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Huntington disease: somatic expansion, pathobiology and therapeutics
No full textExpansion of simple DNA repeats causes over 45 human, predominantly neurodegenerative, inherited disorders. Huntington disease is a fatal, inherited, neurodegenerative disease caused by a CAG repeat expansion in the huntingtin gene (HTT), resulting in a toxic polyglutamine tract in the huntingtin protein. The disease leads to progressive motor, cognitive and psychiatric decline, primarily resulting from loss of medium spiny neurons in the striatum. Although Huntington disease has long been viewed as a consequence of age-dependent toxicity from mutant huntingtin, genome-wide association studies have identified genetic modifiers, mostly DNA repair genes, that significantly influence disease onset and progression. These findings point to somatic CAG repeat expansions in affected tissues as a key pathological mechanism. This emerging paradigm suggests that disease progression is not solely protein-driven but also shaped at the DNA level, a mechanism that is shared among other repeat expansion disorders. Therapeutically, this discovery opens new opportunities: interventions to limit somatic repeat expansion might be effective across multiple repeat expansion diseases and, when combined with disease-specific approaches, such as huntingtin lowering in Huntington disease, might offer more effective and longer-lasting clinical benefits than either strategy in isolation. This approach also poses challenges, determining the optimal point for therapeutic intervention and how best to establish phenotypic improvement in clinical trials when the target tissue is the brain
Keeping people down, in (line) and out: structural stigma and ‘missingness’ in healthcare
No full textRecent years have seen the development of conceptualisations of stigma which have moved beyond individual-level analyses towards exploring how stigma operates across multiple levels. While empirical research has examined the impact of stigma across various domains, there remains scant research exploring the lived experience of structural stigma. In this article, we examine structural stigma as a driver of multiple missed appointments, or ‘missingness’, in health care. We draw on qualitative data from 61 interviews with health and social care professionals and experts-by-experience of missingness in the United Kingdom, focusing on three stigmatised statuses: people from marginalised racial and ethnic groups, including those in the asylum system; people with mental health conditions; and people experiencing problem substance use. We adapt Link and colleagues’ schema of stigma outcomes—keeping people down, in, and away—to explore how structural stigma shapes access to and experiences of health care. Our findings demonstrate a range of such processes through which barriers to effective engagement occur, and suggest that a focus on structural stigma will benefit policy, practice, and future research in this area
Second victim syndrome in surgeons: systematic review and meta-analysis of the impact of adverse events on surgeons
Get PDFBackground:
Second victim syndrome (SVS) is characterized by negative psychological and psychosomatic effects on a healthcare provider after an adverse care event. The aim of this systematic review and meta-analysis was to characterize the symptoms of SVS experienced by surgeons and factors affecting their impact, as well as understand common coping strategies that surgeons employ to deal with them.
Methods:
A systematic review of five electronic databases was conducted without restrictions on publication date or language in January 2025. Second victim syndrome, surgeon, and adverse event and their synonyms were used as search terms. Records were screened, quality assessed, and data extracted by two independent researchers. Both qualitative and quantitative studies were included and narratively synthesized. A meta-analysis was performed using a random effects model to calculate the overall prevalence rates of symptoms and coping methods.
Results:
A total of 36 papers were included in the analysis from 6629 retrieved records. Anxiety (56.3% (95% c.i. 45.8% to 66.3%)), guilt (53.8% (95% c.i. 41.3% to 65.8%)), sadness (48.3% (95% c.i. 34.6% to 62.3%)), and sleep disturbance (50.5% (95% c.i. 38.4% to 62.5%)) were the most commonly reported symptoms. Talking to either colleagues (72.5% (95% c.i. 65.6% to 78.4%)) or family/friends (52.0% (95% c.i. 40.6% to 63.2%)) were the most commonly employed coping strategies. The sex and level of experience of the surgeon and the severity of the event were identified as potential predictors of deleterious impact.
Conclusion:
SVS significantly impacts surgeons’ global well-being, leading to burnout and attrition. Effective interventions require a multifaceted approach, including peer support, resilience training, and institutional changes that normalize emotional responses, encourage disclosure, and address barriers to seeking help. Targeted support for at-risk groups may also be necessary
Recommendations for adapting an online mindfulness program for people living with spinal cord injury: results from a pilot online survey with an integrated knowledge translation approach
No full textPurpose: To determine the implementation considerations for an online mindfulnessbased intervention (MBI) tailored to individuals with spinal cord injury (SCI) and
determine whether the identified preferences vary by demographic and clinical
characteristics.
Materials and methods: This study was a cross-sectional, online survey using an
integrated knowledge translation (iKT) approach. Adults with SCI across Canada and
the United States participated in this study. Participants stated their preferences and
importance of different aspects of the program (e.g. delivery format, session structure).
The survey content was informed by an earlier qualitative study and the Template for
Intervention Description and Replication (TIDieR) framework.
Results: 361 adults with SCI (225 males, mean age 36 (SD 8.61)) completed the survey.
Prerecorded webinars were the most preferred format for an online MBI. The preferred
duration and frequency of the program were 6–8weeks and 2 sessions per week,
respectively. The preferred session length was 30–45min. Participants preferred having
the program be introduced during inpatient SCI rehabilitation.
Conclusions: This study identified the preferred adaptations for an online MBI for
individuals with SCI in Canada and the United States. Survey results will inform the
development and implementation of a tailored online MBI that is relevant and
meaningful to individuals with SCI
Shaping antimalarials: a geometry-first approach to PfCLK3 covalent inhibitors
Get PDFThe emergence ofPlasmodium falciparumresistance to frontline therapies highlights the urgent need for new antimalarial agents. The essential, multistage kinase PfCLK3 is a validated target, and covalent kinase inhibitors (CKIs) offer potential for durable inhibition. However, CKI design has largely prioritised warhead reactivity over the geometric requirements which govern covalent bond formation. Herein, we describe a geometry-first approach to optimize covalent PfCLK3 inhibitors, starting from the highly reactive chloroacetamide SB4–17 (2). Systematic variation of warhead and linker geometry revealed that maintaining the α-reactive geometry of the chloroacetamide scaffold enables covalent engagement of Cys368 with substantially less reactive electrophiles. Notably, the methyl sulfamate analogue SB5–171 (14) showed potent antiparasitic activity (EC50 = 104 nM) and improved metabolic stability (t1/2 = 35 min in mouse hepatocytes). These findings demonstrate that geometric optimization can decouple covalent engagement from high intrinsic reactivity, providing a rational framework for designing selective, drug-like CKIs
Threats to academic freedom online and offline in France: culture wars, identity politics, and the Islamo-gauchisme controversy
No full textDevelopment as the imperialism of 'free' trade: rights, liberalism and the engineering of African economies
No full textDoes options trading reduce the demand for conditional accounting conservatism?
No full textWe examine if options trading via organized markets reduces conditional conservatism by alleviating information asymmetry. We build upon and extend prior evidence that options trading enhances stock market informational efficiency. Focusing on a large sample of firms from 1997 to 2019, we show that options trading volume is a determinant of the demand for conditional conservatism, as it is associated with less conditional conservatism in financial reporting. Moreover, firms reduce their level of conditional conservatism after being listed on the options market and upon entering the Penny Pilot Program. Options trading's effect on conditional conservatism is greater among small firms, firms with low asset tangibility, firms with long investment cycles and firms with higher external financing needs. We also document that options trading prominently influences conditional conservatism when investor sentiment is high
Drug-loaded nanoparticles for intra-articular injection
Get PDFDrug loaded nanoparticles (NPs) were developed as a model intra-articular injection (IAI) formulation to mitigate early stage osteoarthritis (OA). Different types of celecoxib-loaded nanoparticles were prepared by a hybrid method that combines homogenization and solvent evaporation. The hydrodynamic diameter of the nanoparticles prepared were approximately 200 nm (PLLA: 238 ± 19 nm; PCL: 249 ± 28 nm; PLA: 252 ± 18 nm; PMMA: 234 ± 21), and zeta potential were about −40 mV (PLLA: −45.3 ± 2.3 mV; PCL: −38.0 ± 0.9 mV; PLA: −44.4 ± 3.2 mV; PMMA: −45.5 ± 2.7 mV). Our friction data evidences that nanoparticles could improve considerably the lubrication between a stainless steel sphere and a silicone elastomer that were used as model substrates. Quartz Crystal Microbalance (QCM) and Atomic Force Microscope (AFM) measurements were carried out to unravel the lubrication mechanism. The magnitude and amount of NPs adsorbed on the surface determines the effect of lubrication. Drug release experiment suggests that nanoparticles could release up to more than one week, when being compared with free celecoxib. NPs formulation exhibited excellent biocompatibility in cytotoxicity of chondrocytes experiment
Monitoring CO2 mineralisation and dissolution at CarbFix2 using inherent isotopes of CO2, H2O and noble gases
No full textMineralising CO2 in mafic and ultramafic geological reservoirs is a rapid and durable means of CO2 storage. To date, verification of mineralisation storage has primarily relied upon externally added or indirect geochemical tracers. Here, we use changes in inherent CO2, H2O and noble gas isotope ratios to monitor CO2 dissolution and mineralisation at the CarbFix2 carbon capture and storage (CCS) project in Iceland. Reductions in CO2/3He ratios between gas inlet and outlet samples of the CarbFix2 scrubbing tower indicate 49 ± 4 % CO2 dissolution in water. We calculate that dissolved CO2 has a CO2/3He of 1.0 ± 0.1 × 1010 and a carbon isotope ratio (δ13C) of -5.0 ± 0.2 ‰ VPDB. CarbFix2 monitoring well isotope data record lower CO2/3He and higher δ13CCO2 than predicted by a baseline scenario where no mineralisation occurs. We model the evolution of injectate CO2/3He and δ13CCO2 for different chronologies of mineralisation and mixing at the reservoir temperature of 265 °C. Oxygen isotope ratios of H2O (δ18O) are key for distinguishing between the remaining injectate and background CO2 in monitoring wells because the combined effects of fractionation and CO2 loss make injectate and background CO2/3He and δ13C indistinguishable. Monitoring well data intersect modelled mineralisation scenarios at similar extents of mineralisation previously recorded. Uncertainties regarding background reservoir fluids and temporal variation of isotope data necessitate additional sampling to further validate this mineralisation verification at CarbFix2. Nevertheless, these initial results are promising for the wider application of inherent isotope tracers to monitor and verify in-situ CO2 mineralisation
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