Search

Abstract.: Ulmus davidiana NAKAI (UDN) has traditionally been used for healing of inflammatory diseases. This study was carried out to investigate the hepatoprotective effect of the glycoprotein isolated from UDN in carbon tetrachloride (CCl4)-induced liver injury. We evaluated the activities of alanine aminotransferase (ALT), lactate dehydrogenase (LDH), thiobarbituric acid-reactive substances (TBARS), and antioxidant enzymes [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx)] activities in CCl4-treated mice. When mice were treated with CCl4 in the absence of UDN glycoprotein, the activities of ALT, LDH, and TBARS were increased, while the antioxidant enzymes activities were decreased. However, when the mice were treated with CCl4 in the presence of UDN glycoprotein, the activities of ALT, LDH, and TBARS were significantly reduced and SOD, CAT, and GPx activities were remarkably increased. In addition, UDN glycoprotein increased the nitric oxide production and decreased the nuclear factor-kappa B and activator protein-1 activation in CCl4treated mice. We also investigated the protective effects of UDN glycoprotein in glucose/glucose oxidase (G/GO)-induced cytotoxicity in primary cultured mouse hepatocytes. UDN glycoprotein markedly inhibited the cell death induced by G/GO. These results suggest that UDN glycoprotein protects against CCl4-induced liver injury in the mouse. Keywords:: Ulmus davidiana NAKAI glycoprotein, antioxidant enzyme, nitric oxide, nuclear factor-kappa B, activator protein-1

Human lung alveolus is a well-structured and coordinated pulmonary unit, allowing them to perform diverse functions. While there has been significant progress in understanding the molecular and cellular mechanisms behind human alveolar development and pulmonary diseases, the underlying mechanisms of alveolar differentiation and disease development are still unclear, mainly due to the limited availability of human tissues and a lack of proper in vitro lung model systems mimicking human lung physiology. In this review, we summarise recent advances in creating human lung organoid models that mimic alveolar epithelial cell types. Moreover, we discuss how lung alveolar organoid systems are being applied to recent cutting-edge research on lung development, regeneration, and diseases., Competing Interests: Conflict of interest No declared, (Copyright © 2024. Published by Elsevier Inc.)

Background: Burnout in health care professionals (HCPs) results from exposure to psychosocial risks at work. Left unaddressed, burnout can lead to chronic health problems, increased staff turnover, reduced work hours, absenteeism, and early retirement from clinical practice, thus impacting patient care. The European Society for Medical Oncology (ESMO) Resilience Task Force (RTF) was established in December 2019 to support the well-being of oncology HCPs globally. This ESMO RTF position paper aims to provide a set of recommendations to optimise well-being and mitigate burnout in oncology, and to help individuals and institutions maintain the delivery of optimal cancer care., Design: Recommendations were developed by a diverse multinational panel of interprofessional experts based on the key findings from three previously reported ESMO RTF surveys., Results: Several recurrent work-related psychosocial risks in oncology were identified; in particular, concerns about workload and professional development. The need for flexible work patterns, continued use of virtual resources, well-being resources, and targeted support for at-risk groups were highlighted as key considerations to safeguard HCPs' health and prevent burnout. In total, 11 recommendations relating to three priority themes were developed: (i) information and training; (ii) resources; (iii) activism and advocacy., Conclusion: Optimising the well-being of oncology HCPs is essential for the provision of high-quality, sustainable care for patients globally. The ESMO RTF will continue its mission and is rolling out several initiatives and activities to support the implementation of these recommendations., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Abstract: Idiopathic multicentric Castleman disease (iMCD) is a rare cytokine-driven disorder characterized by systemic inflammation, generalized lymphadenopathy, and organ dysfunction. Here, we present an unusual occurrence of iMCD in identical twins and examined the immune milieu within the affected lymphoid organs and the host circulation using multiomic high-dimensional profiling. Using spatial enhanced resolution omics sequencing (Stereo-seq) transcriptomic profiling, we performed unsupervised spatially constrained clustering to identify different anatomic structures, mapping the follicles and interfollicular regions. After a cell segmentation approach, interleukin 6 (IL-6) pathway genes significantly colocalized with endothelial cells and fibroblastic reticular cells, confirming observations using a single-cell sequencing approach (10× Chromium). Furthermore, single-cell sequencing of peripheral blood mononuclear cells revealed an "inflammatory" peripheral monocytosis enriched for the expression of S100A family genes in both twins. In summary, we provided evidence of the putative cell-of-origin of IL-6 signals in iMCD and described a distinct monocytic host immune response phenotype through a unique identical twin model., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Abstract: High prevalence of IDH mutations in seronegative rheumatoid arthritis (RA) with myeloid neoplasm, elevated 2-hydroxyglutarate, dysregulated innate immunity, and proinflammatory microenvironment suggests causative association between IDH mutations and seronegative RA. Our findings merit investigation of IDH inhibitors as therapeutics for seronegative IDH-mutated RA., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

This report describes the arthroscopic transtibial pullout repair technique using multiple simple stitch (MSS), which was used to treat a medial meniscus posterior root tear (MMPRT) of the knee. The most commonly used technique to address this type of MMPRT is currently arthroscopic transtibial pullout repair. MSS pullout repair technique can provide excellent pullout strength and large tissue-bone contact area, which facilitates successful healing potential. This MSS pullout repair technique may be suggested as another useful option that can be used in the treatment of MMPRT., Competing Interests: The authors report the following potential conflicts of interest or sources of funding: Supported by the 10.13039/501100002560Soonchunhyang University Research Fund and the 10.13039/501100003052Ministry of Trade, Industry and Energy (MOTIE), Korea, under the “Industrial Innovation Infrastructure Establishment Project” (reference number P0018140) supervised by the 10.13039/501100003661Korea Institute for Advancement of Technology (KIAT). The authors report no conflicts of interest in the authorship and publication of this article. Full ICMJE author disclosure forms are available for this article online, as supplementary material., (© 2024 The Authors.)

Background: Treatment-resistant schizophrenia (TRS) affects a substantial proportion of patients who do not respond adequately to antipsychotic medications, yet the underlying biological mechanism remains poorly understood. This study investigates the link between the genetic predisposition to schizophrenia and TRS., Methods: 857 individuals diagnosed with schizophrenia were divided into TRS (n = 142) and non-TRS (n = 715) based on well-defined TRS criteria. Polygenic risk scores (PRS) were calculated using schizophrenia genome-wide association summary statistics from East-Asian and European ancestry populations. PRS was estimated using both P-value thresholding and Bayesian framework methods. Logistic regression analyses were performed to differentiate between TRS and non-TRS individuals., Results: The schizophrenia PRS derived from the East-Asian training dataset effectively distinguished between TRS and non-TRS individuals (R 2 = 0.029, p = 4.86 ×10 -5 , p T = 0.1, OR = 1.52, 95% CI = 1.242-1.861), with higher PRS values observed in the TRS group. Similar PRS analysis was conducted based on the European ancestry GWAS summary statistics, but we found superior prediction based on the East-Asian ancestry discovery data., Conclusion: This study reveals an association between common risk variants for schizophrenia and TRS status, suggesting that the genetic burden of schizophrenia may partly contribute to treatment resistance in individuals with schizophrenia. These findings propose the potential use of genetic risk factors for early TRS identification and timely access to clozapine. However, the ancestral background of the discovery sample is crucial for successfully implementing PRS in clinical settings., Competing Interests: Declaration of Competing Interest JL has received honoraria from Otsuka, Janssen, Lundbeck and Sumitomo Pharmaceuticals. All other authors declare they have no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Geographic-based healthcare determinants and choice of anesthesia have been shown to be associated with maternal morbidity and mortality. We explored whether differences in maternal outcomes based on maternal residence, and anesthesia type for cesarean and vaginal birth, exist., Methods: This study was a retrospective multi-state analysis; patient residence was the predictor variable of interest and a composite binary measure of maternal end-organ injury or inpatient mortality was the primary outcome. Our secondary outcomes included a binary measure of anesthesia type for cesarean birth (general vs. neuraxial [NA]) and NA analgesia for vaginal birth (no NA vs. NA). Our predictor variable of interest was patient residency (reference category central metropolitan areas of >1 million population), fringe large metropolitan county, medium metropolitan, small metropolitan, micropolitan, and non-metropolitan or micropolitan county., Results: Women residing in micropolitan (OR 1.17; 95% CI 1.09 to 1.27) and non-metropolitan or micropolitan counties (OR 1.14; 95% CI 1.04 to 1.24) had the highest adjusted increased odds of adverse maternal outcomes. Those residing in suburban, medium, and small metropolitan areas underwent general anesthesia less often during cesarean births than those residing in urban areas. Patients residing in micropolitan rural (OR 2.07; 95% CI 2.02 to 2.12) and non-metropolitan or micropolitan (2.25; 95% CI 2.16 to 2.34) counties underwent vaginal births without NA analgesia more than twice as often as those residing in urban areas., Conclusions: Rural-urban disparities in maternal end-organ damage and mortality exist and anesthesia choice may play an important role in these disparate outcomes., Competing Interests: Declaration of interests 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 Ltd. All rights reserved.)

We have previously demonstrated that acute ingestion of inorganic nitrate (NO 3 - )-rich beetroot juice (BRJ), a source of nitric oxide (NO) via the NO 3 - → nitrite (NO 2 - ) → NO pathway, can improve muscle speed and power in older individuals. It is not known, however, whether this effect is maintained or perhaps even enhanced with repeated ingestion, or if tolerance develops as with organic nitrates, e.g., nitroglycerin. Using a double-blind, placebo-controlled, crossover design, we therefore studied 16 community-dwelling older (age 71 ± 5 y) individuals after both acute and short-term (i.e., daily for 2 wk) BRJ supplementation. Blood samples were drawn and blood pressure was measured periodically during each ∼3 h experiment, with muscle function determined using isokinetic dynamometry. Acute ingestion of BRJ containing 18.2 ± 6.2 mmol of NO 3 - increased plasma NO 3 - and NO 2 - concentrations 23 ± 11 and 2.7 ± 2.1-fold over placebo, respectively. This was accompanied by 5 ± 11% and 7 ± 13% increases in maximal knee extensor speed (Vmax) and power (Pmax), respectively. After daily supplementation for 2 wk, BRJ ingestion elevated NO 3 - and NO 2 - levels 24 ± 12 and 3.3 ± 4.0-fold, respectively, whereas Vmax and Pmax were 7 ± 9% and 9 ± 11% higher than baseline. No changes were observed in blood pressure or in plasma markers of oxidative stress with either acute or short-term NO 3 - supplementation. We conclude that both acute and short-term dietary NO 3 - supplementation result in similar improvements in muscle function in older individuals. The magnitudes of these improvements are sufficient to offset the decline resulting from a decade or more of aging and are therefore likely to be clinically significant., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: To summarize the current evidence and to make recommendations for antenatal fetal health surveillance (FHS) to detect perinatal risk factors and potential fetal decompensation in the antenatal period and to allow for timely intervention to prevent perinatal morbidity and/or mortality., Target Population: Pregnant individuals with or without maternal, fetal, or pregnancy-associated perinatal risk factors for antenatal fetal decompensation., Options: To use basic and/or advanced antenatal testing modalities, based on risk factors for potential fetal decompensation., Outcomes: Early identification of potential fetal decompensation allows for interventions that may support fetal adaptation to maintain well-being or expedite delivery., Benefits, Harms, and Costs: Antenatal FHS in pregnant individuals with identified perinatal risk factors may reduce the chance of adverse outcomes. Given the high false-positive rate, FHS may increase unnecessary interventions, which may result in harm, including parental anxiety, premature or operative birth, and increased use of health care resources. Optimization of surveillance protocols based on evidence-informed practice may improve perinatal outcomes and reduce harm., Evidence: Medline, PubMed, Embase, and the Cochrane Library were searched from inception to January 2022, using medical subject headings (MeSH) and key words related to pregnancy, fetal monitoring, fetal movement, stillbirth, pregnancy complications, and fetal sonography. This document represents an abstraction of the evidence rather than a methodological review., Validation Methods: The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See online Appendix A (Tables A1 for definitions and A2 for interpretations of strong and weak recommendations)., Intended Audience: All health care team members who provide care for or education to obstetrical patients, including maternal fetal medicine specialists, obstetricians, family physicians, midwives, nurses, nurse practitioners, and radiologists., Summary Statements: RECOMMENDATIONS., (Copyright © 2023. Published by Elsevier Inc.)

Background and Aims: Research suggests that meat intake may increase the risk of coronary heart disease (CHD), but most studies take place in Western countries, where the types and amount of meat products consumed differ from those in Asian countries. We aimed to identify the association between meat intake and CHD risk in Korean male adults, using the Framingham risk score., Methods and Results: We used data from the Korean Genome and Epidemiology Study (KoGES) Health Examinees (HEXA) study, including 13,293 Korean male adults. We estimated the association of meat intake with ≥20% 10-year CHD risk using Cox proportional hazards regression models to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs). Subjects with the highest total meat intake had a 53% (model 4: HR 1.53, 95% CI 1.05-2.21) increased 10-year CHD risk compared to those with the lowest intake. Those with the highest red meat intake had a 55% (model 3: HR 1.55, 95% CI 1.16-2.06) increased 10-year CHD risk compared to those with the lowest intake. No association was observed between poultry or processed meat intake and 10-year CHD risk., Conclusions: Consumption of total meat and red meat was associated with a higher risk of CHD in Korean male adults. Further studies are needed to provide criteria for the appropriate meat intake by meat type to reduce CHD risk., 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 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Biomolecular interactions underpin most processes inside the cell. Hence, a precise and quantitative understanding of molecular association and dissociation events is crucial, not only from a fundamental perspective, but also for the rational design of biomolecular platforms for state-of-the-art biomedical and industrial applications. In this context, atomic force microscopy (AFM) appears as an invaluable experimental technique, allowing the measurement of the mechanical strength of biomolecular complexes to provide a quantitative characterization of their interaction properties from a single molecule perspective. In the present review, the most recent methodological advances in this field are presented with special focus on bioconjugation, immobilization and AFM tip functionalization, dynamic force spectroscopy measurements, molecular recognition imaging and theoretical modeling. We expect this work to significantly aid in grasping the principles of AFM-based force spectroscopy (AFM-FS) technique and provide the necessary tools to acquaint the type of data that can be achieved from this type of experiments. Furthermore, a critical assessment is done with other nanotechnology techniques to better visualize the future prospects of AFM-FS., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Locally advanced renal cell carcinoma (RCC) can rarely invade into adjacent abdominal viscera without clinical evidence of distant metastases. The role of multivisceral resection (MVR) of involved adjacent organs at the time of radical nephrectomy (RN) remains poorly described and quantified. Using a national database, we aimed to evaluate the association between RN+MVR and 30-day postoperative complications., Methods and Materials: We conducted a retrospective cohort study of adult patients undergoing RN for RCC with and without MVR between 2005 and 2020 using the ACS-NSQIP database. The primary outcome was a composite of any of the following 30-day major postoperative complications: mortality, reoperation, cardiac event, and neurologic event. Secondary outcomes included individual components of the composite primary outcome, as well as infectious and venous thromboembolic complications, unplanned intubation and ventilation, transfusion, readmission, and prolonged length of stay (LOS). Groups were balanced using propensity score matching. Likelihood of complications was assessed by conditional logistic regression adjusted for unbalanced total operation time. Postoperative complications were compared by Fisher's exact test among subtypes of resection., Results: A total of 12,417 patients were identified: 12,193 (98.2%) undergoing RN alone and 224 (1.8%) undergoing RN+MVR. Patients undergoing RN+MVR were more likely to experience major complications (odds ratio [OR] 2.46; 95% confidence interval [CI] 1.28-4.74). However, there was no significant association between RN+MVR and postoperative mortality (OR 2.49; 95% CI 0.89-7.01). RN+MVR was associated with higher rates of reoperation (OR 7.85; 95% CI 2.38-25.8), sepsis (OR 5.45; 95% CI 1.83-16.2), surgical site infection (OR 4.41; 95% CI 2.14-9.07), blood transfusion (OR 2.24; 95% CI 1.55-3.22), readmission (OR 1.78; 95% CI 1.11-2.84), infectious complications (OR 2.62; 95% CI 1.62-4.24), and longer hospital stay (5 days [IQR 3-8] vs. 4 days [IQR 3-7]; OR 2.31 [95% CI 2.13-3.03]).  There was no heterogeneity in the association between subtype of MVR and major complication rate., Conclusion: Undergoing RN+MVR is associated with an increased risk of 30-day postoperative morbidity, including infectious complications, reoperation, blood transfusion, prolonged LOS, and readmission., Competing Interests: Conflict of interest The authors declare that they have no competing interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The trochanteric soft tissue attenuates impact force or absorbs impact energy during a fall on the hip (thereby helps to reduce a risk of hip fracture). While the benefits should be affected by contractions of muscles spanning the hip joint, no information is available to date. We examined how the stiffness (force attenuation capacity) and energy absorption of the trochanteric soft tissue were affected by hip muscle activation during a fall. Thirteen healthy young individuals (5 males, 8 females) participated in the pelvis release experiment. Falling trials were acquired with three muscle contraction conditions: 0-20% ("relaxed"), 20-50% ("moderate"), and 60-100% ("maximal") of the maximal voluntary isometric contraction of the gluteus medius muscle. During trials, we measured real-time force and deformation behaviour of the trochanteric soft tissue. Outcome variables included the stiffness and energy absorption of the soft tissue. The stiffness and energy absorption ranged from 56.1 to 446.9 kN/m, and from 0.15 to 2.26 J, respectively. The stiffness value increased with muscle contraction, and 59% greater in "maximal" than "relaxed" condition (232.2 (SD = 121.4) versus 146.1 (SD = 49.9)). However, energy absorption decreased with muscle contraction, and 58.9% greater in "relaxed" than "maximal" condition (0.89 (SD = 0.63) versus 0.56 (SD = 0.41)). Our results provide insights on biomechanics of the trochanteric soft tissue ("natural" padding device) during impact stage of a fall, suggesting that soft tissues' protective benefits are largely affected by the level of muscle contraction., 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 © 2022 Elsevier Ltd. All rights reserved.)

Introduction: Pharmacists play a key role in tackling the global public health threat of antimicrobial resistance (AMR) through contributing to antimicrobial stewardship (AMS) practices. Professional pharmacy organisations describe this AMS role in position statements. Understanding how this role is described, including the why and potential impact is a first step to understanding how this issue is described to the profession, and framed in advocacy., Objective: To examine how pharmacy's role in optimising antimicrobial use is articulated in pharmacy professional organisations' position statements., Methods: Publicly available AMR position statements were sourced between February 2021 and May 2021 from the available websites of all International Pharmaceutical Federation (FIP) member organisations, supplemented by a general engine search. Descriptive analysis was conducted with a focus on four key themes of interest: 1) rationale for pharmacists' involvement in AMS) 2) characterisation of pharmacists' AMS role; 3) perceived impact of pharmacists' involvement in AMS; and 4) perceived enablers and/or barriers to AMS involvement., Results: 17 position statements were sourced and analysed. Professional pharmacy organisations appear to focus on characterising pharmacists as advisors and educators as their primary role in AMS, with this function supported by their medication knowledge and accessibility as a health service. Specific settings, such as hospital or community pharmacy, were often highlighted in the documents, and were associated with the framing of the capacity and nature of pharmacists' involvement in AMS. However, the limitations of pharmacists and their positions were not discussed., Conclusions: There is an opportunity for future research to explore the concordance between the expectation of pharmacists' involvement in AMS as outlined in these position statements, with the reality of their involvement. This is of importance in the primary care setting, as a key access point to antimicrobials globally., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background and Aims: Studies have revealed a positive relationship between milk consumption and hypertension. However, few researchers have investigated the association between milk consumption and changes in blood pressure (BP) in South Korean adults. Therefore, we examined the association between milk intake and the management and risk of hypertension in South Korean adults., Methods and Results: Participants were selected from the Health Examinees study. The definition of hypertension was based on the guidelines of the Korean Society of Hypertension. The participants were divided into three groups according to changes between baseline and follow-up BP data. Milk consumption was assessed using food frequency questionnaires. In both men and women, the higher milk consumption group had increased odds of trends of BP improvement (OR: 1.249, 95% CI: 1.043-1.496, p for trend: 0.2271 in men; OR: 1.147, 95% CI: 1.014-1.297, p for trend: 0.0293 in women) and decreased odds of trends of worsening (OR: 0.861, 95% CI: 0.756-0.980, p for trend: <0.0001 in men, OR: 0.866, 95% CI: 0.794-0.943, p for trend: 0.0010 in women) compared to those of the non-consumption group. In the prospective study, milk intake was inversely associated with hypertension risk (HR: 0.900, 95% CI: 0.811-0.999, p for trend: 0.0076 in men; HR: 0.879, 95% CI: 0.814-0.949, p for trend: 0.0002 in women)., Conclusion: Increased intake of milk was inversely related to the risk of increased BP, with a decreased risk of hypertension events., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2022 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Introduction: Prepectoral implant-based breast reconstruction (PIBR) has regained popularity, despite decades-long preference for subpectoral implant placement. This paper aims to compare patient-reported outcomes (PRO) between prepectoral and subpectoral approaches to implant-based breast reconstruction (IBBR). The primary PRO was with the BREAST-Q, and postoperative pain scores, while the secondary outcomes were complication rates., Methods: A comprehensive literature search of the PubMed library was performed. All studies on patients undergoing IBBR after mastectomy that compared prepectoral to subpectoral placement and PROM or postoperative pain were included., Results: A total of 3789 unique studies of which 7 publications with 216 and 332 patients who received prepectoral and subpectoral implants, respectively, were included for meta-analysis. Patients with prepectoral implant placement had significantly higher satisfaction with the outcome (p = 0.03) and psychosocial well-being (p = 0.03) module scores. The pain was lower in patients with prepectoral implants on postoperative day 1 (p<0.01) and day 7 (p<0.01). The subgroup analysis of prepectoral breast implants showed that complete acellular dermal matrix coverage had lower rates of wound dehiscence (p<0.0001), but there were no significant differences in complications between one-stage and two-stage procedures., Conclusion: Overall, patients with prepectoral implants reported higher BREAST-Q scores and lower postoperative pain and lower complications rates than patients with subpectoral implants. In appropriately selected patients, prepectoral implant placement with ADM coverage, be it the primary placement of an implant or placement of a tissue expander before definitive implant placement, should be the modality of choice in patients who choose IBBR. Further research should focus on patient selection, strategies to reduce cost and cost-benefit analysis of PIBR., (Copyright © 2022 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Background: Acute aortic syndrome is associated with aortic medial degeneration. 18 F-sodium fluoride ( 18 F-NaF) positron emission tomography (PET) detects microscopic tissue calcification as a marker of disease activity., Objectives: In a proof-of-concept study, this investigation aimed to establish whether 18 F-NaF PET combined with computed tomography (CT) angiography could identify aortic medial disease activity in patients with acute aortic syndrome., Methods: Patients with aortic dissection or intramural hematomas and control subjects underwent 18 F-NaF PET/CT angiography of the aorta. Aortic 18 F-NaF uptake was measured at the most diseased segment, and the maximum value was corrected for background blood pool activity (maximum tissue-to-background ratio [TBR max ]). Radiotracer uptake was compared with change in aortic size and major adverse aortic events (aortic rupture, aorta-related death, or aortic repair) over 45 ± 13 months., Results: Aortic 18 F-NaF uptake co-localized with histologically defined regions of microcalcification and elastin disruption. Compared with control subjects, patients with acute aortic syndrome had increased 18 F-NaF uptake (TBR max : 1.36 ± 0.39 [n = 20] vs 2.02 ± 0.42 [n = 47] respectively; P < 0.001) with enhanced uptake at the site of intimal disruption (+27.5%; P < 0.001). 18 F-NaF uptake in the false lumen was associated with aortic growth (+7.1 mm/year; P = 0.011), and uptake in the outer aortic wall was associated with major adverse aortic events (HR: 8.5 [95% CI: 1.4-50.4]; P = 0.019)., Conclusions: In patients with acute aortic syndrome, 18 F-NaF uptake was enhanced at sites of disease activity and was associated with aortic growth and clinical events. 18 F-NaF PET/CT holds promise as a noninvasive marker of disease severity and future risk in patients with acute aortic syndrome. ( 18 F Sodium Fluoride PET/CT in Acute Aortic Syndrome [FAASt]; NCT03647566)., Competing Interests: Funding Support and Author Disclosure All funding support is from the United Kingdom. Mr Syed and Drs Fletcher, Dweck, Shah, and Tavares, Mr Kaczynki, and Dr Newby were supported by the British Heart Foundation (FS/18/31/33676, FS/19/15/34155, FS/11/014, FS/14/78/31020, CH/09/002, RG/16/10/32375, RE/18/5/34216). Dr Dweck has received the Sir Jules Thorn Award for Biomedical Research 2015 (15/JTA). Dr Newby has received a Wellcome Trust Senior Investigator Award (WT103782AIA). Dr van Beek has been supported by the Scottish Imaging Network—a Platform of Scientific Excellence (SINAPSE). Edinburgh Clinical Research Facility and Edinburgh Imaging Facility are supported by NHS Research Scotland. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022. Published by Elsevier Inc.)

Introduction: The treatment landscape in invasive primary carcinoma of the urethra of urothelial histology closely aligns that of locally advanced urothelial carcinoma of the bladder. The survival benefit of perioperative chemotherapy for men undergoing radical surgery for primary urethral urothelial carcinoma (UUC) has not yet been well-elucidated., Patients and Methods: Using the National Cancer Database (NCDB), we identified men diagnosed with non-metastatic invasive UUC (T2-4 N0-2 M0) from 2004 to 2016 treated with radical extirpative surgery. We compared OS between patients who had received peri-operative neoadjuvant (NAC) or adjuvant (AC) chemotherapy and those who had not using Kaplan-Meier curves and multivariable Cox proportional hazards regression model., Results: A total of 191 patients met inclusion criteria. 113 patients (59.2%) did not receive chemotherapy, while 39 (20.4%) and 39 (20.4%) received NAC and AC, respectively. Median follow-up was 28.0 months. Upon multivariable analysis, receipt of NAC (HR 0.50, 95% CI 0.28-0.91, P = .02) decreased the risk of all-cause mortality, while receipt of AC (HR 0.76, 95% CI 0.41-1.41) was not significantly associated with an OS benefit, as compared to no chemotherapy., Conclusion: Our study is the first to evaluate treatment specific outcomes in male patients with primary carcinoma of the urethra. We observed that neoadjuvant chemotherapy in men with UUC was associated with OS benefit. The utilization of NAC may improve survival, consistent with urothelial carcinoma of the bladder., (Copyright © 2022. Published by Elsevier Inc.)

Neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD) are a heterogeneous group of disorders characterized by progressive degeneration of neurons. NDDs threaten the lives of millions of people worldwide and regretfully remain incurable. It is well accepted that dysfunction of mitochondria underlies the pathogenesis of NDDs. Dysfunction of mitochondria results in energy depletion, oxidative stress, calcium overloading, caspases activation, which dominates the neuronal death of NDDs. Therefore, mitochondria are the preferred target for intervention of NDDs. So far various mitochondria-targeting drugs have been developed and delightfully some of them demonstrate promising outcome, though there are still some obstacles such as targeting specificity, delivery capacity hindering the drugs development. In present review, we will elaborately address 1) the strategy to design mitochondria targeting drugs, 2) the rescue mechanism of respective mitochondria targeting drugs, 3) how to evaluate the therapeutic effect. Hopefully this review will provide comprehensive knowledge for understanding how to develop more effective drugs for the treatment of NDDs., (© 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Alloantibodies are a significant barrier to successful transplantation. While desensitization has emerged, efficacy is limited. Interleukin-6 (IL-6) is an important mediator of inflammation and immune cell activation. Persistent IL-6 production increases the risk for alloantibody production. Here we report our experience with clazakizumab (anti-IL-6) for desensitization of highly HLA-sensitized patients (HS). From March 2018 to September 2020, 20 HS patients were enrolled in an open label pilot study to assess safety and limited efficacy of clazakizumab desensitization. Patients received PLEX, IVIg, and clazakizumab 25 mg monthly X6. If transplanted, graft function, pathology, HLA antibodies and regulatory immune cells were monitored. Transplanted patients received standard immunosuppression and clazakizumab 25 mg monthly posttransplant. Clazakizumab was well tolerated and associated with significant reductions in class I and class II antibodies allowing 18 of 20 patients to receive transplants with no DSA rebound in most. Significant increases in T reg and B reg cells were seen posttransplant. Antibody-mediated rejection occurred in three patients. The mean estimated glomerular filtration rate at 12 months was 58 ± 29 ml/min/1.73 m 2 . Clazakizumab was generally safe and associated with significant reductions in HLA alloantibodies and high transplant rates for highly-sensitized patients. However, confirmation of efficacy for desensitization requires assessment in randomized controlled trials., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Impairment in real-world social functioning is observed in individuals at Ultra-High Risk (UHR) of psychosis. Both social skills and negative symptoms appear to influence real-world functioning. This study aims to examine the psychometric properties of a social skills measure, the High-Risk Social Challenge task (HiSoC), and evaluate the relationship between social skills, negative symptoms, and real-world functioning in UHR individuals., Methods: HiSoC data was analysed in 87 UHR individuals and 358 healthy controls. Exploratory factor analysis (EFA) was used to evaluate the factor structure of the HiSoC task. Convergent and divergent validity were assessed. Negative symptoms were assessed on the Positive and Negative Syndrome Scale (PANSS) and real-world functioning was indexed by the Global Assessment of Functioning (GAF). Commonality analysis was used to partition unique and shared variance of HiSoC and negative symptoms with real-world functioning., Results: EFA yielded a three-factor structure of HiSoC consisting of Affect, Odd behaviour and language, and Social-interpersonal. The HiSoC task discriminated UHR and healthy controls (p < 0.001, Cohen's d = 0.437-0.598). Commonality analysis revealed that the unique variance of the social amotivation subdomain of negative symptoms was the strongest predictor of GAF (p < .001, R 2 = .480). Shared variance of 3.7% between HiSoC Social-interpersonal and social amotivation was observed in relation to functioning., Conclusion: The HiSoC is a psychometrically valid task that is sensitive to identify social skill deficits in UHR. While social skills are related to functioning, experiential negative symptoms appear to be an important target for improving real-world functional outcomes., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Introduction: Interleukin-6 (IL-6) is an important mediator of inflammation and activation of T cells, B cells, and plasma cells. Excessive IL-6 production is linked to human diseases characterized by unregulated antibody production, including alloimmunity, where persistence of donor-specific antibodies (DSAs), chronic active antibody-mediated rejection (cAMR), and graft loss are noted. Here, we report our experience investigating clazakizumab, a novel IL-6 inhibitor, in treating human leukocyte antigen (HLA)-sensitized patients with cAMR., Methods: Between February 2018 and January 2019, 10 adults with biopsy-proven cAMR were enrolled in a phase 2, single-center, open-label study. Patients received clazakizumab 25 mg subcutaneously (s.c.) monthly for 12 months, with a 6-month protocol biopsy. Primary end points included patient survival, graft survival, estimated glomerular filtration rate (eGFR), and safety. Secondary end points assessed immune markers (DSAs, IgG, T-regulatory [Treg] cells). At 12 months, stable patients entered a long-term extension (LTE)., Results: LTE patients received clazakizumab for >2.5 years. Mean eGFRs showed significant declines from -24 months to study initiation (0 months) (52.8 ± 14.6 to 38.11 ± 12.23 ml/min per 1.73 m 2 , P  = 0.03). However, after initiation of clazakizumab, eGFR stabilized at (41.6 ± 14.2 and 38.1 ± 20.3 ml/min per 1.73 m 2 , at 12 and 24 months, respectively). Banff 2017 analysis of pre- and post-treatment biopsies showed reductions in g+ptc and C4d scores. DSA reductions were seen in most patients. Adverse events (AEs) were minimal, and 2 graft losses occurred, both in patients who discontinued clazakizumab therapy at 6 months and 12 months after study initiation., Conclusion: In this small cohort of patients with cAMR, clazakizumab treatment showed a trend toward stabilization of eGFR and reductions in DSA and graft inflammation. No significant safety issues were observed. A randomized, placebo-controlled clinical trial (IMAGINE) of clazakizumab in cAMR treatment is underway (NCT03744910)., (© 2022 International Society of Nephrology. Published by Elsevier Inc.)

Background: Immune checkpoint-inhibitor (ICI)-based therapy is the standard of care for first-line treatment of metastatic renal cell carcinoma (mRCC). It is unclear whether prior removal of the primary tumor influences the efficacy of these treatments. We performed a systematic review and meta-analysis of studies of first-line ICI in mRCC to determine whether the efficacy of ICI-therapy, compared to sunitinib, is altered based on receipt of prior nephrectomy., Methods: We systematically reviewed studies indexed in MEDLINE (PubMed), Embase, and Scopus and conference abstracts from relevant medical societies as of August 2020 to identify randomized clinical trials assessing first-line immunotherapy-based regimes in mRCC. Studies were included if overall survival (OS) and progression-free survival (PFS) outcomes were reported with data stratified by nephrectomy status. We pooled hazard ratios (HRs) stratified by nephrectomy status and performed random effects meta-analysis to assess the null hypothesis of no difference in the survival advantage of immunotherapy-based regimes based on nephrectomy status, while accounting for study level correlations., Results: Among 6 randomized clinical trials involving 5,121 patients, 3,968 (77%) had undergone prior nephrectomy. We found an overall survival benefit for immunotherapy-based regimes, compared to sunitinib, among both patients who had undergone nephrectomy (HR 0.75, 95% CI 0.63 -0.88) and those who had not (HR 0.74, 95% CI 0.59 -0.92), without evidence of difference based on nephrectomy history (P = 0.70; I 2  = 36%). Results assessing PFS were similar (P = 0.45, I 2  = 0%)., Conclusions: These clinical data suggest that prior nephrectomy does not affect the efficacy of ICI-based regimens in mRCC relative to sunitinib., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: COVID-19 has had a significant impact on the well-being and job performance of oncology professionals globally. The European Society for Medical Oncology (ESMO) Resilience Task Force collaboration set out to investigate and monitor well-being since COVID-19 in relation to work, lifestyle and support factors in oncology professionals 1 year on since the start of the pandemic., Methods: An online, anonymous survey was conducted in February/March 2021 (Survey III). Key outcome variables included risk of poor well-being or distress (expanded Well-Being Index), feeling burnout (single item from expanded Well-Being Index), and job performance since COVID-19. Longitudinal analysis of responses to the series of three surveys since COVID-19 was carried out, and responses to job demands and resources questions were interrogated. SPSS V.26.0/V.27.0 and GraphPad Prism V9.0 were used for statistical analyses., Results: Responses from 1269 participants from 104 countries were analysed in Survey III: 55% (n = 699/1269) female, 54% (n = 686/1269) >40 years, and 69% (n = 852/1230) of white ethnicity. There continues to be an increased risk of poor well-being or distress (n = 464/1169, 40%) and feeling burnout (n = 660/1169, 57%) compared with Survey I (25% and 38% respectively, P < 0.0001), despite improved job performance. Compared with the initial period of the pandemic, more participants report feeling overwhelmed with workload (45% versus 29%, P < 0.0001). There remain concerns about the negative impact of the pandemic on career development/training (43%), job security (37%). and international fellowship opportunities (76%). Alarmingly, 25% (n = 266/1086) are considering changing their future career with 38% (n = 100/266) contemplating leaving the profession., Conclusion: Oncology professionals continue to face increased job demands. There is now significant concern regarding potential attrition in the oncology workforce. National and international stakeholders must act immediately and work closely with oncology professionals to draw up future-proof recovery plans., Competing Interests: Disclosure KHJL is currently funded by the Wellcome-Imperial 4i Clinical Research Fellowship, and reports speaker honorarium from Janssen, outside the submitted work. KP’s institution received speaker fees or honoraria for consultancy/advisory roles from AstraZeneca, Eli Lilly, Gilead Sciences, Medscape, Merck Sharp & Dohme (MSD), Novartis, Pfizer, Pierre Fabre, Hoffmann La Roche, Mundipharma, PharmaMar, Seagen, Teva, and Vifor Pharma; KP’s institution received research grants from MSD and Sanofi; KP received travel support from AstraZeneca, Novartis, Pfizer, PharmaMar, and Roche; all outside the submitted work. CO reports research funding and honoraria from Roche; travel grant and honoraria from medac Pharma and Ipsen Pharma; and travel grant from PharmaMar; outside the submitted work. EÉ reports speaker honoraria, travel support and advisory board: Bayer, Roche, Servier, Amgen, Pierre-Fabre, Sanofi Aventis, MSD, and Merck Serono; outside the submitted work. TA reports personal fees from Pierre Fabre and CeCaVa; personal fees and travel grants from Bristol Myers Squibb (BMS); grants, personal fees, and travel grants from Novartis; and grants from NeraCare, Sanofi, and SkylineDx; all outside the submitted work. PG reports personal fees from Roche, MSD, BMS, Boerhinger-Ingelheim, Pfizer, AbbVie, Novartis, Lilly, AstraZeneca, Janssen, Blueprint Medicines, Takeda, Gilead, and ROVI, outside the submitted work. ML acted as a consultant for Roche, AstraZeneca, Lilly, and Novartis, and received honoraria from Theramex, Roche, Novartis, Takeda, Pfizer, Sandoz, and Lilly, outside the submitted work. CBW reports speaker honoraria, travel support, and participation in advisory boards: Bayer, BMS, Celgene, GlaxoSmithKline (GSK), Merck, Rafael, RedHil, Roche, Servier, Shire/Baxalta, Sirtex, and Taiho, as well as research support from Roche, outside the submitted work. JBAGH reports personal fees for advisory role in Neogene Tx; grants and fees paid to institution from BMS, MSD, Novartis, BioNTech, Amgen; and fees paid to institution from Achilles Tx, GSK, Immunocore, Ipsen, Merck Serono, Molecular Partners, Pfizer, Roche/Genentech, Sanofi, Seattle Genetics, Third Rock Ventures, Vaximm; outside the submitted work. CH reports being Director of a private company Hardy People Ltd, outside the submitted work. SB reports research grant (institution) from AstraZeneca, Tesaro, and GSK; honoraria for advisory boards or lectures from Amgen, AstraZeneca, Genmab, Immunogen, Mersana, MSD, Merck Serono, OncXerna, Pfizer, Roche, Shattuck Labs, Clovis, Takeda outside the submitted work. KM, KK, MOC, ET, BD, and GM have declared no conflicts of interest., (Copyright © 2021. Published by Elsevier Ltd.)

Nuclear pore complexes (NPC) regulate molecular traffics on nuclear envelope, which plays crucial roles during cell fate specification and diseases. The viral accessory protein NSP9 of SARS-CoV-2 is reported to interact with nucleoporin 62 (NUP62), a structural component of the NPC, but its biological impact on the host cell remain obscure. Here, we established new cell line models with ectopic NSP9 expression and determined the subcellular destination and biological functions of NSP9. Confocal imaging identified NSP9 to be largely localized in close proximity to the endoplasmic reticulum. In agreement with the subcellular distribution of NSP9, association of NSP9 with NUP62 was observed in cytoplasm. Furthermore, the overexpression of NSP9 correlated with a reduction of NUP62 expression on the nuclear envelope, suggesting that attenuating NUP62 expression might have contributed to defective NPC formation. Importantly, the loss of NUP62 impaired translocation of p65, a subunit of NF-κB, upon TNF-α stimulation. Concordantly, NSP9 over-expression blocked p65 nuclear transport. Taken together, these data shed light on the molecular mechanisms underlying the modulation of host cells during SARS-CoV-2 infection., 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 © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)