Exceptional electronic transport and quantum oscillations in thin bismuth crystals grown inside van der Waals materials.

Confining materials to two-dimensional forms changes the behaviour of the electrons and enables the creation of new devices. However, most materials are challenging to produce as uniform, thin crystals. Here we present a synthesis approach where thin crystals are grown in a nanoscale mould defined by atomically flat van der Waals (vdW) materials. By heating and compressing bismuth in a vdW mould made of hexagonal boron nitride, we grow ultraflat bismuth crystals less than 10 nm thick. Due to quantum confinement, the bismuth bulk states are gapped, isolating intrinsic Rashba surface states for transport studies. The vdW-moulded bismuth shows exceptional electronic transport, enabling the observation of Shubnikov-de Haas quantum oscillations originating from the (111) surface state Landau levels. By measuring the gate-dependent magnetoresistance, we observe multi-carrier quantum oscillations and Landau level splitting, with features originating from both the top and bottom surfaces. Our vdW mould growth technique establishes a platform for electronic studies and control of bismuth's Rashba surface states and topological boundary modes1-3. Beyond bismuth, the vdW-moulding approach provides a low-cost way to synthesize ultrathin crystals and directly integrate them into a vdW heterostructure.

Assessing the stability and sporicidal efficacy of oxidizing disinfectants.

BACKGROUND: The role of the healthcare environment in the transmission of clinical pathogens is well established. EN 17126:2018 was developed to address the need for regulated sporicidal product testing and includes a realistic medical soil to enable validation of products that claim combined cleaning and disinfection efficacy. AIM: To investigate the chemical stability and sporicidal efficacy of oxidizing disinfectant products in the presence of simulated clean and medical dirty conditions. METHODS: Disinfectant stability and sporicidal efficacy were evaluated in like-for-like ratios of soil:product. Disinfectants were exposed to simulated test soils and free chlorine, chlorine dioxide or peracetic acid concentrations were measured using standard colorimetric methods. Efficacy of disinfectants against C. difficile R027 endospores was assessed as per EN 17126:2018. Comparisons of performance between clean and medical dirty conditions were performed using one-way analysis of variance. Correlation analysis was performed using Pearson product-moment correlation. FINDINGS: Performance of chlorine-releasing agents (sodium dichloroisocyanurate, chlorine dioxide and hypochlorous acid) was concentration dependent, with 1000 ppm chlorine showing reduced stability and efficacy in dirty conditions. By contrast, peracetic acid product demonstrated stability and consistently achieved efficacy in dirty conditions. CONCLUSION: These results have implications for clinical practice, as ineffective environmental decontamination may increase the risk of transmission of pathogens that can cause healthcare-associated infections.

Acetaminophen influences musculoskeletal signaling but not adaptations to endurance exercise training.

Acetaminophen (ACE) is a widely used analgesic and antipyretic drug with various applications, from pain relief to fever reduction. Recent studies have reported equivocal effects of habitual ACE intake on exercise performance, muscle growth, and risks to bone health. Thus, this study aimed to assess the impact of a 6-week, low-dose ACE regimen on muscle and bone adaptations in exercising and non-exercising rats. Nine-week-old Wistar rats (n = 40) were randomized to an exercise or control (no exercise) condition with ACE or without (placebo). For the exercise condition, rats ran 5 days per week for 6 weeks at a 5% incline for 2 min at 15 cm/s, 2 min at 20 cm/s, and 26 min at 25 cm/s. A human equivalent dose of ACE was administered (379 mg/kg body weight) in drinking water and adjusted each week based on body weight. Food, water intake, and body weight were measured daily. At the beginning of week 6, animals in the exercise group completed a maximal treadmill test. At the end of week 6, rats were euthanized, and muscle cross-sectional area (CSA), fiber type, and signaling pathways were measured. Additionally, three-point bending and microcomputer tomography were measured in the femur. Follow-up experiments in human primary muscle cells were used to explore supra-physiological effects of ACE. Data were analyzed using a two-way ANOVA for treatment (ACE or placebo) and condition (exercise or non-exercise) for all animal outcomes. Data for cell culture experiments were analyzed via ANOVA. If omnibus significance was found in either ANOVA, a post hoc analysis was completed, and a Tukey's adjustment was used. ACE did not alter body weight, water intake, food intake, or treadmill performance (p > .05). There was a treatment-by-condition effect for Young's Modulus where placebo exercise was significantly lower than placebo control (p < .05). There was no treatment by condition effects for microCT measures, muscle CSA, fiber type, or mRNA expression. Phosphorylated-AMPK was significantly increased with exercise (p < .05) and this was attenuated with ACE treatment. Furthermore, phospho-4EBP1 was depressed in the exercise group compared to the control (p < .05) and increased in the ACE control and ACE exercise group compared to placebo exercise (p < .05). A low dose of ACE did not influence chronic musculoskeletal adaptations in exercising rodents but acutely attenuated AMPK phosphorylation and 4EBP1 dephosphorylation post-exercise.

Going beyond political ideology: A computational analysis of civic trust in science.

Numerous studies have been conducted to identify the factors that predict trust/distrust in science. However, most of these studies are based on closed-ended survey research, which does not allow researchers to gain a more nuanced understanding of the phenomenon. This study integrated survey analysis conducted within the United States with computational text analysis to reveal factors previously obscured by traditional survey methodologies. Even after controlling for political ideology-which has been the most significant explanatory factor in determining trust in science within a survey framework-we found those with concerns over boundary-crossing (i.e. concerns or perceptions that science overlaps with politics, the government, and funding) were less likely to trust science than their counterparts.

Trade-offs in land-based carbon removal measures under 1.5 °C and 2 °C futures.

Land-based carbon removals, specifically afforestation/reforestation and bioenergy with carbon capture and storage (BECCS), vary widely in 1.5 °C and 2 °C scenarios generated by integrated assessment models. Because underlying drivers are difficult to assess, we use a well-known integrated assessment model, GCAM, to demonstrate that land-based carbon removals are sensitive to the strength and scope of land-based mitigation policies. We find that while cumulative afforestation/reforestation and BECCS deployment are inversely related, they are both typically part of cost-effective mitigation pathways, with forestry options deployed earlier. While the CO2 removal intensity (removal per unit land) of BECCS is typically higher than afforestation/reforestation over long time horizons, the BECCS removal intensity is sensitive to feedstock and technology choices whereas the afforestation/reforestation removal intensity is sensitive to land policy choices. Finally, we find a generally positive relationship between agricultural prices and removal effectiveness of land-based mitigation, suggesting that some trade-offs may be difficult to avoid.

Life in the PFAS lane: The impact of perfluoroalkyl substances on photosynthesis, cellular exudates, nutrient cycling, and composition of a marine microbial community.

Perfluoroalkyl substances (PFAS) are of great ecological concern, however, exploration of their impact on bacteria-phytoplankton consortia is limited. This study employed a bioassay approach to investigate the effect of unary exposures of increasing concentrations of PFAS (perfluorooctane sulfonate (PFOS) and 6:2 fluorotelomer sulfonate (6:2 FTS)) on microbial communities from the northwestern Gulf of Mexico. Each community was examined for changes in growth and photophysiology, exudate production and shifts in community structure (16S and 18S rRNA genes). 6:2 FTS did not alter the growth or health of phytoplankton communities, as there were no changes relative to the controls (no PFOS added). On the other hand, PFOS elicited significant phototoxicity (p < 0.05), altering PSII antennae size, lowering PSII connectivity, and decreasing photosynthetic efficiency over the incubation (four days). PFOS induced a cellular protective response, indicated by significant increases (p < 0.001) in the release of transparent exopolymer particles (TEP) compared to the control. Eukaryotic communities (18S rRNA gene) changed substantially (p < 0.05) and to a greater extent than prokaryotic communities (16S rRNA gene) in PFOS treatments. Community shifts were concentration-dependent for eukaryotes, with the low treatment (5 mg/L PFOS) dominated by Coscinodiscophyceae (40 %), and the high treatment (30 mg/L PFOS) marked by a Trebouxiophyceae (50 %) dominance. Prokaryotic community shifts were not concentration dependent, as both treatment levels became depleted in Cyanobacteriia and were dominated by members of the Bacteroidia, Gammaproteobacteria, and Alphaproteobacteria classes. Further, PFOS significantly decreased (p < 0.05) the Shannon diversity and Pielou's evenness across treatments for eukaryotes, and in the low treatment (5 mg/L PFOS) for prokaryotes. These findings show that photophysiology was not impacted by 6:2 FTS but PFOS elicited toxicity that impacted photosynthesis, exudate release, and community composition. This research is crucial in understanding how PFOS impacts microbial communities.

Comparison of histological delineations of medial temporal lobe cortices by four independent neuroanatomy laboratories.

The medial temporal lobe (MTL) cortex, located adjacent to the hippocampus, is crucial for memory and prone to the accumulation of certain neuropathologies such as Alzheimer's disease neurofibrillary tau tangles. The MTL cortex is composed of several subregions which differ in their functional and cytoarchitectonic features. As neuroanatomical schools rely on different cytoarchitectonic definitions of these subregions, it is unclear to what extent their delineations of MTL cortex subregions overlap. Here, we provide an overview of cytoarchitectonic definitions of the entorhinal and parahippocampal cortices as well as Brodmann areas (BA) 35 and 36, as provided by four neuroanatomists from different laboratories, aiming to identify the rationale for overlapping and diverging delineations. Nissl-stained series were acquired from the temporal lobes of three human specimens (two right and one left hemisphere). Slices (50 µm thick) were prepared perpendicular to the long axis of the hippocampus spanning the entire longitudinal extent of the MTL cortex. Four neuroanatomists annotated MTL cortex subregions on digitized slices spaced 5 mm apart (pixel size 0.4 µm at 20× magnification). Parcellations, terminology, and border placement were compared among neuroanatomists. Cytoarchitectonic features of each subregion are described in detail. Qualitative analysis of the annotations showed higher agreement in the definitions of the entorhinal cortex and BA35, while the definitions of BA36 and the parahippocampal cortex exhibited less overlap among neuroanatomists. The degree of overlap of cytoarchitectonic definitions was partially reflected in the neuroanatomists' agreement on the respective delineations. Lower agreement in annotations was observed in transitional zones between structures where seminal cytoarchitectonic features are expressed less saliently. The results highlight that definitions and parcellations of the MTL cortex differ among neuroanatomical schools and thereby increase understanding of why these differences may arise. This work sets a crucial foundation to further advance anatomically-informed neuroimaging research on the human MTL cortex.

Longitudinal volumetric changes in amygdala subregions in frontotemporal dementia.

Amygdala atrophy has been found in frontotemporal dementia (FTD), yet the specific changes of its subregions across different FTD phenotypes remain unclear. The aim of this study was to investigate the volumetric alterations of the amygdala subregions in FTD phenotypes and how they evolve with disease progression. Patients clinically diagnosed with behavioral variant FTD (bvFTD) (n = 20), semantic dementia (SD) (n = 20), primary nonfluent aphasia (PNFA) (n = 20), Alzheimer's disease (AD) (n = 20), and 20 matched healthy controls underwent whole brain structural MRI. The patient groups were followed up annually for up to 3.5 years. Amygdala nuclei were segmented using FreeSurfer, corrected by total intracranial volumes, and grouped into the basolateral, superficial, and centromedial subregions. Linear mixed effects models were applied to identify changes in amygdala subregional volumes over time. At baseline, bvFTD, SD, and AD displayed global amygdala volume reduction, whereas amygdala volume appeared to be preserved in PNFA. Asymmetrical amygdala atrophy (left > right) was most pronounced in SD. Longitudinally, SD and PNFA showed greater rates of annual decline in the right basolateral and superficial subregions compared to bvFTD and AD. The findings provide comprehensive insights into the differential impact of FTD pathology on amygdala subregions, revealing distinct atrophy patterns that evolve over disease progression. The characterization of amygdala subregional involvement in FTD and their potential role as biomarkers carry substantial clinical implications.

Utilisation of specialist epilepsy services and antiseizure medication adherence rates in a cohort of people with epilepsy (PWE) accessing emergency care.

BACKGROUND: An epilepsy-related attendance at A&E is associated an increased risk of subsequent death within 6 months. Although further work is required to provide a definitive explanation to account for these findings, in the interim it would seem reasonable that services are designed to ensure timely access and provide support at a time of greatest risk. We aim to determine the frequency of patients accessing specialist neurology services following an epilepsy-related admission/unscheduled care episode and consider ASM adherence at the point of attendance. METHODS: Patients were identified retrospectively via the NHS Greater Glasgow and Clyde live integrated epilepsy Dashboard following an unscheduled epilepsy-related admission or A&E attendance between 1st January 2022 and 30th June 2022. We calculated adherence to anti-seizure medication for a period of 6 months prior to admission and defined poor medication adherence as a medication possession ratio of less than 80 %. We evaluated the rate of any outpatient neurology clinic attendance in the subsequent 3, 6 and 12 months following an epilepsy-related unscheduled care episode. Additional clinical information was identified via the electronic patient records. RESULTS: Between 1st Jan 2022 and 30th June 2022, there were 266 emergency care seizure-related attendances. The mean age at attendance was 46 years (range: 16-91). Most of PWE were males (63 %) and 37 % were females. Epilepsy classification-29.3 % had GGE, 41.7% had focal epilepsy, and in 29 % of cases the epilepsy was unclassified. Of the admissions, 107/ 266 (40.2 %) generated follow-up within 6 months of attendance. Poor medication adherence was noted in 54/266 (20.3 %). 28.2 % of cases had input from on-call neurology service during admission/ED attendance, and of those 60 % had ASM adjusted. 18 % of attendances had a background diagnosis of learning disability. One-third of attendances of PWE had a history of mental health disorder 35 % (93/266). 25 % of ED attendances noted an active history of alcohol consumption misuse or/and recreational drug use. 14 (5.5 %) of PWE died during the period of interest (12 months following the last ED visit). In 6/14 (42.3 %) death was associated with poor medication adherence. CONCLUSION: This study demonstrates that a significant proportion of patients who experienced seizure-related admissions/ attendance did not access specialist neurology services in a timely manner. In addition, poor medication adherence remains a problem for a substantial number of people living with epilepsy. Early access to specialist services may go some way to improving care and reducing excessive mortality in PWE by allowing anti-seizure medication to be titrated and poor medication adherence to be addressed in those at greatest risk.

Exploring graded profiles of hippocampal atrophy along the anterior-posterior axis in semantic dementia and Alzheimer's disease.

Mounting evidence indicates marked hippocampal degeneration in semantic dementia (SD) however, the spatial distribution of hippocampal atrophy profiles in this syndrome remains unclear. Using a recently developed parcellation approach, we extracted hippocampal volumes from four distinct subregions running from anterior to posterior along the longitudinal axis (anterior, intermediate rostral, intermediate caudal, and posterior). Volumetric differences in hippocampal subregions were compared between 21 SD, 24 matched Alzheimer's disease (AD), and 27 healthy older Control participants. Despite comparable overall hippocampal volume loss, SD and AD groups diverged in terms of the magnitude of atrophy along the anterior-posterior axis of the hippocampus. Global hippocampal atrophy was observed in AD, with no discernible gradation or lateralisation. In contrast, SD patients displayed graded bilateral hippocampal atrophy, most pronounced on the left-hand side, and concentrated in anterior relative to posterior subregions. Finally, we found preliminary evidence that disease-specific vulnerability along the anterior-posterior axis of the hippocampus was associated with canonical clinical features of these syndromes.

Comparison of histological delineations of medial temporal lobe cortices by four independent neuroanatomy laboratories.

The medial temporal lobe (MTL) cortex, located adjacent to the hippocampus, is crucial for memory and prone to the accumulation of certain neuropathologies such as Alzheimer's disease neurofibrillary tau tangles. The MTL cortex is composed of several subregions which differ in their functional and cytoarchitectonic features. As neuroanatomical schools rely on different cytoarchitectonic definitions of these subregions, it is unclear to what extent their delineations of MTL cortex subregions overlap. Here, we provide an overview of cytoarchitectonic definitions of the cortices that make up the parahippocampal gyrus (entorhinal and parahippocampal cortices) and the adjacent Brodmann areas (BA) 35 and 36, as provided by four neuroanatomists from different laboratories, aiming to identify the rationale for overlapping and diverging delineations. Nissl-stained series were acquired from the temporal lobes of three human specimens (two right and one left hemisphere). Slices (50 µm thick) were prepared perpendicular to the long axis of the hippocampus spanning the entire longitudinal extent of the MTL cortex. Four neuroanatomists annotated MTL cortex subregions on digitized (20X resolution) slices with 5 mm spacing. Parcellations, terminology, and border placement were compared among neuroanatomists. Cytoarchitectonic features of each subregion are described in detail. Qualitative analysis of the annotations showed higher agreement in the definitions of the entorhinal cortex and BA35, while definitions of BA36 and the parahippocampal cortex exhibited less overlap among neuroanatomists. The degree of overlap of cytoarchitectonic definitions was partially reflected in the neuroanatomists' agreement on the respective delineations. Lower agreement in annotations was observed in transitional zones between structures where seminal cytoarchitectonic features are expressed more gradually. The results highlight that definitions and parcellations of the MTL cortex differ among neuroanatomical schools and thereby increase understanding of why these differences may arise. This work sets a crucial foundation to further advance anatomically-informed human neuroimaging research on the MTL cortex.

Clonal hematopoiesis and acquired genetic abnormalities of the red cell: An historical review.

Several syndromes affecting the red cell that mimic those induced by germline mutations may result from a somatic mutation that accompanies a myeloid malignancy. These syndromes are most notable in cases of myelodysplastic syndrome, but they are not limited to any one category of myeloid neoplasm. Their occurrence in males exceed the male predominance that is evident in myeloid neoplasms. The syndromes include disorders of globin chain synthesis (α- and ß-thalassemia), heme synthesis (erythropoietic porphyria and erythropoietic uroporphyria), red cell membrane structure (elliptocytosis and spherocytosis), red cell enzyme activity (pyruvate kinase deficiency, glucose-6-phosphate dehydrogenase deficiency) and lowered expression of red cell ABO blood group antigens. This historical review describes the path to uncovering these acquired syndromes and their causal somatic mutations, where known. These syndromes often go unrecognized because of the dominant concern of the primary neoplasm. They may add to the healthcare needs of the patient.

Impaired Discrimination of Electrocutaneous Stimulation in the Paretic Hand of Stroke Survivors.

Artificial sensory feedback via electrocutaneous stimulation can be used to assist or rehabilitate stroke survivors with sensory deficits. Conveying the magnitude of tactile stimuli is an important aspect of artificial sensory feedback. Here, we explore how stroke-related sensory deficits impact the ability of electrocutaneous stimulation to convey the magnitude of tactile stimuli. Using classical psychophysical methods, we quantified the threshold of detection and the just-noticeable difference of electrocutaneous stimulation current in five stroke survivors with unilateral sensory deficits. We show significantly greater (40%) stimulation currents are needed for initial perception on the paretic hand compared to the non-paretic hand. We also show significantly greater percent changes in stimulation current (140%) are needed for reliable incremental perception on the paretic hand compared to the non-paretic hand. Lastly, we show little correlation between electrocutaneous discrimination performance and clinical sensory assessments of light-touch and spatial mechanoperception. These findings can help guide the implementation of artificial sensory feedback as an assistive or rehabilitative intervention for individuals experiencing sensory loss after a stroke.Clinical Relevance- Our results can help guide the implementation of electrical stimulation as an assistive or rehabilitative intervention for individuals with sensory loss after stroke.

Differential Use of Radiotherapy Fractionation Regimens in Prostate Cancer.

Importance: Technical advances in treatment of prostate cancer and a better understanding of prostate cancer biology have allowed for hypofractionated treatment courses using a higher dose per fraction. Use of ultrahypofractionated stereotactic body radiotherapy (SBRT) has also been characterized. Objective: To characterize US national trends of different RT fractionation schemes across risk groups of prostate cancer. Design, Setting, and Participants: This retrospective cohort study used data collected by the National Cancer Database (NCDB) to characterize the fractionation regimens used for 302 035 patients diagnosed as having prostate cancer from January 1, 2004, to December 31, 2020, who underwent definitive RT. The analysis was performed between February 1 and April 30, 2023. Exposure: Stereotactic body RT or ultrahypofractionation, defined as 5 or fewer fractions of external beam RT (EBRT), moderate hypofractionation, defined as 20 to 28 fractions of EBRT, or conventional fractionation, defined as all remaining EBRT fractionation schemes. Main Outcomes and Measures: Temporal trends and clinical and sociodemographic factors associated with SBRT, moderate hypofractionation, and conventional fractionation use. Results: A total of 302 035 men receiving EBRT for localized prostate cancer between 2004 and 2020 were identified (40.1% aged 60-69 years). Black patients comprised 17.6% of this cohort; White patients, 77.9%; and other races and ethnicities, 4.5%. Patients with low-risk disease comprised 17.5% of the cohort; favorable intermediate-risk disease, 23.5%; unfavorable intermediate-risk disease, 23.9%; and high-risk disease, 35.1%. Treatment consisted of conventional fractionation for 81.2%, moderate hypofractionation for 12.9%, and SBRT for 6.0%. The rate of increase over time in patients receiving SBRT compared with conventional fractionation was higher (adjusted odds ratio [AOR] for 2005 vs 2004, 3.18 [95% CI, 2.04-4.94; P < .001]; AOR for 2020 vs 2004, 264.69 [95% CI, 179.33-390.68; P < .001]) than the rate of increase in patients receiving moderate hypofractionation compared with conventional fractionation (AOR for 2005 vs 2004, 1.05 [95% CI, 0.98-1.12; P = .19]; AOR for 2020 vs 2004, 4.41 [95% CI, 4.15-4.69; P < .001]). Compared with White patients, Black patients were less likely to receive SBRT compared with conventional fractionation or moderate hypofractionation (AOR for conventional fractionation, 0.84 [95% CI, 0.80-0.89; P < .001]; AOR for moderate hypofractionation, 0.77 [95% CI, 0.72-0.81; P < .001]). Compared with 2019, patients treated with all fractionation regimens declined in 2020 by 24.4%. Conclusions and Relevance: In this hospital-based cohort study of patients with prostate cancer treated with definitive EBRT, use of moderate hypofractionation and SBRT regimens for definitive prostate cancer treatment has increased from 2004 to 2020. Despite this increasing trend, findings suggest potential health care disparities for Black patients receiving EBRT for localized prostate cancer. The number of patients treated with EBRT in the year 2020 decreased, coinciding with official onset of the COVID-19 pandemic in March 2020.

Sleep related rhythmic movement disorder: phenotypic characteristics and treatment response in a paediatric cohort.

OBJECTIVE: To describe phenotypic, polysomnographic characteristics, impact, and treatment response in children with sleep related rhythmic movement disorder (SR-RMD). BACKGROUND: There is limited research on SR-RMD. We have developed a systematic clinical evaluation of children with SR-RMD to improve understanding and treatment. METHODS: A retrospective chart review of 66 children at a UK tertiary hospital. Baseline assessment included validated screening questionnaires to study autism spectrum characteristics, general behaviour and sensory profile. A standardised questionnaire assessed impact on sleep quality and daytime wellbeing of child and family. Polysomnography data were collated. RESULTS: Children were aged 0.9-16.3 years (78.8% male). 51.5% had a neurodevelopmental disorder, most commonly autism spectrum disorder. High rates of behavioural disturbance and sensory processing differences were reported, not confined to children with neurodevelopmental disorders. Parents reported concerns about risk of injury, loss of sleep and persistence into adulthood. Daytime wellbeing was affected in 72% of children and 75% of other family members. Only 31/48 children demonstrated rhythmic movements during video-polysomnography, occupying on average 6.1% of time in bed. Most clusters occurred in the settling period but also arose from N1, N2 and REM sleep and wake after sleep onset. Melatonin was prescribed to 52 children, all but one were extended-release preparations. 24/27 children with available data were reported to improve with melatonin. CONCLUSIONS: SR-RMD places a significant burden on child and family wellbeing. Our novel findings of sensory processing differences in this population and parent reported therapeutic response to extended-release melatonin offer potential avenues for future research.

Cardiovascular Disease and Stroke in Immune TTP-Challenges and Opportunities.

Advances in the management of immune thrombotic thrombocytopenic purpura (iTTP) have dramatically improved outcomes of acute TTP episodes, and TTP is now treated as a chronic, relapsing disorder. It is now recognized that iTTP survivors are at high risk for vascular disease, with stroke and myocardial infarction occurring at younger ages than in the general population, and cardiovascular disease is the leading cause of premature death in this population. iTTP appears to have a phenotype of accelerated vascular aging with a particular predilection for cerebral circulation, and stroke is much more common than myocardial infarction. In addition to traditional cardiovascular risk factors, low ADAMTS13 activity during clinical remission may be a risk factor for some of these outcomes, such as stroke. Recent studies also suggest that Black patients, who are disproportionately affected by iTTP in the United States, are at higher risk of adverse cardiovascular outcomes, likely due to multifactorial reasons. Additional research is required to establish the risk factors and mechanisms underlying these complications in order to institute optimal screening strategies and identify interventions to improve outcomes.

A randomized phase II trial of MR-guided prostate stereotactic body radiotherapy administered in 5 or 2 fractions for localized prostate cancer (FORT).

BACKGROUND: Ultra-hypofractionated regimens for definitive prostate cancer (PCa) radiotherapy are increasingly utilized due in part to promising safety and efficacy data complemented by greater patient convenience from a treatment course requiring fewer sessions. As such, stereotactic body radiation therapy (SBRT) is rapidly emerging as a standard definitive treatment option for patients with localized PCa. The commercially available magnetic resonance linear accelerator (MR-LINAC) integrates MR imaging with radiation delivery, providing several theoretical advantages compared to computed tomography (CT)-guided radiotherapy. MR-LINAC technology facilitates improved visualization of the prostate, real-time intrafraction tracking of prostate and organs-at-risk (OAR), and online adaptive planning to account for target movement and anatomical changes. These features enable reduced treatment volume margins and improved sparing of surrounding OAR. The theoretical advantages of MR-guided radiotherapy (MRgRT) have recently been shown to significantly reduce rates of acute grade ≥ 2 GU toxicities as reported in the prospective randomized phase III MIRAGE trial, which compared MR-LINAC vs CT-based 5 fraction SBRT in patients with localized PCa (Kishan et al. JAMA Oncol 9:365-373, 2023). Thus, MR-LINAC SBRT-utilizing potentially fewer treatments-is warranted and clinically relevant for men with low or intermediate risk PCa electing for radiotherapy as definitive treatment. METHODS/DESIGN: A total of 136 men with treatment naïve low or intermediate risk PCa will be randomized in a 1:1 ratio to 5 or 2 fractions of MR-guided SBRT using permuted block randomization. Randomization is stratified by baseline Expanded PCa Index Composite (EPIC) bowel and urinary domain scores. Patients undergoing 5 fractions will receive 37.5 Gy to the prostate over 10-14 days and patients undergoing 2 fractions will receive 25 Gy to the prostate over 7-10 days. The co-primary endpoints are GI and GU toxicities as measured by change scores in the bowel and urinary EPIC domains, respectively. The change scores will be calculated as pre-treatment (baseline) score subtracted from the 2-year score. DISCUSSION: FORT is an international, multi-institutional prospective randomized phase II trial evaluating whether MR-guided SBRT delivered in 2 fractions versus 5 fractions is non-inferior from a gastrointestinal (GI) and genitourinary (GU) toxicity standpoint at 2 years post-treatment in men with low or intermediate risk PCa. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04984343 . Date of registration: July 30, 2021. PROTOCOL VERSION: 4.0, Nov 8, 2022.