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Objective We aim to assess which variables are associated with recruitment failure of obstetrical and gynaecological randomised controlled trials (RCTs), leading to an extension of the study period.Design Nationwide study.Setting A cohort of RCTs supported by the trial centre of the Dutch Consortium of Obstetrics and Gynaecology.Population We included 83 RCTs that recruited patients between 1 March 2003 and 1 December 2023.Main outcome measures Main outcome was recruitment target not achieved within 6 months after the preplanned recruitment period. Secondary outcomes were recruitment target not achieved within an extension period of at least 12 months and premature termination of the trial. In all RCTs, we collected information on variables with a potential effect on recruitment failure, recorded at five levels; patient, doctor, participating centre, study organisation and study design.Results In total, 46 of 83 RCTs (55%) did not achieve their targeted recruitment within the preplanned study period with a maximal extension period of 6 months. The most relevant variables for recruitment failure in multivariable risk prediction modelling were presence of a no-treatment arm (where treatment is standard clinical practice), a compensation fee of less than €200 per included patient, funding of less than €350 000, while a preceding pilot study lowered this risk.Conclusions We identified that the presence of a no-treatment arm, low funding and a low compensation fee per included patient were the most relevant risk factors for recruitment failure within the preplanned period, while a preceding pilot study lowered this risk. Awareness of these variables is important when designing future studies.

Abstract Background In women with unexplained infertility, tubal flushing with oil-based contrast during hysterosalpingography leads to significantly more live births as compared to tubal flushing with water-based contrast during hysterosalpingography. However, it is unknown whether incorporating tubal flushing with oil-based contrast in the initial fertility work-up results to a reduced time to conception leading to live birth when compared to delayed tubal flushing that is performed six months after the initial fertility work-up. We also aim to evaluate the effectiveness of tubal flushing with oil-based contrast during hysterosalpingography versus no tubal flushing in the first six months of the study. Methods This study will be an investigator-initiated, open-label, international, multicenter, randomized controlled trial with a planned economic analysis alongside the study. Infertile women between 18 and 39 years of age, who have an ovulatory cycle, who are at low risk for tubal pathology and have been advised expectant management for at least six months (based on the Hunault prediction score) will be included in this study. Eligible women will be randomly allocated (1:1) to immediate tubal flushing (intervention) versus delayed tubal flushing (control group) by using web-based block randomization stratified per study center. The primary outcome is time to conception leading to live birth with conception within twelve months after randomization. We assess the cumulative conception rate at six and twelve months as two co-primary outcomes. Secondary outcomes include ongoing pregnancy rate, live birth rate, miscarriage rate, ectopic pregnancy rate, number of complications, procedural pain score and cost-effectiveness. To demonstrate or refute a shorter time to pregnancy of three months with a power of 90%, a sample size of 554 women is calculated. Discussion The H2Oil-timing study will provide insight into whether tubal flushing with oil-based contrast during hysterosalpingography should be incorporated in the initial fertility work-up in women with unexplained infertility as a therapeutic procedure. If this multicenter RCT shows that tubal flushing with oil-based contrast incorporated in the initial fertility work-up reduces time to conception and is a cost-effective strategy, the results may lead to adjustments of (inter)national guidelines and change clinical practice. Trial registration number The study was prospectively registered in International Clinical Trials Registry Platform (Main ID: EUCTR2018-004153-24-NL).

Abstract Background In women with unexplained infertility, tubal flushing with oil-based contrast during hysterosalpingography (HSG) increases ongoing pregnancy and subsequent live birth rates when compared to tubal flushing with water-based contrast. It is currently unclear whether an HSG with oil-based contrast also results in more ongoing pregnancies and live births in women of advanced age, women with ovulation disorders, and women with potential tubal pathology when compared to an HSG with water-based contrast. Methods We plan an international, multicentre, open-label, randomized controlled trial (RCT) studying three groups of infertile women who have an indication for tubal patency testing according to their treating physician and additionally; (1) are 39 years of age or older, (2) have an ovulation disorder or (3) have a high risk for tubal pathology based on their medical history. Women with an allergy for iodinated contrast medium are excluded, as are women with diabetes, hyperprolactinemia or untreated hyper- or hypothyroidism, and women with a partner with severe male infertility. After informed consent, women will be randomly allocated to the intervention, tubal flushing with the use of oil-based contrast during HSG or the control group, tubal flushing with the use of water-based contrast during HSG in a 1:1 ratio by the web-based system Castor. The primary endpoint will be ongoing pregnancy leading to live birth with conception within six months after randomization. Secondary outcomes are other pregnancy outcomes, used fertility treatments, adverse events and cost-effectiveness. Based on the expected ongoing pregnancy rate of 17% in the control group and 27% in the intervention group, the sample size will be 930 women (465 per group). Study inclusion is expected to be complete in four years. Discussion This multicentre RCT will establish whether, for women of advanced age, women with ovulatory disease, and women who have a high risk for tubal pathology, there is a fertility enhancing effect of tubal flushing with oil-based contrast during HSG and whether the use of this contrast medium is cost-effective. Trial Registration The study was prospectively registered in the Netherlands Trial Register on August 1st 2019 as ‘H2Oil2’ (reference number NL7925, https://www.trialregister.nl/trial/7925 ).

Trypanosoma cruzi, the etiological agent of Chagas disease, is a parasite known for its diverse genotypic variants, or Discrete Typing Units (DTUs), which have been associated with varying degrees of tissue involvement. However, aspects such as parasite attachment remain unclear. It has been suggested that the TcI genotype is associated with cardiac infection, the most common involved site in chronic human infection, while TcII is associated with digestive tract involvement. Traditional models for T. cruzi infection provide limited in vivo observation, making it challenging to observe the dynamics of parasite-host interactions. This study evaluates the cardiac attachment of trypomastigotes from TcI and TcII DTUs in zebrafish larvae. Labeled trypomastigotes were injected in the duct of Cuvier of zebrafish larvae and tracked by stereomicroscopy and light-sheet fluorescence microscopy (LSFM). Remarkably, it was possible to observe TcI parasites adhered to the atrium, atrioventricular valve, and circulatory system, while TcII trypomastigotes demonstrated adhesion to the atrium, atrioventricular valve, and yolk sac extension. When TcI and TcII were simultaneously injected, they both attached to the heart; however, more of the TcII trypomastigotes were observed attached to this organ. Although TcII DTU has previously been associated with digestive tissue infection, both parasite variants showed cardiac tissue attachment in this in vivo model. [ABSTRACT FROM AUTHOR]

Background/Objectives: Body surface area is one of the most important anthropometric parameters in medicine. The study's primary objective is to compare the consistency of the BSA estimation results through applying available formulas. Other objectives include determining the ability of these formulas to discriminate between death and survival in patients, comparing the formulas' diagnostic features, and investigating whether the risk associated with a low BSA is independent of BMI. Methods: This study included 1029 patients (median age, 54 years; female, 13.7%; NYHA I/II/III/IV, 6.3%/36.5%/47.7%/9.5%) diagnosed with heart failure. For each patient, BSA was calculated using 25 formulas. Over the 3-year observation period, 31.2% of the patients died. Results: The average BSA value of the optimal discrimination thresholds was 1.79 m2 ± 0.084 m2 and the BSA difference between the estimators with the lowest (BSAMeeh1879) and the highest (BSANwoye1989) optimal discrimination thresholds was 0.42 m2. The lowest mortality rate was 35.2% and occurred in the subgroup of individuals with BSA values below the optimal discrimination threshold using the BSASchlich2010 estimator. The highest mortality was predicted when the estimator BSAMeeh1879 or BSALivingston&Lee2001 was used. Conclusions: Our study showed a relatively good concordance of 25 BSA estimators in BSA assessment in patients, without extremes of weight or height being known to disrupt it. All BSA estimators presented a significant, although weak, ability to discriminate death from survival at 3-year follow-up; however, BSA is not a very good predictor of HF mortality at 3 years. The higher risk of death in smaller patients, as shown by BSA, was independent of BMI in all but two BSA estimators. [ABSTRACT FROM AUTHOR]

This study reveals a significant presence of ticks and tick-borne pathogens in urban recreational areas of Tallinn, Estonia. During the period of May–June 2018, 815 Ixodes ticks were collected from an area of 11,200 m2 using the flagging method. Tick density reached up to 18.8 ticks per 100 m2, indicating a high concentration of ticks in these urban green spaces. Pathogen analysis demonstrated that 34% of the collected ticks were infected with at least one pathogen. Specifically, Borrelia burgdorferi s.l., the causative agent of Lyme borreliosis, was detected in 17.4% of the ticks; Rickettsia spp. was detected in 13.5%; Neoehrlichia mikurensis was detected in 5.5%; Borrelia miyamotoi was detected in 2.6%; and Anaplasma phagocytophilum and tick-borne encephalitis virus were detected in 0.5% each. These findings indicate that the prevalence and abundance of ticks and tick-borne pathogens in these urban environments are comparable to or even exceed those observed in natural endemic areas. Given the increasing incidence of Lyme borreliosis in Central and Northern Europe, the risk of tick bites and subsequent infection in urban recreational sites should not be underestimated. Public health measures, including enhanced awareness and precautionary information, are essential to mitigate the risk of tick-borne diseases in these urban settings. [ABSTRACT FROM AUTHOR]

Advancements in genome assembly and sequencing technology have made whole genome sequence (WGS) data and reference genomes accessible to study polyploid species. Compared to popular reduced‐representation sequencing approaches, the genome‐wide coverage and greater marker density provided by WGS data can greatly improve our understanding of polyploid species and polyploid biology. However, biological features that make polyploid species interesting also pose challenges in read mapping, variant identification, and genotype estimation. Accounting for characteristics in variant calling like allelic dosage uncertainty, homology between subgenomes, and variance in chromosome inheritance mode can reduce errors. Here, I discuss the challenges of variant calling in polyploid WGS data and discuss where potential solutions can be integrated into a standard variant calling pipeline. [ABSTRACT FROM AUTHOR]

Reference 1 Kamphuis D. The effectiveness of immediate versus delayed tubal flushing with oil-based contrast in women with unexplained infertility (H2Oil-timing study): study protocol of a randomized controlled trial. B Correction: BMC Women's Health 23, 233 (2023) b B https://doi.org/10.1186/s12905-023-02385-1 b Following publication of the original article [[1]], in this article the "Trial registration number" under the abstract has been updated and the same will read as follow: Trial registration number: The study was prospectively registered in International Clinical Trials Registry Platform (Main ID: EUCTR2018-004153-24-NL). [Extracted from the article]

Background: Ixodid ticks, particularly Rhipicephalus sanguineus s.l., are important vectors of various disease-causing agents in dogs and humans in Cuba. However, our understading of interactions among tick-borne pathogens (TBPs) in infected dogs or the vector R. sanguineus s.l. remains limited. This study integrates microfluidic-based high-throughput real-time PCR data, Yule's Q statistic, and network analysis to elucidate pathogen-pathogen interactions in dogs and ticks in tropical western Cuba. Methods: A cross-sectional study involving 46 client-owned dogs was conducted. Blood samples were collected from these dogs, and ticks infesting the same dogs were morphologically and molecularly identified. Nucleic acids were extracted from both canine blood and tick samples. Microfluidic-based high-throughput real-time PCR was employed to detect 25 bacterial species, 10 parasite species, 6 bacterial genera, and 4 parasite taxa, as well as to confirm the identity of the collected ticks. Validation was performed through end-point PCR assays and DNA sequencing analysis. Yule's Q statistic and network analysis were used to analyse the associations between different TBP species based on binary presence-absence data. Results: The study revealed a high prevalence of TBPs in both dogs and R. sanguineus s.l., the only tick species found on the dogs. Hepatozoon canis and Ehrlichia canis were among the most common pathogens detected. Co-infections were observed, notably between E. canis and H. canis. Significant correlations were found between the presence of Anaplasma platys and H. canis in both dogs and ticks. A complex co-occurrence network among haemoparasite species was identified, highlighting potential facilitative and inhibitory roles. Notably, H. canis was found as a highly interconnected node, exhibiting significant positive associations with various taxa, including A. platys, and E. canis, suggesting facilitative interactions among these pathogens. Phylogenetic analysis showed genetic diversity in the detected TBPs. Conclusions: Overall, this research enhances our understanding of TBPs in Cuba, providing insights into their prevalence, associations, and genetic diversity, with implications for disease surveillance and management. [ABSTRACT FROM AUTHOR]

To date, many randomized studies have proven the importance of evaluating clinical and anamnestic data in the initial diagnosis of genital endometriosis. Clinical assessment of “classic” complaints of patients, which are characteristic of genital endometriosis, allows to predict the presence of endometriosis with a high probability, which is an important component of choosing the optimal treatment tactics. Despite a fairly significant number of developed questionnaires for the assessment of endometriosis symptoms, none of them has been widely used among domestic clinicians. Implementation of a diary of symptoms of endometriosis in practice will allow to more carefully assess the general pain of endometriosis, the impact on the patient’s quality of life, and also to evaluate the quality of the chosen method of treatment. The aim of the study: on the basis of a retrospective analysis of patients’ disease histories, assessment of the presence of clinical and anamnestic data characteristic of genital endometriosis in accordance with the obtained results of pathohistologically confirmed endometriosis. Materials and methods. We performed a retrospective analysis of 160 patient histories. The criteria for selecting patients with genital endometriosis were the presence of the following symptoms: premenstrual pain syndrome, dysmenorrhea, dyspareunia, the nature of menstrual discharge (brown discharge before and after menstruation), chronic pelvic pain, as well as confirmation, with the help of histopathological examination, of genital endometriosis. Results. By comparing the obtained data on pain symptoms with the clinical diagnosis made on the basis of histopathological examination, it can be concluded that the symptoms were most likely caused by endometriosis. Conclusions. Clinical and anamnestic data most characteristic of genital endometriosis were found in 138 (86.25 %) patients, data on the frequency of combination of painful symptoms were as follows: combination of two symptoms in 27.50 % (n = 44), three symptoms in 26.88 % (n = 43), four symptoms in 14.38 % (n = 23) and five studied symptoms in 6.25 % (n = 10), which in turn influenced the choice of the expected volume of surgical intervention and contributed to the establishment of a clinical diagnosis. The description of pain symptoms is quite limited, since the assessment of the characteristic symptoms of genital endometriosis did not include: conducting additional examinations in order to exclude additional causes of functional pain in the pelvis, the description of pain symptoms was incomplete, which, in turn, minimized the assessment of the adverse impact on daily activities, work or the quality of life in general, characteristic of pain symptoms, there is no clear difference between chronic pelvic pain and dysmenorrhea, the absence of data regarding the work of the gastrointestinal tract and urinary system, regarding the symptoms of genital endometriosis, which may indicate damage to the above-mentioned departments. [ABSTRACT FROM AUTHOR]

Micro-environmental factors, including stromal and immune cells, cytokines, and circulating hormones are well recognized to determine cancer progression. Melanoma cell growth was recently shown to be suppressed by cholecystokinin/gastrin (CCK) receptor antagonists, and our preliminary data suggested that melanoma patients with Helicobacter gastritis (which is associated with elevated serum gastrin) might have an increased risk of cancer progression. Therefore, in the present study, we examined how gastrin may act on melanoma cells. In 89 melanoma patients, we found a statistically significant association between circulating gastrin concentrations and melanoma thickness and metastasis, which are known risk factors of melanoma progression and prognosis. Immunocytochemistry using a validated antibody confirmed weak to moderate CCK2R expression in both primary malignant melanoma cells and the melanoma cell lines SK-MEL-2 and G361. Furthermore, among the 219 tumors in the Skin Cutaneous Melanoma TCGA Pan-Cancer dataset showing gastrin receptor (CCKBR) expression, significantly higher CCKBR mRNA levels were linked to stage III–IV than stage I–II melanomas. In both cell lines, gastrin increased intracellular calcium levels and stimulated cell migration and invasion through mechanisms inhibited by a CCK2 receptor antagonist. Proteomic studies identified increased MMP-2 and reduced TIMP-3 levels in response to gastrin that were likely to contribute to the increased migration of both cell lines. However, the effects of gastrin on tumor cell invasion were relatively weak in the presence of the extracellular matrix. Nevertheless, dermal fibroblasts/myofibroblasts, known also to express CCK2R, increased gastrin-induced cancer cell invasion. Our data suggest that in a subset of melanoma patients, an elevated serum gastrin concentration is a risk factor for melanoma tumor progression, and that gastrin may act on both melanoma and adjacent stromal cells through CCK2 receptors to promote mechanisms of tumor migration and invasion. [ABSTRACT FROM AUTHOR]

STUDY QUESTION What is the influence of dietary interventions, namely the low fermentable oligo-, di-, mono-saccharides, and polyols (Low FODMAP) diet and endometriosis diet, on endometriosis-related pain and quality of life (QoL) compared to a control group? SUMMARY ANSWER After adhering to a dietary intervention for 6 months, women with endometriosis reported less pain and an improved QoL compared to baseline whereas, compared to the control group, they reported less bloating and a better QoL in 3 of 11 domains. WHAT IS KNOWN ALREADY Standard endometriosis treatment can be insufficient or may be accompanied by unacceptable side effects. This has resulted in an increasing interest in self-management strategies, including the appliance of the Low FODMAP diet and the endometriosis diet (an experience-based avoidance diet, developed by women with endometriosis). The Low FODMAP diet has previously been found effective in reducing endometriosis-related pain symptoms, whereas only limited studies are available on the efficacy of the endometriosis diet. A survey study recently found the endometriosis diet effective in improving QoL but currently no guidelines on use of the diet exist. STUDY DESIGN, SIZE, DURATION A prospective one-center pilot study was performed between April 2021 and December 2022. Participants could choose between adherence to a diet—the Low FODMAP diet or endometriosis diet—or no diet (control group). Women adhering to a diet received extensive guidance from a dietician in training. The follow-up period was 6 months for all three groups. For all outcomes, women adhering to the diets were compared to their baseline situation and to the control group. PARTICIPANTS/MATERIALS, SETTING, METHODS We included women diagnosed with endometriosis (surgically and/or by radiologic imaging) who reported pain scores ≥3 cm on the visual analogue score (0–10 cm) for dysmenorrhea, deep dyspareunia, and/or chronic pelvic pain. The primary endpoint focused on pain reduction for all pain symptoms, including dysuria, bloating, and tiredness. Secondary endpoints, assessed via questionnaires, focused on QoL, gastro-intestinal health, and diet adherence. MAIN RESULTS AND THE ROLE OF CHANCE A total of 62 participants were included in the low FODMAP diet (n = 22), endometriosis diet (n = 21), and control group (n = 19). Compared to their baseline pain scores, participants adhering to a diet reported less pain in four of six symptoms (range P  < 0.001 to P  = 0.012) and better scores in 6 of 11 QoL domains (range P  < 0.001 to P  = 0.023) after 6 months. Compared to the control group, analyzed longitudinally over the 6-month follow-up period, participants applying a diet reported significant less bloating (P  = 0.049), and better scores in 3 of 11 QoL domains (range P  = 0.002 to P  = 0.035). LIMITATIONS, REASONS FOR CAUTION No sample size was calculated since efficacy data were lacking in the literature. In order to optimize dietary adherence, randomization was not applied, possibly resulting in selection bias. WIDER IMPLICATIONS OF THE FINDINGS Our study suggests that women could benefit from adherence to a dietary intervention, since we found lower pain scores and better QoL after 6 months. However, caution is implied since this is a pilot study, no sample size was calculated, and data on long-term effects (>6 months) are lacking. The results of this pilot study underline the importance of further research and the drawing up of guidelines. STUDY FUNDING/COMPETING INTEREST(S) A.v.H. reports receiving a travel grant from Merck outside the scope of this study. J.W. S.V. J.T. and B.D.B. have no conflicts of interest to report. A.d.V. reports having received KP-register points for internship guidance of J.W. performing paid consultations with endometriosis patients outside the study and receiving reimbursements for educational lectures at the local hospital (Albert Schweitzer Ziekenhuis, Dordrecht, the Netherlands). A.S. reports having received expenses for travel and hotel costs as an invited speaker from ESHRE. This was outside the scope of this study. M.v.W. reports that she is a Co-Ed of Cochrane Gynecology and Fertility. V.M. reports receiving travel and speaker's fees from Guerbet and research grants from Guerbet, Merck and Ferring. The department of reproductive medicine (V.M.) of the Amsterdam UMC, location VUmc, has received several research and educational grants from Guerbet, Merck and Ferring not related to the submitted work. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

Background: The discovery and development of immune checkpoint inhibitors (ICIs) has significantly enhanced the arsenal of immunotherapy treatments available for cancer patients. The identification of biomarkers that are indicative of an individual's sensitivity to treatment with ICIs is useful for screening SCLC patients prior to commencement of any ICIs based immunotherapy. However, the relationship between GBP5 and the prognosis of SCLC immunotherapy is still unclear and requires further study.Methods: We downloaded two SCLC datasets, namely the George-SCLC and Jiang-SCLC cohorts. We used the TIDE algorithm to predict the efficacy of immunotherapy for SCLC patients. The QuanTIseq, MCPcounter, and EPIC algorithms are used to calculate the proportions of immune cells in SCLC patients. Additionally, we retrospectively collected 35 SCLC samples from the first affiliated hospital of the Hengyang Medical school.Results: Patients in each cohort were devided into two groups with high (GBP5-High) and low (GBP5-Low) expression of GBP5. In both cohorts, the GBP5-High population had a higher proportion of patients that responded well to immunotherapy (responders) (p < 0.05). In addition, both GBP5-High subgroups had significantly increased cytotoxicity, chemokines, antigen presenting, and TNF family related genes. We also determined that GBP5 was related to high-level infiltration of B cells, CD4+T cells, CD8+T cells and NK cells.Conclusion: In this study, we found that GBP5 has the potential to be used as a biomarker of ICIs efficacy for SCLC patients. GBP5 is related to the quantity of inflammatory molecules, a high level of immune infiltration, and a highly activated immune response pathway. [ABSTRACT FROM AUTHOR]

Background: In women with unexplained infertility, tubal flushing with oil-based contrast during hysterosalpingography leads to significantly more live births as compared to tubal flushing with water-based contrast during hysterosalpingography. However, it is unknown whether incorporating tubal flushing with oil-based contrast in the initial fertility work-up results to a reduced time to conception leading to live birth when compared to delayed tubal flushing that is performed six months after the initial fertility work-up. We also aim to evaluate the effectiveness of tubal flushing with oil-based contrast during hysterosalpingography versus no tubal flushing in the first six months of the study. Methods: This study will be an investigator-initiated, open-label, international, multicenter, randomized controlled trial with a planned economic analysis alongside the study. Infertile women between 18 and 39 years of age, who have an ovulatory cycle, who are at low risk for tubal pathology and have been advised expectant management for at least six months (based on the Hunault prediction score) will be included in this study. Eligible women will be randomly allocated (1:1) to immediate tubal flushing (intervention) versus delayed tubal flushing (control group) by using web-based block randomization stratified per study center. The primary outcome is time to conception leading to live birth with conception within twelve months after randomization. We assess the cumulative conception rate at six and twelve months as two co-primary outcomes. Secondary outcomes include ongoing pregnancy rate, live birth rate, miscarriage rate, ectopic pregnancy rate, number of complications, procedural pain score and cost-effectiveness. To demonstrate or refute a shorter time to pregnancy of three months with a power of 90%, a sample size of 554 women is calculated. Discussion: The H2Oil-timing study will provide insight into whether tubal flushing with oil-based contrast during hysterosalpingography should be incorporated in the initial fertility work-up in women with unexplained infertility as a therapeutic procedure. If this multicenter RCT shows that tubal flushing with oil-based contrast incorporated in the initial fertility work-up reduces time to conception and is a cost-effective strategy, the results may lead to adjustments of (inter)national guidelines and change clinical practice. Trial registration number: The study was prospectively registered in International Clinical Trials Registry Platform (Main ID: EUCTR2018-004153-24-NL). [ABSTRACT FROM AUTHOR]

Aging is a major risk factor associated with increased morbidity and mortality rates observed during respiratory infections. In this study, we investigated the role of influenza virus infections in the establishment of premature cellular senescence and paracrine macrophage-activated inflammation. We observed in our murine model a premature aging by the appearance of senescent cells in the lungs after 21 d of influenza A virus infection. By using murine ex vivo lung models, the influence of TNF-a on the establishment of cellular senescence was detectable. Our findings were proven by using conditioned media of infected human monocytederived macrophages on primary lung fibroblasts. Here, a distinct expression of senescence-associated parameters could be confirmed. Furthermore, senescent cells in the lungs strongly influenced subsequent viral infections. Our data demonstrated a higher viral load in senescent primary lung fibroblasts, indicating an intracellular effect on viral replication. Transcriptomic data revealed an increased regulation of JAK/STAT signaling in senescent IAVinfected cells accompanied with increased TRAIL expression. Additionally, senescent cells indicating low pH values, accelerating viral replication. Our study provides new insights into pathomechanisms of virus-induced cellular senescence. Hence, IAV infection induces premature senescence and subsequent infections in senescent cells lead to an increased viral replication. [ABSTRACT FROM AUTHOR]

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Simple Summary: Breast cancer continues to be the number one cause of cancer mortality among women. Because breast cancer is a heterogenous disease there is a need for a more personalized approach to treatment. Such an approach requires the understanding of the molecular root cause of each cancer and the identification of the responsible molecule(s) or pathway(s). SigmaR1 is a receptor implicated in certain types of breast cancer and represents a promising target for a new generation of personalized treatments. However, there is a need for understanding its precise cellular role in order to target it effectively. This article reviews the current knowledge about SigmaR1 in breast cancer biology and potential treatment and proposes a new model as to how SigmaR1 operates within the cell in order to devise new effective ways for utilizing it in the clinic. Despite the major progress in treating breast cancer, recurrence remains a problem and types such as triple-negative breast cancer still lack targeted medicine. The orphan Sigma receptor1 (SigmaR1) has emerged as a target in breast cancer, but its mechanism of action is unclear and hinders clinical utility. SigmaR1 is widely expressed in organ tissues and localized to various sub-cellular compartments, particularly the endoplasmic reticulum (ER), the mitochondrial-associated membranes (MAMs) and the nuclear envelope. As such, it involves diverse cellular functions, including protein quality control/ER stress, calcium signaling, cholesterol homeostasis, mitochondrial integrity and energy metabolism. Consequently, SigmaR1 has been implicated in a number of cancers and degenerative diseases and thus has been intensively pursued as a therapeutic target. Because SigmaR1 binds a number of structurally unrelated ligands, it presents an excellent context-dependent therapeutic target. Here, we review its role in breast cancer and the current therapies that have been considered based on its known functions. As SigmaR1 is not classified as an oncoprotein, we propose a model in which it serves as an oligomerization adaptor in key cellular pathways, which may help illuminate its association with variable diseases and pave the way for clinical utility in personalized medicine. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer patients, particularly with glioblastoma (GBM), are at increased risk for thrombosis. This risk is further increased upon treatment with chemotherapy. Tissue factor (TF) is the initiator of the extrinsic coagulation pathway and expressed by GBM cells. Chemotherapy is known to affect TF expression and activity in several cancer types, but the effect of the commonly used chemotherapeutic agents Temozolomide and Lomustine on TF in GBM is unknown. In this study, we describe a promoting role for these agents on TF procoagulant activity and TF gene and protein expression in three GBM cell lines. This may explain the increased risk of thrombosis in GBM patients undergoing chemotherapy. Our findings may have implications for future GBM treatment since patients with high TF levels may benefit from anticoagulant treatment by decreasing the risk of chemotherapy-induced thrombosis in GBM. Glioblastoma (GBM) patients have one of the highest risks of venous thromboembolism (VTE), which is even further increased upon treatment with chemotherapy. Tissue factor (TF) is the initiator of the extrinsic coagulation pathway and expressed by GBM cells. In this study, we aimed to examine the effect of routinely used chemotherapeutic agents Temozolomide (TMZ) and Lomustine (LOM) on TF procoagulant activity and expression in GBM cells in vitro. Three human GBM cell lines (U-251, U-87, U-118) were exposed to 100 µM TMZ or 30 µM LOM for 72 h. TF procoagulant activity was assessed via an FXa generation assay and TF gene and protein expression through qPCR and Western blotting. The externalization of phosphatidylserine (PS) was studied using Annexin V flow cytometry. Treatment with TMZ and LOM resulted in increased procoagulant activity in all cell lines. Furthermore, both agents induced procoagulant activity in the supernatant and tumor-cell-secreted extracellular vesicles. In line, TF gene and protein expression were increased upon TMZ and LOM treatment. Additionally, PS externalization and induction of inflammatory-associated genes were observed. Overall, the chemotherapeutic modalities TMZ and LOM induced procoagulant activity and increased TF gene and protein expression in all GBM cell lines tested, which may contribute to the increased VTE risk observed in GBM patients undergoing chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Suicide is considered a fundamental problem in discussions on public and global health. Thus, the current study aimed to review the prevalence of and reasons for successful suicide attempts in heroin users. Methods: This study was conducted by systematically searching the electronic databases of PubMed, Scopus, Web of Science, and PsycINFO from 1960/1/1 to 2021/11/1 based on the PRISMA checklist and using MeSH keywords with no temporal or linguistic limitations. The primary and secondary impacts of suicide were identified, and all studies following an observational design (cohort, case-control, and cross-sectional studies) were included in the research. Data analysis was performed using Stata version 13. Finally, 17 studies were included in the work process for systematic review and meta-analysis. Findings: The results showed the most frequent reasons for suicide among the studied individuals were gender (being female), youngness, heroin overdose, multi-drug abuse, history of repeated suicide attempts, history of psychiatric disorder (especially depression), joblessness, homelessness, distorted family relationships, etc. Moreover, the results of synthesizing the studies revealed the prevalence of suicide attempts equaled the effect size (95% CI = 0.3 [0.23-0.37]) among these individuals, and the prevalence of successful suicides approached the effect size (95% CI = 0.03 [0.01-0.05]). Conclusion: The results of the present study showed the high prevalence of suicidal thoughts and suicide attempts among the heroin-abusing population. Furthermore, according to the findings, the prevalence of unsuccessful suicide attempts was ten times more than that of successful ones in the target population. [ABSTRACT FROM AUTHOR]

STUDY QUESTIONS The objective of this study is to evaluate the effectiveness and cost-effectiveness of surgical treatment of women suffering from pain due to an ovarian endometrioma when compared to treatment with medication (analgesia and/or hormones). The primary outcome is defined as successful pain reduction (−30% reduction of pain) measured by the numeric rating scale (NRS) after 6 months. Secondary outcomes include successful pain reduction after 12 and 18 months, quality of life, affective symptoms, cost-effectiveness, recurrence rate, need of adjuvant medication after surgery, ovarian reserve, adjuvant surgery and budget impact. WHAT IS KNOWN ALREADY Evidence suggests that both medication and surgical treatment of an ovarian endometrioma are effective in reducing pain and improving quality of life. However, there are no randomised studies that compare surgery to treatment with medication. STUDY DESIGN, SIZE, DURATION This study will be performed in a research network of university and teaching hospitals in the Netherlands. A multicentre randomised controlled trial and parallel prospective cohort study in patients with an ovarian endometrioma, with the exclusion of patients with deep endometriosis, will be conducted. After obtaining informed consent, eligible patients will be randomly allocated to either treatment arm (medication or surgery) by using web-based block randomisation stratified per centre. A successful pain reduction is set at a 30% decrease on the NRS at 6 months after randomisation. Based on a power of 80% and an alpha of 5% and using a continuity correction, a sample size of 69 patients in each treatment arm is needed. Accounting for a drop-out rate of 25% (i.e. loss to follow up), we need to include 92 patients in each treatment arm, i.e. 184 in total. Simultaneously, a cohort study will be performed for eligible patients who are not willing to be randomised because of a distinct preference for one of the two treatment arms. We intend to include 100 women in each treatment arm to enable standardization by inverse probability weighting, which means 200 patients in total. The expected inclusion period is 24 months with a follow-up of 18 months. PARTICIPANTS/MATERIALS, SETTING, METHODS Premenopausal women (age ≥ 18 years) with pain (dysmenorrhoea, pelvic pain or dyspareunia) and an ovarian endometrioma (cyst diameter ≥ 3 cm) who visit the outpatient clinic will make up the study population. Patients with signs of deep endometriosis will be excluded. The primary outcome is successful pain reduction, which is defined as a 30% decrease of pain on the NRS at 6 months after randomisation. Secondary outcomes include successful pain reduction after 12 and 18 months, quality of life and affective symptoms, cost-effectiveness (from a healthcare and societal perspective), number of participants needing additional surgery, need of adjuvant medication after surgery, ovarian reserve and recurrence rate of endometriomas. Measurements will be performed at baseline, 6 weeks and 6, 12 and 18 months after randomisation. STUDY FUNDING/COMPETING INTEREST(S) This study is funded by ZonMw, a Dutch organization for Health Research and Development, project number 80-85200-98-91041. The Department of Reproductive Medicine of the Amsterdam UMC location VUmc has received several research and educational grants from Guerbet, Merck KGaA and Ferring not related to the submitted work. B.W.J. Mol is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for ObsEva, Merck KGaA and Guerbet. V. Mijatovic reports grants from Guerbet, grants from Merck and grants from Ferring outside the submitted work. All authors declare that they have no competing interests concerning this publication. TRIAL REGISTRATION NUMBER Dutch Trial Register (NTR 7447, http://www.trialregister.nl). TRIAL REGISTRATION DATE 2 January 2019 DATE OF FIRST PATIENT'S ENROLMENT First inclusion in randomised controlled trial October 4, 2019. First inclusion in cohort May 22, 2019. [ABSTRACT FROM AUTHOR]

Background: Influenza is one of the most important viral infections globally. Viral RNA-dependent RNA polymerase (RdRp) consists of the PA, PB1, and PB2 subunits, and the amino acid residues of each subunit are highly conserved among influenza A virus (IAV) strains. Due to the high mutation rate and emergence of drug resistance, new antiviral strategies are needed. Host cell factors are involved in the transcription and replication of influenza virus. Here, we investigated the role of galectin-3, a member of the β-galactoside-binding animal lectin family, in the life cycle of IAV infection in vitro and in mice. Methods: We used galectin-3 knockout and wild-type mice and cells to study the intracellular role of galectin-3 in influenza pathogenesis. Body weight and survival time of IAV-infected mice were analyzed, and viral production in mouse macrophages and lung fibroblasts was examined. Overexpression and knockdown of galectin-3 in A549 human lung epithelial cells were exploited to assess viral entry, viral ribonucleoprotein (vRNP) import/export, transcription, replication, virion production, as well as interactions between galectin-3 and viral proteins by immunoblotting, immunofluorescence, co-immunoprecipitation, RT-qPCR, minireplicon, and plaque assays. We also employed recombinant galectin-3 proteins to identify specific step(s) of the viral life cycle that was affected by exogenously added galectin-3 in A549 cells. Results: Galectin-3 levels were increased in the bronchoalveolar lavage fluid and lungs of IAV-infected mice. There was a positive correlation between galectin-3 levels and viral loads. Notably, galectin-3 knockout mice were resistant to IAV infection. Knockdown of galectin-3 significantly reduced the production of viral proteins and virions in A549 cells. While intracellular galectin-3 did not affect viral entry, it increased vRNP nuclear import, RdRp activity, and viral transcription and replication, which were associated with the interaction of galectin-3 with viral PA subunit. Galectin-3 enhanced the interaction between viral PA and PB1 proteins. Moreover, exogenously added recombinant galectin-3 proteins also enhanced viral adsorption and promoted IAV infection in A549 cells. Conclusion: We demonstrate that galectin-3 enhances viral infection through increases in vRNP nuclear import and RdRp activity, thereby facilitating viral transcription and replication. Our findings also identify galectin-3 as a potential therapeutic target for influenza. [ABSTRACT FROM AUTHOR]

Aims: This study aimed to determine the impact of heart failure (HF) on clinical outcomes in patients with atrial fibrillation (AF). Methods and results: We analysed data from Polish participants of the EURObservational Research Programme‐AF General Long‐Term Registry. The primary endpoint was all‐cause death, and the secondary endpoints included hospital readmissions, cardiovascular (CV) interventions, thromboembolic and haemorrhagic events, rhythm control interventions, and other CV or non‐CV diseases development during one‐year follow up. Overall, 688 patients with available data on HF were included into analysis; 51% (n = 351) had HF; of these 48% (n = 168) had reduced ejection fraction (HFrEF), 22% (n = 77) mid‐range EF (HFmrEF), and 30% (n = 106) preserved EF (HFpEF). Compared with patients without HF, those with HF had higher mortality rate (aHR 5.61; 95% CI 1.94–16.22, P < 0.01). Patients with HF (vs. without HF) had more often CV interventions (10% vs. 5.4%, P = 0.046) and events (14% vs. 7.1%, P = 0.02), and had less often atrial arrhythmia‐related hospital admissions (6.8% vs. 15%, P < 0.01). Over follow‐up, patients with HFmrEF and HFpEF had similar mortality rate versus HFrEF (aHR 0.45, 95% CI 0.13–1.57, P = 0.45 for HFmrEF and aHR 0.54, 95% CI 0.20–1.48, P = 0.54 for HFpEF). Mortality rate was similar among rhythm versus rate control group (aHR 0.34; 95% CI 0.10–1.16; P = 0.34). Conclusions: AF patients with HF have greater mortality rate and more CV interventions/events. No statistically significant difference in long‐term outcomes between patients with HFrEF, HFmrEF, and HFpEF highlights the need to develop therapeutic strategies targeting functional status and survival for patients with HF and AF. [ABSTRACT FROM AUTHOR]

Information on the pattern of acute poisonings in hospitals of Birjand city, Iran, is limited. This study aimed to address this knowledge gap by examining the admissions in a major poisoning center in eastern Iran. This cross-sectional study included patients admitted to the Imam Reza Hospital in Birjand over 12 months. Medical records of the poisoned patients were reviewed, and the study variables were used for data analysis. During the study period, 534 cases of acute poisonings were evaluated. The patient's ages ranged from 12 to 84 years, with a high rate of poisonings between 15 and 35 years. The female predominance in poisoning cases was 52.1%. Most cases of poisonings occurred in spring, and the common route of exposure was oral (93.1%). The incidence of poisoning in married couples, uneducated patients, and residents of urban areas was 56.5%, 90.1%, and 74.6%, respectively. Patients with a previous medical history experienced addiction and psychiatric disorders. Intentional poisoning accounted for 23.4% of acute poisoning cases referred to the hospital in the current study. The main groups of toxicants were pharmaceutical products (48.1%), narcotics (25.8%), chemical products (10.1%), envenomation (7.1%), and alcohol (1.7%). The mean hospital stay was 2.5 ± 3.0 days, and the final treatment outcome was complete recovery, except for one patient intoxicated by warfarin and alprazolam. Our results indicate that the high toxicity cases were related to pharmaceutical product and opioids abuse, especially methadone (8.4%), alprazolam (7.9%), clonazepam (7.5%), and acetaminophen (9.9%) taken orally and more commonly happened at home. Due to the high rate of deliberate poisonings, especially among young adults and students, monitoring drug distribution and exceptional attention to mental health should be seriously considered by national health authorities to prevent suicide attempts. [ABSTRACT FROM AUTHOR]