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Renalase is a secreted flavoprotein with anti-inflammatory and pro-cell survival properties. COVID-19 is associated with disordered inflammation and apoptosis. We hypothesized that blood renalase levels would correspond to severe COVID-19 and survival. In this retrospective cohort study, clinicopathologic data and blood samples were collected from hospitalized COVID-19 subjects (March—June 2020) at a single institution tertiary hospital. Plasma renalase and cytokine levels were measured and clinical data abstracted from health records. Of 3,450 COVID-19 patients, 458 patients were enrolled. Patients were excluded if

Abstract Background Checkpoint inhibitors (CPI) have revolutionized the treatment of metastatic melanoma, but most patients treated with CPI eventually develop progressive disease. Local therapy including surgery, ablation or stereotactic body radiotherapy (SBRT) may be useful to manage limited progression, but criteria for patient selection have not been established. Previous work has suggested progression-free survival (PFS) after local therapy is associated with patterns of immunotherapy failure, but this has not been studied in patients treated with CPI. Methods We analyzed clinical data from patients with metastatic melanoma who were treated with antibodies against CTLA-4, PD-1 or PD-L1, either as single-agent or combination therapy, and identified those who had disease progression in 1 to 3 sites managed with local therapy. Patterns of CPI failure were designated by independent radiological review as growth of established metastases or appearance of new metastases. Local therapy for diagnosis, palliation or CNS metastases was excluded. Results Four hundred twenty-eight patients with metastatic melanoma received treatment with CPI from 2007 to 2018. Seventy-seven have ongoing complete responses while 69 died within 6 months of starting CPI; of the remaining 282 patients, 52 (18%) were treated with local therapy meeting our inclusion criteria. Local therapy to achieve no evidence of disease (NED) was associated with three-year progression-free survival (PFS) of 31% and five-year disease-specific survival (DSS) of 60%. Stratified by patterns of failure, patients with progression in established tumors had three-year PFS of 70%, while those with new metastases had three-year PFS of 6% (P = 0.001). Five-year DSS after local therapy was 93% versus 31%, respectively (P = 0.046). Conclusions Local therapy for oligoprogression after CPI can result in durable PFS in selected patients. We observed that patterns of failure seen during or after CPI treatment are strongly associated with PFS after local therapy, and may represent a useful criterion for patient selection. This experience suggests there may be an increased role for local therapy in patients being treated with immunotherapy.

Background Checkpoint inhibitors (CPIs) are thought to be effective against cutaneous melanoma in part because of the large burden of somatic mutations (neoantigens) generated from exposure to ultraviolet radiation. However, rare melanoma subtypes arising from acral skin, mucosal surfaces, and the uveal tract are largely sun-shielded. Genomic studies show these sun-shielded melanomas have a paucity of neoantigens and unique biology; they are thought to be largely resistant to immunotherapy. It has not been definitively shown that CPI improves survival in metastatic sun-shielded melanoma.Methods We reviewed a single institutional experience using antibodies against CTLA-4, PD-1 and/or PD-L1 to treat patients with metastatic melanoma. Primary tumor histology was categorized as cutaneous, unknown, acral, mucosal, or uveal. We studied demographic data, treatment characteristics, and overall survival (OS) after CPI.Results We treated 428 patients with metastatic melanoma from 2007 to 2019. Primary tumors were cutaneous in 283 (66%), unknown in 55 (13%), acral in 22 (5%), mucosal in 38 (9%), and uveal in 30 (7%). Patients with metastatic disease from cutaneous primary tumors had median OS after CPI of 45 months compared with 17 months for acral (p=0.047), 18 months for mucosal (p=0.003), and 12 months for uveal (p

Abstract Background Endometriosis appears to have a multilayered etiology, with genetic and epigenetic factors each contributing half of the pathogenesis. The molecular processes that underlie the onset of endometriosis are yet unclear, but it is assumed that an important contributor in the etiopathology of the disease is DNA methylation. Methods We conducted a systematic review of the literature regarding DNA methylation in endometriosis following PRISMA guidelines. Records were obtained from PubMed and Web of Science on May 31, 2024. Original research articles analyzing regional or genome-wide DNA methylation in patients with confirmed endometriosis (by surgery and/or histological examination) were given consideration for inclusion. Only human studies were included, and there were no restrictions on the types of tissue that was analyzed (i.e., endometrium, blood, or fetal tissue). The study selection process was run by two manual reviewers. In parallel, an adapted virtual artificial intelligence-powered reviewer operated study selection and results were compared with the manual reviewers’ selection. Studies were divided into targeted (e.g., single gene or region level) and epigenome-wide association studies. For each, we extracted a list of genes studied with precise location of CpGs analyzed and the DNA methylation status according to the groups compared. Quality assessment of studies was performed following the Newcastle–Ottawa scale. Quality of evidence was graded following the Grading of Recommendations Assessment, Development and Evaluation. Results A total of 955 studies were screened, and 70 were identified as relevant for systematic review. Our analyses displayed that endometriosis could be polyepigenetic and with alterations in specific genes implicated in major signaling pathways contributing to the disease etiopathology (cell proliferation, differentiation, and division [PI3K-Akt and Wnt-signaling pathway], cell division [MAPK pathway], cell adhesion, cell communication, developmental processes, response to hormone, apoptosis, immunity, neurogenesis, and cancer). Conclusion Our systematic review indicates that endometriosis is associated with DNA methylation modifications at specific genes involved in key endometrial biological processes, particularly in the ectopic endometrium. As DNA methylation appears to be an integral component of the pathogenesis of endometriosis, the identification of DNA methylation biomarkers would likely help better understand its causes and aggravating factors as well as potentially facilitate its diagnosis and support the development of new therapeutic approaches. Graphical abstract DNA methylation modifications are observed in both eutopic and ectopic endometrium in endometriosis compared to the healthy endometrium, and their localization may influence important biological pathways of the female reproductive system. DMP: Differentially methylated position. DMR: Differentially methylated region.

Abstract Background Endometriosis, affecting 10% of women in their reproductive years, remains poorly understood. Both individual and environmental unexplained factors are implicated in this heterogenous condition. This study aims to examine the influence of a Western diet on endometriosis lesion development in mice and to uncover the mechanisms involved. Methods Mice were fed either a control diet or a Western diet (high in fatty acids and low in fiber) for 4 weeks. Endometriosis was then surgically induced, and lesion development was monitored by ultrasound. After 7 weeks, the mice were sacrificed for analysis of lesion characteristics through RT-qPCR, immunohistochemistry, and flow cytometry. Additionally, the intestinal microbiota was assessed using 16S rRNA gene sequencing. Results Mice on the Western diet developed lesions that were significantly twice as large compared to those on the control diet. These lesions exhibited greater fibrosis and proliferation, alongside enhanced macrophage activity and leptin pathway expression. Changes in the intestinal microbiota were significantly noted after endometriosis induction, regardless of diet. Notably, mice on the Western diet with the most substantial lesions showed a loss of Akkermansia Muciniphila in their intestinal microbiota. Conclusions A Western diet significantly exacerbates lesion size in a mouse model of endometriosis, accompanied by metabolic and immune alterations. The onset of endometriosis also leads to substantial shifts in intestinal microbiota, suggesting a potential link between diet, intestinal health, and endometriosis development. Graphical Abstract

Background: Nebivolol is a β-adrenergic receptor antagonist that has intrinsic activity on β3-adrenergic receptors (β3-ARs). Previous studies suggest that nebivolol inhibits bFGF-induced vascular smooth muscle cell (VSMC) proliferation and migration and vascular injury-induced neointima formation through activation of β3-ARs. However, our recently published data shown that activation of β3-ARs produced the opposite results, suggesting that the mechanisms of nebivolol-mediated effects are not fully understood. The current project was to study the mechanisms of nebivolol’s effects on bFGF-induced VSMC proliferation and migration by comparing to the selective β3-AR agonist, CL316,243. Methods: VSMCs isolated from Sprague Dawley rat aortas were pretreated with nebivolol or CL316,243 followed by stimulation with bFGF. Cell proliferation and migration and phosphorylation of ERK and AKT were measured. Results: We found that pretreatment of VSMCs with nebivolol produced biphasic effects on bFGF-induced VSMC proliferation, manifested as potentiation at lower concentrations and inhibition at the higher concentration. The effects of low concentrations of nebivolol on bFGF-induced VSMC proliferation was blocked by the selective β3-AR antagonist, SR59230A. Nebivolol inhibited bFGF-induced cell migration at all concentrations tested. In addition, only higher concentrations of nebivolol significantly inhibited bFGF-induced AKT phosphorylation but not ERK phosphorylation whereas CL316,243 at all concentrations tested significantly enhanced bFGF-induced VSMC proliferation and migration and higher concentrations of CL316,243 not only enhanced bFGF-induced AKT phosphorylation but also ERK phosphorylation. Conclusion: Our data suggest that the effect of nebivolol on bFGF-induced cell proliferation is concentration-dependent. The enhancement on bFGF-induced cell proliferation at lower concentrations appears to be mainly mediated by activation of β3-ARs but the inhibitory effects on bFGF-mediated cell proliferation as well as migration may occur through different mechanisms. AKT signaling is only involved in high concentrations of nebivolol-mediated effects.

Adrenomedullin 2 plays diverse physiological roles such as regulating cardiovascular functions and blood pressure. It was reported that adrenomedullin 2 can activate protein kinase C in murine ventricular myocytes to augment cardiomyocyte contractile function. Using a protein kinase Cα knockout mouse model, we show here that adrenomedullin 2 activates extracellular-signal-regulated kinase in a protein kinase Cα-independent mechanism in endothelial cells.

Abstract Background Ex vivo tissue morphometric (TM) measurements have been proposed as a quality marker for colorectal cancer (CRC) surgery. However, their survival associations require clarification. This study aimed to evaluate the feasibility of capturing TM measurements based on ex vivo fresh specimen images and explore the association between these TM measurements and survival outcomes. Methods A prospective cohort study at Concord Hospital, Sydney was conducted with Stage I to III CRC patients (2009–2019) who underwent an anterior resection (AR) or right hemicolectomy (RH). Using high-resolution digital photographs of fresh CRC specimens, ex vivo tissue morphometric (TM) measurements—resected mesentery area (TM A), distances from high vascular tie to tumour (TM B) and bowel wall (TM C), and bowel length (TM D)—were recorded using Image J. Overall survival (OS) and disease-free survival (DFS) estimates and their associations to clinicopathological variables were investigated with Kaplan–Meier and Cox regression analyses. Linear regression models tested association between TM measurements and lymph node (LN) yield. Results Of the 1,425 patients who underwent CRC surgery, TM measurements were performed on 312 patients, with an average age of 69.4 years (SD 12.3), of whom 52.9% were male. The majority had an AR (57.8%). Among AR patients, a 5-year OS rate of 77.4% and a DFS rate of 70.1% were observed, with TM measurements bearing no relationship to survival outcomes. Similarly, RH patients exhibited a 5-year OS rate of 67.2% and a DFS rate of 63.1%, with TM measurements again showing no association with survival. Only TM D (P = 0.02) measurements were associated with the number of LNs examined. Conclusion This study successfully demonstrates the feasibility of measuring TM measurements on photographs of ex vivo fresh specimens following CRC surgery. The lack of association with survival outcomes questions the utility of TM measurements as a quality metric of CRC surgery.

Abstract Background Safer conception services are needed to minimize HIV transmission among HIV sero-discordant couples desiring pregnancy. Few studies have evaluated the choices couples make when they are offered multiple safer conception methods or real-world method acceptability. This paper addresses an important knowledge gap regarding factors that influence the choice of safer conception methods, couples' actual experiences using safer conception methods, and why some couples switch safer conception methods. Methods Between February and June 2019, we conducted semi-structured in-depth interviews among 14 men and 17 women, representing 17 couples who exited the SAFER study—a pilot safer conception study for HIV sero-discordant couples in Zimbabwe that offered couples a choice of ART with monthly viral load monitoring (ART/VL), oral PrEP, vaginal insemination, and semen washing. All couples in SAFER had used at least two safer conception methods. Results We found that safer conception method choice often centered around a desire for intimacy, condomless sex, and certainty in the conception process, particularly for men. Method-related attributes such as familiarity, perceived ease of use, side effects, and perceived level of effectiveness in preventing HIV and achieving pregnancy influenced method choice, switching, and satisfaction. Concerns were expressed about each safer conception method and couples were willing to try different methods until they found method(s) that worked for them. The majority of participants reported having positive experiences using safer conception, especially those using ART/VL + PrEP, citing that they were able to attempt pregnancy for the first time with peace of mind and experienced joy and satisfaction from being able to achieve pregnancy safely. Conclusions The differences in method preferences and experiences voiced by participants in this study and in other studies from the region point to the importance of having a variety of safer conception options in the service delivery package and addressing concerns about paternity, intimacy, and method-related attributes to enable HIV sero-discordant couples to safely achieve their reproductive goals.

Decision-making on childbearing and safer conception use in HIV sero-different couples involves an intricate balance of individual desires and perceived HIV acquisition risk. This paper addresses an important knowledge gap regarding HIV sero-different couples’ considerations and the relationship and power dynamics involved when deciding to use a safer conception method. Between February and June 2019, we conducted semi-structured in-depth interviews among 14 men and 17 women, representing 17 couples, who exited the SAFER study – a pilot study assessing the feasibility, acceptability and cost-effectiveness of a safer conception programme for HIV sero-different couples in Zimbabwe. All couples in SAFER were provided with a choice of safer conception methods and were followed for up to 12 months of pregnancy attempts and 3 months following pregnancy. While couples generally perceived their safer conception discussions to be easy and consensus-driven, the decision-making process also involved complex gender dynamics and trade-offs in relationship power, which resulted in differing interpretations of what constituted a joint or shared couple decision. Participants regarded effective couple communication as an essential component of and precursor to good safer conception conversations and requested additional training in couple communication. Couples relied on information from healthcare providers to kickstart their safer conception discussions. Safer conception programmes should address relationship power imbalances, promote effective couple communication and offer healthcare provider support to enable HIV sero-different couples to make informed choices about conception in a manner that upholds their safety and reproductive autonomy.

Abstract Biomarker identification could help in deciphering endometriosis pathophysiology in addition to their use in the development of non invasive diagnostic and prognostic approaches, that are essential to greatly improve patient care. Despite extensive efforts, no single potential biomarker or combination has been clinically validated for endometriosis. Many studies have investigated endometriosis-associated biological markers in specific tissues, but an integrative approach across tissues is lacking. The aim of this review is to propose a comprehensive overview of identified biomarkers based on tissue or biological compartment, while taking into account endometriosis phenotypes (superficial, ovarian or deep, or rASRM stages), menstrual cycle phases, treatments and symptoms. We searched PubMed and Embase databases for articles matching the following criteria: 'endometriosis' present in the title and the associated term 'biomarkers' found as Medical Subject Headings (MeSH) terms or in all fields. We restricted to publications in English and on human populations. Relevant articles published between 01 January 2005 (when endometriosis phenotypes start to be described in papers) and 01 September 2022 were critically analysed and discussed. Four hundred forty seven articles on endometriosis biomarkers that included a control group without endometriosis and provided specific information on endometriosis phenotypes are included in this review. Presence of information or adjustment controlling for menstrual cycle phase, symptoms and treatments is highlighted, and the results are further summarized by biological compartment. The 9 biological compartments studied for endometriosis biomarker research are in order of frequency: peripheral blood, eutopic endometrium, peritoneal fluid, ovaries, urine, menstrual blood, saliva, feces and cervical mucus. Adjustments of results on disease phenotypes, cycle phases, treatments and symptoms are present in 70%, 29%, 3% and 6% of selected articles, respectively. A total of 1107 biomarkers were identified in these biological compartments. Of these, 74 were found in several biological compartments by at least two independent research teams and only 4 (TNF-a, MMP-9, TIMP-1 and miR-451) are detected in at least 3 tissues with cohorts of 30 women or more. Integrative analysis is a crucial step to highlight potential pitfalls behind the lack of success in the search for clinically relevant endometriosis biomarkers, and to illuminate the physiopathology of this disease. Graphical Abstract

Technological developments have impacted all sectors, including the education sector. This requires the education sector, especially the learning sector, to be innovative. Be innovative in implementing learning, one of them is using e-learning such as Learning Management Systems (LMS) and others. This research aims to determine the effectiveness of using LMS in the lectures of Teacher Professional Education (PPG) students. This research is experimental research, with a sample of PPG students. Data analysis using N-Gain and t-test. Based on the research results, it was found that student learning outcomes had increased. As many as 77.8% of students' learning outcomes were of medium criteria, and 22.2% were high. Based on the t-test results, using LMS media can effectively achieve learning outcomes in PPG student learning evaluations. This research for Islamic education management implies that it can be a reference for future researchers to study the use of LMS in distance learning in Islamic educational institutions more profoundly and comprehensively.

The golden generation of the Indonesian nation is superior, and the millennial generation needs to be prepared to face the social order culture, world of work, scientific advances, technology, and digitization of big data. Therefore we need an educational process that links and matches with the industrial world and global changes in the future without abandoning noble character. Character education for Indonesia's golden generation is also carried out in Islamic educational institutions, namely Islamic boarding schools; Islamic boarding schools can be seen as social capital in developing Indonesian human resources. The concept of character education is also carried out and applied at the Aufia Thayyiba International Islamic Boarding School Agam West Sumatra Islamic Boarding School, with the principles of Panca Jiwa Pondok, in building the character of the golden generation of the Indonesian nation. This study aimed to determine the formation of the nature of the golden age of the Indonesian country based on the Panca Jiwa Pondok at the Aufia Thayyiba International Islamic Boarding School Agam Islamic Boarding School, West Sumatra. This research is qualitative research using a phenomenological approach. The subjects of this study were the director of the boarding school, the leadership of the boarding school, and the teachers. Data collection methods are interviews with purposive sampling techniques, observation, and documentation. The data is then analyzed using the inductive method, which emphasizes and describes the words and draws conclusions from these observations. The study results show that the formation of the character of the golden generation of the Indonesian nation is Aufia Thayyiba Agam International Islamic Boarding School by making the Panca Jiwa Pondok a philosophical foundation for its students to build character coupled with excellent programs and suitable methods.

This paper explores the potential application and challenges of blockchain technology in addressing the complex issues surrounding international migration within the African Union (AU). It provides an overview of blockchain technology, its features, and potential applications. The paper delves into the pressing challenges faced by the AU concerning international migration, including illegal migration, human trafficking, and the absence of secure and efficient systems for processing and tracking migrants. By utilizing blockchain technology, this paper examines how these challenges can be mitigated through secure and transparent identity verification, improved movement tracking, and enhanced access to services. Furthermore, this paper discusses the existing literature on the topic, highlighting blockchain technology's potential benefits and challenges in the context of international migration within the AU. The paper concludes with recommendations for future research and the adoption of blockchain technology to address the challenges of international migration within the AU.

Abstract Introduction BAY1128688 is a selective inhibitor of aldo-keto reductase family 1 member C3 (AKR1C3), an enzyme implicated in the pathology of endometriosis and other disorders. In vivo animal studies suggested a potential therapeutic application of BAY1128688 in treating endometriosis. Early clinical studies in healthy volunteers supported the start of phase IIa. Objective This manuscript reports the results of a clinical trial (AKRENDO1) assessing the effects of BAY1128688 in adult premenopausal women with endometriosis-related pain symptoms over a 12-week treatment period. Methods Participants in this placebo-controlled, multicenter phase IIa clinical trial (NCT03373422) were randomized into one of five BAY1128688 treatment groups: 3 mg once daily (OD), 10 mg OD, 30 mg OD, 30 mg twice daily (BID), 60 mg BID; or a placebo group. The efficacy, safety, and tolerability of BAY1128688 were investigated. Results Dose-/exposure-dependent hepatotoxicity was observed following BAY1128688 treatment, characterized by elevations in serum alanine transferase (ALT) occurring at around 12 weeks of treatment and prompting premature trial termination. The reduced number of valid trial completers precludes conclusions regarding treatment efficacy. The pharmacokinetics and pharmacodynamics of BAY1128688 among participants with endometriosis were comparable with those previously found in healthy volunteers and were not predictive of the subsequent ALT elevations observed. Conclusions The hepatotoxicity of BAY1128688 observed in AKRENDO1 was not predicted by animal studies nor by studies in healthy volunteers. However, in vitro interactions of BAY1128688 with bile salt transporters indicated a potential risk factor for hepatotoxicity at higher doses. This highlights the importance of in vitro mechanistic and transporter interaction studies in the assessment of hepatoxicity risk and suggests further mechanistic understanding is required. Clinical Trial Registration NCT03373422 (date registered: November 23, 2017)

This essay begins with preliminary observations about the nature of agnosticism. Based on the term’s etymology, in this essay an agnostic about some proposition (e.g., God exists) is someone who does not know whether the proposition is true. Being an agnostic about the truth of a proposition is compatible with the proposition appearing to be true or the state of affairs obtains but incompatible with an agnostic knowing its truth or that the state of affairs obtains. (Reference to propositions and states of affairs is intended to be inclusive, rather than a controversial metaphysical distinction.) Based on apparent virtues and vices, reasons are offered about when agnosticism (or the profession of agnosticism) is virtuous or philosophically desirable and when either actual agnosticism or its profession seems to be a vice or undesirable. The essay concludes with challenging Anthony Kenny’s case for agnosticism about theism based on the virtue of humility. The central claims about apparent virtues and vices rest on the positive epistemic standing of appearances as defended by many so-called “common sense philosophers” Thomas Reid, Roderick Chisholm, and, more recently, Thomas Nagel’s thesis about the justified status of the appearance of values.

[This corrects the article DOI: 10.1371/journal.pone.0254850.].

Abstract Background The role of adjuvant chemotherapy (AC) in stage III rectal cancer (RC) has been argued based on evidence from its use in colon cancer. Previous trials have analysed disease-free and overall survivals as endpoints, rather than disease recurrence. This study compares the competing risks incidences of recurrence and cancer-specific death between patients who did and did not receive AC for stage III RC. Methods Consecutive patients who underwent a potentially curative resection for stage III RC (1995–2019) at Concord Hospital, Sydney, Australia, were studied. AC was considered following multidisciplinary discussion. Primary outcome measures were the competing risks incidences of disease recurrence and cancer-specific death. Associations between these outcomes and use of AC (and other variables) were tested by regression modelling. Results Some 338 patients (213 male, mean age 64.4 years [SD12.7]) were included. Of these, 208 received AC. The use of AC was associated with resection year (adjusted OR [aOR] 1.74, 95%CI 1.27–2.38); age ≥75 years (aOR0.04, 95%CI 0.02–0.12); peripheral vascular disease (aOR0.08, 95%CI 0.01–0.74); and postoperative abdomino-pelvic abscess (aOR0.23, 95%CI 0.07–0.81). One hundred fifty-seven patients (46.5%) were diagnosed with recurrence; death due to RC occurred in 119 (35.2%). After adjustment for the competing risk of non-cancer death, neither recurrence nor RC-specific death was associated with AC (HR0.97, 95%CI 0.70–1.33 and HR0.72, 95%CI 0.50–1.03, respectively). Conclusion This study found no significant difference in either recurrence or cancer-specific death between patients who did and did not receive AC following curative resection for stage III RC.