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Weakly interacting massive particles (WIMPs) may interact with a virtual pion that is exchanged between nucleons. This interaction channel is important to consider in models where the spin-independent isoscalar channel is suppressed. Using data from the first science run of the LUX-ZEPLIN dark matter experiment, containing 60 live days of data in a 5.5 tonne fiducial mass of liquid xenon, we report the results on a search for WIMP-pion interactions. We observe no significant excess and set an upper limit of 1.5 × 10−46 cm2 at a 90% confidence level for a WIMP mass of 33 GeV/c2 for this interaction.

Patients with chronic inflammatory disorders such as psoriasis have an increased risk of cardiovascular disease and elevated levels of LL37, a cathelicidin host defense peptide that has both antimicrobial and proinflammatory properties. To explore whether LL37 could contribute to the risk of heart disease, we examined its effects on lipoprotein metabolism and show that LL37 enhanced LDL uptake in macrophages through the LDL receptor (LDLR), scavenger receptor class B member 1 (SR-B1), and CD36. This interaction led to increased cytosolic cholesterol in macrophages and changes in expression of lipid metabolism genes consistent with increased cholesterol uptake. Structure-function analysis and synchrotron small-angle x-ray scattering showed structural determinants of the LL37-LDL complex that underlie its ability to bind its receptors and promote uptake. This function of LDL uptake is unique to cathelicidins from humans and some primates and was not observed with cathelicidins from mice or rabbits. Notably, Apoe-/- mice expressing LL37 developed larger atheroma plaques than did control mice, and a positive correlation between plasma LL37 and oxidized phospholipid on apolipoprotein B (OxPL-apoB) levels was observed in individuals with cardiovascular disease. These findings provide evidence that LDL uptake can be increased via interaction with LL37 and may explain the increased risk of cardiovascular disease associated with chronic inflammatory disorders.

BackgroundThe purpose of this study was to investigate the relationship between preoperative aspartate aminotransferase-to-platelet ratio index (APRI) and postoperative complications following total hip arthroplasty (THA).MethodsAll THA for osteoarthritis patients from 2007 to 2020 within the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) database were included in this study. Subjects were subsequently divided into cohorts based on APRI. Four groups, including normal range, some liver damage, significant fibrosis, and cirrhosis groups, were created. Comparisons between groups were made for demographics, past medical history, and rate of major and minor complications. Other outcomes included readmission, reoperation, discharge destination, mortality, periprosthetic fracture, and postoperative hip dislocation. Multivariate logistic regression analysis was performed to determine the role of preoperative APRI in predicting adverse outcomes. Statistical significance was set at p

Yi-Wen Chen,1,2 Ai-Chia He,3 Tzu-Yun Huang,1,3 De-Hao Lai,3 Yi-Ping Wang,1 Wei-Wen Liu,1,3 Wei-Ting Kuo,1,3 Hsin-Han Hou,1,3 Shih-Jung Cheng,1,3 Chen-Yi Lee,1 Wei-Chun Chuang,1 Che-Chen Chang,4 Bor-Shiunn Lee1,3 1Department of Dentistry, National Taiwan University Hospital, Taipei, 100229, Taiwan; 2Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei, 100229, Taiwan; 3Graduate Institute of Oral Biology, School of Dentistry, National Taiwan University, Taipei, 100229, Taiwan; 4Department of Chemistry, National Taiwan University, Taipei, 10617, TaiwanCorrespondence: Bor-Shiunn Lee, Graduate Institute of Oral Biology, School of Dentistry, National Taiwan University, No. 1, Changde Street, Taipei, 100229, Taiwan, Tel +886-2-23123456 ext 66846, Fax +886-2-2383-1346, Email leebs@ntu.edu.twIntroduction: Cisplatin is one of the most effective chemotherapeutic drugs used in oral cancer treatment, but systemic administration has side effects. The purpose of this study was to evaluate the effect of iontophoresis on the enhancement of cisplatin release from cisplatin-encapsulated chitosan nanoparticles.Methods: The effect of different mass ratios of chitosan to tripolyphosphate (TPP) (5:1, 10:1, 15:1, 20:1) on the encapsulation efficiency of cisplatin was investigated. Uptake of cisplatin-encapsulated chitosan by cells was observed using a confocal laser scanning microscope. The cell viability at different cisplatin concentrations was examined using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Three iontophoresis methods, namely constant-current chronopotentiometry (CCCP), cyclic chronopotentiometry (CCP), and differential pulse voltammetry (DPV), were used to enhance cisplatin release from cisplatin-encapsulated chitosan nanoparticles. In addition, mouse oral squamous cell carcinoma cell lines were implanted into the mouse oral mucosa to induce oral cancer. The effects of enhanced cisplatin release by CCCP, CCP, and DPV on tumor suppression in mice were evaluated. Tumors and lymph nodes were isolated for hematoxylin-eosin staining and immunohistochemistry staining including Ki-67 and pan CK after sacrifice. Inductively coupled plasma mass spectrometry was conducted to quantify the platinum content within the tumors.Results: The results showed that nanoparticles with a mass ratio of 15:1 exhibited the highest cisplatin encapsulation efficiency (approximately 15.6%) and longest continued release (up to 35 days) in phosphate buffered saline with a release rate of 100%. Cellular uptake results suggested that chitosan nanoparticles were delivered to the cytoplasm via endocytosis. The results of the MTT assay revealed that the survival rate of cells decreased as the cisplatin concentration increased. The CCP (1 mA, on:off = 1 s: 1 s) and DPV (0– 0.06 V) groups were the most effective in inhibiting tumor growth, and both groups exhibited the lowest percentage of Ki-67 positive and pan CK positive.Conclusion: This study is the first to investigate and determine the efficacy of DPV in enhancing in vivo drug release from nanoparticles for the treatment of cancer in animals. The results suggest that the CCP and DPV methods have the potential to be combined with surgery for oral cancer treatment. Keywords: oral cancer, cisplatin, chitosan, nanoparticle, iontophoresis

Dennis K Ledford,1 Warner W Carr,2 Wendy C Moore,3 Njira L Lugogo,4 Arjun Mohan,4 Bradley Chipps,5 Alexander R Mackie,6 Andrew W Lindsley,7 Joseph Spahn,6 Christopher S Ambrose8 1Division of Allergy and Immunology, University of South Florida, Tampa, FL, USA; 2Allergy & Asthma Associates of Southern California, Mission Viejo, CA, USA; 3Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA; 4Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA; 5Capital Allergy & Respiratory Disease Center, Sacramento, CA, USA; 6BioPharmaceuticals Medical, AstraZeneca, Wilmington, DE, USA; 7US Medical Affairs, Amgen, Thousand Oaks, CA, USA; 8BioPharmaceuticals Medical, AstraZeneca, Gaithersburg, MD, USACorrespondence: Christopher S Ambrose, AstraZeneca, One MedImmune Way, Gaithersburg, MD, 20878, USA, Tel +1 301-398-4454, Email chris.ambrose@astrazeneca.comPurpose: Younger age of asthma onset (AAO) has been associated with an allergic phenotype, whereas eosinophilic phenotypes have been associated with older AAO. In randomized trials, biologic efficacy among adults with severe asthma (SA) has varied by age at asthma onset. To determine whether these associations observed in trials apply to real-world outcomes, this study examined biologic effectiveness by AAO and biologic class in a large, real-world cohort.Patients and methods: CHRONICLE is an ongoing, real-world study of US adults with subspecialist-treated SA receiving biologics, maintenance corticosteroids, or who are uncontrolled on high-dosage inhaled corticosteroids with additional controllers. Patients enrolled between February 2018 and February 2022 who initiated a biologic for SA and had complete data for analysis were included. A locally estimated scatterplot smoothing (LOESS) analysis was used to plot the relationship between percentage exacerbation rate reduction and AAO by biologic class.Results: Of 578 patients with complete data, 198, 149, and 231 were diagnosed with asthma at age < 18, 18– 39, and ≥ 40 years, respectively. Across subgroups, patients were predominantly White (72– 78%), female (67– 73%), and commercially insured (54– 71%). In the LOESS analysis, exacerbation rate reductions were similar for anti-IgE and anti–IL-5/5R and anti–IL-4R subgroups with younger AAO, but the exacerbation rate reduction diminished for patients with older AAO receiving anti-IgE therapy, particularly with asthma onset age ≥ 40 years.Conclusion: Clinicians should consider age of onset in biologic treatment decisions, given reduced effectiveness of omalizumab in patients with asthma onset at age ≥ 40 years.Clinicaltrials.gov Identifier: NCT03373045.Keywords: Biologics, severe asthma, anti-interleukin therapy, anti-immunoglobulin E therapy, effectiveness, age of asthma onset

Kush S Patel,1 Ronald J Anderson,1,&ast; Carolyn B Becker,1,&ast; William C Taylor,1,&ast; Anne F Liu,1,&ast; Anubodh S Varshney,2,&ast; Nadaa B Ali,1,&ast; Barbara J Nath,3,&ast; Stephen R Pelletier,4 Helen M Shields,1 Nora Y Osman1 1Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA; 2Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Palo Alto, CA, USA; 3Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; 4Office of Medical Education, Harvard Medical School, Boston, MA, USA&ast;These authors contributed equally to this workCorrespondence: Helen M Shields, Department of Medicine, Brigham and Women’s Hospital, 75 Francis St, Boston, MA, 02115, USA, Tel +1 617 678 6077, Fax +1 617 525 8740, Email hmshields@bwh.harvard.eduPurpose: Coaching is a well-described means of providing real-time, actionable feedback to learners. We aimed to determine whether dual coaching from faculty physicians and real inpatients led to an improvement in history-taking skills of clerkship medical students.Patients and Methods: Expert faculty physicians (on Zoom) directly observed 13 clerkship medical students as they obtained a history from 26 real, hospitalized inpatients (in person), after which students received immediate feedback from both the physician and the patient. De-identified audio-video recordings of all interviews were scored by independent judges using a previously validated clinical rating tool to assess for improvement in history-taking skills between the two interviews. Finally, all participants completed a survey with Likert scale questions and free-text prompts.Results: Students’ history-taking skills – specifically in the domains of communication, medical knowledge and professional conduct – on the validated rating tool, as evaluated by the independent judges, did not significantly improve between their first and second patient interviews. However, students rated the dual coaching as overwhelmingly positive (average score of 1.43, with 1 being Excellent and 5 being Poor), with many appreciating the specificity and timeliness of the feedback. Patients also rated the experience very highly (average score of 1.23, with 1 being Excellent and 5 being Poor), noting that they gained new insights into medical training.Conclusion: Students value receiving immediate and specific feedback and real patients enjoy participating in the feedback process. Dual physician-patient coaching is a unique way to incorporate more direct observation into undergraduate medical education curricula.Keywords: direct observation, immediate feedback, medical student education, real patients, virtual teaching

Chi-Han Lin,1,2,&ast; Yung-Chia Kuo,1– 3,&ast; Hsuan-Chih Kuo,1– 3,&ast; Ching-Ting Wang,4 Shi-Ming Lin,1,5 Alan Chao-Wei Lee,1,6 Ming-Chin Yu,1,6,7 Wei-Chen Lee,1,6 Cherry Chiao-Erh Chen,2,3 Jason Chia-Hsun Hsieh1– 3 1College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan; 2Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, 333, Taiwan; 3Division of Hematology-Oncology, Department of Internal Medicine, New Taipei City Municipal TuCheng Hospital, New Taipei City, 236, Taiwan; 4Registered Nurse, Case Manager of Nursing Department, Chang Gung Memorial Hospital, Linkou, Taoyuan, 333, Taiwan; 5Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou and College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan; 6Department of Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, 333, Taiwan; 7Department of Surgery, New Taipei City Municipal TuCheng Hospital, New Taipei City, 236, Taiwan&ast;These authors contributed equally to this workCorrespondence: Jason Chia-Hsun Hsieh, Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, No. 5, Fu-Hsin Street, Gueishan District, Taoyuan City, 333, Taiwan, Tel +886-3-3281200 Ext 8825, Email wisdom5000@gmail.comBackground: Hepatitis often occurs after initiating immune checkpoint inhibitor (ICI) treatment. The time and grade of hepatitis after ICI starts and the prognostic role of immune-related hepatitis in patients with advanced hepatocellular carcinoma (aHCC) remain unclear.Methods: In this real-world analysis, we enrolled aHCC patients receiving ICIs, documented the highest level of liver enzymes during/after ICIs, and analyzed the survival impact of different hepatitis patterns.Results: One hundred and ninety-three aHCC patients receiving ICIs were recruited. During ICIs, 88.6% of patients experienced aspartate transaminase (AST) elevations (Grade III/IV: 7.8%). For alanine transaminase (ALT), 81.3% had elevated levels (Grade III/IV: 3.6%), and 41.5% of patients had elevated bilirubin levels (Grade 3/4: 6.7%). The median AST, ALT, and total bilirubin values significantly increased after ICI treatment initiated (all p < 0.001) and, similarly, after excluding progressive disease (p = 0.014, p = 0.002, p < 0.001). The median time of hepatitis occurrence is from the 4.0th to 15.9th weeks. Multivariable analysis showed that patterns of liver enzyme change of AST and total bilirubin in patients receiving ICIs significantly correlate to overall survival (OS, p = 0.009 and 0.001, respectively). After ICI termination, patients with elevated bilirubin (p = 0.003) and AST (p = 0.005) would indicate poor survival, with adjustment of viral hepatitis and ICI responses.Conclusion: Hepatitis emerges between the 4th and 20th weeks post-ICI initiation. Changes in liver enzymes during ICI therapy do not directly affect OS, implying the safety of ICI use when corticosteroids are promptly administered if clinically indicated.Keywords: hepatitis, immune checkpoint inhibitor, advanced hepatocellular carcinoma, liver enzymes, overall survival

Background: /Objective. An explosion in global obesity epidemic poses threats to the healthcare system by provoking risks of many debilitating diseases, including cognitive dysfunction. Physical activity has been shown to alleviate the deleterious effects of obesity-associated cognitive deficits across the lifespan. Given the strong neuroprotective role of brain-derived neurotrophic factor (BDNF) and exercise training as a known modulator for its elevation, this systematic review sought to examine the strength of the association between exercise and BDNF levels in healthy people with overweight and obesity. Methods: Six electronic databases (PubMed, MEDLINE, EMBASE, Web of Science, Ovid Nursing Database, and SPORTDiscus) were searched from their inceptions through December 2022. The primary outcome of interest was BDNF levels. Interventional studies (randomized and quasi-experimental) with English full text available were included. Risk of bias of the included studies was assessed using the Physiotherapy Evidence Database Scale. Data were extracted for meta-analyses by random-effects models. Results: Thirteen studies (n = 750), of which 69.2% (9/13) had low risk of bias, were included. In the meta-analysis, exercise interventions had no significant effect on resting BDNF levels (standardized mean difference: −0.30, 95% CI -0.80 to 0.21, P = 0.25). Subgroup analyses also indicated no effects of age and types of control groups being compared on moderating the association. Conclusion: To further inform the role of BDNF in obesity-related cognitive functioning, rigorous studies with larger samples of participants and raw data available were imperatively deserved.

Ting Yang,1– 4,&ast; Han-Rui Wang,1– 4,&ast; Ya-Kui Mou,1– 4,&ast; Wan-Chen Liu,1– 4 Yao Wang,1– 4 Xiao-Yu Song,1– 4 Chao Ren,1– 5 Xi-Cheng Song1– 4 1Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, People’s Republic of China; 2Shandong Provincial Key Laboratory of Neuroimmune Interaction and Regulation, Yantai Yuhuangding Hospital, Yantai, People’s Republic of China; 3Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Yantai, People’s Republic of China; 4Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Qingdao University, Yantai, People’s Republic of China; 5Department of Neurology, Yantai Yuhuangding Hospital, Qingdao University, Yantai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xi-Cheng Song, Department of Otolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, No. 20, East Road, Zhifu District, Yantai, 264000, People’s Republic of China, Tel +86535 6691999, Fax +865356240341, Email drxchsong@163.com Chao Ren, Department of Neurology, Yantai Yuhuangding Hospital, Qingdao University, No. 20, East Road, Zhifu District, Yantai, 264000, People’s Republic of China, Tel +865356691999, Fax +86535 6240341, Email renchaotg@126.comAbstract: Patients with allergic rhinitis (AR) have a high incidence of sleep disorders, such as insomnia, which can easily exacerbate nasal symptoms. The aggravation of nasal symptoms further promotes the deterioration of sleep disorders, forming a vicious cycle. Severe cases may even trigger psychological and neurological issues, such as anxiety, depression, and cognitive impairment, causing significant distress to patients, making clinical diagnosis and treatment difficult, and increasing costs. Furthermore, satisfactory therapeutics remain lacking. As the pathogenesis of AR-associated sleep disorders is not clear and research is still insufficient, paying attention to and understanding AR-related sleep disorders is crucial in clinical practice. Multiple studies have shown that the most crucial issues in current research on AR and sleep are analyzing the relationship between AR and sleep disorders, searching for the influencing factors, and investigating potential targets for diagnosis and treatment. This review aimed to identify and summarize the results of relevant studies using “AR” and “sleep disorders” as search terms. In addition, we evaluated the correlation between AR and sleep disorders and examined their interaction and potential mechanisms, offering a foundation for additional screening of potential diagnostic biomarkers and therapeutic targets.Keywords: allergic rhinitis, biological rhythm, immune inflammatory, neurological regulation, sleep disorders

OBJECTIVES: This study examined the associations between implemented disability-related policies and practices (DPP) and sustained employment among partially disabled employees in The Netherlands. METHODS: Employer survey data on implemented DPP were linked to register data on employment outcomes of partially disabled employees (N=6103 employees from N=366 employers). DPP included six domains based on 48 elements: sick leave policy, occupational health and safety services (OHS), prevention policy, reintegration policy, reintegration practices within the current employer and reintegration practices towards another employer. DPP domains were standardized on a 0–1 scale. Separate logistic regression models were estimated for DDP domains on one-year sustained employment adjusted for employee characteristics, firm size, and sector. RESULTS: Almost all organizations implemented at least one element of DPP on prevention policy, OHS, sick leave policy, and reintegration practices within the current employer, and two-thirds on reintegration policy and reintegration practices towards another employer. Implemented DPP on prevention policy [odds ratio (OR) 2.3, 95% confidence interval (CI) 1.3–4.0], OHS (OR 1.9, 95% CI 1.1–3.2), and sick leave policy (OR 1.8, 95% CI 1.0–3.3) were positively associated with sustained employment. No significant results were found for reintegration policy and both reintegration practices domains. Stratified analysis showed that DDP domains were particularly associated with sustained employment in larger organizations and in the private sector. CONCLUSIONS: Implemented DPP related to sick leave policy, OHS and prevention policy are associated with sustained employment among partially disabled employees, in particular in larger organizations and in the private sector.

In the recent Baksan Experiment on Sterile Transitions (BEST), a suppressed rate of neutrino absorption on a gallium target was observed, consistent with earlier results from neutrino source calibrations of the SAGE and GALLEX/GNO solar neutrino experiments. The BEST Collaboration, utilizing a 3.4 MCi Cr51 neutrino source, found observed-to-expected counting rates at two very short baselines of R=0.791±0.05 and 0.766±0.05, respectively. Among recent neutrino experiments, BEST is notable for the simplicity of both its neutrino spectrum, line neutrinos from an electron-capture source whose intensity can be measured to a estimated precision of 0.23%, and its absorption cross section, where the precisely known rate of electron capture to the gallium ground state, Ge71(e-,νe)Ga71(g.s.), establishes a minimum value. However, the absorption cross section uncertainty is a common systematic in the BEST, SAGE, and GALLEX/GNO neutrino source experiments. Here we update that cross section, considering a variety of electroweak corrections and the role of transitions to excited states, to establish both a central value and reasonable uncertainty, thereby enabling a more accurate assessment of the statistical significance of the gallium anomalies. Results are given for Cr51 and Ar37 sources. The revised neutrino capture rates are used in a reevaluation of the BEST and gallium anomalies.

Evidence for a flavor asymmetry between the ū and d¯ quark distributions in the proton has been found in deep-inelastic scattering and Drell-Yan experiments. The pronounced dependence of this flavor asymmetry on x (fraction of nucleon momentum carried by partons) observed in the Fermilab E866 Drell-Yan experiment suggested a drop of the d¯(x)/ū(x) ratio in the x>0.15 region. We report results from the SeaQuest Fermilab E906 experiment with improved statistical precision for d¯(x)/ū(x) in the large x region up to x=0.45 using the 120 GeV proton beam. Two different methods for extracting the Drell-Yan cross section ratios, σpd/2σpp, from the SeaQuest data give consistent results. The d¯(x)/ū(x) ratios and the d¯(x)-ū(x) differences are deduced from these cross section ratios for 0.13

Yi-Rong Lin,1 Wu-Chou Lin,1,2 Mei-Yao Wu,3– 5 Cheng-Li Lin,6 Su-Tso Yang,1,7,&ast; Hung-Rong Yen1,4,5,8,&ast; 1Graduate Institute of Chinese Medicine, School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, 404, Taiwan; 2Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung, 404, Taiwan; 3School of Post-Baccalaureate Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, 404, Taiwan; 4Department of Chinese Medicine, China Medical University Hospital, Taichung, 404, Taiwan; 5Research Center for Traditional Chinese Medicine, Department of Medical Research, China Medical University Hospital, Taichung, 404, Taiwan; 6Management Office for Health Data, China Medical University Hospital, Taichung, 404, Taiwan; 7Department of Radiology, China Medical University Hospital, Taichung, 404, Taiwan; 8Chinese Medicine Research Center, China Medical University, Taichung, 404, Taiwan&ast;These authors contributed equally to this workCorrespondence: Hung-Rong Yen, School of Chinese Medicine, College of Chinese Medicine, China Medical University, 91 Hsueh-Shih Road, North District, Taichung, 404328, Taiwan, Tel +886-4-22053366 ext. 3001, Fax +886-4-22365141, Email hungrongyen@mail.cmu.edu.tw Su-Tso Yang, Department of Radiology, China Medical University Hospital, 2 Yude Road, North District, Taichung, 404327, Taiwan, Tel +886-4-22052121 ext. 5470, Fax +886-4-22365141, Email yangst@mail.cmu.edu.twBackground: Many patients with dysfunctional uterine bleeding (DUB) seek traditional medicine consultations. This study intended to investigate the association of complementary Chinese herbal medicine (CHM) with the surgery rate in patients with DUB in Taiwan.Methods: We enrolled 43,027 patients with newly diagnosed DUB (ICD-9-CM codes 626.8) from the National Health Insurance Research Database in Taiwan during the period of 1997 to 2010. Among them, 38,324 were CHM users, and 4703 did not receive CHM treatment. After performing a 1:1 propensity-score match based on patients’ age (per 5 years), comorbidities, conventional drugs, childbirth status, duration from the diagnosis year of DUB and index year, there were an equal number (n=4642) of patients in the CHM cohort and non-CHM cohort. The outcome measurement was the comparison of incidences of surgical events, including hysterectomy and endometrial ablation, in the two cohorts before the end of 2013.Results: CHM users had a lower incidence of surgery than non-CHM users (adjusted HR 0.27, 95% CI: 0.22– 0.33). The cumulative incidence of surgery was significantly lower in the CHM cohort during the follow-up period (Log rank test, p < 0.001). A total of 146 patients in the CHM cohort (4.99 per 1000 person-years) and 485 patients in the non-CHM cohort (20.19 per 1000 person-years) received surgery (adjusted HR 0.27, 95% CI: 0.22– 0.33). CHM also reduced the risk of surgery in DUB patients with or without comorbidities. Regardless of childbirth status or whether patients took NSAIDs, tranexamic acid or progesterone, fewer patients in the CHM cohort underwent surgery than in the non-CHM cohort. The most commonly prescribed single herb and formula were Yi-Mu-Cao (Herba Leonuri) and Jia-Wei-Xiao-Yao-San, respectively.Conclusion: The real-world data revealed that CHM is associated with a reduced surgery rate in DUB patients. This information may be provided for further clinical investigations and policy-making.Keywords: complementary and alternative medicine, Chinese herbal medicine, dysfunctional uterine bleeding, hysterectomy, National Health Insurance Research Database, surgery

Yen-Hao Chen,1– 4 Wan-Ting Huang,5 Wen-Chin Lee,6 Ching-Mei Chen,5 Fu-Jen Cheng,7 Chia-Te Kung,7 Chin-Chou Wang,8 Liang-Jen Wang,9 Yu-Che Ou,10 Shau-Hsuan Li1 1Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 833, Taiwan; 2School of Medicine, College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan; 3School of Medicine, Chung Shan Medical University, Taichung, 402, Taiwan; 4Department of Nursing, School of Nursing, Fooyin University, Kaohsiung, 831, Taiwan; 5Department of Laboratory Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 833, Taiwan; 6Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 833, Taiwan; 7Department of Emergency Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 833, Taiwan; 8Department of Occupational Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 833, Taiwan; 9Department of Child and Adolescent Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 833, Taiwan; 10Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 833, TaiwanCorrespondence: Shau-Hsuan Li, Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung City, 833, Taiwan, Email lee.a0928@msa.hinet.netBackground: The aim of this study was to investigate the role of phthalate in patients with esophageal squamous cell carcinoma (ESCC).Methods: A total of 116 ESCC patients and 58 controls without any known histories of malignancies were enrolled. All eight urine phthalate metabolites were measured to assess phthalate levels. Clinical and urine phthalate metabolite profiles were compared between subgroups to identify differences, and the effects of phthalates on clinical ESCC outcomes were also examined.Results: The concentrations of some urine phthalate metabolites were higher in the ESCC group than in the control group, including mono-(3-carboxypropyl) phthalate (MCPP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono-n-butyl phthalate (MnBP). Higher concentrations of urine phthalate metabolites were associated with clinical T3–T4 status. Patients with higher concentration of mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-2-ethylhexyl phthalate (MEHP), and MEOHP had lower 1-year and 2-year overall survival (OS) rates than those with lower concentrations of these metabolites in our univariate analysis. Multivariate analysis showed that urinary MEHP of ≥ 3 μg/L and clinical stage IVB were independent prognostic factors for worse OS.Conclusion: The results of our study showed that urine phthalate metabolites are elevated in ESCC patients and associated with advanced tumor stage, and that a high urinary concentration of MEHP is an independent prognostic factor of worse OS.Keywords: phthalate, esophageal cancer, squamous cell carcinoma, survival

Background: Bruises commonly occur in children and are often due to minor accidental injuries. However, they can also occur in bleeding disorders or inflicted injuries (physical abuse) and is often the most common visible manifestation of child physical abuse. Objective: This paper aims at highlighting the factors that should raise concern about non- accidental injury (physical abuse) in children presenting with bruising and the approach to their evaluation. Method: This paper is based ona manual literature search and review of relevant papers sourced from Pubmed using the search terms “bruising, non-accidental injuries in children, evaluation. Conclusion: It is instructive to carefully and thoroughly evaluate bruise in children utilizing peer review and the necessary ancillary tests. It is also advisable to always consider other possible causes of bruise and bruise-like lesions in forming opinion about suspected bruise as implications of false diagnosis are grave.

Yang Zhao,1,&ast; Yi-Han Wang,2,&ast; Wei-Chao Tu,1 Da-Wei Wang,1 Mu-Jun Lu,3,4 Yuan Shao1 1Department of Urology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, Shanghai, 201800, People’s Republic of China; 2Department of Urology, Sixth People’s Hospital South Campus Affiliated to Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 3Department of Urology and Andrology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 4Shanghai Institute of Andrology, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Mu-Jun Lu; Yuan Shao, Email lumujun@163.com; shaoyuan10772@163.comBackground: Chronic kidney disease (CKD) is a significant worldwide health concern that leads to high mortality rates. The bioactive substance costunolide (CTD) has demonstrated several pharmacological effects and holds promise as a CKD treatment. This study aims to investigate the impact of CTD on CKD and delve into its mechanisms of action.Methods: Unilateral ureteral obstruction (UUO) methods and renal fibrosis mice models were created. Various concentrations of CTD were injected into UUO mice models to investigate the therapeutic effects of CTD on renal fibrosis of mice. Then, renal morphology, pathological changes, and the expression of genes related to fibrosis, inflammation and ferroptosis were analysed. RNA sequencing was utilized to identify the main biological processes and pathways involved in renal injury. Finally, both overexpression and inhibition of IKKβ were studied to examine their respective effects on fibrosis and inflammation in both in vitro and in vivo models.Results: CTD treatment was found to significantly alleviate fibrosis, inflammation and ferroptosis in UUO-induced renal fibrosis mice models. The results of RNA sequencing suggested that the IKKβ acted as key regulatory factor in renal injury and the expression of IKKβ was increased in vitro and in vivo renal fibrosis model. Functionally, down-regulated IKKβ expression inhibits ferroptosis, inflammatory cytokine production and collagen deposition. Conversely, IKKβ overexpression exacerbates progressive renal fibrosis. Mechanistically, CTD alleviated renal fibrosis and inflammation by inhibiting the expression of IKKβ and attenuating IKKβ/NF-κB pathway.Conclusion: This study demonstrates that CTD could mitigate renal fibrosis, ferroptosis and inflammation in CKD by modulating the IKKβ/NF-κB pathway, which indicates targeting IKKβ has an enormous potential for treating CKD. Keywords: chronic kidney disease, costunolide, renal fibrosis, IKKβ/NF-κB pathway

Northern myotis Myotis septentrionalis are one of the bat species most affected by white-nose syndrome (WNS), and disease-induced declines may cause compounding effects when combined with other threats such as habitat loss and fragmentation. Recent evidence suggests that peripheral populations are persisting in post-WNS years; however, the environmental factors that influence the occurrence of this species along the Atlantic Coastal Plain are virtually unknown. We conducted a large-scale acoustic survey on 3 islands: Long Island, New York, and Martha’s Vineyard and Nantucket, Massachusetts, USA, and used a multi-scale occupancy modeling approach to determine the landscape and abiotic factors affecting the distribution of northern myotis. Our estimates of occupancy and detection probability suggest widespread presence across the islands. At the local (200 m) scale, we identified strong negative effects of development on Long Island and Nantucket and a strong positive effect of forest habitat on Martha’s Vineyard. None of the variables we measured sufficiently explained the landscape (1 km2) occupancy of this species, which was very high (ψ = 0.81-0.97), representing an outlier for this species in the post-WNS landscape. The lack of association at the landscape scale suggests that general differences in land cover are not a driving factor of higher occupancy of peripheral northern myotis populations, while local site-specific conditions may be supporting critical foraging or roosting habitat. Because islands are particularly vulnerable to human-driven habitat alteration due to the constraint of limited space, and development pressure is expected to increase, this study provides a baseline to enable managers to assess the effects of future environmental disturbances and monitor population trends to support long-term survival of northern myotis.

Chun-Yan Zhang, Yu-Shen Yang, Meng-Qin Pei, Xin-Li Chen, Wei-can Chen, He-Fan He Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, People’s Republic of ChinaCorrespondence: He-Fan He, Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, People’s Republic of China, Tel +86 15860905262, Email 15860905262@163.comAbstract: Postoperative cognitive dysfunction (POCD) is a neurological complication associated with surgery and anesthesia that is commonly observed in older patients, and it can significantly affect patient prognosis and survival. Therefore, predicting and preventing POCD is important. Regional cerebral oxygen saturation (rSO2) reflects cerebral perfusion and oxygenation, and decreased intraoperative cerebral oxygen saturation has been reported to increase the risk of POCD. In this review, we elucidated the important relationship between the decline in rSO2 and risk of POCD in older patients. We also emphasized the importance of monitoring rSO2 during surgery to predict and prevent adverse perioperative cognitive outcomes. The findings reveal that incorporating intraoperative rSO2 monitoring into clinical practice has potential benefits, such as protecting cognitive function, reducing perioperative adverse outcomes, and ultimately improving the overall quality of life of older adults.Keywords: anesthesia, surgery, prognosis, perioperative adverse outcome, cognitive function

Materials whose luminescence can be switched by optical stimulation drive technologies ranging from superresolution imaging1-4, nanophotonics5, and optical data storage6,7, to targeted pharmacology, optogenetics, and chemical reactivity8. These photoswitchable probes, including organic fluorophores and proteins, can be prone to photodegradation and often operate in the ultraviolet or visible spectral regions. Colloidal inorganic nanoparticles6,9 can offer improved stability, but the ability to switch emission bidirectionally, particularly with near-infrared (NIR) light, has not, to our knowledge, been reported in such systems. Here, we present two-way, NIR photoswitching of avalanching nanoparticles (ANPs), showing full optical control of upconverted emission using phototriggers in the NIR-I and NIR-II spectral regions useful for subsurface imaging. Employing single-step photodarkening10-13 and photobrightening12,14-16, we demonstrate indefinite photoswitching of individual nanoparticles (more than 1,000 cycles over 7 h) in ambient or aqueous conditions without measurable photodegradation. Critical steps of the photoswitching mechanism are elucidated by modelling and by measuring the photon avalanche properties of single ANPs in both bright and dark states. Unlimited, reversible photoswitching of ANPs enables indefinitely rewritable two-dimensional and three-dimensional multilevel optical patterning of ANPs, as well as optical nanoscopy with sub-Å localization superresolution that allows us to distinguish individual ANPs within tightly packed clusters.

In recent years, the field of neuroscience has increasingly recognized the importance of studying animal behaviors in naturalistic environments to gain deeper insights into ethologically relevant behavioral processes and neural mechanisms. The common marmoset (Callithrix jacchus), due to its small size, prosocial nature, and genetic proximity to humans, has emerged as a pivotal model toward this effort. However, traditional research methodologies often fail to fully capture the nuances of marmoset social interactions and cooperative behaviors. To address this critical gap, we developed the Marmoset Apparatus for Automated Pulling (MarmoAAP), a novel behavioral apparatus designed for studying cooperative behaviors in common marmosets. MarmoAAP addresses the limitations of traditional behavioral research methods by enabling high-throughput, detailed behavior outputs that can be integrated with video and audio recordings, allowing for more nuanced and comprehensive analyses even in a naturalistic setting. We also highlight the flexibility of MarmoAAP in task parameter manipulation which accommodates a wide range of behaviors and individual animal capabilities. Furthermore, MarmoAAP provides a platform to perform investigations of neural activity underlying naturalistic social behaviors. MarmoAAP is a versatile and robust tool for advancing our understanding of primate behavior and related cognitive processes. This new apparatus bridges the gap between ethologically relevant animal behavior studies and neural investigations, paving the way for future research in cognitive and social neuroscience using marmosets as a model organism.

IntroductionPituitary adenomas (PAs) are benign tumors with high prevalence and, occasionally, aggressive course. The tumorigenesis of these lesions is not completely understood at the molecular level. BAK1 and BAX proteins play fundamental roles in apoptosis and seem to interact with VDAC proteins, whose expressions have been markedly altered in cancer, impacting their prognosis.Objectiveto evaluate the gene expression of VDAC1, VDAC2, BAK1 and BAX and their association with clinical and imaging characteristics in PA.MethodsClinical-epidemiological data were collected from 117 tumor samples from patients affected by PA. Invasiveness was assessed by the Knosp scale. Gene expression was examined by real-time PCR. Relative expression analysis was performed by 2^(-DDCt) method.ResultsThe sample was mainly composed of women (69/117 – 57.2%). Tumor subtypes observed were Non-Functioning (NF) (73/117 – 62.4%), Acromegaly (24/117 – 20.5%) and Cushing’s Disease (CD) (20/117 – 17.1%). Compared to normal tissue, there was a significant reduction in VDAC1 expression in the Acromegaly (p=0.029) and NF (p=0.002) groups. BAX expression was lower in all groups (p

The Mu2e and COMET μ→e conversion experiments are expected to significantly advance limits on new sources of charged lepton flavor violation. Almost all theoretical work in the field has focused on just two operators. However, general symmetry arguments lead to a μ→e conversion rate with six response functions, each of which, in principle, is observable by varying nuclear properties of targets. We construct a nucleon-level nonrelativistic effective theory (NRET) to clarify the microscopic origin of these response functions and to relate rate measurements in different targets. This exercise identifies three operators and their small parameters that control the NRET operator expansion. We note inconsistencies in past treatments of these parameters. The NRET is technically challenging, involving 16 operators, several distorted electron partial waves, bound muon upper and lower components, and an exclusive nuclear matrix element. We introduce a trick for treating the electron Coulomb effects accurately, which enables us to include all of these effects while producing transition densities whose one-body matrix elements can be evaluated analytically, greatly simplifying the nuclear physics. We derive bounds on operator coefficients from existing and anticipated μ→e conversion experiments. We discuss how similar NRET formulations have impacted dark matter phenomenology, noting that the tools this community has developed could be adapted for charged lepton flavor violation studies.

Over the next decade new μ→e conversion searches at Fermilab (Mu2e) and J-PARC (COMET, DeeMe) are expected to advance limits on charged lepton flavor violation (CLFV) by more than four orders of magnitude. By considering the consequence of P and CP on elastic μ→e conversion and the structure of possible charge and current densities, we show that rates are governed by six nuclear responses and a single scale, q/mN, where q≈mμ is the momentum transferred from the leptons to the nucleus. To relate this result to microscopic formulations of CLFV, we construct in nonrelativistic effective theory (NRET) the CLFV nucleon-level interaction, pointing out the relevance of the dimensionless scales y=(qb2)2>|v→N|>|v→μ|>|v→T|, where b is the nuclear size, v→N and v→μ are the nucleon and muon intrinsic velocities, and v→T is the target recoil velocity. We discuss previous work, noting the lack of a systematic treatment of the various small parameters. Because the parameter y is not small, a proper calculation of μ→e conversion requires a full multipole expansion of the nuclear response functions, an apparently daunting task with Coulomb-distorted electron partial waves. We demonstrate that the multipole expansion can be carried out to high precision by introducing a simplifying local momentum qeff for the electron. Previous work has been limited to simple charge or spin interactions, thereby treating the nucleus effectively as a point particle. We show that such formulations are not compatible with the general form of the μ→e conversion rate, failing to generate three of the six allowed nuclear response functions. The inclusion of the nucleon velocity v→N yields an NRET with 16 operators and a rate of the general form. Consequently, in the current discovery era for CLFV, it provides the most sensible starting point for experimental analysis, defining what can and cannot be determined about CLFV from the highly exclusive process of μ→e conversion. Finally, we expand the NRET operator basis to account for the effects of v→μ, associated with the muon's lower component, generating corrections to the CLFV coefficients of the point-nucleus response functions. Using advanced shell-model methods, we compute μ→e conversion rates for a series of experimental targets, deriving bounds on the coefficients of the CLFV operators. These calculations are the first to include a general basis of CLFV operators, full evaluation of the associated nuclear response functions, and an accurate treatment of electron and muon Coulomb effects. We discuss target selection as an experimental "knob"that can be turned to probe the microscopic origins of CLFV. We describe two types of coherence that enhance certain CLFV operators and selection rules that blind elastic μ→e conversion to others. We discuss the matching of the NRET onto higher level effective field theories, such as those constructed at the light quark level, noting opportunities to build on existing work in direct detection of dark matter. We discuss the relation of μ→e conversion to μ→e+γ and μ→3e, showing how MEG II and Mu3e results will complement those of Mu2e and COMET. Finally we describe a accompanying script - in Mathematica and Python versions - that can be used to compute μ→e conversion rates in various nuclear targets for the full set of NRET operators.

Yi-Ting Lin,1 Wei-Chung Tsai,1 Hsueh-Yu Lu,1 Shih-Yuan Fang,1 Hsiang-Wen Chan,1 Chung-Hsiung Huang1,2 1Department of Food Science, National Taiwan Ocean University, Keelung, Taiwan; 2Center for Marine Bioscience and Biotechnology, National Taiwan Ocean University, Keelung, 20224, TaiwanCorrespondence: Chung-Hsiung Huang, Department of Food Science, National Taiwan Ocean University, Keelung, Taiwan, Tel +886-2-2462-2192 ext. 5116, Email huangch@mail.ntou.edu.twBackground: Due to its prevalence, recurrence, and the emergence of drug-resistance, Candida vaginitis significantly impacts the well-being of women. Although cinnamon essential oil (CEO) possesses antifungal activity, its hydrophobic properties limit its clinical application.Purpose: To overcome this challenge, a nanoemulsification technology was employed to prepare cinnamon essential oil-nanoemulsion (CEO@NE), and its therapeutic efficacy and action mechanism for Candida vaginitis was investigated in vivo and in vitro.Materials and Methods: CEO@NE, composed of 4% CEO, 78% distilled water, and 18% Tween 80, was prepared by ultrasonic nanoemulsification. The physical properties, anti-Candida activity, cytotoxicity, immunomodulatory potential and storage stability of CEO@NE were explored. Subsequently, the effect of intravaginal CEO@NE treatment on Candida vaginitis was investigated in mice. To comprehend the possible mechanism of CEO@NE, an analysis was conducted to ascertain the production of intracellular reactive oxygen species (ROS) in C. albicans.Results: CEO@NE, with the droplet size less than 100 nm and robust storage stability for up to 8 weeks, exhibited comparable anti-Candida activity with CEO. CEO@NE at the concentration lower than 400 μg/mL had no cytotoxic and immunomodulatory effects on murine splenocytes. Intravaginal treatment of CEO@NE (400 μg/mL, 20 μL/day/mouse for 5 consecutive days) curbed Candida colonization, ameliorated histopathological changes, and suppressed inflammatory cytokine production in mice intravaginally challenged with C. albicans. Notably, this treatment preserved the density of vaginal lactic acid bacteria (LAB) crucial for vaginal health. Co-culturing C. albicans with CEO@NE revealed concentration-dependent augmentation of intracellular ROS generation and ensuing cell death. In addition, co-culturing LPS-stimulated murine splenocytes with CEO@NE yielded a decrease in the generation of cytokines.Conclusion: This discovery provides insight into the conceivable antifungal and anti-inflammatory mechanisms of CEO@NE to tackle Candida vaginitis. CEO@NE offers a promising avenue to address the limitations of current treatments, providing novel strategy for treating Candida vaginitis.Keywords: anti-inflammation, Candida vaginitis, cinnamon essential oil, nanoemulsion, reactive oxygen species

Abstract Background Excessive use of short-acting β2 agonists (SABA) in patients with asthma continues to be a notable concern due to its link to higher mortality rates. Global relevance of SABA overuse in asthma management cannot be understated, it poses significant health risk to patients with asthma and imposes burden on healthcare systems. This study, as part of global SABINA progamme, aimed to describe the prescribing patterns and clinical outcomes associated with SABA use in the Chinese population. Methods Retrospective cohort study was conducted using anonymized electronic healthcare records of Clinical Data Analysis and Reporting System (CDARS) from Hong Kong Hospital Authority (HA). Patients newly diagnosed with asthma between 2011 and 2018 and aged ≥12 years were included, stratified by SABA use (≤2, 3–6, 7–10, or ≥11 canisters/year) during one-year baseline period since asthma diagnosis date. Patients were followed up from one-year post-index until earliest censoring of events: outcome occurrence and end of study period (31 December 2020). Cox proportional regression and negative binomial regression were used to estimate the mortality risk and frequency of hospital admissions associated with SABA use respectively, after adjusting for age, sex, Charlson Comorbidity Index (CCI), and inhaled corticosteroid (ICS) dose. Outcomes include all-cause, asthma-related, and respiratory-related mortality, frequency of hospital admissions for any cause, and frequency of hospital admissions due to asthma. Results 17,782 patients with asthma (mean age 46.7 years, 40.8% male) were included and 59.1% of patients were overusing SABA (≥ 3 canisters per year). Each patient was prescribed a median of 5.61 SABA canisters/year. SABA overuse during baseline period was associated with higher all-cause mortality risk compared to patients with ≤2 canisters/year. Association was dose-dependent, highest risk in those used ≥11 canisters/year (adjusted hazard ratio: 1.42, 95% CI: 1.13, 1.79) and 3–6 canisters/year (adjusted hazard ratio: 1.22, 95% CI: 1.00, 1.50). Higher SABA prescription volume associated with increased frequency of hospital admissions with greatest risk observed in 7–10 canisters/year subgroup (adjusted rate ratio: 4.81, 95% CI: 3.66, 6.37). Conclusions SABA overuse is prevalent and is associated with increased all-cause mortality risk and frequency of hospital admissions among the patients with asthma in Hong Kong.

Kai-Yu Wang,1 Yi-Chuan Chen,1,2 Jau-Yuan Chen,1,2 Song-Seng Loke,3 Wei-Chung Yeh,4 Wen-Cheng Li1,2,5 1Department of Family Medicine, Chang-Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; 2College of Medicine, Chang Gung University, Taoyuan, Taiwan; 3Department of Family Medicine, Chang-Gung Memorial Hospital at Kaohsiung, Kaohsiung, Taiwan; 4Department of Family Medicine, Chang-Gung Memorial Hospital at Keelung, Keelung, Taiwan; 5Department of Health Management, Xiamen Chang-Gung Hospital, Xiamen, People’s Republic of ChinaCorrespondence: Wen-Cheng Li, Email win3135@hotmail.comBackground: Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been recognized as a valuable biomarker for identifying the risk of cardiovascular diseases and inflammation. Furthermore, there is strong evidence to suggest that metabolic syndrome is closely associated with chronic inflammation. Accordingly, the present study endeavors to examine the potential correlation between metabolic syndrome and the levels of Lp-PLA2.Methods: To explore the relationship between Lp-PLA2 levels and metabolic syndrome, and to establish the predictive cut-off value of Lp-PLA2, a retrospective analysis was conducted using medical data from a sample of 3549 Chinese adults (comprising 2182 men and 1367 women) aged between 18 and 50 years, who had undergone health check-ups. In addition, the study also sought to investigate any potential differences in Lp-PLA2 levels based on sex and age.Results: The analysis of the data indicated that participants had a mean age of 44.2 years, a mean Lp-PLA2 level of 589 IU/L, and a metabolic syndrome prevalence of 22%. Lp-PLA2 levels were significantly different between males and females, and a significant correlation was observed between Lp-PLA2 levels and clinical and metabolic characteristics, including BMI, cholesterol, and triglycerides. Interestingly, Lp-PLA2 demonstrated potential as an indicator of metabolic syndrome, particularly in females, despite other biomarkers, such as TG/HDL-C and WHR, exhibiting better area under the curve.Conclusion: Our findings suggest that Lp-PLA2 may serve as a useful biomarker for identifying individuals at risk of developing metabolic syndrome, particularly in females. Further research is needed to explore the potential of Lp-PLA2 as a diagnostic and therapeutic target for metabolic syndrome.Keywords: Lp-PLA2, lipoprotein, metabolic syndrome, cardiovascular risk, and lipid profile

Antimicrobial peptides have been isolated from various organisms and play an essential role in defense against infections. They are small peptides (less than 60 amino acids) with broad-spectrum antibacterial activity. In teleosts, pituitary adenylate cyclase-activating polypeptide (PACAP) has been demonstrated to have direct antimicrobial activity against several aquatic pathogens, including those from the genus Flavobacterium. Our goal was to examine the impacts of PACAP and route of administration on the immune response of Nile tilapia (Oreochromis niloticus). Over the course of four studies, tilapia (416.1 ± 116.7 g) randomly assigned to replicate tanks were administered with either PACAP-38 or a modified form of PACAP-38 via intraperitoneal (i.p.) injection, bath, nares flush, or gill flush, and compared to PBS controls. In the first two studies, following individual treatments, tilapia underwent a bath exposure (40 L tank for 45 min) to F. columnare (isolate ALG-00-530; at 2.1 × 108 CFU/ml) or sham exposure without the addition of the bacterial culture. Fish were sampled before exposure, 48 h after stimulation, at 1 day after the onset of mortality in exposed tanks, and resolution of mortality. Tilapia that received i.p. injection of PACAP-38 showed significantly lower mortality from F. columnare (10 %) than those receiving PBS i.p. (25 %). However, bath immersion of fish, both with and without F. columnare, resulted in significant mortality due to secondary infections with Edwardsiella tarda. Administration of modified PACAP-38 via nares/gill flush, or i.p. injection did not, however, result in significantly fewer mortalities compared to sham/PBS. Furthermore, the same modified form of PACAP-38 also induced inflammatory gene expression in the spleen, and eosinophilic granule cell aggregation in the nares, following flushing. The data from the first study suggest that PACAP-38 induces protection against infection and stress mainly through a reduction of inflammatory-il1β expression. Moreover, data analysis of spleen samples from these two studies also indicates that PACAP-38 might have more anti-inflammatory impacts than its modified form. In the fourth trial, after exposing tilapia to low temperature (15–17 °C) for 30 min (cold stress), the PACAP-38 treated group had significantly lower cortisol levels compared to both PBS injected group and the negative control. Due to the observed impacts of PACAP-38 treatment on the immunophysiology of Nile tilapia, its potential for therapeutic use should be further investigated.

The recovery of long-term climate proxy records with seasonal resolution is rare because of natural smoothing processes, discontinuities and limitations in measurement resolution. Yet insolation forcing, a primary driver of multimillennial-scale climate change, acts through seasonal variations with direct impacts on seasonal climate1. Whether the sensitivity of seasonal climate to insolation matches theoretical predictions has not been assessed over long timescales. Here, we analyse a continuous record of water-isotope ratios from the West Antarctic Ice Sheet Divide ice core to reveal summer and winter temperature changes through the last 11,000 years. Summer temperatures in West Antarctica increased through the early-to-mid-Holocene, reached a peak 4,100 years ago and then decreased to the present. Climate model simulations show that these variations primarily reflect changes in maximum summer insolation, confirming the general connection between seasonal insolation and warming and demonstrating the importance of insolation intensity rather than seasonally integrated insolation or season duration2,3. Winter temperatures varied less overall, consistent with predictions from insolation forcing, but also fluctuated in the early Holocene, probably owing to changes in meridional heat transport. The magnitudes of summer and winter temperature changes constrain the lowering of the West Antarctic Ice Sheet surface since the early Holocene to less than 162 m and probably less than 58 m, consistent with geological constraints elsewhere in West Antarctica4-7.

Dual-phase xenon time projection chamber (TPC) detectors have demonstratedsuperior search sensitivities to dark matter over a wide range of particlemasses. To extend their sensitivity to include low-mass dark matterinteractions, it is critical to characterize both the light and chargeresponses of liquid xenon to sub-keV nuclear recoils. In this work, we report anew nuclear recoil calibration in the LUX detector $\textit{in situ}$ usingneutron events from a pulsed Adelphi Deuterium-Deuterium neutron generator. Wedemonstrate direct measurements of light and charge yields down to 0.45 keV(1.4 scintillation photons) and 0.27 keV (1.3 ionization electrons),respectively, approaching the physical limit of liquid xenon detectors. Wediscuss the implication of these new measurements on the physics reach ofdual-phase xenon TPCs for nuclear-recoil-based low-mass dark matter detection.

We present the results from combining machine learning with the profile likelihood fit procedure, using data from the Large Underground Xenon (LUX) dark matter experiment. This approach demonstrates reduction in computation time by a factor of 30 when compared with the previous approach, without loss of performance on real data. We establish its flexibility to capture nonlinear correlations between variables (such as smearing in light and charge signals due to position variation) by achieving equal performance using pulse areas with and without position-corrections applied. Its efficiency and scalability furthermore enables searching for dark matter using additional variables without significant computational burden. We demonstrate this by including a light signal pulse shape variable alongside more traditional inputs, such as light and charge signal strengths. This technique can be exploited by future dark matter experiments to make use of additional information, reduce computational resources needed for signal searches and simulations, and make inclusion of physical nuisance parameters in fits tractable.

We have designed and tested a large-area (0.15 m2) neutron detector based on neutron capture on 6Li. The neutron detector design has been optimized for the purpose of tagging the scattering angle of keV-scale neutrons. These neutron detectors would be employed to calibrate the low-energy (

Mei-Yu Lv,1,2 Ling-Ling Jin,2,3 Xi-Qiao Sang,2 Wen-Chao Shi,2 Li-Xia Qiang,2 Qing-Yan Lin,4 Shou-De Jin2 1Department of Respiratory Medicine, Harbin Medical University Cancer Hospital, Harbin, 150001, People’s Republic of China; 2Department of Respiratory Medicine, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, People’s Republic of China; 3Department of Critical Care medicine, the Second Affiliated Hospital of Xi ‘an Jiaotong University, Xi’an, Shaanxi, China; 4Department of Respiratory Medicine, Heilongjiang Provincial Hospital, Harbin, 150001, People’s Republic of ChinaCorrespondence: Shou-De Jin, Department of Respiratory Medicine, The Fourth Affiliated Hospital of Harbin Medical University, No. 37 Yiyuan Street, Nangang District, Harbin, 150001, People’s Republic of China, Tel/Fax +86 0451-85939123, Email jinshoude@163.comPurpose: The typical characteristic of COPD is airway remodeling, affected by environmental and genetic factors. However, genetic studies on COPD have been limited. Currently, the Abhd2 gene is found to play a critical role in maintaining alveolar architecture and stability. The research aims to investigate the predictive value of Abhd2 for airway remodeling in COPD and its effect on TGF-β regulation.Methods: In humans, Abhd2 protein was obtained from peripheral blood monocytes. Peripheral blood TGF-β, pulmonary surfactant proteins (SPs), metalloproteinases, inflammatory indicators (WBC, NEU, NLR, EOS, CRP, PCT, D-Dimer), chest CT (airway diameter and airway wall thickness), pulmonary function, and blood gas analysis were used to assess airway remodeling. In animals, Abhd2 deficient mice (Abhd2Gt/Gt) using gene trapping and C57BL6 mice were injected intraperitoneally with CSE to construct COPD models. HE staining, Masson staining and immunohistochemistry were used to observe the pathological changes of airway in mice, and RT-PCR, WB, ELISA and immunofluorescence were used to detect the expression of secreted proteins and EMT markers.Results: COPD patients with worse pulmonary function and higher airway remodeling-related inflammatory factors had lower Abhd2 protein expression. Moreover, indicators followed the same trend for COPD patients grouped by prognosis (Group A vs Group B). Serum TGF-β was negatively correlated with Abhd2 protein expression, FEV1/FVC, FEV1, and FEV1% PRED. In mice, Abhd2 depletion promoted deposition of TGF-β, leading to more pronounced emphysema, airway thickening, increased alveolar macrophage infiltration, decreased AECII number and SPs, and EMT phenomenon.Conclusion: Downregulation of Abhd2 can promote airway remodeling in COPD by modulating repair after injury and EMT via TGF-β. This study suggests that Abhd2 may serve as a biomarker for assessing airway remodeling and guiding prognosis in COPD.Keywords: alpha/beta hydrolase 2, COPD, TGF-β, airway remodeling, EMT

Wang Chun Kwok,1 Terence Chi Chun Tam,1 James Chung Man Ho,1 David Chi Leung Lam,1 Mary Sau-Man Ip,1 Pak Leung Ho2 1Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, People’s Republic of China; 2Department of Microbiology and Carol Yu Centre for Infection, Queen Mary Hospital, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, People’s Republic of ChinaCorrespondence: Pak Leung Ho, Department of Microbiology and Carol Yu Centre for Infection, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Pokfulam, Hong Kong Special Administrative Region, People’s Republic of China, Tel +852-2255-2584, Fax +852 2855 1241, Email plho@hku.hkIntroduction: Nirmatrelvir-ritonavir (NMV-r) and molnupiravir (MOL) were developed as out-patient anti-viral for mild COVID-19. There was limited data on their role in treating COVID-19 for hospitalized patients, especially among adult patients who are unvaccinated and had chronic respiratory diseases.Methods: A territory-wide retrospective study was conducted in Hong Kong to compare the efficacy of NMV-r and MOL against COVID-19 in unvaccinated adult patients with asthma, chronic obstructive pulmonary disease, bronchiectasis and interstitial lung diseases presenting with moderate COVID-19 from 16th February 2022 to 15th March 2023.Results: A total of 1354 patients were included, 738 received NMV-r and 616 received MOL. NMV-r was more effective in reducing 90-day mortality with adjusted hazard ratios (aHR) of 0.508 (95% confidence interval [CI] = 0.314– 0.822, p = 0.006). Patients who received NMV-r also had significantly shorter length of stay (LOS) than those receiving MOL, with median LOS of 4 (Interquartile range [IQR] = 2– 7) for NMV-r and 6 (IQR = 3– 10) for MOL (p-value < 0.001). There was no statistically significant difference in the development of respiratory failure and severe respiratory failure in the two groups.Discussion: NMV-r was more effective than MOL among unvaccinated adults with chronic respiratory diseases who were hospitalized for moderate COVID-19 without hypoxaemia on admission.Keywords: asthma, COPD, bronchiectasis, interstitial lung disease, molnupiravir, nirmatrelvir-ritonavir, COVID-19

Background: The lifestyles of preschoolers have become physically inactive and sedentary, their eating habits unhealthy, and their sleep routines increasingly disturbed. Parental involvement appears crucial to combat the unhealthy lifestyle of preschoolers. Because of the recognized barriers to traditional face-to-face interventions, easy access and lower costs make electronic health (eHealth) interventions appealing. However, whether parent-based eHealth intervention may be harnessed to improve the aforementioned lifestyle behaviors of preschoolers is currently unclear, a gap that this systematic review intends to address. This study aims to systematically review the current literature concerning the effectiveness of parent-based eHealth intervention on the physical activity, dietary behaviors, and sleep of preschoolers. Method: This systematic review conforms to the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement. Six databases (EMBASE, PubMed, MEDLINE, Web of Science, SPORTDiscus, and PsycINFO) were retrieved for the period from January 2000 to December 2022. Studies were eligible if 1 they were quantitative study design; 2 eHealth interventions in which parents were the change agents targeted children aged 3–6 years; 3 interventions examined the effectiveness of eHealth or incorporated eHealth as one of the intervention modalities; 4 at least one variable included in either primary or secondary outcome had to concentrate on the physical activity, diet, and sleep of preschoolers; 5 publication type was limited to the English language and peer-reviewed journal articles; 6 study settings were confined to family- or parent-based ones. The risk of bias was assessed, based upon Version 2 of the Cochrane risk-of-tool for randomized trials (RoB2). Results: Twelve studies were screened. No significant group-by-time improvement in physical activity was found in studies related to physical activity outcomes. Two studies reported a significant difference between groups concerning motor ability, with one study indicating improved object control with the other reporting improvement in both object control and locomotor skills. Of the studies related to dietary behavior outcomes, six studies reported a significant difference at the posttest compared to the control group, in terms of vegetable and fruit intake, sugar-sweetened drinks, reduced candy consumption, and improved non-core food. Three studies reported a significant difference between groups in sleep duration at the end of the posttest, with the result of one study limited to preference-only participants. None of the reviewed studies found a significant difference between groups for sleep problems. Conclusion: Parent-based eHealth interventions were not significantly effective in improving physical activity and reducing sleep problems in preschoolers, but the majority of studies have found that this type of intervention significantly improves the dietary behaviors and sleep duration of preschoolers. High-quality, robustly designed studies to balance the intervention dosage and sequence are needed to investigate the effectiveness of parent-based eHealth intervention on physical activity, dietary behaviors, and sleep in preschoolers, particularly those raised in other cultural background, which may significantly impact their lifestyle. Trial registration: International Prospective Register of Systematic Review (PROSPERO): CRD42023418861.

Da-Li Xu,1 Xiao-Mei Zhang,2 Xue-Ying Tian,2 Xian-Jun Wang,2 Lin Zhao,1 Meng-Ying Gao,1 Lian-Feng Li,1 Jia-Qi Zhao,1 Wu-Chun Cao,1,3,&ast; Shu-Jun Ding2,&ast; 1Department of Epidemiology, School of Public Health, Cheeloo College of Medicine, Shandong UniversityJinan, Shandong, People’s Republic of China; 2Shandong Provincial Key Laboratory of Communicable Disease Control and Prevention, Department of Communicable Disease Control and Prevention, Shandong Center for Disease Control and Prevention, Jinan, Shandong Province, People’s Republic of China; 3State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shu-Jun Ding, Shandong Provincial Key Laboratory of Communicable Disease Control and Prevention, Department of Communicable Disease Control and Prevention, Shandong Center for Disease Control and Prevention, 16992 Jingshi Road, Jinan, Shandong Province, People’s Republic of China, Tel/Fax +86 531 82679587, Email dsj_jn@126.com Wu-Chun Cao, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, 20 Dong-da Street, Beijing, People’s Republic of China, Email caowuchun@126.comPurpose: To characterize the cytokine profile of patients with severe fever with thrombocytopenia syndrome (SFTS) in relation to disease severity.Patients and Methods: 60 laboratory-confirmed SFTS patients and 12 healthy individuals from multi-centers in Shandong Province of China were included, and all patients were divided into fatal patients (9) and recovered patients (51) due to their final outcomes. Multiplex-microbead immunoassays were conducted to estimate levels of 27 cytokines in the sera of patients and controls.Results: The results showed that levels of IL-2, IL-4, IL-6, IL-7, IL-8, IL-15, IL-1RA, G-CSF, GM-CSF, IFN-γ, TNF-α, basic FGF, PDGF-BB, RANTES, IP-10, MIP-1α, MIP-1β, MCP-1, and Eotaxin differed significantly among the SFTS fatal patients, recovered patients, and the healthy controls (all p< 0.05). Compared to the healthy controls, the fatal patients and recovered patients had reduced levels of IL-2, IL-4, IL-7, PDGF-BB, RANTES, and Eotaxin, while the levels of PDGF-BB and RANTES were significantly lower in fatal patients compared to recovered patients. The increasing levels of IL-6, IL-8, IL-15, IL-1RA, G-CSF, GM-CSF, IFN-γ, TNF-α, basic FGF, IP-10, MIP-1α, MIP-1β, and MCP-1 were observed in fatal patients (all p< 0.05), and the levels of IL-6, IP-10, MIP-1α, and MCP-1 were significantly higher than other two groups. The Spearman correlation analysis indicated a positive correlation between platelet count and PDGF-BB levels (p< 0.05), while the white blood cell count had a negative correlation with MIP-1 level (p< 0.05).Conclusion: The research exhibited that the SFTS virus (SFTSV) caused an atypical manifestation of cytokines. The levels of IL-6, IP-10, MIP-1α, and MCP-1 had been observed a positive association with the severity of the illness.Keywords: SFTS, SFTSV, cytokines, fatal patients, correlation analysis

Lien Wang,1,2 Xiaowei Chen,1 Xiaojing Gu,1 Heidi De Smedt,3 Vanina Popova,3 Dong-Jing Fu,4 Carla M Canuso,4 Wayne C Drevets,2 Guang Chen2 1Janssen Research & Development, LLC, Janssen Pharmaceutical Companies of Johnson & Johnson, Shanghai, People’s Republic of China; 2Janssen Research & Development, LLC, Janssen Pharmaceutical Companies of Johnson & Johnson, Brisbane, CA, USA; 3Janssen Research & Development, LLC, Janssen Pharmaceutical Companies of Johnson & Johnson, Beerse, Belgium; 4Janssen Research & Development, LLC, Janssen Pharmaceutical Companies of Johnson & Johnson, Raritan, NJ, USACorrespondence: Guang Chen, Janssen Fellow, Scientific Director, Translational Research, Mood DAS, Neuroscience Therapeutic Area, Janssen R & D, LLC, Janssen Pharmaceutical Companies of Johnson and Johnson, 3210 Merryfield Row, Room 1908, San Diego, CA, 92121, USA, Tel +1 (240) 602 7950, Email guangchenmd@gmail.comPurpose: This meta-analysis assessed whether atypical antipsychotics (AAPs) and esketamine nasal spray (ESK-NS), which are mechanistically distinct, differ in antidepressant outcomes.Patients and Methods: Data were extracted from 12 trials of ESK-NS or AAPs in depressed patients (4276) with inadequate response or resistance to conventional antidepressants. Montgomery-Åsberg Depression Rating Scale (MADRS) score reductions from baseline and response rates (≥ 50% reduction) were analyzed.Results: At endpoint, the estimated MADRS score reduction of pooled ESK-NS arms was greater than pooled AAP arms (+9.16 points, p < 0.0001). The reduction also was greater in the pooled control arms of the ESK-NS trials than the pooled control arms of the AAP trials (+7.57 points, p < 0.0001). The mean difference in the reductions between pooled ESK-NS and control arms was 1.87 points greater than that between pooled AAP and control arms, but this difference was not significant (95% CI: − 4.49, 0.74, p = 0.16). Relative to their respective control arms, the mean difference in response rates was 25% for the pooled ESK-NS and 9% for the pooled AAP arms; the mean response rate was 16% greater in the pooled ESK-NS studies than the pooled AAP studies (p = 0.0004). Comparisons against specific AAPs showed mean differences in the MADRS score reductions at 1 week between the experimental and control arms that were numerically larger in the ESK-NS trials than in the aripiprazole trials (mean difference of 1.71 points, p = 0.06) and the brexpiprazole trials (mean difference of 2.05 points, p = 0.02).Conclusion: The ESK-NS arms showed numerically larger MADRS score reductions at week-1 and endpoint, and a significantly larger response rate compared with AAP arms. Prospective studies involving direct comparisons are warranted to compare the relative efficacy between these treatment regimens.Keywords: major depressive disorder, treatment resistant depression, adjunctive and conjunctive treatment, atypical antipsychotics, esketamine nasal spray, rapid-acting

Kang Nien How,1,2,&ast; Wen Chung Ho,1,2,&ast; Meroshini Sundaran,1,2,&ast; Wan Syazween Lyana Wan Ahmal Kammal,1,2,&ast; Poh Ying Lim,3 Wilson Chew4 1Dermatology Unit, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor, Malaysia; 2Hospital Sultan Abdul Aziz Shah, Universiti Putra Malaysia, Serdang, Selangor, Malaysia; 3Department of Community Health, Universiti Putra Malaysia, Serdang, Selangor, Malaysia; 4Beiersdorf (Malaysia) Sdn Bhd, Petaling Jaya, Selangor, Malaysia&ast;These authors contributed equally to this workCorrespondence: Kang Nien How, Dermatology Unit, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor, 43400, Malaysia, Tel +603 97695601, Email hkangnien@upm.edu.myPurpose: We aim to evaluate the effectiveness and tolerability of a sunscreen formulation containing licochalcone A (LicA) and L-carnitine (LC) as an adjuvant to adapalene in the management of acne and post-acne pigmentation (PAH).Patients and Methods: A randomized, double-blind, active comparator-controlled trial of 51 patients aged 18 years or older with a clinical diagnosis of mild-to-moderate acne vulgaris was conducted at the Hospital Sultan Abdul Aziz Shah, Universiti Putra Malaysia. The efficacy and tolerability of once-daily adapalene 1.0% were assessed during the 2-week run-in period. Subsequently, patients were randomized to receive either an add-on investigational LicA-containing sunscreen or niacinamide-containing comparator sunscreen every 4 hourly during daytime for 4 weeks. Patients were followed up at Weeks 2 and 4 to assess for improvement in acne severity, PAH, calorimetric parameters and cutaneous tolerability.Results: Two weeks of adapalene usage significantly improved acne severity; however, up to 52% of patients experienced dryness, burning and stinging. Adding LicA-containing or comparator sunscreens was associated with further improvement in acne severity, PAH and calorimetric parameters at the study endpoint. No significant differences in the cutaneous tolerability profiles were observed between treatment groups. Notably, significantly fewer patients receiving LicA-containing sunscreen developed scaliness at Week 4 compared with those in the comparator group. In addition, more patients receiving LicA-containing sunscreen reported less dryness, burning and stinging reactions than the comparator group. Importantly, more patients receiving LicA-containing sunscreen agreed that their treatment led to excellent improvement than the comparator group; of note, one patient reported that their condition worsened with the receipt of the comparator product.Conclusion: The concurrent use of LicA–containing sunscreen with adapalene may improve the cutaneous tolerance to adapalene among Malaysian patients.Keywords: acne vulgaris, cosmeceuticals, retinoids, sunscreen agents, skin pigmentation

Chrong-Reen Wang,1 Wei-Chieh Lin,2 Tak-Wah Wong3 1Division of Rheumatology and Immunology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan; 2Division of Critical Care Medicine, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan; 3Department of Dermatology, National Cheng Kung University Hospital, Tainan, TaiwanCorrespondence: Chrong-Reen Wang, Department of Internal Medicine, National Cheng Kung University Hospital, 138 Sheng-Li Road, Tainan, 70403, Taiwan, Email wangcr@mail.ncku.edu.twIntroduction: In East Asia, more than half of patients with amyopathic dermatomyositis (ADM) have interstitial lung disease (ILD). There is up to 50% 6-month mortality in MDA5-positive ILD refractory to corticosteroid (CS) combined with immunosuppressant therapy.Patient Details: A 39-year-old local woman had a 1-month history of reddish-purple discoloration around the eyelids (heliotrope rash), and erythematous areas on the upper back and posterior neck (shawl sign) as well as on the front of her chest (V sign), followed by dry cough and mild dyspnea for 1 week. She had normal muscle strength, muscle-enzyme concentrations, and muscular magnetic resonance images. Laboratory tests showed hypoxemia, increased ferritin and CRP levels, and positive MDA5 antibodies. High-resolution chest computed tomography revealed bilateral ground-glass opacity. She received a diagnosis of anti-MDA5-positive ADM with early-stage ILD.Intervention: Pulse methylprednisolone and cyclophosphamide therapies were initiated, followed by high-dose CS treatment. Immediate-release twice-daily 5 mg tofacitinib (Tof) has been demonstrated to be effective induction therapy for early-stage ILD in anti-MDA5-positive ADM. Owing to the patient’s preference for once-daily therapy, 11 mg extended-release Tof was prescribed 4 weeks after starting the initial pulse CS treatment for ILD.Outcomes: Respiratory symptoms and cutaneous manifestations were absent and the use of CS spared 5 months after initiating Tof therapy. Laboratory examinations exhibited normalized ferritin/oxygen levels, and chest images displayed completely resolved pulmonary infiltration. ILD remains under adequate control with Tof monotherapy without recurrence at 5 months.Lessons: Owing to a rapid decline in higher mortality in anti-MDA5-positive ADM patients with ILD, early detection with prompt initiation of extended-release Tof induction therapy might achieve a beneficial outcome.Keywords: amyopathic dermatomyositis, positive MDA5 antibody, interstitial lung disease, extended-release tofacitinib, Janus kinase inhibitor

Susmita Aryal,1 Sanghyo Park,1 Hyungkyu Park,1 Chaewon Park,1 Woo Cheol Kim,1 Deepika Thakur,1 Young-Joo Won,2 Jaehong Key1 1Department of Biomedical Engineering, Yonsei University, Wonju, Gangwon Province, 26493, Korea; 2Division of Health Administration, College of Software Digital Healthcare Convergence, Yonsei University, Wonju, Gangwon State, 26493, KoreaCorrespondence: Jaehong Key, Department of Biomedical Engineering, Yonsei University, 1 Yonseidae-Gil, Wonju, Gangwon State, 26493, Korea, Tel +82-33-760-2857, Fax +82-33-760-2919, Email jkey@yonsei.ac.krAbstract: Lung cancer is one of the most common malignant tumors worldwide and is characterized by high morbidity and mortality rates and a poor prognosis. It is the leading cause of cancer-related death in the United States and worldwide. Most patients with lung cancer are treated with chemotherapy, radiotherapy, or surgery; however, effective treatment options remain limited. In this review, we aim to provide an overview of clinical trials, ranging from Phase I to III, conducted on drug delivery systems for lung cancer treatment. The trials included oral, inhaled, and intravenous administration of therapeutics. Furthermore, the study also talks about the evolving paradigm of targeted therapy and immunotherapy providing promising directions for personalized treatment. In addition, we summarize the best results and limitations of these drug delivery systems and discuss the potential capacity of nanomedicine.Keywords: lung cancer, clinical trials, nanomedicine, oral, intravenous, inhalation

Context. One of the long-term goals of exoplanet science is the atmospheric characterization of dozens of small exoplanets in order to understand their diversity and search for habitable worlds and potential biosignatures. Achieving this goal requires a space mission of sufficient scale that can spatially separate the signals from exoplanets and their host stars and thus directly scrutinize the exoplanets and their atmospheres.Aims. We seek to quantify the exoplanet detection performance of a space-based mid-infrared (MIR) nulling interferometer that measures the thermal emission of exoplanets. We study the impact of various parameters and compare the performance with that of large single-aperture mission concepts that detect exoplanets in reflected light.Methods. We have developed an instrument simulator that considers all major astrophysical noise sources and coupled it with Monte Carlo simulations of a synthetic exoplanet population around main-sequence stars within 20 pc of the Sun. This allows us to quantify the number (and types) of exoplanets that our mission concept could detect. Considering single visits only, we discuss two different scenarios for distributing 2.5 yr of an initial search phase among the stellar targets. Different apertures sizes and wavelength ranges are investigated.Results. An interferometer consisting of four 2 m apertures working in the 4–18.5 μ.m wavelength range with a total instrument throughput of 5% could detect up to ≈550 exoplanets with radii between 0.5 and 6 R⊕ with an integrated S/N ≥ 7. At least ≈160 of the detected exoplanets have radii ≤1.5 R⊕. Depending on the observing scenario, ≈25–45 rocky exoplanets (objects with radii between 0.5 and 1.5 R⊕) orbiting within the empirical habitable zone (eHZ) of their host stars are among the detections. With four 3.5 m apertures, the total number of detections can increase to up to ≈770, including ≈60–80 rocky eHZ planets. With four times 1 m apertures, the maximum detection yield is ≈315 exoplanets, including ≤20 rocky eHZ planets. The vast majority of small, temperate exoplanets are detected around M dwarfs. The impact of changing the wavelength range to 3–20 μm or 6–17 μm on the detection yield is negligible.Conclusions. A large space-based MIR nulling interferometer will be able to directly detect hundreds of small, nearby exoplanets, tens of which would be habitable world candidates. This shows that such a mission can compete with large single-aperture reflected light missions. Further increasing the number of habitable world candidates, in particular around solar-type stars, appears possible via the implementation of a multi-visit strategy during the search phase. The high median S/N of most of the detected planets will allow for first estimates of their radii and effective temperatures and will help prioritize the targets for a second mission phase to obtain high-S/N thermal emission spectra, leveraging the superior diagnostic power of the MIR regime compared to shorter wavelengths.

SettingImproved HIV monitoring and evaluation (M&E) is urgently needed to help close gaps in inpatient infant provider-initiated testing and counseling (PITC) and pediatric case identification. A revised reporting system was piloted on the Breastfeeding Ward at Hospital Central de Maputo in Maputo, Mozambique.ObjectiveTo demonstrate how a simplified reporting system designed for pediatric inpatient ward registers can be used to easily calculate key PITC indicators, including testing coverage, HIV status, linkage to antiretroviral therapy, maternal testing, and point-of-care nucleic acid testing.DesignThis was a retrospective review of PITC data documented in the ward discharge register for all inpatient infants with charts closed from January 1 to June 30, 2020.ResultsAt chart closure, 97.7% of infants (477/488) had known serostatus: 76.3% were not exposed (364/477), 15.3% were exposed (73/477), 1.9% definitively non-infected (9/477), and 6.5% infected (31/477). There was a 26.9% positivity rate (14/52) for infant point-of-care nucleic acid testing. Of all HIV-infected infants, 80.6% (25/31) were linked to antiretroviral therapy by the time of discharge. Preferred maternal testing was done in 80.5% of eligible mothers (276/343), with 3.0% newly positive (8/276).ConclusionThis straightforward PITC reporting system enabled simple calculation of key indicators needed for standard M&E, contributed to quality improvement efforts to increase testing coverage, and could be easily adapted for use in other settings.

The Baksan Experiment on Sterile Transitions (BEST) was designed to investigate the deficit of electron neutrinos ν_{e} observed in previous gallium-based radiochemical measurements with high-intensity neutrino sources, commonly referred to as the "gallium anomaly," which could be interpreted as evidence for oscillations between ν_{e} and sterile neutrino (ν_{s}) states. A 3.414-MCi ^{51}Cr ν_{e} source was placed at the center of two nested Ga volumes and measurements were made of the production of ^{71}Ge through the charged current reaction, ^{71}Ga(ν_{e},e^{-})^{71}Ge, at two average distances. The measured production rates for the inner and the outer targets, respectively, are [54.9_{-2.4}^{+2.5}(stat)±1.4(syst)] and [55.6_{-2.6}^{+2.7}(stat)±1.4(syst)] atoms of ^{71}Ge/d. The ratio (R) of the measured rate of ^{71}Ge production at each distance to the expected rate from the known cross section and experimental efficiencies are R_{in}=0.79±0.05 and R_{out}=0.77±0.05. The ratio of the outer to the inner result is 0.97±0.07, which is consistent with unity within uncertainty. The rates at each distance were found to be similar, but 20%-24% lower than expected, thus reaffirming the anomaly. These results are consistent with ν_{e}→ν_{s} oscillations with a relatively large Δm^{2} (>0.5  eV^{2}) and mixing sin^{2}2θ (≈0.4).