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Identifying drug targets for schizophrenia through gene prioritization
Full text linkSchizophrenia genome-wide association studies (GWASes) have identified >250 significant loci and prioritized >100 disease-related genes. However, gene prioritization efforts have mostly been restricted to locus-based methods that ignore information from the rest of the genome. To more accurately characterize genes involved in schizophrenia etiology, we applied a combination of highly-predictive tools to a published GWAS of 67,390 schizophrenia cases and 94,015 controls. We combined both locus-based methods (fine-mapped coding variants, distance to GWAS signals) and genome-wide methods (PoPS, MAGMA, ultra-rare coding variant burden tests). We extracted genes that 1) are targeted by existing drugs that could potentially be repurposed for schizophrenia, 2) are predicted to be druggable, or 3) may be testable in rodent models. We prioritized 101 schizophrenia genes, including 15 that are targeted by approved or investigational drugs (e.g., DRD2, GRIN2A, CACNA1C, GABBR2). Of these, 7 have never been tested in clinical trials for schizophrenia or other psychiatric disorders (e.g., AKT3). Seven genes are not targeted by any existing small molecule drugs, but are predicted to be druggable (e.g., GRM1). We prioritized two potentially druggable genes in loci that are shared with an addiction GWAS (PDE4B and VRK2). We curated a high-quality list of 101 genes that likely play a role in the development of schizophrenia. Developing or repurposing drugs that target these genes may lead to a new generation of schizophrenia therapies. Rodent models of addiction more closely resemble the human disorder than rodent models of schizophrenia. As such, genes prioritized for both disorders could be explored in rodent addiction models, potentially facilitating drug development
Motion compensated spin echo cardiac diffusion tensor imaging in multiple cardiac phases using an ultrahigh gradient strength scanner
No full textBackground
Cardiac diffusion tensor imaging (cDTI) has traditionally relied on inefficient stimulated echo techniques to robustly assess microstructural changes over the cardiac cycle. Ultrahigh gradient strength systems (>80mT/m) allow shorter motion compensated diffusion encoding. This study compares the ability of high and ultrahigh strength gradient systems to provide systolic and diastolic motion compensated spin echo (MCSE) cDTI.
Methods
Second order MCSE sequences were developed for a research-only Siemens 3 T Connectom (300mT/m maximum gradient amplitude per axis) and breath hold cDTI was acquired at peak systole and end diastole. Acquisitions used the maximum achievable gradient strength (GUH, 116mT/m) and also limited to typical high gradient strengths (GH, 66mT/m based on 80mT/m maximum allowable), giving TE=48ms and 58ms respectively. Data were acquired at 2.8×2.8x8mm3, b=500 s/mm2 (8 averages) and b=150 s/mm2 (2 averages) in 6 encoding directions.
Results
22 healthy subjects were recruited. 20/21 and 21/22 systolic acquisitions at GUH and GH respectively met the >50% criteria of the circumferential myocardium showing the expected transmural variation in helix angle. For GUH and GH (16/20) 80% and (16/22) 73% of diastolic acquisitions were successful respectively. SNR was increased using GUH compared to GH (median [IQR]: 112.9 [3.8] vs. 9.6 [2.9], p=0.0002 diastole, 15.6 [5.9] vs. 12.5 [6.7], p=0.006 systole). Using GUH fractional anisotropy was lower in systole (0.349 [0.040] vs. 0.373 [0.019], p=0.002) and GUH transmural helix angle gradient (HAG) was steeper in diastole (-0.70 [0.17] vs. -0.55 [0.12] ˚/%, p=0.04). At both GUH and GH, sheetlet angle (|E2A|) was higher in systole than in diastole (30.7 [7.3] vs. 21.3 [6.7]˚ p=10-4 and 32.6 [10.9] vs. 26.0 [7.4]˚, p=0.03 respectively). Differences in HAG between phases were only apparent with GH (-0.88 [0.23] vs. -0.55 [0.15], p=10-4) and differences in the mean diffusivity only with GUH (1.64 [0.11] vs. 1.52 [0.24] x10-3mm2/s, p=0.002).
Conclusion
Ultrahigh strength gradient systems deliver higher SNR for MCSE and more robust imaging in diastole. While further work is required to further improve the reliability in diastole, at ultrahigh gradient strengths, cDTI using MCSE can identify dynamic changes in the cardiac microstructure. These findings will lead to more widespread use of multiphase MCSE in cDTI clinical research
Corneal stromal thinning and posterior irregularity after DMEK: Clinical observations and biophysical hypotheses
Full text linkPurpose: The aim of this study was to identify factors associated with significant postoperative stromal thinning in eyes undergoing Descemet membrane endothelial keratoplasty (DMEK). Methods: This was a retrospective, multicenter interventional study. Eyes that underwent DMEK at Royal Liverpool University Hospital (UK) and ASST Spedali Civili di Brescia (Italy) were included. Eyes were stratified into 2 groups based on the final central corneal thickness (CCT): <500 μm and ≥500 μm. Demographic, clinical, and tomographic parameters were analyzed, including age, preoperative CCT, best corrected visual acuity (BCVA), posterior and total corneal power, and donor endothelial cell density (ECD). Hyperopic shift was defined as an increase of ≥+0.5 D in posterior corneal power or a decrease of ≤–1.0 D in total corneal power. Results: Among 150 eyes (120 patients), those with a final CCT <500 μm were significantly older (mean [SD], 74.5 [9.9] vs. 68.7 [11.5] years; P = 0.001). Hyperopic shift occurred in 43% of eyes with complete tomographic data and correlated with a greater percentage reduction in CCT after DMEK (−25.5% [15.6%] vs. −16.4% [12.4%], P = 0.02). A larger proportional CCT reduction was observed in eyes with a final CCT <500 μm and was associated with the presence of preoperative posterior stromal ripples. No significant differences were observed in final BCVA, donor ECD, or treatment center. Conclusions: Greater reductions in corneal thickness are associated with postoperative stromal thinning and hyperopic shift after DMEK. Preoperative stromal ripples are associated with greater reductions in corneal thickness after DMEK. Stromal remodeling appears influenced by endothelial recovery and preoperative biomechanical status, supporting emerging hypotheses on keratocyte loss and osmotic imbalance
Intensive community care services for adolescents with acute psychiatric emergencies: trial feasibility findings from the pilot phase of a multi-centre randomised controlled trial
Full text linkBackground
Adolescents experiencing psychiatric emergencies often require intensive intervention to avoid hospital admission and support their transition into education, employment, or training (EET). Intensive Community Care Services (ICCS) offer a potential alternative to inpatient care. This pilot study aimed to assess the feasibility of conducting a randomised controlled trial (RCT) to evaluate the effectiveness of ICCS compared to treatment as usual (TAU) in reducing time to start or return to EET.
Methods
A multi-centre, parallel-group, single-blinded randomised controlled trial (RCT) with an internal pilot phase was conducted across seven NHS Trusts in the UK. Adolescents aged 12–17 experiencing psychiatric emergencies were randomised to ICCS or treatment as usual (TAU). The primary outcome was time to start or return to EET within six months. Secondary outcomes included clinical symptoms, functioning, service satisfaction, service use, and health-related quality of life. Descriptive statistics and hazard ratios were calculated to explore group differences. Feasibility was assessed against pre-specified progression criteria.
Results
Thirty-six adolescents were randomised during the internal pilot phase. The recruitment rate did not meet the progression criteria, and continuation to a full evaluation trial was deemed unfeasible. During follow-up, 83.3% (n = 30) returned to EET, with a median time to EET of nine days (IQR: 1–49). Median time to EET was shorter in the ICCS group (6 days) compared to TAU (12 days), with a hazard ratio of 1.34 (95% CI: 0.63–2.86). ICCS was associated with improved service satisfaction, clinical symptoms, and functioning. The average cost per participant was higher in the TAU group (£15,155, SD 31,560) compared to ICCS (£7,063, SD 10,605), with minimal differences in quality-adjusted life years (QALYs). Fourteen safety events were reported across both groups.
Conclusions
A full evaluation trial was not feasible due to recruitment challenges, primarily arising from limited-service capacity to deliver two treatment pathways concurrently. Despite this, ICCS showed promising trends in clinical and functional outcomes and may offer a viable alternative to inpatient care. Further research is needed to explore the implementation and effectiveness of ICCS in routine practice
Targeting neutrophil function as therapy for hidradenitis suppurativa
Full text linkHidradenitis suppurativa (HS) is a chronic, recurrent inflammatory skin disease characterized by painful nodules, abscesses, and epithelialized tunnels, predominantly affecting flexural regions. With a global prevalence of approximately 1%, HS has a significant negative impact on quality of life. Multi-omics and histopathology studies have revealed a complex interplay between innate and adaptive immunity in HS, with neutrophils emerging as important drivers of inflammation. While therapies targeting TNF-α and IL-17 isoforms offer a degree of benefit, significant unmet need remains. Neutrophil signatures in HS lesions and the circulation underscore the rationale for selective modulation of neutrophil function. Strategies advancing through clinical trials include inhibition of chemokine-mediated trafficking, neutrophil serine protease inactivation and suppression of neutrophil extracellular traps (NETs), which amplify inflammatory and autoimmune responses. These emerging therapies mark a significant shift toward targeted neutrophil modulation, offering new opportunities to improve outcomes for patients with HS
Exciton coherence propagation measured with non-local four-wave mixing micro-spectroscopy
Full text linkCoherence transfer is a multi-disciplinary topic of interest, including chemistry, biology, and physics. In quantum technologies, achieving non-local coherent coupling between solid-state qubits is of the utmost importance. Here, we demonstrate that excitons—i.e., electron–hole pairs bound by the Coulomb force within a quantum well—can act as a medium for mesoscopic optical coherence transfer in semiconductors. To this end, we use a femtosecond laser pulse to resonantly generate excitons within the light cone. These excitons can then either recombine radiatively or scatter out of the light cone, gaining an in-plane momentum in the process. In samples without disorder, such as the CdTe quantum wells used here, the resulting fast excitons can diffuse over mesoscopic distances before recombining radiatively. Using coherent nonlinear micro-spectroscopy, we carry out exciton time-of-flight measurements. Specifically, we monitor the spatio-temporal propagation of launched exciton wave packets, selectively observing their coherence or density on a scale of up to 10 µm. Our proof-of-principle experiment demonstrates that free excitons inherit a phase modulation from the optical pulsed excitation and can generate coherent links within excitonic circuits, offering a higher level of miniaturisation and compactness than photonic or polaritonic architectures
Activation of pancreatic acinar cells by very low concentrations of cholecystokinin: mechanism and implications for physiology and pathology
Full text linkCholecystokinin (CCK) is one of the three classical gut hormones. CCK is also, in contrast to the other two principal gut hormones (gastrin and secretin), an important neurotransmitter with widespread actions in the brain and in the periphery. Although not signposted by its name, one of the key physiological actions of CCK is to activate the secretion of an enzyme-rich neutral fluid produced by the pancreatic acinar cells. In general, hormones activate their target cells at concentrations that are much lower than those of neurotransmitters but, even in this context, the pancreatic acinar cells are extraordinarily sensitive to extremely low CCK concentrations (low pM). We explore the mechanism underlying this exceptional sensitivity as well as its consequences. The focus is on the intracellular transduction pathways that are activated when acinar cell CCK receptors are excited by the hormone. Uniquely, three different intracellular receptors – all linked to release of Ca2+ from intracellular stores – are required for CCK to elicit secretion. The implications of this unusual arrangement for both pancreatic physiology and pathophysiology are discussed
Antecedents and outcomes of a later attention–deficit hyperactivity disorder (ADHD) diagnosis in females
Full text linkBackground: Females are less likely than males to be diagnosed with attention–deficit hyperactivity disorder (ADHD). When diagnosed, females are older than males. Aims: In this study, we examined the childhood antecedents of later ADHD diagnosis and its impact on adolescent/emerging adult outcomes, with a focus on females. Method: In this cohort study, we used data from a Welsh nation-wide electronic cohort of 13 593 individuals (n = 2680 (19.7%) females) diagnosed with ADHD and 578 793 individuals (n = 286 734 (49.5%) females) without ADHD. We compared females with later diagnoses (ages 12–25) to those with earlier, timely diagnoses (ages 5–11) and no diagnosis, in terms of childhood (ages 5–11) antecedents and adolescent/adult (ages 12–25) outcomes. We also tested for sex differences. Results: Although females with earlier ADHD diagnosis showed more health and educational difficulties in childhood than those with later diagnosed ADHD (odds ratios ranged from 0.18 to 0.92), there was clear evidence of these difficulties in females with later diagnosed ADHD, compared with females without ADHD (odds ratios: 1.07–9.02). In adolescence/early adulthood, females with later diagnosed ADHD used more healthcare services and had worse mental health, educational and socioeconomic outcomes than females diagnosed earlier (odds ratios: 1.39–4.96) and those without ADHD (odds ratios: 1.54–23.98). Many of these outcomes were exacerbated in females compared with males. Conclusions: The results demonstrate that later ADHD diagnosis is associated with significant negative outcomes by adolescence and disproportionately disadvantages females. Despite later diagnosis, there was clear evidence of childhood mental health and educational difficulties when compared with females without ADHD. Therefore, timely childhood ADHD diagnosis may help to mitigate later risks, especially for females
The anatomy of an access control reader: a cybersecurity perspective
Full text linkAccess control readers are the first line of defence for organizations to restrict access to their facilities to the people who are supposed to be there. Such readers represent a major investment for organizations and are replaced every 7–10 years. The choice of reader and credential made at the time the system was designed and installed may be vulnerable to an array of attacks, such as credential cloning and data transmission exploits, which would allow a threat actor to pass through an entrance undetected. Once the threat actor has entered the building, the people and/or assets that the organization are responsible for are at risk. Access control readers have a number of interfaces based on different technologies that may be attacked to learn more about the configuration and other features of the device. This information may then be used to craft an attack on a real system. To the best of our knowledge, this is the first paper that outlines the various technologies incorporated into these products and draws upon this data to present the first model of the contemporary access control reader. The model is then further developed by considering the cybersecurity implications of each of the technologies found in an access control reader. Finally, based on known attack vectors, the model may be used as a risk assessment framework for readers and credentials. From this foundation, a series of further research topics are then proposed
Skin integrity and wound management education in the pre-registration nursing curricula [Editorial]
No full textFor many years there has been a drive to characterise what student nurses need to know about skin integrity and wounds (Holloway et al, 2018). However, the complexity of curriculum design has made this challenging, in part because the ‘Future Nurse’ (Nursing and Midwifery Council [NMC] 2018) needs to know so much! So, is right to push the agenda for one speciality at the potential detriment of others? Equally there is a valid argument that maintenance of skin integrity could help to reduce the risk of other conditions, for example pressure ulcers (PU), moisture associated skin damage (MASD) and skin tears. While progress seems to have been slow in terms of pushing the skin and wound agenda in pre-registration education, in my opinion we are making headway