Visualizing alpha-synuclein and iron deposition in M83 mouse model of Parkinson's disease in vivo.

Abnormal alpha-synuclein (αSyn) and iron accumulation in the brain play an important role in Parkinson's disease (PD). Herein, we aim to visualize αSyn inclusions and iron deposition in the brains of M83 (A53T) mouse models of PD in vivo. The fluorescent pyrimidoindole derivative THK-565 probe was characterized by means of recombinant fibrils and brains from 10- to 11-month-old M83 mice. Concurrent wide-field fluorescence and volumetric multispectral optoacoustic tomography (vMSOT) imaging were subsequently performed in vivo. Structural and susceptibility weighted imaging (SWI) magnetic resonance imaging (MRI) at 9.4 T as well as scanning transmission x-ray microscopy (STXM) were performed to characterize the iron deposits in the perfused brains. Immunofluorescence and Prussian blue staining were further performed on brain slices to validate the detection of αSyn inclusions and iron deposition. THK-565 showed increased fluorescence upon binding to recombinant αSyn fibrils and αSyn inclusions in post-mortem brain slices from patients with PD and M83 mice. Administration of THK-565 in M83 mice showed higher cerebral retention at 20 and 40 min post-intravenous injection by wide-field fluorescence compared to nontransgenic littermate mice, in congruence with the vMSOT findings. SWI/phase images and Prussian blue indicated the accumulation of iron deposits in the brains of M83 mice, presumably in the Fe3+ form, as evinced by the STXM results. In conclusion, we demonstrated in vivo mapping of αSyn by means of noninvasive epifluorescence and vMSOT imaging and validated the results by targeting the THK-565 label and SWI/STXM identification of iron deposits in M83 mouse brains ex vivo.

Low-profile versus standard-profile stent grafts in the treatment of abdominal aortic aneurysm: a case-matched study.

Introduction: Endovascular aortic repair (EVAR) is nowadays a widespread method of managing abdominal aortic aneurysm (AAA). Low-profile stent grafts (LPSGs) enable treatment of patients with complex and anatomically challenging aneurysms, and facilitate a percutaneous and thus less invasive procedure. Aim: To assess the outcomes of EVAR with low-profile versus standard-profile stent grafts (SPSGs). Material and methods: Thirty-one patients with abdominal aortic aneurysms (AAA) were treated by endovascular aortic repair (EVAR) using LPSGs. The control group of patients treated with SPSGs was matched with MedCalc software. The clinical records and the preoperative and follow-up computed tomography angiography of patients who underwent endovascular treatment of AAA were included in this study. Results: Patients in the LPSG group had significantly more often low access vessel diameter (< 6 mm) compared to the SPSG group (38.7% vs. 6.7%, p = 0.003). In 1-year follow-up, there was no rupture, no infection, no conversion to open repair and no aneurysm-related death. Five secondary interventions were necessary in the SPSG group and only 1 in the LPSG group (p = 0.09). Type of stent graft was not a risk factor of perioperative complications, presence of endoleak or reintervention (p > 0.05). Risk factors for perioperative complications were COPD and conical neck (OR = 6.3, 95% CI: 1.5-25, p = 0.01 and OR = 6.2, 95% CI: 1-39.76, p = 0.04). The risk factor for endoleak was lower maximal aneurysm diameter. The risk factor for reintervention was proximal neck diameter (OR = 0.77, 95% CI: 0.-0.97, p = 0.03). Conclusions: Our study showed that use of LPSGs is a safe and viable method for patients with narrow access vessels who are not eligible for standard-profile systems.

Efficient characterization of multiple binding sites of small molecule imaging ligands on amyloid-beta, tau and alpha-synuclein.

PURPOSE: There is an unmet need for compounds to detect fibrillar forms of alpha-synuclein (αSyn) and 4-repeat tau, which are critical in many neurodegenerative diseases. Here, we aim to develop an efficient surface plasmon resonance (SPR)-based assay to facilitate the characterization of small molecules that can bind these fibrils. METHODS: SPR measurements were conducted to characterize the binding properties of fluorescent ligands/compounds toward recombinant amyloid-beta (Aß)42, K18-tau, full-length 2N4R-tau and αSyn fibrils. In silico modeling was performed to examine the binding pockets of ligands on αSyn fibrils. Immunofluorescence staining of postmortem brain tissue slices from Parkinson's disease patients and mouse models was performed with fluorescence ligands and specific antibodies. RESULTS: We optimized the protocol for the immobilization of Aß42, K18-tau, full-length 2N4R-tau and αSyn fibrils in a controlled aggregation state on SPR-sensor chips and for assessing their binding to ligands. The SPR results from the analysis of binding kinetics suggested the presence of at least two binding sites for all fibrils, including luminescent conjugated oligothiophenes, benzothiazole derivatives, nonfluorescent methylene blue and lansoprazole. In silico modeling studies for αSyn (6H6B) revealed four binding sites with a preference for one site on the surface. Immunofluorescence staining validated the detection of pS129-αSyn positivity in the brains of Parkinson's disease patients and αSyn preformed-fibril injected mice, 6E10-positive Aß in arcAß mice, and AT-8/AT-100-positivity in pR5 mice. CONCLUSION: SPR measurements of small molecules binding to Aß42, K18/full-length 2N4R-tau and αSyn fibrils suggested the existence of multiple binding sites. This approach may provide efficient characterization of compounds for neurodegenerative disease-relevant proteinopathies.

EMG coherence of foot and ankle muscles increases with a postural challenge in men.

BACKGROUND: The functional role of intrinsic foot muscles in the control of standing balance is often overlooked in rehabilitation, partly because the interactions with ankle muscles are poorly understood. RESEARCH QUESTION: How does coactivation of Flexor Digitorum Brevis (FDB) and soleus (SOL) vary across standing tasks of increasing difficulty. METHODS: Postural sway (Centre of Pressure, CoP) and the electromyographic (EMG) activity of FDB, SOL, Medial Gastrocnemius (MG) and Tibialis Anterior (TA) were measured during bipedal standing, tandem stance, one-legged balance, and standing on toes. Coherence of the rectified EMG signals for SOL and FDB in two bandwidths (0-5 and 10-20 Hz) was calculated as a coactivation index. RESULTS AND SIGNIFICANCE: The CoP sway and the EMG activity of all muscles was greater (P<0.05) for the three difficult tasks. Significant coherence between the SOL and FDB EMG activity was found in both frequency regions: 0-5 and 10-20 Hz. The coherence integral increased with the difficulty of the postural task, especially in the 10-20 Hz band. The findings underscore the important role of FDB in the control of standing balance across tasks and its coactivation with SOL. Clinical recommendations to improve balance control need to consider the interaction between the plantar flexor and intrinsic-foot muscles.

Giant stem tetrapod was apex predator in Gondwanan late Palaeozoic ice age.

Current hypotheses of early tetrapod evolution posit close ecological and biogeographic ties to the extensive coal-producing wetlands of the Carboniferous palaeoequator with rapid replacement of archaic tetrapod groups by relatives of modern amniotes and lissamphibians in the late Carboniferous (about 307 million years ago). These hypotheses draw on a tetrapod fossil record that is almost entirely restricted to palaeoequatorial Pangea (Laurussia)1,2. Here we describe a new giant stem tetrapod, Gaiasia jennyae, from high-palaeolatitude (about 55° S) early Permian-aged (about 280 million years ago) deposits in Namibia that challenges this scenario. Gaiasia is represented by several large, semi-articulated skeletons characterized by a weakly ossified skull with a loosely articulated palate dominated by a broad diamond-shaped parasphenoid, a posteriorly projecting occiput, and enlarged, interlocking dentary and coronoid fangs. Phylogenetic analysis resolves Gaiasia within the tetrapod stem group as the sister taxon of the Carboniferous Colosteidae from Euramerica. Gaiasia is larger than all previously described digited stem tetrapods and provides evidence that continental tetrapods were well established in the cold-temperate latitudes of Gondwana during the final phases of the Carboniferous-Permian deglaciation. This points to a more global distribution of continental tetrapods during the Carboniferous-Permian transition and indicates that previous hypotheses of global tetrapod faunal turnover and dispersal at this time2,3 must be reconsidered.

Effects of plyometric training techniques on vertical jump performance of basketball players.

The aim of our study was to compare the effects of two different plyometric training programs (targeting knee extensors or plantar flexors) on jump height and strength of leg muscles. Twenty-nine male basketball players were assigned to the knee-flexed (KF), knee-extended (KE), or control groups. In addition to regular training, the KF group performed plyometric jumps (10 sets of 10 jumps, 3 sessions/week, 4 weeks) from 50 cm boxes with the knee flexed (90°-120°), whereas the KE group performed the jumps from 30 cm boxes with the knee much more extended (130°-170°). Jumping ability was evaluated with squat jumps (SJs), countermovement jumps (CMJs), and drop jumps from 20 cm (DJ20) and 40 cm (DJ40). Knee and ankle muscles were assessed during maximal isokinetic and isometric tests, and EMG activity was recorded from vastus lateralis and medial gastrocnemius. The KF group increased SJ (+10%, d = 0.86) and CMJ (+11%, d = 0.70) but decreased DJ40 height (-7%, d = -0.40). Conversely, the KE group increased DJ20 (+10%, d = 0.74) and DJ40 (+12%, d = 0.77) but decreased SJ height (-4%, d = -0.23). The reactivity index during DJs increased (+10% for DJ20, d = 0.47; +20% for DJ40, d = 0.91) for the KE group but decreased (-10%, d = -0.48) for the KF group during DJ40. Plantar flexor strength increased for the KE group (d = 0.72-1.00) but not for the KF group. Negative transfer across jumps is consistent with the principle of training specificity. Basketball players interested to perform fast rebounds in their training should avoid plyometric jumps with large knee flexions and long contact times.

VHEE FLASH sparing effect measured at CLEAR, CERN with DNA damage of pBR322 plasmid as a biological endpoint.

Ultra-high dose rate (UHDR) irradiation has been shown to have a sparing effect on healthy tissue, an effect known as 'FLASH'. This effect has been studied across several radiation modalities, including photons, protons and clinical energy electrons, however, very little data is available for the effect of FLASH with Very High Energy Electrons (VHEE). pBR322 plasmid DNA was used as a biological model to measure DNA damage in response to Very High Energy Electron (VHEE) irradiation at conventional (0.08 Gy/s), intermediate (96 Gy/s) and ultra-high dose rates (UHDR, (2 × 109 Gy/s) at the CERN Linear Electron Accelerator (CLEAR) user facility. UHDRs were used to determine if the biological FLASH effect could be measured in the plasmid model, within a hydroxyl scavenging environment. Two different concentrations of the hydroxyl radical scavenger Tris were used in the plasmid environment to alter the proportions of indirect damage, and to replicate a cellular scavenging capacity. Indirect damage refers to the interaction of ionising radiation with molecules and species to generate reactive species which can then attack DNA. UHDR irradiated plasmid was shown to have significantly reduced amounts of damage in comparison to conventionally irradiated, where single strand breaks (SSBs) was used as the biological endpoint. This was the case for both hydroxyl scavenging capacities. A reduced electron energy within the VHEE range was also determined to increase the DNA damage to pBR322 plasmid. Results indicate that the pBR322 plasmid model can be successfully used to explore and test the effect of UHDR regimes on DNA damage. This is the first study to report FLASH sparing with VHEE, with induced damage to pBR322 plasmid DNA as the biological endpoint. UHDR irradiated plasmid had reduced amounts of DNA single-strand breaks (SSBs) in comparison with conventional dose rates. The magnitude of the FLASH sparing was a 27% reduction in SSB frequency in a 10 mM Tris environment and a 16% reduction in a 100 mM Tris environment.

Explaining the influence of practice on the grooved pegboard times of older adults: role of force steadiness.

The purpose was to identify the variables that can explain the variance in the grooved pegboard times of older adults categorized as either fast or slow performers. Participants (n = 28; 60-83 years) completed two experimental sessions, before and after 6 practice sessions of the grooved pegboard test. The 2 groups were identified based on average pegboard times during the practice sessions. Average pegboard time during practice was 73 ± 11 s for the fast group and 85 ± 13 s for the slow group. Explanatory variables for the pegboard times before and after practice were the durations of 4 peg-manipulation phases and 12 measures of force steadiness (coefficient of variation [CV] for force) during isometric contractions with the index finger abductor and wrist extensor muscles. Time to complete the grooved pegboard test after practice decreased by 25 ± 11% for the fast group and by 28 ± 10% for the slow group. Multiple regression models explained more of the variance in the pegboard times for the fast group before practice (Adjusted R2 = 0.85) than after practice (R2 = 0.51), whereas the variance explained for the slow group was similar before (Adjusted R2 = 0.67) and after (Adjusted R2 = 0.64) practice. The explanatory variables differed between before and after practice for the fast group but only slightly for the slow group. These findings indicate that performance-based stratification of older adults can identify unique adjustments in motor function that are independent of chronological age.

Is it the people or the place? The remarkable 30-year period of integrative physiology research in the Carlson Gymnasium at the University of Colorado Boulder.

Historically, programs of physical education and sport were housed in gymnasium buildings on academic campuses. As physical education evolved to the more scientifically focused successor departments of exercise science and kinesiology, faculty specialization developed in the physiology of exercise. With time, some faculty broadened their research to study the integrative physiology of other biological states and stressors. Through this series of events, a small group of integrative physiologists was formed in the Carlson Gymnasium at the University of Colorado Boulder during the 1990s with the goal of conducting novel biomedical research. The challenges were daunting: no contemporary core laboratory facilities, lack of temperature control, piercing external noise, pests, regular flooding, electrical power outages, and lack of funds for renovation. Despite these obstacles, the group established an innovative program of translational physiological research ranging from high-throughput molecular analyses to cell models to rodent studies to clinical trials in humans. These investigators supported their work with grant awards from the National Institutes of Health (NIH), Department of Defense, National Aeronautics and Space Administration (NASA), American Heart Association, and private research foundations totaling ∼$80 M in direct costs from the late 1980s to 2020. Collectively, the faculty and their laboratory personnel published ∼950 articles in peer-reviewed scientific journals. Over that period, 379 undergraduate students, 340 graduate students, 84 postdoctoral fellows, and dozens of junior research faculty received scientific training in Carlson, supported by >$21 M in extramural funding. What was accomplished by this handful of integrative physiologists speaks to the importance of the qualities of the investigators rather than their research facilities in determining scientific success.

Tuneable redox-responsive albumin-hitchhiking drug delivery to tumours for cancer treatment.

This paper outlines a novel drug delivery system for highly cytotoxic mertansine (DM1) by conjugating to an albumin-binding Evans blue (EB) moiety through a tuneable responsive disulfide linker, providing valuable insights for the development of effective drug delivery systems toward cancer therapy.

Differentiation of different dibenzothiophene (DBT) desulfurizing bacteria via surface-enhanced Raman spectroscopy (SERS).

Fossil fuels are considered vital natural energy resources on the Earth, and sulfur is a natural component present in them. The combustion of fossil fuels releases a large amount of sulfur in the form of SO x in the atmosphere. SO x is the major cause of environmental problems, mainly air pollution. The demand for fuels with ultra-low sulfur is growing rapidly. In this aspect, microorganisms are proven extremely effective in removing sulfur through a process known as biodesulfurization. A major part of sulfur in fossil fuels (coal and oil) is present in thiophenic structures such as dibenzothiophene (DBT) and substituted DBTs. In this study, the identification and characterization of DBT desulfurizing bacteria (Chryseobacterium sp. IS, Gordonia sp. 4N, Mycolicibacterium sp. J2, and Rhodococcus sp. J16) based on their specific biochemical constituents were conducted using surface-enhanced Raman spectroscopy (SERS). By differentiating DBT desulfurizing bacteria, researchers can gain insights into their unique characteristics, thus leading to improved biodesulfurization strategies. SERS was used to differentiate all these species based on their biochemical differences and different SERS vibrational bands, thus emerging as a potential technique. Moreover, multivariate data analysis techniques such as principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) were employed to differentiate these DBT desulfurizing bacteria on the basis of their characteristic SERS spectral signals. For all these isolates, the accuracy, sensitivity, and specificity are above 90%, and an AUC (area under the curve) value of close to 1 was achieved for all PLS-DA models.

Carbon dots as dual inhibitors of tau and amyloid-beta aggregation for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of senile dementia, presenting a significant challenge for the development of effective treatments. AD is characterized by extracellular amyloid plaques and intraneuronal neurofibrillary tangles. Therefore, targeting both hallmarks through inhibition of amyloid beta (Aß) and tau aggregation presents a promising approach for drug development. Carbon dots (CD), with their high biocompatibility, minimal cytotoxicity, and blood-brain barrier (BBB) permeability, have emerged as promising drug nanocarriers. Congo red, an azo dye, has gathered significant attention for inhibiting amyloid-beta and tau aggregation. However, Congo red's inability to cross the BBB limits its potential to be used as a drug candidate for central nervous system (CNS) diseases. Furthermore, current studies only focus on using Congo red to target single disease hallmarks, without investigating dual inhibition capabilities. In this study, we synthesized Congo red-derived CD (CRCD) by using Congo red and citric acid as precursors, resulting in three variants, CRCD1, CRCD2 and CRCD3, based on different mass ratios of precursors. CRCD2 and CRCD3 exhibited sustained low cytotoxicity, and CRCD3 demonstrated the ability to traverse the BBB in a zebrafish model. Moreover, thioflavin T (ThT) aggregation assays and AFM imaging revealed CRCD as potent inhibitors against both tau and Aß aggregation. Notably, CRCD1 emerged as the most robust inhibitor, displaying IC50 values of 0.2 ± 0.1 and 2.1 ± 0.5 µg/mL against tau and Aß aggregation, respectively. Our findings underscore the dual inhibitory role of CRCD against tau and Aß aggregation, showcasing effective BBB penetration and positioning CRCD as potential nanodrugs and nanocarriers for the CNS. Hence, CRCD-based compounds represent a promising candidate in the realm of multi-functional AD therapeutics, offering an innovative formulation component for future developments in this area. STATEMENT OF SIGNIFICANCE: This article reports Congo red-derived carbon dots (CRCD) as dual inhibitors of tau and amyloid-beta (Aß) aggregation for the treatment of Alzheimer's disease (AD). The CRCD are biocompatible and show strong fluorescence, high stability, the ability to cross the blood-brain barrier, and the function of addressing two major pathological features of AD.

SERS characterization of biochemical changes associated with biodesulfurization of dibenzothiophene using Gordonia sp. HS126-4N.

In this study, Gordonia sp. HS126-4N was employed for dibenzothiophene (DBT) biodesulfurization, tracked over 9 days using SERS. During the initial lag phase, no significant spectral changes were observed, but after 48 h, elevated metabolic activity was evident. At 72 h, maximal bacterial population correlated with peak spectrum variance, followed by stable spectral patterns. Despite 2-hydroxybiphenyl (2-HBP) induced enzyme suppression, DBT biodesulfurization persisted. PCA and PLS-DA analysis of the SERS spectra revealed distinctive features linked to both bacteria and DBT, showcasing successful desulfurization and bacterial growth stimulation. PLS-DA achieved a specificity of 95.5 %, sensitivity of 94.3 %, and AUC of 74 %, indicating excellent classification of bacteria exposed to DBT. SERS effectively tracked DBT biodesulfurization and bacterial metabolic changes, offering insights into biodesulfurization mechanisms and bacterial development phases. This study highlights SERS' utility in biodesulfurization research, including its use in promising advancements in the field.

Epidemiology of fractures in adults of African ancestry with diabetes mellitus: A systematic review and meta-analysis.

Diabetes mellitus (DM) is associated with increased fracture risk in White adults. However, the impact of DM on fractures in Black adults is unknown. This systematic review and meta-analysis investigated the association between DM and fractures in adults of African ancestry. MEDLINE, Scopus, CINAHL and Embase databases were searched from their inception up to November 2023 for all studies in the English language investigating the epidemiology of fractures (prevalence, incidence, or risk) in Black men and women (age ≥ 18 years) with type 1 or type 2 DM. Effect sizes for prevalence of previous fractures (%) and incident fracture risk (hazard ratio [HR]) were calculated using a random-effects model on Stata (version 18.0). There were 13 eligible studies, of which 12 were conducted in Black adults from the United States, while one was conducted in adults of West African ancestry from Trinidad and Tobago. We found no fracture data in Black adults with DM living in Africa. Five studies were included in a meta-analysis of incident fracture risk, reporting data from 2926 Black and 6531 White adults with DM. There was increased risk of fractures in Black adults with DM compared to non-DM (HR = 1.65; 95 % confidence interval [CI]: 1.14, 2.39). The risk of fractures was also higher in White adults with DM compared to non-DM (HR = 1.31; 95 % CI: 1.06, 1.61) among these studies. Five studies were included in a meta-analysis of fracture prevalence, of which three also reported fracture prevalence in White adults. There were 175 previous fractures among 993 Black adults with DM and 384 previous fractures among 1467 White adults with DM, with a pooled prevalence of 17.5 % (95 % CI: 15.4, 19.6) and 25.8 % (95 % CI: 4.8, 46.8), respectively. Our results indicate a high burden of fractures in Black adults with DM.

Gene Transfection Efficiency Improvement with Lipid Conjugated Cationic Carbon Dots.

An ideal vehicle with a high transfection efficiency is crucial for gene delivery. In this study, a type of cationic carbon dot (CCD) known as APCDs were first prepared with arginine (Arg) and pentaethylenehexamine (PEHA) as precursors and conjugated with oleic acid (OA) for gene delivery. By tuning the mass ratio of APCDs to OA, APCDs-OA conjugates, namely, APCDs-0.5OA, APCDs-1.0OA, and APCDs-1.5OA were synthesized. All three amphiphilic APCDs-OA conjugates show high affinity to DNA through electrostatic interactions. APCDs-0.5OA exhibit strong binding with small interfering RNA (siRNA). After being internalized by Human Embryonic Kidney (HEK 293) and osteosarcoma (U2OS) cells, they could distribute in both the cytoplasm and the nucleus. With APCDs-OA conjugates as gene delivery vehicles, plasmid DNA (pDNA) that encodes the gene for the green fluorescence protein (GFP) can be successfully delivered in both HEK 293 and U2OS cells. The GFP expression levels mediated by APCDs-0.5OA and APCDs-1.0OA are ten times greater than that of PEI in HEK 293 cells. Furthermore, APCDs-0.5OA show prominent siRNA transfection efficiency, which is proven by the significantly downregulated expression of FANCA and FANCD2 proteins upon delivery of FANCA siRNA and FANCD2 siRNA into U2OS cells. In conclusion, our work demonstrates that conjugation of CCDs with a lipid structure such as OA significantly improves the gene transfection efficiency, providing a new idea about the designation of nonviral carriers in gene delivery systems.

Temporal context effects on suboptimal choice.

Choice can be driven both by rewards and stimuli that signal those rewards. Under certain conditions, pigeons will prefer options that lead to less probable reward when the reward is signaled. A recently quantified model, the Signal for Good News (SiGN) model, assumes that in the context of uncertainty, signals for a reduced delay to reward reinforce choice. The SiGN model provides an excellent fit to previous results from pigeons and the current studies are the first to test a priori quantitative predictions. Pigeons chose between a suboptimal alternative that led to signaled 20% food and an optimal alternative that led to 50% food. The duration of the choice period was manipulated across conditions in two experiments. Pigeons strongly preferred the suboptimal alternative at the shorter durations and strongly preferred the optimal alternative at the longer durations. The results from both experiments fit well with predictions from the SiGN model and show that altering the duration of the choice period has a dramatic effect in that it changes which of the two options pigeons prefer. More generally, these results suggest that the relative value of options is not fixed, but instead depends on the temporal context.

Evaluating the clinical and cost-effectiveness of a conservative approach to oxygen therapy for invasively ventilated adults in intensive care: Protocol for the UK-ROX trial.

Background: In the United Kingdom, around 184,000 adults are admitted to an intensive care unit (ICU) each year with over 30% receiving mechanical ventilation. Oxygen is the commonest therapeutic intervention provided to these patients but it is unclear how much oxygen should be administered for the best clinical outcomes. Methods: The UK-ROX trial will evaluate the clinical and cost-effectiveness of conservative oxygen therapy (the minimum oxygen concentration required to maintain an oxygen saturation of 90% ± 2%) versus usual oxygen therapy in critically ill adults receiving supplemental oxygen when invasively mechanically ventilated in ICUs in England, Wales and Northern Ireland. The trial will recruit 16,500 patients from approximately 100 UK adult ICUs. Using a deferred consent model, enrolled participants will be randomly allocated (1:1) to conservative or usual oxygen therapy until ICU discharge or 90 days after randomisation. Objectives: The primary clinical outcome is all cause mortality at 90 days following randomisation. Discussion: The UK-ROX trial has received ethical approval from the South Central - Oxford C Research Ethics Committee (Reference: 20/SC/0423) and the Confidentiality Advisory Group (Reference: 22/CAG/0154). The trial commenced in May 2021 and, at the time of publication, 95 sites had opened to recruitment.

First in vitro measurement of VHEE relative biological effectiveness (RBE) in lung and prostate cancer cells using the ARES linac at DESY.

Very high energy electrons (VHEE) are a potential candidate for radiotherapy applications. This includes tumours in inhomogeneous regions such as lung and prostate cancers, due to the insensitivity of VHEE to inhomogeneities. This study explores how electrons in the VHEE range can be used to perform successful in vitro radiobiological studies. The ARES (accelerator research experiment at SINBAD) facility at DESY, Hamburg, Germany was used to deliver 154 MeV electrons to both prostate (PC3) and lung (A549) cancer cells in suspension. Dose was delivered to samples with repeatability and uniformity, quantified with Gafchromic film. Cell survival in response to VHEE was measured using the clonogenic assay to determine the biological effectiveness of VHEE in cancer cells for the first time using this method. Equivalent experiments were performed using 300 kVp X-rays, to enable VHEE irradiated cells to be compared with conventional photons. VHEE irradiated cancer cell survival was fitted to the linear quadratic (LQ) model (R2 = 0.96-0.97). The damage from VHEE and X-ray irradiated cells at doses between 1.41 and 6.33 Gy are comparable, suggesting similar relative biological effectiveness (RBE) between the two modalities. This suggests VHEE is as damaging as photon radiotherapy and therefore could be used to successfully damage cancer cells during radiotherapy. The RBE of VHEE was quantified as the relative doses required for 50% (D0.5) and 10% (D0.1) cell survival. Using these values, VHEE RBE was measured as 0.93 (D0.5) and 0.99 (D0.1) for A549 and 0.74 (D0.5) and 0.93 (D0.1) for PC3 cell lines respectively. For the first time, this study has shown that 154 MeV electrons can be used to effectively kill lung and prostate cancer cells, suggesting that VHEE would be a viable radiotherapy modality. Several studies have shown that VHEE has characteristics that would offer significant improvements over conventional photon radiotherapy for example, electrons are relatively easy to steer and can be used to deliver dose rapidly and with high efficiency. Studies have shown improved dose distribution with VHEE in treatment plans, in comparison to VMAT, indicating that VHEE can offer improved and safer treatment plans with reduced side effects. The biological response of cancer cells to VHEE has not been sufficiently studied as of yet, however this initial study provides some initial insights into cell damage. VHEE offers significant benefits over photon radiotherapy and therefore more studies are required to fully understand the biological effectiveness of VHEE.

White matter hyperintensity patterns: associations with comorbidities, amyloid, and cognition.

BACKGROUND: White matter hyperintensities (WMHs) are often measured globally, but spatial patterns of WMHs could underlie different risk factors and neuropathological and clinical correlates. We investigated the spatial heterogeneity of WMHs and their association with comorbidities, Alzheimer's disease (AD) risk factors, and cognition. METHODS: In this cross-sectional study, we studied 171 cognitively unimpaired (CU; median age: 65 years, range: 50 to 89) and 51 mildly cognitively impaired (MCI; median age: 72, range: 53 to 89) individuals with available amyloid (18F-flutementamol) PET and FLAIR-weighted images. Comorbidities were assessed using the Cumulative Illness Rating Scale (CIRS). Each participant's white matter was segmented into 38 parcels, and WMH volume was calculated in each parcel. Correlated principal component analysis was applied to the parceled WMH data to determine patterns of WMH covariation. Adjusted and unadjusted linear regression models were used to investigate associations of component scores with comorbidities and AD-related factors. Using multiple linear regression, we tested whether WMH component scores predicted cognitive performance. RESULTS: Principal component analysis identified four WMH components that broadly describe FLAIR signal hyperintensities in posterior, periventricular, and deep white matter regions, as well as basal ganglia and thalamic structures. In CU individuals, hypertension was associated with all patterns except the periventricular component. MCI individuals showed more diverse associations. The posterior and deep components were associated with renal disorders, the periventricular component was associated with increased amyloid, and the subcortical gray matter structures was associated with sleep disorders, endocrine/metabolic disorders, and increased amyloid. In the combined sample (CU + MCI), the main effects of WMH components were not associated with cognition but predicted poorer episodic memory performance in the presence of increased amyloid. No interaction between hypertension and the number of comorbidities on component scores was observed. CONCLUSION: Our study underscores the significance of understanding the regional distribution patterns of WMHs and the valuable insights that risk factors can offer regarding their underlying causes. Moreover, patterns of hyperintensities in periventricular regions and deep gray matter structures may have more pronounced cognitive implications, especially when amyloid pathology is also present.