Heparin pretreatment in ST segment elevation myocardial infarction: a systematic review and meta-analysis.

BACKGROUND: Unfractionated heparin (UFH) is frequently administered before percutaneous coronary intervention in patients with ST segment elevation myocardial infarction (STEMI). Current guidelines, however, do not provide clear recommendations for UFH pretreatment before arrival at the coronary catheterization laboratory. METHODS: Between June and July 2023, we systematically searched PubMed, Embase, and Cochrane databases for studies comparing UFH pretreatments in patients with STEMI. A random-effects meta-analysis and meta-regression analyses were performed. RESULTS: Fourteen studies were included, of which four were randomized clinical trials. A total of 76 446 patients were included: 31 238 in the pretreatment group and 39 208 in the control group. Our meta-analysis revealed lower all-cause mortality for the pretreatment strategy when compared with the control group, albeit with high heterogeneity [pooled odds ratio (OR) = 0.61, 95% confidence interval (CI): 0.49-0.76, P < 0.01; I2 = 77%]; lower in-hospital cardiogenic shock (pooled OR = 0.68, 95% CI: 0.58-0.78, P < 0.21; I2 = 27%) and a higher rate of spontaneous reperfusion events (pooled OR = 1.68, 95% CI: 1.47-1.91, P < 0.01; I2 = 79%). In terms of major bleeding, the UFH pretreatment strategy further revealed a decreased rate of events (pooled OR = 0.85, 95% CI: 0.73-0.99, P = 0.40; I2 = 4%). CONCLUSION: Our study suggests that UFH pretreatment in patients with STEMI undergoing primary percutaneous coronary intervention was associated with reduced all-cause mortality, cardiogenic shock, enhancing reperfusion rates while diminishing major bleeding events.

Effect of Cyclin-Dependent Kinase 4/6 Inhibitors on Circulating Cells in Patients with Metastatic Breast Cancer.

The combination of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) with endocrine therapy (ET) is the standard-of-care for estrogen receptor (ER)-positive, HER2-negative (ER+/HER2- advanced/metastatic breast cancer (mBC). However, the impact of CDK4/6i on circulating immune cells and circulating tumor cells (CTCs) in patients receiving CDK4/6i and ET (CDK4/6i+ET) remains poorly understood. This was a prospective cohort study including 44 patients with ER+/HER2- mBC treated with CDK4/6i+ET in either first or second line. Peripheral blood samples were collected before (baseline) and 3 months (t2) after therapy. Immune cell's subsets were quantified by flow cytometry, and microfluidic-captured CTCs were counted and classified according to the expression of cytokeratin and/or vimentin. Patients were categorized according to response as responders (progression-free survival [PFS] ≥ 6.0 months; 79.1%) and non-responders (PFS < 6.0 months; 20.9%). CDK4/6i+ET resulted in significant changes in the hematological parameters, including decreased hemoglobin levels and increased mean corpuscular volume, as well as reductions in neutrophil, eosinophil, and basophil counts. Specific immune cell subsets, such as early-stage myeloid-derived suppressor cells, central memory CD4+ T cells, and Vδ2+ T cells expressing NKG2D, decreased 3 months after CDK4/6i+ET. Additionally, correlations between the presence of CTCs and immune cell populations were observed, highlighting the interplay between immune dysfunction and tumor dissemination. This study provides insights into the immunomodulatory effects of CDK4/6i+ET, underscoring the importance of considering immune dynamics in the management of ER+/HER2- mBC.

Erratum: Effect of transdermal drug delivery patches on the stratum corneum: in vivo inspection with a handheld terahertz probe: publisher's note.

[This corrects the article on p. 3064 in vol. 15, PMID: 38855675.].

DNA damage targeted therapy for advanced breast cancer.

Breast cancer (BC) is the most prevalent malignancy affecting women worldwide, including Portugal. While the majority of BC cases are sporadic, hereditary forms account for 5-10% of cases. The most common inherited mutations associated with BC are germline mutations in the BReast CAncer (BRCA) 1/2 gene (gBRCA1/2). They are found in approximately 5-6% of BC patients and are inherited in an autosomal dominant manner, primarily affecting younger women. Pathogenic variants within BRCA1/2 genes elevate the risk of both breast and ovarian cancers and give rise to distinct clinical phenotypes. BRCA proteins play a key role in maintaining genome integrity by facilitating the repair of double-strand breaks through the homologous recombination (HR) pathway. Therefore, any mutation that impairs the function of BRCA proteins can result in the accumulation of DNA damage, genomic instability, and potentially contribute to cancer development and progression. Testing for gBRCA1/2 status is relevant for treatment planning, as it can provide insights into the likely response to therapy involving platinum-based chemotherapy and poly[adenosine diphosphate (ADP)-ribose] polymerase inhibitors (PARPi). The aim of this review was to investigate the impact of HR deficiency in BC, focusing on BRCA mutations and their impact on the modulation of responses to platinum and PARPi therapy, and to share the experience of Unidade Local de Saúde Santa Maria in the management of metastatic BC patients with DNA damage targeted therapy, including those with the Portuguese c.156_157insAlu BRCA2 founder mutation.

A preclinical model of severe NASH-like liver injury by chronic administration of a high-fat and high-sucrose diet in mice.

Non-alcoholic fatty liver disease (NAFLD) is a progressive liver disease, affecting 38% of adults globally. If left untreated, NAFLD may progress to more advanced forms of the disease, including non-alcoholic steatohepatitis (NASH), liver cirrhosis, and fibrosis. Early NAFLD detection is critical to prevent disease progression. Using an obesogenic high-fat and high-sucrose (HF/HS) diet, we characterized the progression of NAFLD in male and female Collaborative Cross CC042 mice after 20-, 40-, and 60-week intervals of chronic HF/HS diet feeding. The incidence and severity of liver steatosis, inflammation, and fibrosis increased in both sexes over time, with male mice progressing to a NASH-like disease state faster than female mice, as indicated by earlier and more pronounced changes in liver steatosis. Histopathological indication of macrovesicular steatosis and gene expression changes of key lipid metabolism genes were found to be elevated in both sexes after 20 weeks of HF/HS diet. Measurement of circulating markers of inflammation (CXCL10 and TNF-α), histopathological analysis of immune cell infiltrates, and gene expression changes in inflammation-related genes indicated significant liver inflammation after 40 and 60 weeks of HF/HS diet exposure in both sexes. Liver fibrosis, as assessed by Picosirius red and Masson's trichrome staining and changes in expression of key fibrosis related genes indicated significant changes after 40 and 60 weeks of HF/HS diet exposure. In conclusion, we present a preclinical animal model of dietary NAFLD progression, which recapitulates human pathophysiological and pathomorphological changes, that could be used to better understand the progression of NAFLD and support development of new therapeutics.

Trust your gut: Establishing confidence in gastrointestinal models - An overview of the state of the science and contexts of use.

The webinar series and workshop titled "Trust Your Gut: Establishing Confidence in Gastrointestinal Models ­ An Overview of the State of the Science and Contexts of Use" was co-organized by NICEATM, NIEHS, FDA, EPA, CPSC, DoD, and the Johns Hopkins Center for Alternatives to Animal Testing (CAAT) and hosted at the National Institutes of Health in Bethesda, MD, USA on October 11-12, 2023. New approach methods (NAMs) for assessing issues of gastrointestinal tract (GIT)- related toxicity offer promise in addressing some of the limitations associated with animal-based assessments. GIT NAMs vary in complexity, from two-dimensional monolayer cell line-based systems to sophisticated 3-dimensional organoid systems derived from human primary cells. Despite advances in GIT NAMs, challenges remain in fully replicating the complex interactions and pro­cesses occurring within the human GIT. Presentations and discussions addressed regulatory needs, challenges, and innovations in incorporating NAMs into risk assessment frameworks; explored the state of the science in using NAMs for evaluating systemic toxicity, understanding absorption and pharmacokinetics, evaluating GIT toxicity, and assessing potential allergenicity; and discussed strengths, limitations, and data gaps of GIT NAMs as well as steps needed to establish confidence in these models for use in the regulatory setting.

Non-animal methods to assess whether chemicals may be toxic to the human digestive tract promise to complement or improve on animal-based methods. These approaches, which are based on human or animal cells and/or computer models, are faced with their own technical challenges and need to be shown to predict adverse effects in humans. Regulators are tasked with evaluating submitted data to best protect human health and the environment. A webinar series and workshop brought together scientists from academia, industry, military, and regulatory authorities from dif­ferent countries to discuss how non-animal methods can be integrated into the risk assessment of drugs, food additives, dietary supplements, pesticides, and industrial chemicals for gastrointestinal toxicity.

Effect of transdermal drug delivery patches on the stratum corneum: in vivo inspection with a handheld terahertz probe.

Transdermal drug delivery patches are a good alternative to hypodermic drug injection. The drug delivery efficiency depends strongly on the hydration of the skin under treatment, and therefore, it is essential to study the effects on the skin induced by the application of these medical-grade patches. Terahertz (THz) spectroscopy shows great promise for non-invasive skin evaluation due to its high sensitivity to subtle changes in water content, low power and non-ionizing properties. In this work, we study the effects of transdermal drug delivery patches (three fully occlusive and three partially occlusive) applied on the upper arms of ten volunteers for a maximum period of 28 h. Three different levels of propylene glycol (0 %, 3 % and 6 %) are added to the patches as excipient. By performing multilayer analysis, we successfully retrieve the water content of the stratum corneum (SC) which is the outermost layer of skin, as well as its thickness at different times before and after applying the patches. This study demonstrates the potential of using THz sensing for non invasive skin monitoring and has wide applications for skin evaluation as well as the development of skin products.

Decompression Associated with Irrigation with Elixir Sanativo® Before Enucleation of Odontogenic Keratocysts: Report of Two Cases

Odontogenic Keratocyst (OKC) is an aggressive cystic lesion of the jaws and one of the most common odontogenic cysts, usually affecting the posterior region of the mandible. Recurrences are frequently recorded and may be directly related to the treatment modality adopted. Two patients presenting OKC were treated by combining decompression and intralesional irrigation with the drug Elixir Sanativo® for 8 months before enucleation surgery. In both patients, the association between decompression and irrigation with Elixir Sanativo® represented a safe and effective method to reduce the preoperative lesion dimensions.

El queratoquiste odontogénico (QO) es una lesión quística agresiva de la mandíbula y es uno de los quistes odontogénicos más frecuentes, que suele afectar a la región posterior de la mandíbula. Las recidivas se registran con frecuencia y pueden estar directamente relacionadas con la modalidad de tratamiento adoptada. Presentación del caso: Dos pacientes que presentaban OKC fueron tratados combinando descompresión e irrigación intralesional con el fármaco Elixir Sanativo® durante 8 meses antes de la cirugía de enucleación. En ambos pacientes, la asociación entre descompresión e irrigación con Elixir Sanativo® representó un método seguro y eficaz para reducir las dimensiones de la lesión preoperatoria.

The effect of black cohosh extract and risedronate coadministration on bone health in an ovariectomized rat model.

Preparations of black cohosh extract are sold as dietary supplements marketed to relieve the vasomotor symptoms of menopause, and some studies suggest it may protect against postmenopausal bone loss. Postmenopausal women are also frequently prescribed bisphosphonates, such as risedronate, to prevent osteoporotic bone loss. However, the pharmacodynamic interactions between these compounds when taken together is not known. To investigate possible interactions, 6-month-old, female Sprague-Dawley rats underwent bilateral ovariectomy or sham surgery and were treated for 24 weeks with either vehicle, ethinyl estradiol, risedronate, black cohosh extract or coadministration of risedronate and black cohosh extract, at low or high doses. Bone mineral density (BMD) of the femur, tibia, and lumbar vertebrae was then measured by dual-energy X-ray absorptiometry (DEXA) at weeks 0, 8, 16, and 24. A high dose of risedronate significantly increased BMD of the femur and vertebrae, while black cohosh extract had no significant effect on BMD individually and minimal effects upon coadministration with risedronate. Under these experimental conditions, black cohosh extract alone had no effect on BMD, nor did it negatively impact the BMD-enhancing properties of risedronate.

Left atrial appendage occlusion for recurrent stroke while on oral anticoagulation: a case series.

Background: Clinical practice guidelines recommend oral anticoagulation (OAC) for stroke prevention in selected patients with atrial fibrillation (AF). However, some patients still experience thrombo-embolic events despite adequate anticoagulation. The optimal management of these cases remains uncertain, leading to practice pattern variability. We present a series of three cases illustrating the use of left atrial appendage occlusion (LAAO) as an adjunctive stroke prevention strategy in AF patients with recurrent thrombo-embolic events despite adequate anticoagulation. Case summary: Case one describes an 89-year-old female on apixaban who presented with a thrombus and underwent successful mechanical thrombectomy. Left atrial appendage occlusion was performed, and no subsequent thrombo-embolic events were reported. Case 2 involves a 72-year-old female on full-dose apixaban who experienced recurrent strokes despite adequate anticoagulation. Thrombectomy was performed twice, and complications arose during LAAO. The patient was discharged on warfarin + clopidogrel and remained event-free at the six-month follow-up. Case 3 features an 88-year-old female on rivaroxaban who experienced recurrent cerebral ischaemic events and gastrointestinal bleeding. Left atrial appendage occlusion using an Amplatzer Amulet™ device was successful, and the patient remained event-free at the one-year follow-up. Discussion: This case series emphasizes the complexity of stroke prevention in AF patients and underscores the need for an individualized approach. Incorporating LAAO alongside OAC can provide additional stroke protection for patients with inadequate response to anticoagulation. Further randomized controlled trials are needed to evaluate the efficacy and safety of this approach. In light of the limited evidence available, these cases contribute to the growing body of knowledge on the potential role of LAAO in secondary stroke prevention in AF patients with recurrent thrombo-embolic events despite appropriate anticoagulation.

Simultaneous measurement of orthogonal terahertz fields via an emission multiplexing scheme.

We propose a polarization sensitive terahertz time-domain spectrometer that can record orthogonally polarized terahertz fields simultaneously, using fibre-coupled photoconductive antennas and a scheme that modulated the emitter's polarization. The s and p channels of the multi-pixel terahertz emitter were modulated at different frequencies, thereby allowing orthogonal waveforms to be demultiplexed from the recorded signal in post-processing. The performance of the multi-pixel emitter used in this multiplexing scheme was comparable to that of a commercial single-polarization H-dipole antenna. The approach allowed two orthogonally polarized terahertz pulses to be recorded with good signal to noise (>1000:1) within half a second. We verified the capability of the spectrometer by characterizing a birefringent crystal and by imaging a polarization-sensitive metamaterial. This work has significant potential to improve the speed of terahertz polarization sensitive applications, such as ellipsometry and imaging.

Comparison between epileptic seizure prediction and forecasting based on machine learning.

Epilepsy affects around 1% of the population worldwide. Anti-epileptic drugs are an excellent option for controlling seizure occurrence but do not work for around one-third of patients. Warning devices employing seizure prediction or forecasting algorithms could bring patients new-found comfort and quality of life. These algorithms would attempt to detect a seizure's preictal period, a transitional moment between regular brain activity and the seizure, and relay this information to the user. Over the years, many seizure prediction studies using Electroencephalogram-based methodologies have been developed, triggering an alarm when detecting the preictal period. Recent studies have suggested a shift in view from prediction to forecasting. Seizure forecasting takes a probabilistic approach to the problem in question instead of the crisp approach of seizure prediction. In this field of study, the triggered alarm to symbolize the detection of a preictal period is substituted by a constant risk assessment analysis. The present work aims to explore methodologies capable of seizure forecasting and establish a comparison with seizure prediction results. Using 40 patients from the EPILEPSIAE database, we developed several patient-specific prediction and forecasting algorithms with different classifiers (a Logistic Regression, a 15 Support Vector Machines ensemble, and a 15 Shallow Neural Networks ensemble). Results show an increase of the seizure sensitivity in forecasting relative to prediction of up to 146% and in the number of patients that displayed an improvement over chance of up to 300%. These results suggest that a seizure forecasting methodology may be more suitable for seizure warning devices than a seizure prediction one.

Coronary angiography after out-of-hospital cardiac arrest without ST-segment elevation: a systematic review and meta-analysis of randomised trials.

BACKGROUND: Out-of-hospital cardiac arrest (OHCA) has a poor prognosis. The optimal timing and role of early coronary angiography (CAG) in OHCA patients without ST-segment elevation remains unclear. The goal of this study is to compare an early CAG versus delayed CAG strategy in OHCA patients without ST elevation. METHODS: We systematically searched PubMed, Embase and Cochrane databases, in June 2022, for randomised controlled trials (RCTs) comparing early versus delayed early CAG. A random effects meta-analysis was performed. RESULTS: A total of seven RCTs were included, providing a total of 1625 patients: 816 in an early strategy and 807 in a delayed strategy. In terms of outcomes assessed, our meta-analysis revealed a similar rate of all-cause mortality (pooled odds ratio [OR] 1.22 [0.99-1.50], P  = 0.06, I 2  = 0%), neurological status (pooled OR 0.94 [0.74-1.21], = 0.65, I 2  = 0%), need of renal replacement therapy (pooled OR 1.11 [0.78-1.74], P  = 0.47, I 2  = 0%) and major bleeding events (pooled OR 1.51 [0.95-2.40], P  = 0.08, I 2  = 69%). CONCLUSION: According to our meta-analysis, in patients who experienced OHCA without ST elevation, early CAG is not associated with reduced mortality or an improved neurological status.

Therapeutic avenues for γδ T cells in cancer.

γδ T cells are regarded as promising effector lymphocytes for next-generation cancer immunotherapies. In spite of being relatively rare in human peripheral blood, γδ T cells are more abundant in epithelial tissues where many tumors develop, and have been shown to actively participate in anticancer immunity as cytotoxic cells or as "type 1" immune orchestrators. A major asset of γδ T cells for tackling advanced cancers is their independence from antigen presentation via the major histocompatibility complex, which clearly sets them apart from conventional αß T cells. Here we discuss the main therapeutic strategies based on human γδ T cells. These include antibody-based bispecific engagers and adoptive cell therapies, either focused on the Vδ1+ or Vδ2+ γδ T-cell subsets, which can be expanded selectively and differentiated or engineered to maximize their antitumor functions. We review the preclinical data that supports each of the therapeutic strategies under development; and summarize the clinical trials being pursued towards establishing γδ T cell-based treatments for solid and hematological malignancies.

Breast Sarcomas, Phyllodes Tumors, and Desmoid Tumors: Turning the Magnifying Glass on Rare and Aggressive Entities.

Breast sarcomas (BSs), phyllodes tumors (PTs), and desmoid tumors (DTs) are rare entities that arise from connective tissue. BSs can be classified as either primary or secondary, whether they develop de novo or after radiation exposure or lymphedema. PIK3CA seems to play an important common role in different BS. Malignant PTs show similar behavior to BSs, while DTs are locally aggressive but rarely metastasize. BSs usually present as unilateral, painless, rapidly growing masses with rare nodal involvement. The diagnosis should be based on magnetic resonance imaging and a core needle biopsy. Staging should comprise a chest computed tomography (CT) scan (except for benign PT and DT), while abdominal and pelvic CT scans and bone scans should be added in certain subtypes. The mainstay of treatment for localized BS is surgery, with margin goals that vary according to subtype. Radiotherapy and chemotherapy can be used as neoadjuvant or adjuvant approaches, but their use in these settings is not standard. Advanced BS should be treated with systemic therapy, consistent with recommendations for advanced soft tissue sarcomas of other topographies. Given the rarity and heterogeneity of these entities, multidisciplinary and multi-institutional collaboration and treatment at reference centers are critical.