Multicentre, randomised, double-blind, placebo-controlled, proof of concept study of LSALT peptide as prevention of acute respiratory distress syndrome and acute kidney injury in patients infected with SARS-CoV-2 (COVID-19).

OBJECTIVE: Dipeptidase-1 (DPEP-1) is a recently discovered leucocyte adhesion receptor for neutrophils and monocytes in the lungs and kidneys and serves as a potential therapeutic target to attenuate inflammation in moderate-to-severe COVID-19. We aimed to evaluate the safety and efficacy of the DPEP-1 inhibitor, LSALT peptide, to prevent specific organ dysfunction in patients hospitalised with COVID-19. DESIGN: Phase 2a randomised, placebo-controlled, double-blinded, trial. SETTING: Hospitals in Canada, Turkey and the USA. PARTICIPANTS: A total of 61 subjects with moderate-to-severe COVID-19. INTERVENTIONS: Randomisation to LSALT peptide 5 mg intravenously daily or placebo for up to 14 days. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary endpoint was the proportion of subjects alive and free of respiratory failure and/or the need for renal replacement therapy (RRT). Numerous secondary and exploratory endpoints were assessed including ventilation-free days, and changes in kidney function or serum biomarkers. RESULTS: At 28 days, 27 (90.3%) and 28 (93.3%) of subjects in the placebo and LSALT groups were free of respiratory failure and the need for RRT (p=0.86). On days 14 and 28, the number of patients still requiring more intensive respiratory support (O2 ≥6 L/minute, non-invasive or invasive mechanical ventilation or extracorporeal membrane oxygenation) was 6 (19.4%) and 3 (9.7%) in the placebo group versus 2 (6.7%) and 2 (6.7%) in the LSALT group, respectively (p=0.14; p=0.67). Unadjusted analysis of ventilation-free days demonstrated 22.8 days for the LSALT group compared with 20.9 in the placebo group (p=0.4). LSALT-treated subjects had a significant reduction in the fold expression from baseline to end of treatment of serum CXCL10 compared with placebo (p=0.02). Treatment-emergent adverse events were similar between groups. CONCLUSION: In a Phase 2 study, LSALT peptide was demonstrated to be safe and tolerated in patients hospitalised with moderate-to-severe COVID-19. TRIAL REGISTRATION NUMBER: NCT04402957.

On-field instrumented mouthguard coupling.

Instrumented mouthguard (iMG) sensors have been developed to measure sports head acceleration events (HAE) in brain injury research. Laboratory validation studies show that effective coupling of iMGs with the human skull is crucial for accurate head kinematics measurements. However, iMG-skull coupling has not been investigated in on-field sports settings. The objective of this study was to assess on-field iMG coupling using infrared proximity sensing and to investigate coupling effects on kinematics signal characteristics. Forty-two university-level men's ice hockey (n = 21) and women's rugby (n = 21) athletes participated in the study, wearing iMGs during 6-7 month in-season periods. Proximity data classified video-verified HAE recordings into four main iMG coupling categories: coupled (on-teeth), decoupling (on-teeth to off-teeth), recoupling (off-teeth to on-teeth) and decoupled (off-teeth). Poorly-coupled HAEs showed significantly higher peak angular acceleration amplitudes and greater signal power in medium-high frequency bands compared with well-coupled HAEs, indicating potential iMG movements independent of the skull. Further, even video-verified true positives included poorly-coupled HAEs, and iMG coupling patterns varied between the men's hockey and women's rugby teams. Our findings show the potential of using proximity sensing in iMGs to identify poorly-coupled HAEs. Utilizing this data screening process in conjunction with video review may mitigate a key source of sensor noise and enhance the overall quality of on-field sports HAE datasets.

An ACT self-help intervention for adults with a visible difference in appearance: A pilot feasibility and acceptability randomized controlled study.

Individuals living with a visible difference in appearance experience high levels of social anxiety, yet self-help interventions for this heterogeneous population are not available. We conducted a pilot trial of a novel Acceptance and Commitment Therapy (ACT) based self-help intervention.Individuals with anxiety about having a visible difference in appearance (n = 284) were randomized to an ACT-based four-week intervention (n = 145) or a waitlist control condition (n = 139). We collected pre and follow-up (four-weeks after the completion of the intervention) data. Primary outcomes included social anxiety and impairments in functioning. Psychological flexibility (PF) was also examined. ANCOVAs, controlling for pre scores, indicated significant improvements in functioning by the intervention group. No significant differences were observed for anxiety and PF between conditions at follow-up. Drop out was 68% for the intervention and 41% for the control group, with no differences in the groups in age, origin, gender, or type of visible difference. Participants in the intervention group found the intervention almost equally, useful (77%) and helpful (73%). An ACT-based self-help intervention can alleviate distress related to visible difference in appearance. More sophisticated designs are needed now, to collect idiographic and longitudinal data and examine personalized changes across time in this population.

Extended difficulties following the use of psychedelic drugs: A mixed methods study.

Long-term adverse experiences following psychedelic use can persist for weeks, months, or even years, and are relatively unexplored in psychedelic research. Our convergent mixed-method study gained quantitative and qualitative data from 608 participants who reported extended difficulties following psychedelic experiences. Data was gathered on the context of use, the nature and duration of the challenges they experienced (including a written description of these), plus a range of possible risk factors and perceived causes. The most common forms of extended difficulty were feelings of anxiety and fear, existential struggle, social disconnection, depersonalization and derealization. For approximately one-third of the participants, problems persisted for over a year, and for a sixth, they endured for more than three years. It was found that a shorter duration of difficulties was predicted by knowledge of dose, drug type and lower levels of difficulty reported during the psychoactive experience, while a narrower range of difficulties was predicted by taking the drug in a guided setting. Implications for psychedelic harm reduction are discussed.

This is your brain on death: a comparative analysis of a near-death experience and subsequent 5-Methoxy-DMT experience.

Introduction: Much research has focused on the modeling of the near-death experience (NDE) by classical and atypical psychedelics; however, to date, no study has reported on the relationship between the NDE and the experience induced by the highly potent, endogenous psychedelic drug 5-Methoxy-DMT (5MeO-DMT). This article presents a case study of an individual who is popularly documented to have had a profound near-death experience while in a coma caused by bacterial meningoencephalitis. Additionally, the individual also subsequently underwent an experience with 5MeO-DMT. Methods: A semi-structured interview was conducted with the subject concerning his experiences with both the NDE and 5MeO-DMT. A basic thematic analysis was performed on both the original text describing the NDE as well as the interview itself, which mainly focused on the subject's experience with 5MeO-DMT. This analysis was organized to identify both the similar and different emergent themes between the two states, with a particular emphasis on the subject's perceptions of the similarities and differences between the experiences. Results: There is a very high level of comparability between the original NDE and psychedelic experiences in general, including shared characteristics such as entering other worlds, meeting menacing or benevolent entities, experiencing synesthesia, perinatal regression, and lucid dreamlike properties. Much comparability was also identified with the 5MeO-DMT experience, in particular the major mystical experiential domains, such as ego dissolution, but especially transcendence of time and space. However, there were also a few unique themes (life review, the deceased, and the threshold) that emerged in the NDE that were not present in the 5MeO-DMT experience or other psychedelic experience studies, suggesting that these themes may be more unique to the NDE. Discussion: Despite such similarities, the participant asserted that his NDE and psychedelic experiences were not similar enough to be attributed to endogenous psychedelics. In this study, we discussed several mechanisms that could potentially account for the NDE, including lucid dreams and perinatal regression. However, the study also explored the possibility that the unique etiology of the participant's NDE, bacterial meningoencephalitis affecting the neocortex, may have triggered similar downstream neural activity as that initiated by psychedelic agents through pyramidal neuronal activation. This hypothesis is presented with appropriate caveats and acknowledged as speculative.

An encounter with the self: A thematic and content analysis of the DMT experience from a naturalistic field study.

Introduction: N,N-Dimethyltryptamine (DMT) is an endogenous serotonergic psychedelic capable of producing radical shifts in an experience that have significant implications for consciousness and its neural correlates, especially given the "disconnected consciousness" suggested by the "breakthrough" DMT state. Its increasing usage and clinical trial indicate the growing importance of a thorough elucidation of the experience's qualitative content, over and above the phenomenological structure. This is particularly in light of the intensely pervasive effects of DMT occasions in all dimensions of the self, which are often ontologically challenging yet potentially transformative. Methods: This is the second report on the first naturalistic field study of DMT use exploring its qualitative analysis. Screened, healthy, anonymized, and experienced DMT users were observed during their non-clinical use of the drug at home (40-75-mg inhaled). In-depth semi-structured interviews, inspired by the micro-phenomenological technique, were employed immediately after their experience. This study reports on the thematic and content analysis of one major domain of the breakthrough experiences elicited, the "self"; where analyses of the "other" were previously reported. A total of 36 post-DMT experience interviews with mostly Caucasian (83%) men (eight women) of a mean of 37 years were predominantly inductively coded. Results: Invariably, profound and highly intense experiences occurred. The first overarching category comprised the onset of effects, encompassing super-ordinate themes including sensory, emotion and body, and space-time shifts; the second category comprised bodily effects, encompassing themes including pleasurable, neutral/both, and uncomfortable; the third category comprised the sensorial effects, encompassing open-eye, visual, and cross-modal and other; the fourth comprised the psychological effects, encompassing memory and language, awareness and sense of self, and time distortions; and the fifth comprised the emotional effects, encompassing positive, neither/both, and challenging experiences. Many further subthemes also illuminate the rich content of the DMT experience. Discussion: The present study provides a systematic and nuanced analysis of the content of the breakthrough DMT state pertaining to one's personal and self-referential experiences of the body, senses, psychology, and emotions. The resonances both with previous DMT studies and other types of extraordinary experiences, such as the alien abduction, shamanic and near-death experiences, are also elaborated upon. Putative neural mechanisms and their promise as a psychotherapeutic agent, especially owing to deep emotional impact, are discussed.

Morpho-mechanistic screening criteria for the echocardiographic detection of rheumatic heart disease.

INTRODUCTION: Screening echocardiography, guided by the current World Heart Federation (WHF) criteria, has important limitations that impede the establishment of large-scale rheumatic heart disease (RHD) control programmes in endemic regions. The criteria misclassify a significant number of normal cases as borderline RHD. Prior attempts to simplify them are limited by incorporation bias due to the lack of an externally validated, accurate diagnostic test for RHD. We set out to assess novel screening criteria designed to avoid incorporation bias and to compare this against the performance of the current WHF criteria. METHODS: The performance of the WHF and the morpho-mechanistic (MM) RHD screening criteria (a novel set of screening criteria that evaluate leaflet morphology, motion and mechanism of regurgitation) as well as a simplified RHD MM 'rule-out' test (based on identifying a predefined sign of anterior mitral valve leaflet restriction for the mitral valve and any aortic regurgitation for the aortic valve) were assessed in two contrasting cohorts: first, a low-risk RHD cohort consisting of children with a very low-risk RHD profile. and second, a composite reference standard (CRS) RHD-positive cohort that was created using a composite of two criteria to ensure a cohort with the highest possible likelihood of RHD. Subjects included in this group required (1) proven, prior acute rheumatic fever and (2) current evidence of predefined valvular regurgitation on echocardiography. RESULTS: In the low-risk RHD cohort (n=364), the screening specificities for detecting RHD of the MM and WHF criteria were 99.7% and 95.9%, respectively (p=0.0002). The MM rule-out test excluded 359/364 cases (98.6%). In the CRS RHD-positive cohort (n=65), the screening sensitivities for the detection of definite RHD by MM and WHF criteria were 92.4% and 89.2%, respectively (p=0.2231). The MM RHD rule-out test did not exclude any cases from the CRS RHD-positive cohort. CONCLUSION: Our proposed MM approach showed an equal sensitivity to the WHF criteria but with significantly improved specificity. The MM RHD rule-out test excluded RHD-negative cases while identifying all cases within the CRS RHD-positive cohort. This holds promise for the development of a two-step RHD screening algorithm to enable task shifting in RHD endemic regions.

Among psychedelic-experienced users, only past use of psilocybin reliably predicts nature relatedness.

BACKGROUND: Past research reports a positive relationship between experience with classic serotonergic psychedelics and nature relatedness (NR). However, these studies typically do not distinguish between different psychedelic compounds, which have a unique psychopharmacology and may be used in specific contexts and with different intentions. Likewise, it is not clear whether these findings can be attributed to substance use per se or unrelated variables that differentiate psychedelic users from nonusers. AIMS: The present study was designed to determine the relative degree to which lifetime experience with different psychedelic substances is predictive of self-reported NR among psychedelic-experienced users. METHODS: We conducted a combined reanalysis of five independent datasets (N = 3817). Using standard and regularized regression analyses, we tested the relationship between degree of experience with various psychedelic substances (binary and continuous) and NR, both within a subsample of psychedelic-experienced participants as well as the complete sample including psychedelic-naïve participants. RESULTS/OUTCOMES: Among people experienced with psychedelics, only past use of psilocybin (versus LSD, mescaline, Salvia divinorum, ketamine, and ibogaine) was a reliable predictor of NR and its subdimensions. Weaker, less reliable results were obtained for the pharmacologically similar N,N-dimethyltryptamine (DMT). Results replicate when including psychedelic-naïve participants. In addition, among people exclusively experience with psilocybin, use frequency positively predicted NR. CONCLUSIONS/INTERPRETATION: Results suggest that experience with psilocybin is the only reliable (and strongest) predictor of NR. Future research should focus on psilocybin when investigating effects of psychedelic on NR and determine whether pharmacological attributes or differences in user expectations/use settings are responsible for this observation.

An enzymatic tandem reaction to produce odor-active fatty aldehydes.

Aldehydes represent a versatile and favored class of flavoring substances. A biocatalytic access to odor-active aldehydes was developed by conversion of fatty acids with two enzymes of the α-dioxygenase pathway. The recombinant enzymes α-dioxygenase (α-DOX) originating from Crocosphaera subtropica and fatty aldehyde dehydrogenase (FALDH) from Vibrio harveyi were heterologously expressed in E. coli, purified, and applied in a coupled (tandem) repetitive reaction. The concept was optimized in terms of number of reaction cycles and production yields. Up to five cycles and aldehyde yields of up to 26% were achieved. Afterward, the approach was applied to sea buckthorn pulp oil as raw material for the enzyme catalyzed production of flavoring/fragrance ingredients based on complex aldehyde mixtures. The most abundant fatty acids in sea buckthorn pulp oil, namely palmitic, palmitoleic, oleic, and linoleic acid, were used as substrates for further biotransformation experiments. Various aldehydes were identified, semi-quantified, and sensorially characterized by means of headspace-solid phase microextraction-gas chromatography-mass spectrometry-olfactometry (HS-SPME-GC-MS-O). Structural validation of unsaturated aldehydes in terms of double-bond positions was performed by multidimensional high-resolution mass spectrometry experiments of their Paternò-Büchi (PB) photoproducts. Retention indices and odor impressions of inter alia (Z,Z)-5,8-tetradecadienal (Z,Z)-6,9-pentadecadienal, (Z)-8-pentadecenal, (Z)-4-tridecenal, (Z)-6-pentadecenal, and (Z)-8-heptadecenal were determined for the first time. KEY POINTS: • Coupled reaction of Csα-DOX and VhFALDH yields chain-shortened fatty aldehydes. • Odors of several Z-unsaturated fatty aldehydes are described for the first time. • Potential for industrial production of aldehyde-based odorants from natural sources.

Acamprosate may be safer than baclofen for the treatment of alcohol use disorder in patients with cirrhosis: a first description of use in real-world clinical practice.

OBJECTIVES: Patients with alcohol use disorder (AUD) and liver cirrhosis benefit from stopping alcohol intake. Baclofen has been trialled for AUD in cirrhosis and appears to be effective. However, in patients without cirrhosis acamprosate is safer and more efficacious. Acamprosate is rarely used in cirrhosis due to safety concerns: the only published report was for 24 h in a controlled setting. Our centre uses both medications off-label in cirrhotic patients. We performed an audit to pragmatically compare the safety of acamprosate to baclofen in these patients. METHODS: The electronic records of patients prescribed acamprosate or baclofen between 01/04/17 and 31/03/20 were retrospectively reviewed. Adverse events and abstinence at last follow-up were compared by Student's t-test, Mann-Whitney U or chi-square test. Confounding variables were evaluated by logistic regression. RESULTS: In total 48 cirrhotic patients taking acamprosate (median 84 days, range 2-524); 44 baclofen (247 days, 8-910) met inclusion criteria. At baseline, 41% had Childs-Pugh B or C cirrhosis. More patients taking baclofen had an unplanned hospital admission or attendance (23 vs 13; P = 0.013) and the mean number per patient was higher (1.6 vs 0.6; P = 0.032). Sub-group analysis revealed increased admissions in actively drinking patients prescribed baclofen to achieve abstinence (mean 2.4 vs 0.6; P = 0.020); acamprosate use was associated with a reduced chance of admission or attendance (OR, 0.284; 0.095-0.854; P = 0.025) independent of treatment length. No difference in efficacy was observed. CONCLUSIONS: In patients with cirrhosis, acamprosate was associated with fewer unplanned admissions than baclofen, hence may be safer despite historical concerns.

Safety, tolerability, pharmacokinetics, and subjective effects of 50, 75, and 100 µg LSD in healthy participants within a novel intervention paradigm: A proof-of-concept study.

BACKGROUND: Classic psychedelics hold promise as therapeutics for psychiatric disorders, but require scalable intervention protocols. This proof-of-concept study evaluated the safety, tolerability, pharmacokinetics, and subjective effects of 50, 75, and 100 µg lysergic acid diethylamide (LSD) in healthy adults within a novel intervention paradigm. METHODS: Up to three participants were administered LSD on the same day in separate rooms, each with a single attendant, after 1 day of preparation. An open-label design and a double-blind placebo-controlled design were used. RESULTS: Ninety-one percent of participants completed the study. Thirty-two adults (mean age = 28.8 years) received 50 (n = 3), 75 (n = 7), 100 (n = 3) LSD, 50 µg followed by 75 µg LSD (n = 9) 1 week apart, or placebo followed by a 75 µg LSD (n = 10) 1 week apart. There were no serious adverse events. Twenty-eight percent of participants experienced at least one expected mild adverse event, with one expected moderate adverse event. The maximum blood plasma levels occurred between 1.2 and 2 h post-administration, with an apparent half-life between 2.8 and 4.3 h. LSD largely induced greater subjective effects versus placebo. CONCLUSION: In the current novel intervention paradigm, 50, 75, and 100 µg LSD are tolerable with favourable safety profiles in healthy adults, only mild adverse events during the day of drug administration, and mystical-type subjective experiences. Future studies are needed to evaluate safety, tolerability, subjective effects, and cost-effectiveness in clinical populations.

Perceptions of safety, subjective effects, and beliefs about the clinical utility of lysergic acid diethylamide in healthy participants within a novel intervention paradigm: Qualitative results from a proof-of-concept study.

BACKGROUND: Classic psychedelics show promise in the treatment of mental health conditions; however, more scalable intervention protocols are needed to maximize access to these novel therapeutics. In this proof-of-concept study, perceptions of safety, subjective effects, and beliefs about the clinical utility of lysergic acid diethylamide (LSD) were evaluated among healthy participants (N = 31) administered 50 to 100 µg LSD in a treatment paradigm conceptualized as more scalable than traditional approaches to administering classic psychedelics. METHODS: Semi-structured interviews assessed participants' expectations, experience, and thoughts on the safety and efficacy of the study design. These interviews were transcribed for thematic analysis relating to perceptions of safety, subjective effects, and beliefs about the clinical utility of LSD. RESULTS: Most participants felt safe throughout the study, with a minority reporting concerns related to having a challenging experience that diminished over time. Participants attributed their feelings of safety to the study structure and support of their attendants, which allowed them to "let go" and immerse themselves in the experience without pre-occupation. Furthermore, participants reported transcendent, mystical-type experiences characteristic of classic psychedelics, with almost half highlighting the prominent role played by music during the acute period of drug action. Finally, participants endorsed support for the clinical utility of LSD in controlled environments, expressing the belief that LSD is safe and has the potential to help others. CONCLUSION: Findings provide preliminary support for the feasibility of this scalable interventional paradigm and set the stage for future critical research with clinical populations.

Serum keratin 19 (CYFRA21-1) is a prognostic biomarker in severe alcoholic hepatitis.

BACKGROUND AND AIMS: Up to 30% of patients with severe alcoholic hepatitis (sAH) die within 3 months of presentation. The degree of ductular reaction, characterized by accumulation of biliary and liver progenitor cells, confers a poor prognosis. Keratin fragments are established serological surrogates of liver injury and keratin 19 (K19) is a histological marker of the ductular reaction. We assessed the relationship between serum K19 levels (viz. CYFRA21-1), histology and outcome in patients with sAH. METHODS: Serum CYFRA21-1 was quantified in pre-treatment serum samples from 824 patients enrolled in the STOPAH trial. The cohort was randomly divided into two groups to test mortality associations; histological analyses were performed using the 87 cases with suitable samples. RESULTS: CYFRA21-1 levels were elevated in sAH and strongly predicted alcoholic steatohepatitis (ASH) on biopsy (area under the receiver operated characteristic [AUROC] 0.785 [95% Confidence Interval 0.602-0.967]) and 90-day survival (AUROC 0.684/0.693). The predictive ability of CYFRA21-1 was comparable with the model of end-stage liver disease (MELD) score and was independently associated with survival in multivariable analysis. CYFRA21-1 moderately correlated with hepatocellular injury markers M30/M65 but displayed a more robust predictive ability. A combination of MELD and CYFRA21-1 conferred a modest improvement in the AUROC value (0.731/0.743). CONCLUSIONS: In sAH serum, CYFRA21-1 levels associate with the presence of ASH on biopsy and independently predict 90-day survival. As a single marker performance is comparable to established scoring systems. Therefore, CYFRA21-1, which is available in many clinical laboratories, may become a useful component of prognostic models.

Managing behavioural and developmental paediatric conditions in rural outpatient clinics: An insight to the challenge ahead.

AIM: The aim of this study is to characterise the nature and caseload of general paediatric outpatient clinics in rural Queensland and to compare the findings with national data. METHODS: A retrospective clinical audit of medical records in paediatric clinics at two rural hospitals was undertaken over a 6-month period. Data extracted included demographics, diagnostic category and onward referral outcomes. The same diagnostic categories were used as the national Children Attending Paediatricians Study (CAPS) to facilitate comparison. RESULTS: A total of 346 records were reviewed, 56 (16.2%) documented Aboriginal and Torres Strait Islander descent. Compared to national data, significantly more children with behavioural/developmental diagnoses were seen in the rural clinics (CAPS 33.8%; rural 59.2%; P < 0.001). In contrast, children presenting with medical conditions (CAPS 48.2%; rural 28.6%; P < 0.001) and mixed medical/developmental conditions (CAPS 17.9%; rural 12.1%; P = 0.006) were seen less frequently in the rural clinics. Referral rates from the rural sites were lower than the rates reported by CAPS for children with behavioural/developmental diagnoses (CAPS 35.9%, rural 24.9%; P = 0.002) and mixed diagnoses (CAPS 40.6%, rural 19.0%; P = 0.005), while there was no difference in referral rates for children with medical diagnoses (CAPS 16.1%, rural 18.2%; P = 0.575). CONCLUSIONS: Rural paediatricians' caseloads are dominated by developmental/behavioural conditions, however children with these conditions are less likely to be referred to allied health and psychology services. The reasons for lower referral rates and specific pressures upon rural health services need to be investigated in future studies to provide better health services for rural children.

The chemical induction of synaesthesia.

OBJECTIVE: Preliminary research suggests that experiences resembling synaesthesia are frequently reported under the influence of a diverse range of chemical substances although the incidence, chemical specificity, and characteristics of these effects are poorly understood. METHODS: Here we surveyed recreational drug users and self-reported developmental synaesthetes regarding their use of 28 psychoactive drugs from 12 different drug classes and whether they had experienced synaesthesia under the influence of these substances. RESULTS: The drug class of tryptamines exhibited the highest incidence rates of drug-induced synaesthesia in controls and induction rates of novel forms of synaesthesia in developmental synaesthetes. Induction incidence rates in controls were strongly correlated with the corresponding induction and enhancement rates in developmental synaesthetes. In addition, the use of lysergic acid diethylamide (LSD) was the strongest predictor of drug-induced synaesthesia in both controls and developmental synaesthetes. Clear evidence was observed for a clustering of synaesthesia-induction rates as a function of drug class in both groups, denoting non-random incidence rates within drug classes. Sound-colour synaesthesia was the most commonly observed type of induced synaesthesia. Further analyses suggest the presence of synaesthesia-prone individuals, who were more likely to experience drug-induced synaesthesia with multiple drugs. CONCLUSIONS: These data corroborate the hypothesized link between drug-induced synaesthesia and serotoninergic activity, but also suggest the possibility of alternative neurochemical pathways involved in the induction of synaesthesia. They further imply that the induction and modulation of synaesthesia in controls and developmental synaesthetes share overlapping mechanisms and that certain individuals may be more susceptible to experiencing induced synaesthesia with different drugs.

Spontaneous Spiritual Awakenings: Phenomenology, Altered States, Individual Differences, and Well-Being.

Spontaneous Spiritual Awakenings (SSAs) are subjective experiences characterised by a sudden sense of direct contact, union, or complete nondual merging (experience of oneness) with a perceived ultimate reality, the universe, "God," or the divine. These profound transformative experiences have scarcely been researched, despite extensive anecdotal evidence suggesting their potential to catalyse drastic, long-term, and often positive shifts in perception, world-view, and well-being. The aims of this study were to investigate the phenomenological variances of these experiences, including the potential differences between SSAs and Spontaneous Kundalini Awakenings (SKAs), a subset of awakening experiences that the authors postulate may produce a higher likelihood of both physical and negative effects; to explore how these experiences compare to other altered states of consciousness (ASCs), including those mediated by certain psychedelic substances; and understand their impact on well-being. Personality trait absorption and temporal lobe lability (TLL) were assessed as predictors of Spontaneous Spiritual and Kundalini Awakenings (SSA/SKAs). A mixed within and between-participants self-report survey design was adopted. A total of 152 participants reporting their most powerful SSA/SKAs completed questionnaires measuring nondual, kundalini, and mystical experience, as well as depth of ASC, and trait absorption and TLL. Spontaneous Kundalini Awakenings were found to be significantly more physical, but not significantly more negative than SSAs, and overall, both sets of experiences were perceived to be overwhelmingly more positive than negative, even in cases where the experience was initially challenging. The phenomenological distribution of SSA/SKAs was similar to other measured ASCs although greater in magnitude, and appeared most similar in distribution and in magnitude to drug-induced ASCs, particularly classic psychedelics DMT and psilocybin. Temporal lobe lability and trait absorption were found to predict the SSA/SKA experience. The limitations and implications of these findings are discussed.

The variable spectrum of anterior mitral valve leaflet restriction in rheumatic heart disease screening.

INTRODUCTION: The World Heart Federation (WHF) screening criteria do not incorporate a strict, reproducible definition of anterior mitral valve leaflet (AMVL) restriction. Using a novel definition, we have identified two distinct AMVL restriction configurations. The first, called "distal tip" AMVL restriction is associated with additional morphological features of rheumatic heart disease (RHD), while the second, "gradual bowing" AMVL restriction is not. This "arch-like" leaflet configuration involves the base to tip of the medial MV in isolation. We hypothesize that this configuration is a normal variant. METHODOLOGY: The prevalence and associated leaflet configurations of AMVL restriction were assessed in schoolchildren with an established "very low" (VLP), "high" (HP), and "very high" prevalence (VHP) of RHD. RESULTS: 936 studies were evaluated (HP 577 cases; VLP 359 cases). Sixty-five cases of "gradual bowing" AMVL restriction were identified in the HP cohort (11.3%, 95% CI 8.9-14.1) and 35 cases (9.7%, 95% CI 7-13.2) in the VLP cohort (P = .47). In the second analyses, an enriched cohort of 43 studies with proven definite RHD were evaluated. "Distal tip" AMVL restriction was identified in all 43 VHP cases (100%) and affected the central portion of the AMVL in all cases. CONCLUSION: "Gradual bowing" AMVL restriction appears to be a normal, benign variant of the MV, not associated with RHD risk nor with any other morphological features of RHD. Conversely, "Distal tip" AMVL restriction was present in all cases in the VHP cohort with no cases exhibiting a straight, nonrestricted central portion of the AMVL. This novel finding requires further investigation as a potential RHD rule-out test of the MV.

An Encounter With the Other: A Thematic and Content Analysis of DMT Experiences From a Naturalistic Field Study.

Introduction: N,N-dimethyltryptamine (DMT) is an endogenous serotonergic psychedelic capable of producing radical shifts in conscious experience. Increasing trends in its use, as well as new trials administering DMT to patients, indicate the growing importance of a thorough elucidation of the qualitative content, over and above structure, which the drug occasions. This is particularly in light of the hyper-real, otherworldly, and often ontologically challenging yet potentially transformative, nature of the experience, not least encounters with apparently non-self social agents. Laboratory studies have been limited by clinical setting and lacking qualitative analyses of experiential content, while online surveys' limitations lie in retrospective design, uncontrolled use, and both of which not guaranteeing 'breakthrough' experiences, i.e., producing very strong psychoactive effects. Methods: We report on the first naturalistic field study of DMT use including its qualitative analysis. Screened, healthy, anonymised and experienced DMT users were observed during their non-clinical use of the drug at home (40-75 mg inhaled). In-depth semi-structured interviews (inspired by the micro-phenomenological technique) were employed immediately after their experience. This paper reports on the thematic analysis of one major domain of the breakthrough experiences elicited, the 'other'. Thirty-six post-DMT experience interviews with mostly Caucasian (83%) males (eight female) of average 37 years were predominantly inductively coded. Results: Invariably, profound and highly intense experiences occurred. The first overarching category comprised the encounter with other 'beings' (94% of reports), encompassing super-ordinate themes including the entities' role, appearance, demeanour, communication and interaction; while the second overarching category comprised experiences of emerging into other 'worlds' (100% of reports), encompassing super-ordinate themes of the scene, the contents and quality of the immersive spaces. Many further mid-level themes and subthemes also illuminate the rich content of the DMT experience. Discussion: The present study provides a systematic and in-depth analysis of the nuanced content of the otherworldly encounter within the breakthrough DMT experience, as well as elaborating on the resonances both with previous DMT studies focusing on entity encounters and other types of extraordinary experiences entailing such encounters. These include the alien abduction, folkloric, shamanic and near-death experience. Putative neural mechanisms of these features of the DMT experience and its promise as a psychotherapeutic agent are discussed in light of such findings.