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Hydromethylthionine sustains truncated tau‐dependent inflammation‐lowering effects in mouse brain
No full textTauopathies are a heterogeneous mixture of neurodegenerative disorders, including Alzheimer's disease and frontotemporal dementia (FTD), characterised by the accumulation of tau filaments in brain tissue. Tau protein aggregation is inhibited by hydromethylthionine (HMT), an effect that appeared to be prevented in clinical trials for subjects already receiving acetylcholinesterase inhibitors or memantine. Since neuroinflammatory responses are associated with tauopathies, we investigated the effect of HMT on the brain immune response and inflammatory status in line 66 (L66) mice, an FTD-like model overexpressing human tau, in the presence of memantine. We determined whether HMT (5 and 15 mg·kg−1), either singly or combined with memantine (20 mg·kg−1), would have a sustained impact on neuroinflammation following the cessation of drug administration. The levels of core tau fragments in L66+/− mice (P301S/G335D-hTau) were decreased in a dose-dependent manner 12 weeks after the last administration of HMT, an effect that was not affected by memantine. HMT lowered the levels of tumour necrosis factor alpha (TNF-α), thus favouring an environment conducive to neuronal protection and repair. HMT sustained increased microglial reactivity after its discontinuation, which may assist in the removal of tau aggregates, but co-administration with memantine prevented the HMT-sustained activation of microglia. These findings indicate that HMT has a beneficial effect in reducing neuroinflammation that accompanies a decrease in the accumulation of truncated tau species and that these benefits are not susceptible to interference by memantine. In turn, the nature of drug interference between HMT and memantine seems to be independent of tau and related to microglia reactivity
Current attitudes to testicular prosthesis insertion during radical orchidectomy—An international perspective
Get PDFObjectives
This study aimed to assess current international clinician practices, attitudes and barriers related to testicular prosthesis implantation in patients with testicular cancer at the time of radical inguinal orchidectomy.
Methods
An international online survey of urologists who perform radical orchidectomy for testicular cancer was developed. The recruitment process used social media and the emailing lists of national urological societies. Responses were collected between 10 February 2021 and 31 May 2021. The primary outcome was the proportion of urologists who always offered testicular prosthesis implantation to patients undergoing radical orchidectomy. Secondary outcomes included the reasons for not offering testicular prosthesis implantation.
Results
A total of 393 respondents took part in the online survey; of these, the majority were from the UK (66%), with the remaining international respondents (34%) from six different continents. Urologists (53%) reported they always offer testicular prosthesis implantation. Of those that offered testicular prosthesis implantation, 28% did so as a secondary procedure after radical orchidectomy, rather than the time of radical orchidectomy (72%). The most frequently selected reasons for not offering testicular prosthesis implantation included concerns about delaying chemotherapy (41%), infection (33%), impaired cosmesis (17%) and lack of availability (17%).
Conclusion
Despite evidence confirming the safety and the psychological benefit of testicular prosthesis implantation during radical orchidectomy, current international practice suggests just over half of urologists always offer this to their patients. Increased clinician awareness of the low risk of complications and high patient satisfaction may act to reduce the perceived barriers in offering testicular prosthesis implantation
Rapid mid-infrared spectral-timing with JWST: GRS 1915+105 during a MIR–bright and X-ray–obscured state
Get PDFWe present mid-infrared (MIR) spectral-timing measurements of the prototypical Galactic microquasar GRS 1915+105. The source was observed with the Mid-Infrared Instrument (MIRI) onboard JWST in June 2023 at a MIR luminosity LMIR ≈ 1036 erg s−1 exceeding past IR levels by about a factor of 10. In contrast, the X-ray flux is much fainter than the historical average, in the source’s now–persistent ‘obscured’ state. The MIRI low-resolution spectrum shows a plethora of emission lines, the strongest of which are consistent with recombination in the hydrogen Pfund (Pf) series and higher. Low amplitude (∼ 1%) but highly significant peak-to-peak photometric variability is found on timescales of ∼ 1,000 s. The brightest Pf (6–5) emission line lags the continuum. Though difficult to constrain accurately, this lag is commensurate with light-travel timescales across the outer accretion disc or with expected recombination timescales inferred from emission line diagnostics. Using the emission line as a bolometric indicator suggests a moderate (∼ 5–30 % Eddington) intrinsic accretion rate. Multiwavelength monitoring shows that JWST caught the source close in-time to unprecedentedly bright MIR and radio long-term flaring. Assuming a thermal bremsstrahlung origin for the MIRI continuum suggests an unsustainably high mass-loss rate during this time unless the wind remains bound, though other possible origins cannot be ruled out. PAH features previously detected with Spitzer are now less clear in the MIRI data, arguing for possible destruction of dust in the interim. These results provide a preview of new parameter space for exploring MIR spectral-timing in XRBs and other variable cosmic sources on rapid timescales
A VLP vaccine platform comprising the core protein of hepatitis B virus with N-terminal antigen capture
Get PDFNanoparticle presentation systems offer the potential to develop new vaccines rapidly in response to emerging diseases, a public health need that has become increasingly evident in the wake of the COVID-19 pandemic. Previously, we reported a nanoparticle scaffold system termed VelcroVax. This was constructed by insertion of a high affinity SUMO binding protein (Affimer), able to recognise a SUMO peptide tag, into the major immunodominant region of VLPs assembled from a tandem (fused dimer) form of hepatitis B virus (HBV) core protein (HBc). Here we describe an alternative form, termed N-VelcroVax, a VLP vaccine platform assembled from a monomeric HBc protein (N-anti-SUMO Affimer HBc 190) with the Affimer inserted at the N-terminus. In contrast to the tandem form of VelcroVax, N-VelcroVax VLPs were expressed well in E. coli. The VLPs effectively bound SUMO-tagged Junín virus glycoprotein, gp1 as assessed by structural and serological analyses. Cryo-EM characterisation of N-VelcroVax complexed with a SUMO-Junín gp1 showed continuous density attributable to the fused Affimer, in addition to evidence of target antigen capture. Collectively, these data suggest that N-VelcroVax has potential as a versatile next generation vaccine scaffold
Predictors of functional outcome at 1 year after stroke: analysis of INTERSTROKE data from Pakistan
No full textBackground and Objective
Identification of early and long-term outcomes after stroke is important in stroke management strategies. The aim of this study was to analyse predictors of independence and functional outcome at 1 and 12 months post-stroke.
Methods
This was a prospective study of patients with first stroke who were enrolled between April 2013 and July 2015 from a single-centre tertiary care hospital in Pakistan. Patients were followed up at 1 and 12 months and assessed using the modified Rankin scale (mRs).
Results
A total of 395 patients with acute first strokes were enrolled. Stroke dependency (mRs score 3-5) was higher in our site at 1 month. At 1 month, 137 (34.6%) of the participants were independent (mRs 0-2), 54.1% (n = 214) were dependent (mRs 3-5) and 11.1% (n = 44) died. At 12 months, 86% (n = 303/351) completed the follow-up. Of 303 participants, 35.3% (n = 107) were independent (mRs 0-2), 35.6% (n = 108) were dependent (mRs 3-5) and 29% (n = 88) had died. Forty-eight patients (14%) were lost to follow-up. Overall mortality was 33% (132/395) in 1 year. At 12 months, no comorbidities (OR 3.26; 95% CI: 1.48-7.21) and normal level of consciousness at onset (OR 3.44; 95% CI: 1.93-6.12) were associated with greater post-stroke independence (mRs 0-2). Out of 395, 111 (28.1%) patients with no or minimal disability at 1 month (mRs 0-2), 32.4% showed worsening of disability (mRs 3-5) at 12 months.
Conclusion
At 1 year, 33% died and 36% were dependent. A large number (60%) of patients with minimal disability at 30 days worsened or died at 1 year
Bilingual language control during single-language production:does relocation to a new linguistic environment change it?
Get PDFA bilingual's two languages are simultaneously active and competing for selection, even when only one language is used. To manage this competition, bilinguals apply language control. We examined how bilinguals apply control across two single-language tasks and how this language control might adapt to the language environment bilinguals live in. We conducted a longitudinal study with Mandarin-English bilinguals who moved from China to the UK and a control group staying in China. Participants completed a picture-naming task and a verbal-fluency task twice, approximately seven months apart. We examined language order effects by comparing performance in each language when it was used first versus after the other language. While the L2 benefited from being used second, L1 performance benefited less or even deteriorated after L2 use. This suggests bilinguals proactively applied language control, especially during L2 use, to manage the anticipated language competition from the L1. However, these effects did not change after relocation to the UK, nor did they differ between the groups. This suggests that while language control is a core part of language production, the language environment a bilingual lives in might not have a defining impact on the exact way this language control is applied
Towards Diverse Program Transformations for Program Simplification
Get PDFBy reducing the number of lines of code, program simplification reduces code complexity, improving software maintainability and code comprehension. While several existing techniques can be used for automatic program simplification, there is no consensus on the effectiveness of these approaches. We present the first study on how real-world developers simplify programs in open-source software projects. By analyzing 382 pull requests from 296 projects, we summarize the types of program transformations used, the motivations behind simplifications, and the set of program transformations that have not been covered by existing refactoring types. As a result of our study, we submitted eight bug reports to a widely used refactoring detection tool, RefactoringMiner, where seven were fixed. Our study also identifies gaps in applying existing approaches for automating program simplification and outlines the criteria for designing automatic program simplification techniques. In light of these observations, we propose SimpT5, a tool to automatically produce simplified programs that are semantically equivalent programs with reduced lines of code. SimpT5 is trained on our collected dataset of 92,485 simplified programs with two heuristics: (1) modified line localization that encodes lines changed in simplified programs, and (2) checkers that measure the quality of generated programs. Experimental results show that SimpT5 outperforms prior approaches in automating developer-induced program simplification
APPROACH: Analysis of Proton versus Photon Radiotherapy in Oligodendroglioma and Assessment of Cognitive Health – study protocol paper for a phase III multicentre, open-label randomised controlled trial
Get PDFIntroduction Oligodendroglioma (ODG) is a rare type of brain tumour, typically diagnosed in younger adults and associated with prolonged survival following treatment. The current standard of care is maximal safe debulking surgery, radiotherapy (RT) and adjuvant procarbazine, lomustine and vincristine (PCV) chemotherapy. Patients may experience long-term treatment-related toxicities, with RT linked to impairments of neurocognitive function (NCF) and health-related quality of life (HRQoL). With proton beam therapy (PBT), radiation dose falls off sharply beyond the target with reduced normal brain tissue radiation doses compared with photon RT. Therefore, PBT might result in reduced radiation-induced toxicity compared with photon RT.
Methods and analysis APPROACH is a multicentre open-label phase III randomised controlled trial of PBT versus photon RT in patients with ODG, investigating the impact of PBT on long-term NCF measured using the European Organisation for Research and Treatment of Cancer (EORTC) Core Clinical Trial Battery Composite (CTB COMP). The trial will randomise 246 participants from 18 to 25 UK RT sites, allocated 1:1 to receive PBT or photon RT, with PBT delivered at one of the two UK PBT centres. Participants with grade 2 and grade 3 ODG will receive 54 Gy in 30 fractions and 59.4 Gy in 33 fractions, respectively, followed by 6×6-weekly cycles of PCV chemotherapy. The trial contains staged analyses, with an internal pilot for feasibility of recruitment at 12 months, early assessment of efficacy at 2 years, futility assessment and final primary endpoint comparison of NCF between arms at 5 years. Secondary endpoints include additional NCF, treatment compliance, acute and late toxicities, endocrinopathies, HRQoL, tumour response, progression-free survival and overall survival.
Ethics and dissemination Ethical approval was obtained from Newcastle North Tyneside REC (reference 22/NE/0232). Final trial results will be published in peer-reviewed journals and adhere to International Committee of Medical Journal Editors (ICMJE) guidelines.
Trial registration number ISRCTN:13390479
A temporal network analysis of complex post-traumatic stress disorder and psychosis symptoms
Get PDFBackground
Symptoms of complex post-traumatic stress disorder (cPTSD) may play a role in the maintenance of psychotic symptoms. Network analyses have shown interrelationships between post-traumatic sequelae and psychosis, but the temporal dynamics of these relationships in people with psychosis and a history of trauma remain unclear. We aimed to explore, using network analysis, the temporal order of relationships between symptoms of cPTSD (i.e. core PTSD and disturbances of self-organization [DSOs]) and psychosis in the flow of daily life.
Methods
Participants with psychosis and comorbid PTSD (N = 153) completed an experience-sampling study involving multiple daily assessments of psychosis (paranoia, voices, and visions), core PTSD (trauma-related intrusions, avoidance, hyperarousal), and DSOs (emotional dysregulation, interpersonal difficulties, negative self-concept) over six consecutive days. Multilevel vector autoregressive modeling was used to estimate three complementary networks representing different timescales.
Results
Our between-subjects network suggested that, on average over the testing period, most cPTSD symptoms related to at least one positive psychotic symptom. Many average relationships persist in the contemporaneous network, indicating symptoms of cPTSD and psychosis co-occur, especially paranoia with hyperarousal and negative self-concept. The temporal network suggested that paranoia reciprocally predicted, and was predicted by, hyperarousal, negative self-concept, and emotional dysregulation from moment to moment. cPTSD did not directly relate to voices in the temporal network.
Conclusions
cPTSD and positive psychosis symptoms mutually maintain each other in trauma-exposed people with psychosis via the maintenance of current threat, consistent with cognitive models of PTSD. Current threat, therefore, represents a valuable treatment target in phased-based trauma-focused psychosis interventions
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