Cornual adenomyosis in Essure® device users and in patients hysterectomized for other causes: A retrospective cohort study.

OBJECTIVE: To determine whether adenomyosis is present in the cornual portion of hysterectomies of symptomatic sterilization device users and in patients hysterectomized for different benign causes and who presented with pelvic pain and/or menstrual alterations. METHODS: An observational, analytical, cross-sectional, single-center, retrospective cohort study was conducted in a secondary level hospital. Cohort 1 consisted of women who had Essure® hysteroscopic sterilization devices inserted between 2009 and 2017, who developed gynecologic symptoms (pelvic pain, heavy menstrual bleeding, and/or abnormal uterine bleeding) and who underwent a hysterectomy for explantation of the devices. Cohort 2 consisted of women with the same gynecologic symptoms, who underwent a hysterectomy for other benign causes. All surgeries were performed by the gynecology team between 2018 and 2022. A descriptive and comparative analysis of sociodemographic, clinical characteristics, and pathologic findings between cohorts was made. RESULTS: In total, 96 patients were studied (cohort 1 included 34 women, cohort 2 included 62 women). Pelvic pain was found to be more frequent in the cohort of Essure users (76.47% vs. 50%, P = 0.012), with a ratio of three times higher in this group (odds ratio 3.25, 95% confidence interval 1.27-8.28). Adenomyosis was more frequently found in the Essure group, both at corporal and cornual portions, the latter being five times higher in this cohort (relative risk = 5.47; 95% confidence interval 1.17-25.64). CONCLUSIONS: The present study may be the first to describe cornual adenomyosis related to Essure devices. These devices may play a role in the development of adenomyosis and, consequently, pelvic pain. However, causality is difficult to establish.

Proteomic Analysis Reveals Trilaciclib-Induced Senescence.

Trilaciclib, a CDK4/6 inhibitor, was approved as a myeloprotective agent for protecting bone marrow from chemotherapy-induced damage in extensive-stage small cell lung cancer (ES-SCLC). This is achieved through the induction of a temporary halt in the cell cycle of bone marrow cells. While it has been studied in various cancer types, its potential in haematological cancers remains unexplored. This research aimed to investigate the efficacy of trilaciclib in haematological cancers. Utilizing mass spectrometry-based proteomics, we examined the alterations induced by trilaciclib in the chronic myeloid leukaemia (CML) cell line, K562. Interestingly, trilaciclib promoted senescence in these cells rather than cell death, as observed in acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL), and myeloma cells. In K562 cells, trilaciclib hindered cell cycle progression and proliferation by stabilising CDK4/6 and downregulating cell cycle-related proteins, along with the concomitant activation of autophagy pathways. Additionally, trilaciclib-induced senescence was also observed in the non-small cell lung carcinoma cell line (NSCLC), A549. These findings highlight trilaciclib's potential as a therapeutic option for haematological cancers and underscore the need to carefully balance senescence induction and autophagy modulation in CML treatment, as well as in NSCLC.

Crowdsourced human-based computational approach for tagging peripheral blood smear sample images from Sickle Cell Disease patients using non-expert users.

In this paper, we present a human-based computation approach for the analysis of peripheral blood smear (PBS) images images in patients with Sickle Cell Disease (SCD). We used the Mechanical Turk microtask market to crowdsource the labeling of PBS images. We then use the expert-tagged erythrocytesIDB dataset to assess the accuracy and reliability of our proposal. Our results showed that when a robust consensus is achieved among the Mechanical Turk workers, probability of error is very low, based on comparison with expert analysis. This suggests that our proposed approach can be used to annotate datasets of PBS images, which can then be used to train automated methods for the diagnosis of SCD. In future work, we plan to explore the potential integration of our findings with outcomes obtained through automated methodologies. This could lead to the development of more accurate and reliable methods for the diagnosis of SCD.

Lymphoid interstitial pneumonia in a patient with systemic lupus erythematosus: Case report and literature review.

Lymphoid interstitial pneumonia (LIP) is a rare form of interstitial pulmonary disease, which has been described in association with a wide range of autoimmune disorders. Although the association of this entity with Sjogren's syndrome is well known, only a few cases are reported in relation to systemic lupus erythematosus (SLE). The aim of this paper is to review the cases reported in literature to date, as well as to describe the characteristics of these patients including the new case presented herein. We will be focusing on the case of a 36-year-old female patient diagnosed with SLE on hydroxychloroquine treatment who develops pleuritic chest pain and progressive dyspnea after 3 years of follow-up. The chest CT scan showed pleural thickening and both multiple and bilateral micronodules. A lung biopsy was also performed, revealing an infiltration of lymphocytes, plasma cells, and histiocytes in the alveolar septa suggestive of LIP. After conducting a review of the literature, we identified seven other cases describing SLE in association with LIP. The majority of them were young women, and LIP tends to appear early in the course of the disease, even as a form of initial presentation in some cases. Symptoms included cough, dyspnea, and pleuritic pain, with the exception of one case which was asymptomatic. It is noteworthy that half of the patients were positive for anti-SSA/anti-SSB autoantibodies, and some of them also met criteria for Sjogren's syndrome. Treatment with steroids and other immunosuppressive agents improved symptoms in all of them.

Azathioprine dose tailoring based on pharmacogenetic information: Insights of clinical implementation.

Azathioprine is commonly used as an immunosuppressive antimetabolite in the treatment of acute lymphoblastic leukemia, autoimmune disorders (such as Crohn's disease and rheumatoid arthritis), and in patients receiving organ transplants. Thiopurine-S-methyltransferase (TPMT) is a cytoplasmic trans-methylase catalyzing the S-methylation of thiopurines. The active metabolites obtained from thiopurines are hydrolyzed into inactive forms by the Nudix hydrolase 15 (NUDT15). The TPMT*2 (defined by rs1800462), *3A (defined by rs1800460 and rs1142345), *3B (defined by rs1800460), *3C (defined by rs1142345), *6 (defined by rs75543815), and NUDT15 rs116855232 genetic variant have been associated, with the highest level of evidence, with the response to azathioprine, and, the approved drug label for azathioprine and main pharmacogenetic dosing guidelines recommend starting with reduced initial doses in TPMT intermediate metabolizer (IM) patients and considering an alternative treatment in TPMT poor metabolizer (PM) patients. This study aims to assess the clinical impact of azathioprine dose tailoring based on TPMT genotyping studying the azathioprine toxicity and efficacy, treatment starts, and dose adjustments during follow-up, comparing TPMT IM/PM and normal metabolizer (NM) patients. It also studied the association of NUDT15 rs116855232 with response to azathioprine in patients receiving a tailored treatment based on TPMT and characterized the TMPT and NUDT15 studied variants in our population. Results show that azathioprine dose reduction in TPMT IM patients (TPMT*1/*2, *1/*3A, or *1/*3C genotypes) is related to lower toxicity events compared to TPMT NM (TPMT *1/*1 genotype), and lower azathioprine dose adjustments during follow-up without showing differences in the efficacy. The results support the hypothesis of existing other genetic variants affecting azathioprine toxicity.

Treatment of Vestibulodynia with Submucosal Injections of IncobotulinumtoxinA into Targeted Painful Points: An Open-Label Exploratory Study.

The studies carried out to date on vulvodynia treatment with botulinum neurotoxin type A (BoNT/A) have followed generic injection protocols and reported contradictory outcomes on its effects. The aim of the present study was thus to propose a protocol for injecting BoNT/A into targeted painful points, to comprehensively assess the clinical effect of BoNT/A treatment and identify the risk/protective factors for successful treatment. Thirty-five vestibulodynia patients were treated with submucosal injections of incobotulinumtoxinA and assessed 8, 12 and 24 weeks after their treatment. Their clinical and pelvic statuses were assessed from self-reported questionnaires (Visual Analogue Scale (VAS), Female Sexual Function Index (FSFI), Marinoff's Dyspareunia Scale (MDS), Hospital Anxiety and Depression Scale (HADS), Catastrophizing Scale (CS)), physical examinations and surface electromyography (sEMG). The patients reported a reduction in provoked vestibulodynia (FSFI, p < 0.01;

Outperformance of interleukin-6 over placental alpha microglobulin-1 in predicting preterm delivery in symptomatic women.

BACKGROUND: Threatened preterm labor is the major cause of hospital admission during the second half of pregnancy. An early diagnosis is crucial for adopting pharmacologic measures to reduce perinatal mortality and morbidity. Current diagnostic criteria are based on symptoms and short cervical length. However, there is a high false-positive rate when using these criteria, which implies overtreatment, causing unnecessary side effects and an avoidable economic burden. OBJECTIVE: This study aimed to compare the use of placental alpha microglobulin-1 and interleukin-6 as vaginal biomarkers combined with cervical length and other maternal characteristics to improve the prediction of preterm delivery in symptomatic women. STUDY DESIGN: A prospective observational study was conducted in women with singleton pregnancies complicated by threatened preterm labor with intact membranes at 24+0 to 34+6 weeks of gestation. A total of 136 women were included in this study. Vaginal fluid was collected with a swab for placental alpha microglobulin-1 determination using the PartoSure test, interleukin-6 was assessed by electrochemiluminescence immunoassay, cervical length was measured by transvaginal ultrasound, and obstetrical variables and newborn details were retrieved from clinical records. These characteristics were used to fit univariate binary logistic regression models to predict time to delivery <7 days, time to delivery <14 days, gestational age at delivery ≤34 weeks, and gestational age at delivery ≤37 weeks, and multivariate binary logistic regression models were fitted with imbalanced and balanced data. Performance of models was assessed by their F2-scores and other metrics, and the association of their variables with a risk or a protective factor was studied. RESULTS: A total of 136 women were recruited, of whom 8 were lost to follow-up and 7 were excluded. Of the remaining 121 patients, 22 had a time to delivery <7 days and 31 had a time to delivery <14 days, and 30 deliveries occurred with a gestational age at delivery ≤34 weeks and 55 with a gestational age at delivery ≤37 weeks. Univariate binary logistic regression models fitted with the log transformation of interleukin-6 showed the greatest F2-scores in most studies, which outperformed those of models fitted with placental alpha microglobulin-1 (log[interleukin-6] vs placental alpha microglobulin-1 in time to delivery <7 days: 0.38 vs 0.30; time to delivery <14 days: 0.58 vs 0.29; gestational age at delivery ≤34 weeks: 0.56 vs 0.29; gestational age at delivery ≤37 weeks: 0.61 vs 0.16). Multivariate logistic regression models fitted with imbalanced data sets outperformed most univariate models (F2-score in time to delivery <7 days: 0.63; time to delivery <14 days: 0.54; gestational age at delivery ≤34 weeks: 0.62; gestational age at delivery ≤37 weeks: 0.73). The performance of prediction of multivariate models was drastically improved when data sets were balanced, and was maximum for time to delivery <7 days (F2-score: 0.88±0.2; positive predictive value: 0.86±0.02; negative predictive value: 0.89±0.03). CONCLUSION: A multivariate assessment including interleukin-6 may lead to more targeted treatment, thus reducing unnecessary hospitalization and avoiding unnecessary maternal-fetal treatment.

Bi-functional particles for real-time phagosome acidification and proteolysis multiplex assay in macrophages.

Phagosome acidification and proteolysis are essential processes in the immune response to contain and eliminate pathogens. In recent years, there has been an increased desire for a rapid and accurate method of assessing these processes in real-time. Here, we outline the development of a multiplexed assay that allows simultaneous monitoring of phagosome acidification and proteolysis in the same sample using silica beads conjugated to pHrodo and DQ BSA. We describe in detail how to prepare the bi-functional particles and show proof of concept using differentially activated macrophages. This multiplexed spectrophotometric assay allows rapid and accurate assessment of phagosome acidification and proteolysis in real-time and could provide valuable information for understanding the immune response to pathogen invasion.

Comparison of Quantitative Mass Spectrometric Methods for Drug Target Identification by Thermal Proteome Profiling.

Thermal proteome profiling (TPP) provides a powerful approach to studying proteome-wide interactions of small therapeutic molecules and their target and off-target proteins, complementing phenotypic-based drug screens. Detecting differences in thermal stability due to target engagement requires high quantitative accuracy and consistent detection. Isobaric tandem mass tags (TMTs) are used to multiplex samples and increase quantification precision in TPP analysis by data-dependent acquisition (DDA). However, advances in data-independent acquisition (DIA) can provide higher sensitivity and protein coverage with reduced costs and sample preparation steps. Herein, we explored the performance of different DIA-based label-free quantification approaches compared to TMT-DDA for thermal shift quantitation. Acute myeloid leukemia cells were treated with losmapimod, a known inhibitor of MAPK14 (p38α). Label-free DIA approaches, and particularly the library-free mode in DIA-NN, were comparable of TMT-DDA in their ability to detect target engagement of losmapimod with MAPK14 and one of its downstream targets, MAPKAPK3. Using DIA for thermal shift quantitation is a cost-effective alternative to labeled quantitation in the TPP pipeline.

Assessing the Phagosome Proteome by Quantitative Mass Spectrometry.

The process of phagocytosis involves a series of defined steps, including the formation of a new intracellular organelle, i.e., the phagosome, and the maturation of the phagosome by fusion with endosomes and lysosomes to produce an acidic and proteolytic environment in which the pathogens are degraded. Phagosome maturation is associated with significant changes in the proteome of phagosomes due to the acquisition of new proteins or enzymes, post-translational modifications of existing proteins, as well as other biochemical changes that ultimately lead to the degradation or processing of the phagocytosed particle. Phagosomes are highly dynamic organelles formed by the uptake of particles through phagocytic innate immune cells; thus characterization of the phagosomal proteome is essential to understand the mechanisms controlling innate immunity, as well as vesicle trafficking. In this chapter, we describe how novel quantitative proteomics methods, such as using tandem mass tag (TMT) labelling or acquiring label-free data using data-independent acquisition (DIA), can be applied for the characterization of protein composition of phagosomes in macrophages.

CYLD in health and disease.

CYLD lysine 63 deubiquitinase (CYLD) is a ubiquitin hydrolase with important roles in immunity and cancer. Complete CYLD ablation, truncation and expression of alternate isoforms, including short CYLD, drive distinct phenotypes and offer insights into CYLD function in inflammation, cell death, cell cycle progression and cell transformation. Research in diverse model systems has shown that these are mediated via CYLD regulation of cellular pathways including the NF-κB, Wnt and TGF-ß pathways. Recent biochemical advances and models have offered new insights into the regulation and function of CYLD. In addition, recent discoveries of gain-of-function germline pathogenic CYLD variants in patients with a neurodegenerative phenotype contrast with the more widely known loss-of-function mutations seen in patients with CYLD cutaneous syndrome and with sporadic cancers. Here, we provide a current review of mechanistic insights into CYLD function gained from CYLD animal models, as well as an update on the role of CYLD in human disease.

Proposal for a Two-Tier Re-classification of Stage IV/M1 domain of Renal Cell Carcinoma into M1 ("Oligometastatic") and M2 ("Polymetastatic") subdomains: Analysis of the Registry for Metastatic Renal Cell Carcinoma (REMARCC).

Purpose: We hypothesized that two-tier re-classification of the "M" (metastasis) domain of the Tumor-Node-Metastasis (TNM) staging of Renal Cell Carcinoma (RCC) may improve staging accuracy than the current monolithic classification, as advancements in the understanding of tumor biology have led to increased recognition of the heterogeneous potential of metastatic RCC (mRCC). Methods: Multicenter retrospective analysis of patients from the REMARCC (REgistry of MetAstatic RCC) database. Patients were stratified by number of metastases into two groups, M1 (≤3, "Oligometastatic") and M2 (>3, "Polymetastatic"). Primary outcome was overall survival (OS). Secondary outcomes were cancer-specific survival (CSS). Cox-regression and Kaplan-Meier (KMA) analysis were utilized for outcomes, and receiver operating characteristic analysis (ROC) was utilized to assess diagnostic accuracy compared to current "M" staging. Results: 429 patients were stratified into proposed M1 and M2 groups (M1 = 286/M2 = 143; median follow-up 19.2 months). Cox-regression revealed M2 classification as an independent risk factor for worsened all-cause mortality (HR=1.67, p=0.001) and cancer-specific mortality (HR=1.74, p<0.001). Comparing M1-oligometastatic vs. M2-polymetastatic groups, KMA revealed significantly higher 5-year OS (36% vs. 21%, p<0.001) and 5-year CSS (39% vs. 17%, p<0.001). ROC analyses comparing OS and CSS, for M1/M2 reclassification versus unitary M designation currently in use demonstrated improved c-index for OS (M1/M2 0.635 vs. unitary M 0.500) and CSS (M1/M2 0.627 vs. unitary M 0.500). Conclusion: Subclassification of Stage "M" domain of mRCC into two clinical substage categories based on metastatic burden corresponds to distinctive tumor groups whose oncological potential varies significantly and result in improved predictive capability compared to current staging.

Complete revascularization with PCI in STEMI patients with multivessel disease, when is the appropriate time? / Revascularización completa mediante ICP en pacientes con STEMI y enfermedad coronaria multivaso, ¿cuál es el momento adecuado?

Abstract Objective: The purpose was to compare the outcomes of patients with ST-elevation myocardial infarction and multivessel coronary artery disease undergoing one-time multivessel revascularization (OTMVR) versus in-hospital staged complete revascularization with percutaneous coronary intervention. Methods: This was a single-center, retrospective, observational, and cohort study, including data from January 2013 to April 2019. A total of 634 patients were included in the study. Comparisons were made between patients who underwent in-hospital staged complete revascularization versus OTMVR. The primary endpoint was all-cause in-hospital mortality, secondary endpoints included cardiovascular complications, all-cause new hospitalization, and mortality evaluated at 30 days and 1 year. In addition, we constructed a logistic regression model for determining the risk factors that predicted mortality. Results: Of the 634 patients, 328 were treated with staged revascularization and 306 with OTMVR. About 76.7% were men, with a mean age of 63.3 years. Less complex coronary lesions and a higher proportion of the left anterior descending artery as the culprit vessel were found in the OTMVR group. Compared with staged revascularization, the primary and secondary endpoints occurred less frequently with OTMVR strategy. Conclusions: OTMVR did not generate more complications and demonstrate better clinical outcomes than in-hospital staged revascularization.

Resumen Objetivo: El propósito fue comparar resultados de pacientes con infarto agudo de miocardio con elevación del segmento ST y enfermedad coronaria multivaso sometidos a revascularización completa de un solo momento frente a revascularización completa por etapas mediante intervención coronaria percutánea. Métodos: Estudio cohorte observacional, retrospectivo, unicéntrico, con datos de enero de 2013 a abril de 2019, incluyendo 634 pacientes. Se compararon resultados entre pacientes sometidos a revascularización completa por etapas frente a revascularización completa en un solo momento. El objetivo primario fue valorar mortalidad intrahospitalaria por cualquier causa y como objetivos secundarios se evaluaron a 30 días y 1 año las complicaciones cardiovasculares, hospitalizaciones y mortalidad. Se construyó un modelo de regresión logística para determinar los factores de riesgo que predijeron mortalidad. Resultados: De 634 pacientes, 328 fueron tratados con revascularización por etapas y 306 con revascularización en una intervención. El 76.7% fueron hombres, con una media de edad de 63.3 años. En el grupo de revascularización de un solo tiempo se encontraron lesiones coronarias menos complejas y una mayor proporción de la arteria descendente anterior como vaso culpable. Comparado con el grupo de revascularización por etapas, los objetivos primarios y secundarios ocurrieron con menos frecuencia en el grupo de revascularización en un solo tiempo. Conclusiones: Comparada con la revascularización intrahospitalaria por etapas, la revascularización en una intervención lleva a mejores desenlaces clínicos sin generar más complicaciones.

SOCS3 deregulation contributes to aberrant activation of the JAK/STAT pathway in precursor T-cell neoplasms.

Despite the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway being frequently altered in T-ALL/LBL, no specific therapy has been approved for T-ALL/LBL patients with constitutive signalling by JAK/STAT, so there is an urgent need to identify pathway members that may be potential therapeutic targets. In the present study, we searched for JAK/STAT pathway members potentially modulated through aberrant methylation and identified SOCS3 hypermethylation as a recurrent event in T-ALL/LBL. Additionally, we explored the implications of SOCS3 deregulation in T-ALL/LBL and demonstrated that SOCS3 counteracts the constitutive activation of the JAK/STAT pathway through different molecular mechanisms. Therefore, SOCS3 emerges as a potential therapeutic target in T-ALL/LBL.

Effect of the Use of Gnrh Analogs in Low-Grade Cerebral Glioma.

Low-grade gliomas are the most common brain tumors in children. This tumor type presents a wide range of clinical, histological, and biological behaviors. In recent years, an association between estrogens and progesterone and the development of tumors has been suggested. A case of a 2-year-old girl is described with a low-grade brain tumor treated with chemotherapy and disease stabilization. The treatment with Decapeptyl® was initiated due to precocious puberty, and the tumor showed a decrease in its solid component-more than 50% of the initial size-three years after starting treatment. Several studies have described the influence of estrogen and progesterone on the development of gliomas, decreasing or increasing their expression in those tumors with greater aggressiveness, respectively. Despite the fact that the tumor-hormonal expression relationship in other tumor types has been evaluated, its role in the treatment of brain tumors remains unknown.

Can Music Decrease Anxiety and Pain During Dental Implant Surgery? A Randomized Clinical Trial.

PURPOSE: Music has proven to be an effective tool in the management of anxiety during some surgical procedures. The aim of this study was to test the effect of baroque (BM) and classical era music (CM) as a nonpharmacological therapy on the control of anxiety and pain levels among patients undergoing dental implant placement surgery. METHODS: A randomized controlled clinical trial of patients attending a dental clinic was conducted. Patients with psychiatric disorders were excluded. Twenty six patients of Spanish nationality requiring single-tooth dental implant were included. Each patient was assigned to 1 of the 3 experimental groups, which acted as an independent variable: Group I (n = 8) listened to BM; Group II (n = 10) listened to CM; and Group III (n = 8) did not listen to music and was the control group (C). The dependent variables were divided into physiological variables and psychological variables. The physiological dependent variables analysed were systolic and diastolic blood pressure, heart rate, and oxygen saturation, recorded at 4 different times during surgery. The Kruskal-Wallis test compared each of these variables between the 3 experimental groups. The psychological dependent variable analyzed was the degree of anxiety, measured by the self-completed Modified Dental Anxiety Scale and Visual Analog Scale (measured before and after surgery). The Wilcoxon statistical test compared degree of anxiety before and after surgery. In all cases, the level of statistical significance was set at P < .05. RESULTS: The mean age of the sample was 46.5 ± 10.6 (range, 24-69 years), 50% male and 50% female. Statistically significant differences in degree of anxiety before and after surgery were found in the BM (P = .027, confidence interval [CI] = 0.146-6.104; BM before = 4.25 ± 3.91 and BM after = 1.13 ± 1.45) and CM groups (P = .044, CI = 0.161-3.039; CM before = 3.10 ± 2.88 and CM after = 1.50 ± 1.43) and were not found in group C (P = .180, CI = 1.104-3.604; C before = 2.63 ± 3.62 and C after = 1.38 ± 1.99). When comparing the perceived pain after the intervention among the 3 groups (C, BM, and CM), no significant differences were observed between them (P = .319; CI = -0.58-1.96; C = 0.75 ± 1.75, BM = 1.25 ± 1.75, and CM = 1.70 ± 1.70). CONCLUSION: Listening to BM and CM reduces anxiety in patients undergoing dental implant placement surgery. Musical flow should be applied in this practice.