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Abstract Background Alpha-emitter radiopharmaceutical therapy (αRPT) has shown promising outcomes in metastatic disease. However, the short range of the alpha particles necessitates dosimetry on a near-cellular spatial scale. Current knowledge on cellular dosimetry is primarily based on in vitro experiments using cell monolayers. The goal of such experiments is to establish cell sensitivity to absorbed dose (AD). However, AD cannot be measured directly and needs to be modeled. Current models, often idealize cells as spheroids in a regular grid (geometric model), simplify binding kinetics and ignore the stochastic nature of radioactive decay. It is unclear what the impact of such simplifications is, but oversimplification results in inaccurate and non-generalizable results, which hampers the rigorous study of the underlying radiobiology. Methods We systematically mapped out 3D cell geometries, clustering behavior, agent binding, internalization, and subcellular trafficking kinetics for a large cohort of live cells under representative experimental conditions using confocal microscopy. This allowed for realistic Monte Carlo-based (micro)dosimetry. Experimentally established surviving fractions of the HER2 + breast cancer cell line treated with a 212Pb-labelled anti-HER2 conjugate or external beam radiotherapy, anchored a rigorous statistical approach to cell sensitivity and relative biological effectiveness (RBE) estimation. All outcomes were compared to a reference geometric model, which allowed us to determine which aspects are crucial model components for the proper study of the underlying radiobiology. Results In total, 567 cells were measured up to 26 h post-incubation. Realistic cell clustering had a large (2x), and cell geometry a small (16.4% difference) impact on AD, compared to the geometric model. Microdosimetry revealed that more than half of the cells do not receive any dose for most of the tested conditions, greatly impacting cell sensitivity estimates. Including these stochastic effects in the model, resulted in significantly more accurate predictions of surviving fraction and RBE (permutation test; p

Abstract Background In 2016, the International Commission on Radiological Protection (ICRP) published the results of Monte Carlo simulations performed using updated and anatomically realistic voxelized phantoms. The resulting specific absorbed fractions are based on more realistic human anatomy than those computed in the stylized, geometrical Cristy–Eckerman (CE) phantom. Despite this development, the ICRP-absorbed fractions have not been widely adopted for radiopharmaceutical dosimetry. To help make the transition, we have established a correspondence between source and target tissues defined in the CE phantom and those defined in the ICRP phantoms. Results The ICRP phantom has 79 source regions and 43 target regions in comparison with the 23 source and 18 target tissue regions defined in the CE phantom. The ICRP phantom provides tissue regions with greater anatomical detail. Some of this additional detail is focused on radiation protection and dosimetry of inhaled/ingested radioactivity. Some, but not all, of this detail is useful and appropriate for radiopharmaceutical therapy. We have established the correspondence between CE and ICRP phantom source and target regions and attempted to highlight the ICRP source tissues relevant to radiopharmaceutical therapy (RPT). This paper provides tables and figures highlighting the correspondences established. Conclusion The results provide assistance in transitioning from CE-stylized phantoms to the anatomically accurate voxelized ICRP phantoms. It provides specific guidance for porting the total absorbed activity for regions as defined in the CE phantom to regions within the ICRP phantoms.

Abstract Radioactive iodine (RAI) is safe and effective in most patients with hyperthyroidism but not all individuals are cured by the first dose, and most develop post-RAI hypothyroidism. Postoperative RAI therapy for remnant ablation is successful in 80–90% of thyroid cancer patients and sometimes induces remission of nonresectable cervical and/or distant metastatic disease but the effective tumor dose is usually not precisely known and must be moderated to avoid short- and long-term adverse effects on other tissues. The Collar Therapy Indicator (COTI) is a radiation detection device embedded in a cloth collar secured around the patient’s neck and connected to a recording and data transmission box. In previously published experience, the data can be collected at multiple time points, reflecting local cervical RAI exposure and correlating well with conventional methods. We evaluated the real-time uptake of RAI in patients with hyperthyroid Graves’ disease and thyroid cancer. We performed a pilot feasibility prospective study. Data were analyzed using R© (version 4.0.3, The R Foundation for Statistical Computing, 2020), and Python (version 3.6, Matplotlib version 3.0.3). The COTI was able to provide a quantitative temporal pattern of uptake within the thyroid in persons with Graves’ disease and lateralized the remnant tissue in persons with thyroid cancer. The study has demonstrated that the portable collar radiation detection device outside of a healthcare facility is accurate and feasible for use after administration of RAI for diagnostic studies and therapy to provide a complete collection of fractional target radioactivity data compared to that traditionally acquired with clinic-based measurements at one or two time-points. Clinical Trials Registration NCT03517579, DOR 5/7/2018.

Abstract Background Actinium-225 is an alpha-particle emitter under investigation for use in radiopharmaceutical therapy. To address limited supply, accelerator-produced 225Ac has been recently made available. Accelerator-produced 225Ac via 232Th irradiation (denoted 225/7Ac) contains a low percentage (0.1–0.3%) of 227Ac (21.77-year half-life) activity at end of bombardment. Using pharmacokinetic modeling, we have examined the dosimetric impact of 227Ac on the use of accelerator-produced 225Ac for radiopharmaceutical therapy. We examine the contribution of 227Ac and its daughters to tissue absorbed doses. The dosimetric analysis was performed for antibody-conjugated 225/7Ac administered intravenously to treat patients with hematological cancers. Published pharmacokinetic models are used to obtain the distribution of 225/7Ac-labeled antibody and also the distribution of either free or antibody-conjugated 227Th. Results Based on our modeling, the tissue specific absorbed dose from 227Ac would be negligible in the context of therapy, less than 0.02 mGy/MBq for the top 6 highest absorbed tissues and less than 0.007 mGy/MBq for all other tissues. Compared to that from 225Ac, the absorbed dose from 227Ac makes up a very small component (less than 0.04%) of the total absorbed dose delivered to the 6 highest dose tissues: red marrow, spleen, endosteal cells, liver, lungs and kidneys when accelerator produced 225/7Ac-conjugated anti-CD33 antibody is used to treat leukemia patients. For all tissues, the dominant contributor to the absorbed dose arising from the 227Ac is 227Th, the first daughter of 227Ac which has the potential to deliver absorbed dose both while it is antibody-bound and while it is free. CONCLUSIONS: These results suggest that the absorbed dose arising from 227Ac to normal organs would be negligible for an 225/7Ac-labeled antibody that targets hematological cancer.

Abstract 99mTc-DMSA is one of the most commonly used pediatric nuclear medicine imaging agents. Nevertheless, there are no pharmacokinetic (PK) models for 99mTc-DMSA in children, and currently available pediatric dose estimates for 99mTc-DMSA use pediatric S values with PK data derived from adults. Furthermore, the adult PK data were collected in the mid-70’s using quantification techniques and instrumentation available at the time. Using pediatric imaging data for DMSA, we have obtained kinetic parameters for DMSA that differ from those applicable to adults. Methods We obtained patient data from a retrospective re-evaluation of clinically collected pediatric SPECT images of 99mTc-DMSA in 54 pediatric patients from Boston’s Children Hospital (BCH), ranging in age from 1 to 16 years old. These were supplemented by prospective data from twenty-three pediatric patients (age range: 4 months to 6 years old). Results In pediatric patients, the plateau phase in fractional kidney uptake occurs at a fractional uptake value closer to 0.3 than the value of 0.5 reported by the International Commission on Radiological Protection (ICRP) for adult patients. This leads to a 27% lower time-integrated activity coefficient in pediatric patients than in adults. Over the age range examined, no age dependency in uptake fraction at the clinical imaging time was observed. Female pediatric patients had a 17% higher fractional kidney uptake at the clinical imaging time than males (P < 0.001). Conclusions Pediatric 99mTc-DMSA kinetics differ from those reported for adults and should be considered in pediatric patient dosimetry. Alternatively, the differences obtained in this study could reflect improved quantification methods and the need to re-examine DMSA kinetics in adults.

Abstract Background Dosimetry for diagnostic agents is performed to assess the risk of radiation detriment (e.g., cancer) associated with the imaging agent and the risk is assessed by computing the effective dose coefficient, e. Stylized phantoms created by the MIRD Committee and updated by work performed by Cristy-Eckerman (CE) have been the standard in diagnostic dosimetry. Recently, the ICRP developed voxelized phantoms, which are described in ICRP Publication 110. These voxelized phantoms are more realistic and detailed in describing human anatomy compared with the CE stylized phantoms. Ideally, all tissues should be represented and their pharmacokinetics collected for an as accurate a dosimetric calculation as possible. As the number of source tissues included increases, the calculated e becomes more accurate. There is, however, a trade-off between the number of source tissues considered, and the time and effort required to measure the time-activity curve for each tissue needed for the calculations. In this study, we used a previously published 68Ga-DOTA-TATE data set to examine how the number of source tissues included for both the ICRP voxelized and CE stylized phantoms affected e. Results Depending upon the number of source tissues included e varied between 14.0–23.5 μSv/MBq for the ICRP voxelized and 12.4–27.7 μSv/MBq for the CE stylized phantoms. Furthermore, stability in e, defined as a < 10% difference between e obtained using all source tissues compared to one using fewer source tissues, was obtained after including 5 (36%) of the 14 source tissues for the ICRP voxelized, and after including 3 (25%) of the 12 source tissues for the CE stylized phantoms. In addition, a 2-fold increase in e was obtained when all source tissues where included in the calculation compared to when the TIAC distribution was lumped into a single reminder-of-body source term. Conclusions This study shows the importance of including the larger tissues like the muscles and remainder-of-body in the dosimetric calculations. The range of e based on the included tissues were less for the ICRP voxelized phantoms using tissue weighting factors from ICRP Publication 103 compared to CE stylized phantoms using tissue weighting factors from ICRP Publication 60.

Abstract Background Studies combining immune checkpoint inhibitors with external beam radiation have shown a therapeutic advantage over each modality alone. The purpose of these works is to evaluate the potential of targeted delivery of high LET radiation to the tumor microenvironment via an immune checkpoint inhibitor. Methods The impact of protein concentration on the distribution of 111In-DTPA-anti-PD-L1-BC, an 111In-antibody conjugate targeted to PD-L1, was evaluated in an immunocompetent mouse model of breast cancer. 225Ac-DOTA-anti-PD-L1-BC was evaluated by both macroscale (ex vivo biodistribution) and microscale (alpha-camera images at a protein concentration determined by the 111In data. Results The evaluation of 111In-DTPA-anti-PD-L1-BC at 1, 3, and 10 mg/kg highlighted the impact of protein concentration on the distribution of the labeled antibody, particularly in the blood, spleen, thymus, and tumor. Alpha-camera images for the microscale distribution of 225Ac-DOTA-anti-PD-L1-BC showed a uniform distribution in the liver while highly non-uniform distributions were obtained in the thymus, spleen, kidney, and tumor. At an antibody dose of 3 mg/kg, the liver was dose-limiting with an absorbed dose of 738 mGy/kBq; based upon blood activity concentration measurements, the marrow absorbed dose was 29 mGy/kBq. Conclusions These studies demonstrate that 225Ac-DOTA-anti-PD-L1-BC is capable of delivering high LET radiation to PD-L1 tumors. The use of a surrogate SPECT agent, 111In-DTPA-anti-PD-L1-BC, is beneficial in optimizing the dose delivered to the tumor sites. Furthermore, an accounting of the microscale distribution of the antibody in preclinical studies was essential to the proper interpretation of organ absorbed doses and their likely relation to biologic effect.

Objective Osteonectin plays a central role in various processes during the development of pancreatic adenocarcinoma. This prospective pilot study was performed to determine the feasibility of serum osteonectin as a screening tool for pancreatic cancer. Methods Blood samples were collected from 15 consecutive patients with newly diagnosed pancreatic cancer and 30 matched healthy controls. Serum osteonectin was measured using an osteonectin enzyme-linked immunosorbent assay kit. The primary outcomes were the diagnostic performance of serum osteonectin and the threshold value for differentiation of patients from controls. Results The median/quartile range of serum osteonectin in patients and controls were 306.8/288.5 ng/mL and 67.5/39.8 ng/mL, respectively. Osteonectin concentrations significantly differed among the study groups. A plasma osteonectin concentration of >100.18 ng/mL as selected by the receiver operating characteristic curves demonstrated an estimated area under the curve of 86% for prediction of pancreatic cancer. Tumour size was a significant predictor of serum osteonectin. A statistically significant difference in serum osteonectin between T1/T2 and T3/T4 tumours was found. Post-hoc comparisons revealed statistically significant differences in the serum osteonectin among the control, T1/T2, and T3/T4 groups. Conclusion Osteonectin may be used as a screening tool for pancreatic cancer, although this must be validated in prospective studies.

Alpha-particle emitter labeled monoclonal antibodies are being actively developed for treatment of metastatic cancer due to the high linear energy transfer (LET) and the resulting greater biological efficacy of alpha-emitters. Our knowledge of high LET particle radiobiology derives primarily from accelerated heavy ion beam studies. In heavy ion beam therapy of loco-regional tumors, the modulation of steep transition to very high LET peak as the particle approaches the end of its track (known as the Bragg peak) enables greater delivery of biologically potent radiation to the deep seated tumors while sparing normal tissues surrounding the tumor with the relatively low LET track segment part of the heavy ion beam. Moreover, fractionation of the heavy ion beam can further enhance the peak-to-plateau relative biological effectiveness (RBE) ratio. In contrast, internally delivered alpha particle radiopharmaceutical therapy lack the control of Bragg peak energy deposition and the dose rate is determined by the administered activity, alpha-emitter half-life and biological kinetics of the radiopharmaceutical. The therapeutic ratio of tumor to normal tissue is mainly achieved by tumor specific targeting of the carrier antibody. In this brief overview, we review the radiobiology of high LET radiations learned from ion beam studies and identify the features that are also applicable for the development of alpha-emitter labeled antibodies. The molecular mechanisms underlying DNA double strand break repair response to high LET radiation are also discussed.

Cancer vaccines are designed to activate and enhance cancer-antigen-targeted T cells that are suppressed through multiple mechanisms of immune tolerance in cancer-bearing hosts. T regulatory cell (Treg) suppression of tumor-specific T cells is one barrier to effective immunization. A second mechanism is the deletion of high avidity tumor-specific T cells, which leaves a less effective low avidity tumor specific T cell repertoire available for activation by vaccines. Treg depleting agents including low dose cyclophosphamide (Cy) and antibodies that deplete CD25-expressing Tregs have been used with limited success to enhance the potency of tumor-specific vaccines. In addition, few studies have evaluated mechanisms that activate low avidity cancer antigen-specific T cells. Therefore, we developed high and low avidity HER-2/neu-specific TCR transgenic mouse colonies specific for the same HER-2/neu epitope to define the tolerance mechanisms that specifically affect high versus low avidity tumor-specific T cells.High and low avidity CD8(+) T cell receptor (TCR) transgenic mice specific for the breast cancer antigen HER-2/neu (neu) were developed to provide a purified source of naïve, tumor-specific T cells that can be used to study tolerance mechanisms. Adoptive transfer studies into tolerant FVB/N-derived HER-2/neu transgenic (neu-N) mice demonstrated that high avidity, but not low avidity, neu-specific T cells are inhibited by Tregs as the dominant tolerizing mechanism. High avidity T cells persisted, produced IFNγ, trafficked into tumors, and lysed tumors after adoptive transfer into mice treated with a neu-specific vaccine and low dose Cy to deplete Tregs. Analysis of Treg subsets revealed a Cy-sensitive CD4(+)Foxp3(+)CD25(low) tumor-seeking migratory phenotype, characteristic of effector/memory Tregs, and capable of high avidity T cell suppression.Depletion of CD25(low) Tregs allows activation of tumor-clearing high avidity T cells. Thus, the development of agents that specifically deplete Treg subsets should translate into more effective immunotherapies while avoiding autoimmunity.

Background: Delayed-onset neurologic changes (DONCs) following spinal deformity surgery are poorly understood and are often devastating., Methods: A retrospective review of cases from 12 hospitals was performed. The clinical and radiographic parameters of patients who experienced a new DONC after spinal deformity correction were evaluated., Results: Eighteen patients, with a mean preoperative major Cobb angle of 75° ± 24°, were included. The mean age at surgery was 13 ± 2 years, and 6 patients (33%) were male. Seven patients had temporary intraoperative neuromonitoring changes. Fourteen patients (78%) had neurologic changes within 24 hours postoperatively (range, 3 to 24 hours). Of 16 patients with blood pressure data, 8 (50%) had at least 1 documented episode of hypotension surrounding the change in neurologic status. No misaligned implants were seen on axial imaging. Fourteen patients (78%) were treated with vasopressors. Sixteen patients (89%) returned to the operating room, and 11 patients (61%) underwent implant removal. Seven patients (39%) sustained a spinal cord infarct, with only 1 (6%) experiencing recovery beyond an ASIA (American Spinal Injury Association Impairment Scale) score of B. Ten (91%) of the 11 patients without an infarct demonstrated recovery (5 patients with an ASIA score of D and 5 with a score of E)., Conclusions: A DONC is a rare complication of spinal deformity surgery. This study represents the largest documented series of DONCs and highlights the multifactorial and still poorly understood nature of this condition. The primary modifiable risk factor may be hypotension in the postoperative period: 50% of patients had a mean arterial pressure below the 5th percentile for their height, as documented around the time of the neurologic change. Eighty-six percent of patients with a spinal cord infarct had minimal neurologic recovery, whereas nearly all of the patients without an infarct did recover function. The management of this condition may include elevation of blood pressure with temporary implant removal., Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: This study was funded through intradepartmental funds secured from the Harrison Foundation. The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJS/I422)., (Copyright © 2025 by The Journal of Bone and Joint Surgery, Incorporated.)

Accurate and early diagnosis of Depression and Anxiety is met with the challenge of comorbid presentations and the neglect of the basic disturbances of self in current diagnostic criteria. Here, we review studies employing functional magnetic resonance imaging (fMRI) with self-based tasks in major depressive disorder (MDD) and anxiety disorders (AD) to determine the transdiagnostic and differential-diagnostic applicability of neural markers related to the self. This systematic review identified three main findings: (I) Large-scale brain-wide changes related to self-dysfunction overlap significantly between MDD and AD. (II) Regional changes are unspecific to tasks and stimuli confirming their specificity to the self as distinguished from other cognitive functions. (III) MDD affects regions related to emotional-cognitive processing like the anterior cingulate cortex, while AD involves prefrontal and insular regions associated with interoceptive and emotional-cognitive regulation. Our systematic review shows the utility of the self as a transdiagnostic marker that exhibits neural topographic similarities across the diagnostic boundaries of MDD and AD. More fine-grained regional differences between MDD and AD can be found within their underlying large scale neural similarities, allowing for their differential-diagnostic specification. In conclusion, we demonstrate the relevance of the self as both a transdiagnostic and differential diagnostic neural marker in MDD and AD., (Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background/objective: Platinum-resistant ovarian cancer (PROC) has limited therapeutic options, and the role of cytoreductive surgery (CRS) in improving survival outcomes remains uncertain. We performed a systematic review to evaluate the oncological benefit of CRS on PROC patients and the associated surgical morbidity and mortality., Methods: We followed a prospective protocol according to PRISMA guidelines. We searched PubMed, Medline, and Embase till October 2024. We used a "Population Intervention Comparator Outcomes (PICO)" framework. Our population included women with epithelial PROC who underwent CRS with/without chemotherapy. Our outcomes included overall survival (OS), progression-free-survival (PFS), post-operative morbidity and mortality and Quality of Life., Results: Our search yielded 6590 citations; six studies (N = 155 patients) were included. There is limited evidence available on the role of CRS in PROC, with notable variation in reported outcomes and outcomes' measures; therefore, we were unable to perform quantitative synthesis. CRS demonstrated survival benefits in well-selected PROC patients, particularly those with limited, isolated recurrences, low tumour burden, and good performance status. Complete resection (R0) was associated with significantly longer OS/PFS compared to those who had suboptimal surgeries (R1/R2)., Conclusions: CRS seems to extend survival in carefully selected PROC patients, especially those with limited disease spread and favourable surgical profiles. Nevertheless, CRS carries substantial surgical risks, and its benefits appear contingent upon achieving R0. Further prospective trials with standardised patient selection criteria are needed to define CRS's role in PROC. At present, CRS in PROC should be considered within a multidisciplinary approach in specialised gynaecological oncology centres, with the careful assessment of patient-specific risk factors and potential for R0 resection.

Neuromorphic computing is a brain-inspired approach to hardware and algorithm design that efficiently realizes artificial neural networks. Neuromorphic designers apply the principles of biointelligence discovered by neuroscientists to design efficient computational systems, often for applications with size, weight and power constraints. With this research field at a critical juncture, it is crucial to chart the course for the development of future large-scale neuromorphic systems. We describe approaches for creating scalable neuromorphic architectures and identify key features. We discuss potential applications that can benefit from scaling and the main challenges that need to be addressed. Furthermore, we examine a comprehensive ecosystem necessary to sustain growth and the new opportunities that lie ahead when scaling neuromorphic systems. Our work distils ideas from several computing sub-fields, providing guidance to researchers and practitioners of neuromorphic computing who aim to push the frontier forward., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. Springer Nature Limited.)

Purpose: To explore health literacy (HL) among parents of children with Hirschsprung disease (HD)., Methods: Norwegian-speaking parents of children under 16 who underwent HD surgery at a tertiary center were surveyed using the Health Literacy Questionnaire-Parent, electronic Health Literacy Scale, General Self-efficacy Scale, and a study-specific questionnaire. Demographics were collected and ethical approval was obtained., Results: Among 132 parents (77 mothers) of 91 children (median age 8 years), high HL scores appeared in the domains "understanding health information" and "active engagement", with lower scores in "provider support", "health information appraisal", and "social support". Higher HL correlated with parents aged over 40 and higher education. Lower scores were seen with non-exclusive Norwegian use at home and not living with the child's other parent. High electronic HL scores were common (mean 3.6, maximum score 5). 69% had high self-efficacy scores (score > 2, maximum score 4). Self-efficacy correlated strongly with higher HL scores., Conclusion: Parents of children with HD feel healthcare providers lack understanding of their child's challenges, experience limited social support and struggle with interpreting health information. We suggest targeted HL interventions for young, lower-educated, non-cohabitating parents and those not primarily speaking the official language at home., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s).)

The number of studies and reviews conducted for the Carboxylesterase gene is limited in comparison with other enzymes. Carboxylesterase (CES) gene or human carboxylesterases (hCES) is a multigene protein belonging to the α/β-hydrolase family. Over the last decade, two major carboxylesterases (CES1 and CES2), located at 16q13-q22.1 on human chromosome 16 have been extensively studied as important mediators in the metabolism of a wide range of substrates. hCES1 is the most widely expressed enzyme in humans, and it is found in the liver. In this review, details regarding CES1 substrates include both inducers (e.g. Rifampicin) and inhibitors (e.g. Enalapril, Diltiazem, Simvastatin) and different types of hCES1 polymorphisms (nsSNPs) such as rs2244613 and rs71647871. along with their effects on various CES1 substrates were documented. Few instances where the presence of nsSNPs exerted a positive influence on certain substrates which are hydrolyzed via hCES1, such as anti-platelets like Clopidogrel when co-administered with other medications such as angiotensin-converting enzyme (ACE) inhibitors were also recorded. Remdesivir, an ester prodrug is widely used for the treatment of COVID-19, being a CES substrate, it is a potent inhibitor of CES2 and is hydrolyzed via CES1. The details provided in this review could give a clear-cut idea or information that could be used for further studies regarding the safety and efficacy of CES1 substrate.

Background: Pyrethroid insecticides are commonly used insecticides. This study was undertaken to characterize the clinical profile and outcome of deliberate self-harm (DSH) with type 1 and type 2 pyrethroids and identify factors associated with need for hospitalization., Methods: This retrospective study was conducted in a tertiary care hospital in South India to study the clinical features, treatment, and outcome of patients with pyrethroid poisoning due to DSH. Patients were categorized as poisoning with type 1 or type 2 pyrethroid compounds. Factors associated with need for hospital admission was explored using bivariate and multivariate regression analysis and expressed as odds ratio (OR) with 95% confidence intervals (CIs)., Results: A total of 379 patients presented with pyrethroid poisoning; 202 (53.3%) patients were male. The median (interquartile range) age was 26 (22-33) years. Transfluthrin (n = 48, 58%) and cypermethrin (n = 149, 50%) were the most frequently implicated type 1 compounds and type 2 compounds, respectively. Of the 130 (34.3%) patients who were admitted, 13 (3.4%) patients required mechanical ventilation. All patients survived. On multivariate logistic regression analysis, ingestion of type 2 pyrethroids (OR: 2.55, 95%CI: 1.31-4.97), history of seizures (OR: 2.62, 95%CI 1.06-6.48), and treatment prior to presentation to the referral hospital (OR: 2.99, 95%CI: 1.87-4.74) were associated with the need for hospitalization., Conclusion: A third of patients with pyrethroid poisoning require hospitalization. Type 2 pyrethroid poisoning is more frequent in clinical practice. Ingestion of type 2 pyrethroids, seizures, and need for pre-hospital treatment are associated with hospitalization., Competing Interests: The authors have none to declare., (© 2023 Director General, Armed Forces Medical Services. Published by Elsevier, a division of RELX India Pvt. Ltd.)

Objective: To develop a universally accepted complexity and experience grading system to guide the safe implementation of robotic and laparoscopic minimally invasive pancreatoduodenectomy (MIPD)., Background: Despite the perceived advantages of MIPD, its global adoption has been slow due to the inherent complexity of the procedure and challenges to acquiring surgical experience. Its wider adoption must be undertaken with an emphasis on appropriate patient selection according to adequate surgeon and center experience., Methods: The International Study Group for Pancreatic Surgery (ISGPS) developed a complexity and experience grading system to guide patient selection for MIPD based on an evidence-based review and a series of discussions., Results: The ISGPS complexity and experience grading system for MIPD is subclassified into patient-related risk factors and provider experience-related variables. The patient-related risk factors include anatomic (main pancreatic and common bile duct diameters), tumor-specific (vascular contact), and conditional (obesity and previous complicated upper abdominal surgery/disease) factors, all incorporated in an A-B-C classification, graded as no, a single, and multiple risk factors. The surgeon and center experience-related variables include surgeon total MIPD experience (cutoffs 40 and 80) and center annual MIPD volume (cutoffs 10 and 30), all also incorporated in an A-B-C classification., Conclusions: This ISGPS complexity and experience grading system for robotic and laparoscopic MIPD may enable surgeons to optimally select patients after duly considering specific risk factors known to influence the complexity of the procedure. This grading system will likely allow for a thoughtful and stepwise implementation of MIPD and facilitate a fair comparison of outcomes between centers and countries., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Mandibular advancement devices are an effective treatment option for obstructive sleep apnea. While their efficacy depends on the degree of mandibular protrusion, other contributing factors influencing the optimal outcome are not fully understood. This magnetic resonance imaging-based pilot study aimed at investigating whether there are promising planimetric parameters that may be related to the optimal therapeutic position. A second aim was to assess possible sex-specific differences. Planimetric data from magnetic resonance imaging taken in the habitual position and four protrusion grades were collected from 11 female and 14 male patients with obstructive sleep apnea (age 45 ± 13.3 years; body mass index 27.6 ± 4.5 kg m -2 ). Data were correlated with outcome as substantiated by polygraphic data obtained at the habitual position and at each of two protrusion positions considered to reveal the highest treatment effect. Protrusion degree and lateral widening of the retropalatal region correlated most strongly (R = 0.56, p < 0.001). Relationships between planimetric data and treatment success were most pronounced at the level of the smallest cross-section, expressed, for example, by a correlation between oxygen desaturation index and lateral diameter (R = -0.4, p = 0.012). Female participants appeared to show improved polygraphic values at a lower protrusion degree than males. Data from magnetic resonance imaging allow for a comprehensive analysis combining insights from planimetric velopharyngeal measurements at different individual protrusion grades and correlation with outcome. The results of this pilot work encourage further evaluation in large-scale studies. These should focus on the velopharyngeal region and investigate the influence of sex more closely., (© 2024 European Sleep Research Society.)

Introduction: International guidelines recommend definitive combination antibiotic therapy for the management of serious infections involving carbapenem-resistant Acinetobacter (CRAB) species. The commonly available combination options include high-dose sulbactam, polymyxins, tetracyclines, and cefiderocol. Scanty prospective data exist to support this approach., Methods: Patients with CRAB bacteraemia, ventilator-associated pneumonia (VAP), or both were categorized based on whether they received combination therapy or monotherapy. The 30-day mortality was compared between the two groups. Inverse probability treatment weighting (IPTW) was done using propensity score (PS) for a balanced comparison between groups., Results: Between January 2021 and May 2023, of the 161 patients with CRAB bacteraemia (n = 55, 34.2%), VAP (n = 46, 28.6%), or both (n = 60, 37.3%) who received appropriate intravenous antibiotic therapy, 70% (112/161) received monotherapy, and the rest received combination therapy. The overall 30-day mortality was 62% (99/161) and not different (p = 0.76) between the combination therapy (31/49, 63.3%) and monotherapy (68/112, 60.7%) groups. The propensity score matching using IPTW did not show a statistical difference (p = 0.47) in 30-day mortality for receiving combination therapy with an adjusted odds ratio (OR) P of 1.29 (0.64, 2.58)., Conclusion: Combination therapy for CRAB infections needs further study in a randomised controlled trial, as this observational study showed no difference in 30-day mortality between monotherapy and combination therapy., (© 2024. The Author(s).)

Background: The Delphi consensus study was carried out under the auspices of the International and Asia-Pacific Hepato-Pancreato-Biliary Associations (IHPBA-APHPBA) to develop practice guidelines for management of gallbladder cancer (GBC) globally., Method: GBC experts from 17 countries, spanning 6 continents, participated in a hybrid four-round Delphi consensus development process. The methodology involved email, online consultations, and in-person discussions. Sixty eight clinical questions (CQs) covering various domains related to GBC, were administered to the experts. A consensus recommendation was accepted only when endorsed by more than 75% of the participating experts., Results: Out of the sixty experts invited initially to participate in the consensus process 45 (75%) responded to the invitation. The consensus was achieved in 92.6% (63/68) of the CQs. Consensus covers epidemiological aspects of GBC, early, incidental and advanced GBC management, definitions for radical GBC resections, the extent of liver resection, lymph node dissection, and definitions of borderline resectable and locally advanced GBC., Conclusions: This is the first international Delphi consensus on GBC. These recommendations provide uniform terminology and practical clinical guidelines on the current management of GBC. Unresolved contentious issues like borderline resectable/locally advanced GBC need to be addressed by future clinical studies., (Copyright © 2024 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Purpose: Physical activity is safe and feasible for individuals with metastatic cancer and may support symptom management. We investigated the extent to which individuals with metastatic cancer are meeting the World Health Organisation (WHO) moderate-vigorous physical activity (MVPA) guideline, factors associated with meeting the guideline, and perceptions about physical activity and receiving physical activity advice., Methods: Data were from UK adults with metastatic breast, prostate, or colorectal cancer who completed the Healthy Lifestyle After Cancer survey (N = 588). Self-reported clinical, demographic, and physical activity (Godin Leisure-Time Exercise Questionnaire) data were collected. Logistic regression models assessed whether clinical and demographic factors were associated with meeting the MVPA guideline., Results: Most (59%) individuals with metastatic cancer were not meeting the WHO guideline of 150 min of MVPA per week. Adjusting for cancer type, the odds of meeting the MVPA guideline were lower for unemployed individuals (OR = 0.47, 95% CI = 0.23-0.77) and ethnic minorities (OR = 0.44, 95% CI = 0.22-0.89), but higher for those with a university education (OR = 1.89, 95% CI = 1.0-3.57). Most (63.5%) participants felt they should be doing more physical activity. However, 70.1% did not receive any physical activity advice or support, despite 73.6% wanting to receive it., Conclusion: People with metastatic cancer may need further support to address inadequate levels of physical activity. The differences observed between demographic sub-groups suggest this may be more beneficial for those less likely to engage in physical activity., Implications for Cancer Survivors: Individuals with metastatic cancer are likely to benefit from increased physical activity support, which considers the needs of diverse demographic groups., (© 2024. The Author(s).)

Objective: To validate the ISGPS definition and grading system of PPAP after pancreatoduodenectomy (PD)., Summary Background Data: In 2022, the International Study Group for Pancreatic Surgery (ISGPS) defined post-pancreatectomy acute pancreatitis (PPAP) and recommended a prospective validation of its diagnostic criteria and grading system., Methods: This was a prospective, international, multicenter study including patients undergoing PD at 17 referral pancreatic centers across Europe, Asia, Oceania, and the United States. PPAP diagnosis required the following three parameters: (1) postoperative serum hyperamylasemia /hyperlipasemia (POH) persisting on postoperative days 1 and 2, (2) radiologic alterations consistent with PPAP, and (3) a clinically relevant deterioration in the patient's condition. To validate the grading system, clinical and economic parameters were analyzed across all grades., Results: Among 2902 patients undergoing PD, 7.5% (n=218) developed PPAP (6.3% grade B and 1.2% grade C). POH occurred in 24.1% of patients. Hospital stay was associated with PPAP grades (No POH/PPAP 10 days (IQR 7-17) days, grade B 22 days (IQR 15-34) days, and grade C 43 days (IQR 27-54) days; P<0.001), as well as intensive care unit admission (No POH/PPAP 5.4%, grade B 12.6%, grade C 82.9%; P<0.010), and hospital readmission rates (No POH/PPAP 7.3%, grade B 16.1%, grade C 18.5%; P<0.05). Costs of grade B and C PPAP were 2 and 11 times greater than uncomplicated clinical course, resp. (P<0.001)., Conclusions: This first prospective, international validation study of the ISGPS definition and grading system for PPAP highlighted the relevant clinical and financial implications of this condition. These results stress the importance of routine screening for PPAP in patients undergoing PD., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Enhancing a patient's functional capacity to withstand the surgical stress by means of multimodal (combined exercise, nutrition and psychological interventions) prehabilitation may potentially lead to improved outcomes in pancreatic cancer surgery., Methodology: A systematic review was undertaken searching PubMed, Google Scholar and Cochrane Library databases, exploring the impact of prehabilitation in pancreatic surgery. Outcomes of interest were adherence to the prehabilitation, functional capacity, overall complications and post-operative length of stay. Pooled analysis was performed using a random-effects model., Results: Twelve studies comprising of 1497 patients were included in the review. Most of the studies seem to lack a multimodal approach. Less than 50 % of the studies reported adherence, which ranged between 27 and 100 %. Functional capacity, in terms of 6-min walk test, showed improvement with prehabilitation. Among the post-operative outcomes, prehabilitation was associated with significant improvement in pulmonary complications (2.4 % versus 6.7 %, RR 0.36, CI 0.17-0.74, p = 0.01, I 2  = 28%). Prehabilitation was not effective in terms of length of stay or readmission rates., Conclusions: Larger studies with multimodal prehabilitation approaches may demonstrate more consistent and clinically meaningful benefits, which would lead to a firm appreciation of its role the management of pancreatic cancer patients undergoing surgery., Competing Interests: Declaration of competing interest HDDB is a member of the global Advisory board of Merck, the Scientific Advisory Board of Senzime, the global Advisory Board of NMD Pharma, the Research Committee and Scientific (SI) Committee of the European Society of Anaesthesiology and Intensive Care and has received research grants from Merck and the Medicines Company., (Copyright © 2024 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Background: The objective of this study was to evaluate the impact of dysglycemia on perioperative outcomes, in patients with and without diabetes, and how prior glycemic control modifies these relationships., Methods: Consecutive surgical patients admitted to six South Australian tertiary hospitals between 2017 and 2023 were included. Blood glucose levels within 48 h pre- and post-operatively were assessed in an adjusted analyses against a priori selected covariates. Dysglycemia metrics were hyperglycemia (>10.0 mmol/L), hypoglycemia (<4.0 mmol/L), glycemic variability (standard deviation of mean blood glucose >1.7 mmol/L), and stress hyperglycemic ratio (SHR). The primary outcome was hospital mortality., Results: Of 52 145 patients, 7490 (14.4%) had recognized diabetes. Inpatient mortality was observed in 787 patients (1.5%), of which 150 (19.1%) had diabetes mellitus. Hyperglycemia was associated with increased mortality in patients with diabetes (odds ratio [OR] = 2.99, 95% CI: 1.63-5.67, p = 0.004) but not in non-diabetics, who instead had an increased odds of intensive care unit (ICU) admission if hyperglycemic (OR = 1.95, 95% CI: 1.40-2.72, p < 0.0001). Glycemic variability was associated with increased mortality in patients with diabetes (OR = 1.46, 95% CI: 1.05-2.01, p < 0.05) but not in non-diabetics. Preoperative glycemic control (HbA1c) attenuated both of these associations in a dose-dependent fashion. Hypoglycemia was associated with increased mortality in non-diabetics (OR = 2.14, 95% CI: 1.92-2.37, p < 0.001) but not in patients with diabetes., Conclusions,: In surgical patients with diabetes, prior exposure to hyperglycemia attenuates the impact of perioperative hyperglycemia and glycemic variability on inpatient mortality and ICU admission. In patients without diabetes mellitus, all absolute thresholds of dysglycemia are associated with ICU admission, unlike those with diabetes, suggesting the need to use more relative measures such as the SHR., (© 2024 The Author(s). Journal of Diabetes published by Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Background: Posterior location of the facial nerve in relation to vestibular schwannoma (VS) is extremely rare., Case Description: An elderly man presented with the right cerebellopontine angle (CPA) syndrome. Magnetic resonance imaging showed the partly cystic and partly solid right CPA lesion extending to the internal auditory meatus. Seventh nerve monitoring showed the facial nerve on the posterior surface of the tumor. At surgery, the facial nerve was seen on the posterior surface of the tumor under the microscope. Partial excision of the tumor was done with preservation of the facial nerve both anatomically and electrophysiologically., Conclusion: The posterior location of the facial nerve should be anticipated in all patients with VS. The surgical strategy must be altered appropriately to preserve the facial nerve., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Surgical Neurology International.)

The REDISCOVER guidelines present 34 recommendations for the selection and perioperative care of borderline-resectable (BR-PDAC) and locally advanced ductal adenocarcinoma of the pancreas (LA-PDAC). These guidelines represent a significant shift from previous approaches, prioritizing tumor biology over anatomical features as the primary indication for resection. Condensed herein, they provide a practical management algorithm for clinical practice. However, the guidelines also highlight the need to redefine LA-PDAC to align with modern treatment strategies and to solve some contradictions within the current definition, such as grouping "difficult" and "impossible" to resect tumors together. Furthermore, the REDISCOVER guidelines highlight several areas requiring urgent research. These include the resection of the superior mesenteric artery, the management strategies for patients with LA-PDAC who are fit for surgery but unable to receive multi-agent neoadjuvant chemotherapy, the approach to patients with LA-PDAC who are fit for surgery but demonstrate high serum Ca 19.9 levels even after neoadjuvant treatment, and the optimal timing and number of chemotherapy cycles prior to surgery. Additionally, the role of primary chemoradiotherapy versus chemotherapy alone in LA-PDAC, the timing of surgical resection post-neoadjuvant/primary chemoradiotherapy, the efficacy of ablation therapies, and the management of oligometastasis in patients with LA-PDAC warrant investigation. Given the limited evidence for many issues, refining existing management strategies is imperative. The establishment of the REDISCOVER registry ( https://rediscover.unipi.it/ ) offers promise of a unified research platform to advance understanding and improve the management of BR-PDAC and LA-PDAC., (© 2024. The Author(s).)

Introduction: The tumor microenvironment (TME) of pancreatic cancer is highly immunosuppressive and characterized by a large number of cancer-associated fibroblasts, myeloid-derived suppressor cells, and regulatory T cells. Stimulator of interferon genes (STING) is an endoplasmic reticulum receptor that plays a critical role in immunity. STING agonists have demonstrated the ability to inflame the TME, reduce tumor burden, and confer anti-tumor activity in mouse models. 2'3' cyclic guanosine monophosphate adenosine monophosphate (2'3'-cGAMP) is a high-affinity endogenous ligand of STING. However, delivering cGAMP to antigen-presenting cells and tumor cells within the cytosol remains challenging due to membrane impermeability and poor stability., Methods: In this study, we encapsulated 2'3'-cGAMP in a lipid nanoparticle (cGAMP-LNP) designed for efficient cellular delivery. We assessed the properties of the nanoparticles using a series of in-vitro studies designed to evaluate their cellular uptake, cytosolic release, and minimal cytotoxicity. Furthermore, we examined the nanoparticle's anti-tumor effect in a syngeneic mouse model of pancreatic cancer., Results: The lipid platform significantly increased the cellular uptake of 2'3'-cGAMP. cGAMP-LNP exhibited promising antitumor activity in the syngeneic mouse model of pancreatic cancer., Discussion: The LNP platform shows promise for delivering exogenous 2'3'-cGAMP or its derivatives in cancer therapy., Competing Interests: Kun Cheng reports a patent application for the lipids used in this article. The authors report no other conflicts of interest in this work., (© 2024 Shaji et al.)

Objective: The objective of the study was to establish an AI-driven decision support system by identifying the most important features in the severity of disease for I ntensive C are U nit (ICU) with M echanical V entilation (MV) requirement, ICU, and I nter M ediate C are U nit (IMCU) admission for hospitalized patients with COVID-19 in South Florida. The features implicated in the risk factors identified by the model interpretability can be used to forecast treatment plans faster before critical conditions exacerbate. Methods: We analyzed eHR data from 5371 patients diagnosed with COVID-19 from South Florida Memorial Healthcare Systems admitted between March 2020 and January 2021 to predict the need for ICU with MV, ICU, and IMCU admission. A Random Forest classifier was trained on patients' data augmented by SMOTE, collected at hospital admission. We then compared the importance of features utilizing different model interpretability analyses, such as SHAP, MDI, and Permutation Importance. Results: The models for ICU with MV, ICU, and IMCU admission identified the following factors overlapping as the most important predictors among the three outcomes: age, race, sex, BMI, diarrhea, diabetes, hypertension, early stages of kidney disease, and pneumonia. It was observed that individuals over 65 years ('older adults'), males, current smokers, and BMI classified as 'overweight' and 'obese' were at greater risk of severity of illness. The severity was intensified by the co-occurrence of two interacting features (e.g., diarrhea and diabetes). Conclusions: The top features identified by the models' interpretability were from the 'sociodemographic characteristics', 'pre-hospital comorbidities', and 'medications' categories. However, 'pre-hospital comorbidities' played a vital role in different critical conditions. In addition to individual feature importance, the feature interactions also provide crucial information for predicting the most likely outcome of patients' conditions when urgent treatment plans are needed during the surge of patients during the pandemic.

Competing Interests: The author has no financial interest to declare in relation to the content of this article.

Competing Interests: Matthieu Lehmann is an employee of Gedeon Richter Suisse, and Julian Jenkins is a scientific advisor to Gedeon Richter Suisse. Paul Barrière received fees as a consultant and/or speaker for Merck, Genevrier, Ferring, Teva, MSD and Gedeon Richter. Jean-Luc Pouly received fees as a consultant and/or speaker for Gedeon Richter. Lauren Amy Boland and Samuel George Bean are employees of Remap Consulting who was commissioned to perform the initial analysis.

Background/Objectives: Perinatal exposure to malnutrition has been hypothesised to influence the development of young-onset cancer (≤50 years of age). This study aimed to determine if perinatal malnutrition in individuals exposed to the Great Famine of China increased their risk of developing young-onset cancer compared to other individuals born prior to the famine. Subjects/Methods: This cross-sectional study involved 7272 participants from the China Health and Nutrition Survey who were classified into four groups based on birth year: participants born between 1953 and 1955 (before the famine) were designated as the pre-famine group (unexposed); the remainder formed perinatal exposure groups comprised of those exposed during the famine (1959-1961), those exposed in the early post-famine period (1962-1964), and those exposed in the late post-famine period (1965-1967). Multivariable adjusted log-binomial regression models were used to calculate the RR and 95% CI of young-onset cancer (including genitourinary cancer) across four groups. Results: Perinatal exposure to early post-famine (RR 2.08; 95%CI 1.04, 4.34; p = 0.043) and the female sex (RR 15.6, 95%CI 4.54, 60.3; p < 0.001) were noted to have a significantly increased risk of young-onset cancer. In addition, the early (RR 13.8; 95%CI 2.68, 253; p = 0.012) and late post-famine (RR 12.3; 95%CI 2.16, 231; p = 0.020) cohorts demonstrated a significantly increased risk of young-onset genitourinary cancer. The latter was accompanied by an increased risk of hypertension (RR 3.30; 95%CI 1.28, 7.87; p = 0.009). Conclusions: Perinatal exposure to famine, especially in females, was associated with a higher risk of young-onset cancer. This was particularly evident for young-onset genitourinary cancers. These findings highlight the potential long-term impact of perinatal malnutrition on young-onset carcinogenesis.

Objective: The REDISCOVER consensus conference aimed at developing and validating guidelines on the perioperative care of patients with borderline-resectable (BR-) and locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC)., Background: Coupled with improvements in chemotherapy and radiation, the contemporary approach to pancreatic surgery supports the resection of BR-PDAC and, to a lesser extent, LA-PDAC. Guidelines outlining the selection and perioperative care for these patients are lacking., Methods: The Scottish Intercollegiate Guidelines Network (SIGN) methodology was used to develop the REDISCOVER guidelines and create recommendations. The Delphi approach was used to reach a consensus (agreement ≥80%) among experts. Recommendations were approved after a debate and vote among international experts in pancreatic surgery and pancreatic cancer management. A Validation Committee used the AGREE II-GRS tool to assess the methodological quality of the guidelines. Moreover, an independent multidisciplinary advisory group revised the statements to ensure adherence to nonsurgical guidelines., Results: Overall, 34 recommendations were created targeting centralization, training, staging, patient selection for surgery, possibility of surgery in uncommon scenarios, timing of surgery, avoidance of vascular reconstruction, details of vascular resection/reconstruction, arterial divestment, frozen section histology of perivascular tissue, extent of lymphadenectomy, anticoagulation prophylaxis, and role of minimally invasive surgery. The level of evidence was however low for 29 of 34 clinical questions. Participants agreed that the most conducive means to promptly advance our understanding in this field is to establish an international registry addressing this patient population ( https://rediscover.unipi.it/ )., Conclusions: The REDISCOVER guidelines provide clinical recommendations pertaining to pancreatectomy with vascular resection for patients with BR-PDAC and LA-PDAC, and serve as the basis of a new international registry for this patient population., Competing Interests: S.G.B.: support from Flinders Foundation grant: 49358025, NHMRC Ideas Grant: 2021009, Pankind 21.R7.INV.CB.UOSA.6.2. F.M.: Tsumura, Inc., Scientific Advisory Board. M.D.C. is a co-PI of a Boston Scientific–sponsored study and he has been awarded an industry grant by Haemonetics, Inc. M.H.: Intuitive Surgical—teaches courses and proctors. The remaining authors report no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

There is a general consensus that schizophrenia (SZ) is characterized by major changes in the sense of self. Phenomenological studies suggest that these changes in the sense of self stem from a basic disturbance, hence the term 'basic self-disturbance'. While imaging studies demonstrate changes in various regions during self-focused tasks, the exact neural correlates of such basic self-disturbances remain unclear. If the self-disturbance is indeed basic and thereby underlies all other symptoms, one would expect it to be related to more global rather than local changes in the brain. Testing this hypothesis, we conducted a systematic review of fMRI studies on self in SZ. Our main findings are 1. Abnormal activity related to the self can be observed in a variety of different regions ranging from higher-order transmodal to lower-order unimodal regions, 2. These findings hold true across different tasks including self-reflection, self-referentiality, and self-agency, and 3. The global neural abnormalities related to the self in SZ correspond to all layers of the self, predominantly the mental and exteroceptive self. Such global neural disturbance of self converges well with the basic self-disturbance as described in phenomenology., Competing Interests: Declaration of competing interest There are no conflicts of interest to report. G.N. is supported by Canadian Institutes of Health Research, Social Sciences and Humanities Research Council, Natural Sciences and Engineering Research Council, New Frontiers in Research Fund, and the UK-Canada AI grant which he holds together with Karl Friston. The funding sources had no involvement in neither the collection, analysis and interpretation of data, nor in the writing of the article nor in the decision to submit the article for publication., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

BRCA genetic testing is available for UK Jewish individuals but the provision of information online for BRCA is unknown. We aimed to evaluate online provision of BRCA information by UK organisations (UKO), UK Jewish community organisations (JCO), and genetic testing providers (GTP). Google searches for organisations offering BRCA information were performed using relevant sets of keywords. The first 100 website links were categorised into UKOs/JCOs/GTPs; additional JCOs were supplemented through community experts. Websites were reviewed using customised questionnaires for BRCA information. Information provision was assessed for five domains: accessibility, scope, depth, accuracy, and quality. These domains were combined to provide a composite score (maximum score = 5). Results were screened ( n = 6856) and 45 UKOs, 16 JCOs, and 18 GTPs provided BRCA information. Accessibility was high (84%,66/79). Scope was lacking with 35% (28/79) addressing >50% items. Most (82%, 65/79) described BRCA -associated cancers: breast and/or ovarian cancer was mentioned by 78%(62/79), but only 34% (27/79) mentioned ≥1 pancreatic, prostate, melanoma. Few websites provided carrier frequencies in the general (24%,19/79) and Jewish populations (20%,16/79). Only 15% (12/79) had quality information with some/minimal shortcomings. Overall information provision was low-to-moderate: median scores UKO = 2.1 (IQR = 1), JCO = 1.6 (IQR = 0.9), and GTP = 2.3 (IQR = 1) (maximum-score = 5). There is a scarcity of high-quality BRCA information online. These findings have implications for UK Jewish BRCA programmes and those considering BRCA testing.

Purpose: To determine normal anatomical variation of abdominal wall musculature. Methods: A retrospective analysis of CT scans was performed on adults (>18 years) with normal abdominal wall muscles. Two radiologists analysed the images independently. Distances from three fixed points in the midline were measured. The fixed points were; P1, mid-way between xiphoid and umbilicus, P2, at the umbilicus, and P3, mid-way between umbilicus and pubic symphysis. From these three fixed points the following measurements were recorded; midline to lateral innermost border of the abdominal wall musculature, midline to lateral edge of rectus abdominis muscle, and midline to medial edges of all three lateral abdominal wall muscles. To obtain aponeurotic width, rectus abdominis width was subtracted from the distance to medial edge of lateral abdominal wall muscle. Results: Fifty normal CT scan were evaluated from between March 2023 to August 2023. Mean width of external oblique aponeurosis at P1 was 16.2 mm (IQR 9.2 mm to 20.7 mm), at P2 was 23.5 mm (IQR 14 mm to 33 mm), and at P3 no external oblique muscle was visible. Mean width of the internal oblique aponeurosis at P1 was 32.1 mm (IQR 17.5 mm to 45 mm), at P2 was 10.13 (IQR 1 mm to 17.5 mm), and at P3 was 9.2 mm (IQR 3.0 mm to 13.7 mm). Mean width of the transversus abdominis aponeurosis at P1 was -25.1 mm (IQR 37.8 mm to -15.0 mm), at P2 was 29.4 mm (IQR 20 mm to 39.8 mm), and at P3 was 20.3 mm (IQR 12 mm to 29 mm). Conclusion: In this study we describe normal anatomical variation of the abdominal wall muscles. Assessing this variability on the pre-operative CT scans of ventral hernia patients allows for detailed operative planning and decision making., Competing Interests: RT and ACJW declare conflicts of interest not directly related to the submitted work: both are consultant advisers for TELA BIO. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Parker, Blake, Halligan, Ishak, Mahrous, Abdelgelil, Windsor, Shanmuganandan, Jakkalasaibaba and Thomas.)

Background & Aims: Reports of a rise in childhood cancer incidence in Australia and globally prompted the investigation of cancer incidence and survival in South Australia (SA) and the Northern Territory (NT) over a 28-year period, with emphasis on Indigenous peoples., Methods: This cross-sectional analysis of two prospective longitudinal databases, the SA and NT Cancer Registries (1990-2017), included all reported cases of childhood cancers. Poisson regression provided estimates of incidence rate ratios and survival was modelled using Cox proportional hazard models for children aged <5 and ≥5 years., Results: A total of 895 patients across SA ( N = 753) and the NT ( N = 142) were ascertained. Overall and in the NT, childhood cancer incidence was higher in males compared with females (IRR 1.19 [1.04-1.35] and 1.43 [1.02-2.01], respectively). Lymphocytic leukemia was the most reported cancer type across all locations. With reference to the 1990-1999 era (181.67/100,000), cancer incidence remained unchanged across subsequent eras in the combined cohort (SA and NT) (2000-2009: 190.55/100,000; 1.06 [0.91-1.25]; 2010-2017: 210.00/100,000; 1.15 [0.98-1.35]); similar outcomes were reflected in SA and NT cohorts. Cancer incidence amongst non-Indigenous children significantly decreased from the 1990-1999 era (278.32/100,000) to the 2000-2009 era (162.92/100,000; 0.58 [0.35-0.97]). Amongst 39 Indigenous children in the NT, incidence rates remained unchanged across eras ( p > 0.05). With reference to the 1990-1999 era, overall survival improved in subsequent eras in SA (2000-2009: HR 0.53 [0.38-0.73]; 2010-2017: 0.44 [0.28-0.68]); however, remained unchanged in the NT (2000-2009: 0.78 [0.40-1.51]; 2010-2017: 0.50 [0.24-1.05]). In the NT, overall survival of Indigenous patients was significantly lower compared with the non-Indigenous cohort (3.42 [1.92-6.10]). While the survival of Indigenous children with cancer significantly improved in the last two eras ( p < 0.05), compared to the 1990-1999 era, no change was noted amongst non-Indigenous children in the NT ( p > 0.05)., Conclusions: The incidence of childhood cancers has remained unchanged over 28-years in SA and the NT. Encouragingly, improved survival rates over time were observed in SA and amongst Indigenous children of the NT. Nevertheless, survival rates in Indigenous children remain lower than non-Indigenous children.

The sodium (Na + ) leak channel (NALCN) is a member of the four-domain voltage-gated cation channel family that includes the prototypical voltage-gated sodium and calcium channels (Na V s and Ca V s, respectively). Unlike Na V s and Ca V s, which have four lateral fenestrations that serve as routes for lipophilic compounds to enter the central cavity to modulate channel function, NALCN has bulky residues (W311, L588, M1145, and Y1436) that block these openings. Structural data suggest that occluded fenestrations underlie the pharmacological resistance of NALCN, but functional evidence is lacking. To test this hypothesis, we unplugged the fenestrations of NALCN by substituting the four aforementioned residues with alanine (AAAA) and compared the effects of Na V , Ca V , and NALCN blockers on both wild-type (WT) and AAAA channels. Most compounds behaved in a similar manner on both channels, but phenytoin and 2-aminoethoxydiphenyl borate (2-APB) elicited additional, distinct responses on AAAA channels. Further experiments using single alanine mutants revealed that phenytoin and 2-APB enter the inner cavity through distinct fenestrations, implying structural specificity to their modes of access. Using a combination of computational and functional approaches, we identified amino acid residues critical for 2-APB activity, supporting the existence of drug binding site(s) within the pore region. Intrigued by the activity of 2-APB and its analogues, we tested compounds containing the diphenylmethane/amine moiety on WT channels. We identified clinically used drugs that exhibited diverse activity, thus expanding the pharmacological toolbox for NALCN. While the low potencies of active compounds reiterate the pharmacological resistance of NALCN, our findings lay the foundation for rational drug design to develop NALCN modulators with refined properties., Competing Interests: Competing interests statement:The authors declare no competing interest.

Objective: The study assessed cost-effectiveness of follitropin alfa biosimilar versus the originator in terms of cost per cumulative live-birth (CLB) for the French healthcare system based on real-world evidence. Follitropin alfa biosimilars have been shown to have comparable clinical outcomes to the originator, in both clinical studies and real-world settings, in terms of oocyte retrieval and cumulative live-birth rate (CLBR). Previous health economic studies comparing the cost-effectiveness of follitropin alfa biosimilars against the originator utilised clinical trial data, leaving ambiguity over cost-effectiveness in real-world settings. Additionally, previous cost-effectiveness analysis has been performed for live-births following only fresh embryo transfers, whereas, fresh and frozen transfers are common in clinical practice. This study investigates the cost per CLB, which more closely models clinical practice., Study Design: A decision-tree cost-effectiveness model was developed based on the total costs and CLBR per ovarian stimulation (OS) for a follitropin alfa biosimilar (Bemfola®, Gedeon Richter Plc, Budapest, Hungary) and the originator (Gonal-f®, Merck KGaA, Darmstadt, Germany). A time horizon of one year from oocyte retrieval to embryo transfer was used but costs from resulting transfers were also included. Clinical inputs were taken from the REOLA real-world study or clinician insights, while acquisition costs were taken from French public databases. The output was cost per CLB following one OS. One-way sensitivity analysis was performed to determine the largest model drivers., Results: Cost per CLB was €18,147 with follitropin alfa biosimilar and €18,834 with the originator, saving €687 per CLB following OS with the biosimilar. When wastage estimates were considered the biosimilar cost saving is estimated to be between €796 and €1155 per CLB further increasing cost savings. Irrespective of wastage, if used ubiquitously throughout France for ART, the biosimilar could save the French health system €13,994,190 or lead to 771 more births when compared to its higher-cost originator. Sensitivity analysis showed that the originator's relative CLBR had the greatest impact on the model., Conclusion: This analysis demonstrates that the follitropin alfa biosimilar, Bemfola®, is a more cost-effective option for OS compared with the originator from a French healthcare payer perspective, in terms of cost per CLB., Competing Interests: ML is an employee of GR, and JJ is a scientific advisor to GR. EA was an employee of GR and is now an external consultant. PB received fees as a consultant and/or speaker for Merck, Genevrier, Ferring, Teva, MSD and GR. JLP received fees as a consultant and/or speaker for GR. LAB and SGB are employees of Remap Consulting who were commissioned to perform this piece of work., (© 2024 The Authors.)

In this perspective, we present our assessment of all of the known accumulated evidence on the role of neoadjuvant therapy in the management of borderline resectable pancreatic cancer highlighting the gaps in the data, the current regimens used and providing a brief insight into the way forward., Competing Interests: Conflict of InterestThe authors declare no competing interests., (© Indian Association of Surgical Oncology 2021.)