Genomic Convergence in Hibernating Mammals Elucidates the Genetics of Metabolic Regulation in the Hypothalamus.

Elucidating the genetic basis of mammalian metabolism could help define mechanisms central to health and disease. Here, we define conserved cis-regulatory elements (CREs) and programs for mammalian metabolic control. We delineate gene expression and chromatin responses in the mouse hypothalamus for 7 steps of the Fed-to-Fasted-to-Refed (FFR) response process. Comparative genomics of hibernating versus non-hibernating lineages then illuminates cis-elements showing convergent changes in hibernators. Hibernators accumulated loss-of-function effects for specific CREs regulating hypothalamic FFR responses. Multi-omics approaches pinpoint key CREs, genes, regulatory programs, and cell types in the divergence of hibernating and homeothermic lineages. The refeeding period after extended fasting is revealed as one critical period of chromatin remodeling with convergent genomic changes. This genetic framework is a step toward harnessing hibernator adaptations in medicine.

Conserved Noncoding Cis-Elements Associated with Hibernation Modulate Metabolic and Behavioral Adaptations in Mice.

Our study elucidates functional roles for conserved cis-elements associated with the evolution of mammalian hibernation. Genomic analyses found topologically associated domains (TADs) that disproportionately accumulated convergent genomic changes in hibernators, including the TAD for the Fat Mass & Obesity (Fto) locus. Some hibernation-linked cis-elements in this TAD form regulatory contacts with multiple neighboring genes. Knockout mice for these cis-elements exhibit Fto, Irx3, and Irx5 gene expression changes, impacting hundreds of genes downstream. Profiles of pre-torpor, torpor, and post-torpor phenotypes found distinct roles for each cis-element in metabolic control, while a high caloric diet uncovered different obesogenic effects. One cis-element promoting a lean phenotype influences foraging behaviors throughout life, affecting specific behavioral sequences. Thus, convergent evolution in hibernators pinpoints functional genetic mechanisms of mammalian metabolic control.

The modulation of the hexosamine biosynthetic pathway impacts the localization of CD36 in macrophages.

CD36 is a type 2 cell surface scavenger receptor expressed in various tissues. In macrophages, CD36 recognizes oxidized low-density lipoprotein (ox-LDL), which promotes the formation of foam cells, the first step toward an atherosclerotic arterial lesion. CD36 possesses a variety of posttranslational modifications, among them N-glycosylation and O-GlcNAc modification. Some of the roles of these modifications on CD36 are known, such as N-linked glycosylation, which provides proper folding and trafficking to the plasma membrane in the human embryonic kidney. This study aimed to determine whether variations in the availability of UDP-GlcNAc could impact Rab-5-mediated endocytic trafficking and, therefore, the cellular localization of CD36. These preliminary results suggest that the availability of the substrate UDP-GlcNAc, modulated in response to treatment with Thiamet G (TMG), OSMI-1 (O-GlcNAcylation enzymes modulators) or Azaserine (HBP modulator), influences the localization of CD36 in J774 macrophages, and the endocytic trafficking as evidenced by the regulatory protein Rab-5, between the plasma membrane and the cytoplasm.

Identifying genomic variant associated with long QT syndrome type 2 in an ecuadorian mestizo individual: a case report.

Introduction: Long QT syndrome (LQTS) is an autosomal dominant inherited cardiac condition characterized by a QT interval prolongation and risk of sudden death. There are 17 subtypes of this syndrome associated with genetic variants in 11 genes. The second most common is type 2, caused by a mutation in the KCNH2 gene, which is part of the potassium channel and influences the final repolarization of the ventricular action potential. This case report presents an Ecuadorian teen with congenital Long QT Syndrome type 2 (OMIM ID: 613688), from a family without cardiac diseases or sudden cardiac death backgrounds. Case presentation: A 14-year-old girl with syncope, normal echocardiogram, and an irregular electrocardiogram was diagnosed with LQTS. Moreover, by performing Next-Generation Sequencing, a pathogenic variant in the KCNH2 gene p.(Ala614Val) (ClinVar ID: VCV000029777.14) associated with LQTS type 2, and two variants of uncertain significance in the AKAP9 p.(Arg1654GlyfsTer23) (rs779447911), and TTN p. (Arg34653Cys) (ClinVar ID: VCV001475968.4) genes were identified. Furthermore, ancestry analysis showed a mainly Native American proportion. Conclusion: Based on the genomic results, the patient was identified to have a high-risk profile, and an implantable cardioverter defibrillator was selected as the best treatment option, highlighting the importance of including both the clinical and genomics aspects for an integral diagnosis.

Exploring the Nature of Arhopalus ferus (Coleoptera: Cerambycidae: Spondylidinae) Pheromone Attraction.

Cerambycid species of the Spondylidinae subfamily are distributed worldwide and are known for being prolific invaders that infest conifers. In New Zealand, Arhopalus ferus (Mulsant), the burnt pine longhorn beetle, is well-established and requires monitoring at high-risk sites such as ports, airports, and sawmills as part of the requirements to meet pine log export standards set by the New Zealand Ministry of Primary Industries (MPI). Currently, its surveillance relies on traps baited with host volatiles (i.e., ethanol and α-pinene). We used volatile collections from adult beetles, electroantennograms, and field trapping bioassays to identify the pheromones emitted by the burnt pine longhorn beetle A. ferus and their effects on its behaviour. We show that A. ferus males emit mainly (E)-fuscumol and geranylacetone, as well as the minor components, α-terpinene and p-mentha-1,3,8-triene, and that all four compounds elicit a dose-dependent response in antennae of both sexes. Traps baited with the binary combination of geranylacetone plus fuscumol captured significantly more female A. ferus than did unbaited traps in two of three field experiments. α-Terpinene did not affect A. ferus trap catches and effects of p-mentha-1,3,8-triene on trap catch were not determined. Our findings provide further evidence of the use of fuscumol and geranylacetone as aggregation-sex pheromones by longhorn beetles in the Spondylidinae subfamily, and suggest that their deployment in survey traps may improve the efficacy of A. ferus monitoring in New Zealand and elsewhere.

TATA-Binding Protein-Based Virtual Screening of FDA Drugs Identified New Anti-Giardiasis Agents.

Parasitic diseases, predominantly prevalent in developing countries, are increasingly spreading to high-income nations due to shifting migration patterns. The World Health Organization (WHO) estimates approximately 300 million annual cases of giardiasis. The emergence of drug resistance and associated side effects necessitates urgent research to address this growing health concern. In this study, we evaluated over eleven thousand pharmacological compounds sourced from the FDA database to assess their impact on the TATA-binding protein (TBP) of the early diverging protist Giardia lamblia, which holds medical significance. We identified a selection of potential pharmacological compounds for combating this parasitic disease through in silico analysis, employing molecular modeling techniques such as homology modeling, molecular docking, and molecular dynamics simulations. Notably, our findings highlight compounds DB07352 and DB08399 as promising candidates for inhibiting the TBP of Giardia lamblia. Also, these compounds and DB15584 demonstrated high efficacy against trophozoites in vitro. In summary, this study identifies compounds with the potential to combat giardiasis, offering the prospect of specific therapies and providing a robust foundation for future research.

Associations between repetitive head impact exposure and midlife mental health wellbeing in former amateur athletes.

Introduction: Repetitive head impacts (RHI) have been suggested to increase the risk of developing a neurodegenerative disease, and many of these individuals develop a preceding mental health diagnosis. Given the lack of studies among amateur athletes, this study aimed to examine mental health outcomes in middle-aged amateur athletes who have been exposed to RHI through contact sport participation. Methods: This is a single site, cohort study involving former amateur athletes aged between 30 and 60 with at least 10 years of organized contact or non-contact sport participation. All participants completed demographic and mental health questionnaires. Mental health outcomes included symptoms related to depression, anxiety, post-traumatic stress disorder (PTSD), attention deficit hyperactive disorder (ADHD), and aggression. Self-reported data on mental health diagnoses and associated prescription were elicited and used to estimate odds ratios (OR). Results: Data from 41 contact athletes and 22 age/sex-matched non-contact athletes were available for analysis. The contact group exhibited a 2.25-fold higher likelihood of being diagnosed with mental health disorders and 1.29-fold higher likelihood of using associated medications compared to the non-contact group. The contact group reported significantly higher PTSD-related symptoms [4.61 (0.03,9.2), p=0.05] compared to the non-contact control group. While not statistically significant, the contact group showed increased depressive [2.37 (0.05, 4.79), p=0.07] and ADHD symptoms [4.53 (0.51, 9.57), p=0.08] compared to controls. In a secondary analysis, a distinct trend emerged within the contact group, revealing pronounced elevations in mental health symptoms among individuals with lower socioeconomic status (<$50,000/year) compared to higher income subgroups, and these symptoms decreased as income levels rose [depression: -3.08 (-4.47, -1.7), p<0.001; anxiety: -1.95 (-3.15, -0.76), p=0.002; ADHD: -4.99 (-8.28, -1.69), p=0.004; PTSD: -4.42 (-7.28, -1.57), p=0.003; aggression: -6.19 (-11.02, -1.36), p=0.01]. This trend was absent in the non-contact control group. Discussion: Our data suggest that even individuals at the amateur level of contact sports have an increased likelihood of being diagnosed with mental health disorders or experiencing mental health symptoms compared to non-contact athletes. Our findings indicate that socioeconomic status may have an interactive effect on individuals' mental health, particularly among those with a long history of RHI exposure.

The Impact of Sex on Antiplatelet and Anticoagulant Thromboprophylaxis in Patients with Peripheral Artery Disease Post-revascularization.

OBJECTIVE: The aim of this prospective study was to 1) objectively quantify the impact of sex on platelet function in patients with PAD taking antiplatelet and anticoagulant medications and 2) to develop and test a personalized, iterative algorithm which personalizes thromboprophylaxis that incorporates platelet function testing. SUMMARY BACKGROUND DATA: Women with Peripheral Artery Disease (PAD) have worse outcomes as compared to their male counterparts in spite of having lower risk factors. This health disparity may be mitigated by personalizing thromboprophylaxis regimens. METHODS: Patients undergoing revascularization were enrolled. Serial thromboelastography (TEG) and TEG with Platelet Mapping (TEG-PM) was performed up to 6-months post-operatively to determine objective coagulation profiles. In a subset of patients, the Antiplatelet Coagulation Exactness (ACE) algorithm was implemented where patients were iteratively evaluated with TEG and given antiplatelet medications to maintain platelet inhibition at >29%. Statistical analysis was performed using unpaired t-test, ANOVA and Fisher's exact test. RESULTS: One hundred and eighty-one patients met study criteria. 58(32%) patients were females and 123(68%) were males. In the Aspirin cohort, females showed significantly greater clot strength as Maximum Amplitude - Arachidonic Acid (MAAA) and significantly lower platelet inhibition than males: [37.26 vs.32.38, P<0.01] and [52.95% vs.61.65%, P<0.05], respectively. In the Clopidogrel cohort, females showed higher Maximum Amplitude - Adenosine Diphosphate (MAADP) [42.58 vs.40.35, P=NS] compared to males. Females on dual antiplatelet therapy had higher MAADP [39.74 vs.35.07, P=NS] and lower platelet inhibition [45.25% vs.54.99%, P=NS] than males. The incidence of thrombosis of the revascularized segment, defined as thrombotic event, was objectively identified on an arterial duplex. Women showed significantly higher thrombotic events than men [22.95% vs.10.57%, P<0.05] on the same medication. In our pilot study, implementation of the ACE algorithm led to a significant decrease in the thrombosis rate (3%), including non-thrombotic events for females, vs. the historic thrombotic rate (22%) from our institution. CONCLUSIONS: Women with PAD exhibited higher platelet reactivity, clot strength, and reduced platelet inhibition in response to antiplatelet therapy. The use of the ACE algorithm to tailor antiplatelet medication in patients with PAD post-revascularization, resulted in a significant decrease in thrombotic event rates. This may serve as an opportune way to mitigate outcome sex-specific disparities caused by inadequate thromboprophylaxis in women.

In vitro and In vivo Biological Activity of Two Aryloxy-naphthoquinones in Mice Infected with Trypanosoma cruzi Strains.

BACKGROUND: Chagas disease, a condition caused by Trypanosoma cruzi, is an endemic disease in Latin American countries that affects approximately eight million people worldwide. It is a continuing public health problem. As nifurtimox and benznidazole are the two pharmacological treatments currently used to treat it, the present research proposes new therapeutic alternatives. Previous studies conducted on naphthoquinone derivatives have found interesting trypanocidal effects on epimastigotes, with the molecules 2-phenoxy-1,4-naphthoquinone (IC50= 50 nM and SI < 250) and 2-(3-nitrophenoxy)-naphthalene-1,4-dione (IC50= 20 nM y SI=625) presenting the best biological activity. METHOD: The present study evaluated the efficacy of in vitro, ex vivo and in vivo models of two aryloxyquinones, 2-phenoxy-1,4-naphthoquinone (1) and 2-(3-nitrophenoxy)-naphthalene-1,4- dione (2), against two Mexican T. cruzi strains in both their epimastigote and blood Trypomastigote stage. Both compounds were evaluated against T. cruzi using a mouse model (CD1) infected with Mexican isolates of T. cruzi, nifurtimox and benznidazole used as control drugs. Finally, the cytotoxicity of the two compounds against the J774.2 mouse macrophage cell line was also determined. RESULT: The in vitro and in vivo results obtained indicated that both quinones were more active than the reference drugs. Compound 1 presents in vivo activity, showing up to 40% parasite reduction after 8 h of administration, a finding which is 1.25 times more effective than the results obtained using nifurtimox. CONCLUSION: These are encouraging results for proposing new naphthoquinone derivatives with potential anti-T. cruzi activity.

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.

Protective role of 17ß-estradiol in alcohol-associated liver fibrosis is mediated by suppression of integrin signaling.

BACKGROUND: Alcohol-associated liver disease is a complex disease regulated by genetic and environmental factors such as diet and sex. The combination of high-fat diet and alcohol consumption has synergistic effects on liver disease progression. Female sex hormones are known to protect females from liver disease induced by high-fat diet. In contrast, they promote alcohol-mediated liver injury. We aimed to define the role of female sex hormones on liver disease induced by a combination of high-fat diet and alcohol. METHODS: Wild-type and protein arginine methyltransferase (Prmt)6 knockout female mice were subjected to gonadectomy (ovariectomy, OVX) or sham surgeries and then fed western diet and alcohol in the drinking water. RESULTS: We found that female sex hormones protected mice from western diet/alcohol-induced weight gain, liver steatosis, injury, and fibrosis. Our data suggest that these changes are, in part, mediated by estrogen-mediated induction of arginine methyltransferase PRMT6. Liver proteome changes induced by OVX strongly correlated with changes induced by Prmt6 knockout. Using Prmt6 knockout mice, we confirmed that OVX-mediated weight gain, steatosis, and injury are PRMT6 dependent, while OVX-induced liver fibrosis is PRMT6 independent. Proteomic and gene expression analyses revealed that estrogen signaling suppressed the expression of several components of the integrin pathway, thus reducing integrin-mediated proinflammatory (Tnf, Il6) and profibrotic (Tgfb1, Col1a1) gene expression independent of PRMT6 levels. Integrin signaling inhibition using Arg-Gly-Asp peptides reduced proinflammatory and profibrotic gene expression in mice, suggesting that integrin suppression by estrogen is protective against fibrosis development. CONCLUSIONS: Taken together, estrogen signaling protects mice from liver disease induced by a combination of alcohol and high-fat diet through upregulation of Prmt6 and suppression of integrin signaling.

Escarlatina estafilocócica como complicación de quemadura por contacto

El Staphylococcus aureus causa una variedad de infecciones localizadas e invasivas supurativas y 3 síndromes mediados por toxinas: Síndrome de choque tóxico estafilocócico (STSS, por sus siglas en ingles), síndrome de piel escaldada estafilocócica (SSSS) e intoxicación alimentaria1. La escarlatina estafilocócica está relacionada con las toxinas del STSS y SSSS. De hecho, se pudieron describir dos síndromes diferentes cada uno relacionado a un tipo de toxina que eran formas atenuadas de estas entidades. El curso de esta patología generalmente es autolimitado, pero puede evolucionar rápidamente a enfermedad severa que ponga en peligro la vida. Un entendimiento de este conjunto de patologías nos permite abordar al paciente de una manera oportuna, manteniendo la vigilancia y en caso de ser necesario intervenir para evitar el advenimiento del STSS que puede desembocar en falla orgánica múltiple e incluso la muerte. Esta revisión se trata de un caso atendido en la unidad de quemados del Hospital del Niño Dr. José Renán Esquivel (HDNJRE) en el mes de mayo del 2023 con quemadura por contacto complicada con escarlatina estafilocócica. (provisto por Infomedic International)

Staphylococcus aureus causes a variety of localized and invasive suppurative infections and 3 toxin-mediated syndromes: staphylococcal toxic shock syndrome (STSS), staphylococcal scalded skin syndrome (SSSS) and food poisoning1 . Staphylococcal scarlet fever is related to STSS and SSSS toxins. In fact, two different syndromes each related to a type of toxin could be described which were attenuated forms of these entities. The course of this pathology is usually self-limiting, but can rapidly progress to severe life-threatening disease. An understanding of this set of pathologies allows us to approach the patient in a timely manner, maintaining vigilance and if necessary intervening to prevent the advent of STSS that can lead to multiple organ failure and even death. This review is about a case treated at the burn unit of the Hospital del Niño Dr. José Renán Esquivel (HDNJRE) in May 2023 with contact burn complicated by staphylococcal scarlet fever. (provided by Infomedic International)

Genomic Surveillance of SARS-CoV-2 Sequence Variants at Universities in Southwest Idaho.

Although the impact of the SARS-CoV-2 pandemic on major metropolitan areas is broadly reported and readily available, regions with lower populations and more remote areas in the United States are understudied. The objective of this study is to determine the progression of SARS-CoV-2 sequence variants in a frontier and remote intermountain west state among university-associated communities. This study was conducted at two intermountain west universities from 2020 to 2022. Positive SARS-CoV-2 samples were confirmed by quantitative real-time reverse transcription-polymerase chain reaction and variants were identified by the next-generation sequencing of viral genomes. Positive results were obtained for 5355 samples, representing a positivity rate of 3.5% overall. The median age was 22 years. Viral genomic sequence data were analyzed for 1717 samples and phylogeny was presented. Associations between viral variants, age, sex, and reported symptoms among 1522 samples indicated a significant association between age and the Delta variant (B 1.167.2), consistent with the findings for other regions. An outbreak event of AY122 was detected August-October 2021. A 2-month delay was observed with respect to the timing of the first documented viral infection within this region compared to major metropolitan regions of the US.

Ecoepidemiology of Chagas Disease in a Biological Corridor in Southeastern Mexico: A Promising Approach to Understand the Risk of Chagas Disease.

Ecoepidemiology is an emerging field that attempts to explain how biotic, environmental, and even social factors influence the dynamics of infectious diseases. Particularly in vector-borne diseases, the study under this approach offers us an overview of the pathogens, vectors, and hosts that coexist in a given region and their ecological determinants. As a result of this, risk predictions can be established in a changing environment and how it may impact human populations. This paper is aimed at evaluating some ecoepidemiological characteristics of Chagas disease in a natural reserve in southeastern Mexico that borders human settlements. We carry out a cross-sectional study in 2022 where we search insects manually and with light traps. We set traps for small mammals and bats and conducted interviews with the inhabitants living around the study site. We identified the presence of Triatoma dimidiata and T. huehuetenanguensis species with a percentage of TcI T. cruzi infection of 68.4% (95% CI: 66.9-69.9). Temperature and humidity were not determining factors for the probability of insect capture. Of the 108 wild mammals (Chiroptera, Rodentia, and Didelphimorphia), none was infected with T. cruzi. Knowledge about Chagas disease in nearby inhabitants is poor, and some characteristics were found on the periphery of dwellings that could offer a refuge for insect vectors. With this information, surveillance strategies can be generated in the study area that reduce the risk of transmission of T. cruzi parasite to humans, and it is expected to motivate the use of this field in future research.

A Study on the Efficacy and Safety of Pipeline Shield Stents and Nonmodified Surface Flow-Diverting Stents in Patients with Intracranial Aneurysms.

BACKGROUND: Few studies have compared the Pipeline Shield stents with previous generations of flow-diverting stents (FDSs) for the treatment of unruptured intracranial aneurysms. This study aimed to evaluate the efficacy and safety of Pipeline Shield stents and FDSs without modified surfaces. METHODS: The present evaluation is a retrospective cohort study of patients endovascularly treated with Pipeline Shield stents or FDSs without modified surfaces for unruptured intracranial aneurysms between January 2014 and June 2022. The data analyzed were obtained from the anonymized database of our institution's interventional radiology service. RESULTS: A total of 147 patients with 155 unruptured intracranial aneurysms were included. Of the 155 aneurysms, 96 were treated with Pipeline Shield stents and 59 with FDSs without modified surfaces. The aneurysms treated with Pipeline Shield stents had higher 6-month (O'Kelly-Marotta [OKM] D; 87.5% vs. 71.4%; P = 0.025) and 1-year (OKM D; 82.5% vs. 63.0%; P = 0.047) occlusion rates than the aneurysms treated using FDSs without modified surfaces. No differences between the devices were found at the 1-year follow-up in the incidence of ischemic stroke (P = 0.939) or hemorrhagic complications (P = 0.559). CONCLUSIONS: Pipeline Shield stents demonstrated superior complete occlusion rates (OKM D) at both the 6-month and the 1-year follow-up assessments compared with nonmodified surface FDSs. No significant differences were found in the safety profiles between the 2 types of stents with regard to thromboembolic complications and ischemic events. Further research with larger study populations is necessary to validate these findings.

Structure-based Virtual Screening from Natural Products as Inhibitors of SARS-CoV-2 Spike Protein and ACE2 Receptor Binding and their Biological Evaluation In vitro.

BACKGROUND: In the last years, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused more than 760 million infections and 6.9 million deaths. Currently, remains a public health problem with limited pharmacological treatments. Among the virus drug targets, the SARS-CoV-2 spike protein attracts the development of new anti-SARS-CoV-2 agents. OBJECTIVE: The aim of this work was to identify new compounds derived from natural products (BIOFACQUIM and Selleckchem databases) as potential inhibitors of the spike receptor binding domain (RBD)-ACE2 binding complex. METHODS: Molecular docking, molecular dynamics simulations, and ADME-Tox analysis were performed to screen and select the potential inhibitors. ELISA-based enzyme assay was done to confirm our predictive model. RESULTS: Twenty compounds were identified as potential binders of RBD of the spike protein. In vitro assay showed compound B-8 caused 48% inhibition at 50 µM, and their binding pattern exhibited interactions via hydrogen bonds with the key amino acid residues present on the RBD. CONCLUSION: Compound B-8 can be used as a scaffold to develop new and more efficient antiviral drugs.

Characterization of the Effect of N-(2-Methoxyphenyl)-1-methyl-1H-benzimidazol-2-amine, Compound 8, against Leishmania mexicana and Its In Vivo Leishmanicidal Activity.

Chemotherapy currently available for leishmaniasis treatment has many adverse side effects and drug resistance. Therefore, the identification of new targets and the development of new drugs are urgently needed. Previously, we reported the synthesis of a N-(2-methoxyphenyl)-1-methyl-1H-benzimidazol-2-amine, named compound 8, with an IC50 value in the micromolar range against L. mexicana, it also inhibited 68.27% the activity of recombinant L. mexicana arginase. Herein, we report studies carried out to characterize the mechanism of action of compound 8, as well as its in vivo leishmanicidal activity. It was shown in our ultrastructural studies that compound 8 induces several changes, such as membrane blebbing, the presence of autophagosomes, membrane detachment and mitochondrial and kinetoplast disorganization, among others. Compound 8 triggers the production of ROS and parasite apoptosis. It reduced 71% of the parasite load of L. mexicana in an experimental model of cutaneous leishmaniasis in comparison with a control. Altogether, the data obtained suggest the potential use of compound 8 in the treatment of cutaneous leishmaniasis.

Application of neural networks for the detection of oral cancer: A systematic review.

One potential application of neural networks (NNs) is the early-stage detection of oral cancer. This systematic review aimed to determine the level of evidence on the sensitivity and specificity of NNs for the detection of oral cancer, following the Preferred Reporting Items for Systematic Reviews and MetaAnalyses (PRISMA) and Cochrane guidelines. Literature sources included PubMed, ClinicalTrials, Scopus, Google Scholar, and Web of Science. In addition, the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool was used to assess the risk of bias and the quality of the studies. Only 9 studies fully met the eligibility criteria. In most studies, NNs showed accuracy greater than 85%, though 100% of the studies presented a high risk of bias, and 33% showed high applicability concerns. Nonetheless, the included studies demonstrated that NNs were useful in the detection of oral cancer. However, studies of higher quality, with an adequate methodology, a low risk of bias and no applicability concerns are required so that more robust conclusions could be reached.

Safety and Efficacy of Endovascular Coils and Non-Flow-Diverting Stents for Management of Unruptured Intracranial Aneurysms: A Location-Specific Outcomes Analysis.

INTRODUCTION: The relationship between the anatomical location of an unruptured saccular aneurysm, the efficacy, and the potential complications associated with coil and non-flow-diverting stents remains poorly documented. Therefore, the aim of this study is to evaluate the efficacy and safety of endovascular treatment based on the anatomical position of the unruptured intracranial aneurysm (UIA). METHODS: A retrospective cohort study was conducted using an anonymized database of patients who underwent endovascular therapy for UIAs between 2014 and 2021. RESULTS: A total of 138 patients with 147 UIAs were included. Immediate Raymond-Roy occlusion class I or II was achieved in 99.2% of patients in all anatomical locations, with a 96.2% occlusion rate at the 12-month follow-up. Complications occurred more frequently in the anterior cerebral artery (35%) and internal carotid artery in its ophthalmic segment (25%). However, the difference was not statistically significant. CONCLUSIONS: Our study shows that endovascular treatment with stents and coils is effective and safe for managing UIAs in various anatomical locations. The incidence of thromboembolic complications was significantly higher for UIAs located in the anterior cerebral artery.

Veteran Caretaker Perspectives of the Need for Childcare Assistance During Health Care Appointments.

PURPOSE: In 2020, Congress passed legislation to establish the national Veterans Child Care Assistance Program (VCAP) targeting eligible veterans receiving care through the Veterans Health Administration (VA). This needs assessment describes the childcare needs of veteran caretakers of young children and explores the implications of inadequate childcare on health care engagement. METHODS: Survey data were collected from 2,000 VA users with dependent children; data were analyzed using standard descriptive statistics. Qualitative data were collected from 19 veterans through focus groups and analyzed using rapid thematic analysis. FINDINGS: More than 75% of veterans surveyed indicated that they required childcare assistance during health care appointments and 73% reported barriers to finding childcare. Prominent barriers included the high cost of childcare and not having a trusted source of childcare. Nearly 58% of survey respondents reported missed or canceled VA health care appointments due to childcare challenges. Furthermore, 35% of surveyed veterans reported that their children had accompanied them to an appointment in the past year. Among these veterans, 59% brought their children into the exam room. Focus group participants discussed how having children present during their health care appointments hampered communication with health care providers. CONCLUSIONS: Veterans report that lack of childcare keeps them from attending and remaining focused on the provider during their health care visits, which could compromise quality of care. As one of the only health systems in the United States that will offer childcare assistance, VCAP presents an opportunity to improve health care access and quality by reducing missed appointments and suboptimal care.