Treatment Sites Research Articles

Influence of a pre‐ageing treatment on the cluster formation and the further ageing route in Al‐Mg‐Si extrusion alloys

In this study the influence of 1‐ and 2‐step pre‐ageing treatments prior to the artificial ageing step to peak age condition for three different 6xxx alloys, from low to high alloy content is investigated. Analysis of the pre‐aged conditions using atom probe tomography (APT) revealed a broad distribution of Mg‐ and Si‐clusters, with some instances of GP I zones present. Additionally, the high alloyed system exhibited a growth of precipitates towards a needle‐like shaped. These clusters formed during the pre‐ageing treatment serve as nucleation sites in the subsequent artificial ageing treatment, leading to an increase in hardness. Microstructural analysis conducted using transmission electron microscopy (TEM) and APT demonstrate a reduction in the average precipitate length and a more narrow size distribution for T6 condition. This indicates that the pre‐ageing treatment results in a decreased portion of already overaged precipitates compared to the direct aged condition. Consequently, the more narrow size distribution of the precipitates lead to more effective hardening of the material, as a higher portion of precipitates is at or close to their optimum size. The investigations highlight the significant influence and positive effect of a pre‐ageing treatment at lower temperatures on the subsequent artificial ageing treatment.This article is protected by copyright. All rights reserved.

Mechanisms of Action in FLASH Radiotherapy: A Comprehensive Review of Physicochemical and Biological Processes on Cancerous and Normal Cells

The advent of FLASH radiotherapy (FLASH-RT) has brought forth a paradigm shift in cancer treatment, showcasing remarkable normal cell sparing effects with ultra-high dose rates (>40 Gy/s). This review delves into the multifaceted mechanisms underpinning the efficacy of FLASH effect, examining both physicochemical and biological hypotheses in cell biophysics. The physicochemical process encompasses oxygen depletion, reactive oxygen species, and free radical recombination. In parallel, the biological process explores the FLASH effect on the immune system and on blood vessels in treatment sites such as the brain, lung, gastrointestinal tract, skin, and subcutaneous tissue. This review investigated the selective targeting of cancer cells and the modulation of the tumor microenvironment through FLASH-RT. Examining these mechanisms, we explore the implications and challenges of integrating FLASH-RT into cancer treatment. The potential to spare normal cells, boost the immune response, and modify the tumor vasculature offers new therapeutic strategies. Despite progress in understanding FLASH-RT, this review highlights knowledge gaps, emphasizing the need for further research to optimize its clinical applications. The synthesis of physicochemical and biological insights serves as a comprehensive resource for cell biology, molecular biology, and biophysics researchers and clinicians navigating the evolution of FLASH-RT in cancer therapy.

Efficient proton arc optimization and delivery through energy layer pre-selection and post-filtering.

Proton arc therapy (PAT) has emerged as a promising approach for improving dose distribution, but also enabling simpler and faster treatment delivery in comparison to conventional proton treatments. However, the delivery speed achievable in proton arc relies on dedicated algorithms, which currently do not generate plans with a clear speed-up and sometimes even result in increased delivery time. This study aims to address the challenge of minimizing delivery time through a hybrid method combining a fast geometry-based energy layer (EL) pre-selection with a dose-based EL filtering, and comparing its performance to a baseline approach withoutfiltering. Three methods of EL filtering were developed: unrestricted, switch-up (SU), and switch-up gap (SU gap) filtering. The unrestricted method filters the lowest weighted EL while the SU gap filtering removes the EL around a new SU to minimize the gantry rotation braking. The SU filtering removes the lowest weighted group of EL that includes a SU. These filters were combined with the RayStation dynamic proton arc optimization framework energy layer selection and spot assignment (ELSA). Four bilateral oropharyngeal and four lung cancer patients' data were used for evaluation. Objective function values, target coverage robustness, organ-at-risk doses and normal tissue complication probability evaluations, as well as comparisons to intensity-modulated proton therapy (IMPT) plans, were used to assess plan quality. The SU gap filtering algorithm performed best in five out of the eight cases, maintaining plan quality within tolerance while reducing beam delivery time, in particular for the oropharyngeal cohort. It achieved up to approximately 22% and 15% reduction in delivery time for oropharyngeal and lung treatment sites, respectively. The unrestricted filtering algorithm followed closely. In contrast, the SU filtering showed limited improvement, suppressing one or two SU without substantial delivery time shortening. Robust target coverage was kept within 1% of variation compared to the PAT baseline plan while organs-at-risk doses slightly decreased or kept about the same for all patients. This study provides insights to accelerate PAT delivery without compromising plan quality. These advancements could enhance treatment efficiency and patientthroughput.

A novel method for rapid estimation of active bone marrow dose for radiotherapy patients in epidemiological studies.

In a dedicated effort to improve the assessment of clonal hematopoiesis (CH) and study leukemia risk following radiotherapy, we are developing a large-scale cohort study among cancer patients who received radiation. To that end, it will be critical to analyze dosimetric parameters of red bone marrow (ABM) exposure in relation to CH and its progression to myeloid neoplasms, requiring reconstruction method for ABM doses of a large-scale patients rapidly and accurately. To support a large-scale cohort study on the assessment of clonal hematopoiesis and leukemia risk following radiotherapy, we present a new method for the rapid reconstruction of ABM doses of radiotherapy among cancer patients. The key idea of the presented method is to segment patient bones rapidly and automatically by matching a whole-body computational human phantom, in which the skeletal system is divided into 34 bone sites, to patient CT images via 3D skeletal registration. The automatic approach was used to segment site-specific bones for 40 radiotherapy patients. Also, we segmented the bones manually. The bones segmented both manually and automatically were then combined with the patient dose matrix calculated by the treatment planning system (TPS) to derive patient ABM dose. We evaluated the performance of the automatic method in geometric and dosimetric accuracy by comparison with the manual approach. The pelvis showed the best geometric performance [volume overlap fraction (VOF): 52% (mean) with 23% (σ) and average distance (AD): 0.8cm (mean) with 0.5cm (σ)]. The pelvis also showed the best dosimetry performance [absorbed dose difference (ADD): 0.7Gy (mean) with 1.0Gy (σ)]. Some bones showed unsatisfactory performances such as the cervical vertebrae [ADD: 5.2Gy (mean) with 10.8Gy (σ)]. This impact on the total ABM dose, however, was not significant. An excellent agreement for the total ABM dose was indeed observed [ADD: 0.4Gy (mean) with 0.4Gy (σ)]. The computation time required for dose calculation using our method was robust (about one minute per patient). We confirmed that our method estimates ABM doses across treatment sites accurately, while providing high computational efficiency. The method will be used to reconstruct patient-specific ABM doses for dose-response assessment in a large cohort study. The method can also be applied to prospective dose calculation within a clinical TPS to support clinical decision making at the point of care.

Factors Associated With Increased Substance Use Disorder Care in VA PTSD Specialty Outpatient Treatment

Objective: Substance use disorders (SUDs) commonly co-occur with posttraumatic stress disorder (PTSD). Understanding PTSD clinics that serve higher percentages of patients with PTSD/SUD is crucial for improving SUD care in clinics with lower percentages of such patients. This study examined the differences between Veterans Affairs (VA) PTSD treatment sites with higher percentages ("High%") and lower percentages ("Low%") of patients with PTSD/SUD as well as exploring the roles of the PTSD/SUD specialists. Methods: The study collected quantitative and qualitative data from 18 clinic directors and 21 specialists from 33 VA PTSD specialty outpatient clinics from 2014 to 2016. The clinics were chosen from the top and bottom quartiles based on two criteria: (1) the percentage of patients with PTSD/SUD and (2) the percentage of patients with PTSD/SUD who completed at least three SUD visits within the first month of their SUD treatment. The interviews sought to identify distinguishing characteristics between the High% and Low% clinics in terms of treatment access and practices for patients with PTSD/SUD. Results: More of the High% clinics reported providing evidence-based, patient-centered, and integrated/concurrent PTSD/SUD treatment and had staff members with more up-to-date knowledge and skills than the Low% clinics. We also found the roles of the PTSD/SUD specialists were demanding and confusing, leading to high turnover rates. Conclusions: The two groups of PTSD clinics differed in three key factors: Resources, knowledge and skills of staff members, and local policies. Future research should focus on addressing resource limitations, knowledge gaps, and local policy disparities in Low% clinics. By emulating the practices of High% clinics, VA PTSD clinics can improve SUD care for patients with PTSD/SUD.

Abstract PO1-19-06: Physical exercise during neoadjuvant chemotherapy for breast cancer as a mean to increase pathological complete response rates: the randomized Neo-ACT trial

Abstract Introduction In early breast cancer, neoadjuvant chemotherapy (NACT) is increasingly used. The proof of efficacy is pathologically complete response (pCR), i.e. the absence of invasive tumour in breast and lymph nodes at surgery. Today, pCR is a common endpoint in pharmaceutical trials since it is significantly associated with survival especially in triple-negative and HER2-positive subtypes. Apart from the mitigation of treatment-related toxicity and symptoms, physical exercise mediates anti-tumoral systemic effects associated with tumour regression in preclinical and clinical models. The aim of Neo-ACT is to test the hypothesis that physical exercise can improve pCR rates in breast cancer patients receiving NACT. Method The Neo-ACT trial is an international prospective clinical trial, randomising T1-3N0-2 breast cancer patients planned for NACT to either a home-based physical exercise intervention supported by a mobile application or routine care. The primary endpoint is pCR; secondary endpoints are patient-reported quality of life, toxicity-related outcomes, and oncological outcomes such as Residual Cancer Burden, objective radiological tumour response, as well as overall, breast cancer-specific and disease-free survival at 2, 5 and 10 years. The intervention consists of a combination of high-intensity interval and resistance training of progressing intensity, and includes two weekly 60-min exercise sessions plus at least 150 min of moderate to vigorous physical activity per week. The Neo-ACT has been registered at clinicaltrials.gov on January 11, 2022 (NCT05184582). Statistical methods Patients will be randomized in a 1:1 fashion. It is anticipated that the rate of the primary endpoint pCR will be approximately 30% in the control arm (all subtypes). We aim to increase the rate of pCR in the experimental arm to 40%, i.e. a 10 percentage points increase, which is regarded clinically relevant since it would translate into improved disease-related outcomes. With a power of 80% and an alpha of 5%, a total of 712 patients have to be included; 356 in each arm. Accounting for a drop-out of 10%, we aim to include 790 patients. Stratification at the moment of computerized randomization is based on site of treatment (hospital) and biological tumour subtype (ER+HER2-, ER+HER2+, ER-HER2+, ER-HER2-). All outcomes will primarily be analysed using an intention-to-treat approach, i.e. all study subjects will belong to the treatment group (exercise intervention or control) they were assigned to, disregarding compliance. As sensitivity analysis, all outcomes will also be analysed using a per-protocol approach, meaning that participants in the intervention group who comply with less than 65% of the prescribed physical exercise program, and participants who complete less than 40% of the planned neoadjuvant systemic therapy (around two 3-weekly courses) will be excluded from analysis. Present accrual The Neo-ACT trial has started enrolment at the first site in December 2022 and since then initiated a further five Swedish and one Finnish site. Until June 15, 2023, 26 participants had been randomized in the trial. A feasibility questionnaire is distributed via the EUBREAST network which officially supports this trial and has added the designation EUBREAST12-R. Further participating sites can be accommodated depending on volume, competing trials and language requirements for the mobile application. Contact: jana.de-boniface@ki.se Citation Format: Jana de Boniface, Cecilia Haddad Ringborg, Renske Altena, Yvonne Wengström. Physical exercise during neoadjuvant chemotherapy for breast cancer as a mean to increase pathological complete response rates: the randomized Neo-ACT trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-19-06.

Abstract PO3-11-05: Sexual dysfunction among Brazilian women with early breast cancer on adjuvant endocrine therapy (ET)

Abstract Background: Sexual dysfunction is a common health problem in women, and it can occur during breast cancer treatment and survivorship. This study aims to determine the frequency of sexual disfunction among Brazilian women with early breast cancer on adjuvant endocrine therapy and to explore its relationships with patients’ clinical and social characteristics, adherence to ET, quality of life, return to work and healthcare insurance. Methodology: Women with history of early-stage ER+ invasive carcinoma of the breast on adjuvant endocrine therapy for at least 6 months were invited to participate of this study. Sexual dysfunction was evaluated using the Female Sexual Function Index questionnaire (FSFI). A score of < 26.55 in FSFI indicates sexual dysfunction. We evaluated sexually active patients (women should have at least one sexual intercourse in the previous four weeks). Demographic and medical information, site of treatment (private versus public), degree of education (completed high school vs not) were reviewed from medical records. Quality of life was assessed using EORTC QLQ C30 and BR-23 forms and adherence to ET was assessed by the Morisky Medication Adherence Scale (MMAS-8). Additionally, patients were interviewed about return to work. Data collection was performed using RedCap software and statistical analyzes were performed on the software R (R Core Team (2022). Qualitative variables were compared between groups using the Chi-square or exact Chi-square test and for quantitative variables the non-parametric Mann-Whitney test was used. Multivariable analysis was performed using Poisson regression. P < 0.05 was considered significant. Analyzes were performed in SAS 9.4. Results: From June 2021 to May 2023, a total of 461 women with ER+ early-stage breast cancer from 12 Brazilian institutions were included in this analysis. The mean age was 56.0 years (range 22-93 ), 47.7% were non-white and 38.7% were premenopausal. A total of 233 women (50.6%) had private insurance and the remaining were treated in public institutions. Median duration of ET use was 2.78 years (range 6 months- 9.61 years).Only 249 (54%) out of 461 patients who accepted to participate in this study declared to have sexual intercourse in the previous 4 weeks before evaluation and composes the population of this analysis. Sexual disfunction according results of FSFI questionnaire was found in 113 (53.3%) participants. Age was significantly associated with sexual dysfunction with women > 40 years-old having higher rates (95.3%) compared with versus younger patients (4.71% p=0.0069). Patients without sexual dysfunction had significantly higher EORTC QLQ C30 Global health status, Physical Functioning, Emotional Functioning, Sexual Functioning and Sexual Enjoyment scores than those with sexual dysfunction (p = 0.0060, p = 0.0242, p = 0 .0353, p = 0.0002 and p < 0.0001 respectively). ET duration between 2 and 5 years vs < 2 years, higher vs lower education level, EORTC QLQ-BR23 breast symptom and sexual functioning higher scores were significantly associated with the occurrence of sexual dysfunction in multivariated analysis (p < 0.05). Conclusion: In our study, only 54% of women evaluated had sexual intercourse in the previous four weeks and from those women 53.3% reported sexual dysfunction. Factors related to sexual dysfunction were higher education level, ET duration between 2 and 5 years, breast symptom and sexual functioning higher scores. div style=margin-top:10px; margin-bottom:20px;>Characteristic with adjusted prevalence ratios for the occurrence of sexual disfunction XX XX PR: prevalence ratio, EORTC: European Organisation for Research and Treatment of Cancer Citation Format: Daniele Assad-Suzuki, Fernanda Moura, Danielle Santos, Sulene Oliveira, Cristiano Souza, Heloísa Resende, Andrea Shimada, Anna Luiza Galvão, Bruno Souza, Amanda Castro, Monalisa Andrade, Yuri Beckedorff, Maria Cristina Magalhães, Carlos Paiva, Angelica Rodrigues, Daniela Pereira, Daniela Rosa, Romualdo Barroso-Sousa. Sexual dysfunction among Brazilian women with early breast cancer on adjuvant endocrine therapy (ET) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-11-05.

Abstract PO2-12-04: Suboptimal adherence to adjuvant endocrine therapy (ET) in Brazilian women with early-stage estrogen receptor-positive (ER+) breast cancer

Abstract Background: Adjuvant ET reduces breast cancer recurrence and increases overall survival among patients with early-stage ER+ breast cancer, however a suboptimal number of patients in fact takes oral medicine as prescribed. In Brazil, there is a paucity of data about adherence to adjuvant ET. This study aims to evaluate adherence to adjuvant ET in Brazilian women with early breast cancer and to evaluate clinical and sociodemographic characteristics associated with higher or lower adherence. Methods: Women with history of early-stage ER+ invasive carcinoma of the breast on adjuvant ET for at least 6 months were invited to participate of this study. Adherence was assessed with questionnaire Morisky Medication Adherence Scale (MMAS-8) and high adherence was defined by a MMAS-8 score=8. Demographic and medical information, site of treatment (private versus public), degree of education (completed high school vs not) were reviewed from medical records. Quality of life was assessed using EORTC QLQ C30 and BR-23 forms, sexuality was evaluated with the Female Sex Function Index questionnaire. Additionally, patients were interviewed about return to work. Data collection was done with RedCap software. Qualitative variables were compared between groups using the Chi-square or exact Chi-square test and for quantitative variables the non-parametric Mann-Whitney test was used. Multivariable analysis was performed using Poisson regression. P < 0.05 was considered significant. Analyzes were performed in SAS 9.4. Results: From June 2021 to May 2023, a total of 461 women with ER+ early-stage breast cancer from 12 Brazilian institutions were included in this analysis. The mean age was 56.0 years (range 22-93), 47.7% were non-white and 38.7% were premenopausal. A total of 233 women (50.6%) had private insurance and the remaining were treated in public institutions. Median duration of ET use was 2.78 years (range 6 months- 9.61 years). High adherence to adjuvant endocrine therapy was present in 55.7% of patients. Median age of high adherent woman was higher than low adherent (p=0.005). Factors significantly associated with high adherence were no use of ovarian suppression (p=0.0095), use of anti-Her2 therapy (p=0.0462). Furthermore, higher scores for EORTC QLQ-C30 global health status (p=0.017) and in specific domains, including role functioning (p=0.007), emotional functioning (p< 0.0001), cognitive functioning (p< 0.001), social functioning (p = 0,0005), higher scores for EORTC BR23 body image (p< 0.001) and future perspective (p = 0.0198) were also associated with high adherence. Higher EORTC QLQ-C30 cognitive function score was the only variable associated with high adherence (p < 0.0001) to ET in multivariate model. Conclusion: Using the MMAS-8, only 55.7% of Brazilian women with stage I-III ER+ breast cancer reported high adherence to endocrine therapy. This suboptimal adherence rate leads to important questions such as the impact on the prognosis of this population Charactheristic with adjusted prevalence ratio for the occurrence of High adherence PR: Prevalence ratio; EORTC: European Organisation for Research and Treatment of Cancer Citation Format: Daniele Assad-Suzuki, Heloísa Resende, Danielle Santos, Fernanda Moura, Sulene Oliveira, Andrea Shimada, Anna Luiza Galvão, Bruno Souza, Amanda Castro, Monalisa Andrade, Yuri Beckedorff, Maria Cristina Magalhães, Cristiano Souza, Carlos Paiva, Daniela Pereira, Angelica Rodrigues, Daniela Rosa, Romualdo Barroso-Sousa. Suboptimal adherence to adjuvant endocrine therapy (ET) in Brazilian women with early-stage estrogen receptor-positive (ER+) breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-12-04.

Safety and Tolerability of Online Adaptive High-Field Magnetic Resonance-Guided Radiotherapy.

In 2018, the first online adaptive magnetic resonance (MR)-guided radiotherapy (MRgRT) system using a 1.5-T MR-equipped linear accelerator (1.5-T MR-Linac) was clinically introduced. This system enables online adaptive radiotherapy, in which the radiation plan is adapted to size and shape changes of targets at each treatment session based on daily MR-visualized anatomy. To evaluate safety, tolerability, and technical feasibility of treatment with a 1.5-T MR-Linac, specifically focusing on the subset of patients treated with an online adaptive strategy (ie, the adapt-to-shape [ATS] approach). This cohort study included adults with solid tumors treated with a 1.5-T MR-Linac enrolled in Multi Outcome Evaluation for Radiation Therapy Using the MR-Linac (MOMENTUM), a large prospective international study of MRgRT between February 2019 and October 2021. Included were adults with solid tumors treated with a 1.5-T MR-Linac. Data were collected in Canada, Denmark, The Netherlands, United Kingdom, and the US. Data were analyzed in August 2023. All patients underwent MRgRT using a 1.5-T MR-Linac. Radiation prescriptions were consistent with institutional standards of care. Patterns of care, tolerability, and technical feasibility (ie, treatment completed as planned). Acute high-grade radiotherapy-related toxic effects (ie, grade 3 or higher toxic effects according to Common Terminology Criteria for Adverse Events version 5.0) occurring within the first 3 months after treatment delivery. In total, 1793 treatment courses (1772 patients) were included (median patient age, 69 years [range, 22-91 years]; 1384 male [77.2%]). Among 41 different treatment sites, common sites were prostate (745 [41.6%]), metastatic lymph nodes (233 [13.0%]), and brain (189 [10.5%]). ATS was used in 1050 courses (58.6%). MRgRT was completed as planned in 1720 treatment courses (95.9%). Patient withdrawal caused 5 patients (0.3%) to discontinue treatment. The incidence of radiotherapy-related grade 3 toxic effects was 1.4% (95% CI, 0.9%-2.0%) in the entire cohort and 0.4% (95% CI, 0.1%-1.0%) in the subset of patients treated with ATS. There were no radiotherapy-related grade 4 or 5 toxic effects. In this cohort study of patients treated on a 1.5-T MR-Linac, radiotherapy was safe and well tolerated. Online adaptation of the radiation plan at each treatment session to account for anatomic variations was associated with a low risk of acute grade 3 toxic effects.

Regulation of Lewis acid sites on ZnO/SiW11Co for tunable photocatalytic activity toward water remediation

The function of surface acidity in catalytic reactions has been well studied in the field of conventional catalysis, nevertheless, regulating surface acidic sites and unveiling its roles during heterogeneous photocatalysis has been less frequently reported. To address this issue, we constructed a novel heterojunction photocatalyst of ZnO/SiW11Co with abundant Lewis acid sites for wastewater treatment. Under visible light irradiation, the optimal ZnO/SiW11Co was found to have the highest photocatalytic activity, achieving a degradation efficiency of 97.7% for Rhodamine B (RhB), 96.1% for tetracycline (TC), and 91.4% for methyl orange (MO). The RhB removal rate remained at 91.3% even after five cycles, indicating excellent stability and practicality of ZnO/SiW11Co. By compositing with SiW11Co, a typical polyoxometalates with unique super acid properties, ZnO/SiW11Co formed plentiful surface Lewis acid sites, as confirmed by the pyridine adsorption FT-IR and NH3-TPD. The as-formed Lewis acid sites could provide more active sites, making it easier for reactants to coordinate to the photocatalyst surface, which reduced the activation energy of photocatalytic reactions and accelerate RhB removal. Density functional theory (DFT) calculations unveiled the redistribution of electron-hole pairs, optimizing the light absorption and charge separation efficiency, which obeyed a Z-scheme mechanism. Combined active species capture experiments and electron spin resonance, •O2−, h+, and •OH were the main active substances for the photocatalytic degradation of RhB. Besides, the possible degradation pathways for RhB were analyzed using liquid chromatography-mass spectrometry (LC-MS). The work provided useful strategy for the design of high-performance photocatalysts via regulating surface Lewis acid sites toward water remediation.

Molecular Docking and Dynamics Study of Acetogenins Targeting Cyclin-dependent Kinase and In vitro Evaluation of Annona Muricata Fruit Extracts using MDA-MB-231 Breast Cancer Cell Line

Background: Overexpressed CDK1 and CDK2 are targeted as potential sites for cancer treatment. Annona muricata fruit has been reported to have more than 100 acetogenins showing cytotoxic activities against cancer cell lines. Hence the study aims to demonstrate the cytotoxicity of ethyl acetate fruit extract, its role in cell cycle progression, and apoptosis using the MDMBA-231 breast cancer cell line. Docking, dynamics, and ADME studies were also demonstrated to generate lead molecules of AM fruit responsible for cancer treatment. Method: Cell viability was quantified by the MTT assay. Cell cycle arrest and apoptotic cells were determined by flow cytometry and PI annexin V-FITC staining by flow cytometry, respectively. Molecular docking, molecular dynamics, and ADME properties of 11 acetogenins were studied using the schrödinger maestro suite 2018-1. Results: The MTT assay revealed IC50 232.9μg/ml with a high degree of cytotoxicity. The extract effectively caused cell cycle arrest at the G2M and S phases; early and late apoptosis was induced at 160 μg/ml and 320 μg/ml. Docking scores of muricin L, J, and annomuricin A complexed with CDK2 and muricin J, K, and L with CDK1 binding energy ranging is mentioned as a molecular dynamic study envisaged muricin j against CDK2 stable hydrogen and hydrophobic interactions with critical residues like ASP-86, GLN-131, HIS-84, LYS-89, PHE80, PHE82, and PHE83 throughout 200 ns (hinge region). ADMET profiling also confirmed that all 11 ligands passed the rule of 5 and 3. The in vitro and in silico studies revealed that these acetogenins could be CDK1 and CDK2 inhibitors for cancer treatment. Conclusion: The in vitro studies presume that the ethyl acetate fruit extract of AM is an excellent cytotoxic agent. In silico studies demonstrated that muricin j could lead molecules to target kinase proteins responsible for cell proliferation. ADME study enlightened us to take 11 acetogenins for the drug discovery process in managing cancer treatment.

Incursion of SARS-CoV-2 BA.2.86.1 variant into Israel: National-scale wastewater surveillance using a novel quantitative real-time PCR assay

The emergence of the SARS-CoV-2 variant BA.2.86.1 raised a considerable concern, due to the large number of potentially virulent mutations. In this study, we developed a novel assay that specifically detects variant BA.2.86.1, and used it to screen environmental samples from wastewater treatment sites across Israel. By using a multiplex assay that included a general SARS-CoV-2 reaction, together with the BA.2.86.1-specific reaction and a control reaction, we quantified the absolute number of viral copies in each sample and its relative abundance, compared with the total copy number of circulating SARS-CoV-2.Evaluation of the new reactions showed that they are both sensitive and specific, detecting down to four copies per reaction, and maintain specificity in the presence of Omicron variants BA.1, 2 and 4 RNA. Examination of 279 samples from 30 wastewater collection sites during August–September 2023 showed that 35 samples (12.5 %) were positive, from 18 sites. Quantitative analysis of the samples showed that the relative abundance of variant BA.2.86.1 with respect to the total viral load of SARS-CoV-2 was very low and consisted between 0.01 % and 0.6 % of the total SARS-CoV-2 circulation.This study demonstrates the importance of combining wastewater surveillance with the development of specialized diagnostic assays, when clinical testing is insufficient. This approach may be useful for timely response by public health authorities in future outbreaks.

Commissioning and first operation of East Japan Heavy Ion Center at Yamagata University

A world smallest carbon ion radiotherapy facility, East Japan Heavy Ion Center, Yamagata University, started treatment operations in February 2021. The treatment system consists of an ECR ion source, an RFQ and IH-type drift tube linac, a 430 MeV/u synchrotron and a spot-scanning irradiation system. It has two treatment rooms, one is a fixed horizontal beam port and the other is a rotating gantry beam port with superconducting magnets. The ECR ion source is the Kei2-type permanent magnet 10 GHz ECR ion source with a maximum field of 0.8 T. All the improvements of the previous facilities are applied to the ion source, such as helium gas-assisted operation and changes in the shape of an anode electrode and an extraction electrode to reduce the discharge. Owing to these improvements, the ion source has been operated stably during the commissioning and clinical operation. The irradiation system of Yamagata University eliminated the plastic block range shifter to realize a compact gantry, and has 600 energy levels to control the beam range in step of 0.5 mm. In order to optimize the beam transport parameters quickly, automation tools for orbit correction were developed. Machine commissioning and clinical commissioning were carried out in parallel to allow treatment to begin earlier. First, the horizontal fixed beam port was commissioned by verifying the dose distribution of the treatment planning system. Then, the gantry beam port was commissioned by full beam distribution measurement for representing beam angle of 90 degree, and other angles were sequentially released after the compatibility measurement of beam position, beam size, and two-dimensional uniformity. In September 2022, we were able to accept all treatment sites. By August 2023, 1151 cancer patients had been treated. Further improvements to increase available gantry angle and to increase beam efficiency are ongoing.

Quality of life in 583 head and neck cancer survivors assessed with the FACE-Q head and neck cancer module

ObjectivesLong-term health-related quality of life (HRQOL) is frequently affected in head and neck cancer (HNC) survivors. Due to the shortage of studies investigating long-term patient-reported outcomes, we investigated long-term HRQOL using the novel FACE-Q HNC Module. MethodsA retrospective cross-sectional single-center study was performed, including all patients who underwent curative treatment for HNC between 2006 and 2013. All eligible patients (n = 863) were invited to participate of whom 540 completed the questionnaires. Additionally, a prospective longitudinal cohort of 43 HNC patients treated between 2020 and 2022 was included who preoperatively filled in the FACE-Q, and at three, six, and 12 months postoperatively. HRQOL domain scores were analyzed to visualize group characteristics by tumor site and type of surgical resection. ResultsBoth surgical and non-surgical HNC treatments predominantly affected long-term functional HRQOL domains (eating, salivation, speech, and swallowing), eating distress, and speaking distress, with distinct profiles depending on tumor site and type of treatment. In contrast, few long-term intergroup differences between HNC patients were observed for appearance, smiling, drooling distress, and smiling distress. Longitudinal data showed significant deterioration across all functional HRQOL domains in the short-term following treatment. Patients predominantly reported long-lasting negative treatment effects at 12 months follow-up for functional domains, whereas psychological domains showed near-complete recovery at group level. ConclusionsAt long-term, various function-related and psychosocial HRQOL domains still are affected in head and neck cancer survivors. The results may serve to better inform patients with regard to specific treatments and highlight HRQOL domains which may potentially be optimized.

Therapeutic Effects of 30 nm Cyclosporin A-Loaded Nanoparticles Using PLGA-PEG-PLGA Triblock Copolymer for Transdermal Delivery in Mouse Models of Psoriasis

This study aimed to evaluate the effectiveness of poly(DL-lactide-co-glycolide)-block-poly(ethylene glycol)-block-poly(DL-lactide-co-glycolide) triblock copolymers (PLGA-PEG-PLGA) as a drug carrier in the treatment of psoriasis. Nanoparticles containing cyclosporin A (CsA) were prepared, and their cytotoxicity and skin irritation properties were investigated. These results revealed that the nanoparticles themselves had no obvious cytotoxicity or skin irritation effects. Furthermore, it was shown that loading CsA into nanoparticles promoted its cellular uptake. The therapeutic effect of CsA-loaded PLGA-PEG-PLGA nanoparticles on psoriasis was evaluated using a mouse model of psoriasis induced by imiquimod. In psoriatic skin, we confirmed that nanoparticles penetrate deep into the skin. Furthermore, it was suggested that by using PLGA-PEG-PLGA, drug carriers could reach the dermal layer, which is the target site for psoriasis treatment. The observation of skin sections after the treatment experiment showed that excessively proliferated keratinocytes were restored to an almost normal state by using PLGA-PEG-PLGA nanoparticles as drug carriers. Additionally, the quantitative measurement results for cytokines revealed that the levels of TNF-α, IL-17A, and IL-22 were significantly decreased compared with those of the group to which CsA suspended in a 20% ethanol solution was administered. These results indicate that PLGA-PEG-PLGA nanoparticles are promising drug carriers for the transdermal administration of CsA.

Clinical study on the impact of the COVID‐19 pandemic on mandibular fractures at a regional core hospital for emergency and critical care medicine in Tokyo, Japan

AbstractAimMaxillofacial trauma is routinely encountered in oral and maxillofacial surgery, especially in cases of mandibular fractures; however, no clinical studies currently exist on the effects of the coronavirus disease (COVID‐19) pandemic on mandibular fractures in Japan. This study aimed to analyze the impact of COVID‐19 on mandibular fractures in Tokyo, Japan.MethodsThis retrospective study included patients with mandibular fractures who visited the Department of Oral Surgery at our hospital between January 2014 and December 2022. We conducted a clinico‐statistical study of patients who presented with mandibular fractures before and during the COVID‐19 pandemic.ResultsThe monthly average number of patients presenting with mandibular fractures decreased significantly in the first to third waves of the COVID‐19 pandemic (p = 0.0191) but increased during the fourth to seventh waves. The median patients' age was 46 and 59 years before and during the COVID‐19 pandemic, respectively, and this difference was significant (p = 0.0275). No significant differences were observed in sex, site of injury, cause, or treatment. However, the day of presentation (same day as injury or 1 day later) differed significantly (p = 0.0091) before and during the COVID‐19 pandemic. A significant decrease in concomitant trauma was observed during the COVID‐19 pandemic compared with the prepandemic period (p = 0.0054).ConclusionsThis study is the first to report the impact of COVID‐19 on mandibular fractures in Japan. The findings differ from those obtained from studies in other countries and provide a good basis for understanding COVID‐19 and preparing for future pandemics.

Multi-institution single geometry plan complexity characteristics based on IROC phantoms.

Clinical intensity modulated radiation therapy plans have been described using various complexity metrics to help identify problematic radiotherapy plans. Most previous studies related to the quantification of plan complexity and their utility have relied on institution-specific plans which can be highly variable depending on the machines, planning techniques, delivery modalities, and measurement devices used. In this work, 1723 plans treating one of only four standardized geometries were simultaneously analyzed to investigate how radiation plan complexity metrics vary across four different sets of common objectives. To assess the treatment plan complexity characteristics of plans developed for Imaging and Radiation Oncology Core (IROC) phantoms. Specifically, to understand the variability in plan complexity between institutions for a common plan objective, and to evaluate how various complexity metrics differentiate relevant groups of plans. 1723 plans treating one of four standardized IROC phantom geometries representing four different anatomical sites of treatment were analyzed. For each plan, 22 MLC-descriptive plan complexity metrics were calculated, and principal component analysis (PCA) was applied to the 22 metrics in order to evaluate differences in plan complexity between groups. Across all metrics, pairwise comparisons of the IROC phantom data were made for the following classifications of the data: anatomical phantom treated, treatment planning system (TPS), and the combination of MLC model and treatment planning system. An objective k-means clustering algorithm was also applied to the data to determine if any meaningful distinctions could be made between different subgroups. The IROC phantom database was also compared to a clinical database from the University of Wisconsin-Madison (UW) which included plans treating the same four anatomical sites as the IROC phantoms using a TrueBeam™ STx and Pinnacle3 TPS. The IROC head and neck and spine plans were distinct from the prostate and lung plans based on comparison of the 22 metrics. All IROC phantom plan group complexity metric distributions were highly variable despite all plans being designed for identical geometries and plan objectives. The clusters determined by the k-means algorithm further supported that the IROC head and neck and spine plans involved similar amounts of complexity and were largely distinct from the prostate and lung plans, but no further distinctions could be made. Plan complexity in the head and neck and spine IROC phantom plans were similar to the complexity encountered in the UW clinical plans. There is substantial variability in plan complexity between institutions when planning for the same objective. For each IROC anatomical phantom treated, the magnitude of variability in plan complexity between institutions is similar to the variability in plan complexity encountered within a single institution database containing several hundred unique clinical plans treating corresponding anatomies in actual patients.

Reduction in time to viral suppression among persons living with HIV in Jamaica between 2017-2019.

HIV viral suppression is important for effective treatment and for reducing new infections. In 2019, only 66% of persons on antiretroviral treatment (ART) in Jamaica were virally suppressed. We aim to compare time to viral suppression by ART initiation year and type of treatment site to understand the implications for programming. We assessed time to viral suppression among 4560 persons who received viral load testing either pre or post ART initiation from 2017-2019. We used descriptive statistics and Kaplan-Meier estimates to compare survival curves by ART year (2017, 2018, 2019), sex and type of treatment site (public and non-governmental organizations). Persons were censored if suppression was not achieved. Mixed effects Cox regression was used to determine the effect of covariates on the likelihood of viral suppression. We report hazard ratios and 95% confidence intervals. Pre-ART viral load testing decreased from 36% in 2017 to 30% in 2019. For post-ART viral load tests, approximately 78% (n = 1589) of persons achieved suppression, 51% (n = 809) were female and 86% (n = 1341) used a public treatment site. The median time to suppression decreased by 3 months from 2017 to 2019. The likelihood of suppression was almost 2 times greater in 2018 (HR = 1.56, CI = 1.39-1.75) and 3 times greater in 2019 (HR = 3.17, CI = 2.76-3.64) compared to 2017. NGO treatment sites were also significantly associated with the likelihood of viral suppression compared to public sites. Pre-ART viral load testing and the time to viral suppression decreased over three years. Initiating ART after 2017 and early use of NGO treatment sites were found to significantly increase the likelihood of achieving suppression. This demonstrates improvements in the national HIV response but there is need to increase the number of persons on ART and achieving viral suppression.

THE USE OF NITINOL CONTINUOUS COMPRESSION IMPLANTS IN ORTHOPAEDIC TRAUMA AND LIMB RECONSTRUCTION SURGERY

IntroductionContinuous compression implants (CCIs) are small memory alloy bone staples that can provide continuous compression across a fracture site, which change shape due to temperature changes. Reviews of CCIs in orthopaedics have documented their use in mainly foot and ankle surgery, with very limited descriptions in trauma. They could be beneficial in the management of complex or open injuries due to their low profile and quick insertion time. The aim of this case series were to clarify the use of CCIs in modern day limb reconstruction practice.Materials & MethodsThis was a single centred study looking retrospectively at prospective data for patients who were treated for an acute fracture or non-union with a CCI between September 2019 and May 2023. Primary outcome was to determine the function and indication of the CCI as judged retrospectively and secondary outcomes investigated unplanned returns to theatre for infection or CCI failure.ResultsSixty patients were eligible with a mean age of 44.2 (range 8–89). Fifty-one patients were treated for acute fractures, nine for non-unions; and almost half (27 patients) had open injuries. There were seven different sites for treatment with a CCI, the most common being tibia (25 patients) and humerus (14 patients). Of the 122 CCIs used, 80 were used as adjuncts for fixation in 48 patients. Their indication as an adjunct fell into three distrinct categories – reduction of fracture (39 CCIs), fixation of key fragments (38 CCIs) and compression (3 CCIs). Of these 48 patients, 4 patients had a frame fixation, 19 had a nail fixation, 24 patients had a plate fixation. Forty-two CCIs were used in isolation as definitive fixation, all were for midfoot dislocations expect an open iliac wing fixation from a machete attack and an isolated paediatric medial malleolus fixation. Two patients returned to theatre for infection and two due to CCI failure.ConclusionsThis series has demonstrated the versality of CCIs across multiple sites of the body and for a large variety of injuries. It has identified, when not used in isolation, three main indications to support traditional orthopaedic fixations. Given the unpredictability in limb reconstruction surgery, the diversity and potential of CCIs could form part of the staple diet in the modern-day practice.

Using extreme value theory to evaluate the leading pedestrian interval road safety intervention

Improving road safety is hugely important with the number of deaths on the world's roads remaining unacceptably high; an estimated 1.3 million people die each year as a result of road traffic collisions. Current practice for treating collision hotspots is almost always reactive: once a threshold level of collisions has been overtopped during some pre‐determined observation period, treatment is applied (e.g., road safety cameras). Traffic collisions are rare, so prolonged observation periods are necessary. However, traffic conflicts are more frequent and are a margin of the social cost; hence, traffic conflict before/after studies can be conducted over shorter time periods. We investigate the effect of implementing the leading pedestrian interval treatment at signalised intersections as a safety intervention in a city in north America. Pedestrian‐vehicle traffic conflict data were collected from treatment and control sites during the before and after periods. We implement a before/after study on post‐encroachment times (PETs) where small PET values denote ‘near‐misses’. Hence, extreme value theory is employed to model extremes of our PET processes, with adjustments to the usual modelling framework to account for temporal dependence and treatment effects.