to be aged 18-24 years, live outside Dublin, have a lower level of education, be born in Ireland, identify as bisexual, be out to fewer people, and not have had sex with a man in the previous 12 months. The same groups of men also had the least knowledge about HIV and were least confident in accessing an HIV test. Men who had never tested for HIV were more likely to prefer testing by their general practitioner (GP) or using home sampling HIV kits and less likely to prefer testing in a sexual health clinic. CONCLUSIONS: HIV prevention and testing programmes for MSM should be targeted towards younger men, those living outside Dublin and those with lower levels of education. We recommend increased promotion and availability of free HIV testing services in a range of clinical and nonclinical settings (including self-sampling and home testing).

Drug use among men who have sex with men in Ireland: Prevalence and associated factors from a national online survey.

BACKGROUND: Little is known about the prevalence and determinants of drug use among men who have sex with men (MSM) in Ireland. The aims of this study were to measure the prevalence of recreational drug use among MSM in a national sample, and to identify sub-groups of MSM who may benefit from targeted preventive interventions. METHODS: The MSM Internet Survey Ireland (MISI) 2015 was a community-recruited, nationally-promoted, self-completed online survey for MSM. MISI 2015 included standardised questions on recreational drugs, poppers, and drugs associated with chemsex (i.e. crystal methamphetamine, GBL/GHB, mephedrone, ketamine). Multivariable-adjusted logistic regression was used to identify factors associated with use of these substances. RESULTS: In the previous year, 36% of MSM used recreational drugs, 33% used poppers, and 7% used drugs associated with chemsex. Five percent were diagnosed HIV-positive. Recreational drug users were significantly younger than non-users (median = 27 vs. 32 years; p < 0.001); popper users were significantly older than non-users (median = 34 vs. 28 years; p < 0.001). The odds of recreational drug use were higher among MSM diagnosed HIV-positive (vs. never tested; AOR 2.27, 95%CI 1.39-3.70). Use of poppers, and use of drugs associated with chemsex, were also higher among MSM diagnosed HIV-positive (vs. never tested; AOR 3.77, 95%CI 2.41-5.90, and AOR 5.87, 95%CI 3.08-11.18 respectively). CONCLUSIONS: The prevalence of recreational drug use is higher among MSM than in the general population in Ireland, and it is particularly high among MSM diagnosed HIV-positive. Targeted harm reduction messages and preventive interventions are warranted to complement population-based approaches to reducing drug use in this population.

A Novel Disease of Big-Leaf Mahogany Caused by Two Fusarium Species in Mexico.

Big-leaf mahogany (Swietenia macrophylla) is valued for its high-quality wood and use in urban landscapes in Mexico. During surveys of mango-producing areas in the central western region of Mexico, symptoms of malformation, the most important disease of mango in the area, were observed on big-leaf mahogany trees. The objectives of this research were to describe this new disease and determine its cause. Symptoms on big-leaf mahogany at four sites in Michoacán, Mexico resembled those of the vegetative phase of mango malformation, including compact, bunched growth of apical and lateral buds, with greatly shortened internodes and small leaves that curved back toward the supporting stem. Of 163 isolates that were recovered from symptomatic tissues, most were identified as Fusarium pseudocircinatum (n = 121) and F. mexicanum (n = 39) using molecular systematic data; two isolates represented unnamed phylospecies within the F. incarnatum-equiseti species complex (FIESC 20-d and FIESC 37-a) and another was in the F. solani species complex (FSSC 25-m). However, only F. mexicanum and F. pseudocircinatum induced malformation symptoms on 14-day-old seedlings of big-leaf mahogany. The results indicate that F. mexicanum and F. pseudocircinatum, previously reported in Mexico as causal agents of mango malformation disease, also affect big-leaf mahogany. This is the first report of this new disease and the first time that F. mexicanum was shown to affect a host other than mango.