Explore the vast range of titles available.

Introduction This study implemented MendelScan, a primary care rare disease case-finding tool, into a UK National Health Service population. Rare disease diagnosis is challenging due to disease complexity and low physician awareness. The 2021 UK Rare Diseases Framework highlights as a key priority the need for faster diagnosis to improve clinical outcomes. Methods and results A UK primary care locality with 68,705 patients was examined. MendelScan encodes diagnostic/screening criteria for multiple rare diseases, mapping clinical terms to appropriate SNOMED CT codes (UK primary care standardised clinical terminology) to create digital algorithms. These algorithms were applied to a pseudo-anonymised structured data extract of the electronic health records (EHR) in this locality to \"flag\" at-risk patients who may require further evaluation. All flagged patients then underwent internal clinical review (a doctor reviewing each EHR flagged by the algorithm, removing all cases with a clear diagnosis/diagnoses that explains the clinical features that led to the patient being flagged); for those that passed this review, a report was returned to their GP. 55 of 76 disease criteria flagged at least one patient. 227 (0.33%) of the total 68,705 of EHR were flagged; 18 EHR were already diagnosed with the disease (the highlighted EHR had a diagnostic code for the same RD it was screened for, e.g. Behcet’s disease algorithm identifying an EHR with a SNOMED CT code Behcet's disease). 75/227 (33%) EHR passed our internal review. Thirty-six reports were returned to the GP. Feedback was available for 28/36 of the reports sent. GP categorised nine reports as \"Reasonable possible diagnosis\" (advance for investigation), six reports as \"diagnosis has already been excluded\", ten reports as \"patient has a clear alternative aetiology\", and three reports as \"Other\" (patient left study locality, unable to re-identify accurately). All the 9 cases considered as \"reasonable possible diagnosis\" had further evaluation. Conclusions This pilot demonstrates that implementing such a tool is feasible at a population level. The case-finding tool identified credible cases which were subsequently referred for further investigation. Future work includes performance-based validation studies of diagnostic algorithms and the scalability of the tool.

Background Symptoms of anxiety and depression are common in patients with terminal illness and multiple challenges exist with timely and effective care in this population. Several centres have reported that one dose of the serotonergic psychedelic psilocybin, combined with therapeutic support, improves these symptoms for up to 6 months in this patient group. Drawing upon related therapeutic mechanisms, 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy may have the potential to achieve similar, positive mental health outcomes in this group. Preliminary evidence also supports the tolerability of MDMA-assisted therapy for anxiety and depression in advanced-stage cancer. Methods Up to 32 participants with advanced-stage cancer and associated depression and anxiety will be randomised in a 1:1 ratio into one of two blinded parallel treatment arms. The intervention group will receive 120 mg (+ 60 mg optional supplemental dose) MDMA-assisted therapy. The psychoactive control group will receive 20 mg oral (+ 10 mg optional supplemental dose) methylphenidate-assisted therapy. For each medication-assisted therapy session, participants will undergo two 90-min therapeutic support sessions in the week preceding, and one 90-min support session the day after the experimental session. A battery of measures (mood, anxiety, quality of life, mystical experience, spiritual wellbeing, attitudes towards death, personality traits, holistic health and wellbeing, connectedness, demoralisation, expectations, qualitative data and safety measures) will be assessed at baseline and through to the end of the protocol. Participants will be followed up until either 12 months post-randomisation or death, whichever occurs first. Discussion This study will examine the effect of MDMA-assisted therapy on symptoms of anxiety and depression in advanced-stage cancer. Potential therapeutic implications include establishing the safety and effectiveness of a novel treatment that may relieve mental suffering in patients with life-threatening illness. Trial registration Trial registered on Australian New Zealand Clinical Trials Registry. Registration number: ACTRN12619001334190p. Date registered: 30/09/2019. URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=378153&showOriginal=true&isReview=true

Acoustic methods are routinely used to provide broad scale information on the geographical distribution of benthic marine habitats and sedimentary environments. Although single-frequency multibeam echosounder surveys have dominated seabed characterisation for decades, multifrequency approaches are now gaining favour in order to capture different frequency responses from the same seabed type. The aim of this study is to develop a robust modelling framework for testing the potential application and value of multifrequency (30, 95, and 300 kHz) multibeam backscatter responses to characterize sediments’ grain size in an area with strong geomorphological gradients and benthic ecological variability. We fit a generalized linear model on a multibeam backscatter and its derivatives to examine the explanatory power of single-frequency and multifrequency models with respect to the mean sediment grain size obtained from the grab samples. A strong and statistically significant (p < 0.05) correlation between the mean backscatter and the absolute values of the mean sediment grain size for the data was noted. The root mean squared error (RMSE) values identified the 30 kHz model as the best performing model responsible for explaining the most variation (84.3%) of the mean grain size at a statistically significant output (p < 0.05) with an adjusted r2 = 0.82. Overall, the single low-frequency sources showed a marginal gain on the multifrequency model, with the 30 kHz model driving the significance of this multifrequency model, and the inclusion of the higher frequencies diminished the level of agreement. We recommend further detailed and sufficient ground-truth data to better predict sediment properties and to discriminate benthic habitats to enhance the reliability of multifrequency backscatter data for the monitoring and management of marine protected areas.

Background: Depressive disorders affect approximately 280 million globally, with many finding treatments ineffective or limited by side effects. Growing evidence suggests that psychedelic therapies may help alleviate depressive symptoms. Among these, lysergic acid diethylamide (LSD) microdosing shows promise for major depressive disorder (MDD). However, research on LSD microdosing in clinical populations remains limited. Objectives: This study aimed to understand the experiences of individuals participating in an open-label trial of LSD microdosing for MDD. Design: Open-label pilot trial in target population (MDD; phase IIa). Methods: Seventeen participants with MDD completed an 8-week LSD microdosing regimen, dosing twice weekly. Following the intervention, participants underwent semi-structured interviews regarding their experiences. Data were analysed using thematic analysis. Results: Themes were grouped into five categories: enhanced self-determination, increased connectedness, improved cognitive processing, better emotional well-being, and negative effects. Conclusion: Reported effects appeared to reinforce one another; that is, self-determination led to feeling more connected, which enhanced cognitive processing and ultimately improved emotional well-being and reduced depressive symptoms. However, this effect was not universal; some individuals reported negative effects or no significant improvement from microdosing LSD. This variability may be due to individual differences in response, insufficient dosage, or the treatment’s lack of effectiveness for some individuals. The presence of side effects highlights the need for a careful titration protocol, while the lack of symptom improvement in some cases reinforces that microdosing is not a guaranteed solution, and expectations should remain realistic. The absence of a placebo control represents a key limitation as it precludes attribution of observed changes specifically to LSD. Trial registration: ANZCTR, ACTRN12623000486628. Registered on 12 May 2023 (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=385758). Plain language summary Depression affects millions of people worldwide, and many find that current treatments either don’t work or have unwanted side effects. Recent research suggests that psychedelic substances, like LSD, may help improve mood when used carefully small amounts. This practice is known as LSD microdosing. Despite growing interest, there is very little controlled research on how LSD microdosing affects people with depression. In this study, we invited 17 adults with depression to take very low doses of LSD twice a week for eight weeks. After the study, we asked them about their experiences to understand how microdosing affected them. Participants reported a range of experiences. Many described feeling more motivated to engage in daily activities, a stronger sense of connection with others, clearer thinking, new personal insights, and overall improvements in emotional well-being. The improvements participants described often seemed to build on each other—for example, feeling more connected encouraged them to take part in more activities, which then helped them feel mentally clearer and emotionally better. However, not everyone benefited. Some participants reported negative experiences or no noticeable improvement, suggesting that microdosing may not work for everyone. The study also did not include a placebo comparison, so it is unclear whether the changes were due specifically to LSD. Overall, these findings suggest that LSD microdosing may offer some people with depression new ways to feel more connected, motivated, and emotionally balanced. At the same time, careful monitoring is important due to potential side effects, and expectations should remain realistic.

Background An advanced cancer diagnosis can be associated with a significant profile of distress. Psychedelic compounds have shown clinically significant effects in the treatment of psychological distress in patients with advanced-stage cancer. Given the challenges of delivering timely and effective intervention in the advanced cancer context, it is possible that an alternative, more pragmatic, approach lies in psychedelic ‘microdosing’. Microdosing refers to repeated administration of psychedelics in sub-hallucinogenic doses. The purpose of this study is to evaluate the feasibility of conducting a full-scale randomised controlled trial comparing psychedelic microdose-assisted–meaning-centred psychotherapy (PA-MCP) to standard meaning-centred psychotherapy (MCP) in New Zealand indigenous (Māori) and non-indigenous people with advanced cancer and symptoms of anxiety and/or depression. Although MCP is a well-established psychotherapeutic treatment in advanced cancer populations, the potential efficacy and effectiveness of this therapy when delivered alongside a standardised microdose regimen of a psychedelic compound have not been investigated. Methods Participants with advanced-stage cancer and symptoms of anxiety and/or depression ( N  = 40; 20 Māori, 20 non-Māori) will be randomised under double-blind conditions to receive 7 sessions of MCP alongside 13 doses of either an LSD microdose (4–20 µg) (PA–MCP) or inactive placebo (placebo-MCP). The feasibility, acceptability, and safety of this intervention and physiological and psychological measures will be recorded at baseline, at each session of MCP, and at a 1-month and 6-month follow-up. Discussion Our findings will evaluate the feasibility, acceptability, and safety of a larger randomised controlled trial and provide an initial indication of the potential benefits of psychedelic microdosing for psychological distress in advanced-stage indigenous and non-indigenous cancer patients. Trial Registration NZCTR, ACTRN12623000478617. Registered 11 May 2023.  https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=385810&isReview=true .

BackgroundFear of falling (FoF) is associated with activity restriction (AR) and reduced quality of life (QoL), leading to loss of independence. Physical and cognitive functions are associated with FoF. Inconsistencies in the mediating role of physical and cognitive function and complex interrelationships require further investigation; These relationships may differ between fallers and non-fallers. Our aim was to investigate the direct and indirect pathways between FoF, activity restriction/avoidance, QoL, and the mediating role of latent (unobserved) variables of physical and cognitive function in both fallers and non-fallers in a cohort of community-dwelling older adults.MethodsData from Wave 1 of The Longitudinal Irish Study of Ageing (TILDA) was used (with permission from ISSDA). The study was approved by the University of Sunderland ethics committee (011063). Outcome measures from TILDA include QoL, FoF, AR, physical function (Timed-Up and Go (TUG) and Grip strength), and cognitive function (Mini-mental State Examination (MMSE)). Data were cleaned (e.g., remove missing or NA) and processed in R Studio (version: 1.4.1106). Welch’s T-test was used to model differences in outcome measures between fallers and non-fallers, fallers with/without FoF, and, non-fallers with/without FoF. Mean difference (MD), 95% confidence (compatibility) intervals (CI) are reported for key comparisons. Structural equation modelling (SEM) will be used to model interrelationships between observed and latent variables, adjusting for medical, health and lifestyle covariates. Multiple models will be run, including imputing missing data.ResultsOur preliminary findings indicate 4761 participants (≥50 years of age) with full datasets; Of which 6.3% reported activity avoidance, 20.7% had FoF, and 20.2% had previously fallen. Compared to non-fallers, fallers had lower QoL scores (MD =-1.66 ; 95% CI =-2.19,-1.14 AU), MMSE (MD =-0.11; 95% CI= -0.24, 0.02) and grip strength (MD = -1.49; 95% CI = -2.18 to 0.80 kg) and higher TUG (MD = 0.45; 95% CI = 0.24,0.67). Fallers with FoF had lower QoL, and grip strength and higher TUG (p <0.001), non-fallers with FoF had lower QoL and grip strength and higher TUG.ConclusionPhysical function and cognitive differences are reported between faller and non-faller groups. SEM will allow for modelling these complex interrelationships between FoF, AR and QoL, mediated via our latent variables (physical and cognitive function). The data will inform health- and activity- promoting strategies to improve QoL in older adults with FoF.

Genetic subtypes of acute lymphoblastic leukaemia (ALL) are used to determine risk and treatment in children. 25% of precursor B-ALL cases are genetically unclassified and have intermediate prognosis. We aimed to use a genome-wide study to improve prognostic classification of ALL in children. We constructed a classifier based on gene expression in 190 children with newly diagnosed ALL (German Cooperative ALL [COALL] discovery cohort) by use of double-loop cross-validation and validated this in an independent cohort of 107 newly diagnosed patients (Dutch Childhood Oncology Group [DCOG] independent validation cohort). Hierarchical cluster analysis with classifying gene-probe sets revealed a new ALL subtype, the underlying genetic abnormalities of which were characterised by comparative genomic hybridisation-arrays and molecular cytogenetics. Our classifier predicted ALL subtype with a median accuracy of 90·0% (IQR 88·3–91·7) in the discovery cohort and correctly identified 94 of 107 patients (accuracy 87·9%) in the independent validation cohort. Without our classifier, 44 children in the COALL cohort and 33 children in the DCOG cohort would have been classified as B-other. However, hierarchical clustering showed that many of these genetically unclassified cases clustered with BCR–ABL1-positive cases: 30 (19%) of 154 children with precursor B-ALL in the COALL cohort and 14 (15%) of 92 children with precursor B-ALL in the DCOG cohort had this BCR–ABL1-like disease. In the COALL cohort, these patients had unfavourable outcome (5-year disease-free survival 59·5%, 95% CI 37·1–81·9) compared with patients with other precursor B-ALL (84·4%, 76·8–92·1%; p=0·012), a prognosis similar to that of patients with BCR–ABL1-positive ALL (51·9%, 23·1–80·6%). In the DCOG cohort, the prognosis of BCR–ABL1-like disease (57·1%, 31·2–83·1%) was worse than that of other precursor B-ALL (79·2%, 70·2–88·3%; p=0.026), and similar to that of BCR–ABL1-positive ALL (32·5%, 2·3–62·7%). 36 (82%) of the patients with BCR–ABL1-like disease had deletions in genes involved in B-cell development, including IKZF1, TCF3, EBF1, PAX5, and VPREB1; only nine (36%) of 25 patients with B-other ALL had deletions in these genes (p=0·0002). Compared with other precursor B-ALL cells, BCR–ABL1-like cells were 73 times more resistant to L-asparaginase (p=0·001) and 1·6 times more resistant to daunorubicin (p=0·017), but toxicity of prednisolone and vincristine did not differ. New treatment strategies are needed to improve outcome for this newly identified high-risk subtype of ALL. Dutch Cancer Society, Sophia Foundation for Medical Research, Paediatric Oncology Foundation Rotterdam, Centre of Medical Systems Biology of the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research, American National Institute of Health, American National Cancer Institute, and American Lebanese Syrian Associated Charities.

In the next several years we will see an increasing number of divestment campaigns spring up among student bodies nationwide. Given this trend, I believe it would be helpful to those interested in divestment at U.Va and other institutions to first examine the discussion that has followed the campaign so far. What is divestment? Is it well argued? Does it make economic sense? Shouldwedivest? If so, what steps should we take? Frequent campaign failures indicate that the divestment argument needs some reworking. The ultimate objectives of this paper are 1) a new argument that elucidates more compelling incentives for U.Va to take action against fossil fuels and 2) a financially responsible reinvestment strategy that reflects the greater values of our university.