Psilocybin therapy has recently emerged as a promising new treatment for depression and other mental health disorders. This chapter summarizes the most recent data on its safety and efficacy. The delivery of psilocybin therapy and its subjective effects are also presented. Furthermore, this chapter outlines our current understanding of psilocybin’s pharmacology and neurobiological effects. Other similar psychedelic substances with encouraging therapeutic potential are briefly presented.

Climate models are biased with respect to real-world observations. They usually need to be adjusted before being used in impact studies. The suite of statistical methods that enable such adjustments is called bias correction (BC). However, BC methods currently struggle to adjust temporal biases. Because they mostly disregard the dependence between consecutive time points. As a result, climate statistics with long-range temporal properties, such as the number of heatwaves and their frequency, cannot be corrected accurately. This makes it more difficult to produce reliable impact studies on such climate statistics. This article offers a novel BC methodology to correct temporal biases. This is made possible by rethinking the philosophy behind BC. We will introduce BC as a time-indexed regression task with stochastic outputs. Rethinking BC enables us to adapt state-of-the-art machine learning (ML) attention models and thereby learn different types of biases, including temporal asynchronicities. With a case study of number of heatwaves in Abuja, Nigeria and Tokyo, Japan, we show more accurate results than current climate model outputs and alternative BC methods.

Background: Despite the utility of administrative health data, there remains a lack of patient-centered outcome measures to meaningfully capture morbidity after traumatic brain injury (TBI). We sought to characterize and validate days at home (DAH) as a feasible measure to assess population-level moderate to severe TBI (msTBI) outcomes and health resource utilization. Methods: We utilized linked health administrative data sources to identify adults with msTBI patients presenting to trauma centers in Ontario injured between 2009-2021. DAH at 180 days reflects the total number of days spent alive and at home excluding the days spent institutionalized in acute care, rehabilitation, inpatient mental health settings or post-acute readmissions. Construct and predictive validity were determined; we additionally estimated minimally important difference (MID) in DAH180days. Results: There were 6340 patients that met inclusion criteria. Median DAH180days were 70 days (interquartile range 0-144). Increased health resource utilization at baseline, older age, increasing cranial injury severity and major extracranial injuries were significantly associated with fewer DAH180days. DAH180days was correlated to DAH counts at 1-3 years. The average MID estimate from anchor-based and distribution-based methods was 18 days. Conclusions: We introduce DAH180days as a feasible and sufficiently responsive patient-centered outcome measure with construct, predictive and face validity in an msTBI population.

Background: The late-onset cerebellar ataxias (LOCAs) have until recently resisted molecular diagnosis. Contributing to this diagnostic gap is that non-coding structural variations, such as repeat expansions, are not fully accessible to standard short-read sequencing analysis. Methods: We combined bioinformatics analysis of whole-genome sequencing and long-read sequencing to search for repeat expansions in patients with LOCA. We enrolled 66 French-Canadian, 228 German, 20 Australian and 31 Indian patients. Pathogenic mechanisms were studied in post-mortem cerebellum and induced pluripotent stem cell (iPSC)-derived motor neurons from 2 patients. Results: We identified 128 patients who carried an autosomal dominant GAA repeat expansion in the first intron of the FGF14 gene. The expansion was present in 61%, 18%, 15% and 10% of patients in the French-Canadian, German, Australian and Indian cohorts, respectively. The pathogenic threshold was determined to be (GAA)≥250, although incomplete penetrance was observed in the (GAA)250-300 range. Patients developed a slowly progressive cerebellar syndrome at an average age of 59 years. Patient-derived post-mortem cerebellum and induced motor neurons both showed reduction in FGF14 RNA and protein expression compared to controls. Conclusions: This intronic, dominantly inherited GAA repeat expansion in FGF14 represents one of the most common genetic causes of LOCA uncovered to date.

Frontal ablation, the combination of submarine melting and iceberg calving, changes the geometry of a glacier's terminus, influencing glacier dynamics, the fate of upwelling plumes and the distribution of submarine meltwater input into the ocean. Directly observing frontal ablation and terminus morphology below the waterline is difficult, however, limiting our understanding of these coupled ice–ocean processes. To investigate the evolution of a tidewater glacier's submarine terminus, we combine 3-D multibeam point clouds of the subsurface ice face at LeConte Glacier, Alaska, with concurrent observations of environmental conditions during three field campaigns between 2016 and 2018. We observe terminus morphology that was predominately overcut (52% in August 2016, 63% in May 2017 and 74% in September 2018), accompanied by high multibeam sonar-derived melt rates (4.84 m d−1 in 2016, 1.13 m d−1 in 2017 and 1.85 m d−1 in 2018). We find that periods of high subglacial discharge lead to localized undercut discharge outlets, but adjacent to these outlets the terminus maintains significantly overcut geometry, with an ice ramp that protrudes 75 m into the fjord in 2017 and 125 m in 2018. Our data challenge the assumption that tidewater glacier termini are largely undercut during periods of high submarine melting.

Ensuring that life-saving antimicrobials remain available as effective treatment options in the face of rapidly rising levels of antimicrobial resistance will require a massive and coordinated global effort. Setting a collective direction for progress is the first step towards aligning global efforts on AMR. This process would be greatly accelerated by adopting a unifying global target — a well-defined global target that unites all countries and sectors. The proposed pandemic instrument — with its focus on prevention, preparedness and response — represents an ideal opportunity to develop and adopt a unifying global target that catalyzes global action on AMR. We propose three key characteristics of a unifying global target for AMR that — if embedded within the pandemic preparedness instrument — could rally public support, funding, and political commitment commensurate with the scale of the AMR challenge.

Background: Mutations in the slow skeletal muscle troponin T (TNNT1) gene cause a congenital nemaline myopathy resulting in death from respiratory insufficiency in early infancy. We report on four French Canadians with a novel congenital TNNT1 myopathy. Methods: Patients underwent lower extremity and paraspinal MRI, quadriceps biopsy and genetic testing. TNNT1 expression in muscle was assessed by quantitative PCR and immunoblotting. Wild type or mutated TNNT1 mRNAs were co-injected with morpholinos in a zebrafish knockdown model to assess for rescue of the morphant phenotype. Results: Four patients shared a novel missense homozygous mutation in TNNT1. They developed from childhood slowly progressive limb-girdle weakness with spinal rigidity and contractures. They suffered from restrictive lung disease and recurrent episodes of rhabdomyolysis. Older patients remained ambulatory into their sixties. Lower extremity MRI showed symmetrical myopathic changes. Paraspinal MRI showed diffuse fibro-fatty involution. Biopsies showed multi-minicores. Nemaline rods were seen in half the patients. TNNT1 mRNA expression was similar in controls and patients, while levels of TNNT1 protein were reduced in patients. Wild type TNNT1 mRNA rescued the zebrafish morphants but mutant transcripts failed to do so. Conclusions: This study expands the spectrum of TNNT1-related myopathy to include a milder clinical phenotype caused by a functionally-confirmed novel mutation.

Spectral-broadening of the APOLLON PW-class laser pulses using a thin-film compression technique within the long-focal-area interaction chamber of the APOLLON laser facility is reported, demonstrating the delivery of the full energy pulse to the target interaction area. The laser pulse at 7 J passing through large aperture, thin glass wafers is spectrally broadened to a bandwidth that is compatible with a 15-fs pulse, indicating also the possibility to achieve sub-10-fs pulses using 14 J. Placing the post-compressor near the interaction makes for an economical method to produce the shortest pulses by limiting the need for high damage, broadband optics close to the final target rather than throughout the entire laser transport system.

Background: Mutations in the slow skeletal muscle troponin T (TNNT1) gene cause a congenital nemaline myopathy resulting in death from respiratory insufficiency in early infancy. We report on four French Canadians with a novel congenital TNNT1 myopathy. Methods: Patients underwent lower extremity and paraspinal MRI, quadriceps biopsy and genetic testing. TNNT1 expression in muscle was assessed by quantitative PCR and immunoblotting. Wild type or mutated TNNT1 mRNAs were co-injected with morpholinos in a zebrafish knockdown model to assess for rescue of the morphant phenotype. Results: Four patients shared a novel missense homozygous mutation in TNNT1. They developed from childhood slowly progressive limb-girdle weakness with spinal rigidity and contractures. They suffered from restrictive lung disease and recurrent episodes of rhabdomyolysis. Older patients remained ambulatory into their sixties. Lower extremity MRI showed symmetrical myopathic changes. Paraspinal MRI showed diffuse fibro-fatty involution. Biopsies showed multi-minicores. Nemaline rods were seen in half the patients. TNNT1 mRNA expression was similar in controls and patients, while levels of TNNT1 protein were reduced in patients. Wild type TNNT1 mRNA rescued the zebrafish morphants but mutant transcripts failed to do so. Conclusions: This study expands the spectrum of TNNT1-related myopathy to include a milder clinical phenotype caused by a functionally-confirmed novel mutation.

While research on bilingual language processing is sensitive to different usage contexts, monolinguals are still often treated as a homogeneous control group, despite frequently using multiple varieties that may require engagement of control mechanisms during lexical access. Adapting a language-switching task for speakers of (Scottish) Standard English and Orcadian Scots, we demonstrate switch cost asymmetries with longer naming latencies when switching back into Orcadian. This pattern, which is reminiscent of unbalanced bilinguals, suggests that Orcadian is the dominant variety of these participants – despite the fact they might be regarded as English monolinguals because of sociolinguistic factors. In conjunction with the observed mixing cost and cognate facilitation effect (indicative of proactive language control and parallel language activation, respectively), these findings show that ‘monolinguals’ need to be scrutinised for routine use of different varieties to gain a better understanding of whether and how mechanisms underlying their lexical access resemble those of bilinguals.

Antarctica's ice shelves modulate the grounded ice flow, and weakening of ice shelves due to climate forcing will decrease their ‘buttressing’ effect, causing a response in the grounded ice. While the processes governing ice-shelf weakening are complex, uncertainties in the response of the grounded ice sheet are also difficult to assess. The Antarctic BUttressing Model Intercomparison Project (ABUMIP) compares ice-sheet model responses to decrease in buttressing by investigating the ‘end-member’ scenario of total and sustained loss of ice shelves. Although unrealistic, this scenario enables gauging the sensitivity of an ensemble of 15 ice-sheet models to a total loss of buttressing, hence exhibiting the full potential of marine ice-sheet instability. All models predict that this scenario leads to multi-metre (1–12 m) sea-level rise over 500 years from present day. West Antarctic ice sheet collapse alone leads to a 1.91–5.08 m sea-level rise due to the marine ice-sheet instability. Mass loss rates are a strong function of the sliding/friction law, with plastic laws cause a further destabilization of the Aurora and Wilkes Subglacial Basins, East Antarctica. Improvements to marine ice-sheet models have greatly reduced variability between modelled ice-sheet responses to extreme ice-shelf loss, e.g. compared to the SeaRISE assessments.

Introduction: CAEP recently developed the acute atrial fibrillation (AF) and flutter (AFL) [AAFF] Best Practices Checklist to promote optimal care and guidance on cardioversion and rapid discharge of patients with AAFF. We sought to assess the impact of implementing the Checklist into large Canadian EDs. Methods: We conducted a pragmatic stepped-wedge cluster randomized trial in 11 large Canadian ED sites in five provinces, over 14 months. All hospitals started in the control period (usual care), and then crossed over to the intervention period in random sequence, one hospital per month. We enrolled consecutive, stable patients presenting with AAFF, where symptoms required ED management. Our intervention was informed by qualitative stakeholder interviews to identify perceived barriers and enablers for rapid discharge of AAFF patients. The many interventions included local champions, presentation of the Checklist to physicians in group sessions, an online training module, a smartphone app, and targeted audit and feedback. The primary outcome was length of stay in ED in minutes from time of arrival to time of disposition, and this was analyzed at the individual patient-level using linear mixed effects regression accounting for the stepped-wedge design. We estimated a sample size of 800 patients. Results: We enrolled 844 patients with none lost to follow-up. Those in the control (N = 316) and intervention periods (N = 528) were similar for all characteristics including mean age (61.2 vs 64.2 yrs), duration of AAFF (8.1 vs 7.7 hrs), AF (88.6% vs 82.9%), AFL (11.4% vs 17.1%), and mean initial heart rate (119.6 vs 119.9 bpm). Median lengths of stay for the control and intervention periods respectively were 413.0 vs. 354.0 minutes (P < 0.001). Comparing control to intervention, there was an increase in: use of antiarrhythmic drugs (37.4% vs 47.4%; P < 0.01), electrical cardioversion (45.1% vs 56.8%; P < 0.01), and discharge in sinus rhythm (75.3% vs. 86.7%; P < 0.001). There was a decrease in ED consultations to cardiology and medicine (49.7% vs 41.1%; P < 0.01), but a small but insignificant increase in anticoagulant prescriptions (39.6% vs 46.5%; P = 0.21). Conclusion: This multicenter implementation of the CAEP Best Practices Checklist led to a significant decrease in ED length of stay along with more ED cardioversions, fewer ED consultations, and more discharges in sinus rhythm. Widespread and rigorous adoption of the CAEP Checklist should lead to improved care of AAFF patients in all Canadian EDs.