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Background: Intramural pregnancy is a very rare type of ectopic pregnancy, which is surrounded by uterine myometrium layer and separates from endometrium. To our knowledge, this abnormal location site of ectopic pregnancy remains likely under-recognized and under-reported. Through this paper, we aim to underscore the role of minimally invasive surgery in this uncommon condition where applicable, especially in low-middle income countries., Case Presentation: A 34-year-old Vietnamese female patient (gravida 3 parity 1) was hospitalized due to a diagnosis of intramural pregnancy. Rapidly, the patient underwent laparoscopy for a removal of ectopic pregnancy mass corresponding to 5-6 weeks of gestation, taking into consideration the possibility of conservative surgery. This surgical intervention was carefully performed under ultrasound guidance at operating room. The surgical management resulted in a favorable outcome, though a hysterectomy and laparotomy could be avoided intentionally in this case., Conclusion: This case report emphasizes the timely detection of intramural pregnancy involving the successful outcome. Moreover, in an early term of intramural pregnancy, uterine conservative management under laparoscopic surgery combined with ultrasound could be a reliable management for this extreme rarity at tertiary center. Further data is required to strengthen this finding., Competing Interests: Declarations. Ethics approval and consent to participate: This report was naturally waived by institutional ethics committee of Tu Du Hospital and prepared in accordance with the ethical standards of the 1964 Helsinki Declaration. Consent for publication: Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal. Competing interests: The authors declare that they have no competing interests., (© 2024. The Author(s).)

Background: Madagascar has made significant progress in the fight against malaria. However, the number of malaria cases yearly increased since 2012. ITNs and IRS are key interventions for reducing malaria in Madagascar. Given the increasing number of cases and limited resources, understanding the cost-effectiveness of these strategies is essential for policy development and resource allocation., Methods: Using a societal perspective, this study aims to estimate the cost of the National Malaria Control Program (NMCP) through the first national malaria strategic plan (implemented over the period 2009-2013) and to assess the cost-effectiveness of two individually implemented malaria control interventions (ITNs and IRS) in two districts, Ankazobe and Brickaville. The cost-effectiveness ratio (CER) of ITN intervention was then compared to the CER of IRS intervention to identify the most cost-effective intervention. The cost of the NMCP and the costs incurred in the implementation of each intervention at the district level were initially estimated. On the basis of two results, the CERs of ITN or IRS correspond to the total cost of ITN or IRS divided by the number of people protected or the number of disability-adjusted life years (DALYs) averted. A deterministic univariate sensitivity analysis was conducted to assess the robustness of the results with a discount rate of 2.5% (0-5%) (costs and DALYs) and a 95% CI (person protected)., Results: From 2009 to 2013, the NMCP cost USD 45.4 million (USD 43.5-47.5, r = 0-5%) per year, equivalent to USD 2.0 per capita per year. IRS implementation costs were four times higher than those of ITNs. The CER of IRS per case protected (USD 295.1 [285.1-306.1], r = 0-5%) was higher than the CER of ITNs (USD 48.6 [USD 46.0-51.5, r = 0-5%] in Ankazobe and USD 26.5 [USD 24.8-28.4, r = 0-5%] in Brickaville). The CERs per DALY averted of IRS was USD 427.6 [USD 413.0-546.3, r = 0-5%] in Ankazobe and, for ITNs, it was USD 85.4 [USD 80.8-90.5, r = 0-5%] in Ankazobe and USD 45.3 [USD 42.2-48.4, r = 0-5%] in Brickaville. Compared to the country GDP per capita (USD PPP 1494.6 in 2013), ITN intervention was "highly cost-effective" while the CER for IRS interventions was sensitive to parameter variation (CI, 95% of persons protected), which ranges from highly cost-effective to only cost-effective (USD 291.5-2004, r = 2.5%)., Conclusion: In the Malagasy context, IRS intervention cost more and was less effective than ITN intervention. Willingness to pay for IRS is questioned. A relevant budget impact analysis should be conducted before a potential extension of this intervention., Competing Interests: Declarations. Ethics approval and consent to participate: The Ministry of Public Health of Madagascar (approval no. 247/MNSANP/SG on 26/03/2013) and the National Ethics Committee of the Ministry of Public Health of Madagascar (approval no. 12/MNSANP/EC on 03/12/2014) approved this study. All surveys followed ethical principles according to the Helsinki Declaration. Written informed consent was obtained from all participants or the parents/tutors of the children before inclusion. Consent for publication: Not Applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: The healthcare sector is rapidly evolving with the rise of digital technology and data-driven decision-making. However, traditional medical education has yet to fully integrate training on managing health-related information, resulting in a significant skills gap among medical and research professionals. This gap is pronounced in low- and middle-income countries (LMICs), where data privacy concerns and inadequate infrastructure hinder efforts to utilise and share health data., Aims: To address this gap, we developed an online, modular course aimed at providing foundational skills on capturing, storing and sharing health data., Methods: The course was developed using the ADDIE(Analyze, Design, Develop, Implement, Evaluate) instructional design model. A needs assessment workshop involving 25 global health proffesionals identified key training gaps which informed the curriculum's development. A multidisciplinary team from six institutions developed the modules. The course was piloted in a face-to-face setting with 37 participants and later adapted for online delivery via the Global Health Network platform. We evaluated the course using Level 1 of Kirkpatrick's model for training evaluation., Results: Six foundational modules were developed: Introduction to Data Management, Data Quality, Data Repositories, Ethics of Data Sharing, Data Governance, and Costing for Data Management. Between December 2020 and April 2024, 6,384 individuals from 90 countries completed the course. Of these, 32% were from Africa, 15% from Asia, 16% from South/Central America and the Caribbean, and 24% from Europe. Summative evaluations, based on voluntary post-module surveys, demonstrated high relevance to participants' learning needs (96.6%) and strong intentions to apply the skills gained (88.3%). Key motivators for enrollment included the course's free access, relevance to professional or academic needs, and trust in the organizations and authors behind the content., Conclusions: The high enrolment and broad geographical reach demonstrates the potential of online training as a cost-effective tool to equip health practitioners and researchers with data literacy skills. Future evaluations will assess its impact on participants' knowledge, behavior, and data-sharing and reuse practices., Competing Interests: Declarations. Ethics approval and consent to participate: This paper describes the development and implementation of a course and includes a summary of anonymized data generated from a service evaluation. According to the NHS Health Research Authority toolkit, service evaluations are not classified as research studies, and therefore are exempt from ethical approval by the Oxford Tropical Research Ethics Committee. Consent for publication: Participation in the feedback survey is voluntary. The survey introduction explains that de-identified data from the survey may be published in a report, scientific journals and/or presented at conferences. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

A research protocol is a document that outlines the proposed research idea and is submitted to funding agencies, institutions, or journals for approval. Writing a research protocol represents a challenge, particularly for early-career researchers. In this guide, we aim to provide detailed guidance with the key components and offer practical tips for crafting a research protocol in line with the various study designs. Specifically, the structure of a research protocol should contain the following items: (1) a title that is specific, catchy, and impressive within the word limitation; (2) an abstract that briefs the critical points of the study; (3) an introduction highlighting the study context from broad to narrow and defining the knowledge gap; (4) a justification underlining the significance of the proposed study; (5) Specific, Measurable, Attainable, Relevant, and Time-bound (SMART) objective(s) and aim(s); (6) a methodology covering seven sub-items, including [i] study design and settings, [ii] study subjects, [iii] sample size calculation and sampling, [iv] participants recruitment and follow-up, [v] questionnaire development, [vi] potential variables and outcomes, and [vii] data analysis plan; (7) dissemination of the results; (8) ethics and conflict of interests; (9) budgets analysis/ funding disclosure; and (10) references. This guide will give an overview of these steps and provide clear and concise tips on how to successfully draft a scientific protocol. With careful planning and appropriate guidance, it is possible to develop a well-structured and compelling protocol to obtain approval for the conduction of the study or funding from agencies, institutions, or organizations., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing of interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Cervical cancer is the fourth most common malignant tumor in childbearing-age women. To date, cervical resection and fertility-sparing surgery are the trends in the era of minimally invasive management. However, a proper management remains crucial. Hereby, we endeavor to underscore an uncommon case of early-stage cervical cancer receiving a tailored surgical technique of abdominal radical trachelectomy at our tertiary referral center and review literature., Case Presentation: A 33-year-old Vietnamese female patient (E1) was hospitalized for a diagnosis of cervical cancer classified as IB1 stage. The patient was treated with fertility-sparing modified abdominal radical trachelectomy surgery. The postoperative outcome was completely favorable. The patient was sent home after 5 days of hospitalization. In addition, she was monitored without complications., Conclusion: Fertility-preserving treatment could be effectively performed with a modified technique of abdominal radical trachelectomy among young women with early-stage cervical cancer. Interdisciplinary management is potentially necessary for favorable outcome. Further data are required for long-term outcomes of pregnancy, recurrent rate, and the risk of pelvic organ prolapse., Competing Interests: Declarations. Ethics approval consent to participate: Ethics approval was naturally waived for case reports by the ethics committee of Tu Du Hospital. The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Informed consent: Informed consent was obtained from the patient for publication of this case report. A copy of the consent is available for review by the Editor-in-Chief of this journal upon request. Competing interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024. The Author(s).)

Objectives: To examine the correlation between healthy lifestyle patterns, their change trajectories, and the risk of multimorbidity in adults., Methods: Based on two representative national cohorts, the English Longitudinal Study of Aging (ELSA) and the Health and Retirement Study (HRS) including adults aged 50 years and over. We employed Cox regression, lifestyle change trajectories, and restricted mean survival times to explore the relationship between lifestyle (assessed by SCORE2, LE'8, and HLS scores) and multimorbidity. We also conducted mediation analysis to investigate the underlying mechanisms., Results: A healthy lifestyle (higher LE'8, higher HLS, or lower SCORE2) can reduce the risk of multimorbidity. 2-10% lower multimorbidity risk per one-point increase in LE'8 and HLS. The hazard ratio of multimorbidity for improvements in unhealthy lifestyles or deterioration in healthy lifestyles compared to always healthy lifestyles ranged from 1.598 to 5.602. Besides, for LE'8 and HLS, participants with higher scores had a slower decrease in survival probability in ELSA. Triglyceride, C-reaction protein, fibrinogen, and cystatin C partly mediate the association between lifestyle and multimorbidity., Conclusions: Keeping a healthy lifestyle over time can help reduce the risk of multimorbidity., (© 2024. The Author(s).)

Malaria is preventable, but the burden of disease remains high with over 249 million cases and 608,000 deaths reported in 2022. Historically, the most important protective interventions have been vector control and chemopreventive medicines with over 50 million children receiving seasonal malaria chemoprevention in the year 2023. Two vaccines are approved and starting to be deployed, bringing additional protection for children up to 36 months. However, the impact of these currently available tools is somewhat limited on various fronts. Vaccines exhibit partial efficacy, are relatively costly, and not accessible in all settings. The challenges encountered with chemoprevention are barriers to acceptability and feasibility, including frequency of dosing, and the lack of options in the first trimester of pregnancy and for women living with HIV. Also, the emergence of resistance against chemopreventive medicines is concerning. To address these limitations, a target product profile (TPP) is proposed as a road map to guide innovation and to boost the quest for novel chemopreventive alternatives. This TPP describes the ideal product attributes, while acknowledging potential trade-offs that may be needed. Critically, it considers the target populations most at risk; primarily infants, children, and pregnant women. Malaria control and elimination requires appropriate chemoprevention, not only in areas of high endemicity and transmission, but also in lower transmission areas where immunity is declining, as well as for travellers from areas where malaria has been eliminated. New medicines should show acceptable safety and tolerability, with high and long protective efficacy. Formulations and costs need to support operational adherence, access, and effectiveness. Next generation long-acting oral and injectable drugs are likely to constitute the backbone of malaria prevention. Therefore, the perspectives of front-line experts in malaria prevention, researchers, and those involved in drug development are captured in the TPP. This inclusive approach aims at concentrating efforts and aligning responses across the community to develop new and transformative medicines., (© 2024. The Author(s).)

Background: Telemedicine provides specialized medical expertise in underserved areas where neurological expertise is frequently not available on a daily basis for hospitalized stroke patients. While tele-consultations are well established in acute stroke assessment, the value of telemedicine-based ward-rounds in the subsequent in-patient stroke management is unknown., Methods: Four telemedicine stroke networks in Germany, implemented in eight out of 16 federal states, participate in this prospective observational multi-center study. We plan to enroll 523 patients hospitalized due to acute (suspected or confirmed) stroke or transient ischemic attack. Each recruited patient will receive both a tele-consultation and an on-site consultation at the same day within the first three days after hospital admission. We will test non-inferiority of telemedicine-based assessments in ward-rounds in terms of quality of medical assessment and recommendations for hospitalized stroke patients. The correctness of the medical assessment and recommendation is defined as positive evaluation (binary, correct vs. in-correct) of six out of six predefined quality indicators by at least two out of three blinded independent raters. The non-inferiority margin for the difference in proportions of correct assessments is set to 5%-points., Discussion: If non-inferiority of telemedicine-based ward-rounds compared to on-site ward-rounds by a neurologist were demonstrated, telemedicine-based neurological consultation for post-acute stroke patients may contribute to deliver evidence-based high-quality stroke care more easily in underserved regions., Trial Registration: DRKS - DRKS00028671 ( https://drks.de/search/de/trial/DRKS00028671 ; registration date 09-27-2022)., (© 2024. The Author(s).)

Monitoring tumor evolution and predicting survival using non-invasive liquid biopsy is an unmet need for glioblastoma patients. The era of proteomics and metabolomics blood analyzes, may help in this context. A case-control study was conducted. Patients were included in the GLIOPLAK trial (ClinicalTrials.gov Identifier: NCT02617745), a prospective bicentric study conducted between November 2015 and December 2022. Patients underwent biopsy alone and received radiotherapy and temozolomide. Blood samples were collected at three different time points: before and after concomitant radiochemotherapy, and at the time of tumor progression. Plasma samples from patients and controls were analyzed using metabolomics and proteomics, generating 371 omics features. Descriptive, differential, and predictive analyses were performed to assess the relationship between plasma omics feature levels and patient outcome. Diagnostic performance and longitudinal variations were also analyzed. The study included 67 subjects (34 patients and 33 controls). A significant differential expression of metabolites and proteins between patients and controls was observed. Predictive models using omics features showed high accuracy in distinguishing patients from controls. Longitudinal analysis revealed temporal variations in a few omics features including CD22, CXCL13, EGF, IL6, GZMH, KLK4, and TNFRSP6B. Survival analysis identified 77 omics features significantly associated with OS, with ERBB2 and ITGAV consistently linked to OS at all timepoints. Pathway analysis revealed dynamic oncogenic pathways involved in glioblastoma progression. This study provides insights into the potential of plasma omics features as biomarkers for glioblastoma diagnosis, progression and overall survival. Clinical implication should now be explored in dedicated prospective trials., (© 2024. The Author(s).)

Background: Social anxiety disorder (SAD) is one of the most prevalent anxiety disorders in Canada. Viable therapy options for the treatment of SAD include CBT being delivered virtually. In Australia, an innovative internet-delivered cognitive-behavioral therapy (iCBT) program for social anxiety has been developed, implemented, and demonstrated as effective. To make available high-quality and real-time evidence in response to the crucial need to access psychological services to meet population mental health needs, we propose to conduct a Canadian adaptation of the iCBT Shyness Program and to examine the program's effectiveness, and implementation in two Canadian provinces (Quebec and Ontario)., Methods: The overall study design is a hybrid effectiveness-implementation study of a quasi-experimental parallel group trial. Prior to implementing the iCBT Shyness Program, it will undergo an initial adaptation to the Canadian context and focus groups will be conducted with key actor groups to discuss the adaptations to the graphics, narration of the lessons, and this to better reflect varying socio-cultural context among Canadian French- and English-speaking populations. We will evaluate the effectiveness of the program in three parallel pathways reflecting real-world pathways: (1) self-refer to the intervention; (2) recommended by a health professional without guidance; and (3) recommended by a health professional, with low-intensity guidance. Data collection will be carried out at baseline, at the beginning of each lesson, 12-week and 6-month follow-up. Outcomes measured will include anxiety and depressive symptoms, psychological distress, disability, as well as health service utilization and satisfaction. Semi-structured interviews will then be conducted with study participants and health care providers to explore facilitating factors and barriers to the implementation of the iCBT adapted program., Discussion: This study will provide evidence on the effectiveness, barriers and facilitating factors to implementing a low-intensity iCBT in the Canadian context for SAD, which will bridge an important care gap for undeserved populations in Canada with SAD. Findings will inform the eventual scaling up of the program in community-based primary care across Canada. This would improve equity of the health care system by helping a large number of Canadians to timely access to mental health services., Trial Registration: clinicaltrials.gov NCT06403995. Prospectively registered on 05/03/2024., (© 2024. The Author(s).)

Background: Epigenetic clocks are mathematical models used to estimate epigenetic age based on DNA methylation at specific CpG sites. As new methylation microarrays are developed and older models discontinued, existing epigenetic clocks might become obsolete. Here, we explored the effects of the changes introduced in the new EPICv2 DNA methylation array on existing epigenetic clocks., Methods: We tested the performance of four epigenetic clocks on the probeset of the EPICv2 array using a dataset of 10,835 samples. We developed a new epigenetic age prediction model compatible across the 450 k, EPICv1, and EPICv2 microarrays and validated it on 2095 samples. We estimated technical noise and intra-subject variation using two datasets with repeated sampling. We used data from (i) cancer survivors who had undergone different therapies, (ii) breast cancer patients and controls, and (iii) an exercise-based interventional study, to test the ability of our model to detect alterations in epigenetic age acceleration in response to theoretically antiaging interventions., Results: The results of the four epiclocks tested are significantly distorted by the EPICv2 probeset, causing an average difference of up to 25 years. Our new model produced highly accurate chronological age predictions, comparable to a state-of-the-art epiclock. The model reported the lowest epigenetic age acceleration in normal populations, as well as the lowest variation across technical replicates and repeated samples from the same subjects. Finally, our model reproduced previous results of increased epigenetic age acceleration in cancer patients and in survivors treated with radiation therapy, and no changes from exercise-based interventions., Conclusion: Existing epigenetic clocks require updates for full EPICv2 compatibility. Our new model translates the capabilities of state-of-the-art epigenetic clocks to the EPICv2 platform and is cross-compatible with older microarrays. The characterization of epigenetic age prediction variation provides useful metrics to contextualize the relevance of epigenetic age alterations. The analysis of data from subjects influenced by radiation, cancer, and exercise-based interventions shows that despite being good predictors of chronological age, neither a pathological state like breast cancer, a hazardous environmental factor (radiation), nor exercise (a beneficial intervention) caused significant changes in the values of the "epigenetic age" determined by these first-generation models., (© 2024. The Author(s).)

Background: Use of electronic health records (EHR) to provide real-world data for research is established, but using EHR to deliver randomised controlled trials (RCTs) more efficiently is less developed. The Allergy AntiBiotics And Microbial resistAnce (ALABAMA) RCT evaluated a penicillin allergy assessment pathway versus usual clinical care in a UK primary care setting. The aim of this paper is to describe how EHRs were used to facilitate efficient delivery of a large-scale randomised trial of a complex intervention embracing efficient participant identification, supporting minimising GP workload, providing accurate post-intervention EHR updates of allergy status, and facilitating participant follow up and outcome data collection. The generalisability of the EHR approach and health economic implications of EHR in clinical trials will be reported in the main ALABAMA trial cost-effectiveness analysis., Methods: A descriptive account of the adaptation of functionality within SystmOne used to deliver/facilitate multiple trial processes from participant identification to outcome data collection., Results: An ALABAMA organisation group within SystmOne was established which allowed sharing of trial functions/materials developed centrally by the research team. The 'ALABAMA unit' within SystmOne was also created and provided a secure efficient environment to access participants' EHR data. Processes of referring consented participants, allocating them to a trial arm, and assigning specific functions to the intervention arm were developed by adapting tools such as templates, reports, and protocols which were already available in SystmOne as well as pathways to facilitate allergy de-labelling processes and data retrieval for trial outcome analysis., Conclusions: ALABAMA is one of the first RCTs to utilise SystmOne EHR functionality and data across the RCT delivery, demonstrating feasibility and applicability to other primary care RCTs., Trial Registration: ClinicalTrials.gov: NCT04108637, registered 05/03/2019. ISRCTN: ISRCTN20579216., (© 2024. The Author(s).)

Background: Patients with migraine are vulnerable to insufficient sleep, but the impact of sleep restriction is largely unknown. In addition, the importance of sleep may be different in patients with migraine who mostly have attack onsets during sleep, so called sleep-related migraine, compared to patients with non-sleep-related migraine. In this study we investigate the effect of sleep restriction on endogenous pain modulation in patients with migraine and healthy controls. We also compared the effect of sleep restriction in sleep-related and in non-sleep-related migraine., Methods: Measurements were conducted in 39 patients with migraine between attacks and 31 controls, once after habitual sleep and once after two consecutive nights of partial sleep restriction. There were 29 and 10 patients with non-sleep-related and sleep-related migraine respectively. Test stimulus was 2-min tonic noxious heat to the left volar forearm. Temporal summation was calculated as the regression coefficient for rated pain in the late part of this 2-min stimulation. Conditioning stimulus was right hand-immersion in 7 °C water. Conditioned pain modulation was defined as the difference in rated pain with and without the conditioning stimulus and was calculated for temporal summation and mean rated pain for the test stimulus. The effect of sleep restriction on temporal summation and conditioned pain modulation was compared in migraine subjects and controls using two-level models with recordings nested in subjects., Results: Conditioned pain modulation for temporal summation of heat pain tended to be reduced after sleep restriction in patients with migraine compared to controls (p = 0.060) and, in an exploratory analysis, was reduced more after sleep restriction in sleep-related than in non-sleep-related migraine (p = 0.017). No other differences between groups after sleep restriction were found for temporal summation or conditioned pain modulation., Conclusion: Patients with migraine may have a subtly altered endogenous pain modulation system. Sleep restriction may have an increased pronociceptive effect on this system, suggesting a mechanism for vulnerability to insufficient sleep in migraine. This effect seems to be larger in sleep-related migraine than in non-sleep-related migraine., (© 2024. The Author(s).)

Single-cell technology depicts integrated tumor profiles including both tumor cells and tumor microenvironments, which theoretically enables more robust diagnosis than traditional diagnostic standards based on only pathology. However, the inherent challenges of single-cell RNA sequencing (scRNA-seq) data, such as high dimensionality, low signal-to-noise ratio (SNR), sparse and non-Euclidean nature, pose significant obstacles for traditional diagnostic approaches. The diagnostic value of single-cell technology has been largely unexplored despite the potential advantages. Here, we present a graph neural network-based framework tailored for molecular diagnosis of primary liver tumors using scRNA-seq data. Our approach capitalizes on the biological plausibility inherent in the intercellular communication networks within tumor samples. By integrating pathway activation features within cell clusters and modeling unidirectional inter-cellular communication, we achieve robust discrimination between malignant tumors (including hepatocellular carcinoma, HCC, and intrahepatic cholangiocarcinoma, iCCA) and benign tumors (focal nodular hyperplasia, FNH) by scRNA data of all tissue cells and immunocytes only. The efficacy to distinguish iCCA from HCC was further validated on public datasets. Through extending the application of high-throughput scRNA-seq data into diagnosis approaches focusing on integrated tumor microenvironment profiles rather than a few tumor markers, this framework also sheds light on minimal-invasive diagnostic methods based on migrating/circulating immunocytes., (© 2024. The Author(s).)

Background: To formulate effective strategies for antimicrobial stewardship (AMS) in primary care, it is crucial to gain a thorough understanding of factors influencing prescribers' behavior within the context. This qualitative study utilizes the Theoretical Domains Framework (TDF) to uncover these influential factors., Methods: We conducted a qualitative study using in-depth interviews and focus group discussions with primary care workers in two provinces in rural Vietnam. Data analysis employed a combined inductive and deductive approach, with the deductive aspect grounded in the TDF., Results: Thirty-eight doctors, doctor associates, and pharmacists participated in twenty-two interviews and two focus group discussions. We identified sixteen themes, directly mapping onto seven TDF domains: knowledge, skills, behavioral regulation, environmental context and resources, social influences, social/professional role and identity, and optimism. Factors driving unnecessary prescription of antibiotics include low awareness of antimicrobial resistance (AMR), diagnostic uncertainty, prescription-based reimbursement policy, inadequate medication supplies, insufficient financing, patients' perception of health insurance medication as an entitlement, and maintaining doctor-patient relationships. Potential factors facilitating AMS activities include time availability for in-person patient consultation, experience in health communication, and willingness to take action against AMR., Conclusion: Utilizing the TDF to systematically analyze and present behavioral determinants offers a structured foundation for designing impactful AMS interventions in primary care. The findings underscore the importance of not only enhancing knowledge and skills but also implementing environmental restructuring, regulation, and enablement measures to effectively tackle unnecessary antibiotic prescribing in this context., (© 2024. The Author(s).)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces immune-mediated diseases. The pathophysiology of COVID-19 uses the following three mechanisms: (1) inflammasome activation mechanism; (2) cGAS-STING signaling mechanism; and (3) SAMHD1 tetramerization mechanism, which leads to IFN-I production. Interactions between the host and virus govern induction, resulting in multiorgan impacts. The NLRP3 with cGAS-STING constitutes the primary immune response. The expression of SARS-CoV-2 ORF3a, NSP6, NSP7, and NSP8 blocks innate immune activation and facilitates virus replication by targeting the RIG-I/MDA5, TRIF, and cGAS-STING signaling. SAMHD1 has a target motif for CDK1 to protect virion assembly, threonine 592 to modulate a catalytically active tetramer, and antiviral IFN responses to block retroviral infection. Plastic and allosteric nucleic acid binding of SAMHD1 modulates the antiretroviral activity of SAMHD1. Therefore, inflammasome activation, cGAS-STING signaling, and SAMHD1 tetramerization explain acute kidney injury, hepatic, cardiac, neurological, and gastrointestinal injury of COVID-19. It might be necessary to effectively block the pathological courses of diverse diseases., (© 2024. The Author(s).)

Background: Numerous studies have examined associations between overweight and obesity and risk of low back pain (LBP), but the exact magnitude of these associations is not yet clear. The purpose of this work was to assess such sex-specific associations in a community-based setting in Norway, taking into account potential relationships with other risk factors., Methods: A cohort study was conducted combining data from two waves of the Trøndelag Health Study, HUNT3 (2006-2008) and HUNT4 (2017-2019). Separate analyses were performed of risk of chronic LBP in HUNT4 among 14,775 individuals without chronic LBP in HUNT3, and of recurrence or persistence in HUNT4 among 5034 individuals with chronic LBP in HUNT3. Relative risks were estimated in generalised linear models for overweight and obesity compared to normal weight. Body size classification was based on values of BMI computed from measurements of height and weight. Chronic LBP was defined as LBP persisting at least 3 months during last year., Results: After adjustment for age, smoking, physical activity in leisure time and work activity, analysis of risk among women produced relative risks 1.11 (95% CI 1.00-1.23) for overweight, 1.36 (95% CI 1.20-1.54) for obesity class I and 1.68 (95% CI 1.42-2.00) for obesity classes II-III. Relative risks among men were 1.10 (95% CI 0.94-1.28) for overweight, 1.36 (95% CI 1.13-1.63) for obesity class I and 1.02 (95% CI 0.70-1.50) for obesity classes II-III, the last estimate being based on relatively few individuals. Analyses of recurrence or persistence indicated similar relationships but with smaller magnitude of relative risks and no drop in risk among obesity classes II-III in men. The change in BMI from HUNT3 to HUNT4 hardly differed between individuals with and without chronic LBP in HUNT3., Conclusions: Risk of chronic LBP increases with higher values of BMI in both sexes, although it is uncertain whether this applies to very obese men. Very obese women carry a particularly large risk. Probabilities of recurrence or persistence of chronic LBP among those already afflicted also increase with higher values of BMI. Adjustment for other factors does not influence relationships with overweight and obesity to any major extent., (© 2024. The Author(s).)

Objectives: This study aimed to evaluate the association between different levels of physical activity and risk of developing type 2 diabetes (T2D) mellitus among adults with prediabetes in Chinese population., Methods: This prospective population-based cohort study included 12,424 participants (mean [SD] age, 52.8 [16.8] years; 82.2% men) with prediabetes at 2014 survey of the Kailuan study. Physical activity information was collected through the International Physical Activity Questionnaire-Short Form and categorized by metabolic equivalent (MET) of task as low, moderate, and high. Cox regression models were built to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between physical activity levels and incident T2D., Results: During a median follow-up of 3.6 years, 2,207 (17.8%) participants developed T2D. The incident rate of T2D were 55.83/1000, 35.14/1000, and 39.61/1000 person-years in the low, moderate, and high physical activity level group, respectively. Both moderate (HR 0.57, 95% CI 0.49 to 0.67) and high (HR 0.76, 95% CI 0.66 to 0.89) physical activity levels were associated with lower risks of developing T2D compared to low physical activity level (P for trend < 0.001). The association between high physical activity level and T2D was primarily observed in participants without metabolic syndrome (P for interaction < 0.001). Moreover, participants with moderate or high levels of physical activity had significantly decreased fasting blood glucose levels during follow-up when compared to those with low level (P group*time < 0.001)., Conclusion: This study suggested that individuals with prediabetes might benefit from moderate and high levels of physical activity., (© 2024. The Author(s).)

Background: Variations in untranslated regions (UTR) alter regulatory pathways impacting phenotype, disease onset, and course of disease. Protein kinase C Zeta (PRKCZ), a serine-threonine kinase, is implicated in cardiovascular, neurological and oncological disorders. Due to limited research on PRKCZ, this study aimed to investigate the impact of UTR genetic variants' on binding sites for transcription factors and miRNA. RNA secondary structure, eQTLs, and variation tolerance analysis were also part of the study., Methods: The data related to PRKCZ gene variants was downloaded from the Ensembl genome browser, COSMIC and gnomAD. The RegulomeDB database was used to assess the functional impact of 5' UTR and 3'UTR variants. The analysis of the transcription binding sites (TFBS) was done through the Alibaba tool, and the Kyoto Encyclopaedia of Genes and Genomes (KEGG) was employed to identify pathways associated with PRKCZ. To predict the effect of variants on microRNA binding sites, PolymiRTS was utilized for 3' UTR variants, and the SNPinfo tool was used for 5' UTR variants., Results: The results obtained indicated that a total of 24 variants present in the 3' UTR and 25 variants present in the 5' UTR were most detrimental. TFBS analysis revealed that 5' UTR variants added YY1, repressor, and Oct1, whereas 3' UTR variants added AP-2alpha, AhR, Da, GR, and USF binding sites. The study predicted TFs that influenced PRKCZ expression. RNA secondary structure analysis showed that eight 5' UTR and six 3' UTR altered the RNA structure by either removal or addition of the stem-loop. The microRNA binding site analysis highlighted that seven 3' UTR and one 5' UTR variant altered the conserved site and also created new binding sites. eQTLs analysis showed that one variant was associated with PRKCZ expression in the lung and thyroid. The variation tolerance analysis revealed that PRKCZ was an intolerant gene., Conclusion: This study laid the groundwork for future studies aimed at targeting PRKCZ as a therapeutic target., (© 2024. The Author(s).)

Background: Measles remains a major public health burden worldwide. Parents often hesitate to vaccinate children with chronic diseases. We investigated the association between the percentage of vaccination and chronic diseases and explore hospital infections' role in the 2017-2019 measles outbreak across northern Vietnam provinces., Methods: A total of 2,064 children aged 0-15 years old admitted for measles to the National Children's Hospital during the outbreak were included in the study. Demographic information, clinical characteristics, vaccination statuses and laboratory examination were extracted from electronic medical records, vaccination records, or interviews with parents when other sources were unavailable., Results: The incidence rate that provincial hospitals sent to the National Children's Hospital was proportional to the population density of their provinces of residence. Early nosocomial transmission of measles was observed before community-acquired cases emerged in many provinces. Among patients aged over 18 months, those with chronic diseases had a proportion of vaccination of 9.4%, lower than patients without chronic diseases at 32.4%. Unvaccinated patients had a higher proportion of hospital-acquired infections with aOR = 2.42 (1.65-3.65), p < 0.001 relative to vaccinated patients. The proportion of hospital-acquired infections was higher among children with chronic diseases compared to those without, with aOR = 3.81 (2.90-5.02), p < 0.001., Conclusion: Measles spread in healthcare settings prior to community cases that occurred in several provinces. We recommend enhancing hospital infection control by increasing staff training and improving early detection and isolation during non-outbreak periods. Measles patients with chronic diseases exhibited lower proportions of vaccination and faced a higher risk of hospital-acquired infections. It is crucial to establish comprehensive vaccination guidelines and enhance parental awareness regarding the significance and safety of measles vaccination to protect these vulnerable individuals., (© 2024. The Author(s).)

Background: Posterior reversible encephalopathy syndrome (PRES) is an uncommon neurological disorder which is characterised by variable symptoms. The transient clinical condition may be underestimated and misdiagnosed as other conditions, especially, among pregnant women with severe preeclampsia, eclampsia, and HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome in the puerperium. We hereby contribute to the literature this rare complication and hightlight the appropriate management of PRES ., Presentation Case: A pregnant woman (gravida 3, parity 2) had a normal antenatal course. However, she was diagnosed with severe preeclampsia and HELLP syndrome at 29 weeks and 5 days of gestation. Therefore, she was indicated for a medical termination of pregnancy following a patient's consent at our tertiary referral hospital. Severely, the patient developed rapidly with altered mental health in early puerperium. In result, PRES was diagnosed based on a brain magnetic resonance imaging (MRI) evidence with typical findings. After a strict multidisciplinary management, the clinical condition improved after 5 days of onset and recovered completely after a 4-month follow-up without any sequelae., Conclusion: In summary, despite its rarity, clinicians ought to be knowledgeable and raise an aware of PRES during pregnancy. Importantly, a brain imaging modalities should be taken into account among pregnant women with neurological symptoms subsequent to severe preeclampsia. In addition to early diagnosis, a timely appropriate treatment with multidisciplinary team is strongly indicated. Further studies with a large case series are required for this uncommon entity., (© 2024. The Author(s).)

Background: Familial Partial Lipodystrophy (FPLD) is a disease with wide clinical and genetic variation, with seven different subtypes described. Until genetic testing becomes feasible in clinical practice, non-invasive tools are used to evaluate body composition in lipodystrophic patients. This study aimed to analyze the different anthropometric parameters used for screening and diagnosis of FPLD, such as thigh skinfold thickness (TS), Köb index (Köbi), leg fat percentage (LFP), fat mass ratio (FMR) and leg-to-total fat mass ratio in grams (LTR), by dual-energy X-ray absorptiometry, focusing on determining cutoff points for TS and LFP within a Brazilian population., Methods: Thirty-seven patients with FPLD and seventy-four healthy controls matched for body mass index, sex and age were studied. Data were collected through medical record review after signing informed consent. All participants had body fat distribution evaluated by skinfolds and DXA measures. Fasting blood samples were collected to evaluate glycemic and lipid profiles. Genetic studies were carried out on all patients. Two groups were categorized based on genetic testing and/or anthropometric characteristics: FPLD+ (positive genetic test) and FPLD1 (negative genetic testing, but positive clinical/anthropometric criteria for FPLD)., Results: Eighteen (48.6%) patients were classified as FPLD+, and 19 (51.4%) as FPLD1. Unlike what is described in the literature, the LMNA variant in codon 582 was the most common. Among the main diagnostic parameters of FPLD, a statistical difference was observed between the groups for, Köbi, TS, LFP, FMR, and LTR. A cutoff point of 20 mm for TS in FPLD women was found, which is lower than the value classically described in the literature for the diagnosis of FPLD. Additionally, an LFP < 29.6% appears to be a useful tool to aid in the diagnosis of these women., Conclusion: Combining anthropometric measurements to assess body fat distribution can lead to a more accurate diagnosis of FPLD. This study suggests new cutoff points for thigh skinfold and leg fat percentage in women with suspected FPLD in Brazil. Further studies are needed to confirm these findings., (© 2024. The Author(s).)

Background: Brominated flame retardants (BFRs) are widely utilized to mitigate the flammability of various materials. Previous studies have revealed the impact of BFRs exposure on hormonal disruption and bone metabolism which are closely related to periodontitis. However, it remains unknown the potential relationship between BFRs and periodontitis. This study aimed to explore the association between BFRs exposure and periodontitis in US adults., Methods: The data analyzed in this study were obtained from the National Health and Nutrition Examination Survey (NHANES) 2009-2014. Twelve serum BFRs were quantified using isotope dilution gas chromatography high-resolution mass spectrometry. Univariable and multivariable logistic regression was employed to evaluate the association between serum BFRs and periodontitis. Bayesian kernel machine regression (BKMR) analyses were utilized to assess the association between mixtures of BFRs and periodontitis., Results: A total of 3311 eligible participants were included. Serum BFRs (PBDE-47, PBDE-99, and PBDE-154) were significantly associated with periodontitis, and the odds ratios (ORs) and corresponding 95% confidence intervals(CIs) were 1.15(1.01,1.29), 1.10(1.01,1.20), and 1.12(1.01,1.25), respectively. Notably, these three BFRs were also significantly associated with the severity of periodontitis. Additionally, the BKMR model revealed a significant association between the mixture of all twelve BFRs and periodontitis., Conclusions: This preliminary study suggests a significant association between specific serum BFRs (PBDE-47, PBDE-99, and PBDE-154) and periodontitis and its severity. Further prospective and experimental studies are warranted to validate our findings., (© 2024. The Author(s).)

Background: Undernutrition, which includes stunting, wasting, and underweight, is a global problem, especially among children of low- and middle-income countries. To our knowledge, this study is first of its type from Afghanistan. Its main objectives were to estimate the prevalence and associated risk factors of stunting, wasting/thinness, and underweight among urban primary school children in Kandahar city of Afghanistan., Methods: This school-based cross-sectional study was conducted among 1205 primary school children aged 6-12 years during a period of six months (October 2022-March 2023). Anthropometric measurements and other data were collected from all the participants. Data were analyzed by using descriptive statistics, Chi square test (using crude odds ratio or COR), and multivariate logistic regression (using adjusted odds ratio or AOR)., Results: Among the 1205 enrolled government school students, 47.4%, 19.5%, and 25.6% had stunting, wasting/thinness, and underweight, respectively. Statistically significant factors associated with stunting were age group 6-9 years (AOR 1.3, 95% CI 1.1-1.7), being girl (AOR 2.3, 95% CI 1.8-3.0), poverty (AOR 2.2, 95% CI 1.5-3.2), large family (AOR 3.0, 95% CI 2.4-3.9), illiterate mother (AOR 1.6, 95% CI 1.0-2.6), jobless head of the family (AOR 3.3, 95% CI 2.3-4.8), and skipping breakfasts (AOR 1.7, 95% CI 1.2-2.3). Main factor associated with wasting/thinness were age group 6-9 years (AOR 30.5, 95% CI 11.8-78.7), skipping breakfasts (AOR 22.9, 95% CI 13.9-37.8), and history of sickness during the past two weeks (AOR 17.0, 95% CI 6.6-43.8). Also, main factors associated with underweight were age group 6-9 years (AOR 2.6, 95% CI 1.6-4.1), skipping breakfasts (AOR 2.6, 95% CI 1.8-3.6), and poor sanitation (AOR 1.9, 95% CI 1.1-3.2)., Conclusions: Stunting, wasting/thinness, and underweight are highly prevalent among primary school children (both girls and boys) in Kandahar city. It is recommended that local government (Afghanistan Ministry of Education and Ministry of Public Health) with the help of international organizations and donor agencies should implement comprehensive school-based feeding programs especially for girls. Health and nutrition education programs should be conducted with emphasis on nutrition of children aged 6-9 years as well as importance of healthy breakfast and good sanitation., (© 2024. The Author(s).)

Objective: To assess the impact of an intervention package on the prescription of antibiotic and subsequently the rate of clinical recovery for non-severe acute febrile illnesses at primary health centers., Methods: Patients over 6 months of age presenting to primary health care centres with fever or history of fever within the past 7 days were randomized to receive either the intervention package constituted of point-of-care tests including COVID-19 antigen tests, a diagnostic algorithm and training and communication packages, or the standard practice. The primary outcomes were antibiotic prescriptions at Day 0 (D0) and the clinical recovery at Day 7 (D7). Secondary outcomes were non-adherence of participants and parents/caregivers to prescriptions, health workers' non-adherence to the algorithm, and the safety of the intervention., Results: A total of 1098 patients were enrolled. 551 (50.2%) were randomized to receive the intervention versus 547 (49.8%) received standard care. 1054 (96.0%) completed follow-up and all of them recovered at D7 in both arms. The proportion of patients with antibiotic prescriptions at D0 were 33.2% (183/551) in the intervention arm versus 58.1% (318/547) under standard care, risk difference (RD) -24.9 (95% CI -30.6 to -19.2, p < 0.001), corresponding to one more antibiotic saved every four (95% CI: 3 to 5) consultations. This reduction was also statistically significant in children from 6 to 59 months (RD -34.5; 95% CI -41.7 to -27.3; p < 0.001), patients over 18 years (RD -35.9; 95%CI -58.5 to -13.4; p = 0.002), patients with negative malaria test (RD -46.9; 95% CI -53.9 to -39.8; p < 0.001), those with a respiratory diagnosis (RD -48.9; 95% CI -56.9 to -41.0, p < 0.001) and those not vaccinated against COVID-19 (-24.8% 95%CI -30.7 to -18.9, p-value: <0.001). A significant reduction in non-adherence to prescription by patients was reported (RD -7.1; 95% CI -10.9 to -3.3; p < 0.001)., Conclusion: The intervention was associated with significant reductions of antibiotic prescriptions and non-adherence, chiefly among patients with non-malaria fever, those with respiratory symptoms and children below 5 years of age. The addition of COVID-19 testing did not have a major impact on antibiotic use at primary health centers., Trial Registration: Clinitrial.gov; NCT04081051 registered on 06/09/2019., (© 2024. The Author(s).)

The diagnosis of neurodegenerative diseases (NDDs) remains challenging, and existing therapeutic approaches demonstrate little efficacy. NDD drug delivery can be achieved through the utilization of nanostructures, hence enabling multimodal NDD theranostics. Nevertheless, both biomembrane and non-biomembrane nanostructures possess intrinsic shortcomings that must be addressed by hybridization to create novel nanostructures with versatile applications in NDD theranostics. Hybrid nanostructures display improved biocompatibility, inherent targeting capabilities, intelligent responsiveness, and controlled drug release. This paper provides a concise overview of the latest developments in hybrid nanostructures for NDD theranostics and emphasizes various engineering methodologies for the integration of diverse nanostructures, including liposomes, exosomes, cell membranes, and non-biomembrane nanostructures such as polymers, metals, and hydrogels. The use of a combination technique can significantly augment the precision, intelligence, and efficacy of hybrid nanostructures, therefore functioning as a more robust theranostic approach for NDDs. This paper also addresses the issues that arise in the therapeutic translation of hybrid nanostructures and explores potential future prospects in this field., (© 2024. The Author(s).)

Background: Medical informed consent stands as an ethical and legal requisite preceding any medical intervention. Hospitalized patients face functional health literacy (FHL) challenges when dealing with informed consent forms (ICFs). The legitimacy of ICFs and informed consent procedures in China remains substantially undisclosed. The study's aim was to investigate if Chinese patients have adequate FHL to be truly informed before providing medical consent., Methods: In this cross-sectional, structured interview-based study, FHL was assessed within the context of the informed consent scenarios in two teaching hospitals (a 1500-bed general tertiary hospital and a 700-bed cancer hospital) affiliated with Shantou University Medical College. Twenty-seven patients admitted across clinical departments, along with their relatives (n = 59), were enrolled in the study after obtaining informed consent. The participants underwent a three-step assessment with two selected ICFs -teach-back skills, perceived understanding (perception), and informed knowledge (cognizance), with each component carrying a maximum score of 10. Data were analyzed with SPSS (version 22.0) for descriptive and inferential statistics, with consideration of significant P values as < 0.05., Results: The median age (IQR and range) of participants was 35.5 (28 - 49 and 13 - 74) years. Most participants had only high school education (24.4%, 21/86) or below high school education (47.7%, 41/86). The median score (IQR) of FHL assessments-teach-back, perception, and cognizance-was 4.0 (2.5, 5.8), 8.0 (6.8, 8.8), and 6.5 (5.5, 8.0) out of 10, respectively. A moderate correlation was observed between the scores of cognizance and teach-back (r = 0.359, P = 0.002) or perception (r = 0.437, P < 0.001). Multivariate linear regression analysis predicted being a patient and having lower education levels as independent risk factors of inadequate FHL (Ps = 0.001). Lack of patient-centeredness in ICFs, time constraints, and poor clinical communication were identified as barriers impeding informed consent., Conclusions: This study demonstrates inadequacy in personal FHL and impaired organizational HL, resulting in compromised informed consent in Chinese teaching hospitals. As a remedy, we propose improving the quality of ICFs and institutionally mandated outcome-focused training on informed consent for all concerned clinicians to enhance medical ethics, ensure quality health care, address patient values, and mitigate potential medical conflicts., (© 2024. The Author(s).)

Background: Recovery from acute COVID-19 may be slow and incomplete: cases of Post-Acute Sequelae of COVID (PASC) are counted in millions, worldwide. We aimed to explore if and how the pre-existing Socio-economic-status (SES) influences such recovery., Methods: We analyzed a database of 1536 consecutive patients from the first wave of COVID-19 in Italy (February-September 2020), previously admitted to our referral hospital, and followed-up in a dedicated multidisciplinary intervention. We excluded those seen earlier than 12 weeks (the conventional limit for a possible PASC syndrome), and those reporting a serious complication from the acute phase (possibly accounting for symptoms persistence). We studied whether the exposition to disadvantaged SES (estimated through the Italian Institute of Statistics's model - ISTAT 2017) was affecting recovery outcomes, that is: symptoms (composite endpoint, i.e. at least one among: dyspnea, fatigue, myalgia, chest pain or palpitations); Health-Related-Quality-of-Life (HRQoL, as by SF-36 scale); post-traumatic-stress-disorder (as by IES-R scale); and lung structural damage (as by impaired CO diffusion, DLCO)., Results: Eight-hundred and twenty-five patients were included in the analysis (median age 59 years; IQR: 50-69 years, 60.2% men), of which 499 (60.5%) were previously admitted to hospital and 27 (3.3%) to Intensive-Care Unit (ICU). Those still complaining of symptoms at follow-up were 337 (40.9%; 95%CI 37.5-42.2%), and 256 had a possible Post-Traumatic Stress Disorder (PTSD) (31%, 95%CI 28.7-35.1%). DLCO was reduced in 147 (19.6%, 95%CI 17.0-22.7%). In a multivariable model, disadvantaged SES was associated with a lower HRQoL, especially for items exploring physical health (Limitations in physical activities: OR = 0.65; 95%CI = 0.47 to 0.89; p = 0.008; AUC = 0.74) and Bodily pain (OR = 0.57; 95%CI = 0.40 to 0.82; p = 0.002; AUC = 0.74). We did not observe any association between SES and the other outcomes., Conclusions: Recovery after COVID-19 appears to be independently affected by a pre-existent socio-economic disadvantage, and clinical assessment should incorporate SES and HRQoL measurements, along with symptoms. The socioeconomic determinants of SARS-CoV-2 disease are not exclusive of the acute infection: this finding deserves further research and specific interventions., (© 2024. The Author(s).)

Background: Participatory approaches have become a widely applied research approach. Despite their popularity, there are many challenges associated with the evaluation of participatory projects. Here we describe an evaluation of a community-based participatory research study of underserved communities in Ho Chi Minh City (HCMC), Vietnam at risk for hepatitis C virus. The goals of our evaluation were to explore the main benefits and challenges of implementing and participating in a participatory study and to describe study impacts., Methods: We conducted two meetings with leaders and members of the participating groups followed by in-depth interviews with 10 participants. We then held a dissemination meeting with over 70 participants, including the representatives of each group, researchers from non-governmental organizations (community-based, national and international), and govenrment officials from the Vietnam Ministry of Health and the Department of Health of HCMC., Results: Results include four categories where we describe first the participatory impacts, followed by the collaborative impacts. Then we describe the benefits and challenges of creating and belonging to one of the groups, from members' and leaders' points of view. Finally, we describe the key suggestions that participants provided for future research., Conclusion: In conclusion, the evaluation approach led to both a research reflection on the 'success' of the project and enabled participants themselves to reflect on the outcomes and benefits of the study from their point of view., (© 2024. The Author(s).)

Background: Data on the dynamics and persistence of humoral immunity against SARS-CoV-2 after primary vaccination with two-dose inactivated vaccine (CoronaVac) are limited. This study evaluated the sequential effects of prior infection, heterologous boosting with mRNA-1273 (Moderna), and the occurrence of Omicron vaccine-breakthrough infection (VBI) thereafter., Methods: We evaluated anti-spike IgG (Abbott) and neutralising (cPASS/GenScript) antibody (nAb) titers up to one year after mRNA-1273 boost in two-dose-CoronaVac-primed Indonesian healthcare workers (August 2021-August 2022). We used linear mixed modeling to estimate the rate of change in antibody levels, and logistic regression to examine associations between antibody levels and VBI., Results: Of 138 participants, 52 (37.7%) had a prior infection and 78 (56.5%) received an mRNA-1273 booster. After two-dose CoronaVac, antibody titers had significantly declined within 180 days, irrespective of prior infection. After mRNA-1273 booster, anti-spike IgG (1.47% decline/day) and Omicron B.1.1.529/BA.2 nAbs declined between day 28-90, and IgG titers plateaued between day 90-360. During the BA.1/BA.2 wave (February-March 2022), 34.6% (27/78) of individuals experienced a VBI (median 181 days after mRNA-1273), although none developed severe illness. VBI was associated with low pre-VBI anti-spike IgG and B.1.1.529/BA.2 nAbs, which were restored post-VBI., Conclusions: mRNA-1273 booster after two-dose CoronaVac did not prevent BA.1/BA.2 VBI. Periodic vaccine boosters may be warranted against emerging SARS-CoV-2 variants., (© 2024. The Author(s).)

Background: Oral squamous cell carcinoma (OSCC) causes significant mortality and morbidity worldwide. Surgical resection with adjuvant radiotherapy remains the standard treatment for locally advanced resectable OSCC. Results from landmark trials have established postoperative concurrent cisplatin-radiotherapy (Cis-RT) as the standard treatment for OSCC patients with high-risk pathologic features. However, cisplatin-related toxicity limits usage in clinical practice. Given the need for effective but less toxic alternatives, we previously conducted a single-arm trial showing favorable safety profiles and promising efficacy of concurrent docetaxel-radiotherapy (Doc-RT)., Methods: In this randomized phase 2 trial, we aimed to compare Doc-RT with the standard Cis-RT in postoperative OSCC patients. Eligible patients had AJCC stage III-IV resectable OSCC with high-risk pathologic features. Two hundred twenty-four patients were enrolled and randomly assigned to receive concurrent Doc-RT or Cis-RT. The primary endpoint was 2-year disease-free survival (DFS). Secondary endpoints included overall survival (OS), locoregional-free survival (LRFS), distant metastasis-free survival (DMFS), and adverse events (AEs). Integrin β1 (ITGB1) expression was analyzed as a biomarker for efficacy., Results: After a median 28.8-month follow-up, 2-year DFS rates were 63.7% for Doc-RT arm and 56.1% for Cis-RT arm (p = 0.55). Meanwhile, Doc-RT demonstrated comparable efficacy to Cis-RT in OS, LRFS, and DMFS. Doc-RT resulted in fewer grade 3 or 4 hematological AEs. Low ITGB1 was associated with improved Doc-RT efficacy versus Cis-RT., Conclusions: This randomized trial directly compared Doc-RT with Cis-RT for high-risk postoperative OSCC patients, with comparable efficacy and less toxicity. ITGB1 merits further validation as a predictive biomarker to identify OSCC patients most likely to benefit from Doc-RT. Findings indicate docetaxel may be considered as a concurrent chemoradiation option in this setting., Trial Registration: www., Clinicaltrials: gov . NCT02923258 (date of registration: October 4, 2016)., (© 2024. The Author(s).)

Background: This study aims to identify disability classes among people with schizophrenia spectrum disorder, depression, anxiety or diabetes via the WHODAS 2.0; investigate the invariance of disability patterns among the four diagnostic groups; and examine associations between disability classes and sociodemographic variables., Methods: Patients seeking treatment for schizophrenia spectrum disorder, depression, anxiety or diabetes (n=1076) were recruited. Latent class analysis was used to identify disability classes based on WHODAS 2.0 responses. Measurement invariance was tested using multi-group latent class analysis. Associations between classes and sociodemographic variables were tested via multinomial logistic regression., Results: A five-class solution was identified; examination of model invariance showed that the partially constrained five-class model was most appropriate, suggesting that class structure was consistent while class membership differed across diagnostic groups. Finally, significant associations were found between class membership and ethnicity, education level, and employment status., Conclusions: The results show the feasibility of using the WHODAS 2.0 to identify and compare different disability classes among people with mental or physical conditions and their sociodemographic correlates. Establishing a typology of different disability profiles will help guide research and treatment plans that tackle not just clinical but also functional aspects of living with either a chronic psychiatric or physical condition., (© 2024. The Author(s).)

Background: Immunotherapy-based combinations have emerged as standard therapies for patients with metastatic renal cell carcinoma (mRCC). Pembrolizumab, a PD-1 inhibitor, combined with epacadostat, an indoleamine 2,3-deoxygenase 1 selective inhibitor, demonstrated promising antitumor activity in a phase 1 study in advanced solid tumors, including mRCC., Methods: KEYNOTE-679/ECHO-302 was a randomized, open-label, parallel-group, multicenter, phase 3 study (NCT03260894) that compared pembrolizumab plus epacadostat with sunitinib or pazopanib as first-line treatment for mRCC. Eligible patients had histologically confirmed locally advanced or metastatic clear cell RCC and had not received systemic therapy. Patients were randomly assigned 1:1 to pembrolizumab 200 mg IV every 3 weeks plus epacadostat 100 mg orally twice daily versus sunitinib 50 mg orally once daily (4 weeks on treatment followed by 2 weeks off treatment) or pazopanib 800 mg orally once daily. Original dual primary end points were progression-free survival and overall survival. Enrollment was stopped when a phase 3 study in melanoma of pembrolizumab plus epacadostat compared with pembrolizumab monotherapy did not meet its primary end point. This protocol was amended, and primary end point was changed to investigator-assessed objective response rate (ORR) per RECIST 1.1., Results: One-hundred-twenty-nine patients were randomly assigned to receive pembrolizumab plus epacadostat (n = 64) or sunitinib/pazopanib (n = 65). Median (range) follow-up, defined as time from randomization to data cutoff, was 10.3 months (2.2-14.3) and 10.3 months (2.7-13.8) in the pembrolizumab plus epacadostat and sunitinib/pazopanib arms, respectively. ORRs were similar between pembrolizumab plus epacadostat (31.3% [95% CI 20.2-44.1] and sunitinib/pazopanib (29.2% [18.6-41.8]). Grade 3-5 treatment-related adverse events occurred in 34.4% and 42.9% of patients in the pembrolizumab plus epacadostat and sunitinib/pazopanib arms, respectively. One patient in the sunitinib/pazopanib arm died of septic shock (not treatment-related). Circulating kynurenine levels decreased in the pembrolizumab plus epacadostat arm, but not to levels observed in healthy subjects., Conclusions: ORRs were similar between pembrolizumab plus epacadostat and sunitinib/pazopanib as first-line treatment in patients with mRCC. Safety and tolerability appeared similar between treatment arms; no new safety concerns were identified. Antitumor responses observed in patients with RCC receiving pembrolizumab plus epacadostat may be driven primarily by pembrolizumab., Clinical Trial Registration: ClinicalTrials.gov; NCT03260894 ., (© 2023. The Author(s).)

Whole genome analysis for microbial genomics is critical to studying and monitoring antimicrobial resistance strains. The exponential growth of microbial sequencing data necessitates a fast and scalable computational pipeline to generate the desired outputs in a timely and cost-effective manner. Recent methods have been implemented to integrate individual genomes into large collections of specific bacterial populations and are widely employed for systematic genomic surveillance. However, they do not scale well when the population expands and turnaround time remains the main issue for this type of analysis. Here, we introduce AMRomics, an optimized microbial genomics pipeline that can work efficiently with big datasets. We use different bacterial data collections to compare AMRomics against competitive tools and show that our pipeline can generate similar results of interest but with better performance. The software is open source and is publicly available at https://github.com/amromics/amromics under an MIT license., (© 2024. The Author(s).)

Background: Inflammatory bowel diseases (IBDs) are associated with high healthcare utilization. This systematic review aimed to summarize what is known about the impact of sex, income, and education on the likelihood of bowel surgery, hospitalization, and use of corticosteroids and biologics among patients with IBD., Methods: We used EMBASE, MEDLINE, CINAHL, and Web of Science to perform a systematic literature search. Pooled hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using random effects meta-analysis for the impact of sex on the likelihood of surgery and hospitalization. In addition, we performed subgroup analyses of the effect of IBD type (Crohn's disease or ulcerative colitis) and age. Finally, meta-regression was undertaken for the year of publication., Results: In total, 67 studies were included, of which 23 studies were eligible for meta-analysis. In the main meta-analysis, male sex was associated with an increased likelihood of bowel surgery (HR 1.42 (95% CI 1.13;1.78), which was consistent with the subgroup analysis for UC only (HR 1.78, 95% CI 1.16; 2.72). Sex did not impact the likelihood of hospitalization (OR 1.05 (95% CI 0.86;1.30), although the subgroup analysis revealed an increased likelihood of hospitalization in CD patients (OR 1.42, 95% CI 1.28;1.58). In 9 of 10 studies, no significant sex-based differences in the use of biologics were reported, although in 6 of 6 studies, female patients had lower adherence to biologics. In 11 of 13 studies, no significant sex-based difference in the use of corticosteroids was reported. The evidence of the impact of income and education on healthcare utilization was sparse and pointed in different directions. The substantial heterogeneity between studies was explained, in part, by differences in IBD type and age., Conclusions: The results of this systematic review indicate that male patients with IBD are significantly more likely to have surgery than female patients with IBD but are not, overall, more likely to be hospitalized, whereas female patients appear to have statistically significantly lower adherence to biologics compared to male patients. Thus, clinicians should not underestimate the impact of sex on healthcare utilization. Evidence for income- and education-based differences remains sparse., Systematic Review Registration: PROSPERO CRD42022315788., (© 2024. The Author(s).)