A mimetic peptide of ACE2 protects against SARS-CoV-2 infection and decreases pulmonary inflammation related to COVID-19.

Since human angiotensin-converting enzyme 2 (ACE2) serves as a primary receptor for SARS-CoV-2, characterizing ACE2 regions that allow SARS-CoV-2 to enter human cells is essential for designing peptide-based antiviral blockers and elucidating the pathogenesis of the virus. We identified and synthesized a 25-mer mimetic peptide (encompassing positions 22-46 of the ACE2 alpha-helix α1) implicated in the S1 receptor-binding domain (RBD)-ACE2 interface. The mimetic (wild-type, WT) ACE2 peptide significantly inhibited SARS-CoV-2 infection of human pulmonary Calu-3 cells in vitro. In silico protein modeling predicted that residues F28, K31, F32, F40, and Y41 of the ACE2 alpha-helix α1 are critical for the original, Delta, and Omicron strains of SARS-CoV-2 to establish the Spike RBD-ACE2 interface. Substituting these residues with alanine (A) or aspartic acid (D) abrogated the antiviral protective effect of the peptides, indicating that these positions are critical for viral entry into pulmonary cells. WT ACE2 peptide, but not the A or D mutated peptides, exhibited significant interaction with the SARS-CoV-2 S1 RBD, as shown through molecular dynamics simulations. Through identifying the critical amino acid residues of the ACE2 alpha-helix α1, which is necessary for the Spike RBD-ACE2 interface and mobilized during the in vitro viral infection of cells, we demonstrated that the WT ACE2 peptide protects susceptible K18-hACE2 mice against in vivo SARS-CoV-2 infection and is effective for the treatment of COVID-19.

Stakeholders' Perceptions on the Implementation of the HPV Vaccine School-Entry Requirement in Puerto Rico during the COVID-19 Pandemic.

This study explored the implementation of the human papillomavirus (HPV) vaccine school-entry requirement in Puerto Rico during the COVID-19 pandemic. We conducted 26 semi-structured interviews with stakeholders and community-based organizations from August 2021 to March 2022. The interview guide was developed using the 2009 Consolidated Framework for Implementation Research (CFIR). The interviews were recorded and transcribed in Spanish. Data were analyzed using applied thematic techniques. These themes included the following: (i) Intervention characteristics: Participants noted that the school-entry requirement was effective in increasing vaccination uptake prior to the pandemic. Issues with the immunization registry were noted; (ii) Outer setting: External influences, access barriers, and an increase in HPV vaccine exemptions since the implementation of the COVID-19 vaccine were discussed; (iii) Inner setting: Communication within organizations and HPV vaccination efforts improved as the pandemic progressed; (iv) Characteristics of individuals: Most agreed with the school-entry requirement, including exemptions; and (v) Process: Results showed the need to reinforce the population's education about HPV and the vaccine. Implementation of the policy was challenging during the early stages of the pandemic due to measures enacted to stop the spread of COVID-19 and focus on the COVID-19 vaccine. Efforts to increase HPV vaccine should focus on increasing HPV vaccine education and creating collaborations.

Override rate of drug-drug interaction alerts in clinical decision support systems: A brief systematic review and meta-analysis.

Primary studies have demonstrated that despite being useful, most of the drug-drug interaction (DDI) alerts generated by clinical decision support systems are overridden by prescribers. To provide more information about this issue, we conducted a systematic review and meta-analysis on the prevalence of DDI alerts generated by CDSS and alert overrides by physicians. The search strategy was implemented by applying the terms and MeSH headings and conducted in the MEDLINE/PubMed, EMBASE, Web of Science, Scopus, LILACS, and Google Scholar databases. Blinded reviewers screened 1873 records and 86 full studies, and 16 articles were included for analysis. The overall prevalence of alert generated by CDSS was 13% (CI95% 5-24%, p-value <0.0001, I^2 = 100%), and the overall prevalence of alert override by physicians was 90% (CI95% 85-95%, p-value <0.0001, I^2 = 100%). This systematic review and meta-analysis presents a high rate of alert overrides, even after CDSS adjustments that significantly reduced the number of alerts. After analyzing the articles included in this review, it was clear that the CDSS alerts physicians about potential DDI should be developed with a focus on the user experience, thus increasing their confidence and satisfaction, which may increase patient clinical safety.

Ligand- and Structure-Based Virtual Screening Identifies New Inhibitors of the Interaction of the SARS-CoV-2 Spike Protein with the ACE2 Host Receptor.

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a fast-spreading viral pathogen and poses a serious threat to human health. New SARS-CoV-2 variants have been arising worldwide; therefore, is necessary to explore more therapeutic options. The interaction of the viral spike (S) protein with the angiotensin-converting enzyme 2 (ACE2) host receptor is an attractive drug target to prevent the infection via the inhibition of virus cell entry. In this study, Ligand- and Structure-Based Virtual Screening (LBVS and SBVS) was performed to propose potential inhibitors capable of blocking the S receptor-binding domain (RBD) and ACE2 interaction. The best five lead compounds were confirmed as inhibitors through ELISA-based enzyme assays. The docking studies and molecular dynamic (MD) simulations of the selected compounds maintained the molecular interaction and stability (RMSD fluctuations less than 5 Å) with key residues of the S protein. The compounds DRI-1, DRI-2, DRI-3, DRI-4, and DRI-5 efficiently block the interaction between the SARS-CoV-2 spike protein and receptor ACE2 (from 69.90 to 99.65% of inhibition) at 50 µM. The most potent inhibitors were DRI-2 (IC50 = 8.8 µM) and DRI-3 (IC50 = 2.1 µM) and have an acceptable profile of cytotoxicity (CC50 > 90 µM). Therefore, these compounds could be good candidates for further SARS-CoV-2 preclinical experiments.

Exploring the secrets of virus entry: the first respiratory syncytial virus carrying beta lactamase.

Background: Respiratory Syncytial Virus (RSV) presents a significant health threat, especially to young children. In-depth understanding of RSV entry mechanisms is essential for effective antiviral development. This study introduces an innovative RSV variant, featuring the fusion of the beta-lactamase (BlaM) enzyme with the RSV-P phosphoprotein, providing a versatile tool for dissecting viral entry dynamics. Methods: Using the AlphaFold2 algorithm, we modeled the tertiary structure of the P-BlaM chimera, revealing structural similarities with both RSV-P and BlaM. Functional assessments, utilizing flow cytometry, quantified beta-lactamase activity and GFP expression in infected bronchial epithelial cells. Western blot analysis confirmed the integrity of P-BlaM within virions. Results: The modeled P-BlaM chimera exhibited structural parallels with RSV-P and BlaM. Functional assays demonstrated robust beta-lactamase activity in recombinant virions, confirming successful P-BlaM incorporation as a structural protein. Quercetin, known for its antiviral properties, impeded viral entry by affecting virion fusion. Additionally, Ulixertinib, an ERK-1/2 inhibitor, significantly curtailed viral entry, implicating ERK-1/2 pathway signaling. Conclusions: Our engineered RSV-P-BlaM chimera emerges as a valuable tool, illuminating RSV entry mechanisms. Structural and functional analyses unveil potential therapeutic targets. Quercetin and Ulixertinib, identified as distinct stage inhibitors, show promise for targeted antiviral strategies. Time-of-addition assays pinpoint quercetin's specific interference stage, advancing our comprehension of RSV entry and guiding future antiviral developments.

Ca2+ signals in human umbilical endothelial cells derived from pregnancy with fetal growth restriction associated with hypertensive disorder.

Fetal growth restriction associated with hypertensive disorders of pregnancy (FGR-HDP) is a prevalent pathology with a higher risk of perinatal morbimortality. In this condition, placental insufficiency and endothelial dysfunction serve key roles. The present prospective cohort study monitored 11 patients with an FGR-HDP and 15 with full-term normotensive pregnancies and studied post-natal intracellular calcium concentration ([Ca2+]i) signals in human umbilical vein endothelial cells (HUVECs). Small fetuses with placental insufficiency were identified using fetal biometry with Doppler velocimetry. Mean gestational age and birth weight were 31.8±4.1 weeks and 1,260±646 g for FGR-HDP and 39.2±0.8 weeks and 3,320±336 g for normal births, respectively. Abnormal umbilical artery Doppler waveforms were found in 64% of neonates with FGR-HDP. A significant percentage (86%) of FGR newborns were admitted to the neonatal intensive care unit at Gustavo Fricke hospital, Viña del Mar, Chile, with one case of death after birth. [Ca2+]i signals were measured by microfluorimetry in Fluo-3-loaded HUVECs from primary cultures. Altered [Ca2+]i signals were observed in HUVECs from FGR-HDP, where the sustained phase of ATP-induced [Ca2+]i responses was significantly reduced compared with the normotensive group. Also, the [Ca2+]i signals induced with 10 mM Ca2+ after depletion of internal Ca2+ stores were significantly higher. The present study provides a better comprehension of the role of altered cytosolic Ca2+ dynamics in endothelial dysfunction and an in vitro model to assess novel therapeutic approaches for decreasing or preventing complications in FGR-HDP.

Host cell factors involved in classical swine fever virus entry.

Classical swine fever virus (CSFV) is an ancient pathogen that continues to pose a threat to animal agriculture worldwide. The virus belongs to the genus Pestivirus and the family Flaviviridae. It causes a multisystemic disease that affects only pigs and is responsible for significant economic losses. CSFV infection is probably a multistep process that involves the proteins in the virus envelope and more than one receptor in the membrane of permissive cells. To date, the cellular receptors essential for CSFV entry and their detailed functions during this process remains unknown. All the viral envelope proteins Erns, E1 and E2 are involved in the entry process to some extent and the experimental approaches conducted until now have helped to unveil their contributions. This review aims to provide an overview of current knowledge on cellular molecules described to be involved in CSFV entry, including complement regulatory protein 46 (CD46), heparan sulphate (HS), Laminin receptor, Integrin ß3, Annexin II, MERKT and ADAM17. This knowledge would not only help to understand the molecular mechanisms involved in pestivirus infection, but also provide a rational basis for the development of nonvaccinal alternatives for CSFV control.

Heridas por proyectil de arma de fuego. Atipicidad en orificios de entrada y el fenómeno de ''cola de cometa": Reporte de caso / Gunshot wounds. Atypicality in entry holes and the "comet tail" phenomenon: Case report

El análisis de los orificios de entrada por proyectil de arma de fuego en una autopsia médico legal representa un importante papel en la determinación de la forma y causa de muerte en casos relacionados con armas de fuego. Su valoración puede proporcionar información valiosa sobre las características del arma utilizada, la distancia entre el arma de fuego y la víctima, entre otros factores que contribuyen a la investigación. El fenómeno de ''cola de cometa" observado en ciertos orificios de entrada es poco frecuente y conocido. Por lo anterior, el objetivo de este artículo es investigar las características y mecanismos de producción de los orificios de entrada con este fenómeno, proporcionando información sobre su formación, las posibles implicaciones y consideraciones médico legales a tomar en cuenta para su diagnóstico de esta causa de muerte. Se presenta un reporte de caso que destaca la descripción del fenómeno de ''cola de cometa" en una investigación forense de la vida real, proporcionando información valiosa sobre su utilidad y potencial para mejorar la precisión del análisis de heridas de bala. Se realizó revisión de artículos científicos, sobre orificios de entrada en heridas por proyectil de arma de fuego con el fenómeno de ''cola de cometa".

The analysis of firearm projectile entry holes in a medicolegal autopsy plays an important role in determining the manner and cause of death in cases involving firearms. The assessment can provide valuable information about the characteristics of the weapon used, the distance between the firearm and the victim, among other factors that contribute to the investigation. The ''comet tail" phenomenon observed in certain entry holes is rare and well known. Therefore, the objective of this article is to investigate the characteristics and mechanisms of production of the entrance orifices with this phenomenon, providing information about their formation, the possible implications, and medical-legal considerations to be taken into account for the diagnosis of this cause of death. A case report is presented highlighting the description of the ''comet tail" phenomenon in a real-life forensic investigation, providing valuable insight into its utility and potential to improve the accuracy of gunshot wound analysis. A review of scientific articles was carried out on entry holes in gunshot wounds with the "comet tail" phenomenon.

Respiratory syncytial virus entry mechanism in host cells: A general overview.

Respiratory syncytial virus (RSV) is a virus that causes acute respiratory infections in neonates and older adults. To infect host cells, the attachment glycoprotein (G) interacts with a cell surface receptor. This interaction determines the specific cell types that are susceptible to infection. RSV possesses a type I fusion protein F. Type I fusion proteins are metastable when rearrangement of the prefusion F occurs; the fusion peptide is exposed transforming the protein into postfusion form. The transition between the prefusion form and its postfusion form facilitates the viral envelope and the host cell membrane to fuse, enabling the virus to enter the host cell. Understanding the entry mechanism employed by RSV is crucial for developing effective antiviral therapies. In this review, we will discuss the various types of viral fusion proteins and explore the potential entry mechanisms utilized by RSV. A deeper understanding of these mechanisms will provide valuable insights for the development of novel approaches to treat RSV infections.

Customizably designed multibodies neutralize SARS-CoV-2 in a variant-insensitive manner.

The COVID-19 pandemic evolves constantly, requiring adaptable solutions to combat emerging SARS-CoV-2 variants. To address this, we created a pentameric scaffold based on a mammalian protein, which can be customized with up to 10 protein binding modules. This molecular scaffold spans roughly 20 nm and can simultaneously neutralize SARS-CoV-2 Spike proteins from one or multiple viral particles. Using only two different modules targeting the Spike's RBD domain, this construct outcompetes human antibodies from vaccinated individuals' serum and blocks in vitro cell attachment and pseudotyped virus entry. Additionally, the multibodies inhibit viral replication at low picomolar concentrations, regardless of the variant. This customizable multibody can be easily produced in procaryote systems, providing a new avenue for therapeutic development and detection devices, and contributing to preparedness against rapidly evolving pathogens.

Reduction of Ca2+ Entry by a Specific Block of KCa3.1 Channels Optimizes Cytotoxic Activity of NK Cells against T-ALL Jurkat Cells.

Degranulation mediated killing mechanism by NK cells is dependent on store-operated Ca2+ entry (SOCE) and has optimum at moderate intracellular Ca2+ elevations so that partial block of SOCE optimizes the killing process. In this study, we tested the effect of the selective blocker of KCa3.1 channel NS6180 on SOCE and the killing efficiency of NK cells from healthy donors and NK-92 cells against T-ALL cell line Jurkat. Patch-clamp analysis showed that only one-quarter of resting NK cells functionally express KCa3.1 current, which increases 3-fold after activation by interleukins 15 and 2. Nevertheless, blockage of KCa3.1 significantly reduced SOCE and intracellular Ca2+ rise induced by IL-15 or target cell recognition. NS6180 (1 µM) decreased NK degranulation at zero time of coculture with Jurkat cells but already after 1 h, the degranulation reached the same level as in the control. Monitoring of target cell death by flow cytometry and confocal microscopy demonstrated that NS6180 significantly improved the killing ability of NK cells after 1 h in coculture with Jurkat cells and increased the Jurkat cell fraction with apoptotic and necrotic markers. Our data evidence a strong dependence of SOCE on KCa3.1 activity in NK cells and that KCa3.1 specific block can improve NK cytotoxicity.

Effects of the Natural Flavonoid Quercetin on Arenavirus Junín Infection.

There is no specific chemotherapy approved for the treatment of pathogenic arenaviruses that cause severe hemorrhagic fever (HF) in the population of endemic regions in America and Africa. The present study reports the effects of the natural flavonoid quercetin (QUER) on the infection of A549 and Vero cells with Junín virus (JUNV), agent of the Argentine HF. By infectivity assays, a very effective dose-dependent reduction of JUNV multiplication was shown by cell pretreatment at 2-6 h prior to the infection at non-cytotoxic concentrations, with 50% effective concentration values in the range of 6.1-7.5 µg/mL. QUER was also active by post-infection treatment but with minor efficacy. Mechanistic studies indicated that QUER mainly affected the early steps of virus adsorption and internalization in the multiplication cycle of JUNV. Treatment with QUER blocked the phosphorylation of Akt without changes in the total protein expression, detected by Western blot, and the consequent perturbation of the PI3K/Akt pathway was also associated with the fluorescence redistribution from membrane to cytoplasm of TfR1, the cell receptor recognized by JUNV. Then, it appears that the cellular antiviral state, induced by QUER treatment, leads to the prevention of JUNV entry into the cell.

Allyl Isothiocianate Induces Ca2+ Signals and Nitric Oxide Release by Inducing Reactive Oxygen Species Production in the Human Cerebrovascular Endothelial Cell Line hCMEC/D3.

Nitric oxide (NO) represents a crucial mediator to regulate cerebral blood flow (CBF) in the human brain both under basal conditions and in response to somatosensory stimulation. An increase in intracellular Ca2+ concentrations ([Ca2+]i) stimulates the endothelial NO synthase to produce NO in human cerebrovascular endothelial cells. Therefore, targeting the endothelial ion channel machinery could represent a promising strategy to rescue endothelial NO signalling in traumatic brain injury and neurodegenerative disorders. Allyl isothiocyanate (AITC), a major active constituent of cruciferous vegetables, was found to increase CBF in non-human preclinical models, but it is still unknown whether it stimulates NO release in human brain capillary endothelial cells. In the present investigation, we showed that AITC evoked a Ca2+-dependent NO release in the human cerebrovascular endothelial cell line, hCMEC/D3. The Ca2+ response to AITC was shaped by both intra- and extracellular Ca2+ sources, although it was insensitive to the pharmacological blockade of transient receptor potential ankyrin 1, which is regarded to be among the main molecular targets of AITC. In accord, AITC failed to induce transmembrane currents or to elicit membrane hyperpolarization, although NS309, a selective opener of the small- and intermediate-conductance Ca2+-activated K+ channels, induced a significant membrane hyperpolarization. The AITC-evoked Ca2+ signal was triggered by the production of cytosolic, but not mitochondrial, reactive oxygen species (ROS), and was supported by store-operated Ca2+ entry (SOCE). Conversely, the Ca2+ response to AITC did not require Ca2+ mobilization from the endoplasmic reticulum, lysosomes or mitochondria. However, pharmacological manipulation revealed that AITC-dependent ROS generation inhibited plasma membrane Ca2+-ATPase (PMCA) activity, thereby attenuating Ca2+ removal across the plasma membrane and resulting in a sustained increase in [Ca2+]i. In accord, the AITC-evoked NO release was driven by ROS generation and required ROS-dependent inhibition of PMCA activity. These data suggest that AITC could be exploited to restore NO signalling and restore CBF in brain disorders that feature neurovascular dysfunction.

Purinergic Activation of Store-Operated Calcium Entry (SOCE) Regulates Cell Migration in Metastatic Ovarian Cancer Cells.

Store-operated calcium entry (SOCE) is an important process in calcium signaling. Its role in physiological and pathological events is well recognized. However, in cancerous systems, the importance of SOCE in relation to the degree of cancer aggressiveness, as well as its regulation by ligands such as purinergic molecules, are not well documented. This study aimed to characterize a differential effect of the P2Y2 receptor (promoted by UTP of 10 µM and inhibited by ARC118925XX of 1 µM) on intracellular calcium response between metastatic (SKOV-3) and non-metastatic (CAOV-3) ovarian cell lines in conditions of normal (1.5 mM) and zero extracellular calcium concentration. The sustained calcium influx observed exclusively in SKOV-3 cells was associated with the presence of SOCE (promoted by thapsigargin (74.81 ± 0.94 ΔF) and sensitive to 2-APB (20.60 ± 0.85 ΔF)), whereas its absence in CAOV-3 cells (26.2 ± 6.1 ΔF) was correlated with a low expression of ORAI1. The relevance of SOCE in metastatic SKOV-3 cells was further corroborated when 2-APB significantly inhibited (40.4 ± 2.8% of covered area) UTP-induced cell migration (54.6 ± 3.7% of covered area). In conclusion, our data suggest that SOCE activation elicited by the P2Y2 receptor is involved in the aggressiveness of ovarian cancer cells.

Inhibitors Targeting Hepatitis C Virus (HCV) Entry.

Infections caused by the Hepatitis C virus (HCV) affect around 70 million people worldwide, leading to serious liver problems, such as fibrosis, steatosis, and cirrhosis, in addition to progressing to hepatocellular carcinoma and becoming globally the main cause of liver disease. Despite great therapeutic advances in obtaining pan-genotypic direct-acting antivirals (DAAs), around 5-10% of affected individuals are unable to eliminate the virus by their own immune system's activity. Still, there are no licensed vaccines so far. In this context, the orchestrated process of virus entry into host cells is a crucial step in the life cycle and the infectivity capability of most viruses. In recent years, the entry of viruses has become one of the main druggable targets used for designing effective antiviral molecules. This goal has come to be widely studied to develop pharmacotherapeutic strategies against HCV, combined or not with DAAs in multitarget approaches. Among the inhibitors found in the literature, ITX 5061 corresponds to the most effective one, with EC50 and CC50 values of 0.25 nM and >10 µM (SI: 10,000), respectively. This SRBI antagonist completed the phase I trial, constituting a promising compound against HCV. Interestingly, chlorcyclizine (an antihistamine drug) showed action both in E1 apolipoproteins (EC50 and CC50 values of 0.0331 and 25.1 µM, respectively), as well as in NPC1L1 (IC50 and CC50 values of 2.3 nM and > 15 µM, respectively). Thus, this review will discuss promising inhibitors targeting HCV entry, discussing their SAR analyzes, recent contributions, and advances in this field.

Predictors of Nursing Home Entry within 36 Months after Hospitalization via the Emergency Department among Persons Aged 75 Years or Older.

OBJECTIVE: We aimed to identify risk factors for nursing home (NH) entry 36 months after hospitalization via the emergency department (ED) in a population of patients aged 75 years or older. METHODS: This was a prospective multicentre cohort. Patients were recruited from the emergency departments (EDs) of nine hospitals. Subjects had been hospitalised in a medical ward in the same hospital as the ED to which they were initially admitted. Subjects who experienced NH entry prior to ED admission were excluded. NH entry has been defined as the incident admission either into an NH or other long-term care facility within the follow-up period. Variables from a comprehensive geriatric assessment of patients were entered into a Cox model with competing risks to predict NH entry during 3 years of follow-up. RESULTS: Among 1306 patients included in the SAFES cohort, 218 (16.7%) who were already in an NH were excluded. The remaining 1088 patients included in the analysis were aged 84 ± 6 years on average. During 3 years of follow-up, 340 (31.3%) entered an NH. The independent risk factors for NH entry were that they: living alone (Hazard ratio (HR) 2.00, had a 95% confidence interval (CI) 1.59-2.54, p < 0.0001), could not independently perform activities of daily living (HR 1.81, 95% CI 1.24-2.64, p = 0.002), and had balance disorders (HR 1.37, 95% CI 1.09-1.73, p = 0.007), dementia syndrome (HR 1.80, 95% CI 1.42-2.29, p < 0.0001) and a risk of pressure ulcers (HR 1.42, 95% CI 1.10-1.82, p = 0.006). CONCLUSION: The majority of the risk factors for NH entry within 3 years after emergency hospitalization are amenable to intervention strategies. It is therefore reasonable to imagine that targeting these features of frailty could delay or prevent NH entry and improve the quality of life of these individuals before and after NH entry.

Attitudes towards HPV and COVID school-entry policies among adults living in Puerto Rico.

Prior to the COVID pandemic, Puerto Rico (PR) had one of the highest Human Papillomavirus (HPV) vaccine rates in the United States. The COVID pandemic and administration of COVID vaccines might have impacted attitudes toward HPV vaccination. This study compared attitudes toward HPV and COVID vaccines with respect to school-entry policies among adults living in PR. A convenience sample of 222 adults (≥21 years old) completed an online survey from November 2021 to January 2022. Participants answered questions about HPV and COVID vaccines, attitudes toward vaccination policies for school-entry, and perceptions of sources of information. We assessed the magnitude of association between the agreement of school-entry policies for COVID and HPV vaccination by estimating the prevalence ratio (PRadjusted) with 95% Confidence Intervals (95% CI). The most trusted source of information for HPV and COVID vaccines were healthcare providers (42% and 17%, respectively) and the CDC (35% and 55%, respectively), while the least trusted were social media (40% and 39%, respectively), and friends and family (23% n = 47, and 17% n = 33, respectively). Most participants agreed that HPV (76% n = 156) and COVID vaccines (69% n = 136) should be a school-entry requirement. Agreement with school policy requiring COVID vaccination was significantly associated with agreement of school policy requiring HPV vaccination (PRadjusted:1.96; 95% CI:1.48-2.61) after controlling for potential confounders. Adults living in PR have an overall positive attitude about mandatory HPV and COVID vaccination school-entry policies, which are interrelated. Further research should elucidate the implications of the COVID pandemic on HPV vaccine attitudes and adherence rates.

Effect of computerized physician order entry inactivation to order complementary studies in an emergency department / [Efecto de la inactivación de las órdenes múltiples para solicitud de estudios complementarios en una central de emergencias.]

Introduction: The computerized provider order entry (CPOE) is a computing tool that could lead to unintended consequences despite its myriad benefits. We aimed to explore the effect of its inactivation on requests for complementary studies and the associated costs. Methods: Cross sectional study at the Emergency Department of Hospital Italiano de Buenos Aires, which included a consecutive sample of pre-intervention (January-February 2020) and post-intervention (2021) consultations. Using secondary bases, the variables included were administrative debits and their respective billing prices. Results: There were 27,671 consultations in 2020 with a total median value of $474, and 20,819 with $1,639 in 2021. After the analysis restricted to the area of ​​moderately complex clinics (excluding COVID-19 consultations), the following was found: a decrease in the median number of practices per consultation (median of 11 vs. 10, p=0.001), a decrease in the request for at least one laboratory practice (45% vs. 39%, p=0.001), without finding significant changes in global costs (median $1,419 vs. $1,081; p=0.122) or in specific laboratory costs (median $1,071 vs. $1,089, p=0.710). Conclusion: Despite inflation, a significant reduction in the number of practices was achieved and overall costs per consultation were maintained. These findings demonstrate the effectiveness of the intervention, but an educational intervention aimed at reminding the potential harm of overuse and the health costs of unnecessary studies will be necessary.

Introducción: La plantilla de órdenes múltiples es una herramienta informática que podría producir consecuencias inadvertidas pese a sus innumerables beneficios. Nos propusimos explorar el efecto de su inactivación sobre las solicitudes de estudios complementarios y los costos asociados. Métodos: Corte transversal en la Central de Emergencias de Adultos del Hospital Italiano de Buenos Aires, que incluyó muestra consecutiva de consultas pre-intervención (Enero-Febrero 2020) y post-intervención (2021). Mediante el uso de bases secundarias, las variables incluidas fueron los débitos administrativos y sus respectivos precios de facturación. Resultados: Hubo 27.671 consultas en 2020 con una mediana de valor total de 474$, y 20.819 con 1.639$ en 2021. Tras el análisis restringido al área de consultorios de moderada complejidad (excluyendo consultas por COVID-19), se encontró: una disminución en la mediana del número de prácticas por consulta (mediana de 11 vs 10, p=0,001), una disminución en la solicitud de al menos una práctica de laboratorio (45% versus 39%, p=0,001), sin encontrar cambios significativos en costos globales (mediana 1.419$ vs 1.081$; p=0,122) ni en costos específicos de laboratorio (mediana 1.071$ vs 1.089$, p=0,710). Conclusión: Pese a la inflación interanual, se logró una reducción significativa en el número de prácticas y se mantuvieron los costos globales por consulta. Estos hallazgos demuestran la efectividad de la intervención, pero serán necesarias medidas educativas que apunten al recordatorio de los potenciales daños en la sobreutilización, y los costos sanitarios de los estudios innecesarios.

The Cytoplasmic Region of SARAF Reduces Triple-Negative Breast Cancer Metastasis through the Regulation of Store-Operated Calcium Entry.

Triple-negative breast cancer has a poor prognosis and is non-responsive to first-line therapies; hence, new therapeutic strategies are needed. Enhanced store-operated Ca2+ entry (SOCE) has been widely described as a contributing factor to tumorigenic behavior in several tumor types, particularly in breast cancer cells. SOCE-associated regulatory factor (SARAF) acts as an inhibitor of the SOCE response and, therefore, can be a potential antitumor factor. Herein, we generated a C-terminal SARAF fragment to evaluate the effect of overexpression of this peptide on the malignancy of triple-negative breast cancer cell lines. Using both in vitro and in vivo approaches, we showed that overexpression of the C-terminal SARAF fragment reduced proliferation, cell migration, and the invasion of murine and human breast cancer cells by decreasing the SOCE response. Our data suggest that regulating the activity of the SOCE response via SARAF activity might constitute the basis for further alternative therapeutic strategies for triple-negative breast cancer.