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Yi-Ran Han,1,* Tian-Hao Wang,2,* Wen-Ping Gong,3,* Jian-Qin Liang,1 Hui-Ru An1 1Department of Tuberculosis, Senior Department of Tuberculosis, The Eighth Medical Center of PLA General Hospital, Beijing, 100091, People’s Republic of China; 2Department of Emergency, The Eighth Medical Center of PLA General Hospital, Beijing, 100091, People’s Republic of China; 3Tuberculosis Prevention and Control Key Laboratory, Beijing Key Laboratory of New Techniques of Tuberculosis Diagnosis and Treatment, Institute for Tuberculosis Research, Senior Department of Tuberculosis, The 8th Medical Center of Chinese PLA General Hospital in China, Beijing, 100091, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hui-Ru An; Jian-Qin Liang, Department of Tuberculosis, Senior Department of Tuberculosis, The Eighth Medical Center of PLA General Hospital, No. 17 of Heishanhu Road, Haidian District, Beijing, 100091, People’s Republic of China, Tel +86 10 66775098, Email anhuiru25@outlook.com; wliangjianqin@126.comObjective: To make a systematic evaluation of the clinical efficacy of thymopentin combined with antituberculous drugs in treating drug-resistant pulmonary TB (PTB).Methods: Relevant studies were retrieved from PubMed, Embase, Cochrane Library, Chinese Biomedical Literature Database, CNKI, and Wanfang Database. STATA software was used to evaluate the differences in focal absorption rate, the time to cough symptom remission, sputum culture-negative rate, CD3+ T, CD4+ T, and CD8+ T cell levels after treatment.Results: A total of 23 randomized controlled trials literature involving 2031 cases were included. Meta-analysis revealed that compared with conventional therapy, the sputum culture-negative rate was significantly increased after 2– 3 months and 6– 9 months of treatment and the whole course of combined thymopentin treatment. The risk ratio (RR, 95% CI) was 1.44 (1.26– 1.64), 1.47 (1.21– 1.78), and 1.27 (1.18– 1.36), respectively. In the combined thymopentin treatment group, the focal absorption rate was higher, with RR (95% CI) = 1.36 (1.25– 1.47), the time of cough remission was shortened, with WMD (95% CI) =− 9.46d (− 10.36,− 8.57) and the differences were all statistically significant. Combined thymopentin therapy could effectively improve the levels of CD3+ T and CD4+ T lymphocytes in patients with drug-resistant PTB after 2– 3 months, 6– 9 months of treatment. The WMD (95% CI) were 9.96% (7.84, 12.08), 4.68% (2.90, 6.47) and 10.26% (7.81, 12.71), 7.21% (6.28, 8.15), respectively, and could also reduce the level of CD8+ T lymphocytes after 2– 3 months and 6– 9 months of treatment. The WMD (95% CI) were − 4.06% (− 4.96, − 3.13), − 3.52%, (− 4.07,− 2.98), respectively, and the differences were all statistically significant.Conclusion: Thymopentin adjuvant treatment for drug-resistant PTB can promote the therapeutic effect and improve the immune indexes in patients with drug-resistant PTB.Keywords: thymopentin, drug resistance, pulmonary TB, immunity, meta-analysis

This study aims to evaluate cognitive conflict in constructing mathematical concepts, based on thinking errors. The data were collected through observations of words or sentences, leading to the derivation of qualitative outputs. Furthermore, the results showed that the two selected subjects experienced cognitive conflicts regarding thinking errors in mathematical concept construction. This selection process was conducted through the provision of the questions obtained in the first semester of mathematics, at Universitas Negeri Makassar, Indonesia. These questions consisted of several indicators, with each of them having three components, namely the main, tracking, and supporting items. Based on the results, two subjects experienced thinking errors in constructing the concept of algebraic root form addition. This emphasized the errors in placing concepts (misplaced), pseudo-thinking, and misanalogy. A conflict was also observed between the initial concept knowledge of using variables in algebraic addition and the new principles understood through the root summation in algebra. Furthermore, there was also a conflict between the concept understanding he had in terms of the addition operation of the root form and a new understanding of the addition operation of the root form in algebra.

Background: Altered sensorium is one of the most common presentations in patients coming to the emergency room. It includes decreased level of consciousness, attention disorder, arousal disorder, and cognitive disorder. The causes of altered sensorium can be varied, some of which are cerebrovascular diseases, alcoholism, cerebral trauma, hypoglycemia, epilepsy, drug intoxication, and neuroinfection. 4–10% of the patients presenting to the emergency department may have altered mental status. The outcome is dependent on early identification and effective treatment using investigations and imaging technologies, and it might range from full recovery to permanent damage to death. Aims and Objectives: (1) To study clinical profile and etiology in altered sensorium patients. (2) To assess outcomes in altered sensorium patients. Materials and Methods: In this prospective cross-sectional study, clinical examination and investigations are done and data are collected using pro forma for patients fulfilling the inclusion criteria. In this study, all altered sensorium patients were evaluated by detailed history, clinical examination, Glasgow Coma Scale (GCS), laboratory investigations, computed tomography brain, and other investigations. All patients were followed up till discharge or death of the patient in the hospital. Results: There were 270 patients who presented with encephalopathy, 184 (68%) were males. The majority of these patients 60 (22.2%) were in the age group of 51–60 years old. The most common cause is neurological in 109 (40.3%) patients, metabolic in 64 (24%) patients, and sepsis in 50 (19%) patients. Ischemic stroke 83 (76%) is the most common neurological cause. Hepatic encephalopathy was the most common cause of metabolic encephalopathy present in 21 (32%) patients. Pneumonia was the most common infection. There were 114 (42.2%) deaths. Septic encephalopathy is the most common cause of mortality. Early presentation to the hospital, higher GCS, and conscious level at presentation were good prognostic markers of outcome in patients, while septic encephalopathy was found to have the worst prognosis. Conclusion: The common etiologies of encephalopathy are neurological followed by metabolic and sepsis. Early presentation to the emergency room within 6 h of symptom onset, higher GCS, neurological and metabolic causes are associated with a good prognosis. The mortality rate was 42.2%. Septic encephalopathy is the most common cause of death with pneumonia being the most common source of infection.

Ting Yang,1– 4,* Han-Rui Wang,1– 4,* Ya-Kui Mou,1– 4,* 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*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

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

Typhoid fever is a systemic infection caused by the Gram-negative bacilli Salmonellae, transmitted via the feaco-oral route. It commonly affects children, leading to complications and death if untreated. This is a report of typhoid fever admissions as seen at ABU Teaching Hospital Zaria over a 13-month period. Objectives: To describe the clinical presentation and management outcomes of children admitted with typhoid fever during a 13-month period. Materials and methods: A retrospective review of demographic, clinical presentation and treatment response of children managed for typhoid fever was conducted. Results were presented as means with standard deviation, proportions, tables, figures and Chisquares with p values. The prevalence of typhoid fever admissions was obtained over the period from 2008-2011. Results: A total of 779 children were admitted from 1st January 2011 to 31st January 2012, out of which 39 (4.9%) had a diagnosis of typhoid fever. There was a significant difference in prevalence of typhoid fever admissions from 2008-2010 compared to 2011 (X2 = 5.6651; p

Amani M Alqarni,1 Leila A Boubshait,1 Dana Ahmed Alnufaily,2 Sajidah J Alalwan,2 Hassn Reda Al Fardan,2 Marwah Foud Alabdulmhsin,2 Malak Abdulrahman Alotaibi,3 Nadeen A Boubshait4 1Family and Community Medicine, Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia; 2College of Medicine, Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia; 3Population Health Management, Ministry of Health, Riyadh, Saudi Arabia; 4College of Medicine, King Faisal University, Al-Ahsa, Saudi ArabiaCorrespondence: Leila A Boubshait, Email laboubshait@iau.edu.saBackground: Internet addiction is increasing worldwide. Internet addiction (IA) refers to excessive Internet usage in an uncontrolled and time-consuming manner, causing loss of time and disruption of daily life. However, the prevalence of IA may vary according to age, sex, and ethnicity, and is more prevalent among college students. There is a strong link between problematic Internet usage and an increased risk of developing Post Traumatic Stress Disorder PTSD and depression symptoms. Medical students were chosen for this study due to their unique stressors, including rigorous academic demands, extensive study hours, and clinical practice requirements. It is critical to address behavioral addictions and their psychological effects in this group, as they are linked to the future quality of healthcare provision compared with their non-medical peers.Objective: To estimate the prevalence of Problematic Internet Use (PIU) in medical students and explore their correlation with the medical students’ PTSD and Patient Health Questionnaire − 9 (PHQ9) scores.Methods: A cross-sectional online survey was conducted including 506 medical students in the second year of medical school up to internship year at Imam Abdulrahman bin Faisal University (IAU) between June 2021 and January 2022. The questionnaire consisted of consent forms, sociodemographic data, and screening tools for PTSD, the GPIU, and PHQ-9.Results: The prevalence of problematic internet usage (PIU) was 30.6% in the sample group. Students with moderate-to-moderately severe PTSD were 1.7 times more likely to have PIU OR (95% CI): 1.7 (1.091, 2.879). Students with moderate to severe depression were 2.2 times more likely to have PIU OR (95% CI); 2.2 (1.333, 3.950).Having a Saudi nationality, lower income, and being single was significantly associated with PIU.Conclusion: Single Saudi medical students with lower income are at risk of developing more problematic internet use. Especially those who score moderate to high on PTSD and PHQ-9 scales.Keywords: university students, academic performance, internet addiction, mental health

Abstract Background Hypoglycaemia is the primary manifestation of all the hepatic types of glycogen storage disease (GSD). In 2008, Glycosade®, an extended-release waxy maize cornstarch, was reported as an alternative to uncooked cornstarch (UCCS) which could prolong the duration of fasting in the GSD population. To date, there has been minimal published experience in (a) young children, (b) the ketotic forms of GSD, and (c) with daytime dosing. The Glyde study was created as a prospective, global initiative to test the efficacy and tolerance of Glycosade use across a broader and more diverse population. Methods A randomised double-blind cross-over fasting study assessing the tolerance and efficacy of Glycosade compared with cornstarch was performed across disease types and ages. Participants and clinicians chose the product deemed superior, whilst still blinded. Participants were followed for 2 years to assess long-term metabolic control, growth, and quality of life. Results Sixty-one participants (age 2–62 years; 59% female) were enrolled, and 58 participants completed the fasting studies (28 GSD I; 30 GSD III, VI, IX). Glycosade improved duration of fasting in GSD I and duration of fasting without ketosis in the ketotic forms. Chronic Glycosade use was chosen by 69% of participants. Those treated with Glycosade for the 2-year chronic phase used fewer doses of therapy while markers of metabolic control remained stable. Conclusion The Glyde study is the first multi-centre international trial demonstrating the efficacy and tolerance of Glycosade in a large cohort of hepatic GSD patients across a diverse international population. The ability to use fewer doses of therapy per day and avoidance of overnight therapy may improve compliance, safety, and quality of life without sacrificing metabolic control.

Georgie M Massen,1 Hannah R Whittaker,1 Sarah Cook,1 Gisli Jenkins,2 Richard J Allen,3,4 Louise V Wain,3,4 Iain Stewart,2 Jennifer K Quint,1 On behalf of DEMISTIFI consortiumAndrew Thorley, Anna Duckworth, Ali-Reza Mohammadi-Nejad, Aloysious Aravinthan, Anthony Harbottle, Armando Mendez Villalon, Chris Scotton, Christopher Denton, Daniel Lea, Dorothee Auer, Ebrima Joof, Eleanor Cox, Elizabeth Eves, Elizabeth Robertson, Emma Blamont, Fasihul Khan, Georgie Massen, Gina Parcesepe, Gisli Jenkins, Gordon Moran, Guruprasad Aithal, Hilary Longhurst, Iain Stewart, Jane Paxton, Jennifer Quint, Karen Piper Hanley, Kate Frost, Leo Casmino, Lisa Chakrabarti, Louise Wain, Margot Roeth, Maria Kaisar, Martin Craig, Michael Nation, Mohammad Alireza Kisomi, Mujdat Zeybel, Neil Guha, Nicholas Selby, Nick Oliver, Nick Selby, Olivia C Leavy, Penny Gowland, Philip Quinlan, Rachel Chambers, Richard Allen, Richard Hubbard, Rob Slack, Rutger Ploeg, Sam Moss, Sara Fawaz, Scott Turner, Shauntelle Quammie, Simon Johnson, Stamatios N Sotiropoulos, Stuart Astbury, Susan Francis, Tom Giles, Valerie Quinn, Wendy Adams, Xin Chen, Zhendi Gong 1School of Public Health, Imperial College London, London, UK; 2National Heart and Lung Institute, Imperial College London, London, UK; 3Department of Population Health Sciences, University of Leicester, Leicester, UK; 4NIHR Leicester Biomedical Research Centre, University of Leicester, Leicester, UK; National Heart and Lung Institute, Imperial College London, London, United Kingdom; University of Exeter, Exeter, United Kingdom; Sir Peter Mansfield Imaging Centre, Mental Health and Clinical Neurosciences, School of Medicine, University of Nottingham, Nottingham NG7 2UH, United Kingdom; Institute for Health Research (NIHR) Nottingham Biomedical Research Ctr, Queens Medical Ctr, Nottingham, United Kingdom; Nottingham Digestive Diseases Centre, Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, UK; Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK; Patient and Public Involvement and Engagement, Nottingham University Hospitals, Nottingham, United Kingdom; Digital Research Service, University of Nottingham, Nottingham, United Kingdom; Department of Clinical and Biomedical Sciences, University of Exeter,Exeter, United Kingdom; Centre for Rheumatology, Royal Free Hospital and University College London, London, UK; Digital Research Service, University of Nottingham, Nottingham, United Kingdom; Mental Health & Clinical Neurosciences,School of Medicine, University ofNottingham, Nottingham, UK; Sir Peter Mansfield Imaging Centre,School of Medicine, University ofNottingham, Nottingham, UK; NIHR Nottingham Biomedical ResearchCentre, Queen’s Medical Centre,University of Nottingham, Nottingham,UK; School of Life Sciences, University of Nottingham, Nottingham, United Kingdom, 2National Public Health Laboratories; Ministry of Health and Social Welfare, Banjul, The Gambia; Sir Peter Mansfield Imaging Centre, School of Physics & Astronomy, University of Nottingham, Nottingham, UK; NIHR Nottingham BRC, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK; Diabetes UK, UK; Diabetes UK, UK; Scleroderma and Raynaud’s UK, UK; Glenfield Hospital, University Hospitals of Leicester NHS Trust, Leicester, UK; Imperial College London, London, United Kingdom; Department of Population Health Sciences, University of Leicester, Leicester, UK; NIHR Leicester Biomedical Research Centre, Leicester, UK; Gisli Jenkins, Margaret Turner Warwick Centre for Fibrosing Lung Disease, National Heart and Lung Institute, Imperial College London, United Kingdom; Gordon W. Moran, NIHR Nottingham BRC, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK; Guruprasad P. Aithal, NIHR Nottingham BRC, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK; Dyskeratosis Congenita (DC) Action, UK; National Heart and Lung Institute, Imperial College London, London, UK; Dyskeratosis Congenita (DC) Action, UK; National Heart and Lung Institute, Imperial College London, London, UK; Division of Gastroenterology and Hepatology, Manchester University NHS Foundation Trust, Manchester, UK; Patient and Public Involvement and Engagement, Nottingham University Hospitals, Nottingham, United Kingdom; Sarcoidosis UK, UK; School of Veterinary Medicine and Science, Sutton Bonington Campus, University of Nottingham, Nottingham, UK; Medical Research Council Versus Arthritis Centre for Musculoskeletal Ageing Research, Nottingham, UK; Department of Population Health Sciences, University of Leicester, Leicester, UK; NIHR Leicester Biomedical Research Centre, University of Leicester, Leicester, UK; University of Nottingham, Nottingham, UK; Nuffield Department of Surgical Sciences, University of Oxford; Sir Peter Mansfield Imaging Center, School of Medicine, University of Nottingham, Nottingham, UK ; Wellcome Centre for Integrative Neuroimaging, Nuffield Department of Clinical Neurosciences, University of Oxford, UK; Quantified Imaging, London, UK; Kidney Research UK, UK; Sir Peter Mansfield Imaging Centre, Mental Health and Clinical Neurosciences, School of Medicine, University of Nottingham, Nottingham NG7 2UH, United Kingdom; NationalInstitute for Health Research (NIHR) Nottingham Biomedical Research Ctr, Queens Medical Ctr, Nottingham, United Kingdom; NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust & University of Nottingham, Nottingham, UK; NIHR Nottingham BRC, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK; Centre for Kidney Research and Innovation, University of Nottingham, Royal Derby Hospital Campus,Derby, UK; Department of Medicine, Imperial College London, London, UK; Centre for Kidney Research and Innovation, School of Medicine, University of Nottingham; Department of Non-communicable Disease Epidemiology, The London School of Hygiene and Tropical Medicine, London, UK; Department of Health Sciences, University of Leicester,Leicester, UK; Universiy of Nottingham, Sir Peter Mansfield Imaging Centre, Nottingham, United Kingdom; The Digital Research Service, University of Nottingham, UK; Centre for Inflammation and Tissue Repair, University College London, London, UK; Department of Population Health Sciences, University of Leicester, Leicester, UK, 2NIHR Leicester Biomedical Research Centre, Leicester, UK; University of Nottingham, Nottingham, UK; Galecto, Stevenage, Hertfordshire, UK; Nuffield Department of Surgical Sciences, University of Oxford, and Biomedical Research Centre Oxford; Imperial College London, London, United Kingdom; University of Nottingham, Nottingham, UK; NIHR Nottingham BRC, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK; University of Norringham, Nottingham, United Kingdom; Centre for Respiratory Research, NIHRRespiratory Biomedical Research Centre,School of Medicine, Biodiscovery Institute,University Park, University of Nottingham,Nottingham, UK; Sir Peter Mansfield Imaging Centre, School of Medicine, University of Nottingham, Nottingham, UK; Wellcome Centre for Integrative Neuroimaging, University of Oxford, Oxford, UK; National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Queens Medical Centre, Nottingham, UK; Nottingham Digestive Diseases Centre, Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, UK; NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK; Sir Peter Mansfield Imaging Centre, School of Physics, University of Nottingham, UK; The Digital Research Service & The Advanced Data Analysis Centre, University of Nottingham, UK; Margaret Turner Warwick Centre for Fibrosing Lung Disease, National Heart and Lung Institute, Imperial College London, United Kingdom; Action for Pulmonary Fibrosis, United Kingdom; School of Computer Science, University of Nottingham, UK; School of Computer Science, University of Nottingham, UKCorrespondence: Georgie M Massen, Email g.massen21@imperial.ac.ukBackground: Electronic healthcare records (EHRs) are used to document diagnoses, symptoms, tests, and prescriptions. Though not primarily collected for research purposes, owing to the size of the data as well as the depth of information collected, they have been used extensively to conduct epidemiological research. The Clinical Practice Research Datalink (CPRD) is an EHR database containing representative data of the UK population with regard to age, sex, race, and social deprivation measures. Fibrotic conditions are characterised by excessive scarring, contributing towards organ dysfunction and eventual organ failure. Fibrosis is associated with ageing as well as many other factors, it is hypothesised that fibrotic conditions are caused by the same underlying pathological mechanism. We calculated the prevalence of fibrotic conditions (as defined in a previous Delphi survey of clinicians) as well as the prevalence of fibrotic multimorbidity (the proportion of people with multiple fibrotic conditions).Methods: We included a random sample of 993,370 UK adults, alive, and enrolled at a UK general practice, providing data to the CPRD Aurum database as of 1st of January 2015. Individuals had to be eligible for linkage to hospital episode statistics (HES) and ONS death registration. We calculated the point prevalence of fibrotic conditions and multi-morbid fibrosis on the 1st of January 2015. Using death records of those who died in 2015, we investigated the prevalence of fibrosis associated death. We explored the most commonly co-occurring fibrotic conditions and determined the settings in which diagnoses were commonly made (primary care, secondary care or after death).Results: The point prevalence of any fibrotic condition was 21.46%. In total, 6.00% of people had fibrotic multimorbidity. Of the people who died in 2015, 34.82% had a recording of a fibrotic condition listed on their death certificate.Conclusion: The key finding was that fibrotic multimorbidity affects approximately 1 in 16 people.Plain Language Summary: Fibrotic conditions are scarring conditions which impact the way an organ functions and eventually lead to organ failure. We studied routinely collected health data from GPs, hospitals, and death certificates to estimate the percentage of UK adults who had fibrotic diseases. We found that 1 in 5 people had at least one fibrotic disease, and we also found that 1 in 16 people had more than one fibrotic disease.Keywords: fibrosis, CPRD, electronic health records, multimorbidity, fibrotic multimorbidity, ONS

Hye-Rin Kang,1,&ast; So Jeong Kim,2,&ast; Ju Gang Nam,3 Young Sik Park,4 Chang-Hoon Lee4 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Veteran Health Service Medical Center, Seoul, 05368, Republic of Korea; 2Division of Pulmonology and Allergy, Hallym University Dongtan Sacred Heart Hospital, Gyeonggi-do, 18450, Republic of Korea; 3Department of Radiology, Seoul National University Hospital, Seoul, 03080, Republic of Korea; 4Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul, 03080, Republic of Korea&ast;These authors contributed equally to this workCorrespondence: Chang-Hoon Lee, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-Ro Jongno-Gu, Seoul, 03080, Republic of Korea, Tel +82-2-2072-4743, Fax +82-2-762-9662, Email kauri670@empal.comIntroduction: Mortality differences in chronic obstructive pulmonary disease (COPD) between nonsmokers and smokers remain unclear. We compared the risk of death associated with smoking and COPD on mortality.Methods: The study included participants aged ≥ 40 years who visited pulmonary clinics and were categorised into COPD or non-COPD and smoker or nonsmoker on the basis of spirometry results and cigarette consumption. Mortality rates were compared between groups using statistical analysis for all-cause mortality, respiratory disease-related mortality, and cardiocerebrovascular disease-related mortality.Results: Among 5811 participants, smokers with COPD had a higher risk of all-cause (adjusted hazard ratio (aHR), 1.69; 95% confidence interval (CI), 1.23– 2.33) and respiratory disease-related mortality (aHR, 2.14; 95% CI, 1.20– 3.79) than nonsmokers with COPD. Non-smokers with and without COPD had comparable risks of all-cause mortality (aHR, 1.39; 95% CI, 0.98– 1.97) and respiratory disease-related mortality (aHR, 1.77; 95% CI, 0.85– 3.68). However, nonsmokers with COPD had a higher risk of cardiocerebrovascular disease-related mortality than nonsmokers without COPD (aHR, 2.25; 95% CI, 1.15– 4.40).Conclusion: The study found that smokers with COPD had higher risks of all-cause mortality and respiratory disease-related mortality compared to nonsmokers with and without COPD. Meanwhile, nonsmokers with COPD showed comparable risks of all-cause and respiratory mortality but had a higher risk of cardiocerebrovascular disease-related mortality compared to nonsmokers without COPD.Keywords: pulmonary disease, chronic obstructive, smokers, nonsmokers, cigarette smoking, comorbidity

Xin-Mei Hu,1,&ast; Can-Can Wang,1,&ast; Yu Xiao,1 Yu Liu,1 Hong-Ri Huang,2 Peng Jiang,1 Ying-Kai Wang,1 Yun-Jin Lin,1 Liang-Cheng Li,3 Zhong-Quan Qi1 1Medical College, Guangxi University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China; 2Department of Research and Development, Guangxi Taimei Rensheng Biotechnology Co., Ltd, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China; 3School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhong-Quan Qi, Guangxi University, Da-Xue-Dong Road No. 100, Xixiangtang District, Nanning, Guangxi Zhuang Autonomous Region, 530004, People’s Republic of China, Tel +8613806001271, Email yxyyz@gxu.edu.cn Liang-Cheng Li, Xiamen University, No. 4221-115, Rm 355, Xiang’an District, Xiang’an, Xiamen Fujian Province, 361102, People’s Republic of China, Tel +8618359206906, Email lchli2013@xmu.edu.cnPurpose: In recent years, exosomes have been proved to be used to treat many diseases. However, due to the lack of uniform quality control standards for exosomes, the safety of exosomes is still a problem to be solved, especially now more and more exosomes are used in clinical trials, and its non-clinical safety evaluation is particularly important. However, there is no safety evaluation standard for exosomes at present. Therefore, this study will refer to the evaluation criteria of therapeutic biological products, adopt non-human primates to evaluate the non-clinical safety of human umbilical cord mesenchymal stem cell exosomes from the general pharmacology and immunotoxicity, aiming at establishing a safety evaluation system of exosomes and providing reference for the clinical application of exosomes in the future.Methods: 3.85 × 1012 exosomes derived from human umbilical cord mesenchymal stem cells were injected into cynomolgus monkeys intravenously. The changes of general clinical conditions, hematology, immunoglobulin, Th1/Th2 cytokines, T lymphocytes and B lymphocytes, and immune organs were observed before and within 14 days after injection.Results: The results showed that exosomes did not have obvious pathological effects on the general clinical conditions, blood, coagulation function, organ coefficient, immunoglobulin, Th1/Th2 cytokines, lymphocytes, major organs, and major immune organs (spleen, thymus, bone marrow) of cynomolgus monkeys. However, the number of granulocyte-macrophage colonies in exosomes group was significantly higher than that in control group.Conclusion: To sum up, the general pharmacological results and immunotoxicity results showed that the injection of 3.85 × 1012 exosomes may have no obvious adverse reactions to cynomolgus monkeys. This dose of exosomes is relatively safe for treatment, which provides basis research for non-clinical safety evaluation of exosomes and provides reliable research basis for future clinical application of exosomes.Keywords: exosomes, cynomolgus monkeys, safety, immunotoxicity

Mohsen Safaei,1,2,&ast; Hossein Mohammadi,3,4,&ast; Salmia Beddu,4 Hamid Reza Mozaffari,5 Razieh Rezaei,2 Roohollah Sharifi,6 Hedaiat Moradpoor,7 Nima Fallahnia,8 Mona Ebadi,9,&ast; Mohd Suzeren Md Jamil,9 Ahmad Rifqi Md Zain,10 Muhammad Rahimi Yusop9 1Division of Dental Biomaterials, School of Dentistry, Kermanshah University of Medical Sciences, Kermanshah, Iran; 2Advanced Dental Sciences and Technology Research Center, School of Dentistry, Kermanshah University of Medical Sciences, Kermanshah, Iran; 3Biomaterials Research Group, School of Materials and Mineral Resources Engineering, Universiti Sains Malaysia, Engineering Campus, Nibong Tebal, Penang, 14300, Malaysia; 4Institute of Energy Infrastructure (IEI), Universiti Tenaga Nasional, Jalan IKRAM UNITEN, Kajang, Selangor, 43000, Malaysia; 5Department of Oral and Maxillofacial Medicine, School of Dentistry, Kermanshah University of Medical Sciences, Kermanshah, Iran; 6Department of Endodontics, School of Dentistry, Kermanshah University of Medical Sciences, Kermanshah, Iran; 7Department of Prosthodontics, School of Dentistry, Kermanshah University of Medical Sciences, Kermanshah, Iran; 8Students Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran; 9Department of Chemical Sciences, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, UKM Bangi, Selangor, 43600, Malaysia; 10Institute of Microengineering and Nanoelectronics (IMEN), Universiti Kebangsaan Malaysia (UKM), Bangi, Selangor, 43600, Malaysia&ast;These authors contributed equally to this workCorrespondence: Ahmad Rifqi Md Zain, Mohd Suzeren Md Jamil, Email rifqi@ukm.edu.my; suzeren@ukm.edu.myAbstract: Metallic dental implants have been extensively used in clinical practice due to their superior mechanical properties, biocompatibility, and aesthetic outcomes. However, their integration with the surrounding soft tissue at the mucosal region remains challenging and can cause implant failure due to the peri-implant immune microenvironment. The soft tissue integration of dental implants can be ameliorated through different surface modifications. This review discussed and summarized the current knowledge of topography-mediated immune response and topography-mediated antibacterial activity in Ti dental implants which enhance soft tissue integration and their clinical performance. For example, nanopillar-like topographies such as spinules, and spikes showed effective antibacterial activity in human salivary biofilm which was due to the lethal stretching of bacterial membrane between the nanopillars. The key findings of this review were (I) cross-talk between surface nanotopography and soft tissue integration in which the surface nanotopography can guide the perpendicular orientation of collagen fibers into connective tissue which leads to the stability of soft tissue, (II) nanotubular array could shift the macrophage phenotype from pro-inflammatory (M1) to anti-inflammatory (M2) and manipulate the balance of osteogenesis/osteoclasia, and (III) surface nanotopography can provide specific sites for the loading of antibacterial agents and metallic nanoparticles of clinical interest functionalizing the implant surface. Silver-containing nanotubular topography significantly decreased the formation of fibrous encapsulation in per-implant soft tissue and showed synergistic antifungal and antibacterial properties. Although the Ti implants with surface nanotopography have shown promising in targeting soft tissue healing in vitro and in vivo through their immunomodulatory and antibacterial properties, however, long-term in vivo studies need to be conducted particularly in osteoporotic, and diabetic patients to ensure their desired performance with immunomodulatory and antibacterial properties. The optimization of product development is another challenging issue for its clinical translation, as the dental implant with surface nanotopography must endure implantation and operation inside the dental microenvironment. Finally, the sustainable release of metallic nanoparticles could be challenging to reduce cytotoxicity while augmenting the therapeutic effects.Keywords: dental implant, nanotopography, roughness, macrophage, immunomodulation, biofilm formation

ABSTRACT Methionine (Met) and cysteine (Cys) are nutrients in broiler diets, responsible for strengthening protein synthesis, immunity, and metabolic regulation. To estimate the ideal digestible Met + Cys:digestible Lysine (Lys) ratio for broilers under a lipopolysaccharide (LPS) inflammatory challenge, 384 male broilers were distributed in a completely randomized 4×2 factorial design, with four ratios of dig. Met + Cys:dig. Lys (0.69, 0.73, 0.77, and 0.81) and two conditions (with or without challenge). Each treatment had eight replicates, with six birds per experimental unit (EU). The evaluated parameters included broilers’ weight gain (WG), feed intake (FI), and feed conversion ratio (FCR); jejunum mRNA transcript levels of nuclear factor kappa-B (NF-Κb), glutathione peroxidase (GPX), superoxide dismutase (SOD), glutathione synthetase (GSS), and methionine adenosyltransferase 2 (MAT2); relative weights of liver and spleen, and fat mass (%) and lean mass (%). A linear regression model would estimate the ideal ratio if an effect had occurred. No interaction (p>0.05) was observed between the factors for all the data, nor did the different ratios had any effect (p>0.05) either. LPS-administered exhibited reduced performance, heavier liver and spleen, and lower GSS expression. Hence, the lowest dig Met + Cys:dig Lys ratio (0.69) was sufficient to maintain the performance parameters, the relative weight of lymphoid organs, fat and lean mass, and NF-Kb, GPX, SOD, GSS, MAT2, and CBS mRNA transcript levels in the jejunum.

Vitamin B12 is an essential nutrient that is not made by plants; consequently, unfortified plant-based foods are not a reliable supply. Recent estimates suggest high rates of vitamin B12 deficiency among the vegetarian and vegan populations, particularly in pregnant women or women of child-bearing age who, for ethical and health reasons, are shifting towards higher consumption of plant-based foods in ever-increasing numbers. Vitamin B12 plays crucial metabolic roles across the life-course and in particular during pregnancy and in early development (first 1000 days of life). Evidence now implicates vitamin B12 deficiency with increased risk to a range of neuro, vascular, immune, and inflammatory disorders. However, the current UK recommended nutrient intake for vitamin B12 does not adequately consider the vitamin B12 deficit for those choosing a plant-based diet, including vegetarianism and in particular veganism, representing a hidden hunger. We provide a cautionary note on the importance of preventing vitamin B12 deficits for those individuals choosing a plant-based diet and the health professionals advising them.

Hot QCD physics studies the nuclear strong force under extreme temperatureand densities. Experimentally these conditions are achieved via high-energycollisions of heavy ions at the Relativistic Heavy Ion Collider (RHIC) and theLarge Hadron Collider (LHC). In the past decade, a unique and substantial suiteof data was collected at RHIC and the LHC, probing hydrodynamics at the nucleonscale, the temperature dependence of the transport properties of quark-gluonplasma, the phase diagram of nuclear matter, the interaction of quarks andgluons at different scales and much more. This document, as part of the 2023nuclear science long range planning process, was written to review the progressin hot QCD since the 2015 Long Range Plan for Nuclear Science, as well ashighlight the realization of previous recommendations, and presentopportunities for the next decade, building on the accomplishments andinvestments made in theoretical developments and the construction of newdetectors. Furthermore, this document provides additional context to supportthe recommendations voted on at the Joint Hot and Cold QCD Town Hall Meeting,which are reported in a separate document.

The thermal stability of zinc aluminate nanoparticles is critical for their use as catalyst supports. In this study, we experimentally show that doping with 0.5 mol % Y2O3 improves the stability of zinc aluminate nanoparticles. The dopant spontaneously segregates to the nanoparticle surfaces in a phenomenon correlated with excess energy reduction and the hindering of coarsening. Y3+ was selected based on atomistic simulations on a 4 nm zinc aluminate nanoparticle singularly doped with elements of different ionic radii: Sc3+, In3+, Y3+, and Nd3+. The segregation energies were generally proportional to ionic radii, with Y3+ showing the highest potential for surface segregation. Direct measurements of surface thermodynamics confirmed the decreasing trend in surface energy from 0.99 for undoped to 0.85 J/m2 for Y-doped nanoparticles. Diffusion coefficients calculated from coarsening curves for undoped and doped compositions at 850 °C were 4.8 × 10-12 cm2/s and 2.5 × 10-12 cm2/s, respectively, indicating the coarsening inhibition induced by Y3+ results from a combination of a reduced driving force (surface energy) and decreased atomic mobility.

Background: Idiopathic intracranial hypertension (IIH) typically manifests with headache, accompanied by papilledema and visual loss, and has a higher prevalence in females. In recent years, ocular sonography, particularly, measurement of optic nerve sheath diameter (ONSD), is being investigated for diagnosis of IIH. Methods: A total of 35 patients over the age of 18 years, fulfilling the modified Dandy's criteria for diagnosis of IIH were included. Patients underwent assessment with magnetic resonance imaging, lumbar puncture, and ocular sonography to measure ONSD and ocular arterial indices. Results: The mean ONSD values (in centimeters) in the right eye of patients with IIH was 0.57 ± 0.13, while it was 0.48 ± 0.03 in controls. In the left eye, the mean ONSD value (cm) was 0.59 ± 0.13 in patients with IIH and 0.48 ± 0.03 in controls. ONSD was significantly higher in cases compared to controls (P < 0.001, Welch test). Pulsatility index of the central retinal artery was significantly higher in cases compared to controls (P < 0.001, Welch test). Resistance index of the ophthalmic artery was statistically significant (P < 0.005, Welch test). Receiver operating characteristic curve analysis revealed a cutoff value of 5.1 mm on the right side and 5 mm on the left side had a sensitivity and specificity of more than 80% for IIH diagnosis. Conclusion: Our study provides insights into the utility of optic nerve sheath measurements and arterial indices in the diagnosis of IIH in a South Indian cohort. Further research is needed to fully understand the longitudinal relationship of these parameters and treatment outcomes in IIH.

Introduction: Tuberous sclerosis complex (TSC) is a rare autosomal dominant disorder. Facial angiofibromas are the most common cutaneous findings of TSC. Treatment modalities such as laser, surgery, and/or cryotherapy are employed. Topical therapy with Sirolimus, an mTOR inhibitor, showed beneficial effects. Objective: To study the effects of topical sirolimus (0.1%) on Facial Angiofibromas in patients of TSC. Methodology: Four patients with facial angiofibromas were included. They applied Sirolimus preparation twice daily, for 3 months. The Facial Angiofibroma Severity Index (FASI) was recorded pre-intervention, at 3 months and after 6 months. Results: All the patients showed a reduction in the FASI score at the end of three months of therapy. In three patients, on discontinuing therapy, there was no change in the FASI score at the end of six months, i.e., FASI 3 and FASI 6 were the same. Conclusion: Topical sirolimus is an effective treatment for facial angiofibroma in patients with TSC.

Lu Zhu,1,&ast; Jing Li,1,&ast; Zhao-Qin Wang,1,2,&ast; Yun-Jia Gu,1 Guo-Na Li,3 Wen-Jia Wang,1 Guang-Bin Pen,1 Qi Li,1 Meng-Die Wu,1 Hui-Rong Liu,1,2 Yan Huang,1,2 Lu-Yi Wu1 1Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 2Shanghai Research Institute of Acupuncture and Meridian, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 3School of Acupuncture, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lu-Yi Wu, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, No. 110 Ganhe Road, Hongkou District, Shanghai City, 200437, People’s Republic of China, Email luyitcm@163.com Yan Huang, Shanghai Research Institute of Acupuncture and Meridian, Shanghai University of Traditional Chinese Medicine, No. 650 Wanping South Road, Xuhui District, Shanghai City, 200030, People’s Republic of China, Email huangyan@shutcm.edu.cnObjective: Moderate-to-severe pain is the most common clinical symptom in patients with hepatocellular carcinoma (HCC).This trial aimed to analyze the clinical efficacy of Transcutaneous electrical acupoint stimulation (TEAS) in patients of HCC with severe pain and provide a reliable reference for optimizing the clinical diagnostic and therapeutic strategies of HCC.Methods: A total of 104 eligible patients were randomly allocated to experimental and control groups in a ratio of 1:1.The treatment was administered for 1 week continuously. Patients in both groups were followed up 1 week after the end of the treatment.The primary outcome measure was the Numerical Rating Scale (NRS) score, whereas the secondary outcome measures included Brief Pain Inventory BPI-Q3, Q4, Q5 scores, analgesic dose, frequency of opioid-induced gastrointestinal side effects, Karnofsky Performance Status (KPS), Quality of Life Scale - Liver Cancer (QOL-LC), and Brief Fatigue Inventory (BFI) scores.Results: The NRS scores of experimental group was significantly lower after treatment and at the follow-up than baseline (average P< 0.01), there were also statistical differences between the groups at the above time points (average P< 0.01). BPI-Q3, -Q4, and -Q5 scores in the experimental group were decreased after treatment when compared with those before treatment (average P< 0.01). Furthermore, there were significant improvements of gastrointestinal side effects, KPS, QOL-LC and BPI in the experimental group after treatment, and the above results were statistically significant compared to the control group.Conclusion: 7-day TEAS treatment can significantly enhance the analgesic effect and maintain for the following week, also reduce the incidence of gastrointestinal side effects caused by opioids, and improve the quality of life of patients with moderate-to-severe HCC-related pain, which has reliable safety and certain clinical promotion value.Keywords: hepatocellular carcinoma pain, transcutaneous electrical acupoint stimulation, cancer pain, randomized controlled trial

The aneurysm of the gastroduodenal artery (AGDA) is a rare, but potentially fatal vascular disease. Chronic pancreatitis is considered to be the leading etiological cause. The most common complication is rupture, which is accompanied by extremely high mortality, due to the rapidly occurring massive blood loss. In such situations, a high index of clinical suspicion, followed by urgent imaging diagnosis and active treatment strategy in case of emergency can prevent a potentially fatal outcome. In the following paper, we present a case of a successfully treated ruptured aneurysm of the gastroduodenal artery(AGDA), that started with minor gastrointestinal bleeding. Endoscopic hemostasis was attempted, followed by an episode of massive recurrent bleeding, requiring emergency operation. A brief literature review, related to the diagnosis and treatment of this rare, but fatal complication of AGDA, is also presented.

Nancy B Lundin,1 Alexandra M Blouin,1 Henry R Cowan,1,2 Aubrey M Moe,1,3 Heather M Wastler,1 Nicholas JK Breitborde1,3 1Early Psychosis Intervention Center, Department of Psychiatry and Behavioral Health, The Ohio State University, Columbus, OH, USA; 2Department of Psychology, Michigan State University, East Lansing, MI, USA; 3Department of Psychology, The Ohio State University, Columbus, OH, USACorrespondence: Nancy B Lundin, Early Psychosis Intervention Center, Department of Psychiatry and Behavioral Health, The Ohio State University, 1670 Upham Drive, Columbus, OH, 43210, USA, Tel +1 614 293 6361, Email Nancy.Lundin@osumc.eduAbstract: Early detection of psychotic-spectrum disorders among adolescents and young adults is crucial, as the initial years after psychotic symptom onset encompass a critical period in which psychosocial and pharmacological interventions are most effective. Moreover, clinicians and researchers in recent decades have thoroughly characterized psychosis-risk syndromes, in which youth are experiencing early warning signs indicative of heightened risk for developing a psychotic disorder. These insights have created opportunities for intervention even earlier in the illness course, ideally culminating in the prevention or mitigation of psychosis onset. However, identification and diagnosis of early signs of psychosis can be complex, as clinical presentations are heterogeneous, and psychotic symptoms exist on a continuum. When a young person presents to a clinic, it may be unclear whether they are experiencing common, mild psychotic-like symptoms, early warning signs of psychosis, overt psychotic symptoms, or symptoms better accounted for by a non-psychotic disorder. Therefore, the purpose of this review is to provide a framework for clinicians, including those who treat non-psychotic disorders and those in primary care settings, for guiding identification and diagnosis of early psychosis within the presenting clinic or via referral to a specialty clinic. We first provide descriptions and examples of first-episode psychosis (FEP) and psychosis-risk syndromes, as well as assessment tools used to diagnose these conditions. Next, we provide guidance as to the differential diagnosis of conditions which have phenotypic overlap with psychotic disorders, while considering the possibility of co-occurring symptoms in which case transdiagnostic treatments are encouraged. Finally, we conclude with an overview of early detection screening and outreach campaigns, which should be further optimized to reduce the duration of untreated psychosis among youth.Keywords: diagnostic assessment, early detection, recent-onset psychosis, clinical high risk for psychosis, psychosis continuum

Chia-Yu Huang,1,2 Mei-Yao Wu,3– 5 Ming-Cheng Huang,2,3 Teng-Shun Yu,6,7 Peter Karl Mayer,3,8,&ast; Hung-Rong Yen2,3,5,8,9,&ast; 1Department of Family Medicine, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, Taiwan; 2Graduate Institute of Chinese Medicine, School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan; 3Department of Chinese Medicine, China Medical University Hospital, Taichung, Taiwan; 4School of Post-Baccalaureate Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan; 5Research Center for Traditional Chinese Medicine, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan; 6Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan; 7College of Medicine, China Medical University, Taichung, Taiwan; 8International Master Program in Acupuncture, College of Chinese Medicine, China Medical University, Taichung, Taiwan; 9Chinese Medicine Research Center, China Medical University, Taichung, 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, 404, Taiwan, ext. 3001 Fax +886-4-22365141, Email hungrongyen@mail.cmu.edu.twPurpose: Disability is the comorbidity of dementia for which there is no available preventive measure. The aim of this study was to investigate the association between acupuncture treatment and the risk of disability development in dementia patients.Patients and Methods: A cohort study was performed using a nationwide health database in Taiwan. The included dementia patients were divided into acupuncture and non-acupuncture cohorts based on whether they received acupuncture treatment during the follow-up period. The variables in the two cohorts were controlled by 1:1 propensity-score matching. The difference in disability development in dementia patients between the acupuncture and non-acupuncture cohorts was also analyzed. Subgroup analyses were performed using socioeconomic variables, comorbidities and anti-dementia agents (donepezil, rivastigmine, galantamine and memantine) used for dementia treatment.Results: A total of 9,760 dementia patients met our inclusion criteria, and patients were divided into an equal number (n=2,422) of acupuncture and non-acupuncture groups, respectively, after 1:1 propensity-score matching. The dementia patients had a lower risk of disability development after acupuncture treatment than those who did not receive acupuncture treatment (adjusted hazard ratio 0.65, 95% confidence interval 0.60– 0.70, p < 0.001). The results were independent of basic variables or comorbidities in the two cohorts. Patients who did not use anti-dementia agents had a lower risk of developing disability after receiving acupuncture intervention than those who used anti-dementia agents.Conclusion: Our results revealed the relationship between acupuncture intervention and decreased risk of developing disability in dementia patients. The results are useful for dementia treatment, trial design and further planning of care programs.Keywords: acupuncture, disability, dementia, traditional Chinese medicine

Haules Robbins Zaniku,1,2 Emilia Connolly,3– 5 Moses Banda Aron,6,7 Beatrice Lydia Matanje,8 Myness Kasanda Ndambo,9 George Complex Talama,10 Fabien Munyaneza,11 Todd Ruderman,8 Jamie Rylance,12,13 Luckson Wandani Dullie,14 Rejani Lalitha,15 Ndaziona Peter Kwanjo Banda,16,&ast; Adamson S Muula17,&ast; 1Department of Physiotherapy, Ministry of Health, Neno District Health Office, Neno, Lilongwe, Malawi; 2Department of Epidemiology and Biostatistics, School of Global and Public Health, Kamuzu University of Health Sciences, Lilongwe, Malawi; 3Department of Partnerships and Policy, Partners in Health/Abwenzi Pa Za Umoyo (PIH/APZU), Neno, Lilongwe, Malawi; 4Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA; 5Division of Hospital Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, 45529, USA; 6Monitoring and Evaluation Department, Partners in Health/Abwenzi Pa Za Umoyo (PIH/APZU), Neno, Lilongwe, Malawi; 7Snakebite Envenoming Department, Research Group Snakebite Envenoming, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany; 8Clinical Department, Partners in Health/Abwenzi Pa Za Umoyo (PIH/APZU), Neno, Lilongwe, Malawi; 9Department of Health Systems and Policy, Training and Research Unit of Excellence (TRUE), Kamuzu University of Health Sciences, Lilongwe, Malawi; 10Programs Directorate, Partners in Hope, Lilongwe, Malawi; 11Research Department, Partners in Health/Abwenzi Pa Za Umoyo (PIH/APZU), Neno, Lilongwe, Malawi; 12Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre, Malawi; 13Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, UK; 14Global Leadership Ecosystem, Partners in Health/Abwenzi Pa za Umoyo (PIH/APZU), Neno, Lilongwe, Malawi; 15Pulmonary Division, Department of Medicine, School of Medicine, Makerere University College of Health Sciences, Kampala, Uganda; 16Department of Medicine, School of Medicine and Oral Health, Kamuzu University of Health Sciences, Lilongwe, Malawi; 17Community and Environmental Health Department, School of Global and Public Health, Kamuzu University of Health Sciences, Lilongwe, Malawi&ast;These authors contributed equally to this workCorrespondence: Haules Robbins Zaniku, Neno District Health Office, P.O. Box 52, Neno, Malawi, Tel +265-994-922-140, Email hrzanikuh@gmail.comIntroduction: Chronic obstructive pulmonary disease (COPD) continues to pose a global public health challenge. However, literature is scarce on the burden of COPD in Malawi. We assessed the prevalence and risk factors for COPD among adults in Neno, Malawi.Methodology: We conducted a population-based analytical cross-sectional study in Neno District between December 2021 and November 2022. Using a multi-stage sampling technique, we included 525 adults aged≥ 40 years. All participants underwent spirometry according to the American Thoracic Society (ATS) guidelines and were interviewed using the IMPALA questionnaire. For this study, we utilized the definition of COPD as a post-bronchodilator FEV1/FVC < 0.70. We collected data using Kobo collect, exported to Microsoft Excel, and analysed using R software. We used descriptive statistics and logistic regression analysis; a p-value of < 0.05 was considered statistically significant.Results: Out of 525 participants, 510 participants were included in the final analysis. Fifty-eight percent of the participants were females (n=296), and 62.2% (n=317) were between 40 and 49 years with a median (IQR) age of 46 (40– 86). For patient characteristics, 15.1% (n=77) were current smokers, and 4.1% (n=21) had a history of pulmonary tuberculosis (PTB). Cough was the most commonly reported respiratory symptom (n=249, 48.8%). The prevalence of COPD was 10.0% (n=51) and higher (15.0%) among males compared to females (6.4%). Factors significantly associated with COPD were age 60 years and above (adjusted odds ratio [aOR] = 3.27, 95% CI: 1.48– 7.34, p< 0.004), ever smoked (aOR = 6.17, 95% CI:1.89– 18.7, p< 0.002), current smoker (aOR = 17.6, 95% CI: 8.47– 38.4, p< 0.001), and previous PTB (aOR = 4.42, 95% CI: 1.16– 15.5, p< 0.023).Conclusion: The cross-sectional prevalence of COPD in rural Malawi is high, especially among males. Factors significantly associated were older age (60 years and above), cigarette smoking, and previous PTB. Longitudinal studies are needed to better understand disease etiology and progression in this setting.Keywords: chronic obstructive pulmonary disease, prevalence, spirometry, associated factors, Malawi

Newcastle disease (ND) is a highly contagious viral disease that constantly threatens poultry production. The velogenic (highly virulent) form of ND inflicts the most damage and can lead to 100% mortality in unvaccinated village chicken flocks. This study sought to characterize responses of local chickens in Ghana after challenging them with lentogenic and velogenic Newcastle disease virus (NDV) strains. At 4 wk of age, chicks were challenged with lentogenic NDV. Traits measured were pre- and post-lentogenic infection growth rates (GR), viral load at 2 and 6 d post-lentogenic infection (DPI), viral clearance rate and antibody levels at 10 DPI. Subsequently, the chickens were naturally exposed to velogenic NDV (vNDV) after anti-NDV antibody titers had waned to levels ≤1:1,700. Body weights and blood samples were again collected for analysis. Finally, chickens were euthanized and lesion scores (LS) across tissues were recorded. Post-velogenic exposure GR; antibody levels at 21 and 34 days post-velogenic exposure (DPE); LS for trachea, proventriculus, intestines, and cecal tonsils; and average LS across tissues were measured. Variance components and heritabilities were estimated for all traits using univariate animal models. Mean pre- and post-lentogenic NDV infection GRs were 6.26 g/day and 7.93 g/day, respectively, but mean post-velogenic NDV exposure GR was -1.96 g/day. Mean lesion scores ranged from 0.52 (trachea) to 1.33 (intestine), with males having significantly higher (P < 0.05) lesion scores compared to females. Heritability estimates for the lentogenic NDV trial traits ranged from moderate (0.23) to high (0.55) whereas those for the vNDV natural exposure trial were very low (≤ 0.08). Therefore, in contrast to the vNDV exposure trial, differences in the traits measured in the lentogenic challenge were more affected by genetics and thus selection for these traits may be more feasible compared to those following vNDV exposure. Our results can form the basis for identifying local chickens with improved resilience in the face of NDV infection for selective breeding to improve productivity.

Songbirds’ vocal mastery is impressive, but to what extent is it a result of practice? Can they, based on experienced mismatch with a known target, plan the necessary changes to recover the target in a practice-free manner without intermittently singing? In adult zebra finches, we drive the pitch of a song syllable away from its stable (baseline) variant acquired from a tutor, then we withdraw reinforcement and subsequently deprive them of singing experience by muting or deafening. In this deprived state, birds do not recover their baseline song. However, they revert their songs toward the target by about 1 standard deviation of their recent practice, provided the sensory feedback during the latter signaled a pitch mismatch with the target. Thus, targeted vocal plasticity does not require immediate sensory experience, showing that zebra finches are capable of goal-directed vocal planning.

Purpose The ‘Biomarkers of heterogeneity in type 1 diabetes’ study cohort was set up to identify genetic, physiological and psychosocial factors explaining the observed heterogeneity in disease progression and the development of complications in people with long-standing type 1 diabetes (T1D).Participants Data and samples were collected in two subsets. A prospective cohort of 611 participants aged ≥16 years with ≥5 years T1D duration from four Dutch Diabetes clinics between 2016 and 2021 (median age 32 years; median diabetes duration 12 years; 59% female; mean glycated haemoglobin (HbA1c) 61 mmol/mol (7.7%); 61% on insulin pump; 23% on continuous glucose monitoring (CGM)). Physical assessments were performed, blood and urine samples were collected, and participants completed questionnaires. A subgroup of participants underwent mixed-meal tolerance tests (MMTTs) at baseline (n=169) and at 1-year follow-up (n=104). Genetic data and linkage to medical and administrative records were also available. A second cross-sectional cohort included participants with ≥35 years of T1D duration (currently n=160; median age 64 years; median diabetes duration 45 years; 45% female; mean HbA1c 58 mmol/mol (7.4%); 51% on insulin pump; 83% on CGM), recruited from five centres and measurements, samples and 5-year retrospective data were collected.Findings to date Stimulated residual C-peptide was detectable in an additional 10% of individuals compared with fasting residual C-peptide secretion. MMTT measurements at 90 min and 120 min showed good concordance with the MMTT total area under the curve. An overall decrease of C-peptide at 1-year follow-up was observed. Fasting residual C-peptide secretion is associated with a decreased risk of impaired awareness of hypoglycaemia.Future plans Research groups are invited to consider the use of these data and the sample collection. Future work will include additional hormones, beta-cell-directed autoimmunity, specific immune markers, microRNAs, metabolomics and gene expression data, combined with glucometrics, anthropometric and clinical data, and additional markers of residual beta-cell function.Trial registration number NCT04977635.