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Michael N Bucci,1 Dennis Oh,2 R Scott Cowan,3 Reginald J Davis,4 Robert Jackson,5 Dwight S Tyndall,6 Daniel Nehls7 1Piedmont Spine and Neurosurgical Group, PA, Greenville, SC, USA; 2Baystate Medical Center, Springfield, MA, USA; 3New England Orthopedic Surgeons, Inc., Springfield, MA, USA; 4Greater Baltimore Medical Center, Baltimore, MD, USA; 5Orange County Neurosurgical Associates, Laguna Hills, CA, USA; 6Orthopedic Specialists of Northwest Indiana, Munster, IN, USA; 7Franciscan Neurosurgery Associates at St. Joseph Medical Center, Tacoma, WA, USA Introduction: Anterior cervical discectomy and fusion (ACDF) has been the gold standard for treating cervical degenerative disc disease (cDDD). The use of anterior plates in ACDF poses an increased risk of complications such as screw or plate dislodgement, soft tissue injury, esophagus perforation, and dysphagia. The ROI-C™ implant system consists of a zero-profile interbody fusion cage with self-locking plates designed for stand-alone fusion without external plates or screws.Objective: The purpose of this report is to describe the ROI-C™ implant system with VerteBRIDGE™ anchor plates, including indications for use, surgical technique, preclinical testing, and clinical study results. The objectives of the clinical study were to assess fusion status, incidence of dysphagia and other device-related complications, and patient reported outcomes.Methods: This was a retrospective, multicenter cohort study of 110 patients who underwent ACDF with ROI-C at seven study centers. Patient charts and radiographs were reviewed for any complications or device malfunction. The final follow-up was conducted prospectively and included collection of neck disability index, and visual analog scale (VAS) neck and arm pain scores.Results: The mean operation time was 73 minutes, and mean blood loss was 25 mL (range 0–75 mL). Mean follow-up was 20.7 months (range 9.5–42.2). Dysphagia was reported in two patients (1.8%), and 99.1% of patients achieved fusion. One patient had radiographically confirmed pseudarthrosis at 12 months that was asymptomatic and did not require surgery. One patient had subsequent surgery owing to adjacent level degeneration. The mean neck disability index, VAS neck pain, and VAS right and left arm pain scores at final follow-up were 19, 26.5, 12.5, and 15.3, respectively.Conclusion: The ROI-C interbody cage with VerteBRIDGE anchor plates achieved a high rate of fusion, with a low incidence of dysphagia. These patients had similar or better outcomes compared to ACDF with anterior plating reported in peer-reviewed literature. Keywords: ROI-C, zero-profile spacer, ACDF, stand-alone cage, cervical disc degeneration

The alligator population at Lake Apopka in central Florida declined dramatically between 1980 and 1987. Endocrine-disrupting chemicals and specifically DDT metabolites have been implicated in the alligators' reproductive failure. The DDT metabolite hypothesis is based largely on the observation of elevated concentrations of p,p-DDE and p,p-DDD in alligator eggs obtained from Lake Apopka in 1984 and 1985. In the following commentary, we draw attention to two nematocides that are established reproductive toxins in humans, dibromochloropropane (DBCP) and ethylene dibromide (EDB), which could also have played a role in the reproductive failure observed in alligators from Lake Apopka in the early 1980s.

Objective: To determine if injury grade (IG) influences outcome; need for operative intervention (OP), blood transfusion, or survival, following blunt pediatric liver (L) and spleen (S) trauma. Methods: A review of 111 children with 114 blunt liver/spleen injuries treated from 1989 to 1995. All hemodynamically stable patients were initially treated non-operatively (NONOP). Diagnosis (L-78, S-36) and grading (L-59, S-34) of injury was made by CT scan or at OP. IG, survival, ISS, hemodynamic stability, blood transfused, associated injuries were analyzed. Results are reported as means. Statistical analysis was performed using Kruskal-Wallis, ANOVA, and Chi-squared tests. Results: Age was 7.4 years, IG was 2.8, ISS was 11.5 and mean transfusion was 12 ml/kg of packed red blood cells (PRBC). 12 of 78 (15%) with liver injuries and 7 of 36 (19%) with splenic injury had OP. Mean IG of 2.8 in OP, was no different than NONOP (p=0.8). IG was similar in transfused vs. no transfusion, 2.8 vs. 2.7 (p=0.4), and in stable vs. unstable, 2.7 vs. 2.9 (p=0.8). Mean PRBC requirement was higher in OP vs. NONOP, 51 vs. 6 ml/kg (p=0.0001), and OP patients had a higher ISS, 17 vs. 10 (p=0.01). There were 77 patients (69%) with associated injuries of whom 15 died (none as a result of liver/spleen injury); and 34 (31%) isolated liver/spleen injuries, with one death. Death was associated with unstable hemodynamics (p=0.0005), a higher ISS, 23 vs. 9.7 (p=0.0005), and higher PRBC, 56 vs. 7 (p=0.0001), but not higher IG, 2.5 vs. 2.8 (p=0.3). Conclusion: Injury grade does not influence outcome following blunt pediatric liver and spleen trauma. Higher ISS, PRBC requirement, and hemodynamic instability predicted need for operation, as well as death., H Grewal MD(*), CW Wagner MD, RJ Jackson MD, SD. Smith MD, FAAP, D Parnell RN, MNSc, S Helmer PhD(*); (*)UKS of Medicine-Wichita, KS 67208 & Arkansas Children's Hospital, Little [...]

Introduction: Because of a more liberal radiographic diagnosis of malrotation, we have seen an increase in the number of Ladd's procedures performed for intestinal malrotation (IM). Concern with postoperative complications prompted a review of our recent experience with surgery for IM. Methods: Between January 1995 and July 1998, 117 children with a diagnosis of IM were retrospectively studied. Patients with abdominal wall defects or CDH were excluded. Results: Mean age at presentation was 22 months. There was a male preponderance (65%). Twenty-five patients (21%) had a history of prematurity. Associated congenital anomalies were present in 31 (26%), consisting of cardiac defects in 20 (17%) and chromosomal abnormalities in 11 (9%). Presenting symptoms included vomiting (79%), abdominal pain (26%) and difficulties with feeding (21%), breathing (21%) and stooling (15%). Emesis was nonbilious in two-thirds of the vomiting patients. UGI w/SBFT was the primary diagnostic study in 106 patients (91%). Fifteen patients had multiple UGI's because of uncertainty of the original diagnosis. A Ladd's procedure was performed in 111 patients (95%). Twenty-three complications occurred in 21 patients, and included small bowel obstruction (15), prolonged ileus (4), wound infection (2), evisceration (1), and pancreatitis (1). Nine deaths occurred; only one was related to IM with necrotic midgut. Reoperation was required in 11 of 15 patients with SBO, on average at POD 49 (range 3-289). Findings at reoperation included adhesive SBO (7), small bowel intussusception (3), and volvulus (2). Preoperative symptoms persisted in 16 patients. Ten had persistent vomiting secondary to GER; 3 of these required subsequent fundoplication. Conclusion: A surprisingly high rate of postoperative complications, particularly SBO, in children undergoing Ladd's procedure for IM was identified. This occurred in the setting of an increased number of children with a radiographic diagnosis of malrotation. A prospective study correlating radiographic and operative findings is ongoing to better define the indication for operation in children with IM., Northrop RC, MD, Wagner CW, MD, Smith SD, MD, FAAP, and Jackson RJ, MD; University of Arkansas for Medical Sciences and Arkansas Children's Hospital, Little Rock, Arkansas [...]

Children in the London Boroughs of Kensington, Chelsea and Westminster have one of the highest levels of caries in England and Wales. In 1997/98, the mean dmft for 5-year-old children was 2.83 with only 45.9% of the children being caries free. The aim of this study was to determine whether teacher-supervised toothbrushing, once a day, at school, during term time, with commercial toothpaste containing 1,450 ppm fluoride, could reduce dental caries in primary school children when compared with children from the same community who did not receive this intervention. A total of 517 children (mean age 5.63 years) were recruited for the study. Class teachers were trained individually by the same dental hygienist in an appropriate toothbrushing technique for young children. Children in the intervention group brushed once a day at school. All examinations were by visual assessment only. All teeth present were assessed using the BASCD criteria. For children in the intervention group, the overall caries increment (2.60) was significantly less (10.9%; p < 0.001) than for children in the non-intervention group (2.92). Among different tooth surfaces, the difference in caries increment between the intervention group (0.78) and the non-intervention group (1.03) was greatest for the proximal surfaces (21.4%; p < 0.01). In conclusion, this study suggests that a programme of daily teacher-supervised toothbrushing with fluoride toothpaste can be effectively targeted into socially deprived communities and a significant reduction in dental caries can thereby be achieved especially among caries-susceptible children. [ABSTRACT FROM AUTHOR]

The design of a community's built environment influences the physical and mental health of its residents. Because few studies have investigated this relationship, the Centers for Disease Control and Prevention hosted a workshop in May 2002 to help develop a scientific research agenda on these issues. Workshop participants' areas of expertise included physical activity, injury prevention, air pollution, water quality, urban planning, transportation, architecture, epidemiology, land use, mental health, social capital, housing, and social marketing. This report describes the 37 questions in the resulting research agenda. The next steps are to define priorities and obtain resources. The proposed research will help identify the best practices for designing new communities and revitalizing old ones in ways that promote physical and mental health. [ABSTRACT FROM AUTHOR]

The potential impact of pesticides on public health is substantial. The U.S. Environmental Protection Agency (U.S. EPA) reports that more than one billion pounds of conventional active pesticide ingredients are used annually in the United States and that 69 million American households, or 85 percent of all families, store and use pesticides in and around the home. Poison control center reports and hospital-based data suggest that the impact of acute pesticide poisoning may be significant. In the absence of a national system for reporting nonoccupational pesticiderelated illnesses, however, it is not possible to accurately estimate the public health impact of pesticide-related morbidity and mortality in the United States. In addition, surveillance is needed to provide information essential for the prevention and control of pesticide-related illness and injury. The National Center for Environmental Health (NCEH) proposes to establish a national surveillance system to monitor pesticide-related health conditions resulting from nonoccupational pesticide exposures. As an initial step, NCEH and U.S. EPA are funding a pilot surveillance project to be tested in 1999. The test will be conducted in a state that already has an occupational pesticide-illness surveillance program; with the knowledge-base and infrastructure already in place, costs and start-up time will be reduced. NCEH and its state and federal partners recognize the need for a national program for surveillance of nonoccupational pesticide-related health effects; however, funding will remain a challenge to establishing an effective and ongoing national surveillance system. [ABSTRACT FROM AUTHOR]

Burning of fossil fuels along with deforestation and ecological disruption have led to the warming of the Earth and climate change. Children are especially vulnerable to adverse health effects of climate change associated changes in the air, soil, and water as their organs are still developing, have a faster breathing rate, higher per pound ingested and inhaled exposures, and greater relative body surface area. To protect this vulnerable population, health care professionals need to play a leading role. In 2015, the American Academy of Pediatrics (AAP) updated their original 2007 Global Climate Change and Children's Health policy statement (again updated in 2024) stating that, "failure to take prompt, substantive action would be an act of injustice to all children." Health care professionals need to educate themselves and their patients of the health risks posed by climate change and incorporate climate change counseling into their practice. They also need to go beyond the framework of the healthcare system and work collaboratively with communities, corporations, and governments to advocate for policies and solutions to mitigate and adapt to climate change. The health and wellbeing of future generations rests upon the actions we take today. IMPACT: Summarizes the adverse effects of increased anthropogenic activity and burning of fossil fuels on planetary and human health Details the increased vulnerability of children to environmental assaults and their long-term effects Provides guidance and resources to health care professionals to empower them to act as advocates for systemic and structural changes that protect children's health., (© 2024. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Data on COVID-19 cases, deaths, hospitalizations, and vaccinations in Oklahoma, USA, have not been systematically described. The relationship between vaccination and COVID-19-related outcomes over time has not been investigated. We graphically described data collected during February 2020-December 2021 and conducted spatiotemporal modeling of monthly increases in COVID-19 cumulative death and hospitalization rates, adjusting for cumulative case rate, to explore the relationship. A 1 percentage point increase (absolute change) in the cumulative vaccination rate was associated with a 6.3% (95% CI 1.4%-10.9%) relative decrease in death outcome during April-June 2021, and a 1.9% (95% CI 1.1%-2.6%) relative decrease in death outcome and 1.1% (95% CI 0.5%-1.7%) relative decrease in hospitalization outcome during July-December 2021; the effect on hospitalizations was driven largely by data from urban counties. Our findings from Oklahoma suggest that increasing cumulative vaccination rates might reduce the increase in cumulative death and hospitalization rates from COVID-19.

Ferroelectric materials promise exceptional attributes including low power dissipation, fast operational speeds, enhanced endurance, and superior retention to revolutionize information technology. However, the practical application of ferroelectric-semiconductor memory devices has been significantly challenged by the incompatibility of traditional perovskite oxide ferroelectrics with metal-oxide-semiconductor technology. Recent discoveries of ferroelectricity in binary oxides such as Zn 1-x Mg x O and Hf 1-x Zr x O have been a focal point of research in ferroelectric information technology. This work investigates the ferroelectric properties of Zn 1-x Mg x O utilizing automated band excitation piezoresponse force microscopy. This findings reveal the coexistence of two ferroelectric subsystems within Zn 1-x Mg x O. A "fringing-ridge mechanism" of polarization switching is proposed that is characterized by initial lateral expansion of nucleation without significant propagation in depth, contradicting the conventional domain growth process observed in ferroelectrics. This unique polarization dynamics in Zn 1-x Mg x O suggests a new understanding of ferroelectric behavior, contributing to both the fundamental science of ferroelectrics and their application in information technology., (© 2024 Wiley‐VCH GmbH.)

Objective: This study aims to prioritise the themes identified from the three gap analyses performed by a combination of scientists, clinicians, patients and members of the public to determine areas in breast cancer care where research is lacking. We also aimed to compare the priorities of areas of agreed research need between patients, the public, clinicians and scientists., Design: A cross-section of patients, public, clinicians and scientists completed a prioritisation exercise to rank the identified themes where research is lacking in breast cancer care., Participants: Patients, clinicians and scientists who have experienced, managed or worked in the field of breast cancer and members of the public., Methods: The research areas identified in the Breast Cancer Campaign, Association of Breast Surgery and North West Breast Research Collaborative gap analyses were outlined as 22 themes in lay terminology. Patients, members of the public, clinicians and scientists were invited to complete the prioritisation exercise, on paper or electronically, ranking the themes from 1 to 22. Comparisons were made with arithmetic mean ranking., Results: Of the 510 prioritisation exercises completed, 179 (35%) participants were patients, 162 (32%) public, 43 (8%) scientists and 122 (24%) clinicians. The theme ranked of highest priority overall was 'better prevention' (arithmetic mean rank 6.4 (SE 0.23)). 'Better prevention' was ranked top or second by patients, public and clinicians (7 (0.39), 4.7 (0.34) and 6.8 (0.5), respectively), however, scientists ranked this as their sixth most important factor (7.7 (0.92)). The public and clinicians had good agreement with patients (r=0.84 and r=0.75, respectively), whereas scientists had moderate agreement with patients (r=0.65). Certain themes were ranked significantly differently by participant groups. Compared with clinicians, patients prioritised research into 'alternative to mammograms', 'diagnostic (cancer) blood test' and 'rare cancers' (OR 2.1 (95% CI 1.3 to 3.5), p=0.002, OR 2.1 (95% CI 1.3 to 3.5), p=0.004 and OR 1.7 (95% CI 1.1 to 2.8), p=0.03). Compared with scientists, patients deprioritised 'better laboratory models' (OR 0.4 (95% CI 0.2 to 0.8), p=0.01)., Conclusion: This study demonstrates that patients, public, clinicians and scientists have different research priorities, with scientists being a particular outlier. This highlights the need to ensure the engagement of patients and public in research funding prioritisation decisions., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Selective fetal growth restriction (sFGR) in monochorionic twin pregnancy, defined as an estimated fetal weight (EFW) of one twin <10th centile and EFW discordance ≥25%, is associated with stillbirth and neurodisability for both twins. The condition poses unique management difficulties: on the one hand, continuation of the pregnancy carries a risk of death of the smaller twin, with a high risk of co-twin demise (40%) or co-twin neurological sequelae (30%). On the other, early delivery to prevent the death of the smaller twin may expose the larger twin to prematurity, with the associated risks of long-term physical, emotional and financial costs from neurodisability, such as cerebral palsy.When there is severe and early sFGR, before viability, delivery is not an option. In this scenario, there are currently three main management options: (1) expectant management, (2) selective termination of the smaller twin and (3) placental laser photocoagulation of interconnecting vessels. These management options have never been investigated in a randomised controlled trial (RCT). The best management option is unknown, and there are many challenges for a potential RCT. These include the rarity of the condition resulting in a small number of eligible pregnancies, uncertainty about whether pregnant women will agree to participate in such a trial and whether they will agree to be randomised to expectant management or active fetal intervention, and the challenges of robust and long-term outcome measures. Therefore, the main objective of the FERN study is to assess the feasibility of conducting an RCT of active intervention vs expectant management in monochorionic twin pregnancies with early-onset (prior to 24 weeks) sFGR., Methods and Analysis: The FERN study is a prospective mixed-methods feasibility study. The primary objective is to recommend whether an RCT of intervention vs expectant management of sFGR in monochorionic twin pregnancy is feasible by exploring women's preference, clinician's preference, current practice and equipoise and numbers of cases. To achieve this, we propose three distinct work packages (WPs). WP1: A Prospective UK Multicentre Study, WP2A: a Qualitative Study Exploring Parents' and Clinicians' Views and WP3: a Consensus Development to Determine Feasibility of a Trial. Eligible pregnancies will be recruited to WP1 and WP2, which will run concurrently. The results of these two WPs will be used in WP3 to develop consensus on a future definitive study. The duration of the study will be 53 months, composed of 10 months of setup, 39 months of recruitment, 42 months of data collection, and 5 months of data analysis, report writing and recommendations. The pragmatic sample size for WP1 is 100 monochorionic twin pregnancies with sFGR. For WP2, interviews will be conducted until data saturation and sample variance are achieved, that is, when no new major themes are being discovered. Based on previous similar pilot studies, this is anticipated to be approximately 15-25 interviews in both the parent and clinician groups. Engagement of at least 50 UK clinicians is planned for WP3., Ethics and Dissemination: This study has received ethical approval from the Health Research Authority (HRA) South West-Cornwall and Plymouth Ethics Committee (REC reference 20/SW/0156, IRAS ID 286337). All participating sites will undergo site-specific approvals for assessment of capacity and capability by the HRA. The results of this study will be published in peer-reviewed journals and presented at national and international conferences. The results from the FERN project will be used to inform future studies., Trial Registration Number: This study is included in the ISRCTN Registry (ISRCTN16879394) and the NIHR Central Portfolio Management System (CPMS), CRN: Reproductive Health and Childbirth Specialty (UKCRN reference 47201)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Progressive supranuclear palsy (PSP) is a neurodegenerative disease characterized by 4R tau deposition in neurons as well as in astrocytes and oligodendrocytes. While astrocytic tau deposits are rarely observed in normal aging (so-called aging-related tau astrogliopathy, ARTAG) and Alzheimer's disease (AD), astrocytic tau in the form of tufted astrocytes is a pathognomonic hallmark of PSP. Classical biochemical experiments emphasized tau synthesis in neurons in the central nervous system, suggesting that astrocytic tau inclusions might be derived from uptake of extracellular neuronal-derived tau. However, recent single-nucleus RNAseq experiments highlight the fact that MAPT, the gene encoding tau, is also expressed by astrocytes, albeit in lower amounts. We, therefore, revisited the question of whether astrocyte-driven expression of tau might contribute to astrocytic tau aggregates in PSP by performing fluorescent in situ hybridization/immunohistochemical co-localization in human postmortem brain specimens from individuals with PSP and AD with ARTAG as well as normal controls. We find that, in PSP but not in AD, tau-immunoreactive astrocytes have higher levels of MAPT mRNA compared to astrocytes that do not have tau aggregates. These results suggest that astrocytic responses in PSP are unique to this tauopathy and support the possibility that fundamental changes in PSP astrocyte-endogenous mRNA biology contribute to increased synthesis of tau protein and underlies the formation of the astrocytic tau deposits characteristic of PSP., (© 2024. The Author(s).)

For the past three decades, apolipoprotein E (APOE) has been known as the single greatest genetic modulator of sporadic Alzheimer disease (AD) risk, influencing both the average age of onset and the lifetime risk of developing AD. The APOEε4 allele significantly increases AD risk, whereas the ε2 allele is protective relative to the most common ε3 allele. However, large differences in effect size exist across ethnoracial groups that are likely to depend on both global genetic ancestry and local genetic ancestry, as well as gene-environment interactions. Although early studies linked APOE to amyloid-β - one of the two culprit aggregation-prone proteins that define AD - in the past decade, mounting work has associated APOE with other neurodegenerative proteinopathies and broader ageing-related brain changes, such as neuroinflammation, energy metabolism failure, loss of myelin integrity and increased blood-brain barrier permeability, with potential implications for longevity and resilience to pathological protein aggregates. Novel mouse models and other technological advances have also enabled a number of therapeutic approaches aimed at either attenuating the APOEε4-linked increased AD risk or enhancing the APOEε2-linked AD protection. This Review summarizes this progress and highlights areas for future research towards the development of APOE-directed therapeutics., (© 2024. Springer Nature Limited.)

Epidemiological studies show that individuals who carry the relatively uncommon APOE ε2 allele rarely develop Alzheimer disease, and if they do, they have a later age of onset, milder clinical course, and less severe neuropathological findings than people without this allele. The contrast is especially stark when compared with the major genetic risk factor for Alzheimer disease, APOE ε4, which has an age of onset several decades earlier, a more aggressive clinical course and more severe neuropathological findings, especially in terms of the amount of amyloid deposition. Here, we demonstrate that brain exposure to APOE ε2 via a gene therapy approach, which bathes the entire cortical mantle in the gene product after transduction of the ependyma, reduces Aβ plaque deposition, neurodegenerative synaptic loss, and, remarkably, reduces microglial activation in an APP/PS1 mouse model despite continued expression of human APOE ε4. This result suggests a promising protective effect of exogenous APOE ε2 and reveals a cell nonautonomous effect of the protein on microglial activation, which we show is similar to plaque-associated microglia in the brain of Alzheimer disease patients who inherit APOE ε2. These data increase the potential that an APOE ε2 therapeutic could be effective in Alzheimer disease, even in individuals born with the risky ε4 allele., Competing Interests: Declaration of interests D.M.H. is on the scientific advisory board of C2N Diagnostics and has equity. D.M.H. is on the scientific advisory board of Denali Therapeutics, Genentech, and Cajal Therapeutics and consults for Asteroid. B.L.D. serves an advisory role with equity in Latus Biosciences, Patch Bio, Voyager Therapeutics, Carbon Biosciences, Spirovant Biosciences, Resilience, Panorama Medicines, Saliogen, and Homology Medicines. She has sponsored research from Novartis, Roche, Latus, Homology Medicines, Saliogen, and Spirovant. B.T.H. is on the scientific advisory board of Latus Bio and has an equity interest. B.T.H. has a family member who works at Novartis, and owns stock in Novartis; he serves on the scientific advisory board of Dewpoint and owns stock. He serves on a scientific advisory board of or is a consultant for AbbVie, Aprinoia Therapeutics, Arvinas, Avrobio, Axial, Biogen, BMS, Cure Alzheimer’s Fund, Cell Signaling, Dewpoint, Eisai, Genentech, Ionis, Latus, Novartis, Sangamo, Sanofi, Seer, Takeda, the US Department of Justice, Vigil, and Voyager. M.S.K., L.T., Y.C., and P.T.R. are founders of and shareholders in Latus Biosciences., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Treatment of juxtarenal and complex neck abdominal aortic aneurysms (AAAs) is now commonly by endovascular rather than open surgical repair (OSR). Published comparisons show poor validity and scientific precision. UK-COMPASS is a comparative cohort study of endovascular treatments vs. OSR for patients with an AAA unsuitable for standard on label endovascular aneurysm repair (EVAR)., Methods: All procedures for AAA in England (November 2017 to October 2019) were identified, AAA anatomy assessed in a Corelab, peri-operative risk scores determined, and propensity scoring used to identify patients suitable for either endovascular treatment or OSR. Patients were stratified by aneurysm neck length (0 - 4 mm, 5 - 9 mm, or ≥ 10 mm) and operative risk; the highest quartile was considered high risk and the remainder standard risk. Death was the primary outcome measure. Endovascular treatments included fenestrated EVAR (FEVAR) and off label standard EVAR (± adjuncts)., Results: Among 8 994 patients, 2 757 had AAAs that were juxtarenal, short neck, or complex neck in morphology. Propensity score stratification and adjustment method comparisons included 1 916 patients. Widespread off label use of standard EVAR devices was noted (35.6% of patients). The adjusted peri-operative mortality rate was 2.9%, lower for EVAR (1.2%; p = .001) and FEVAR (2.2%; p = .001) than OSR (4.5%). In standard risk patients with a 0 - 4 mm neck, the mortality rate was 7.4% following OSR and 2.3% following FEVAR. Differences were smaller for patients with a neck length ≥ 5 mm: 2.1% OSR vs. 1.0% FEVAR. At 3.5 years of follow up, the overall mortality rate was 20.7% in the whole study population, higher following FEVAR (27.6%) and EVAR (25.2%) than after OSR (14.2%). However, in the 0 - 4 mm neck subgroup, overall survival remained equivalent. The aneurysm related mortality rate was equivalent between treatments, but re-intervention was more common after EVAR and FEVAR than OSR., Conclusion: FEVAR proves notably safer than OSR in the peri-operative period for juxtarenal aneurysms (0 - 4 mm neck length), with comparable midterm survival. For patients with short neck (5 - 9 mm) and complex neck (≥ 10 mm) AAAs, overall survival was worse in endovascularly treated patients compared with OSR despite relative peri-operative safety. This warrants further research and a re-appraisal of the current clinical application of endovascular strategies, particularly in patients with poor general survival outlook owing to comorbidity and age., (Copyright © 2024 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.)

Synapse loss correlates with cognitive decline in Alzheimer's disease, and soluble oligomeric amyloid beta (Aβ) is implicated in synaptic dysfunction and loss. An important knowledge gap is the lack of understanding of how Aβ leads to synapse degeneration. In particular, there has been difficulty in determining whether there is a synaptic receptor that binds Aβ and mediates toxicity. While many candidates have been observed in model systems, their relevance to human AD brain remains unknown. This is in part due to methodological limitations preventing visualization of Aβ binding at individual synapses. To overcome this limitation, we combined two high resolution microscopy techniques: array tomography and Förster resonance energy transfer (FRET) to image over 1 million individual synaptic terminals in temporal cortex from AD (n = 11) and control cases (n = 9). Within presynapses and post-synaptic densities, oligomeric Aβ generates a FRET signal with transmembrane protein 97. Further, Aβ generates a FRET signal with cellular prion protein, and post-synaptic density 95 within post synapses. Transmembrane protein 97 is also present in a higher proportion of post synapses in Alzheimer's brain compared to controls. We inhibited Aβ/transmembrane protein 97 interaction in a mouse model of amyloidopathy by treating with the allosteric modulator CT1812. CT1812 drug concentration correlated negatively with synaptic FRET signal between transmembrane protein 97 and Aβ. In human-induced pluripotent stem cell derived neurons, transmembrane protein 97 is present in synapses and colocalizes with Aβ when neurons are challenged with human Alzheimer's brain homogenate. Transcriptional changes are induced by Aβ including changes in genes involved in neurodegeneration and neuroinflammation. CT1812 treatment of these neurons caused changes in gene sets involved in synaptic function. These data support a role for transmembrane protein 97 in the synaptic binding of Aβ in human Alzheimer's disease brain where it may mediate synaptotoxicity., (© 2024. The Author(s).)

Objective: GATA6 is a key regulator of the classical phenotype in pancreatic ductal adenocarcinoma (PDAC). Low GATA6 expression associates with poor patient outcome. GATA4 is the second most expressed GATA factor in the pancreas. We assessed whether, and how, GATA4 contributes to PDAC phenotype and analysed the association of expression with outcome and response to chemotherapy., Design: We analysed PDAC transcriptomic data, stratifying cases according to GATA4 and GATA6 expression and identified differentially expressed genes and pathways. The genome-wide distribution of GATA4 was assessed, as well as the effects of GATA4 knockdown. A multicentre tissue microarray study to assess GATA4 and GATA6 expression in samples (n=745) from patients with resectable was performed. GATA4 and GATA6 levels were dichotomised into high/low categorical variables; association with outcome was assessed using univariable and multivariable Cox regression models., Results: GATA4 messenger RNA is enriched in classical, compared with basal-like tumours. We classified samples in 4 groups as high/low for GATA4 and GATA6 . Reduced expression of GATA4 had a minor transcriptional impact but low expression of GATA4 enhanced the effects of GATA6 low expression. GATA4 and GATA6 display a partially overlapping genome-wide distribution, mainly at promoters. Reduced expression of both proteins in tumours was associated with the worst patient survival. GATA4 and GATA6 expression significantly decreased in metastases and negatively correlated with basal markers., Conclusions: GATA4 and GATA6 cooperate to maintain the classical phenotype. Our findings provide compelling rationale to assess their expression as biomarkers of poor prognosis and therapeutic response., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Apolipoprotein E (ApoE) is a multifaceted secreted molecule synthesized in the CNS by astrocytes and microglia, and in the periphery largely by the liver. ApoE has been shown to impact the integrity of the blood-brain barrier, and, in humans, the APOE4 allele of the gene is reported to lead to a leaky blood-brain barrier. We used allele specific knock-in mice expressing each of the common (human) ApoE alleles, and longitudinal multiphoton intravital microscopy, to directly monitor the impact of various ApoE isoforms on blood-brain barrier integrity. We found that humanized APOE4, but not APOE2 or APOE3, mice show a leaky blood-brain barrier, increased MMP9, impaired tight junctions, and reduced astrocyte end-foot coverage of blood vessels. Removal of astrocyte-produced ApoE4 led to the amelioration of all phenotypes while the removal of astrocyte-produced ApoE3 had no effect on blood-brain barrier integrity. This work shows a cell specific gain of function effect of ApoE4 in the dysfunction of the BBB and implicates astrocyte production of ApoE4, possibly as a function of astrocytic end foot interactions with vessels, as a key regulator of the integrity of the blood-brain barrier., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Introduction: Pancreatic cancer is a leading cause of cancer deaths worldwide. Screening for this disease has potential to improve survival. It is not feasible, with current screening modalities, to screen the asymptomatic adult population. However, screening of individuals in high-risk groups is recommended. Our study aims to provide resources and data that will inform strategies to screen individuals with new-onset diabetes (NOD) for pancreatic cancer., Methods and Analysis: The United Kingdom Early Detection Initiative (UK-EDI) for pancreatic cancer is a national, prospective, observational cohort study that aims to recruit 2500 individuals with NOD (<6 months postdiagnosis) aged 50 years and over, with follow-up every 6 months, over a 3-year period. For study eligibility, diagnosis of diabetes is considered to be clinical measurement of haemoglobin A1c ≥48 mmol/mol. Detailed clinical information and biospecimens will be collected at baseline and follow-up to support the development of molecular, epidemiological and demographic biomarkers for earlier detection of pancreatic cancer in the high-risk NOD group. Socioeconomic impacts and cost-effectiveness of earlier detection of pancreatic cancer in individuals with NOD will be evaluated. The UK-EDI NOD cohort will provide a bioresource for future early detection research to be conducted., Ethics and Dissemination: The UK-EDI study has been reviewed and approved by the London-West London and GTAC Research Ethics Committee (Ref 20/LO/0058). Study results will be disseminated through presentations at national and international symposia and publication in peer-reviewed, Open Access journals., Competing Interests: Competing interests: EC, LO, WG, CH and PG are named as inventors on GB patent GBGB1806002.0; PCT/GB2019/050998, submitted by the University of Liverpool, that covers the measurement of adiponectin and IL-1Ra as a biomarker for early detection of pancreatic cancer., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: Evidence-based models for providing effective and comprehensive care for Alzheimer's disease and related dementias exist but have yet to be successfully implemented at scale. The Alzheimer's and Dementia Care Program (ADC Program) is an effective comprehensive dementia care model that is being disseminated across the United States. This qualitative study examines barriers and facilitators to implementing the model among early adopting sites., Methods: This study included semi-structured interviews with a total of 21 clinical site leaders and Dementia Care Specialists from a total of 11 sites across the US. Interviews were audio recorded, transcribed, and coded using Dedoose qualitative analysis software. Coding scheme development and data interpretation were informed by Rogers' Diffusion of Innovations framework., Results: Key themes are organized in line with Rogers' framework. These include: the innovation-decision process, implementation and characteristics of the innovation, and sustainability., Conclusions: Across the three overarching themes presented in this manuscript, the importance of engagement from site leaders, the multifaceted nature of the dementia care specialist role, and the value of technical assistance from qualified experts are apparent. However, for this work to continue to be successful, there needs to be more appropriate payment to cover needed services and a mechanism for supporting comprehensive dementia care over time., (© 2022 The American Geriatrics Society.)

Cryogels consisting of polyvinyl alcohol and iron (II, III) oxide magnetic nanoparticles coated with a model drug-acetaminophen, were developed as a tunable platform for thermally triggered drug release, based on shape-selective heat transfer. Two different shapes of cryogels; discs and spherical caps, were formed via adding polymer-nanoparticle-drug mixtures into 3D printed molds, followed by freeze-thawing five times. No additional chemical crosslinking agents were used for gel formation and the iron oxide nanoparticles were coated with acetaminophen using only citric acid as a hydrogen-bonding linker. The two gel shapes displayed varying levels of acetaminophen release within 42-50 °C, which are ideal temperatures for hyperthermia induced drug delivery. The amount and time of drug-release were shown to be tunable by changing the temperature of the medium and the shape of the gels, while keeping all other factors (ex. gel volume, surface area, polymer/nanoparticle concentrations and drug-loading) constant. The discs displayed higher drug release at all temperatures while being particularly effective at lower temperatures (42-46 °C), in contrast to the spherical caps, which were more effective at higher temperatures (48-50 °C). Magnetic hyperthermia-mediated thermal imaging and temperature profiling studies revealed starkly different heat transfer behavior from the two shapes of gels. The disc gels retained their structural integrity up to 51 °C, while the spherical caps were stable up to 59 °C, demonstrating shape-dependent robustness. The highly customizable physicochemical features, facile synthesis, biocompatibility and tunable drug release ability of these cryogels offer potential for their application as a low cost, safe and effective platform for hyperthermia-mediated drug delivery, for external applications such as wound care/muscle repair or internal applications such as melanoma treatment., (© 2022. The Author(s).)

The problem of associating a continuous covariate, or biomarker, against a time-to-event outcome, is that it often requires categorisation of the covariate. This can lead to bias, loss of information and a poor representation of any underlying relationship. Here, two methods are proposed for estimating the effects of a continuous covariate on a time-to-event endpoint using weighted kernel estimators. The first method aims to estimate a density function for a time-to-event endpoint conditional on some covariate value whilst the second uses a joint density estimator. The results are visualisations in the form of surface plots that show the effects of a covariate without any need for categorisation. Both methods can aid interpretation and analysis of covariates against a time-to-event endpoint., (© 2021 John Wiley & Sons Ltd.)

Objective: Abdominal aortic aneurysms (AAAs) with adverse morphology of the aneurysm neck are "complex". Techniques employed to repair complex aneurysms include open surgical repair (OSR) and a number of on label endovascular techniques such as fenestrated endovascular aneurysm repair (FEVAR) and endovascular aneurysm repair (EVAR) with adjuncts (including chimneys and endo-anchors), as well as off label use of standard EVAR. The aim was to conduct a network meta-analysis (NMA) of published comparative outcomes., Data Sources: An electronic search was performed in Embase, MEDLINE, and the Cochrane Central Register of Controlled Trials (CENTRAL). These databases were interrogated using the PubMed interface and the Healthcare Databases Advanced Search (HDAS) interface developed by the National Institute of Health and Care Excellence., Review Methods: Online databases were interrogated up to April 2020. Studies were included if they compared outcomes between at least two methods of repair for complex aneurysms (those with at least one adverse neck feature: absent/short neck, conicality, angulation, calcification, large diameter, and thrombus). The primary outcome measure was peri-operative death. Pre-registration was done in PROSPERO (CRD42020177482)., Results: The search identified 24 observational studies and 7854 patients who underwent OSR, FEVAR, off label EVAR, or chimney EVAR. No comparative studies included EVAR with endo-anchors. NMA was performed on 23 studies that reported outcomes of aneurysms with short/absent infrarenal neck. Compared with OSR, off label EVAR (relative risk [RR] 0.10, 95% confidence interval [CI] 0.01 - 0.41) and FEVAR (RR 0.62, 95% CI 0.32-0.94) were associated with lower peri-operative mortality. This difference was not seen at the midterm follow up (30 months). Compared with OSR, FEVAR was associated with a lower peri-operative myocardial infarction (MI) rate (RR 0.37, 95% CI 0.16 - 0.62) but a higher midterm re-intervention rate (hazard ratio 1.65, 95% CI 1.04 - 2.66). All studies had a "moderate" or "high" risk of bias. Confidence in the network findings (GRADE) was generally "low"., Conclusion: This NMA demonstrated a peri-operative survival benefit for off label EVAR and FEVAR compared with OSR, potentially due to reduced risk of MI. FEVAR carries a greater midterm re-intervention risk than OSR, with potential implications for cost effectiveness. There is paucity of comparative data for cases with adverse neck features other than short length., (Copyright © 2022 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.)

Purpose: The trend of atherosclerotic plaque feature evolution is unclear in stroke patients with and without recurrence. We aimed to use three-dimensional whole-brain magnetic resonance vessel wall imaging to quantify the morphological changes of causative lesions during medical therapy in patients with symptomatic intracranial atherosclerotic disease., Methods: Patients with acute ischemic stroke attributed to intracranial atherosclerotic disease were retrospectively enrolled if they underwent both baseline and follow-up magnetic resonance vessel wall imaging. The morphological features of the causative plaque, including plaque volume, peak normalized wall index, maximum wall thickness, degree of stenosis, pre-contrast plaque-wall contrast ratio, and post-contrast plaque enhancement ratio, were quantified and compared between the non-recurrent and recurrent groups (defined as the recurrence of a vascular event within 18 months of stroke)., Results: Twenty-nine patients were included in the final analysis. No significant differences were found in plaque features in the baseline scan between the non-recurrent ( n  = 22) and recurrent groups ( n  = 7). The changes in maximum wall thickness (-13.32% vs. 8.93%, P  = 0.026), plaque-wall contrast ratio (-0.82% vs. 3.42%, P  = 0.005) and plaque enhancement ratio (-11.03% vs. 9.75%, P  = 0.019) were significantly different between the non-recurrent and recurrent groups. Univariable logistic regression showed that the increase in plaque-wall contrast ratio (odds ratio 3.22, 95% confidence interval 1.55-9.98, P  = 0.003) was related to stroke recurrence., Conclusion: Morphological changes of plaque features on magnetic resonance vessel wall imaging demonstrated distinct trends in symptomatic intracranial atherosclerotic disease patients with and without stroke recurrence.

Introduction: In one-third of all abdominal aortic aneurysms (AAAs), the aneurysm neck is short (juxtarenal) or shows other adverse anatomical features rendering operations more complex, hazardous and expensive. Surgical options include open surgical repair and endovascular aneurysm repair (EVAR) techniques including fenestrated EVAR, EVAR with adjuncts (chimneys/endoanchors) and off-label standard EVAR. The aim of the UK COMPlex AneurySm Study (UK-COMPASS) is to answer the research question identified by the National Institute for Health Research Health Technology Assessment (NIHR HTA) Programme: 'What is the clinical and cost-effectiveness of strategies for the management of juxtarenal AAA, including fenestrated endovascular repair?', Methods and Analysis: UK-COMPASS is a cohort study comparing clinical and cost-effectiveness of different strategies used to manage complex AAAs with stratification of physiological fitness and anatomical complexity, with statistical correction for baseline risk and indication biases. There are two data streams. First, a stream of routinely collected data from Hospital Episode Statistics and National Vascular Registry (NVR). Preoperative CT scans of all patients who underwent elective AAA repair in England between 1 November 2017 and 31 October 2019 are subjected to Corelab analysis to accurately identify and include every complex aneurysm treated. Second, a site-reported data stream regarding quality of life and treatment costs from prospectively recruited patients across England. Site recruitment also includes patients with complex aneurysms larger than 55 mm diameter in whom an operation is deferred (medical management). The primary outcome measure is perioperative all-cause mortality. Follow-up will be to a median of 5 years., Ethics and Dissemination: The study has received full regulatory approvals from a Research Ethics Committee, the Confidentiality Advisory Group and the Health Research Authority. Data sharing agreements are in place with National Health Service Digital and the NVR. Dissemination will be via NIHR HTA reporting, peer-reviewed journals and conferences., Trial Registration Number: ISRCTN85731188., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

The roles of APOE ε4 and APOE ε2-the strongest genetic risk and protective factors for Alzheimer's disease-in glial responses remain elusive. We tested the hypothesis that APOE alleles differentially impact glial responses by investigating their effects on the glial transcriptome from elderly control brains with no neuritic amyloid plaques. We identified a cluster of microglial genes that are upregulated in APOE ε4 and downregulated in APOE ε2 carriers relative to APOE ε3 homozygotes. This microglia- APOE cluster is enriched in phagocytosis-including TREM2 and TYROBP -and proinflammatory genes, and is also detectable in brains with frequent neuritic plaques. Next, we tested these findings in APOE knock-in mice exposed to acute (lipopolysaccharide challenge) and chronic (cerebral β-amyloidosis) insults and found that these mice partially recapitulate human APOE -linked expression patterns. Thus, the APOE ε4 allele might prime microglia towards a phagocytic and proinflammatory state through an APOE-TREM2-TYROBP axis in normal aging as well as in Alzheimer's disease., Competing Interests: Competing interests The authors declare no competing interests.