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Menopause-associated mood disorder is characterized by emotional depression, anxiety, and stress, which accompany hypogonadism in women in the menopausal phase. The current treatment for menopause-associated mood disorder provides only symptomatic relief and is associated with many side effects. Supplementation with vitamin E has been shown to be effective in ameliorating anxiety and depression. However, the effects of vitamin E and its underlying mechanism in ameliorating menopause-associated mood disorders remain uncertain. This work evaluated the effects of α-tocopherol and tocotrienol-rich palm oil extract on depressive and anxiety-related phenotypes induced by estrogen deficiency through ovariectomy in mice. Our study revealed that ovariectomized mice exhibited alterations in behavior indicative of depressive- and anxiety-like behaviors. The serum corticosterone level, a glucocorticoid hormone associated with stress, was found to be elevated in ovariectomized mice as compared to the sham group. Oral administration of α-tocopherol (50 and 100 mg/kg) and tocotrienol-rich palm oil extract (100 and 200 mg/kg) for 14 days alleviated these behavioral changes, as observed in open field, social interaction, and tail suspension tests. However, treatment with tocotrienol-rich palm oil extract, but not α-tocopherol, modulated the depressive- and anxiety-like responses in ovariectomized mice subjected to chronic restraint stress. Both treatments suppressed the elevated serum corticosterone level. Our findings suggested that α-tocopherol and tocotrienol-rich palm oil extract alleviated menopause-associated mood disorder, at least in part, by modulating the hypothalamic-pituitary-adrenal (HPA) axis. The findings of this study can provide a new foundation for the treatment of menopause-associated depressive- and anxiety-like phenotypes, for the betterment of psychological wellbeing., Competing Interests: Declaration of competing interest The authors would like to declare that there's no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This publication is the first to report current, global, pediatric oral extemporaneous compounding practices. Complete survey responses were received from 479 participants actively involved in compounding across all the World Health Organization (WHO) regions. The survey addressed oral formulation of extemporaneous liquids, including the use of commercial or in-house vehicles, flavoring excipients, source of formulation recipes, and beyond use dates (BUDs). Over 90% of the survey participants prepared oral liquids. Solid dosage forms, comprising capsules and powder papers (sachets), were also frequently prepared for children, albeit to a lesser extent. The top 20 active pharmaceutical ingredients compounded for children, globally, were: omeprazole, captopril, spironolactone, propranolol, furosemide, phenobarbital, hydrochlorothiazide, ursodeoxycholic acid, sildenafil, melatonin, clonidine, enalapril, dexamethasone, baclofen, caffeine, chloral hydrate, trimethoprim, atenolol, hydrocortisone, carvedilol and prednisolone. Diuretics, drugs for acid-related disorders, and beta-blockers were the top three most frequently compounded classes per the WHO Anatomical Therapeutic Chemical (ATC) classification system. The principal need identified for the practice of extemporaneous compounding for children was the development of an international, open-access formulary that includes validated formulations, as well as updated compounding literature and guidelines. Furthermore, improved access to data from stability studies to allow compounding of formulations with extended BUDs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Digital tomosynthesis has shown potential for increasing specificity and sensitivity compared to radiography for low-dose chest imaging. Prior investigation of the s-DCT system indicated potential, but additional iteration with improved scan speed, power, and angular span was necessary for translation., Purpose: The study aims to demonstrate and characterize a second-generation stationary digital chest tomosynthesis (s-DCT) scanner with increased x-ray energy, tube current, and larger angular span., Methods: The second-generation s-DCT system employed a meter-long linear carbon nanotube (CNT) source array integrated with a digital detector and patient imaging table. Tube output, focal spot size, modulation transfer function (MTF), artifact spread function (ASF), and imaging performance were evaluated. A lung phantom with simulated nodules was imaged for clinical task-based demonstration., Results: The scanner achieved a 6 s scan time, significantly improved from the prior generation's 16 s. The x-ray tube exhibited good current stability, with 20.4 ± 0.6 mA tube current and focal spot size aligned with specifications (IEC 0.8). The MTF confirmed enhanced spatial resolution of 2.4 lp/mm, comparable to commercial chest tomosynthesis systems. The ASF indicated improved depth resolution (5.2 mm, previously 9.5 mm). Phantom imaging showcased visualization of both high and low-attenuation lung nodules., Conclusion: The second-generation s-DCT system exhibited improved performance in terms of tube power, scan time, and image quality. Enhanced in-plane and depth resolution, along with faster imaging, suggest potential clinical benefits for improved diagnoses. Further clinical validation is warranted to ascertain the system's clinical utility., (© 2024 American Association of Physicists in Medicine.)

Gynostemma pentaphyllum (Thunb.) Makino is a perennial creeping herb belonging to the Cucurbitaceae family that has a long history of usage in traditional oriental medicine. Gypenosides are the primary bioactive compounds in Gynostemma pentaphyllum. Because of the medicinal value of gypenosides, functional food and supplements containing gypenosides have been promoted and consumed with popularity, especially among Asian communities. This review presented the progress made in the research of pharmacological properties of gypenosides on diseases of the nervous system and their possible mechanism of action. To date, preclinical studies have demonstrated the therapeutic effects of gypenosides in alleviating neuropsychiatric disorders like depression, Parkinson's disease, Alzheimer's disease, secondary dementia, stroke, optic neuritis, etc. Pharmacological studies have discovered that gypenosides can modulate various major signaling pathways like NF-κB, Nrf2, AKT, ERK1/2, contributing to the neuroprotective properties. However, there is a dearth of clinical research on gypenosides, with current investigations on the compounds being mainly conducted in vitro and on animals. Future studies focusing on isolating and purifying novel gypenosides and investigations on exploring the potential molecular mechanism underlying their biological activities are warranted, which may serve as a foundation for further clinical trials for the betterment of human health., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Current clinical small molecule x-ray CT agents are effective but pose risks such as nephrotoxicity, short blood circulation time, limiting scan durations, potential thyroid impact, and immune responses. These challenges drive the development of kidney-safe x-ray nanoparticle (NP)-based contrast agents (CAs), though translation to clinical practice is hindered by chemical complexities and potential toxicity. We have engineered an intravenous, injectable, and safe blood pool NP-based CT CAs at a clinical-equivalent dose of ∼300 mgI/kg (∼2 mL/kg), ideal for vascular and hepatic imaging which are limited by clinical agents. Our iodinated lipid nanodroplet emulsions (ILNEs) contrast agent offers high x-ray attenuation thus improved contrast enhancement, extended stability, and exceptional batch-to-batch consistency. It also boasts a straightforward and scalable manufacturing process with minimal protein interaction, prolonged blood residency (∼4h), and hepatic clearance within 3 days, avoiding nephrotoxicity. Studies in vitro, in mice, and 16.6kg porcine animal model studies confirm its safety, cytocompatibility, and absence of tissue damage. Blood, and thyroid-stimulating hormone (TSH) analyses, and kidney and liver function tests, also support further toxicity evaluations for clinical translation.

The development of an effective and broadly protective influenza vaccine against circulating and emerging strains remains elusive. In this study, we evaluated a potentially universal influenza vaccine based on single-component self-assembling protein nanoparticles (1c-SApNPs) presenting the conserved matrix protein 2 ectodomain (M2e) from influenza A and B viruses (IAV and IBV, respectively). We previously designed a tandem antigen comprising three IAV M2e domains of human, avian/swine, and human/swine origins (termed M2ex3). The M2ex3-presenting 1c-SApNPs conferred complete protection in mice against sequential lethal challenges with H1N1 and H3N2. To broaden this protection to cover IBVs, we designed a series of antigens incorporating different arrangements of three IAV M2e domains and three copies of IBV M2e. Tandem repeats of IAV and IBV (termed influenza A-B) M2e arrayed on the I3-01v9a 60-mer 1c-SApNP, when formulated with an oil-in-water emulsion adjuvant, generated greater M2e-specific immunogenicity and protective efficacy than the soluble influenza A-B M2e trimer, indicated by higher survival rates and reduced weight loss post-challenge. Importantly, one of the influenza A-B M2e SApNP constructs elicited 100% protection against a lethal influenza A/Puerto Rico/8/1934 (H1N1) challenge in mice and 70% protection against a lethal influenza B/Florida/4/2006 (Yamagata lineage) challenge, the latter of which has not been reported in the literature to date. Our study thus provides a promising M2e-based single-component universal vaccine candidate against the two major types of influenza virus circulating in humans.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder affecting women of reproductive age globally. Emerging evidence suggests that the dysregulation of microRNAs (miRNAs) and gut dysbiosis are linked to the development of PCOS. In this study, the effects of Lacticaseibacillus paracasei subsp. paracasei DSM 27449 (DSM 27449) were investigated in a rat model of PCOS induced by letrozole. The administration of DSM 27449 resulted in improved ovarian function, reduced cystic follicles, and lower serum testosterone levels. Alterations in miRNA expressions and increased levels of the pro-apoptotic protein Bax in ovarian tissues were observed in PCOS-like rats. Notably, the administration of DSM 27449 restored the expression of miRNAs, including miR-30a-5p, miR-93-5p, and miR-223-3p, leading to enhanced ovarian function through the downregulation of Bax expressions in ovarian tissues. Additionally, 16S rRNA sequencing showed changes in the gut microbiome composition after letrozole induction. The strong correlation between specific bacterial genera and PCOS-related parameters suggested that the modulation of the gut microbiome by DSM 27449 was associated with the improvement of PCOS symptoms. These findings demonstrate the beneficial effects of DSM 27449 in ameliorating PCOS symptoms in letrozole-induced PCOS-like rats, suggesting that DSM 27449 may serve as a beneficial dietary supplement with the therapeutic potential for alleviating PCOS.

Objective. This study explores the feasibility of a stationary gantry cardiac gated computed tomography (CT) with carbon nanotube (CNT) linear x-ray source arrays. Approach. We developed a stationary gantry CT system utilizing multipixel CNT x-ray sources. Given the advantages of straightforward x-ray pulse control with these sources, we investigated the potential for gated prospective imaging. We implemented prospective respiratory and cardiac gating control and evaluated the system through dynamic phantom imaging studies followed by imaging of a porcine model. Main Results. The findings revealed minimal anatomical motion artifacts in the heart and lungs, confirming successful physiologic gated acquisition in stationary gantry cardiac CT. This indicates the potential of this imaging approach for reducing artifacts and improving image quality. Significance. This study demonstrates the feasibility of prospective physiological gating with CNT x-ray sources in a stationary gantry setup for cardiac imaging. This approach could potentially alleviate the need for beta blocker administration during cardiac CT scans, thereby increasing the flexibility of the imaging system and enabling the imaging of a wider variety of patient cardiac conditions., (© 2024 Institute of Physics and Engineering in Medicine.)

Extended reality (XR) simulations are becoming increasingly common in educational settings, particularly in medical education. Advancing XR devices to enhance these simulations is a booming field of research. This study seeks to understand the value of a novel, non-wearable mixed reality (MR) display during interactions with a simulated holographic patient, specifically in taking a medical history. Twenty-one first-year medical students at the University of North Carolina at Chapel Hill participated in the virtual patient (VP) simulations. On a five-point Likert scale, students overwhelmingly agreed with the statement that the simulations helped ensure they were progressing along learning objectives related to taking a patient history. However, they found that, at present, the simulations can only partially correct mistakes or provide clear feedback. This finding demonstrates that the novel hardware solution can help students engage in the activity, but the underlying software may need adjustment to attain sufficient pedagogical validity., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Institutional Review Board of the University of North Carolina at Chapel Hill issued approval 21-1197. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: Jeremiah S. Heneghan declare(s) non-financial support and employment from BioMojo LLC. Mr. Heneghan is the co-founder and Chief Design Officer for Biomojo LLC, which created and retains all licenses to the simulation software described in this intervention but not the hardware used. . Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Alexander et al.)

Atopic dermatitis (AD) is a chronic, allergic inflammatory skin disorder that lacks a definite cure. Using a mouse DNCB-induced AD-like skin lesions model, this study evaluated the potential therapeutic utility of tHGA as an oral and topical treatment for AD. Male BALB/c mice were sensitised and challenged with 1% and 0.5% DNCB on their shaved dorsal skin. Mice in the treatment group were administered tHGA (20, 40, and 80 mg/kg) orally three times per week for 2 weeks, or tHGA (0.2%, 1%, and 5%) topically once daily for 12 days. On day 34, the mice were euthanized, and blood and dorsal skin samples were obtained for analysis. All doses of orally and topically administered tHGA significantly improved scratching, epidermal thickness, blood eosinophilia and mast cell infiltration. There was a minor discrepancy between the two routes of administration, with orally treated tHGA showing significant reductions in Scoring of Atopic Dermatitis (SCORAD), tissue eosinophil infiltration, serum IgE and skin IL-4 levels with treatment of 40 and 80 mg/kg tHGA, whereas topically applied tHGA showed significant reductions in all dosages. These findings suggest that tHGA exhibited therapeutic potential for AD as both oral and topical treatment ameliorates AD-like symptoms in the murine model., (© 2024. The Author(s).)

Introduction: Metastasis is responsible for 90% of cancer-related deaths worldwide. However, the potential inhibitory effects of metastasis by various anticancer drugs have been left largely unexplored. Existing preclinical models primarily focus on antiproliferative agents on the primary tumor to halt the cancer growth but not in metastasis. Unlike primary tumors, metastasis requires cancer cells to exert sufficient cellular traction force through the actomyosin machinery to migrate away from the primary tumor site. Therefore, we seek to explore the potential of cellular traction force as a novel readout for screening drugs that target cancer metastasis., Methods: In vitro models of invasive and non-invasive breast cancer were first established using MDA-MB-231 and MCF-7 cell lines, respectively. Cellular morphology was characterized, revealing spindle-like morphology in MDA-MB-231 and spherical morphology in MCF-7 cells. The baseline cellular traction force was quantified using the Traction force Microscopy technique. Cisplatin, a paradigm antimetastatic drug, and 5-Fluorouracil (5FU), a non-antimetastatic drug, were selected to evaluate the potential of cellular traction force as a drug testing readout for the in vitro cancer metastasis., Results: MDA-MB-231 cells exhibited significantly higher baseline cellular traction force compared to MCF-7 cells. Treatment with Cisplatin, an antimetastatic drug, and 5-Fluorouracil (5FU), a non-antimetastatic drug, demonstrated distinct effects on cellular traction force in MDA-MB-231 but not in MCF-7 cells. These findings correlate with the invasive potential observed in the two models., Conclusion: Cellular traction force emerges as a promising metric for evaluating drug efficacy in inhibiting cancer metastasis using in vitro models. This approach could enhance the screening and development of novel anti-metastatic therapies, addressing a critical gap in current anticancer drug research., Competing Interests: Conflict of interestAll authors, namely HYL, XHL, WXL, YZL, YSO, OS, and LHC, declare no competing interests, and there are no conflicts to disclose., (© The Author(s) 2024.)

Endometriosis is a common cause of infertility, pelvic pain, and dysmenorrhea and there are prior case reports of lesion detection using an 18F-fluoroestradiol (FES) tracer with positron emission tomography (PET). We aimed to further investigate the use of the FES tracer in the context of PET-magnetic resonance (PET-MR) imaging. We administered FES to 6 patients and then imaged them using a Siemens mMR PET-MR scanner. Each patient was taken to surgery within 30 days after imaging, and surgical visualization served as the gold-standard for diagnosis. PET did not prove to be as sensitive as MR (50% per-patient sensitivity versus 67% per-patient and 35% versus 48% per-lesion), and did not show any additional sites over and above MR. When MR was used to localize lesions on PET after imaging, there was insufficient evidence of an association between total tracer uptake and reported pain intensity (P=0.25). FES PET-MR offers no additional value to MR for endometriosis., Competing Interests: None., (AJNMMI Copyright © 2024.)

Dual-energy cone beam computed tomography (DE-CBCT) has been shown to provide more information and improve performance compared to a conventional single energy spectrum CBCT. Here we report a low-cost DE-CBCT by spectral filtration of a carbon nanotube x-ray source array. The x-ray photons from two focal spots were filtered respectively by a low and a high energy filter. Projection images were collected by alternatively activating the two beams while the source array and detector rotated around the object, and were processed by a one-step materials decomposition and reconstruction method. The performance of the DE-CBCT scanner was evaluated by imaging a water-equivalent plastic phantom with inserts containing known densities of calcium or iodine and an anthropomorphic head phantom with dental implants. A mean energy separation of 15.5 keV was achieved at acceptable dose rates and imaging time. Accurate materials quantification was obtained by materials decomposition. Metal artifacts were reduced in the virtual monoenergetic images synthesized at high energies. The results demonstrated the feasibility of high quality DE-CBCT imaging by spectral filtration without using either an energy sensitive detector or rapid high voltage switching., (© 2024. The Author(s).)

Rheumatoid arthritis is an autoimmune disease whose early onset correlates with dysregulated citrullination, a process catalyzed by peptidylarginine deiminase isoform 4 (PADI-4). Here, we report that PADI-4 is a novel target of vitamin B12, a water-soluble vitamin that serves as a cofactor in DNA synthesis and the metabolism of fatty and amino acids. Vitamin B12 preferentially inhibited PADI-4 over PADI-2 with comparable inhibitory activity to the reference compound Cl-amidine in enzymatic inhibition assays, and reduced total cellular citrullination levels including that of histone H3 citrullination mediated by PADI-4. We also demonstrated that hydroxocobalamin, a manufactured form of vitamin B12, significantly ameliorated the severity of collagen type II antibody induced arthritis (CAIA) in mice and diminished gene expression of the rheumatoid inflammatory factors and cytokines IL17A, TNFα, IL-6, COX-II and ANXA2, as well PADI-4. Therefore, the use of vitamin B12 to treat rheumatoid arthritis merits further study., Competing Interests: Declaration of competing interest The authors declare no conflict of interest, (Copyright © 2024 Elsevier Inc. All rights reserved.)

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of rare conditions predominantly affecting small vessels of skin, musculoskeletal, pulmonary, renal, and rarely central and peripheral nervous systems. Isolated neurological manifestations of AAV are uncommon and challenging to diagnose. Cocaine has been reported as a potential trigger for the development of AAV. There are only a few case reports of isolated neurological involvement in cocaine-induced AAV with poorly characterized histopathological features. We present a unique case of AAV with isolated neurological manifestations presenting with multiple cranial neuropathies, leptomeningeal enhancement on imaging and histopathologic evidence of small-vessel vasculitis in the leptomeninges and brain and extensive dural fibrosis in a patient with cocaine abuse. The patient's progressive neurological deficits were controlled after starting immunosuppression with rituximab and prednisone. We also reviewed the literature to provide the diagnostic overview of AAV and evaluate intervention options. To our knowledge, this is the first case of AAV with isolated neurological manifestations and histopathologic evidence of small-vessel vasculitis in a patient with cocaine abuse. Patients with multiple cranial neuropathies and meningeal involvement should be screened for AAV, especially if they have a history of cocaine abuse., (© 2024. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Purpose: Endometriosis is an estrogen-dependent disorder of menstruating primates where tissues similar to the inner lining of the uterus exist "ectopically" outside of the uterus. The ectopic endometrium, like the endometrium within the uterus, expresses estrogen receptors (ER) and progesterone receptors (PR) and undergoes hormone-dependent cell proliferation and bleeding each menstrual cycle. The goal of this study was to conduct abdominopelvic positron emission tomography (PET) scans with computed tomography (CT) imaging of rhesus macaques (Macaca mulatta) using radiotracers that target ER and PR [16α-[ 18 F]fluoroestradiol (FES) and 12-[ 18 F]fluoro-furanyl-nor-progesterone (FFNP)] in individuals with and without endometriosis. We also aimed to determine if menstrual cycle phase and/or the presence of endometriosis affected the uptake of these radiotracers., Procedures: Rhesus macaques with either clinically diagnosed endometriosis (n = 6) or no endometriosis (n = 4) underwent PET/CT scans with FES. A subset of the animals also underwent PET/CT scans with FFNP. Standard uptake values corrected for body weight (SUVs) were obtained for each radiotracer in target and background tissues (e.g., intestinal). We performed repeated measure analysis of variance tests to determine how uterine and background uptake differed with scan time, phase of the menstrual cycle, and disease state., Results: Abdominopelvic PET/CT could not resolve small, individual endometriotic lesions. However, macaques with endometriosis displayed higher uterine uptake compared to those without the disorder. Radiotracer uptake differed by menstrual cycle phase with increased uterine uptake of both radiotracers in the proliferative phase of the menstrual cycle. Background intestinal uptake of FFNP increased over time after infusion, but only during the proliferative phase., Conclusions: PET/CT with FES and FFNP support the concept that ER and PR levels are altered in individuals with endometriosis. This highlights the impact of the disease on typical reproductive tract function and may provide a novel pathway for the identification of individuals with endometriosis., (© 2023. The Author(s), under exclusive licence to World Molecular Imaging Society.)

Objective: Caffeine provides neuroprotection following hypoxic-ischemic injury in animals. We characterized the safety of escalating doses of caffeine in infants with hypoxic-ischemic encephalopathy (HIE) receiving therapeutic hypothermia., Study Design: Phase I trial of infants undergoing therapeutic hypothermia for HIE receiving IV caffeine 20 mg/kg followed by up to two daily doses of 5 mg/kg (n = 9) or 10 mg/kg (n = 8). Safety was evaluated based on adverse events and frequency of pre-specified outcomes compared to data from the Whole-Body Hypothermia for HIE trial (Shankaran, 2005)., Results: Twelve of 17 (71%) infants had ≥1 adverse event during the study period. The frequency of clinical outcomes related to HIE were not statistically different from outcomes in infants receiving hypothermia in the Whole-Body Hypothermia for HIE trial., Conclusion: Caffeine administration was well tolerated. A larger study is required to determine the optimal dose and evaluate drug safety and efficacy., Clinical Trial: ClinicalTrials.gov Identifier: NCT03913221., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Cone beam computed tomography (CBCT) is known to suffer from strong scatter and cone beam artifacts. The purpose of this study is to develop and characterize a rapidly scanning carbon nanotube (CNT) field emission x-ray source array to enable a multisource CBCT (ms-CBCT) image acquisition scheme which has been demonstrated to overcome these limitations. A CNT x-ray source array with eight evenly spaced focal spots was designed and fabricated for a medium field of view ms-CBCT for maxillofacial imaging. An external multisource collimator was used to confine the radiation from each focal spot to a narrow cone angle. For ms-CBCT imaging, the array was placed in the axial direction and rapidly scanned while rotating continuously around the object with a flat panel detector. The x-ray beam profile, temporal and spatial resolutions, energy and dose rate were characterized and evaluated for maxillofacial imaging. The CNT x-ray source array achieved a consistent focal spot size of 1.10 ± 0.04 mm × 0.84 ± 0.03 mm and individual beam cone angle of 2.4°±0.08 after collimation. The x-ray beams were rapidly switched with a rising and damping times of 0.21 ms and 0.19 ms, respectively. Under the designed operating condition of 110 kVp and 15 mA, a dose rate of 8245 μ Gy s -1 was obtained at the detector surface with the inherent Al filtration and 2312 μ Gy s -1 with an additional 0.3 mm Cu filter. There was negligible change of the x-ray dose rate over many operating cycles. A ms-CBCT scan of an adult head phantom was completed in 14.4 s total exposure time for the imaging dose in the range of that of a clinical CBCT scanner. A spatially distributed CNT x-ray source array was designed and fabricated. It has enabled a new multisource CBCT to overcome some of the main inherent limitations of the conventional CBCT., (© 2024 Institute of Physics and Engineering in Medicine.)

Background: Digital subtraction angiography (DSA) yields high cumulative radiation dosages (RD) delivered to patients. We present a temporal interpolation of low frame rate angiograms as a method to reduce cumulative RDs., Methods: Patients undergoing interventional evaluation and treatment of cerebrovascular vasospasm following subarachnoid hemorrhage were retrospectively identified. DSAs containing pre- and post-intervention runs capturing the full arterial, capillary, and venous phases with at least 16 frames each were selected. Frame rate reduction (FRR) of the original DSAs was performed to 50%, 66%, and 75% of the original frame rate. Missing frames were regenerated by sampling a gamma variate model (GVM) fit to the contrast response curves to the reduced data. A formal reader study was performed to assess the diagnostic accuracy of the "synthetic" studies (sDSA) compared to the original DSA., Results: Thirty-eight studies met inclusion criteria (average RD 1,361.9 mGy). Seven were excluded for differing views, magnifications, or motion. GVMs fit to 50%, 66%, and 75% FRR studies demonstrated average voxel errors of 2.0 ± 2.5% (mean ± standard deviation), 6.5 ± 1.5%, and 27 ± 2%, respectively for anteroposterior projections, 2.0 ± 2.2%, 15.0 ± 3.1%, and 14.8 ± 13.0% for lateral projections, respectively. Reconstructions took 0.51 s/study. Reader studies demonstrated an average rating of 12.8 (95% CI 12.3-13.3) for 75% FRR, 12.7 (12.2-13.2) for 66% FRR and 12.0 (11.5-12.5) for 50% FRR using Subjective Image Grading Scale. Kendall's coefficient of concordance resulted in W = 0.506., Conclusion: FRR by 75% combined with GVM reconstruction does not compromise diagnostic quality for the assessment of cerebral vasculature., Relevance Statement: Using this novel algorithm, it is possible to reduce the frame rate of DSA by as much as 75%, with a proportional reduction in radiation exposure, without degrading imaging quality., Key Points: • DSA delivers some of the highest doses of radiation to patients. • Frame rate reduction (FRR) was combined with bolus tracking to interpolate intermediate frames. • This technique provided a 75% FRR with preservation of diagnostic utility as graded by a formal reader study for cerebral angiography performed for the evaluation of cerebral vasospasm. • This approach can be applied to other types of angiography studies., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Multisource cone beam computed tomography CBCT (ms-CBCT) has been shown to overcome some of the inherent limitations of a conventional CBCT. The purpose of this study was to evaluate the accuracy of ms-CBCT for measuring the bone mineral density (BMD) of mandible and maxilla compared to the conventional CBCT. The values measured from a multi-detector CT (MDCT) were used as substitutes for the ground truth. An anthropomorphic adult skull and tissue equivalent head phantom and a homemade calibration phantom containing inserts with varying densities of calcium hydroxyapatite were imaged using the ms-CBCT, the ms-CBCT operating in the conventional single source CBCT mode, and two clinical CBCT scanners at similar imaging doses; and a clinical MDCT. The images of the anthropomorphic head phantom were reconstructed and registered, and the cortical and cancellous bones of the mandible and the maxilla were segmented. The measured CT Hounsfield Unit (HU) and Greyscale Value (GV) at multiple region-of-interests were converted to the BMD using scanner-specific calibration functions. The results from the various CBCT scanners were compared to that from the MDCT. Statistical analysis showed a significant improvement in the agreement between the ms-CBCT and MDCT compared to that between the CBCT and MDCT., (© 2024. The Author(s).)

Background: Older age and frailty are associated with worse postoperative outcomes and prolonged length of stay (LOS). In this study, we aimed to analyze the long-term outcomes after the implementation of our geriatric surgical service (GSS)., Methods: This was a single-center retrospective study from July 2010 to December 2021 on patients aged ≥75 years or patients aged ≥65 years with frailty. Our GSS includes multidisciplinary assessment and optimization by specialized nurses, physiotherapists, anesthetists, dietitians, and geriatricians. Cumulative sum (CUSUM) analysis was used to assess the performance of our GSS. Our primary outcome was defined as the presence of 30-day mortality, prolonged LOS ≥ 14 days, and/or >10% decrease in the modified Barthel Index at 6 weeks, which depicts the failure of GSS. A downsloping CUSUM curve implies consecutive cases of success., Results: There were 233 patients with a mean age of 79.0 ± 4.9 years; of these, 73 patients (31.3%) were frail. The overall 30-day mortality (1.7%), Clavien-Dindo ≥ grade IIIA complications (12.0%), and LOS (median, 7.0 days) were low. The CUSUM analysis showed 3 phases with overall sustained improvement in outcomes. Transient inconsistency in the second phase (during midimplementation of GSS) may be due to the early adoption of laparoscopic surgery (44.6% vs 24.1%; adjusted P =.031) and expansion of service to include patients with higher perioperative risks (weighted Charlson Comorbidity Index score ≥4: 64.9% vs 38.0%; adjusted P =.002) in the second period compared with the first period. The outcomes subsequently improved in the third phase after overcoming the learning curve., Conclusion: Our GSS showed sustained performance over the past decade. Good quality surgery and surgeon-led geriatric service are paramount for good postoperative outcomes., Competing Interests: Declaration of competing interest All of the authors have no conflicts of interest., (Copyright © 2023 Society for Surgery of the Alimentary Tract. Published by Elsevier Inc. All rights reserved.)

The development of a cross-protective pan-influenza A vaccine remains a significant challenge. In this study, we designed and evaluated single-component self-assembling protein nanoparticles (SApNPs) presenting the conserved extracellular domain of matrix protein 2 (M2e) as vaccine candidates against influenza A viruses. The SApNP-based vaccine strategy was first validated for human M2e (hM2e) and then applied to tandem repeats of M2e from human, avian, and swine hosts (M2ex3). Vaccination with M2ex3 displayed on SApNPs demonstrated higher survival rates and less weight loss compared to the soluble M2ex3 antigen against the lethal challenges of H1N1 and H3N2 in mice. M2ex3 I3-01v9a SApNPs formulated with a squalene-based adjuvant were retained in the lymph node follicles over 8 weeks and induced long-lived germinal center reactions. Notably, a single low dose of M2ex3 I3-01v9a SApNP formulated with a potent adjuvant, either a Toll-like receptor 9 (TLR9) agonist or a stimulator of interferon genes (STING) agonist, conferred 90% protection against a lethal H1N1 challenge in mice. With the ability to induce robust and durable M2e-specific functional antibody and T cell responses, the M2ex3-presenting I3-01v9a SApNP provides a promising pan-influenza A vaccine candidate.

The prevalence of house dust mite (HDM) allergy, especially in Asian countries with rapid urbanization, has been increasing. House dust mites thrive in places with relatively high humidity. With the combination of climate change, naturally high humidity, and urbanization, tropical countries like Malaysia are becoming a hotspot for HDM allergy fast. With a previously reported sensitization rate of between 60 and 80%, it is a worrying trend for Malaysia. However, due to incomplete and out-of-date data, as seen by the limited study coverage in the past, these numbers do not paint a complete picture of the true HDM allergy scene in Malaysia. This review briefly discusses the HDM fauna, the HDM sensitization rate, the common diagnosis and therapeutic tools for HDM allergy in Malaysia, and makes suggestions for possible improvements in the future. This review also highlights the need of more comprehensive population-based prevalence studies to be done in Malaysia, encompassing the three main HDMs-Dermatophagoides pteronyssinus, Dermatophagoides farinae, and Blomia tropicalis-as the lack of up-to-date studies failed to give a clearer picture on the current scenario of HDM allergy in Malaysia. Future studies will be beneficial to the nation in preparing a better blueprint for the management and treatment of HDM allergy., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Professional organisations exist as international or national organisations, with each country establishing at least one national professional association. There remains a knowledge gap about factors that influence professional organisational involvement of pharmacists and pharmaceutical scientists. This study aims to explore the motivators and barriers of pharmacy professionals holding organisation membership from a global perspective., Methods: An online questionnaire was developed and disseminated between May and July 2021. The survey was open to all pharmacists and pharmaceutical scientists. The survey consisted of four sections; demographic information, questions about professional organisations, about the International Pharmaceutical Federation (FIP) and its impact on the members. Data were analysed descriptively., Results: A total of 1033 complete survey responses were received and included in the analysis. Of all respondents, 761 (73.7%) respondents were current members of a professional organisation and 272 (26.3%) were not members of any professional organisation. Overall, findings demonstrated networking, education, training and professional development opportunities as the main interests and anticipated activities, while the lack of clarity or need to join organisation, time, and financial constraints as the main barriers of pharmacy professionals holding membership. The majority of FIP members are satisfied with current FIP activities, and anticipate further networking opportunities, educational resources and grants made available to members., Conclusions: Understanding the perceptions and needs, as well as factors that influence engagement of pharmacists and pharmaceutical scientists is the key to enhancing membership. Professional organisations are highly encouraged to strengthen and target activities according to the identified motivators and barriers., (© 2023. Dr. Zaheer-Ud-Din Babar and Auckland UniServices Ltd.)

The use of needles to access sites within organs is fundamental to many interventional medical procedures both for diagnosis and treatment. Safely and accurately navigating a needle through living tissue to a target is currently often challenging or infeasible because of the presence of anatomical obstacles, high levels of uncertainty, and natural tissue motion. Medical robots capable of automating needle-based procedures have the potential to overcome these challenges and enable enhanced patient care and safety. However, autonomous navigation of a needle around obstacles to a predefined target in vivo has not been shown. Here, we introduce a medical robot that autonomously navigates a needle through living tissue around anatomical obstacles to a target in vivo. Our system leverages a laser-patterned highly flexible steerable needle capable of maneuvering along curvilinear trajectories. The autonomous robot accounts for anatomical obstacles, uncertainty in tissue/needle interaction, and respiratory motion using replanning, control, and safe insertion time windows. We applied the system to lung biopsy, which is critical for diagnosing lung cancer, the leading cause of cancer-related deaths in the United States. We demonstrated successful performance of our system in multiple in vivo porcine studies achieving targeting errors less than the radius of clinically relevant lung nodules. We also demonstrated that our approach offers greater accuracy compared with a standard manual bronchoscopy technique. Our results show the feasibility and advantage of deploying autonomous steerable needle robots in living tissue and how these systems can extend the current capabilities of physicians to further improve patient care.

Fucoidans are a class of long chain sulfated polysaccharides and have multiple biological functions. Herein, four natural fucoidans extracted from Fucus vesiculosus, F. serratus, Laminaria japonica and Undaria pinnatifida, were tested for their HCoV-OC43 inhibition and found to demonstrate EC 50 values ranging from 0.15 to 0.61 µg/mL. That from U. pinnatifida exhibited the most potent anti-HCoV-OC43 activity with an EC 50 value of 0.15 ± 0.02 µg/mL, a potency largely independent of its sulfate content. Comparison of the gene expression profiles of fucoidan-treated and untreated cells infected with HCoV-OC43 revealed that fucoidan treatment effectively diminished HCoV-OC43 gene expressions associated with induced chemokines, cytokines and viral activities. Further studies using a highly fucoidan-resistant HCoV-OC43 determined that fucoidan inhibited HCoV-OC43 infection via interfering with viral entry and led to the identification of the specific site on the N-terminal region of spike protein, that located adjacent to the host cell receptor binding domain, targeted by the virus. Furthermore, in a SARS-CoV-2 pseudovirus neutralization assay, fucoidan also blocked SARS-CoV-2 entry. In vitro and in vivo, fucoidan decreased SARS-CoV-2 viral loads and inhibited viral infection in Calu-3 or Vero E6 cells and SARS-CoV-2 infected hamsters, respectively. Fucoidan was also found to inhibit furin activity, and reported furin inhibitors were found to inhibit viral infection by wild type HCoV-OC43 or SARS-CoV-2. Accordingly, we conclude that fucoidans inhibit coronaviral infection by targeting viral spike protein and host cell furin to interfere with viral entry., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective . The aim of this study was to investigate the feasibility of improving the image quality and accuracy of cone beam computed tomography (CBCT) by replacing the conventional wide cone angle x-ray tube with a distributed x-ray source array positioned in the axial direction. Approach . The multisource CBCT (ms-CBCT) design was experimentally simulated using a benchtop scanner with a carbon nanotube x-ray tube and a flat-panel detector. The source was collimated and translated in the axial direction to simulate a source array with a reduced cone angle for each beam. An adjacent scatter ratio subtraction (ASRS) method was implemented for residual scatter reduction. Several phantoms were imaged using the ms-CBCT and conventional CBCT configurations under otherwise similar conditions. The Requirements of the ms-CBCT design on the x-ray source and detector were evaluated. Main results . Compared to the conventional CBCT, the ms-CBCT design with 8 sources and ASRS significantly improved the image quality and accuracy, including: (1) reducing the cupping artifact from 15% to 3.5%; (2) reducing the spatial nonuniformity of the CT Hounsfield unit values from 38.0 to 9.2; (3) improving the contrast-to-noise ratio of the low contrast objects (acrylic and low density polyethylene inserts) against the water-equivalent background by ∼20% and (4) reducing the root-mean-square error of the HU values by 70%, from 420.1 to 124.4. The imaging dose and scanning time used by the current clinical CBCT for maxillofacial imaging can be achieved by current source and detector technologies. Significance . The ms-CBCT design significantly reduces the scatter and improves the image quality and accuracy compared to the conventional CBCT., (© 2023 Institute of Physics and Engineering in Medicine.)

Background and Purpose: Lateral C1-C2 spinal punctures are uncommon procedures performed by radiologists for access to CSF and contrast injection when a lumbar approach is contraindicated and an alternate method of access becomes necessary. There are limited opportunities to learn and practice the technique. We aimed to develop and assess the efficacy of a low-cost, reusable cervical spine phantom for training in fluoroscopically guided lateral C1-C2 spinal puncture., Materials and Methods: The phantom was constructed with a cervical spine model, an outer tube representing the thecal sac, an inner balloon representing the spinal cord, and polyalginate to replicate soft tissue. The total cost of materials was approximately US $70. Workshops were led by neuroradiology faculty experienced in the procedure using the model under fluoroscopy. Survey questions were assessed on a 5-point Likert scale. Participants were given pre- and postsurveys assessing comfort, confidence, and knowledge of steps., Results: Twenty-one trainees underwent training sessions. There was significant improvement in comfort level (Δ: 2.00, SD: 1.00, P value < .001); confidence (Δ: 1.52 points, SD: 0.87, P value < .001); and knowledge (Δ: 2.19, SD: 0.93, P value < .001). Eighty-one percent of participants found the model "very helpful" (5/5 on Likert scale), and all participants were "very likely" to recommend this workshop to others., Conclusions: This cervical phantom model is affordable and replicable and demonstrates training utility to prepare residents for performing lateral C1-C2 spinal puncture. This is a rare procedure, so the use of a phantom model before patient encounters is invaluable to resident education and training., (© 2023 by American Journal of Neuroradiology.)

Purpose: To explore the feasibility of measuring ventilation defect percentage (VDP) using 19 F MRI during free-breathing wash-in of fluorinated gas mixture with postacquisition denoising and to compare these results with those obtained through traditional Cartesian breath-hold acquisitions., Methods: Eight adults with cystic fibrosis and 5 healthy volunteers completed a single MR session on a Siemens 3T Prisma. 1 H Ultrashort-TE MRI sequences were used for registration and masking, and ventilation images with 19 F MRI were obtained while the subjects breathed a normoxic mixture of 79% perfluoropropane and 21% oxygen (O 2 ). 19 F MRI was performed during breath holds and while free breathing with one overlapping spiral scan at breath hold for VDP value comparison. The 19 F spiral data were denoised using a low-rank matrix recovery approach., Results: VDP measured using 19 F VIBE and 19 F spiral images were highly correlated (r = 0.84) at 10 wash-in breaths. Second-breath VDPs were also highly correlated (r = 0.88). Denoising greatly increased SNR (pre-denoising spiral SNR, 2.46 ± 0.21; post-denoising spiral SNR, 33.91 ± 6.12; and breath-hold SNR, 17.52 ± 2.08)., Conclusion: Free-breathing 19 F lung MRI VDP analysis was feasible and highly correlated with breath-hold measurements. Free-breathing methods are expected to increase patient comfort and extend ventilation MRI use to patients who are unable to perform breath holds, including younger subjects and those with more severe lung disease., (© 2023 International Society for Magnetic Resonance in Medicine.)

Objective: The goal of this work was to methodically evaluate, optimize, and validate a self-supervised machine learning algorithm capable of real-time automatic registration and fluoroscopic localization of the spine using a single radiograph or fluoroscopic frame., Methods: The authors propose a two-dimensional to three-dimensional (2D-3D) registration algorithm that maximizes an image similarity metric between radiographic images to identify the position of a C-arm relative to a 3D volume. This work utilizes digitally reconstructed radiographs (DRRs), which are synthetic radiographic images generated by simulating the x-ray projections as they would pass through a CT volume. To evaluate the algorithm, the authors used cone-beam CT data for 127 patients obtained from an open-source de-identified registry of cervical, thoracic, and lumbar scans. They systematically evaluated and tuned the algorithm, then quantified the convergence rate of the model by simulating C-arm registrations with 80 randomly simulated DRRs for each CT volume. The endpoints of this study were time to convergence, accuracy of convergence for each of the C-arm's degrees of freedom, and overall registration accuracy based on a voxel-by-voxel measurement., Results: A total of 10,160 unique radiographic images were simulated from 127 CT scans. The algorithm successfully converged to the correct solution 82% of the time with an average of 1.96 seconds of computation. The radiographic images for which the algorithm converged to the solution demonstrated 99.9% registration accuracy despite utilizing only single-precision computation for speed. The algorithm was found to be optimized for convergence when the search space was limited to a ± 45° offset in the right anterior oblique/left anterior oblique, cranial/caudal, and receiver rotation angles with the radiographic isocenter contained within 8000 cm3 of the volumetric center of the CT volume., Conclusions: The investigated machine learning algorithm has the potential to aid surgeons in level localization, surgical planning, and intraoperative navigation through a completely automated 2D-3D registration process. Future work will focus on algorithmic optimizations to improve the convergence rate and speed profile.

Clinical trials of combined IDO/PD1 blockade in metastatic melanoma (MM) failed to show additional clinical benefit compared to PD1-alone inhibition. We reasoned that a tryptophan-metabolizing pathway other than the kynurenine one is essential. We immunohistochemically stained tissues along the nevus-to-MM progression pathway for tryptophan-metabolizing enzymes (TMEs; TPH1, TPH2, TDO2, IDO1) and the tryptophan transporter, LAT1. We assessed tryptophan and glucose metabolism by performing baseline C11-labeled α-methyl tryptophan (C11-AMT) and fluorodeoxyglucose (FDG) PET imaging of tumor lesions in a prospective clinical trial of pembrolizumab in MM (clinicaltrials.gov, NCT03089606). We found higher protein expression of all TMEs and LAT1 in melanoma cells than tumor-infiltrating lymphocytes (TILs) within MM tumors ( n  = 68). Melanoma cell-specific TPH1 and LAT1 expressions were significantly anti-correlated with TIL presence in MM. High melanoma cell-specific LAT1 and low IDO1 expression were associated with worse overall survival (OS) in MM. Exploratory optimal cutpoint survival analysis of pretreatment 'high' vs. 'low' C11-AMT SUV max of the hottest tumor lesion per patient revealed that the 'low' C11-AMT SUV max was associated with longer progression-free survival in our clinical trial ( n  = 26). We saw no such trends with pretreatment FDG PET SUV max . Treatment of melanoma cell lines with telotristat, a TPH1 inhibitor, increased IDO expression and kynurenine production in addition to suppression of serotonin production. High melanoma tryptophan metabolism is a poor predictor of pembrolizumab response and an adverse prognostic factor. Serotoninergic but not kynurenine pathway activation may be significant. Melanoma cells outcompete adjacent TILs, eventually depriving the latter of an essential amino acid., Competing Interests: Funding for the LCCC1531 trial was provided by Merck & Co., Inc., (© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Uncleaved prefusion-optimized (UFO) design can stabilize diverse HIV-1 envelope glycoproteins (Envs). Single-component, self-assembling protein nanoparticles (1c-SApNP) can display 8 or 20 native-like Env trimers as vaccine candidates. We characterize the biophysical, structural, and antigenic properties of 1c-SApNPs that present the BG505 UFO trimer with wildtype and modified glycans. For 1c-SApNPs, glycan trimming improves recognition of the CD4 binding site without affecting broadly neutralizing antibodies (bNAbs) to major glycan epitopes. In mice, rabbits, and nonhuman primates, glycan trimming increases the frequency of vaccine responders (FVR) and steers antibody responses away from immunodominant glycan holes and glycan patches. The mechanism of vaccine-induced immunity is examined in mice. Compared with the UFO trimer, the multilayered E2p and I3-01v9 1c-SApNPs show 420 times longer retention in lymph node follicles, 20-32 times greater presentation on follicular dendritic cell dendrites, and up-to-4 times stronger germinal center reactions. These findings can inform future HIV-1 vaccine development., (© 2023. The Author(s).)

Parkinson's disease (PD) is a neurodegenerative disease characterized by motor deficits and marked neuroinflammation in various brain regions. The pathophysiology of PD is complex and mounting evidence has suggested an association with the dysregulation of microRNAs (miRNAs) and gut dysbiosis. Using a rotenone-induced PD mouse model, we observed that administration of Lactobacillus plantarum PS128 (PS128) significantly improved motor deficits in PD-like mice, accompanied by an increased level of dopamine, reduced dopaminergic neuron loss, reduced microglial activation, reduced levels of inflammatory factors, and enhanced expression of neurotrophic factor in the brain. Notably, the inflammation-related expression of miR-155-5p was significantly upregulated in the proximal colon, midbrain, and striatum of PD-like mice. PS128 reduced the level of miR-155-5p, whereas it increased the expression of suppressor of cytokine signaling 1 (SOCS1), a direct target of miR-155-5p and a critical inhibitor of the inflammatory response in the brain. Alteration of the fecal microbiota in PD-like mice was partially restored by PS128 administration. Among them, Bifidobacterium , Ruminiclostridium &#95;6, Bacteroides , and Alistipes were statistically correlated with the improvement of rotenone-induced motor deficits and the expression of miR-155-5p and SOCS1. Our findings suggested that PS128 ameliorates motor deficits and exerts neuroprotective effects by regulating the gut microbiota and miR-155-5p/SOCS1 pathway in rotenone-induced PD-like mice.

Chemokine CXCL4L1, a homologue of CXCL4, is a more potent antiangiogenic ligand. Its structural property is correlated with the downstream receptor binding. The two chemokines execute their functions by binding the receptors of CXCR3A and CXCR3B. The receptors differ by an extra 51-residue extension in the CXCR3B N-terminus. To understand the binding specificity, a GB1 protein scaffold was used to carry different CXCR3 extracellular elements, and artificial CXCL4 and CXCL4L1 monomers were engineered for the binding assay. We first characterized the molten globule property of CXCL4L1. The structural property causes the CXCL4L1 tetramer to dissociate into monomers in low concentrations, but native CXCL4 adopts a stable tetramer structure in solution. In the titration experiments, the combination of the CXCR3A N-terminus and receptor extracellular loop 2 provided moderate and comparable binding affinities to CXCL4 and CXCL4L1, while sulfation on the CXCR3A N-terminal tyrosine residues provided binding specificity. However, the CXCR3B N-terminal extension did not show significant enhancement in the binding of CXCL4 or CXCL4L1. This result indicates that the tendency to form a chemokine monomer and the binding affinity together contribute the high antiangiogenic activity of CXCL4L1.

Cone beam computed tomography (CBCT) is widely used in medical and dental imaging. Compared to a multidetector CT, it provides volumetric images with high isotropic resolution at a reduced radiation dose, cost and footprint without the need for patient translation. The current CBCT has several intrinsic limitations including reduced soft tissue contrast, inaccurate quantification of X-ray attenuation, image distortions and artefacts, which have limited its clinical applications primarily to imaging hard tissues and made quantitative analysis challenging. Here we report a multisource CBCT (ms-CBCT) which overcomes the short-comings of the conventional CBCT by using multiple narrowly collimated and rapidly scanning X-ray beams from a carbon nanotube field emission source array. Phantom imaging studies show that, the ms-CBCT increases the accuracy of the Hounsfield unit values by 60%, eliminates the cone beam artefacts, extends the axial coverage, and improves the soft tissue contrast-to-noise ratio by 30-50%, compared to the CBCT configuration., Competing Interests: Competing interests The authors declare the following competing interests: O.Z. has equity ownership and serves on the board of directors of XinVisio, LLC., to which the technologies used or evaluated in this project have been licensed, and NuRay Co., Ltd, which manufactures the X-ray sources used in this study. J.L. has equity ownership in XinVisio, LLC. and NuRay Co. Ltd. O.Z., J.L., C.R.I., Y.Z.L., and B.L. are co-inventors of licensed technology evaluated in this study. All activities have been approved by the institutional COI committee. All other authors declare no competing interests.

Introduction: Sarcopenia, defined as low skeletal muscle mass and poor muscle function, has been associated with worse postoperative recovery. This study aims to evaluate the significance of low muscle mass in the elderly who require emergency surgeries and the postoperative outcomes., Method: Data from the emergency laparotomy database were retrieved from Khoo Teck Puat Hospital, Singapore, between 2016 and 2019. A retrospective analysis was performed on patients aged 65 years and above. Data collected included skeletal muscle index (SMI) on computed tomography scan, length of stay, complications and mortality. Low muscle mass was determined based on 25th percentile values and correlation with previous population studies., Results: A total of 289 patients were included for analysis. Low muscle mass was defined as L3 SMI of <22.09cm2/m2 for females and <33.4cm2/m2 for males, respectively. Seventeen percent of our patients were considered to have significantly low muscle mass. In this group, the length of stay (20.8 versus 16.2 P =0.041), rate of Clavien-Dindo IV complications (18.4% vs 7.5% P =0.035) and 1-year mortality (28.6% vs 14.6%, P =0.03) were higher. Further multivariate analysis showed that patients with low muscle mass had increased mortality within a year (odds ratio 2.16, 95% confidence interval 1.02-4.55, P =0.04). Kaplan-Meier analysis also shows that the 1-year overall survival was significantly lower in patients with low muscle mass., Conclusion: Patients with low muscle mass have significantly higher post-surgical complication rates and increased mortality.

The availability of highly effective CFTR modulators is revolutionizing the treatment of cystic fibrosis (CF) and drastically improving outcomes. MRI-based imaging modalities are now emerging as highly sensitive endpoints, particularly in the setting of mild lung disease. Adult CF patients were recruited from a single center prior to starting treatment with E/T/I. The following studies were obtained before and after one month on treatment: spirometry, multiple breath nitrogen washout (MBW), 1H UTE MRI (structural images) and 19F MRI (ventilation images). Changes between visits were calculated, as were correlations between FEV1, lung clearance index (LCI), MRI structural scores, and MRI-based ventilation descriptors. Eight subjects had complete datasets for evaluation. Consistent with prior clinical trials, FEV1 and LCI improved after 28 days of E/T/I use. 1H UTE MRI detected improvements in bronchiectasis/airway wall thickening score and mucus plugging score after 28 days of therapy. 19F MRI demonstrated improvements in fractional lung volume with slow gas washout time (FLV↑tau2) and ventilation defect percentage (VDP). Improvements in FLV↑tau2 and VDP correlated with improvement in FEV1 (r = 0.81 and 0.86, respectively, p < 0.05). This observational study establishes the ability of 19F MRI and 1H UTE MRI to detect improvements in lung structure and function after E/T/I treatment. This study supports further development of 19F MRI and 1H UTE MRI as outcome measures for cystic fibrosis research and drug development.

A subset of individuals who recover from coronavirus disease 2019 (COVID-19) develop post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (PASC), but the mechanistic basis of PASC-associated lung abnormalities suffers from a lack of longitudinal tissue samples. The mouse-adapted SARS-CoV-2 strain MA10 produces an acute respiratory distress syndrome in mice similar to humans. To investigate PASC pathogenesis, studies of MA10-infected mice were extended from acute to clinical recovery phases. At 15 to 120 days after virus clearance, pulmonary histologic findings included subpleural lesions composed of collagen, proliferative fibroblasts, and chronic inflammation, including tertiary lymphoid structures. Longitudinal spatial transcriptional profiling identified global reparative and fibrotic pathways dysregulated in diseased regions, similar to human COVID-19. Populations of alveolar intermediate cells, coupled with focal up-regulation of profibrotic markers, were identified in persistently diseased regions. Early intervention with antiviral EIDD-2801 reduced chronic disease, and early antifibrotic agent (nintedanib) intervention modified early disease severity. This murine model provides opportunities to identify pathways associated with persistent SARS-CoV-2 pulmonary disease and test countermeasures to ameliorate PASC.

An ageing population with higher rates of helping seeking behaviour and treatment utilization is a worldwide phenomenon with no exception to Singapore. As elderly patients are fast becoming an increasing large part of our surgical practice, their long term outcomes are particularly important., Objective: We take stock of our local experience in a high volume tertiary centre in Singapore, Tan Tock Seng Hospital by reviewing the number of surgical procedures performed for elderly patients (65 years old and above) across a decade and reviewing their post-operative outcomes., Methods: This retrospective cohort study included elderly patients (>= aged 65) who underwent surgical procedures under general anaesthesia from January 2008 to December 2019. Demographic data, nature of operation, preoperative American Society of Anaesthesiologists (ASA) status of patients and surrogate markers of outcome including average length of stay (ALOS), 30 and 90-day mortality were retrospectively analysed., Results: Across a 12-year period, we observed a nearly overall two-fold increase in the number of surgical procedures for elderly patients from 1,129 cases in 2008 to 2,118 cases in 2019. The ALOS for elderly surgical patients trended downwards from an average of 12.3 days in 2008 to 9.0 days in 2019. All cause 30-day mortality rate of elderly patients dropped from 5.8% in 2008 to 2.7% in 2019., Conclusion: The landscape for general surgery in the elderly is changing in the context of advances in health care and a paradigm shift in treatment beliefs and perspectives. Ultimately, informed decision making, patient engagement and empowerment by the surgeon are keys to better outcomes and improved patient experience., (© 2022 Royal Australasian College of Surgeons.)