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In lactating mothers, the high calcium (Ca2+) demand for milk production triggers significant bone loss1. Although oestrogen normally counteracts excessive bone resorption by promoting bone formation, this sex steroid drops precipitously during this postpartum period. Here we report that brain-derived cellular communication network factor 3 (CCN3) secreted from KISS1 neurons of the arcuate nucleus (ARCKISS1) fills this void and functions as a potent osteoanabolic factor to build bone in lactating females. We began by showing that our previously reported female-specific, dense bone phenotype2 originates from a humoral factor that promotes bone mass and acts on skeletal stem cells to increase their frequency and osteochondrogenic potential. This circulatory factor was then identified as CCN3, a brain-derived hormone from ARCKISS1 neurons that is able to stimulate mouse and human skeletal stem cell activity, increase bone remodelling and accelerate fracture repair in young and old mice of both sexes. The role of CCN3 in normal female physiology was revealed after detecting a burst of CCN3 expression in ARCKISS1 neurons coincident with lactation. After reducing CCN3 in ARCKISS1 neurons, lactating mothers lost bone and failed to sustain their progeny when challenged with a low-calcium diet. Our findings establish CCN3 as a potentially new therapeutic osteoanabolic hormone for both sexes and define a new maternal brain hormone for ensuring species survival in mammals.

Si-Wei You,1 Ming-Mei Wu,2 Fang Kuang,2 Kin-Sang Cho,3 Kwok-Fai So4,5 1Department of Ophthalmology, Xijing Hospital, 2Institute of Neurosciences, The Fourth Military Medical University, Xi’an, China; 3Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA; 4GHM Institute of CNS Regeneration, Key Laboratory of Brain Function and Diseases, Jinan University, Guangzhou, 5Department of Ophthalmology, The State Key laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong SAR, China Abstract: Optic neuropathy refers to disorders involving the optic nerve (ON). Any damage to ON or ON-deriving neurons, the retinal ganglion cells (RGCs), may lead to the breakdown of the optical signal transmission from the eye to the brain, thus resulting in a partial or complete vision loss. The causes of optic neuropathy include trauma, ischemia, inflammation, compression, infiltration, and mitochondrial damages. ON injuries include primary and secondary injuries. During these injury phases, various factors orchestrate injured axons to die back and become unable to regenerate, and these factors could be divided into two categories: extrinsic and intrinsic. Extrinsic inhibitory factors refer to the environmental conditions that influence the regeneration of injured axons. The presence of myelin inhibitors and glial scar, lack of neurotrophic factors, and inflammation mediated by injury are regarded as these extrinsic factors. Extrinsic factors need to trigger the intracellular signals to exert inhibitory effect. Proper regulation of these intracellular signals has been shown to be beneficial to ON regeneration. Intrinsic factors of RGCs are the pivotal reasons that inhibit ON regeneration and are closely linked with extrinsic factors. Intracellular cyclic adenosine monophosphate (cAMP) and calcium levels affect axon guidance and growth cone response to guidance molecules. Many genes, such as Bcl-2, PTEN, and mTOR, are crucial in cell proliferation, axon guidance, and growth during development, and play important roles in the regeneration and extension of RGC axons. With transgenic mice and related gene regulations, robust regeneration of RGC axons has been observed after ON injury in laboratories. Although various means of experimental treatments such as cell transplantation and gene therapy have achieved significant progress in neuronal survival, axonal regeneration, and restoration of the visual function after ON injury, many unresolved scientific problems still exist for their clinical applications. Therefore, we still need to overcome hurdles before developing effective therapy to treat optic neuropathy diseases in patients. Keywords: retinal ganglion cells, optic nerve injury, neuronal survival, axonal regeneration, vision restoration

Eng Hui Gan,1 Wen Wei Woo,1 Kheong Fang Seng,1 Pall Singh,2 Ming Yueh Lee,3 Vui Yin Kong,4 Say Peng Khoo,4 Mun Wai Lee,5 Liau Kok Liang6 1International Specialist Eye Centre, Kuala Lumpur, Selangor, Malaysia; 2Tun Hussein Onn National Eye Hospital, Petaling Jaya, Selangor, Malaysia; 3Parkcity Medical Centre, Kuala Lumpur, Selangor, Malaysia; 4Synergy Specialist Eye Centre, Kota Kinabalu, Sabah, Malaysia; 5LEC Eye Centre, Ipoh, Perak, Malaysia; 6Mahkota Medical Centre, Melaka, MalaysiaCorrespondence: Eng Hui Gan, International Specialist Eye Centre (ISEC) Kuala Lumpur, Level 8 Centrepoint South MidValley City, Kuala Lumpur, 59200, Malaysia, Tel +603 2284 8989, Fax +603 2284 4330, Email ganenghui@yahoo.com.myBackground: Ocular surface disease (OSD) severity varies among glaucoma patients and is exacerbated by intraocular pressure (IOP)-lowering medications.Purpose: To determine OSD prevalence and dry eye severity among glaucoma patients at nine private clinics in Malaysia.Methods: This multicentre, cross-sectional observational study recruited glaucoma patients undergoing routine eye examinations, with IOP ≤ 21mmHg receiving anti-glaucoma eye drops. OSD was assessed through National Eye Institute (NEI) scoring, tear film break-up time (TBUT), hyperaemia grading, Schirmer’s tests and questionnaires on symptom evaluation, OSD index and quality of life (QoL).Results: Our cohort (n = 406, mostly male, ethnically Chinese, mean 63.5 ± 11.5 years, mean IOP 15.34 ± 2.95mmHg) frequently used prostaglandin analogues or PGA/beta-blockers and had cornea total NEI scores of 3.64 ± 2.76, mostly with minimal (51.2%) or mild (40.4%) epitheliopathy. Mean TBUT was 6.59 ± 3.08s (25.0%) in patients with severe lipid deficiency dry eye (DE). Bulbar conjunctiva hyperemia (70.4%) and palpebral conjunctiva hyperemia (68.0%) were mild. Schirmer’s test showed that most had tear deficiency (70.2%) with severe DE (38.9%). Questionnaires reported ocular symptoms in few patients, but 69.2% had DE symptoms (13.1% moderate/severe). While QoL was good, several patients had QoL and OSD index scores suggesting some adaptation to ocular symptoms and discomfort, with most patients being unconcerned (43– 60%) by the occurrence of eye drop side effects (75.4%).Conclusion: Normal-mild DE or OSD can be asymptomatic, and the symptoms are unlikely to bother most patients. However, as OSD severity varies in patients with glaucoma, it should be evaluated using questionnaires and clinical tests to ensure that subjectively asymptomatic individuals are not missed.Keywords: glaucoma, ocular surface disease, prevalence, questionnaires, clinical tests

Abdullah A Alrasheed,1,2 Khalid F Alsadhan,1,2 Nawaf F Alfawzan,2 Nasser M AbuDujain,2 Ali H Alnasser,3 Hisham Almousa3 1Family and Community Medicine Department, College of Medicine, King Saud University, Riyadh, Saudi Arabia; 2Family and Community Medicine Department, King Saud University Medical City, Riyadh, Saudi Arabia; 3College of Medicine, King Saud University, Riyadh, Saudi ArabiaCorrespondence: Abdullah A Alrasheed, Tel +966114670836, Email aalrasheed1@ksu.edu.saBackground: Isotretinoin is an effective treatment for acne but can cause side effects such as changes in blood lipids and liver enzymes. Laboratory monitoring is essential during treatment, but there is variation in monitoring practices.Aim: This study aims to investigate the relationship between isotretinoin therapy and its effects on complete blood count in Saudi Arabia to improve patient outcomes.Methods: The study was a retrospective cohort study conducted at King Khalid University Hospital in Riyadh, Saudi Arabia, between January 2016 and December 2020. Following the inclusion and exclusion criteria, 515 patients were randomly selected for the study. The data was analyzed using SPSS, and descriptive statistics and paired samples t-tests were employed to analyze the data.Results: In this study, 515 patients were enrolled. Of these participants, 76.7% (n=395) were females and 23.3% (n=120) were males. The mean age of the study participants was 23.98± 7.4 years and ranged between 16 and 65 years. The mean dose of Isotretinoin administered was 27.65± 9.6 mg/day, with a range of 10– 60 mg/day. The mean BMI of the study participants was 24.3± 4.1 kg/m2, ranging from 14.3 to 44.8 kg/m2. Regarding the effect of Isotretinoin on laboratory measures, significant statistical differences were found in hemoglobin measurements (t=− 3.379, p=0.001), platelets (t=− 3.169, p=0.002), neutrophils (%) (t=3.107, p=0.002), total cholesterol (t=− 13.017, p=0.000), AST (t=− 6.353, p=0.000), ALT (t=− 4.352, p=0.000), HDL (t=2.446, p=0.015), and LDL (t=− 12.943, p=0.000). However, there were no significant statistical differences in the measurements of WBC, neutrophils (count), or triglycerides. In the Chi-square analysis and Fisher’s Exact test to identify the interaction between BMI, dose, and gender on abnormal lab results, significant interaction was found between participants’ BMI and abnormal HDL measurements (p=0.006). Furthermore, there were significant interactions between Isotretinoin dose (either less than 30 mg/day or 30 mg/day or more) and abnormal neutrophil count (p=0.04), abnormal HDL measurements (p=0.010), and abnormal triglycerides measurements (p=0.020). Moreover, a statistically significant interaction was found between participants’ gender and abnormal hemoglobin measurements (p=0.006), abnormal total cholesterol (p=0.016), abnormal AST measurements (p=0.001), abnormal ALT measurements (p=0.000), abnormal HDL measurements (p=0.000), and abnormal triglycerides measurements (p=0.007).Conclusion: In conclusion, the study found that isotretinoin therapy has significant effects on several laboratory measures, including hemoglobin, platelets, neutrophils, total cholesterol, AST, ALT, HDL, and LDL. The study also revealed significant interactions between BMI, dose, gender, and abnormal lab results.Keywords: Isotretinoin, acne treatment, laboratory monitoring, blood lipids, liver enzymes, Saudi Arabia

Xue-Song Mi,1,2 Ti-Fei Yuan,3,4 Yong Ding,1 Jing-Xiang Zhong,1 Kwok-Fai So4,5 1Department of Ophthalmology, First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, People’s Republic of China; 2Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, People’s Republic of China; 3School of Psychology, Nanjing Normal University, Nanjing, People’s Republic of China; 4Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong; 5Guangdong-Hongkong-Macau Institute of Central Nervous System, Jinan University, Guangzhou, People’s Republic of China Abstract: Diabetic retinopathy (DR) is the most common complication of diabetes mellitus in the eye. Although the clinical treatment for DR has already developed to a relative high level, there are still many urgent problems that need to be investigated in clinical and basic science. Currently, many in vivo animal models and in vitro culture systems have been applied to solve these problems. Many approaches have also been used to establish different DR models. However, till now, there has not been a single study model that can clearly and exactly mimic the developmental process of the human DR. Choosing the suitable model is important, not only for achieving our research goals smoothly, but also, to better match with different experimental proposals in the study. In this review, key problems for consideration in choosing study models of DR are discussed. These problems relate to clinical relevance, different approaches for establishing models, and choice of different species of animals as well as of the specific in vitro culture systems. Attending to these considerations will deepen the understanding on current study models and optimize the experimental design for the final goal of preventing DR. Keywords: animal model, in vitro culture, ex vivo culture, neurovascular dysfunction

Xue-Song Mi,1,2 Ti-Fei Yuan,3,4 Kwok-Fai So2,4,5 1Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Guangzhou, People’s Republic of China; 2Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, People’s Republic of China; 3School of Psychology, Nanjing Normal University, Nanjing, People’s Republic of China; 4Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, People’s Republic of China; 5GHM Institute of CNS Regeneration, Jinan University, Guangzhou, People’s Republic of China Abstract: Normal tension glaucoma (NTG) is a progressive optic neuropathy that mimics primary open-angle glaucoma, but lacks the findings of elevated intraocular pressure or other mitigating factors that can lead to optic neuropathy. The present review summarized the causes, genetics, and mechanisms underlying NTG in both animal models and human patients. We also proposed that the neurovascular unit is a therapeutic target for NTG management. Keywords: aging, genetics, neurovascular unit, primary open-angle glaucoma, treatment

Supply chain process is interdependent. Starting from procurement of raw materials, production, distribution, and finally the goods reaching consumers will influence each other. The costs of goods and services will be somewhat impacted by these social habits. Producers and merchants must comprehend these social behaviors in order to properly establish prices and the distribution of goods. This includes determining the prices of goods and services. Offering manufacturers who participate in cooperative advertising schemes money for a percentage of the costs connected with local advertising encourages retailers to launch additional promotional activities. The aim of this research is to investigate how cooperative pricing and advertising can improve supply chain coordination using consumer demand functions. A model based on game theory that takes the dynamics of power in the supply. A series of numerical simulations is presented to illustrate the optimal solution of channel members based on scenarios that illustrate, understand and compare the fundamental results of the game models. The results of this research are that retail price decisions are influenced by the level of competition and product differentiation. The results show that retail margins depend on local ( ) and national ( ) advertising effectiveness values. In addition, retailers can gain greater profits by setting higher prices in conditions of low price elasticity but must consider consumer sensitivity to price to maximize profits.

Human skeletal stem cells (hSSCs) hold tremendous therapeutic potential for developing new clinical strategies to effectively combat congenital and age-related musculoskeletal disorders. Unfortunately, refined methodologies for the proper isolation of bona fide hSSCs and the development of functional assays that accurately recapitulate their physiology within the skeleton have been lacking. Bone marrow-derived mesenchymal stromal cells (BMSCs), commonly used to describe the source of precursors for osteoblasts, chondrocytes, adipocytes and stroma, have held great promise as the basis of various approaches for cell therapy. However, the reproducibility and clinical efficacy of these attempts have been obscured by the heterogeneous nature of BMSCs due to their isolation by plastic adherence techniques. To address these limitations, our group has refined the purity of individual progenitor populations that are encompassed by BMSCs by identifying defined populations of bona fide hSSCs and their downstream progenitors that strictly give rise to skeletally restricted cell lineages. Here, we describe an advanced flow cytometric approach that utilizes an extensive panel of eight cell surface markers to define hSSCs; bone, cartilage and stromal progenitors; and more differentiated unipotent subtypes, including an osteogenic subset and three chondroprogenitors. We provide detailed instructions for the FACS-based isolation of hSSCs from various tissue sources, in vitro and in vivo skeletogenic functional assays, human xenograft mouse models and single-cell RNA sequencing analysis. This application of hSSC isolation can be performed by any researcher with basic skills in biology and flow cytometry within 1-2 days. The downstream functional assays can be performed within a range of 1-2 months.

This White Paper aims at highlighting the important benefits in the science reach of the EIC. High luminosity operation is generally desirable, as it enables producing and harvesting scientific results in a shorter time period. It becomes crucial for programs that would require many months or even years of operation at lower luminosity.

BackgroundPeripheral vascular disease remains a leading cause of vascular morbidity and mortality worldwide despite advances in medical and surgical therapy. Besides traditional approaches, which can only restore blood flow to native arteries, an alternative approach is to enhance the growth of new vessels, thereby facilitating the physiological response to ischemia.MethodsThe ActinCreER/R26VT2/GK3 Rainbow reporter mouse was used for unbiased in vivo survey of injury-responsive vasculogenic clonal formation. Prospective isolation and transplantation were used to determine vessel-forming capacity of different populations. Single-cell RNA-sequencing was used to characterize distinct vessel-forming populations and their interactions.ResultsTwo populations of distinct vascular stem/progenitor cells (VSPCs) were identified from adipose-derived mesenchymal stromal cells: VSPC1 is CD45-Ter119-Tie2+PDGFRa-CD31+CD105highSca1low, which gives rise to stunted vessels (incomplete tubular structures) in a transplant setting, and VSPC2 which is CD45-Ter119-Tie2+PDGFRa+CD31-CD105lowSca1high and forms stunted vessels and fat. Interestingly, cotransplantation of VSPC1 and VSPC2 is required to form functional vessels that improve perfusion in the mouse hindlimb ischemia model. Similarly, VSPC1 and VSPC2 populations isolated from human adipose tissue could rescue the ischemic condition in mice.ConclusionsThese findings suggest that autologous cotransplantation of synergistic VSPCs from nonessential adipose tissue can promote neovascularization and represents a promising treatment for ischemic disease.

Bone- and cartilage-related diseases, such as osteoporosis and osteoarthritis, affect millions of people worldwide, impairing their quality of life and increasing mortality. Osteoporosis significantly increases the bone fracture risk of the spine, hip, and wrist. For successful fracture treatment and to facilitate proper healing in the most complicated cases, one of the most promising methods is to deliver a therapeutic protein to accelerate bone regeneration. Similarly, in the setting of osteoarthritis, where degraded cartilage does not regenerate, therapeutic proteins hold great promise to promote new cartilage formation. For both osteoporosis and osteoarthritis treatments, targeted delivery of therapeutic growth factors, with the aid of hydrogels, to bone and cartilage is a key to advance the field of regenerative medicine. In this review article, we propose five important aspects of therapeutic growth factor delivery for bone and cartilage regeneration: (1) protection of protein growth factors from physical and enzymatic degradation, (2) targeted growth factor delivery, (3) controlling GF release kinetics, (4) long-term stability of regenerated tissues, and (5) osteoimmunomodulatory effects of therapeutic growth factors and carriers/scaffolds.

BackgroundCyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC.MethodsWithin the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated.ResultsHigh-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss.ConclusionThis study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.

Kuo-Feng Hua,1,2,* Hsien-Ta Hsu,3,4,* May-Shu Huang,5,6 Hsiao-Wen Chiu,1 Wei-Ting Wong,1 Chien-Hsiu Peng,1 Yu-Bei Lin,1 Ann Chen,7 Chien-Chun Wang,8,9 Chung-Hua Hsu,10,11 Chun-Hsien Wu,12 Wen-Yu Lin,1,12 Chen-Lung Ho,13 Lan-Hui Li14 1Department of Biotechnology and Animal Science, National Ilan University, Ilan, Taiwan; 2Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan; 3Division of Neurosurgery, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan; 4School of Medicine, Buddhist Tzu Chi University, Hualien, Taiwan; 5Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; 6Department of Laboratory Medicine, Mackay Memorial Hospital, Taipei, Taiwan; 7Department of Pathology, Hualien Tzu Chi Hospital, Hualien, Taiwan; 8Infectious Disease Division, Linsen, Chinese Medicine and Kunming Branch, Taipei City Hospital, Taipei, Taiwan; 9Kunming Prevention and Control Center, Taipei City Hospital, Taipei, Taiwan; 10Linsen, Chinese Medicine and Kunming Branch, Taipei City Hospital, Taipei, Taiwan; 11Institute of Traditional Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; 12Division of Cardiology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; 13Division of Wood Cellulose, Taiwan Forestry Research Institute, Taipei, Taiwan; 14Department of Laboratory Medicine, Linsen, Chinese Medicine and Kunming Branch, Taipei City Hospital, Taipei, Taiwan*These authors contributed equally to this workCorrespondence: Lan-Hui Li, Department of Laboratory Medicine, Linsen, Chinese Medicine and Kunming Branch, Taipei City Hospital, 100, Kunming Street, Wanhua District, Taipei City, 108203, Taiwan, Tel +886-2-23703739 # 1438, Fax +886-2-23885259, Email A1525@tpech.gov.twPurpose: The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, crucial in infectious and inflammatory diseases by regulating IL-1β, presents a target for disease management. Neisseria gonorrhoeae causes gonorrhea in over 87 million people annually, with previous research revealing NLRP3 inflammasome activation in infected macrophages. No natural products have been reported to counteract this activation. Exploring honokiol, a phenolic compound from Chinese herbal medicine, we investigated its impact on NLRP3 inflammasome activation in N. gonorrhoeae-infected macrophages.Methods: Honokiol’s impact on the protein expression of pro-inflammatory mediators was analyzed using ELISA and Western blotting. The generation of intracellular H2O2 and mitochondrial reactive oxygen species (ROS) was detected through specific fluorescent probes (CM-H2DCFDA and MitoSOX, respectively) and analyzed by flow cytometry. Mitochondrial membrane integrity was assessed using specific fluorescent probes (MitoTracker and DiOC2(3)) and analyzed by flow cytometry. Additionally, the effect of honokiol on the viability of N. gonorrhoeae was examined through an in vitro colony-forming units assay.Results: Honokiol effectively inhibits caspase-1, caspase-11 and GSDMD activation and reduces the extracellular release of IL-1β, NLRP3, and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) in N. gonorrhoeae-infected macrophages. Detailed investigations have demonstrated that honokiol lowers the production of H2O2 and the phosphorylation of ERK1/2 in N. gonorrhoeae-infected macrophages. Importantly, the phosphorylation of JNK1/2 and p38 and the activation of NF-κB remain unaffected. Moreover, honokiol reduces the N. gonorrhoeae-mediated generation of reactive oxygen species within the mitochondria, preserving their integrity. Additionally, honokiol suppresses the expression of the pro-inflammatory mediator IL-6 and inducible nitric oxide synthase induced by N. gonorrhoeae independently of NLRP3. Impressively, honokiol exhibits in vitro anti-gonococcal activity against N. gonorrhoeae.Conclusion: Honokiol inhibits the NLRP3 inflammasome in N. gonorrhoeae-infected macrophages and holds great promise for further development as an active ingredient in the prevention and treatment of symptoms associated with gonorrhea.Keywords: Neisseria gonorrhoeae, honokiol, NLRP3 inflammasome, mitochondria, bactericiide

Kasper Fjellhaugen Hjuler,1,2 Louise Faurskov Møller,2,3 Cathrine Dawn Büttner Elgaard,2,3 Laura Gaïni,4 Lars Iversen,2,3 Tirill Fjellhaugen Hjuler5 1Department of Dermatology, Aalborg University Hospital, Aalborg, Denmark; 2Danish National Centre for Autoimmune Diseases, Aarhus University Hospital, Aarhus, Denmark; 3Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark; 4Institute of Psychology, Aarhus University, Aarhus, Denmark; 5Department of Child and Adolescent Psychiatry, Aarhus University Hospital, Aarhus, DenmarkCorrespondence: Kasper Fjellhaugen Hjuler, Department of Dermatology, Aalborg University Hospital, Mølleparkvej 4, Aalborg, DK-9000, Denmark, Tel +4531244813, Email kf.hjuler@rn.dkPurpose: Immune-mediated inflammatory diseases (eg, axial spondylitis, psoriasis, psoriatic arthritis, Crohn’s disease, ulcerative colitis, and hidradenitis suppurativa) are common diseases that exert an extensive effect on the health-related quality of life, particularly when multiple concomitant conditions are present. Previous reports indicate that the traditional siloed approach to care can lead to a lack of patient centricity and inefficient disease management. In this article, we aimed to evaluate an interdisciplinary program for the treatment of immune-mediated inflammatory diseases compared to routine clinical practice.Patients and Methods: This was a mixed-method study, combining qualitative and quantitative data. Patients with co-occurrence of ≥ 2 immune-mediated inflammatory diseases treated in an interdisciplinary clinic (n = 48) or traditional usual care (n = 17) answered open-ended questions about their care experiences. Two independent coders blinded to patients’ treatment group coded three aspects of the narratives provided by the patients’ responses: Themes, Emotional valence, and Personal growth (ie, redemption). Themes were analyzed descriptively to explore possible differences between patients assigned to the interdisciplinary clinic and patients assigned to the usual care setting. Group differences in patients’ emotional experiences were assessed, and we examined potential group differences in positive personal growth.Results: Our findings indicate that an interdisciplinary combined clinic approach provides benefits for patients with multiple inflammatory diseases towards the usual setup. Patients experienced benefits on a number of specific quality-of-life themes including acceptance, optimism, disease understanding, personal growth, and better disease control. The narratives of the patients in the interdisciplinary group were significantly more emotionally positive and included more positive personal growth compared to the usual care group.Conclusion: The findings indicate a patient-reported benefit, especially from the holistic approach and cross-specialty combined consultations in an interdisciplinary clinic compared to usual specialized healthcare, which was underscored by narratives highlighting an overall improved quality of life.Keywords: patient-centered healthcare, interdisciplinary care, psoriasis, psoriatic arthritis, axial spondylitis, inflammatory bowel disease, hidradenitis suppurativa

Eduardo Jorge Fonseca Lima,1,2 Luiza Campos Corrêa de Araújo,1 Karine Ferreira Agra,2 Ana Julia Xavier Mendoza,1 Julia Pierre de Brito Siebra,1 Carmina Silva dos Santos2,3 1Department of Medicine, Faculdade Pernambucana de Saúde, Recife, Pernambuco, Brazil; 2Lato Sensu Postgraduate Department, Instituto de Medicina Integral Professor Fernando Figueira, Recife, Pernambuco, Brazil; 3Nursing Department, Faculdade Pernambucana de Saúde, Recife, Pernambuco, BrazilCorrespondence: Eduardo Jorge Fonseca Lima, Instituto de Medicina Integral Professor Fernando Figueira, Rua dos Coelhos, N° 300, Boa Vista, Recife, Pernambuco, Brazil, Tel +5581 21224166, Email eduardojorge@imip.org.brIntroduction: Community-acquired pneumonia (CAP) is one of the most common causes of childhood morbidity and mortality, causing about two million deaths per year worldwide. The complicated CAP (CCAP) results from the worsening of CAP. Their incidence has reduced in the last 30 years due to vaccination. However, the coronavirus disease (COVID-19) pandemic reduced vaccination coverage, resulting in increased incidence of CCAP in 2021 and 2022.Objective: To analyze the clinical and epidemiological profile of CAP in children under five years of age in two periods: pre- (2018 to 2019) and during the COVID-19 pandemic (2020 to 2022).Methods: This cross-sectional retrospective study was conducted at the Professor Fernando Figueira Institute of Integral Medicine (IMIP). We analyzed the sociodemographic and clinical variables of children with CAP aged below five years who were admitted to IMIP from 2018 to 2022. Analysis encompassed the Pearson’s Chi-square test, Fischer’s exact test, and Student’s T tests.Results: A total of 468 children were analyzed: 382 in the pre-pandemic period and 86 during the COVID-19 pandemic. Concerning the antibiotic therapy, the most prescribed was Ampicillin (45.00%) in both periods. The combination of Oxacillin and Ceftriaxone was prescribed in 6.86% of cases in the pre-pandemic period; this value increased to 20.90% during the COVID-19 pandemic. Pleural effusion represented 12.10% of cases in the pre-pandemic period and 24.40% during the COVID-19 pandemic. The presence of pleural empyema went from 1.60% to 8.20%, and necrotizing pneumonia from 1.30% to 5.90% in the respective periods. Regarding ICU admission, 5.30% were admitted during the pre-pandemic period and 34.10% during the COVID-19 pandemic. Clinical suspicion of influenza presented a positivity rate of 17.60%.Conclusion: Children with CAP presented a higher frequency of complications during the COVID-19 pandemic. Further research is needed to find the cause of increased CAP complications in this period.Keywords: pneumonia, bacterial, children, COVID-19, pleural effusion

BackgroundRecently, we showed a >60% difference in 5-year survival for patients with tubo-ovarian high-grade serous carcinoma (HGSC) when stratified by a 101-gene mRNA expression prognostic signature. Given the varied patient outcomes, this study aimed to translate prognostic mRNA markers into protein expression assays by immunohistochemistry and validate their survival association in HGSC.MethodsTwo prognostic genes, FOXJ1 and GMNN, were selected based on high-quality antibodies, correlation with protein expression and variation in immunohistochemical scores in a preliminary cohort (n = 134 and n = 80, respectively). Six thousand four hundred and thirty-four (FOXJ1) and 5470 (GMNN) formalin-fixed, paraffin-embedded ovarian neoplasms (4634 and 4185 HGSC, respectively) represented on tissue microarrays from the Ovarian Tumor Tissue Analysis consortium underwent immunohistochemical staining and scoring, then univariate and multivariate survival analysis.ResultsConsistent with mRNA, FOXJ1 protein expression exhibited a linear, increasing association with improved overall survival in HGSC patients. Women with >50% expression had the most favourable outcomes (HR = 0.78, 95% CI 0.67-0.91, p 35% GMNN expression showed a trend for better outcomes, though this was not significant.ConclusionWe provide foundational evidence for the prognostic value of FOXJ1 in HGSC, validating the prior mRNA-based prognostic association by immunohistochemistry.

The bone marrow is the daily production site for hundreds of billions of blood cells. A new study adds evidence that, during ageing, signals emanating from bone-marrow stromal cells shift to produce inflammatory factors that skew blood-cell output, driving age-related tissue deterioration.

In 2018, the Endourology Disease Group for Excellence (EDGE) published a prospective trial comparing dusting versus basketing during ureteroscopy. One hundred fifty-nine patients were included in the original analysis, which found no difference in stone-free rate at 3 months. We report the intermediate and long-term outcomes of patients included in the original trial. Two analyses were performed. At 1-year, a retrospective chart review was performed, and data collected on stone episodes, Emergency Department (ED) visits, hospital admissions and surgical interventions. To obtain long-term outcomes, the four sites with the largest initial accrual were included in a second phase of data collection with updated analyses. The patients from those sites were contacted, re-consented, and data were collected on stone surgical interventions, stone episodes, stone recurrences on imaging, emergency department (ED) visits, and hospital admissions for stone-related care since their original procedure. One-year follow-up data were collected in 111 of the original 159 (69.8%) patients from the nine sites. There were no statistically significant differences in the number of painful episodes, ED visits, hospital admissions, or surgical interventions. 94 patients from four sites were included in the long-term analysis. There were no statistically significant differences in surgical interventions, painful stone episodes, stone recurrence on imaging, ED visits or hospitalizations for stone-related events between the two groups. Long-term outcomes of dusting versus basketing during ureteroscopy indicate that there are no significant differences in clinical outcomes between the two surgical modalities.

Background Memory complaints are the early symptoms of cognitive impairment, and they usually bring anxiety about cognitive deterioration among the elderly population. Musical interventions were demonstrated to relieve dementia symptoms. This pilot study investigated the potential benefits of rhythmic musical intervention, African drumming, on cognitive function and mood status with traditional and digital assessments for elderly participants. Method Participants were recruited through social media. The musical intervention was arranged by drumming instructors certified by the Hong Kong Association of African Drumming. Participants joined regular training classes with eight lessons, which covered rhythmic clapping and drumming, power control, and overall performance with songs. The inclusion criteria included the following: (1) age over 50; (2) self-reported complaints of memory loss; (3) the ability to use digital devices, such as a smartphone; and (4) can understand the content of questionnaires and follow the intervention schedules. Those with hearing impairment, failure to use Chinese, and active psychosis or dementia were excluded. Cognitive function was measured by the Hong Kong version of the Montreal Cognitive Assessment (HK-MoCA) and a digital platform, ScreenMat. Anxiety and depression levels were assessed by the State–Trait Anxiety Inventory (STAI) and Geriatric Depression Scale (GDS-15). All assessments were performed before and after the drumming classes. The outcomes were compared using the Wilcoxon signed rank test with 0.05 as the significance level. Result Twenty-two participants joined this study with an attendance rate of 90%. The overall cognitive function of the participants was good with an average score of 27 for HK-MoCA. After eight sessions of African drum intervention, the cognitive function did not show a significant improvement, but the response time of answering the digital cognitive questions was significantly faster than before the intervention (−39.9 s, p = 0.03). The response time for the short-term memory function was most significantly reduced (−13.5 s, p = 0.017). The anxiety and depression scores (i.e. STAI and GDS) also significantly improved ( p

Abstract Mesonephric‐type (or ‐like) adenocarcinomas (MAs) of the ovary are an uncommon and aggressive histotype. They appear to arise through transdifferentiation from Müllerian lesions creating diagnostic challenges. Thus, we aimed to develop a histologic and immunohistochemical (IHC) approach to optimize the identification of MA over its histologic mimics, such as ovarian endometrioid carcinoma (EC). First, we screened 1,537 ovarian epithelial neoplasms with a four‐marker IHC panel of GATA3, TTF1, ER, and PR followed by a morphological review of EC to identify MA in retrospective cohorts. Interobserver reproducibility for the distinction of MA versus EC was assessed in 66 cases initially without and subsequently with IHC information (four‐marker panel). Expression of PAX2, CD10, and calretinin was evaluated separately, and survival analyses were performed. We identified 23 MAs from which 22 were among 385 cases initially reported as EC (5.7%) and 1 as clear cell carcinoma. The interobserver reproducibility increased from fair to substantial (κ = 0.376–0.727) with the integration of the four‐marker IHC panel. PAX2 was the single most sensitive and specific marker to distinguish MA from EC and could be used as a first‐line marker together with ER/PR and GATA3/TTF1. Patients with MA had significantly increased risk of earlier death from disease (hazard ratio = 3.08; 95% CI, 1.62–5.85; p

Kareemah Salem Alshurtan, Saad Yousef Aldhaifi, Khalid Abdulkarim Alshammari, Othman Mohammed Alodayli, Khalid Falah Alqahtani, Sarah Yousef Aldhaifi Department of Internal Medicine and Adult Critical Care, College of Medicine, University of Ha’il, Ha’il, Saudi ArabiaCorrespondence: Kareemah Salem Alshurtan, Department of Internal Medicine and Adult Critical Care, College of Medicine, University of Ha’il, Ha’il, Saudi Arabia, Email K.alshurtan@uoh.edu.saBackground: Burnout Syndrome constitutes a critical concern in healthcare, particularly among practitioners operating in high-stress, critical care settings. Understanding the multifaceted factors contributing to burnout in this context is pivotal for devising effective interventions and promoting the well-being of critical care professionals.Objective: To investigate the prevalence, contributing factors, and potential interventions related to Burnout Syndrome among critical care health providers in Saudi Arabia.Methods: A cross-sectional research design was employed, gathering data from a sample of critical care health providers, including medical practitioners. A self-administered structured electronic questionnaire was used, incorporating the Maslach Burnout Inventory (MBI) with its three subscales: emotional exhaustion, depersonalization, and personal accomplishment. The target population was male and female critical care health providers over 18 years age, most participants lies between 25 years to 34 years.Results: Statistical analysis shows significant disparities in response distribution (p< 0.05), highlighting the importance of understanding encounters with emotional exhaustion, personal accomplishment, and depersonalization. The Durbin-Watson statistic indicated limited autocorrelation, and collinearity tolerance values suggested nominal intercorrelations among predictors. A significant positive correlation was found between the “Depersonalization Loss of Empathy MBI” factor and the outcome variables, indicating complex relationships between emotional exhaustion, personal accomplishment, and depersonalization.Conclusion: The study highlights the multifaceted nature of burnout, revealing intricate relationships between emotional exhaustion, personal accomplishment, and depersonalization. These findings collectively form an important foundation for future guidelines and interventions to enhance the well-being of healthcare professionals.Keywords: maslach burnout inventory, MBI, emotional exhaustion, depersonalization, personal accomplishment, high-stress environments, healthcare professionals, work-related stress, occupational burnout

Kathleen F Pirollo,1 Manish Moghe,1 Miaoyin Guan,1 Antonina S Rait,1 Aibing Wang,1 Sang-Soo Kim,1,2 Esther H Chang,1 Joe B Harford2 1Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, 20057, USA; 2SynerGene Therapeutics, Inc., Potomac, MD, 20854, USACorrespondence: Esther H Chang, Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road N.W., Research Building E420, Washington, DC, 20057, USA, Tel +1 202 687 8418, Email change@georgetown.eduIntroduction: Organophosphates are among the deadliest of known chemicals based on their ability to inactivate acetylcholinesterase in neuromuscular junctions and synapses of the central and peripheral nervous systems. The consequent accumulation of acetylcholine can produce severe acute toxicities and death. Oxime antidotes act by reactivating acetylcholinesterase with the only such reactivator approved for use in the United States being 2-pyridine aldoxime methyl chloride (a.k.a., pralidoxime or 2-PAM). However, this compound does not cross the blood–brain barrier readily and so is limited in its ability to reactivate acetylcholinesterase in the brain.Methods: We have developed a novel formulation of 2-PAM by encapsulating it within a nanocomplex designed to cross the blood–brain barrier via transferrin receptor-mediated transcytosis. This nanocomplex (termed scL-2PAM) has been subjected to head-to-head comparisons with unencapsulated 2-PAM in mice exposed to paraoxon, an organophosphate with anticholinesterase activity.Results and Discussion: In mice exposed to a sublethal dose of paraoxon, scL-2PAM reduced the extent and duration of cholinergic symptoms more effectively than did unencapsulated 2-PAM. The scL-2PAM formulation was also more effective than unencapsulated 2-PAM in rescuing mice from death after exposure to otherwise-lethal levels of paraoxon. Improved survival rates in paraoxon-exposed mice were accompanied by a higher degree of reactivation of brain acetylcholinesterase.Conclusion: Our data indicate that scL-2PAM is superior to the currently used form of 2-PAM in terms of both mitigating paraoxon toxicity in mice and reactivating acetylcholinesterase in their brains.Keywords: lipid nanoparticle, nanodelivery, organophosphate, paraoxon, blood–brain barrier, transcytosis

Hasan M Bahrani,1 Khitam Fakhir Alhasseny2 1American Eye & Retina Center, Erbil, Iraq; 2Pediatric Ophthalmology Department, Ibn Al-Haytham Teaching Eye Hospital, Baghdad, IraqCorrespondence: Khitam Fakhir Alhasseny, Email dr.ketam@gmail.comBackground: Stage 4 and 5 retinopathy of prematurity (ROP) is a serious condition that may require surgical intervention at some point. Timely intervention is a key element and, with the peculiarity of eyes among this group that necessities a certain level of surgical standards, operations cannot be undertaken in any surgical eye center.Aim of the Study: To recognize the outcomes of vitrectomy in Iraqi preterm babies with stage 4 and 5 ROP, and to study factors that might increase the risk of re-detachment in operated eyes.Methods: A prospective cohort study undertaken from November 2020 to June 2023 for Iraqi preterm babies presenting with stage 4 and 5 ROP requiring surgical intervention. Each patient had a follow-up duration of 9 months. The primary follow-up outcome was anatomical success rate (flat versus detached), and the secondary outcome was to identify the postoperative complications.Results: This study enrolled 19 children; 11 males and eight females (number of eyes operated on was was 31), with a mean gestational age of 29.4± 2.1 weeks. There were six (19.4%) eyes that did not develop any complications, five (16.1%) eyes developed postoperative vitreous hemorrhage, five (16.1%) eyes developed cataract, three (9.7%) eyes underwent a second vitrectomy, and seven (22.6%) eyes developed secondary glaucoma. The surgical success rates were 90.9% for stage 4a, 57.1% for stage 4b, and 33.3% for stage 5a.Conclusion: This study presented the first surgical experience for vitrectomy in children with retinopathy of prematurity in our country, and the results were encouraging with an overall surgical success rate of 64.5%, and 19.4% of eyes did not develop any complication until the 1-year of follow-up.Keywords: retinopathy of prematurity, vitrectomy, scleral buckle, premature infants, lens sparing vitrectomy

Peter Alter,1 Cosmina Stoleriu,2 Kathrin Kahnert,3,4 Markus Oliver Henke,5 Robert Bals,6 Franziska C Trudzinski,7 Henrik Watz,8 Tim Speicher,1 Sandra Söhler,1 Tobias Welte,9 Klaus F Rabe,10,11 Emiel FM Wouters,12,13 Claus F Vogelmeier,1 Rudolf A Jörres14 1Department of Medicine, Pulmonary, Critical Care and Sleep Medicine, Philipps University of Marburg (UMR), Member of the German Center for Lung Research (DZL), Marburg, Germany; 2Asklepios Lungenklinik Gauting, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Gauting, Germany; 3Department of Medicine V, LMU University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, Germany; 4MediCenterGermering, Germering, Germany; 5Klinik für Innere Medizin und Pneumologie, Krankenhaus Martha-Maria, Munich, Germany; 6Department of Internal Medicine V, Pulmonology, Allergology, Intensive Care Medicine, Saarland University Hospital, Homburg, Germany; 7Department of Pneumology and Critical Care Medicine, Thoraxklinik, University of Heidelberg, Translational Lung Research Center Heidelberg (TLRC-H), Member of the Center for Lung Research (DZL), Heidelberg, Germany; 8Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany; 9Clinic for Pneumology, Hannover Medical School, Member of the German Center for Lung Research (DZL), Hannover, Germany; 10LungenClinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany; 11Department of Medicine, Christian-Albrechts-University, Kiel, Germany; 12Department of Respiratory Medicine, Maastricht University Medical Centre, Maastricht, Netherlands; 13Ludwig Boltzmann Institute for Lung Health, Vienna, Austria; 14Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, LMU University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, GermanyCorrespondence: Peter Alter, Department of Medicine, Pulmonary, Critical Care and Sleep Medicine, Philipps University of Marburg (UMR), Member of the German Center for Lung Research (DZL), Baldingerstrasse 1, Marburg, 35033, Germany, Tel +49 6421 5866140, Email Alter@uni-marburg.deBackground: Many patients with chronic obstructive pulmonary disease (COPD) continue smoking. We used data from the “real-life” COSYCONET COPD cohort to evaluate whether these patients differed from patients with COPD who either had ceased smoking prior to inclusion or ceased during the follow-up time of the study.Methods: The analysis was based on data from visits 1– 5 (covering 4.5 years), including all patients with the diagnosis of COPD who were either ex-smokers or smokers and categorized as GOLD 1– 4 or the former GOLD 0 category. We compared the characteristics of smokers and ex-smokers at baseline (visit 1), as well as the course of lung function in the follow-up of permanent ex-smokers, permanent smokers and incident ex-smokers (smokers at visit 1 who ceased smoking before visit 5). We also identified baseline factors associated with subsequent smoking cessation.Results: Among 2500 patients who were ever-smokers, 660 were current smokers and 1840 ex-smokers at baseline. Smokers were younger than ex-smokers (mean 61.5 vs 66.0 y), had a longer duration of smoking but fewer pack-years, a lower frequency of asthma, higher forced expiratory volume in 1 sec (FEV1, 59.4 vs 55.2% predicted) and higher functional residual capacity (FRC, 147.7 vs 144.3% predicted). Similar results were obtained for the longitudinal subpopulation, comprising 713 permanent ex-smokers, 175 permanent smokers, and 55 incident ex-smokers. When analyzing the time course of lung function, higher FRC, lower FEV1 and the presence of asthma (p < 0.05 each) were associated with incident cessation prior to visit 5, while less airway obstruction was associated with smoking continuation.Conclusion: These findings, which were consistent in the cross-sectional and longitudinal analyses, suggest that lung hyperinflation was associated with being or becoming ex-smoker. Possibly, it is perceived by patients as one of the factors motivating their attempts to quit smoking, independent from airway obstruction.Keywords: COPD, smoking, smoking cessation, airway obstruction, lung hyperinflation

Cell-free RNA from liquid biopsies can be analyzed to determine disease tissue of origin. We extend this concept to identify cell types of origin using the Tabula Sapiens transcriptomic cell atlas as well as individual tissue transcriptomic cell atlases in combination with the Human Protein Atlas RNA consensus dataset. We define cell type signature scores, which allow the inference of cell types that contribute to cell-free RNA for a variety of diseases.

Molecular characterization of cell types using single-cell transcriptome sequencing is revolutionizing cell biology and enabling new insights into the physiology of human organs. We created a human reference atlas comprising nearly 500,000 cells from 24 different tissues and organs, many from the same donor. This atlas enabled molecular characterization of more than 400 cell types, their distribution across tissues, and tissue-specific variation in gene expression. Using multiple tissues from a single donor enabled identification of the clonal distribution of T cells between tissues, identification of the tissue-specific mutation rate in B cells, and analysis of the cell cycle state and proliferative potential of shared cell types across tissues. Cell type-specific RNA splicing was discovered and analyzed across tissues within an individual.

Tubo-ovarian high-grade serous carcinomas (HGSC) are highly proliferative neoplasms that generally respond well to platinum/taxane chemotherapy. We recently identified minichromosome maintenance complex component 3 (MCM3), which is involved in the initiation of DNA replication and proliferation, as a favorable prognostic marker in HGSC. Our objective was to further validate whether MCM3 mRNA expression and possibly MCM3 protein levels are associated with survival in patients with HGSC. MCM3 mRNA expression was measured using NanoString expression profiling on formalin-fixed and paraffin-embedded tissue (N = 2355 HGSC) and MCM3 protein expression was assessed by immunohistochemistry (N = 522 HGSC) and compared with Ki-67. Kaplan-Meier curves and the Cox proportional hazards model were used to estimate associations with survival. Among chemotherapy-naïve HGSC, higher MCM3 mRNA expression (one standard deviation increase in the score) was associated with longer overall survival (HR = 0.87, 95% CI 0.81-0.92, p

Kuo-Feng Hua,1,2,&ast; Lan-Hui Li,3,&ast; Hsin-Chiao Yu,4 Wei-Ting Wong,1 Hsien-Ta Hsu4,5 1Department of Biotechnology and Animal Science, National Ilan University, Yilan, 26047, Taiwan; 2Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, 404333, Taiwan; 3Department of Laboratory Medicine, Linsen, Chinese Medicine and Kunming Branch, Taipei City Hospital, Taipei, 108, Taiwan; 4Division of Neurosurgery, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, 231, Taiwan; 5School of Medicine, Buddhist Tzu Chi University, Hualien, 970, Taiwan&ast;These authors contributed equally to this workCorrespondence: Hsien-Ta Hsu, Division of Neurosurgery, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, No. 289, Jianguo Road, Xindian Dist, New Taipei City, 231016, Taiwan, Tel +866-2-6628-9779, Email j1208192@ms45.hinet.netPurpose: Intervertebral disc (IVD) degeneration, associated with aging, may cause low back pain and disability, with obesity as a significant risk factor. In a prior study, we found a positive correlation between IVD degeneration and levels of matrix metalloproteinase-1 (MMP-1) and leptin. Yet, the interaction between MMP-1 and leptin in IVD degeneration is unclear. Our research seeks to explore leptin’s influence on MMP-1 expression and the underlying mechanisms in human intervertebral disc cartilage endplate-derived stem cells, specifically SV40 cells.Methods: The mRNA and protein expression in leptin-stimulated SV40 cells were assessed using RT-real-time PCR and Western blotting or ELISA, respectively. We examined leptin-mediated RhoA activation through a GTP-bound RhoA pull-down assay. Furthermore, the phosphorylation levels of mitogen-activated protein kinases and AKT in leptin-stimulated SV40 cells were analyzed using Western blotting. The activation of NF-κB by leptin was investigated by assessing phosphorylation of IKKα/β, IκBα, and NF-κB p65, along with the nuclear translocation of NF-κB p65. To understand the underlying mechanism behind leptin-mediated MMP-1 expression, we employed specific inhibitors.Results: Leptin triggered the mRNA and protein expression of MMP-1 in SV40 cells. In-depth mechanistic investigations uncovered that leptin heightened RhoA activity, promoted ERK1/2 phosphorylation, and increased NF-κB activity. However, leptin did not induce phosphorylation of JNK1/2, p38, or AKT. When we inhibited RhoA, ERK1/2, and NF-κB, it resulted in a decrease in MMP-1 expression. Conversely, inhibition of reactive oxygen species and NADPH oxidase did not yield the same outcome. Additionally, inhibiting RhoA or ERK1/2 led to a reduction in leptin-induced NF-κB activation. Moreover, inhibiting RhoA also decreased leptin-mediated ERK1/2 phosphorylation.Conclusion: These results indicated that leptin induced MMP-1 expression in SV40 cells through the RhoA/ERK1/2/NF-κB axis. This study provided the pathogenic role of leptin and suggested the potential therapeutic target for IVD degeneration. Keywords: intervertebral disc degeneration, leptin, matrix metalloproteinase, intervertebral disc cartilage endplate-derived stem cells, RhoA, ERK1/2

The Mediterranean Sea provides habitat for globally threatened cetaceans. The Hellenic Trench is an Important Marine Mammal Area, providing core habitat for sperm whales Physeter macrocephalus and Cuvier’s beaked whales Ziphius cavirostris. Surveys have characterized distributions of these species in near-shore areas (

Haymanot Nigatu Alemu,1 Solomon Berhe Wubneh,2 Abezash Hayiso Yute,3 Kalkidan Firdawek Tekletsadik,3 Bekeltu Mesfin Ofgea,3 Belayneh Ayanaw Kassie4 1Department of Clinical Midwifery, School of Midwifery, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia; 2Department of Obstetrics and Gynecology, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia; 3Department of General Midwifery, School of Midwifery, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia; 4Department of Women’s and Family Health, School of Midwifery, College of Medicine and Health Sciences, University of Gondar, Gondar, EthiopiaCorrespondence: Haymanot Nigatu Alemu, Tel +251920256611, Email haymnigat@gmail.comBackground: Birth registration is the official and permanent recording of a child’s birth within a civil registry, according to the legal requirements of a country. Although the Sustainable Development Goal targets providing legal identity for all by 2030, birth registration levels remain critically low. Therefore, this study aimed to assess postpartum women’s knowledge of and attitudes towards birth registration and its associated factors in Northwest Ethiopia.Methods: An institution-based cross-sectional study was conducted from September 1– 30/2022 among 422 participants who were selected using systematic random sampling. A pretested and structured interviewer-administered questionnaire was used to collect the data. Data were entered into EPI Info 7 and analyzed using SPSS version 25. A multivariable logistic regression model was fitted to identify the factors associated with knowledge and attitudes towards birth registration. Variables with a p-value of < 0.05 were considered to be significantly associated with the dependent variable.Results: Among the participants, 41.7% had good knowledge of birth registration. Less than one-quarter (22.6%) had a favorable attitude towards birth registration. Having a college and above educational level (AOR = 4.01, 95% CI: 2.3– 8.4), being urban resident (AOR = 3.4, 95% CI: 3.1– 7.4) and full exposure to media (AOR = 3.02, 95% CI: 1.5– 5.7) were associated with knowledge of birth registration. Having primary educational status (AOR = 2.04, 95% CI: 2.96– 8.31), being fully exposed to different media (AOR = 2.32, 95% CI: 1.22– 11.36) and having four or more antenatal care visits (AOR = 5.10, 95% CI: 1.18– 14.35) were associated with favorable attitudes towards birth registration.Conclusion: Postpartum women had poor knowledge of and attitudes towards birth registration. Increasing educated women at all levels, awareness rising through different media and integration of birth registration with antenatal care is crucial for realizing the registration of all births by 2030.Keywords: birth notification, birth registration, civil registration, vital statistics, postpartum women

Lan-Hui Li,1 Hsiao-Wen Chiu,2 Wei-Ting Wong,2 Ko-Chieh Huang,3 Tzu-Wen Lin,3 Shui-Tein Chen,3 Kuo-Feng Hua2,4 1Department of Laboratory Medicine, Linsen, Chinese Medicine and Kunming Branch, Taipei City Hospital, Taipei, Taiwan; 2Department of Biotechnology and Animal Science, National Ilan University, Yilan, Taiwan; 3ALPS Biotech Co. Ltd, Taipei, Taiwan; 4Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, TaiwanCorrespondence: Kuo-Feng Hua, Department of Biotechnology and Animal Science, National Ilan University, No. 1, Sec. 1, Shennong Road, Yilan, 260, Taiwan, Tel +886 3 931 7626, Fax +886 3 935 4794, Email kuofenghua@gmail.comPurpose: Coronavirus disease 2019 (COVID-19) poses a global health challenge with widespread transmission. Growing concerns about vaccine side effects, diminishing efficacy, and religious-based hesitancy highlight the need for alternative pharmacological approaches. Our study investigates the impact of the ethanol extract of Antrodia cinnamomea (AC), a native medicinal fungus from Taiwan, on COVID-19 in both in vitro and in vivo contexts.Methods: We measured the mRNA and protein levels of angiotensin-converting enzyme-2 (ACE2) in human lung cells using real-time reverse transcriptase-polymerase chain reaction and Western blotting, respectively. Additionally, we determined the enzymatic activity of ACE2 using the fluorogenic peptide substrate Mca-YVADAPK(Dnp)-OH. To assess the impact of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, we used SARS-CoV-2 pseudovirus infections in human embryonic kidney 293T cells expressing ACE2 to measure infection rates. Furthermore, we evaluated the in vivo efficacy of AC in mitigating COVID-19 by conducting experiments on hamsters infected with the Delta variant of SARS-CoV-2.Results: AC effectively decreased ACE2 mRNA and protein levels, a critical host receptor for the SARS-CoV-2 spike protein, in human lung cells. It also prevented the spike protein from binding to human lung cells. Dehydrosulphurenic acid, an isolate from AC, directly inhibited ACE2 protease activity with an inhibitory constant of 1.53 μM. In vitro experiments showed that both AC and dehydrosulphurenic acid significantly reduced the infection rate of SARS-CoV-2 pseudovirus. In hamsters infected with the Delta variant of SARS-CoV-2, oral administration of AC reduced body weight loss and improved lung injury. Notably, AC also inhibited IL-1β expression in both macrophages and the lung tissues of SARS-CoV-2-infected hamsters.Conclusion: AC shows potential as a nutraceutical for reducing the risk of SARS-CoV-2 infection by disrupting the interaction between ACE2 and the SARS-CoV-2 spike protein, and for preventing COVID-19-associated lung inflammation.Graphical Abstract: Keywords: coronavirus disease 2019, angiotensin-converting enzyme-2, severe acute respiratory syndrome coronavirus 2, Antrodia cinnamomea, the intracellular sensor NACHT, LRR, PYD domain-containing protein 3 inflammasome, cytokine

Yi-Jan Wu,1,2 Shu-Sen Chang,3 Hsien-Yi Chen,4 Kai-Fan Tsai,2,5 Wen-Chin Lee,2,5 I-Kuan Wang,6,7 Chern-Horng Lee,8 Chao-Yu Chen,1,2 Shou-Hsuan Liu,1,2 Cheng-Hao Weng,1,2 Wen-Hung Huang,1,2 Ching-Wei Hsu,1,2 Tzung-Hai Yen1,2 1Department of Nephrology, Clinical Poison Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan City, Taiwan; 2College of Medicine, Chang Gung University, Taoyuan City, Taiwan; 3Institute of Health Behaviors and Community Sciences, Department of Public Health, College of Public Health, National Taiwan University, Taipei City, Taiwan; 4Department of Emergency Medicine, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan City, Taiwan; 5Division of Nephrology, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung Branch, Kaohsiung City, Taiwan; 6Department of Nephrology, China Medical University Hospital, Taichung City, Taiwan; 7College of Medicine, China Medical University, Taichung City, Taiwan; 8Division of General Internal Medicine and Geriatrics, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan City, TaiwanCorrespondence: Tzung-Hai Yen, Department of Nephrology, Clinical Poison Center, Chang Gung Memorial Hospital, Linkou Branch, 5 Fu-Hsing Street, Kweishan, Taoyuan City, Taiwan, Tel +886 3 3281200 ext 8181, Fax +886 3 3282173, Email m19570@cgmh.org.twBackground and Purpose: There is an overall paucity of data regarding the human toxicity of chlorpyrifos and cypermethrin pesticide mixture. Both organophosphate and pyrethroid insecticides are metabolized by carboxylesterases. Thus, its pesticide combination, organophosphates may boost the toxicity of pyrethroids via inhibited its detoxification by carboxylesterases. This study examined the clinical course, laboratory tests, and outcomes of patients with chlorpyrifos, cypermethrin or their pesticide mixture poisoning, and to determine what association, if any, might exist between these findings.Patients and Methods: Between 2000 and 2021, 121 patients poisoned with chlorpyrifos, cypermethrin, or their pesticide mixture were treated at Chang Gung Memorial Hospital. Patients were categorized as chlorpyrifos (n=82), cypermethrin (n=27) or chlorpyrifos and cypermethrin (n=12) groups. Demographic, clinical, laboratory and mortality data were collected for analysis.Results: The patients experienced a broad range of clinical symptoms, including aspiration pneumonia (44.6%), salivation (42.5%), acute respiratory failure (41.3%), acute kidney injury (13.9%), seizures (7.5%), hypotension (2.6%), etc. Leukocytosis (12,700± 6600 /uL) and elevated serum C-reactive protein level (36.8± 50.4 mg/L) were common. The acute respiratory failure rate was 41.3%, comprising 48.8% in chlorpyrifos, 11.1% in cypermethrin as well as 58.3% in chlorpyrifos and cypermethrin poisoning. Patients with chlorpyrifos and cypermethrin pesticide mixture poisoning suffered higher rates of acute respiratory failure (P=0.001) and salivation (P=0.001), but lower Glasgow Coma Scale score (P=0.011) and serum cholinesterase level (P< 0.001) than other groups. A total of 17 (14.0%) patients expired. The mortality rate was 14.0%, including 17.1% in chlorpyrifos, 3.7% in cypermethrin as well as 16.7% in chlorpyrifos and cypermethrin poisoning. No significant differences in mortality rate were noted (P=0.214).Conclusion: Chlorpyrifos pesticide accounted for the major toxicity of the pesticide mixture. While the data show a higher rate of respiratory failure in the chlorpyrifos and cypermethrin pesticide mixture group than others, other measures of toxicity such as mortality and length of stay were not increased.Keywords: chlorpyrifos, cypermethrin, pesticide mixture, poisoning, acute respiratory failure, mortality

Sexually dimorphic tissues are formed by cells that are regulated by sex hormones. While a number of systemic hormones and transcription factors are known to regulate proliferation and differentiation of osteoblasts and osteoclasts, the mechanisms that determine sexually dimorphic differences in bone regeneration are unclear. To explore how sex hormones regulate bone regeneration, we compared bone fracture repair between adult male and female mice. We found that skeletal stem cell (SSC) mediated regeneration in female mice is dependent on estrogen signaling but SSCs from male mice do not exhibit similar estrogen responsiveness. Mechanistically, we found that estrogen acts directly on the SSC lineage in mice and humans by up-regulating multiple skeletogenic pathways and is necessary for the stem cell's ability to self- renew and differentiate. Our results also suggest a clinically applicable strategy to accelerate bone healing using localized estrogen hormone therapy.

Fracture healing is highly dependent on an early inflammatory response in which prostaglandin production by cyclo-oxygenases (COX) plays a crucial role. Current patient analgesia regimens favor opioids over Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) since the latter have been implicated in delayed fracture healing. While animal studies broadly support a deleterious role of NSAID treatment to bone-regenerative processes, data for human fracture healing remains contradictory. In this study, we prospectively isolated mouse and human skeletal stem cells (SSCs) from fractures and compared the effect of various NSAIDs on their function. We found that osteochondrogenic differentiation of COX2-expressing mouse SSCs was impaired by NSAID treatment. In contrast, human SSCs (hSSC) downregulated COX2 expression during differentiation and showed impaired osteogenic capacity if COX2 was lentivirally overexpressed. Accordingly, short- and long-term treatment of hSSCs with non-selective and selective COX2 inhibitors did not affect colony forming ability, chondrogenic, and osteogenic differentiation potential in vitro. When hSSCs were transplanted ectopically into NSG mice treated with Indomethacin, graft mineralization was unaltered compared to vehicle injected mice. Thus, our results might contribute to understanding species-specific differences in NSAID sensitivity during fracture healing and support emerging clinical data which conflicts with other earlier observations that NSAID administration for post-operative analgesia for treatment of bone fractures are unsafe for patients.

The skeletal system is generated and maintained by its progenitors, skeletal stem cells (SSCs), across the duration of life. Gradual changes associated with aging result in significant differences in functionality of SSCs. Declines in bone and cartilage production, increase of bone marrow adipose tissue, compositional changes of cellular microenvironments, and subsequent deterioration of external and internal structures culminate in the aged and weakened skeleton. The features and mechanisms of skeletal aging, and of its stem and progenitor cells in particular, are topics of recent investigation. The discovery of functionally homogeneous SSC populations with a defined cell surface phenotype has allowed for closer inspection of aging in terms of its effects on transcriptional regulation, cell function, and identity. Here, we review the aspects of SSC aging on both micro- and macroscopic levels. Up-to-date knowledge of SSC biology and aging is presented, and directions for future research and potential therapies are discussed. The realm of SSC-mediated bone aging remains an important component of global health and a necessary facet in our understanding of human aging.

Pulmonary arterial hypertension is an incurable disease marked by dysregulated metabolism, both at the cellular level in the pulmonary vasculature, and at the whole-body level characterized by impaired exercise oxygen consumption. Though both altered pulmonary vascular metabolism and abnormal exercise physiology are key markers of disease severity and pulmonary arterial remodeling, their precise interactions are relatively unknown. Herein we review normal pulmonary vascular physiology and the current understanding of pulmonary vascular cell metabolism and cardiopulmonary response to exercise in Pulmonary arterial hypertension. We additionally introduce a newly developed international collaborative effort aimed at quantifying exercise-induced changes in pulmonary vascular metabolism, which will inform about underlying pathophysiology and clinical management. We support our investigative approach by presenting preliminary data and discuss potential future applications of our research platform.

Loss of skeletal integrity during ageing and disease is associated with an imbalance in the opposing actions of osteoblasts and osteoclasts1. Here we show that intrinsic ageing of skeletal stem cells (SSCs)2 in mice alters signalling in the bone marrow niche and skews the differentiation of bone and blood lineages, leading to fragile bones that regenerate poorly. Functionally, aged SSCs have a decreased bone- and cartilage-forming potential but produce more stromal lineages that express high levels of pro-inflammatory and pro-resorptive cytokines. Single-cell RNA-sequencing studies link the functional loss to a diminished transcriptomic diversity of SSCs in aged mice, which thereby contributes to the transformation of the bone marrow niche. Exposure to a youthful circulation through heterochronic parabiosis or systemic reconstitution with young haematopoietic stem cells did not reverse the diminished osteochondrogenic activity of aged SSCs, or improve bone mass or skeletal healing parameters in aged mice. Conversely, the aged SSC lineage promoted osteoclastic activity and myeloid skewing by haematopoietic stem and progenitor cells, suggesting that the ageing of SSCs is a driver of haematopoietic ageing. Deficient bone regeneration in aged mice could only be returned to youthful levels by applying a combinatorial treatment of BMP2 and a CSF1 antagonist locally to fractures, which reactivated aged SSCs and simultaneously ablated the inflammatory, pro-osteoclastic milieu. Our findings provide mechanistic insights into the complex, multifactorial mechanisms that underlie skeletal ageing and offer prospects for rejuvenating the aged skeletal system.

Background: Ocular prosthesis (OP) is produced and fitted by eye care personnel called Ocularist. OP is made from cryolite glass or acrylic resin. OP can either be customized or stock and it is commonly inserted by 6-8 weeks following destructive ocular surgery. Aim: The aim of this study was to ascertain the knowledge and awareness of ocular prosthesis among students of School of Optical Dispensary Technology, Birnin Kebbi, Nigeria. Materials and methods: This was a cross-sectional study conducted over 3 months (1st April 2022-30th June 2022) among the students of School of Optical dispensary technology using self-administered questionnaires. The questionnaires extracted information on the socio-demographic characteristics such as age, sex, tribe, religion, marital status, year of study and knowledge of ocular prosthesis among the students. Data was analyzed using SPPS version 21. Results: One hundred and thirteen questionnaires were distributed to all the students in the school and 97 students participated in the study leading to a response rate of 86 %. There were 47(48.5%) males and 50 (51.5%) females aged between 16 - 40 (mean age 24±5) years. Most of the participants 72 (74.2%) agreed that eye care (management of patient with eye problem) is a team work. Most (67, 69%) participants have heard about ocular prosthesis mainly through Seminar/Teaching (32%) and television (26%). Overall, third year students had adequate knowledge (73%) of ocular prosthesis compared with second year (49%) and first year (43%) students. Conclusion: The awareness of ocular prosthesis among students of School of Optical dispensary technology Birnin Kebbi appeared better with number of years spent in the school. The importance of seminar/teaching and television in the dissemination of health information is underscored.

ObjectiveTo evaluate the outcomes of excision and primary anastomosis (EPA) for radiation-associated bulbomembranous stenoses using a multi-institutional analysis. The treatment of radiation-associated urethral stenosis is typically complex owing to the adverse impact of radiation on adjacent tissue.MethodsAn IRB-approved multi-institutional retrospective review was performed on patients who underwent EPA for bulbomembranous urethral stenosis following prostate radiotherapy. Preoperative patient demographics, operative technique, and postoperative outcomes were abstracted from 1/2007-6/2018. Success was defined as voiding per urethra without the need for endoscopic treatment and a minimum follow-up of 12 months.ResultsOne hundred and thirty-seven patients from 10 centers met study criteria with a mean age of 69.3 years (50-86), stenosis length of 2.3 cm (1-5) and an 86.9% (119/137) success rate at a mean follow-up 32.3 months (12-118). Univariate Cox regression analysis identified increasing patient age (P = .02), stricture length (P

The 2017–2027 National Academies' Decadal Survey, Thriving on Our Changing Planet, recommended Surface Biology and Geology (SBG) as a “Designated Targeted Observable” (DO). The SBG DO is based on the need for capabilities to acquire global, high spatial resolution, visible to shortwave infrared (VSWIR; 380–2500 nm; ~30 m pixel resolution) hyperspectral (imaging spectroscopy) and multispectral midwave and thermal infrared (MWIR: 3–5 μm; TIR: 8–12 μm; ~60 m pixel resolution) measurements with sub-monthly temporal revisits over terrestrial, freshwater, and coastal marine habitats. To address the various mission design needs, an SBG Algorithms Working Group of multidisciplinary researchers has been formed to review and evaluate the algorithms applicable to the SBG DO across a wide range of Earth science disciplines, including terrestrial and aquatic ecology, atmospheric science, geology, and hydrology. Here, we summarize current state-of-the-practice VSWIR and TIR algorithms that use airborne or orbital spectral imaging observations to address the SBG DO priorities identified by the Decadal Survey: (i) terrestrial vegetation physiology, functional traits, and health; (ii) inland and coastal aquatic ecosystems physiology, functional traits, and health; (iii) snow and ice accumulation, melting, and albedo; (iv) active surface composition (eruptions, landslides, evolving landscapes, hazard risks); (v) effects of changing land use on surface energy, water, momentum, and carbon fluxes; and (vi) managing agriculture, natural habitats, water use/quality, and urban development. We review existing algorithms in the following categories: snow/ice, aquatic environments, geology, and terrestrial vegetation, and summarize the community-state-of-practice in each category. This effort synthesizes the findings of more than 130 scientists.

Kai-Fang Hua,1,2 Bo-Yang Jing,3 Yan-Hui Wu1,4 1Department of Endocrinology, Xiang’an Hospital of Xiamen University, Xiamen, Fujian, People’s Republic of China; 2School of Medicine, Xiamen University, Xiamen, Fujian, People’s Republic of China; 3Hai Yuan College, Kunming Medical University, Kunming, Yunnan, People’s Republic of China; 4National Metabolic Management Center, Xiang’an Hospital of Xiamen University, Xiamen, Fujian, People’s Republic of ChinaCorrespondence: Yan-Hui Wu, Department of Endocrinology, Xiang’an Hospital of Xiamen University, 2000 Xiang’ an East Road, Xiamen, Fujian, 361102, People’s Republic of China, Tel +8613089998806, Email mabelwyh@163.comPurpose: This study aimed to further quantify the relationship between insulin antibodies (IAs) and the 2-hour insulin to C-peptide molar ratio (2h-ICPR) using a multiple linear regression model in T2DM patients.Methods: A total of 274 T2DM patients from April 2019 to December 2022 in Xiang’an Hospital of Xiamen University were included in this study. Multiple Linear Model Fitting was conducted on the candidate independent variables (age, BMI, HbA1c, and 2h-ICPR) for the multiple linear regression. The linear relationship between insulin antibodies (IAs) and the significant independent variables was presented by making multiple linear regression equations.Results: The total demographic characteristics of the included patients were as follows: age (51.92± 13.10 years), BMI (24.94± 3.99 kg/m2), HbA1c (9.70± 2.39%), 2h-ICPR (0.12± 0.11), and IAs (0.37± 1.12COI). Linear relationships of independent variables: age (r=0.163, p=0.007), 2h-ICPR (r=0.259, p=0.001), BMI (r=0.007, p=0.907) and 2h-ICPR (r=0.092, p=0.129). Multiple linear regression: age (unstandardized β=0.014, 95% CI: 0.004– 0.024, p=0.004), 2h-ICPR (unstandardized β=2.758, 95% CI: 1.555– 3.962, p≤ 0.001). The regression equation: .Conclusion: The quantitative relationship between 2h-ICPR and insulin antibodies was . 2h-ICPR can be a preliminary screening indicator for insulin antibody testing in patients with type 2 diabetes.Keywords: insulin, insulin antibodies, C-peptide, multiple linear regression model

Liangjie Lu,1 Haiming Fang,1 Mengchao Gu,1 Huihan Wang,2 Qiuxia Yu,3 Aqiong Chen,3 Kai-feng Gan1 1Department of Orthopaedics, Li Huili Hospital Affiliated to Ningbo University, Ningbo, 315040, People’s Republic of China; 2Department of Orthopaedics, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, 450007, People’s Republic of China; 3Department of Rheumatology, Li Huili Hospital Affiliated to Ningbo University, Ningbo, 315040, People’s Republic of ChinaCorrespondence: Kai-feng Gan, Tel +86-15724288924, Email gankaifeng1982@163.comPurpose: This study aimed to compare the changes in the expression of microRNA Let-7i in peripheral blood mononuclear cells (PBMCs) of patients with ankylosing spondylitis (AS) and the correlation between Let-7i and innate pro-inflammatory factors. It is necessary to search for a new biomarker to guide the prognosis of AS.Methods: A total of 10 patients with AS and 10 healthy volunteers were selected as AS and control groups, respectively. The expression levels of Let-7i, Toll-like receptor 4 (TLR4), nuclear factor-κB (NF-κB), and interferon-gamma (IFN-γ) in PBMCs were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting (WB) to explore the relationship between Let-7i and pro-inflammatory factors. Furthermore, the relationship between Let-7i and TLR4 was determined by the luciferase reporter technology.Results: The expression level of Let-7i in PBMCs of patients with AS was significantly lower than that of healthy control. The expression levels of TLR4, NF-κB, and IFN-γ in PBMCs derived from patients with AS were significantly higher than those of healthy control. The results show that Let-7i manipulation can regulate lipopolysaccharide (LPS)-induced TLR4 and IFN-γ expression in CD4+ T cells of patients with AS. The overexpression of Let-7i in T cells of patients with AS can suppress TLR4 and IFN-γ LPS-induced expression levels of cellular mRNA and protein. Let-7i can directly interfere TLR4-3’untranslated region (UTR) sequence and regulate the expression of the TLR4 gene in Jurkat T cells.Conclusion: Let-7i may be involved in the pathogenesis of AS, and Let-7i expression in PBMCs may be helpful for the diagnosis and treatment of AS in the future.Keywords: ankylosing spondylitis, Let-7i, TLR4, innate inflammatory

Background and Objective: Head injury is caused by server physical force to the head, and it can be open or closed. In a closed trauma, the skull is not broken, but the impact may damage the brain, skull, scalp and underlying tissue and blood vessels of the head. Therefore, the aim of this study is to find the relationship between head injury and several parameters including the serum level of interleukin-6, interleukin-8 and copper (Cu) in these patients. Methods: This study was conducted at the Neurosurgical Teaching Hospital in Baghdad/Iraq and comprised 60 patients with head injuries in the age range of 20-80 years, who were matched to 30 healthy controls. Five mL blood samples were taken around 8 hours after the injury. Serum IL-6 and IL-8 were measured by the Enzyme Linked Immunosorbent Assay (ELISA), whereas Cu was measured by the Atomic Absorption Spectrophotometer (AAS). The results were compared withween the two groups. Findings: The results revealed that there were no significant differences in age (p=0.169), gender (p=0.434) and BMI (p=0.102) between head injury patients and healthy subjects. The results revealed a significant increase in serum IL-6 (177.45±55.12 & 83.43±22.98) and IL-8 (181.19±61.77 & 49.99±15.32) levels in patients as compared to healthy subjects (p

Background: Patients with mitral stenosis (MS) may be predisposed to acute cerebrovascular events (ACE) and peripheral thromboembolic events (TEE). Concomitant atrial fibrillation (AF), mitral annular calcification (MAC) and rheumatic heart disease (RHD) are independent risk factors. Our aim was to evaluate the incidence of ACEs in MS patients and the implications of AF, MAC and RHD on thromboembolic risks. Methods: This systematic review was registered on PROSPERO (CRD42021291316). Six databases were searched from inception to 19th December 2021. The clinical outcomes were composite ACE, ischaemic stroke/transient ischaemic attack (TIA) and peripheral TEE. Results: We included 16 and 9 papers, respectively, in our qualitative and quantitative analyses. The MS cohort with AF had the highest incidence of composite ACE (31.55%; 95% CI 3.60–85.03; I2 = 99%), followed by the MAC (14.85%; 95% CI 7.21–28.11; I2 = 98%), overall MS (8.30%; 95% CI 3.45–18.63; I2 = 96%) and rheumatic MS population (4.92%; 95% CI 3.53–6.83; I2 = 38%). Stroke/TIA were reported in 29.62% of the concomitant AF subgroup (95% CI 2.91–85.51; I2 = 99%) and in 7.11% of the overall MS patients (95% CI 1.91–23.16; I2 = 97%). However, the heterogeneity of the pooled incidence of clinical outcomes in all groups, except the rheumatic MS group, was substantial and significant. The logit-transformed proportion of composite ACE increased by 0.0141 (95% CI 0.0111–0.0171; p

Yu-Ling Chen,1– 3,&ast; Yu-Dan Liang,4,&ast; Kai-Feng Guo,2 Zhen Huang,2 Wen-Qi Feng3 1Rehabilitation Department of the Panyu Central Hospital, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 2Rehabilitation Department of the Panyu Central Hospital, Guangzhou, People’s Republic of China; 3Department of Acupuncture and Moxibustion of the YiBin Hospital of Traditional Chinese Medicine, YiBin, People’s Republic of China; 4Department of Acupuncture and Rehabilitation, the Affiliated Jiangmen Traditional Chinese Medicine Hospital of Jinan University, Jiangmen, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhen Huang, Rehabilitation Department of the Panyu Central Hospital, No. 8 Fuyu Road, Qiaonan District, Guangzhou, 511400, People’s Republic of China, Tel +86 18922238059, Email Mishz@126.com Wen-Qi Feng, Department of Acupuncture and Moxibustion of the YiBin Hospital of Traditional Chinese Medicine, No. 2 Dawan Road, Nanan District, YiBin, 644000, People’s Republic of China, Tel +86 13629031868, Email Moonly1981@163.comPurpose: Acupuncture is widely used to relieve shoulder pain. A survey was conducted in order to recognize hotspots and frontiers of acupuncture for shoulder pain from the year 2000– 2022.Methods: The Web of Science Core Collection was used to collect literature related to acupuncture therapy for shoulder pain, which spanned January 2000 to August 2022. The number of publications yearly, countries/institutions, journals, and keywords was analyzed and visualized in shoulder pain with acupuncture therapy by CiteSpace v.5.7.R5.Results: We totally analyzed 214 articles that met the inclusion criteria. The overall trend of publication volume continues to increase. The most productive authors in the field were César Fernández las Peñas and José L Arias-Buría, and the most influential author was Green S. Kyung Hee University and the People’s Republic of China had the highest volume of publications, respectively. The most influential journal is Pain with high citation and impact factor. The hot keywords were “acupuncture”, “shoulder pain”, “dry needling”, “randomized trial”, and “injection”. The research frontier in acupuncture for treating chronic shoulder pain was mainly “mechanism”.Conclusion: Over the last 22 years, the findings of this bibliometric analysis have provided research trends and frontiers in clinical research on acupuncture therapy for patients with shoulder pain, which identifying hot topics and exploring new directions for the future may be helpful to researchers. Studying mechanisms underlying acupuncture therapy for shoulder pain remains a focus of future research.Keywords: acupuncture, shoulder pain, bibliometric analysis, CiteSpace