Assessing the effect of interpretation design traits on zoo visitor engagement.

In the past few decades, zoos have undergone a transformation from places of entertainment to centers for conservation, with education becoming a particular focus. Interpretation in zoos is a near-universal method for delivering education in zoos and has been shown to prompt learning and pro-conservation behavior change. However, there is limited understanding on how interpretation design itself can influence visitor engagement. Using unobtrusive visitor observations (n = 3890), this study measures visitor engagement of multiple pieces of interpretation with various design "traits," to provide a comprehensive overview of the key traits related to increased visitor engagement. The proportion of visitors who stopped at the interpretation (attraction power), and how long they stopped for (holding power), were our two outcome variables. From our models, we found that attraction and holding power are most strongly influenced by the type of interpretation, with interactive interpretation seeing nearly four times as many visitors stop, and for more than six times longer, when compared to standard text and graphics interpretation. We also found that location was significantly related to attraction power, with visitors more likely to stop at interpretation in more immersive exhibits. Lastly, interpretation containing images of humans were related to a higher holding power. We hope our findings will be used as a guide for designing interpretation that is both attractive and interesting to zoo visitors, maximizing the conservation education value of zoo-based interpretation.

Characterisation of sensor kinase by CD spectroscopy: golden rules and tips.

This is a review that describes the golden rules and tips on how to characterise the molecular interactions of membrane sensor kinase proteins with ligands using mainly circular dichroism (CD) spectroscopy. CD spectroscopy is essential for this task as any conformational change observed in the far-UV (secondary structures (α-helix, ß-strands, poly-proline of type II, ß-turns, irregular and folding) and near-UV regions [local environment of the aromatic side-chains of amino acid residues (Phe, Tyr and Trp) and ligands (drugs) and prosthetic groups (porphyrins, cofactors and coenzymes (FMN, FAD, NAD))] upon ligand addition to the protein can be used to determine qualitatively and quantitatively ligand-binding interactions. Advantages of using CD versus other techniques will be discussed. The difference CD spectra of the protein-ligand mixtures calculated subtracting the spectra of the ligand at various molar ratios can be used to determine the type of conformational changes induced by the ligand in terms of the estimated content of the various elements of protein secondary structure. The highly collimated microbeam and high photon flux of Diamond Light Source B23 beamline for synchrotron radiation circular dichroism (SRCD) enable the use of minimal amount of membrane proteins (7.5 µg for a 0.5 mg/ml solution) for high-throughput screening. Several examples of CD titrations of membrane proteins with a variety of ligands are described herein including the protocol tips that would guide the choice of the appropriate parameters to conduct these titrations by CD/SRCD in the best possible way.

Chaperone-like effect of ceftriaxone on HEWL aggregation: A spectroscopic and computational study.

BACKGROUND: Lysozyme is a widely distributed enzyme present in a variety of tissue and body fluids. Human and hen egg white lysozyme are used as validated model to study protein folding and stability and to understand protein misfolding and aggregation. We recently found that ceftriaxone, a ß-lactam antibiotic able to overcome the blood-brain barrier, successfully eliminated the cellular toxic effects of misfolded proteins as Glial Fibrillary Acidic Protein (GFAP) and α-synuclein. To further understand the anti-amyloidogenic properties of ceftriaxone, we studied its activity towards lysozyme aggregation with the aim to investigate a possible chaperone-like activity of this molecule. METHODS: Here we present the results obtained from fluorescence and synchrotron radiation circular dichroism spectroscopies and from molecular docking and molecular dynamics about the lysozyme-ceftriaxone interaction at neutral and acidic pH values. RESULTS: We found that ceftriaxone exhibits comparable affinity constants to lysozyme in both experimental pH conditions and that its addition enhanced lysozyme stability reducing its aggregation propensity in acidic conditions. Computational methods allowed the identification of the putative binding site of ceftriaxone, thus rationalizing the spectroscopic results. CONCLUSIONS: Spectroscopy data and molecular dynamics indicated a protective effect of ceftriaxone on pathological aggregation phenomena suggesting a chaperone-like effect of this molecule on protein folding. General significance These results, in addition to our previous studies on α-synuclein and GFAP, confirm the property of ceftriaxone to inhibit the pathological protein aggregation of lysozyme also by a chaperone-like mechanism, extending the potential therapeutic application of this molecule to some forms of human hereditary systemic amyloidosis.

Lack of durable disease control with chemotherapy for mycosis fungoides and Sézary syndrome: a comparative study of systemic therapy.

Numerous systemic treatment options exist for patients with mycosis fungoides (MF) and Sézary syndrome (SS), but no large comparative studies are published. To study the efficacy of treatments, a retrospective analysis of our cutaneous lymphoma database was undertaken, with 198 MF/SS patients undergoing systemic therapies. The primary end point was time to next treatment (TTNT). Patients with advanced-stage disease made up 53%. The median follow-up time from diagnosis for all alive patients was 4.9 years (range 0.3-39.6), with a median survival of 11.4 years. Patients received a median of 3 lines of therapy (range 1-13), resulting in 709 treatment episodes. Twenty-eight treatment modalities were analyzed. The median TTNT for single- or multiagent chemotherapy was only 3.9 months (95% confidence interval [CI] 3.2-5.1), with few durable remissions. α-interferon gave a median TTNT of 8.7 months (95% CI 6.0-18.0), and histone deacetylase inhibitors (HDACi) gave a median TTNT of 4.5 months (95% CI 4.0-6.1). When compared directly with chemotherapy, interferon and HDACi both had greater TTNT (P < .00001 and P = .01, respectively). This study confirms that all chemotherapy regimens assessed have very modest efficacy; we recommend their use be restricted until other options are exhausted.

Purification of bacterial membrane sensor kinases and biophysical methods for determination of their ligand and inhibitor interactions.

This article reviews current methods for the reliable heterologous overexpression in Escherichia coli and purification of milligram quantities of bacterial membrane sensor kinase (MSK) proteins belonging to the two-component signal transduction family of integral membrane proteins. Many of these methods were developed at Leeds alongside Professor Steve Baldwin to whom this review is dedicated. It also reviews two biophysical methods that we have adapted successfully for studies of purified MSKs and other membrane proteins-synchrotron radiation circular dichroism (SRCD) spectroscopy and analytical ultracentrifugation (AUC), both of which are non-immobilization and matrix-free methods that require no labelling strategies. Other techniques such as isothermal titration calorimetry (ITC) also share these features but generally require high concentrations of material. In common with many other biophysical techniques, both of these biophysical methods provide information regarding membrane protein conformation, oligomerization state and ligand binding, but they possess the additional advantage of providing direct assessments of whether ligand binding interactions are accompanied by conformational changes. Therefore, both methods provide a powerful means by which to identify and characterize inhibitor binding and any associated protein conformational changes, thereby contributing valuable information for future drug intervention strategies directed towards bacterial MSKs.

Mycosis fungoides and Sézary syndrome: Current challenges in assessment, management and prognostic markers.

Mycosis fungoides and Sézary syndrome are the most common variants of the cutaneous T-cell lymphomas. Assessment of a patient with a suspected diagnosis requires thorough history taking and physical examination, in combination with skin biopsy. In some cases flow cytometry, molecular studies and imaging are also required in order to diagnose and stage the disease. Staging is derived from the tumour-node-metastasis-blood classification and is currently our best attempt to stratify prognosis and hence guide management in this complex disease. Many other clinical, biological and pathological factors may help to distinguish groups at risk and predict prognosis more accurately. Management remains heavily guided by staging, such that patients with early-stage disease generally begin treatment with skin-directed or local therapies and those with advanced-stage disease have many treatment options, including chemotherapy, the use of biological agents, local and total body radiotherapy, as well as haematopoietic stem cell transplantation. Besides staging, many other patient-related factors influence the treatment strategy, particularly where symptom relief is paramount. There are many challenges remaining in the study of Mycosis fungoides and Sézary syndrome and, given the rarity of the disease, concerted worldwide efforts are required to conduct efficient and effective research.

Is Stent on a String the New Gold Standard for Postureteroscopy Ureteral Drainage? Evidence from a Systematic Review.

Introduction: Ureteral stents are widely used throughout urologic surgery, most commonly following ureteroscope (URS) procedures. This systematic review aims to assess the current evidence concerning stent on string (SOS) placed after URS and compare it with stents without strings (SWOSs). Methods: A systematic review was conducted on several databases using the preferred reporting items for systematic review and meta-analysis (PRISMA) methodology for studies in English language, for patients of all age groups, who had an SOS after URS for stone disease. Results: Of 1210 records identified, a total of 22 studies (20 adult and 2 pediatric studies) were included, with a total of 8382 patients. Of these, 3427 (40.9%) had SOSs inserted and 434 (11%) were in the pediatric age group. Our results show that SOS provides several advantages, and compared with SWOS, they were in situ for less time, with no difference in complications such as urinary tract infection or urinary symptoms. Furthermore, significant cost savings, less pain on removal, and high rates of safe home removal were reported in SOS, with >90% patients reporting that they would be happy to remove their SOSs at home. However, a small risk of stent dislodgment must be considered when making decisions regarding SOS placement after URS. Conclusion: SOS provides an excellent option after URS, especially in those patients with no intraoperative complication, and their placement is done as a routine insertion based on surgeon preference. These stents reduce dwell time, pain, cost, risks, and suffering involved from prolonged stenting, and majority of patients are happy to remove it themselves at home. Although their use seems to be still restricted in the current endourology practices, they are likely to become the new gold standard for routine URS in future, with more shared decision making and patient-reported outcome measures coming into the mainstream.

Correction of curvature in single stage hypospadias repair with foreskin reconstruction.

INTRODUCTION: Many surgeons offer foreskin reconstruction (FR) as a routine part of hypospadias repair. We present a step-by-step video of the procedure of Tubularised Incised Plate (TIP) repair, FR and dorsal plication through a ventral skin incision. MATERIALS AND METHODS: A ventral incision is made between the inner preputial mucosa and the outer skin extending below the meatus. Ventral degloving is carried out. The dissection is extended laterally around the corporal bodies. The point of maximal curvature (PMC) is marked on the dorsal midline. A vertical incision is made and closed transversely with 5-0 prolene suture in a Heineke- Mikulicz fashion. Urethroplasty is performed in 2 layers using 7-0 polydioxanone (PDS). Spongioplasty and ventral dartos are used as barrier layers. Glansplasty is performed in 2 layers.FR is carried out in 3 layers. DISCUSSION: Curvature correction is key to good outcome. Dorsal degloving can be achieved through a ventral incision allowing exposure of the dorsal midline for plication sutures. RESULTS: The patient had good cosmetic and functional outcome at 1 month follow up. CONCLUSION: FR can be safely performed during TIP repair for distal hypospadias repair. Curvature of less than 30° can be corrected through a ventral incision only.

Autologous hematopoietic stem cell transplantation for multiple myeloma in the age of CAR T cell therapy.

Chimeric antigen receptor (CAR) T cell therapy has revolutionized the management of relapsed and refractory myeloma, with excellent outcomes and a tolerable safety profile. High dose chemotherapy with autologous hematopoietic stem cell transplantation (AHCT) is established as a mainstream of newly diagnosed multiple myeloma (NDMM) management in patients who are young and fit enough to tolerate such intensity. This standard was developed based on randomized trials comparing AHCT to chemotherapy in the era prior to novel agents. More recently, larger studies have primarily shown a progression free survival (PFS) benefit of upfront AHCT, rather than overall survival (OS) benefit. There is debate about the significance of this lack of OS, acknowledging the potential confounders of the chronic nature of the disease, study design and competing harms and benefits of exposure to AHCT. Indeed upfront AHCT may not be as uniquely beneficial as we once thought, and is not without risk. New quadruple-agent regimens are highly active and effective in achieving a deep response as quantified by measurable residual disease (MRD). The high dose chemotherapy administered with AHCT imposes a burden of short and long-term adverse effects, which may alter the disease course and patient's ability to tolerate future therapies. Some high-risk subgroups may have a more valuable benefit from AHCT, though still ultimately suffer poor outcomes. When compared to the outcomes of CAR T cell therapy, the question of whether AHCT can or indeed should be deferred has become an important topic in the field. Deferring AHCT may be a personalized decision in patients who achieve MRD negativity, which is now well established as a key prognostic factor for PFS and OS. Reserving or re-administering AHCT at relapse is feasible in many cases and holds the promise of resetting the T cell compartment and opening up options for immune reengagement. It is likely that personalized MRD-guided decision making will shape how we sequence in the future, though more studies are required to delineate when this is safe and appropriate.

Blast Exposure Associations With Hearing Loss and Self-Reported Hearing Difficulty.

OBJECTIVE: Examine associations between military blast exposures on hearing loss and self-reported hearing difficulties among Active-Duty Service Members (ADSM) and Veterans from the Noise Outcomes in Servicemembers Epidemiology (NOISE) study. STUDY DESIGN: Cross-sectional. SETTING: Multi-institutional tertiary referral centers. METHODS: Blast exposure was assessed with a comprehensive blast questionnaire. Outcome measures included pure-tone hearing thresholds; Speech Recognition in Noise Test; Hearing Handicap Inventory for Adults (HHIA); and Speech, Spatial and Qualities of Hearing Scale (SSQ)-12. RESULTS: Twenty-one percent (102/494) of ADSM and 36.8% (196/533) of Veterans self-reported blast exposure. Compared to ADSM without blast exposure, blast-exposed ADSM had increased odds of high frequency (3-8 kHz) and extended-high frequency (9-16 kHz) hearing loss (odds ratio [OR] = 2.5, CI: 1.3, 4.7; OR = 3.7, CI: 1.9, 7.0, respectively). ADSM and Veterans with blast exposure were more likely than their nonblast exposed counterparts to report hearing difficulty on the HHIA (OR = 1.9, CI: 1.1, 3.3; OR = 2.1, CI: 1.4, 3.2, respectively). Those with self-reported blast exposure also had lower SSQ-12 scores (ADSM mean difference = -0.6, CI: -1.0, -0.1; Veteran mean difference: -0.9, CI: -1.3, -0.5). CONCLUSION: Results suggest that blast exposure is a prevalent source of hearing injury in the military. We found that among ADSM, blast exposure was associated with hearing loss, predominately in the higher frequencies. Blast exposure was associated with poorer self-perceived hearing ability in ADSM and Veterans. IRB: #FWH20180143H Joint Base San Antonio (JBSA) Military Healthcare System; #3159/9495 Joint VA Portland Health Care System (VAPORHCS) Oregon Health and Science University (OHSU).

Can paediatric surgical registrars safely perform supervised hypospadias surgery?

INTRODUCTION: Hypospadias repair is regarded as a technically demanding, complex procedure, with variable outcomes. Therefore, it tends to be performed by consultants, with limited trainee involvement. We aimed to study the clinical outcomes of supervised registrars performing proximal and distal hypospadias repairs, compared to their consultant mentors. METHODS: We undertook a retrospective review of all primary hypospadias repairs performed between April 2013-April 2022 at our tertiary paediatric urology centre. Redo repairs and patients lost to follow-up were excluded. Pre-operative anatomy, theatre time, grade of primary surgeon (registrar (trainees and non-training middle grades) or consultant), operative technique, follow-up duration, complications, and reoperation rates were recorded. The procedures were assessed in two groups according to the primary operator: registrar or consultant. The Zwisch scale is used to describe level of consultant support. Registrars as primary operators received "passive help" or "supervision" (Zwisch levels 3/4). Consultants as primary operators provided registrars with "show-and-tell" or "active help" (Zwisch levels 1/2). RESULTS: 270 procedures performed on 228 patients met the inclusion criteria. 109 were performed by registrars and 161 by consultants. In both groups, median age was two years (p = 0.23). Median theatre time was similar (registrars 2.8 h vs. consultants 2.7 h, p = 0.88), as was median follow-up (registrars 25months, vs. consultants 21months, p = 0.99). Operations performed by registrars were 76% distal and 24% proximal; and by consultants were 62% distal and 38% proximal. The overall urethroplasty complication rate was similar, at 24% for registrars and 23% for consultants (p = 0.89). The summary table shows the distribution of different complications. Re-operation rate was 16% in both groups (p = 0.99). Complications were further assessed according to operation type (TIP vs. two-stage repair). DISCUSSION: Contrary to popular belief amongst hypospadiologists, we found complication rates were similar for registrar and consultant surgeons. We question that involvement of registrars increases complications. The literature demonstrates safety of trainee performance of limited steps of the procedure. However our institution permits registrars to perform up to the whole hypospadias repair under direct supervision, with no predefined limit to their involvement. CONCLUSION: Paediatric surgical registrars can be safely supervised to have substantial involvement in proximal and distal hypospadias repair, without compromising the duration or outcomes of surgery. We hope that allowing more registrar involvement can lead to faster acquisition of surgical skills, whilst remaining under the safety of senior supervision. Increasing opportunities for those with an aptitude for hypospadias repair can equip them with skills and confidence for entering fellowship training.

Military and Nonmilitary TBI Associations with Hearing Loss and Self-Reported Hearing Difficulty among Active-Duty Service Members and Veterans.

OBJECTIVE: Identify associations between self-reported history of military and nonmilitary traumatic brain injury (TBI) on hearing loss and hearing difficulty from the Noise Outcomes in Servicemembers Epidemiology (NOISE) study. STUDY DESIGN: Cross-sectional. SETTING: Multi-institutional tertiary referral centers. PATIENTS: Four hundred seventy-three Active-Duty Service members (ADSM) and 502 veterans. EXPOSURE: Self-reported history of no TBI, military TBI only, nonmilitary TBI only, both military and nonmilitary TBI. MAIN OUTCOME MEASURES: Pure-tone hearing thresholds, Speech Recognition In Noise Test (SPRINT), Hearing Handicap Inventory for Adults (HHIA), and Speech, Spatial and Qualities of Hearing Scale (SSQ)-12. RESULTS: 25% (120/473) of ADSM and 41% (204/502) of veterans self-reported a TBI. Military TBI was associated with poorer hearing thresholds in all frequency ranges in veterans (adjusted mean difference, 1.8 dB; 95% confidence interval [CI], 0.5-3.0; 3.3, 0.8-5.8; 5.1; 1.7-8.5, respectively), and in the high frequency range in ADSM (mean difference, 3.2 dB; 95% CI, 0.1-6.3). Veterans with military TBI only and nonmilitary TBI only had lower odds of correctly identifying speech in noise than veterans with no TBI (odds ratio [OR], 0.78; 95% CI, 0.72-0.83; 0.90; 0.84-0.98). ADSM with a military TBI (OR, 5.7; 95% CI, 2.6-12.5) and veterans with any TBI history (OR, 2.5; 95% CI, 1.5-4.3; OR, 2.2; 95% CI, 1.3-3.8; OR, 4.5; 95% CI, 2.1-9.8) were more likely to report hearing difficulty on HHIA. SSQ-12 results corroborated HHIA findings. CONCLUSIONS: Military TBI was associated with poorer hearing thresholds in veterans and ADSM, and poorer SPRINT scores in veterans. Military TBI was associated with poorer self-perceived hearing ability in ADSM. All types of TBI were associated with poorer self-perceived hearing ability in veterans, although the strength of this association was greatest for military TBI.

Can critical care transport be safely reduced in children intubated during emergency management of status epilepticus in the United Kingdom: a national audit with case-control analysis.

OBJECTIVE: This study describes the baseline clinical characteristics, predictors of successful extubation at referring hospitals and short-term outcomes of children intubated for status epilepticus and referred to United Kingdom (UK) paediatric critical care transport teams (PCCTs). DESIGN: Multicentre audit with case-control analysis, conducted between 1 September 2018 and 1 September 2020. SETTING: This study involved 10 UK PCCTs. PATIENTS: Children over 1 month of age intubated during emergency management for status epilepticus (SE), referred to UK PCCTs. Patients with trauma, requiring time-critical neurosurgical intervention or those with a tracheostomy were excluded. INTERVENTIONS: No interventions were implemented. MEASUREMENTS AND MAIN RESULTS: Out of the 1622 referrals for SE, 1136 (70%) were intubated at referral. The median age was 3 years (IQR 1.25-6.54 years). Among the intubated children, 396 (34.8%) were extubated locally by the referring team, with 19 (4.8%) requiring reintubation. Therefore, the overall rate of successful extubation was 33% (377/1136). There was significant variation between PCCTs, with local extubation rates ranging from 2% to 74%. Multivariable analyses showed region/PCCT, contributing diagnosis, acute changes on CT, preceding encephalopathy and type of continuous sedation (midazolam) used postintubation were significantly associated with transfer to a critical care unit. CONCLUSION: This study highlights wide regional variation in early extubation practices. Regions with high successful extubation rates have established extubation guidelines from PCCTs. Successful extubation represents critical care transports that have been avoided.

The Hidden Enemy: Mal de Débarquement Syndrome and Its Impact on Military Operations.

Mal de Débarquement Syndrome (MdDS) is a poorly understood vestibular disorder that frequently affects military personnel exposed to motion during transportation and deployment. It is characterized by a persistent sensation of motion often experienced after disembarking from a ship or other mode of transportation. It can significantly affect a service member's balance, coordination, attention, and focus, which can then substantially impact their quality of life, ability to perform their military duties, and overall mission readiness. Despite its potential impact, comprehensive studies on MdDS are scarce, especially within the military. The unique conditions of military service, including frequent travel, long flights, maritime deployments, and high-stress environments, make the military well suited to study MdDS. Increased awareness and understanding of MdDS is crucial for everyone in the military-from medical personnel responsible for the diagnosis and treatment of MdDS to commanders who must consider the operational impact of impaired personnel.

Vocal Fold Thinning in Transgender Patients.

PURPOSE: Transgender individuals strive to match their voice and gender identity. An increased glottal gap is often noted on stroboscopy without a clear etiology. We hypothesize this gap can be quantified and results from hormone replacement therapy impacting laryngeal tissues. METHODS: Videostroboscopy exams were retrospectively collected for transgender patients from a tertiary care laryngology practice over two years. Data included hormone duration/type and voice therapy duration. Modal pitch videostroboscopy frame counts determined the open quotient in consecutive vocal fold cycles. Glottal opening was measured using the widest still frame gap during stroboscopy with fully adducted arytenoids. RESULTS: Sixteen transgender patients, along with male and female controls, were included, with 15 patients on hormone therapy (mean = 18 months). Voice therapy, employed in 9/16 patients, ranged from 0 to 23 months (mean = 10.67). One-way ANOVA testing revealed a difference between the open quotient in transgender individuals, males, and females.Tukey's post hoc test identified transgender patients as different from both male (P <0.001) and female (P = 0.037) controls. Length of hormone therapy did not correlate to glottal area measurement or open quotient. Conversely, voice therapy length correlated to increased glottal area (Kendall's Tau = 0.03). Mean phonation time, VHI-10, and mean pitch did not correlate to measured glottal area on stroboscopy. CONCLUSIONS: The increased glottal gap noted in many transgender patients, quantified via the open quotient, differs from male and female controls. Results suggest these findings may correlate to duration of voice therapy.

Pharmacokinetics of N,N-dimethyltryptamine in Humans.

BACKGROUND AND OBJECTIVE: N,N-dimethyltryptamine (DMT) is a psychedelic compound under development for the treatment of major depressive disorder (MDD). This study evaluated the preclinical and clinical pharmacokinetics and metabolism of DMT in healthy subjects. METHODS: The physiochemical properties of DMT were determined using a series of in vitro experiments and its metabolic profile was assessed using monoamine oxidase (MAO) and cytochrome P450 (CYP) inhibitors in hepatocyte and mitochondrial fractions. Clinical pharmacokinetics results are from the phase I component of a phase I/IIa randomised, double-blind, placebo-controlled, parallel-group, dose-escalation trial (NCT04673383). Healthy adults received single escalating doses of DMT fumarate (SPL026) via a two-phase intravenous (IV) infusion. Dosing regimens were calculated based on pharmacokinetic modelling and predictions with progression to each subsequent dose level contingent upon safety and tolerability. RESULTS: In vitro clearance of DMT was reduced through the inhibition of MAO-A, CYP2D6 and to a lesser extent CYP2C19. Determination of lipophilicity and plasma protein binding was low, indicating that a high proportion of DMT is available for distribution and metabolism, consistent with the very rapid clinical pharmacokinetics. Twenty-four healthy subjects received escalating doses of DMT administered as a 10-min infusion over the dose range of 9-21.5 mg (DMT freebase). DMT was rapidly cleared for all doses: mean elimination half-life was 9-12 min. All doses were safe and well tolerated and there was no relationship between peak DMT plasma concentrations and body mass index (BMI) or weight. CONCLUSION: This is the first study to determine, in detail, the full pharmacokinetics profile of DMT following a slow IV infusion in humans, confirming rapid attainment of peak plasma concentrations followed by rapid clearance. These findings provide evidence which supports the development of novel DMT infusion regimens for the treatment of MDD. CLINICAL TRIAL REGISTRATION: Registered on ClinicalTrials.gov (NCT04673383).

Safety, tolerability, pharmacodynamic and wellbeing effects of SPL026 (dimethyltryptamine fumarate) in healthy participants: a randomized, placebo-controlled phase 1 trial.

Background: Due to their potential impact on mood and wellbeing there has been increasing interest in the potential of serotonergic psychedelics such as N,N-dimethyltryptamine (DMT) in the treatment of major depressive disorder (MDD). Aim: The aim of Part A of this study was to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamic (PD) profile of escalating doses of SPL026 (DMT fumarate) in psychedelic-naïve healthy participants to determine a dose for administration to patients with MDD in the subsequent Phase 2a part of the trial (Part B: not presented in this manuscript). Methods: In the Phase 1, randomized, double-blind, placebo-controlled, parallel-group, single dose-escalation trial, psychedelic-naïve participants were randomized to placebo (n = 8) or four different escalating doses [9, 12, 17 and 21.5 mg intravenously (IV)] of SPL026 (n = 6 for each dose) together with psychological support from 2 therapy team members. PK and acute (immediately following dosing experience) psychometric measures [including mystical experience questionnaire (MEQ), ego dissolution inventory (EDI), and intensity rating visual analogue scale (IRVAS)] were determined. Additional endpoints were measured as longer-term change from baseline to days 8, 15, 30 and 90. These measures included the Warwick and Edinburgh mental wellbeing scale and Spielberger's state-trait anxiety inventory. Results: SPL026 was well tolerated, with an acceptable safety profile, with no serious adverse events. There was some evidence of a correlation between maximum plasma concentration and increased IRVAS, MEQ, and EDI scores. These trends are likely to require confirmation in a larger sample size. Using the analysis of the safety, tolerability, PD, PK results, doses of 21.5 mg SPL026 were the most likely to provide an intense, tolerated experience. Conclusion: Based on the data obtained from this part of the trial, a dose of 21.5 mg SPL026 given as a 2-phase IV infusion over 10 min (6 mg/5 min and 15.5 mg/5 min) was selected as the dose to be taken into patients in Part B (to be presented in a future manuscript).Clinical trial registration:www.clinicaltrials.gov, identifier NCT04673383; https://www.clinicaltrialsregister.eu, identifier 2020-000251-13; https://www.isrctn.com/, identifier ISRCTN63465876.

Social Media and Cyber-Bullying in Autistic Adults.

Social media can lead to rejection, cyber-bullying victimisation, and cyber-aggression, and these experiences are not fully understood as experienced by autistic adults. To investigate this, 78 autistic adults completed self-report measures of social media use, cyber-bullying victimisation, cyber-aggression, and self-esteem. High levels of social media use were found to be associated with an increased risk of cyber-victimisation; whereas self-esteem was positively correlated with feelings of belonging to an online community and negatively correlated with feelings of being ignored on social network sites and chat rooms. Future studies are needed to further investigate the experience of cyber-bullying victimisation of autistic adults.

CLK1/CLK2-driven signalling at the Leishmania kinetochore is captured by spatially referenced proximity phosphoproteomics.

Kinetochores in the parasite Leishmania and related kinetoplastids appear to be unique amongst eukaryotes and contain protein kinases as core components. Using the kinetochore kinases KKT2, KKT3 and CLK2 as baits, we developed a BirA* proximity biotinylation methodology optimised for sensitivity, XL-BioID, to investigate the composition and function of the Leishmania kinetochore. We could detect many of the predicted components and also discovered two novel kinetochore proteins, KKT24 and KKT26. Using KKT3 tagged with a fast-acting promiscuous biotin ligase variant, we took proximity biotinylation snapshots of the kinetochore in synchronised parasites. To quantify proximal phosphosites at the kinetochore as the parasite progressed through the cell cycle, we further developed a spatially referenced proximity phosphoproteomics approach. This revealed a group of phosphosites at the kinetochore that were highly dynamic during kinetochore assembly. We show that the kinase inhibitor AB1 targets CLK1/CLK2 (KKT10/KKT19) in Leishmania leading to defective cytokinesis. Using AB1 to uncover CLK1/CLK2 driven signalling pathways important for kinetochore function at G2/M, we found a set of 16 inhibitor responsive kinetochore-proximal phosphosites. Our results exploit new proximity labelling approaches to provide a direct analysis of the Leishmania kinetochore, which is emerging as a promising drug target.