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RE-1 silencing transcription factor (REST) is a key repressor of neural genes. REST is upregulated under stress signals, aging and neurodegenerative diseases, but although it is upregulated, its function is lost in Alzheimer's Disease. However, why it becomes inactive remains unclear. Here, we show that the NAD-dependent deacetylase SIRT6 regulates REST expression, location and activity. In the absence of SIRT6, REST is overexpressed but mislocalized, leading to a partial loss of its activity and causing it to become toxic. SIRT6 deficiency abrogates REST and EZH2 interaction, perturbs the location of REST to the heterochromatin Lamin B ring, and leads to REST target gene overexpression. SIRT6 reintroduction or REST methyl-mimic K494M expression rescues this phenotype, while an acetyl-mimic mutant loses its function even in WT cells. Our studies define a novel regulatory switch where, depending on SIRT6 presence, the function of REST is regulated by post-translational modifications on K494 (Ac/me), affecting neuronal gene expression. In WT cells (left), REST functions as a repressor due to its methylation, which allows proper localization and interaction with EZH2. In SIRT6 KO cells (right), REST is overexpressed, but it is mislocalized and acetylated instead of methylated, impairing its interaction with EZH2. REST localizes in the cytoplasm in autophagosomes. The overall increase in REST without SIRT6 results in non-functional and toxic REST proteins. During aging, SIRT6 declines in the brain, while REST is upregulated to protect it. In pathological aging, where SIRT6 levels are very low, the increase in REST without SIRT6 results in non-functional and toxic REST., (© 2024. The Author(s).)

Background: Dysmenorrhea, or menstrual pain, is a subjective experience, and can only be assessed by patient-reported outcomes. These instruments should be reliable, valid and responsive., Aim: To identify and critically appraise the available evidence for the measurement properties of specific patient-reported outcome measures used for dysmenorrhea., Methods: The PRISMA statement was used to report this systematic review. Databases searched were PubMed, SCOPUS, CINAHL, Web of Science, ScienceDirect and Google Scholar (April 2021; updated on February 2023). Original studies with primary data collection, with no restriction on language and publication date that reported psychometric properties of one or more dysmenorrhea-related patient-reported outcome measure. The literature searches, selection of studies, data extraction and assessment of the risk of bias were performed independently by two reviewers and followed the COSMIN guidelines., Results: Thirty studies were analysed in this review, and 19 patient-reported outcome measures were evaluated. The instruments varied in relation to the measured construct and measurement properties (validity, reliability and responsiveness). The methodological quality of the studies and the quality of evidence of the patient-reported outcome measures were variable. Among the 13 studies that reported the development of patient-reported outcome measures, most had inadequate methodological quality, and the overall rating was insufficient or inconsistent., Conclusions: The Dysmenorrhea Symptom Interference (DSI) scale was the only identified patient-reported outcome measure that has the potential to be recommended because of its sufficient rating combined with moderate quality of evidence for content validity. Future studies should further evaluate the measurement properties of the existing patient-reported outcome measures, or develop new patient-reported outcome measures following the COSMIN methodology., Patient or Public Contribution: Not applicable as this is a systematic review., Trial Registration: PROSPERO protocol: CRD42021244410. Registration on April 22, 2021., (© 2024 John Wiley & Sons Ltd.)

Bacterial peritonitis infections comprise a life-threatening clinical condition in domestic animals that commonly lead to sepsis and high mortality. A set of bacterial pathogens have been identified in septic peritonitis in livestock and companion animals. Nonetheless, most descriptions are restricted to case reports or limited to only one domestic species, and a restrict number of comprehensive studies involving this infection has focused on a great number of domestic animals. Here, we retrospectively investigated selected epidemiological data (with an emphasis in outcome), clinical signs, bacteriological culturing, and in vitro antimicrobial susceptibility patterns of microorganisms isolated of peritoneal fluid from 160 domestic animals (2009-2023) compatible with septic peritonitis. Bacteria were isolated from 71.9% (115/160) of the peritoneal fluid from 75 dogs (75/115 = 65.2%), 22 cats (22/115 = 19.1%), 14 horses (14/115 = 12.2%), and 4 cattle (4/115 = 3.5%). Among animals with bacterial isolation, Escherichia coli (34/115 = 29.6%), alfa-hemolytic Streptococcus (12/115 = 10.4%), Staphylococcus aureus (8/115 = 6.9%), beta-hemolytic Streptococcus (7/115 = 6.1%), and Pasteurella multocida (6/115 = 5.2%) were predominant in pure culture, in addition to a miscellaneous of other bacteria isolated in minor frequency, e.g., Pseudomonas sp., Trueperella pyogenes, Klebsiella pneumoniae, and Salmonella sp. In general, in vitro susceptibility tests of isolates revealed that florfenicol, chloramphenicol, and amoxicillin/clavulanic acid showed moderate effectivity (≥ 60%). Conversely, most of isolates exhibited resistance mainly to trimethoprim/sulfamethoxazole, enrofloxacin, and penicillin (> 60%). Additionally, multidrug resistance was found in 42.6% (49/115) of the isolates. Data related to the outcome were available in 37.4% (43/115) of animals that had bacterial isolation and, from these, the mortality rate was 79.1% (34/43), with a significant association (p < 0.036) between mortality and septic peritonitis by gram-negative bacteria. Neoplasia (7/43 = 16.3%), pneumonia/pulmonary abscess (5/43 = 11.6%), hepatitis (5/43 = 11.6%), metritis/pyometra (4/43 = 9.3%), and gall bladder rupture (3/43 = 7%) represented the probable main sources of septic peritonitis. Anorexia (34/115 = 29.6%), emesis (29/115 = 25.2%), lethargy (26/115 = 22.6%), respiratory distress (25/115 = 21.7%), ascites (20/115 = 17.4%), and fever (19/115 = 16.5%) were the most frequent clinical signs among animals with bacterial isolation. A variety of bacteria were isolated in the peritoneal fluid of animals, with a predominance of Enterobacteriaceae, streptococci, and staphylococci, highlighting the opportunistic nature of the pathogens in septic peritonitis. High in vitro multidrug resistance of isolates and high mortality of animals reinforce the need for early diagnosis and therapy based on the in vitro antimicrobial profile of the pathogens involved in septic peritonitis. Our results contribute to the etiological characterization, clinical-epidemiological findings, and vigilance of multidrug-resistant bacteria in septic peritonitis among livestock and companion animals., (© 2024. The Author(s) under exclusive licence to Sociedade Brasileira de Microbiologia.)

Background: Nursing professionals are key to providing safe care that improves patient outcomes. Hence, it is essential to focus on developing nurses' patient safety competencies and principles., Purpose: This review examined the effectiveness of educational interventions in developing patient safety knowledge, skills, behaviors, and attitudes in undergraduate nursing students., Methods: The search strategy aimed to identify published and unpublished studies in databases and grey literature. Studies were assessed using the Joanna Briggs Institute critical appraisal tools., Results: A total of 36 studies met the inclusion criteria. The teaching methods employed single or combined interventions and the educational interventions suggested either improvements in outcomes or no impact., Conclusion: The effectiveness of educational interventions to develop patient safety competencies in undergraduate nursing students, either as a single or combined strategy, was mixed. Further research is needed to provide more robust evidence on which teaching method for patient safety is most effective., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc.)

We identify and present Brazil's most common behavioral and heuristic biases in judicial decision-making. Through bibliographic and specific cases, we notice the occurrence of the representativeness heuristic, availability heuristic, anchoring heuristic (anchoring effect), confirmation bias, and affect heuristic bias in Brazilian judicial decisions. We also present the current state of Brazilian legislation and its amendments that aim at impartiality in the production, the assessment of evidence, and the judge's conviction. Finally, we present the suggestions and initiatives that aim to mitigate biases and heuristics in judicial decision-making in Brazil, especially with awareness techniques, the replacement of judges by algorithms, and the review of judicial decisions by collegiate bodies.

A novel, yet simple, airborne microplastic (MP) sampling approach using global pollen monitoring equipment was applied to identify, characterise and quantify outdoor airborne MPs for the first time. Modification of Burkard spore trap tape adhesive provided particle capture and facilitated downstream spectroscopy analysis. 36 polymer types were identified from a total of 21 days sampling using Burkard spore traps at two locations (United Kingdom and South Africa). MPs were detected in 95 % of daily samples. Mean MP particle levels were 2.0 ± 0.9 MP m -3 (11 polymer types) in Hull (U.K.), during March, 2.9 ± 2.0 MP m -3 (16 types) in Hull in July, and 11.0 ± 5.7 MP m -3 (29 types) in Gqeberha, (S.A.) in August 2023. The most abundant polymer type was nylon (Gqeberha). The approach was compared with two passive sampling methods whereby 27 polymer types were identified and of these, 6 types were above the limit of quantification (LOQ), with poly(methacrolein:styrene) (PMA/PS) the most abundant. Irregularly shaped MPs < 100 µm in length were predominant from all sampling approaches. For the first time, airborne MPs were chemically characterised and quantified using volumetric pollen sampling equipment, representing a viable approach for future airborne MP monitoring., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: The aim is to determine the effect on healing and functionality of patients after 1 year of biceps augmentation of a rotator cuff repair (RCR) compared to RCR plus long head of the biceps (LHB) tenotomy. In addition, to analyse the main factors involved in the recovery after the surgery., Methods: A prospective, comparative, non-randomized study (Level of Evidence III) was conducted. Patients with repairable rotator cuff tears were allocated to either the control group, with a double row transosseous equivalent RCR with LHB tenotomy, or the RCR+augmentation with LHB group. Patients were evaluated for radiological (MRI), clinical (cuff size, Patte and Goutallier scales) and functional variables (Constant and American Shoulder and Elbow Surgeons [ASES] scales) before the intervention. At 1-year follow-up cuff healing was confirmed through MRI and functional evaluation with Constant, ASES, simple shoulder test [SST] and Disabilities of the Arm, Shoulder and Hand scales., Results: Seventy-seven patients underwent control or RCR+augmentation with LHB, there were no preoperative differences between the groups. After 1 year of the surgery, re-rupture occurred in 38.5% and 16% of the patients in control and RCR+augmentation with LHB groups, respectively ( p  = .026). Total functionality was higher ( p  < .05) in RCR+augmentation with LHB than in the control group: Constant, SST and ASES scales. Among the explored factors involved in healing, re-rupture occurred in 100% of the cases with high fatty degeneration. Besides, higher initial functionality (Constant scale) and RCR+augmentation with LHB increased the odds of healing (odds ratio [OR] = 1.12 [1.04-1.21]; OR = 5 [1, 61], respectively), while higher cuff length had a detrimental effect (OR = 0.92 [0.85-0.99])., Conclusion: RCR+augmentation with LHB achieves a higher healing percentage and a better functional evolution than RCR+LHB tenotomy, 1 year after cuff repair. Fatty degeneration, cuff length and initial functionality are the main factors involved in cuff healing., Level of Evidence: Level III randomized controlled trial., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Journal of Experimental Orthopaedics published by John Wiley & Sons Ltd on behalf of European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Thrombotic microangiopathy (TMA), characterized by microangiopathic hemolytic anemia, thrombocytopenia, and multisystem organ dysfunction, is a life-threatening disease. Patients with TMA who do not exhibit a severe ADAMTS-13 deficiency (defined as a disintegrin-like and metalloprotease with thrombospondin type 1 motif no. 13 activity ≥10%: TMA-13n) continue to experience elevated mortality rates. This study explores the prognostic indicators for augmented mortality risk or necessitating chronic renal replacement therapy (composite outcome: CO) in TMA-13n patients. We included 42 TMA-13n patients from January 2008 to May 2018. Median age of 41 years and 60% were female. At presentation, 62% required dialysis, and 57% warranted intensive care unit admission. CO was observed in 45% of patients, including a 9-patient mortality subset. Multivariate logistic regression revealed three independent prognostic factors for CO: early administration of eculizumab (median time from hospitalization to eculizumab initiation: 5 days, range 0-19 days; odds ratio [OR], 0.14; 95% confidence interval [CI], 0.02-0.94), presence of neuroradiological lesions (OR, 6.67; 95% CI, 1.12-39.80), and a PLASMIC score ≤4 (OR, 7.39; 95% CI, 1.18-46.11). In conclusion, TMA-13n patients exhibit a heightened risk of CO in the presence of low PLASMIC scores and neuroradiological lesions, while early eculizumab therapy was the only protective factor., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The use in the clinical practice of the vast amount of genomic data generated by current sequencing technologies constitutes a bottleneck for the progress of Precision Medicine (PM). Various problems inherent to the genomics domain (i.e., dispersion, heterogeneity, discrepancies, lack of standardization, and data quality issues) remain unsolved. In this paper, we present the Delfos platform, a conceptual model-based solution developed following a rigorous methodological and ontological background, whose main aim is to minimize the impact of these problems when transferring the research results to clinical practice. This paper presents the SILE method that provides methodological support for the Delfos platform, the Conceptual Schema of the Genome that provides a shared understanding of the domain, and the technological architecture behind the implementation of the platform. This paper also exemplifies the use of the Delfos platform through two use cases that involve the study of the DNA variants associated with the risk of developing Dilated Cardiomyopathies and Neuroblastoma.

A portable and highly sensitive sensor was designed for the specific detection of 3,4-methyl-enedioxy-methamphetamine (MDMA), in a range of field-testing situations. The sensor can detect MDMA in street samples, even when other controlled substances drugs, or adulterants are present. In this work, we report for the first time a sensor using electroactive molecularly imprinted polymer nanoparticles computationally designed to recognize MDMA and then produced using solid phase synthesis. A composite comprising chitosan, reduced graphene oxide, and molecularly imprinted polymer nanoparticles synthesized for MDMA for the first time was immobilized on screen-printed carbon electrodes. The sensors displayed a satisfactory sensitivity (106.8 nA × μM -1 ), limit of detection (1.6 nM; 0.31 ng/mL), and recoveries (92-99%). The accuracy of the results was confirmed through validation using Ultra-High Performance Liquid Chromatography coupled with tandem Mass Spectrometry (UPLC-MS/MS). This technology could be used in forensic analysis and make it possible to selectively detect MDMA in street samples., (© 2023 John Wiley & Sons, Ltd.)

Background: Epigenetic changes that lead to long-term neuroadaptations following opioid exposure are not well understood. We examined how histone demethylase JMJD3 in the nucleus accumbens (NAc) influences heroin seeking after abstinence from self-administration., Methods: Male Sprague Dawley rats were trained to self-administer heroin. Western blotting and quantitative polymerase chain reaction were performed to quantify JMJD3 and bone morphogenetic protein (BMP) pathway expression in the NAc (n = 7-11/group). Pharmacological inhibitors or viral expression vectors were microinfused into the NAc to manipulate JMJD3 or the BMP pathway member SMAD1 (n = 9-11/group). The RiboTag capture method (n = 3-5/group) and viral vectors (n = 7-8/group) were used in male transgenic rats to identify the contributions of D1- and D2-expressing medium spiny neurons in the NAc. Drug seeking was tested by cue-induced response previously paired with drug infusion., Results: Levels of JMJD3 and phosphorylated SMAD1/5 in the NAc were increased after 14 days of abstinence from heroin self-administration. Pharmacological and virus-mediated inhibition of JMJD3 or the BMP pathway attenuated cue-induced seeking. Pharmacological inhibition of BMP signaling reduced JMJD3 expression and H3K27me3 levels. JMJD3 bidirectionally affected seeking: expression of the wild-type increased cue-induced seeking whereas expression of a catalytic dead mutant decreased it. JMJD3 expression was increased in D2 + but not D1 + medium spiny neurons. Expression of the mutant JMJD3 in D2 + neurons was sufficient to decrease cue-induced heroin seeking., Conclusions: JMJD3 mediates persistent cellular and behavioral adaptations that underlie heroin relapse, and this activity is regulated by the BMP pathway., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: The present study aimed to investigate the effects of post-activation performance enhancement (PAPE) after three warm-up protocols on back squat performance in trained men., Methods: Fourteen resistance-trained men performed conditioning activity (CA) with high-load (HL-CA), low-load (LL-CA), or usual specific warm-up as a control (CON). HL-CA consisted of one set of three repetitions with 90% of one repetition maximum (RM); LL-CA consisted of one set of six repetitions with 45% of 1 RM performed at maximal velocity; CON involved eight repetitions with 45% of 1 RM at controlled velocity. The participant's performance was measured using the total number of repetitions and volume load (reps × load × sets)., Results: There were no significant differences between warm-up for the total number of repetitions ( p = 0.17) or total volume load ( p = 0.15). There was no difference between conditions for the number of repetitions (main condition effect; p = 0.17); however, participants achieved a significantly higher volume load after HL-PAPE than after CON for the first set ( p = 0.04)., Conclusion: High or low equated-load CA used as warm-up strategies did not potentiate subsequent performance enhancement in multiple-set back squat exercise performed until muscle failure in comparison with usual warm-up., Competing Interests: Daniel Souza, Anderson Silva, Arthur Vale, Alana Pessoni, Luan Galvão, Murilo Araujo, Celio de Paula Júnior, Carlos Vieira, Amilton Vieira and Paulo Gentil declare that they have no competing interests., (© 2024 Souza et al.)

Objective: To evaluate the chemical composition and effects of Artemisia vulgaris (AV) hydroalcoholic extract (HEAV) on breast cancer cells (MCF-7 and SKBR-3), chronic myeloid leukemia (K562) and NIH/3T3 fibroblasts., Methods: Phytochemical analysis of HEAV was done by high-performance liquid chromatography-mass (HPLC) spectrometry. Viability and cell death studies were performed using trypan blue and Annexin/FITC-7AAD, respectively. Ferrostatin-1 (Fer-1) and necrostatin-1 (Nec-1) were used to assess the mode of HEAV-induced cell death and acetoxymethylester (BAPTA-AM) was used to verify the involvement of cytosolic calcium in this event. Cytosolic calcium measurements were made using Fura-2-AM., Results: HEAV decreased the viability of MCF-7, SKBR-3 and K562 cells (P<0.05). The viability of HEAV-treated K562 cells was reduced compared to HEAV-exposed fibroblasts (P<0.05). Treatment of K562 cells with HEAV induced cell death primarily by late apoptosis and necrosis in assays using annexin V-FITC/7-AAD (P<0.05). The use of Nec-1 and Fer-1 increased the viability of K562 cells treated with HEAV relative to cells exposed to HEAV alone (P<0.01). HEAV-induced Ca 2+ release mainly from lysosomes in K562 cells (P<0.01). Furthermore, BAPTA-AM, an intracellular Ca 2+ chelator, decreased the number of non-viable cells treated with HEAV (P<0.05)., Conclusions: HEAV is cytotoxic and activates several modalities of cell death, which are partially dependent on lysosomal release of Ca 2+ . These effects may be related to artemisinin and caffeoylquinic acids, the main compounds identified in HEAV., (© 2023. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Camera traps became the main observational method of a myriad of species over large areas. Data sets from camera traps can be used to describe the patterns and monitor the occupancy, abundance, and richness of wildlife, essential information for conservation in times of rapid climate and land-cover changes. Habitat loss and poaching are responsible for historical population losses of mammals in the Atlantic Forest biodiversity hotspot, especially for medium to large-sized species. Here we present a data set from camera trap surveys of medium to large-sized native mammals (>1 kg) across the Atlantic Forest. We compiled data from 5380 ground-level camera trap deployments in 3046 locations, from 2004 to 2020, resulting in 43,068 records of 58 species. These data add to existing data sets of mammals in the Atlantic Forest by including dates of camera operation needed for analyses dealing with imperfect detection. We also included, when available, information on important predictors of detection, namely the camera brand and model, use of bait, and obstruction of camera viewshed that can be measured from example pictures at each camera location. Besides its application in studies on the patterns and mechanisms behind occupancy, relative abundance, richness, and detection, the data set presented here can be used to study species' daily activity patterns, activity levels, and spatiotemporal interactions between species. Moreover, data can be used combined with other data sources in the multiple and expanding uses of integrated population modeling. An R script is available to view summaries of the data set. We expect that this data set will be used to advance the knowledge of mammal assemblages and to inform evidence-based solutions for the conservation of the Atlantic Forest. The data are not copyright restricted; please cite this paper when using the data., (© 2024 The Ecological Society of America.)

Purpose: Menstrual characteristics can affect a woman's productivity at work and college, but studies in a general population of adult women are scarce. In addition, it is important to know which menstrual symptoms are most associated with presenteeism in women to promote specific health actions. The present study aimed to assess menstrual symptoms associated with presenteeism in adult women., Methods: Online cross-sectional study in which menstrual characteristics, including menstrual flow, age of menarche, menstrual pain and cycle duration were assessed by a self-report questionnaire. The menstrual pain intensity was assessed by Numerical Rating Scale, and the presenteeism, by the Stanford Presenteeism Scale-6 (SPS-6). Women were divided in two groups, with and without presenteeism, based on the SPS-6 cutoff point. Data were analyzed by binary logistic regression and presented as odds ratios (OR)., Results: Among the 430 women who participated in the study, 44.2% were classified as with presenteeism. Women with severe menstrual flow were more likely to have presenteeism (OR = 2.12) compared with women with mild and moderate menstrual flow. The higher menstrual pain intensity the higher the chances of a woman presenting with presenteeism (OR = 1.29)., Conclusions: These menstrual characteristics (intensity of menstrual flow and menstrual pain) seem to affect women's productivity at work and/or college, and should be assessed in research and clinical practice. Thus, public policies on women's health can be carried out based on these results., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The autosomal recessive defect of aromatic L-amino acid decarboxylase (AADC) leads to a severe neurological disorder with manifestation in infancy due to a pronounced, combined deficiency of dopamine, serotonin and catecholamines. The success of conventional drug treatment is very limited, especially in patients with a severe phenotype. The development of an intracerebral AAV2-based gene delivery targeting the putamen or substantia nigra started more than 10 years ago. Recently, the putaminally-delivered construct, Eladocagene exuparvovec has been approved by the European Medicines Agency and by the British Medicines and Healthcare products Regulatory Agency. This now available gene therapy provides for the first time also for AADC deficiency (AADCD) a causal therapy, leading this disorder into a new therapeutic era. By using a standardized Delphi approach members of the International Working Group on Neurotransmitter related Disorders (iNTD) developed structural requirements and recommendations for the preparation, management and follow-up of AADC deficiency patients who undergo gene therapy. This statement underlines the necessity of a framework for a quality-assured application of AADCD gene therapy including Eladocagene exuparvovec. Treatment requires prehospital, inpatient and posthospital care by a multidisciplinary team in a specialized and qualified therapy center. Due to lack of data on long-term outcomes and the comparative efficacy of alternative stereotactic procedures and brain target sites, a structured follow-up plan and systematic documentation of outcomes in a suitable, industry-independent registry study are necessary., (© 2023 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Objective: Dysmenorrhea is the pain related to menstruation; to screen for the symptoms, a working ability, location, intensity of days of pain, and dysmenorrhea (WaLIDD) score was created. The purpose of this work was to culturally adapt and assess the measurement properties of the WaLIDD score for dysmenorrhea in Brazilian women., Methods: In this cross-sectional online study, we evaluated women with and without dysmenorrhea. Criterion validity and construct validity were assessed, respectively, by the Receiver Operator Characteristic (ROC) curve and correlations with the bodily pain and social functioning domains of medical outcomes study 36-item short-form health survey (SF-36), self-report of absenteeism and Stanford Presenteeism Scale for presenteeism. Test-retest reliability and measurement errors were assessed, respectively, by intraclass correlation coefficient (ICC) and Bland and Altman Graph., Results: 430 women completed the test, 238 (55.4%) women had dysmenorrhea, and 199 (46.3%) answered the questionnaire twice for the retest. The cutoff points ≥4, ≥5, and ≥5 could discriminate between women with and without dysmenorrhea, absenteeism, and presenteeism related to dysmenorrhea, respectively. Correlations between SF-36 - pain and social functioning domains and WaLIDD score were weak to strong and negative. For WaLIDD total Score, ICC was 0.95 and the limits of agreement were -1.54 and 1.62., Conclusion: WaLIDD score is a short, valid and reliable instrument to screen and predict dysmenorrhea and could predict absenteeism and presenteeism related to dysmenorrhea in Brazilian women., Competing Interests: Conflicts to interest: none to declare., (© 2024. Federação Brasileira de Ginecologia e Obstetrícia. All rights reserved.)

Innovative midwifery-led collaborative care models have the potential to build on grassroots approaches to make transformative change within systems that work with families. Rainier Valley Midwives operates the Bundle Birth Project, a successful program that serves communities who are at higher risk for poor birth outcomes and face barriers to adequate medical, prenatal, and postpartum care, including Black, Indigenous, and persons of color. This project offers wraparound perinatal care services to provide a missing community of support to traditionally marginalized families before, during, and after birth while also bridging the gaps between midwives and physicians who attend births in different settings. By strengthening and formalizing the relationships between different types of perinatal providers including community-based doulas and lactation support professionals, this midwifery-led initiative improves the continuity and quality of care available to families including immigrant, refugee, and families of color in south Seattle, Washington., (© 2023 by the American College of Nurse‐Midwives.)

In this Letter, we propose and experimentally demonstrate the first, to our knowledge, integrated liquid-crystal-based (LC-based) variable-tap devices for visible-light amplitude modulation. These devices leverage the birefringence of LC medium to actively tune the coupling coefficient between two waveguides. First, we develop the device structure, theory of operation, and design procedure. Next, we summarize the fabrication and LC packaging procedure for these devices. Finally, we experimentally demonstrate amplitude modulation with 15.4-dB tap-port extinction within ±3.1 V for a 14-µm-long device at a 637-nm operating wavelength. These small-form-factor variable-tap devices provide a compact and low-power solution to integrated visible-light amplitude modulation and will enable future high-density integrated visible-light systems.

Background: Primary dysmenorrhea (PD) is an etiological cyclic pelvic pain related to the menstrual period; it can negatively impact women's quality of life and productivity. The aim of the present study was to estimate the prevalence of PD and analyze associated symptoms in Brazilian women., Methods: An online cross-sectional study was carried out in Brazil, with a structured questionnaire regarding dysmenorrhea and associated symptoms. PD intensity was measured with the Numerical Rating Scale for Pain and classified as mild (1-3), moderate (4-7) and severe (> 8). The association between qualitative variables was performed using Pearson's Chi-Square Test. The quantification of this association was measured using multinomial logistic regression models, with calculation of Odds Ratio and confidence interval. A significance level of 5% was considered., Results: A total of 10,070 women were included. Most participants classified PD intensity as moderate (40.4%, 41.9% and 49.7%) and severe (21.2%, 24.8% and 28.4%) in the previous month, 3 months and 5 years, respectively. The most common symptoms associated with PD were irritability, abdominal distension sensation, anxiety and feeling more emotional. The increased of the risk (OR > 1.0) for moderate and severe PD-related pain intensity is related to age, nulliparity and presence PD since adolescence., Conclusion: There is a high prevalence of PD among Brazilian women, and the most common symptoms reported were irritability, abdominal distension sensation, anxiety and feeling more emotional., (© 2024. The Author(s).)

Background: Maintenance monotherapy with ritonavir-boosted darunavir has yielded variable outcomes and is not recommended. Trial samples offer valuable opportunities for detailed studies. We analysed samples from a 48 week trial in Cameroon to obtain a detailed characterization of drug resistance., Methods: Following failure of NNRTI-based therapy and virological suppression on PI-based therapy, participants were randomized to ritonavir-boosted darunavir (n = 81) or tenofovir disoproxil fumarate/lamivudine +ritonavir-boosted lopinavir (n = 39). At study entry, PBMC-derived HIV-1 DNA underwent bulk Protease and Reverse Transcriptase (RT) sequencing. At virological rebound (confirmed or last available HIV-1 RNA ≥ 60 copies/mL), plasma HIV-1 RNA underwent ultradeep Protease and RT sequencing and bulk Gag-Protease sequencing. The site-directed mutant T375A (p2/p7) was characterized phenotypically using a single-cycle assay., Results: NRTI and NNRTI resistance-associated mutations (RAMs) were detected in 52/90 (57.8%) and 53/90 (58.9%) HIV-1 DNA samples, respectively. Prevalence in rebound HIV-1 RNA (ritonavir-boosted darunavir, n = 21; ritonavir-boosted lopinavir, n = 2) was 9/23 (39.1%) and 10/23 (43.5%), respectively, with most RAMs detected at frequencies ≥15%. The resistance patterns of paired HIV-1 DNA and RNA sequences were partially consistent. No darunavir RAMs were found. Among eight participants experiencing virological rebound on ritonavir-boosted darunavir (n = 12 samples), all had Gag mutations associated with PI exposure, including T375N, T375A (p2/p7), K436R (p7/p1) and substitutions in p17, p24, p2 and p6. T375A conferred 10-fold darunavir resistance and increased replication capacity., Conclusions: The study highlights the high resistance barrier of ritonavir-boosted darunavir while identifying alternative pathways of resistance through Gag substitutions. During virological suppression, resistance patterns in HIV-1 DNA reflect treatment history, but due to technical and biological considerations, cautious interpretation is warranted., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Young blood plasma is known to confer beneficial effects on various organs in mice and rats. However, it was not known whether plasma from young adult pigs rejuvenates old rat tissues at the epigenetic level; whether it alters the epigenetic clock, which is a highly accurate molecular biomarker of aging. To address this question, we developed and validated six different epigenetic clocks for rat tissues that are based on DNA methylation values derived from n = 613 tissue samples. As indicated by their respective names, the rat pan-tissue clock can be applied to DNA methylation profiles from all rat tissues, while the rat brain, liver, and blood clocks apply to the corresponding tissue types. We also developed two epigenetic clocks that apply to both human and rat tissues by adding n = 1366 human tissue samples to the training data. We employed these six rat clocks to investigate the rejuvenation effects of a porcine plasma fraction treatment in different rat tissues. The treatment more than halved the epigenetic ages of blood, heart, and liver tissue. A less pronounced, but statistically significant, rejuvenation effect could be observed in the hypothalamus. The treatment was accompanied by progressive improvement in the function of these organs as ascertained through numerous biochemical/physiological biomarkers, behavioral responses encompassing cognitive functions. An immunoglobulin G (IgG) N-glycosylation pattern shift from pro- to anti-inflammatory also indicated reversal of glycan aging. Overall, this study demonstrates that a young porcine plasma-derived treatment markedly reverses aging in rats according to epigenetic clocks, IgG glycans, and other biomarkers of aging., (© 2023. The Author(s).)

Objective: Sporadic and familial amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disease that results in loss of motor neurons and, in some patients, associates with frontotemporal dementia (FTD). Apart from the accumulation of proteinaceous deposits, emerging literature indicates that aberrant mitochondrial bioenergetics may contribute to the onset and progression of ALS/FTD. Here we sought to investigate the pathophysiological signatures of mitochondrial dysfunction associated with ALS/FTD., Methods: By means of label-free mass spectrometry (MS) and mRNA sequencing (mRNA-seq), we report pre-symptomatic changes in the cortices of TDP-43 and FUS mutant mouse models. Using tissues from transgenic mouse models of mitochondrial diseases as a reference, we performed comparative analyses and extracted unique and common mitochondrial signatures that revealed neuroprotective compensatory mechanisms in response to early damage., Results: In this regard, upregulation of both Acyl-CoA Synthetase Long-Chain Family Member 3 (ACSL3) and mitochondrial tyrosyl-tRNA synthetase 2 (YARS2) were the most representative change in pre-symptomatic ALS/FTD tissues, suggesting that fatty acid beta-oxidation and mitochondrial protein translation are mechanisms of adaptation in response to ALS/FTD pathology., Conclusions: Together, our unbiased integrative analyses unveil novel molecular components that may influence mitochondrial homeostasis in the earliest phase of ALS.

Background and Objectives: Current treatment guidelines for restless legs syndrome (RLS) recommend treatment be initiated with non-dopaminergic drugs. Given the potential role of orexins in the pathophysiology of RLS, we performed a pilot, proof-of-concept study to investigate the therapeutic effects of suvorexant, a dual orexin receptor antagonist (DORA), on sleep and sensory/motor symptoms in individuals with idiopathic RLS., Methods: This was a randomized, double-blind, crossover and placebo-controlled study. Inclusion criteria were diagnosis with idiopathic RLS, an International RLS Study Group Severity Rating Scale (IRLS) score > 15, and the absence of significant RLS symptoms before 9 pm. Following washout from any previous central nervous system (CNS)-active drugs, patients were randomized to receive either suvorexant or placebo for two consecutive 2-week treatment periods. Treatment was administered at 9 pm at a fixed dose of 10 mg/day during the first week, and 20 mg during the second week. Primary and coprimary endpoints were wake after sleep onset (WASO) and total sleep time (TST), respectively, while IRLS rating scale score, multiple suggested immobilization tests (m-SIT), and periodic limb movements (PLMs) were secondary endpoints. RLS severity was measured weekly using the IRLS and Clinical Global Improvement (CGI) scales. m-SIT were also performed between 8 pm and midnight at the end of each treatment phase and were followed by a sleep study., Results: A total of 41 participants were randomized, 40 of whom completed the study. Compared with placebo, treatment with suvorexant significantly improved RLS symptoms (according to IRLS total score, CGI, and the m-SIT), PLM during sleep, and PLM with arousal. Improvement of RLS symptoms was greater in those who had not been exposed to dopaminergic agents in the past. Sleep architecture also improved with significant changes in TST, WASO, sleep onset latency, sleep efficiency, non rapid-eye movement stage 1 (N1) %, non rapid-eye movement stage 2 (N2) %, and rapid eye movement (REM) %. Suvorexant was well tolerated in RLS, with few and mild adverse events., Conclusions: Our results provide the first proof of evidence of the therapeutic efficacy of DORAs in improving sleep and sensory and motor symptoms in RLS. Given orexin's role in pain and sensory processing, potential mechanisms of action are discussed., Classification of Evidence: The study provides class II evidence supporting the therapeutic efficacy of suvorexant in patients with RLS with sleep disturbance., Trial Registration: EudraCT#: 2017-004580-12., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The disruption of mitochondrial dynamics has been identified in cardiovascular diseases, including pulmonary hypertension (PH), ischemia-reperfusion injury, heart failure, and cardiomyopathy. Mitofusin 2 (Mfn2) is abundantly expressed in heart and pulmonary vasculature cells at the outer mitochondrial membrane to modulate fusion. Previously, we have reported reduced levels of Mfn2 and fragmented mitochondria in pulmonary arterial endothelial cells (PAECs) isolated from a sheep model of PH induced by pulmonary over-circulation and restoring Mfn2 normalized mitochondrial function. In this study, we assessed the effect of increased expression of Mfn2 on mitochondrial metabolism, bioenergetics, reactive oxygen species production, and mitochondrial membrane potential in control PAECs. Using an adenoviral expression system to overexpress Mfn2 in PAECs and utilizing 13 C labeled substrates, we assessed the levels of TCA cycle metabolites. We identified increased pyruvate and lactate production in cells, revealing a glycolytic phenotype (Warburg phenotype). Mfn2 overexpression decreased the mitochondrial ATP production rate, increased the rate of glycolytic ATP production, and disrupted mitochondrial bioenergetics. The increase in glycolysis was linked to increased hypoxia-inducible factor 1α (HIF-1α) protein levels, elevated mitochondrial reactive oxygen species (mt-ROS), and decreased mitochondrial membrane potential. Our data suggest that disrupting the mitochondrial fusion/fission balance to favor hyperfusion leads to a metabolic shift that promotes aerobic glycolysis. Thus, therapies designed to increase mitochondrial fusion should be approached with caution.

Background: Since March 2011, more than 1 million people, mostly men, have been arrested, detained, and tortured by the Assad regime. Published literature does not reflect the evolution of symptoms after male sexual and physical violence in detention. This cohort study examines the constellation and evolution of self-reported symptoms after male conflict-related sexual violence (CRSV) in Syrian state detention., Methods: Sexual, psychological, and physical symptoms and conditions experienced by a cohort of 106 male detainees after CRSV in Syrian regime detention were evaluated over a ten-year period (2012-2022). Men sought forensic medical expert evaluations (FMEs) to document torture and later consented to semi-structured interviews (SSIs), a median of 8.8 years after their detention. A standard data collection tool was used to assess symptoms and conditions during FMEs (Time 3), and at the time of the SSI (Time 4), during which men also reported symptoms experienced during detention (Time 1) and after detention release (Time 2)., Findings: 30.2% of men spent more than 1 year in detention and 9.4% were detained >5 years. 90% reported being slapped, punched, kicked, hit with objects, 60.4% of men reported torture with multiple devices, and 48.1% reported being burned or electrocuted. Multiple sexual violence types were reported during detention: 97.2% forced nudity, 45.3% violence to genitals or anus, 30.2% collective sexual humiliation, and 9.4% rape. Men recalled nearly universal presence of acute pain, bleeding wounds, skin infections, sleep disturbances, fear, sadness, anxiety, and despair during detention. By Time 4, acute physical and psychological conditions were fading or absent, while scars, avoidance, intrusive memories, lack of trust, self-isolation, chronic pain, anger, and low self-esteem were reported by ≥50%. The most persistently reported symptoms following detention through the SSI included scars, pain, intrusive memories, and avoidance in ≥50% of men. At the SSI, 26.4% of men reported erectile dysfunction and 23.6% challenges with sexual relations., Interpretation: Men reported persistent symptoms and conditions years after CRSV, torture and detention. The unique constellation of findings and their evolution in male CRSV survivors, particularly increasing rates of anger, distrust, and self-isolation, must urgently inform design and delivery of support services and health care., Funding: This study was funded by the United Kingdom Foreign Commonwealth and Development Office and the Arts and Humanities Research Council through the project 'Understanding and Addressing the Impact of Invisibility on Conflict-Related Male Sexual Violence in Syria'., Competing Interests: Authors Kivlahan and Elliott serve as medical and legal expert consultants to Synergy for Justice and as researchers for Synergy for Justice and the funding entity UK Foreign Commonwealth and Development Office and the Arts and Humanities Research Council. Elliott also serves as a Deployable Civilian Expert for UK Foreign Commonwealth and Development Office, working with LDHR from 2012 to 2015 as a UK expert. Author Garcia-Pereira served as a paid consultant to LDHR for data analyses. Authors AlSharif, Halak, Yonso, AlHafez, and Odaimi consultants to LDHR. Author Aswad serves as executive director (a paid employee of LDHR), and in that capacity, manages other LDHR grants not directly relevant to the submitted work and accepts only travel expenses for his attendance at human rights meetings. There are no other conflicts to disclose., (© 2023 The Authors.)

Herein, we introduce an innovative experimental assembly based on a high-speed disperser and a water recirculator connected to a double-wall stainless steel container as a new and effective pathway for an eco-friendly and controlled synthesis of mesoporous silica particles (MSPs). With the setup, we demonstrated a one-pot encapsulation of the particles with an inhibitor benzotriazole (BTA) to produce a smart nano/microcontainer for potential use in anticorrosive coatings. One advantage of the experimental setup is the high volume of reactant solution that can be used, yet with good control of solution temperature and stirring conditions, which increases the yield and saves laboratory time. The results obtained from the modified Stöber method show the successful preparation of near-spherical and "bean-shaped" nanometer-size (∼310 nm) MSPs with high benzotriazole encapsulation capacity (46 wt %). More so, the one-pot BTA encapsulated mesoporous silica approach revealed monodispersed spherical particles at optimal temperature and stirring conditions with a mean diameter of ∼1.1 μm and a BTA encapsulation of 23 wt %. The synthesized particles show pH responsiveness and can be further optimized and applied as nanocarriers in smart anticorrosive coatings. The experimental assembly adopted in this work represents a new, scalable approach for the synthesis of mesoporous silica particles.

Background: Vaccination remains crucial for protection against severe SARS-CoV-2 infection, especially for people of advanced age, however, optimal dosing regimens are as yet lacking., Methods: EU-COVAT-1-AGED Part A is a randomised controlled, adaptive, multicentre phase II trial evaluating safety and immunogenicity of a 3rd vaccination (1st booster) in individuals ≥75 years. Fifty-three participants were randomised to full-doses of either mRNA-1273 (Spikevax®, 100 µg) or BNT162b2 (Comirnaty®, 30 µg). The primary endpoint was the rate of 2-fold circulating antibody titre increase 14 days post-vaccination measured by quantitative electrochemiluminescence (ECL) immunoassay, targeting RBD region of Wuhan wild-type SARS-CoV-2. Secondary endpoints included the changes in neutralising capacity against wild-type and 25 variants of concern at 14 days and up to 12 months. Safety was assessed by monitoring of solicited adverse events (AEs) for seven days after on-study vaccination. Unsolicited AEs were collected until the end of follow-up at 12 months, SAEs were pursued for a further 30 days., Results: Between 08th of November 2021 and 04th of January 2022, 53 participants ≥75 years received a COVID-19 vaccine as 1st booster. Fifty subjects (BNT162b2 n = 25/mRNA-1273 n = 25) were included in the analyses for immunogenicity at day 14. The primary endpoint of a 2-fold anti-RBD IgG titre increase 14 days after vaccination was reached for all subjects. A 3rd vaccination of full-dose mRNA-1273 provided higher anti-RBD IgG titres (Geometric mean titre) D14 mRNA-127310711 IU/mL (95 %-CI: 8003;14336) vs. BNT162b2: 7090 IU/mL (95 %-CI: 5688;8837). We detected a pattern showing higher neutralising capacity of full-dose mRNA-1273 against wild-type as well as for 23 out of 25 tested variants., Interpretation: Third doses of either BNT162b2 or mRNA-1273 provide substantial circulating antibody increase 14 days after vaccination. Full-dose mRNA-1273 provides higher antibody levels with an overall similar safety profile for people ≥75 years., Funding: This trial was funded by the European Commission (Framework Program HORIZON 2020)., Competing Interests: Declaration of Competing Interest JN no conflicts declared. JS has received research grants by the Ministry of Education and Research (BMBF) and Basilea Pharmaceuticals; has received speaker honoraria by AbbVie, Pfizer and Gilead; has been a consultant to Gilead, Produkt & Markt GmbH, Alvea Vax and Micron Research and has received travel grants by German Society for Infectious Diseases (DGI) and Meta-Alexander Foundation. AJC no conflicts declared. JFI has received research grants by the Instituto de Salud Carlos III, Ministry of Science. Spain. Has received grants or research contracts from Laboratorios Faes, Normon, Pfizer, Italfarmaco, GSK, Prestige, has been a consultant or has received speaker honoraria from Faes, Normon, Cinfa, Mundipharma, Abbott, Novartis and docency colaborations from Abbvie. MA has received research grants from Pfizer and Gilead. Contributed to educational activities organized/supported by Pfizer, Roche, Gilead, GSK, Moderna and Sanofi. All honoraria from these activities are paid to the Institution. UB no conflicts declared. SH no conflicts declared. JSG has received speaker honoraria from Gilead and Pfizer, outside of the submitted work. LT no conflicts declared. MZ has received honoraria for lecturing courses by Pfizer Malaysia; is now an employee with AiCuris AG. AC no conflicts declared. JG no conflicts declared. AGL no conflicts declared. PM has received honoraria from Gilead and AstraZeneca, outside of the submitted work. RN no conflicts declared. CG no conflicts declared. GS no conflicts declared. AH no conflicts declared. SKS no conflicts declared. KL no conflicts declared. CL no conflicts declared. HG no conflicts declared. SMK has received grants from Pfizer, MSD, Huvepharma, AiCuris, Astra Zeneca, Mylan, Janssen pharma. FK no conflicts declared. LY no conflicts declared. MP no conflicts declared. PK reports grants or contracts from German Federal Ministry of Research and Education (BMBF) B-FAST (Bundesweites Forschungsnetz Angewandte Surveillance und Testung) and NAPKON (Nationales Pandemie Kohorten Netz, German National Pandemic Cohort Network) of the Network University Medicine (NUM) and the State of North Rhine-Westphalia; Consulting fees Ambu GmbH, Gilead Sciences, Mundipharma Resarch Limited, Noxxon N.V. and Pfizer Pharma; Honoraria for lectures from Akademie für Infektionsmedizin e.V., Ambu GmbH, Astellas Pharma, BioRad Laboratories Inc., Datamed GmbH, European Confederation of Medical Mycology, Gilead Sciences, GPR Academy Ruesselsheim, HELIOS Kliniken GmbH, Lahn-Dill-Kliniken GmbH, medupdate GmbH, MedMedia GmbH, MSD Sharp & Dohme GmbH, Pfizer Pharma GmbH, Scilink Comunicación Científica SC, streamedup! GmbH and University Hospital and LMU Munich; Participation on an Advisory Board from Ambu GmbH, Gilead Sciences, Mundipharma Resarch Limited and Pfizer Pharma; A pending patent currently reviewed at the German Patent and Trade Mark Office (DE 10 2021 113 007.7); Other non-financial interests from Elsevier, Wiley and Taylor & Francis online outside the submitted work. OAC reports grants or contracts from Amplyx, Basilea, BMBF, Cidara, DZIF, EU-DG RTD (101037867), F2G, Gilead, Matinas, MedPace, MSD, Mundipharma, Octapharma, Pfizer, Scynexis; Consulting fees from Abbvie, Amplyx, Biocon, Biosys, Cidara, Da Volterra, Gilead, IQVIA, Janssen, Matinas, MedPace, Menarini, Molecular Partners, MSG-ERC, Noxxon, Octapharma, Pfizer, PSI, Scynexis, Seres; Honoraria for lectures from Abbott, Abbvie, Al-Jazeera Pharmaceuticals, Astellas, Gilead, Grupo Biotoscana/United Medical/Knight, Hikma, MedScape, MedUpdate, Merck/MSD, Mylan, Noscendo, Pfizer, Shionogi; Payment for expert testimony from Cidara; Participation on a Data Safety Monitoring Board or Advisory Board from Actelion, Allecra, Cidara, Entasis, IQVIA, Janssen, MedPace, Paratek, PSI, Pulmocide, Shionogi, The Prime Meridian Group; A patent at the German Patent and Trade Mark Office (DE 10 2021 113 007.7); Stocks from CoRe Consulting, EasyRadiology; Other interests from DGHO, DGI, ECMM, EHA, ISHAM, MSG-ERC, Wiley., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Patient satisfaction after breast cancer surgery has an impact on body image, sexual function, self-esteem, and quality of life and may differ from the perception of the attending physician. This study aimed to compare the aesthetic outcomes and satisfaction with conservative oncoplastic surgeries, mastectomies, and total breast reconstruction., Methods: We included 760 women diagnosed with invasive breast carcinoma or phyllodes tumors who returned at least 6 months after surgery or radiotherapy at two public hospitals and a private clinic between 2014 and 2022. Data was collected prospectively from patients and retrospectively from their medical records using a specific form after obtaining their informed consent. Aesthetic outcomes and quality of life were assessed using the BREAST-Q©, Harris Scale, and BCCT.core software. Data were evaluated using the SPSS statistical software. Statistical significance was set at p < 0.05. This study was approved by the hospital ethics committees., Results: A total of 405 (53.29%) partial and 355 (46.71%) total reconstructions were included. Patients who underwent partial reconstruction were older and had higher body mass index. Patients who underwent total reconstruction had larger tumors with advanced clinical and pathological stages. Clinical and surgical complications occurred more frequently in the total reconstruction group. A greater number of reparative surgeries and lipofilling procedures were required for total reconstruction. According to the BREAST-Q, the partial reconstruction group showed significantly higher levels of women's satisfaction with their breasts, the surgical outcomes, psychosocial and sexual well-being, provision of information, and the reconstructive surgeon. Only physical well-being was slightly higher in the total reconstruction group. In most cases, the results were rated good or excellent. Physicians considered partial reconstructions to have better results than total reconstructions, although this difference was not perceived by the BCCT.core software., Conclusion: Women who underwent partial breast reconstruction had higher levels of satisfaction in several domains, lower frequency of complications, and required fewer surgeries to complete their reconstruction than women who underwent total reconstruction. Physicians were also more satisfied with the results of partial reconstructions., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest. There are no sources of support for the reported work, including grants, equipment and drugs, and no funding was received for this work from any organization., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Endogenous hydrogen sulfide (H 2 S) produced by cystathionine β-synthase (CBS) and cystathionine-γ lyase (CSE) has emerged as a novel uterine vasodilator contributing to pregnancy-associated increases in uterine blood flow, which safeguard pregnancy health. Uterine artery (UA) H 2 S production is stimulated via exogenous estrogen replacement and is associated with elevated endogenous estrogens during pregnancy through the selective upregulation of CBS without altering CSE. However, how endogenous estrogens regulate uterine artery CBS expression in pregnancy is unknown. This study was conducted to test a hypothesis that endogenous estrogens selectively stimulate UA CBS expression via specific estrogen receptors (ER). Treatment with E 2 β (0.01 to 100 nM) stimulated CBS but not CSE mRNA in organ cultures of fresh UA rings from both NP and P (gestational day 20, GD20) rats, with greater responses to all doses of E 2 β tested in P vs. NP UA. ER antagonist ICI 182,780 (ICI, 1 µM) completely attenuated E 2 β-stimulated CBS mRNA in both NP and P rat UA. Subcutaneous injection with ICI 182,780 (0.3 mg/rat) of GD19 P rats for 24 h significantly inhibited UA CBS but not mRNA expression, consistent with reduced endothelial and smooth muscle cell CBS (but not CSE) protein. ICI did not alter mesenteric and renal artery CBS and CSE mRNA. In addition, ICI decreased endothelial nitric oxide synthase mRNA in UA but not in mesenteric or renal arteries. Thus, pregnancy-augmented UA CBS/H 2 S production is mediated by the actions of endogenous estrogens via specific ER in pregnant rats.