The inhibitory and transcriptional effects of the epigenetic repurposed drugs hydralazine and valproate in lymphoma cells.

Lymphoma is a disease that affects countless lives each year. In order to combat this disease, researchers have been exploring the potential of DNMTi and HDACi drugs. These drugs target the cellular processes that contribute to lymphomagenesis and treatment resistance. Our research evaluated the effectiveness of a combination of two such drugs, hydralazine (DNMTi) and valproate (HDACi), in B-cell and T-cell lymphoma cell lines. Here we show that the combination of hydralazine and valproate decreased the viability of cells over time, leading to the arrest of cell-cycle and apoptosis in both B and T-cells. This combination of drugs proved to be synergistic, with each drug showing significant growth inhibition individually. Microarray analyses of HuT 78 and Raji cells showed that the combination of hydralazine and valproate resulted in the up-regulation of 562 and 850 genes, respectively, while down-regulating 152 and 650 genes. Several proapoptotic and cell cycle-related genes were found to be up-regulated. Notably, three and five of the ten most up-regulated genes in HuT 78 and Raji cells, respectively, were related to immune function. In summary, our study suggests that the combination of hydralazine and valproate is an effective treatment option for both B- and T-lymphomas. These findings are highly encouraging, and we urge further clinical evaluation to validate our research and potentially improve lymphoma treatment.

Revolutionizing Healthcare: Qure.AI's Innovations in Medical Diagnosis and Treatment.

Qure.AI, a leading company in artificial intelligence (AI) applied to healthcare, has developed a suite of innovative solutions to revolutionize medical diagnosis and treatment. With a plethora of FDA-approved tools for clinical use, Qure.AI continually strives for innovation in integrating AI into healthcare systems. This article delves into the efficacy of Qure.AI's chest X-ray interpretation tool, "qXR," in medicine, drawing from a comprehensive review of clinical trials conducted by various institutions. Key applications of AI in healthcare include machine learning, deep learning, and natural language processing (NLP), all of which contribute to enhanced diagnostic accuracy, efficiency, and speed. Through the analysis of vast datasets, AI algorithms assist physicians in interpreting medical data and making informed decisions, thereby improving patient care outcomes. Illustrative examples highlight AI's impact on medical imaging, particularly in the diagnosis of conditions such as breast cancer, heart failure, and pulmonary nodules. AI can significantly reduce diagnostic errors and expedite the interpretation of medical images, leading to more timely interventions and treatments. Furthermore, AI-powered predictive analytics enable early detection of diseases and facilitate personalized treatment plans, thereby reducing healthcare costs and improving patient outcomes. The efficacy of AI in healthcare is underscored by its ability to complement traditional diagnostic methods, providing physicians with valuable insights and support in clinical decision-making. As AI continues to evolve, its role in patient care and medical research is poised to expand, promising further advancements in diagnostic accuracy and treatment efficacy.

Exploring how non-clinical factors in childbirth care shape users' experiences in public health facilities in rural Chiapas, Mexico: a qualitative study using the WHO health systems responsiveness framework.

INTRODUCTION: Many Mexicans face barriers to receive delivery care from qualified professionals, especially indigenous and poor sectors of the population, which represent most of the population in the state of Chiapas. When access to institutional delivery care is an option, experiences with childbirth care are often poor. This underscores the need for evidence to improve the quality of services from the user's perspective. The present study was conceived with the objective of understanding how non-clinical aspects of care shape women's birthing experiences in public health institutions in Chiapas. METHODS: We conducted an exploratory qualitative study. Data collection consisted in 20 semi-structured interviews to women who had delivered in a public health facility in Chiapas during the last six months prior to the interview. For the design of the interview guide we used the WHO health system responsiveness framework, which focus on the performance of the health system in terms of the extent to which it delivers services according to the "universally legitimate expectations of individuals" and focuses on the non-financial and non-clinical qualities of care. The resulting data were analyzed using thematic analysis methodology. RESULTS: We identified a total of 16 themes from the data, framed in eight categories which followed the eight domains of the WHO health systems responsiveness framework: Choice of the provider and the facility, prompt attention, quality of basic amenities, access to social support, respectful treatment, privacy, involvement in decisions, and communication. We shed light on the barriers women face in receiving prompt care, aspects of health facilities that impact women's comfort, the relevance of being provided with adequate food and drink during institutional delivery, how accompaniment contributes positively to the birthing experience, the aspects of childbirth that women find important to decide on, and how providers' interpersonal behaviors affect the birthing experience. CONCLUSIONS: We have identified non-clinical aspects of childbirth care that are important to the user experience and that are not being satisfactorily addressed by public health institutions in Chiapas. This evidence constitutes a necessary first step towards the design of strategies to improve the responsiveness of the Chiapas health system in childbirth care.

Evaluation of the implementation of a community health worker-led COVID-19 contact tracing intervention in Chiapas, Mexico, from March 2020 to December 2021.

BACKGROUND: Mexico is one of the countries with the greatest excess death due to COVID-19. Chiapas, the poorest state in the country, has been particularly affected. Faced with an exacerbated shortage of health professionals, medical supplies, and infrastructure to respond to the pandemic, the non-governmental organization Compañeros En Salud (CES) implemented a COVID-19 infection prevention and control program to limit the impact of the pandemic in the region. We evaluated CES's implementation of a community health worker (CHW)-led contact tracing intervention in eight rural communities in Chiapas. METHODS: Our retrospective observational study used operational data collected during the contract tracing intervention from March 2020 to December 2021. We evaluated three outcomes: contact tracing coverage, defined as the proportion of named contacts that were located by CHWs, successful completion of contact tracing, and incidence of suspected COVID-19 among contacts. We described how these outcomes changed over time as the intervention evolved. In addition, we assessed associations between these three main outcomes and demographic characteristics of contacts and intervention period (pre vs. post March 2021) using univariate and multivariate logistic regression. RESULTS: From a roster of 2,177 named contacts, 1,187 (54.5%) received at least one home visit by a CHW and 560 (25.7%) had successful completion of contact tracing according to intervention guidelines. Of 560 contacts with complete contact tracing, 93 (16.6%) became suspected COVID-19 cases. We observed significant associations between sex and coverage (p = 0.006), sex and complete contact tracing (p = 0.049), community of residence and both coverage and complete contact tracing (p < 0.001), and intervention period and both coverage and complete contact tracing (p < 0.001). CONCLUSIONS: Our analysis highlights the promises and the challenges of implementing CHW-led COVID-19 contact tracing programs. To optimize implementation, we recommend using digital tools for data collection with a human-centered design, conducting regular data quality assessments, providing CHWs with sufficient technical knowledge of the data collection system, supervising CHWs to ensure contact tracing guidelines are followed, involving communities in the design and implementation of the intervention, and addressing community member needs and concerns surrounding stigmatization arising from lack of privacy.

Mutant p53 Gain-of-Function Induces Migration and Invasion through Overexpression of miR-182-5p in Cancer Cells.

The master-key TP53 gene is a tumor suppressor that is mutated in more than 50% of human cancers. Some p53 mutants lose their tumor suppressor activity and acquire new oncogenic functions, known as a gain of function (GOF). Recent studies have shown that p53 mutants can exert oncogenic effects through specific miRNAs. We identified the differentially expressed miRNA profiles of the three most frequent p53 mutants (p53R273C, p53R248Q, and p53R175H) after their transfection into the Saos-2 cell line (null p53) as compared with p53WT transfected cells. The associations between these miRNAs and the signaling pathways in which they might participate were identified with miRPath Software V3.0. QRT-PCR was employed to validate the miRNA profiles. We observed that p53 mutants have an overall negative effect on miRNA expression. In the global expression profile of the human miRNome regulated by the p53R273C mutant, 72 miRNAs were underexpressed and 35 overexpressed; in the p53R175H miRNAs profile, our results showed the downregulation of 93 and upregulation of 10 miRNAs; and in the miRNAs expression profile regulated by the p53R248Q mutant, we found 167 decreased and 6 increased miRNAs compared with p53WT. However, we found overexpression of some miRNAs, like miR-182-5p, in association with processes such as cell migration and invasion. In addition, we explored whether the induction of cell migration and invasion by the p53R48Q mutant was dependent on miR-182-5p because we found overexpression of miR-182-5p, which is associated with processes such as cell migration and invasion. Inhibition of mutant p53R248Q and miR-182-5p increased FOXF2-MTSS1 levels and decreased cell migration and invasion. In summary, our results suggest that p53 mutants increase the expression of miR-182-5p, and this miRNA is necessary for the p53R248Q mutant to induce cell migration and invasion in a cancer cell model.

Ultrasound evaluation of a new surface reference line to describe sural nerve location and safe zones to consider in posterior leg approaches.

PURPOSE: Several authors have described methods to predict the sural nerve pathway with non-proportional numerical distances, but none have proposed a person-proportional, reproducible method with anatomical references. The aim of this research is to describe ultrasonographically the distance and crossing zone between a surface reference line and the position of the sural nerve. METHODS: Descriptive cross-sectional study, performed between January and April 2022 in patients requiring foot surgery who met inclusion criteria. The sural nerve course in the posterior leg was located and marked using ultrasound. Landmarks were drawn with a straight line from the medial femoral condyle to the tip of the fibula. Four equal zones were established in the leg by subdividing the distal half of the line. This way, areas based on simple anatomical proportions for each patient were studied. The distance between the marking and the ultrasound nerve position was measured in these 4 zones, creating intersection points and safety areas. Location and distances from the sural nerve to the proposed landmarks were assessed. RESULTS: One-hundred and four lower limbs, 52 left and 52 right, assessed in 52 patients were included. The shortest median distance of the nerve passage was 2.9 mm from Point 2. The sural nerve intersection was 60/104 (57.7%) in Zone B, 21/104 (20.1%) in Zone C and 19/104 (18.3%) in Zone A. Safety zones were established. Average 80.5% of coincidence in sural nerve localization was found in the distal half of the leg, in relation to the surface reference line when comparing both legs of each patient. CONCLUSIONS: This study proposes a simple, reproducible, non-invasive and, for the first time, person-proportional method, that describes the distance and location of the main areas of intersection of the sural nerve with points and zones (risk and safe zones) determined by a line guided by superficial anatomical landmarks. Its application when surgeons plan and perform posterior leg approaches will help to avoid iatrogenic nerve injuries. LEVEL OF EVIDENCE: IV.

An approach to cellular tropism of SARS-CoV-2 through protein-protein interaction and enrichment analysis.

COVID-19, caused by SARS-CoV-2, is a primarily pulmonary disease that can affect several organs, directly or indirectly. To date, there are many questions about the different pathological mechanisms. Here, we generate an approach to identify the cellular-level tropism of SARS-CoV-2 using human proteomics, virus-host interactions, and enrichment analysis. Through a network-based approach, the molecular context was visualized and analyzed. This procedure was also performed for SARS-CoV-1. We obtained proteomes and interactomes from 145 different cells corresponding to 57 different tissues. We discarded the cells without the proteins known for interacting with the virus, such as ACE2 or TMPRSS2. Of the remaining cells, a gradient of susceptibility to infection was observed. In addition, we identified proteins associated with the coagulation cascade that can be directly or indirectly affected by viral proteins. As a whole we identified 55 cells that could be potentially controlled by the virus, with different susceptibilities, mainly being pneumocytes, heart, kidney, liver, or small intestine cells. These results help to explain the molecular context and provide elements for possible treatments in the current situation. This strategy may be useful for other viruses, especially those with limited reported PPI, such as a new virus.

Integration of Hot Isostatic Pressing and Heat Treatment for Advanced Modified γ-TiAl TNM Alloys.

The conventional processing route of TNM (Ti-Nb-Mo) alloys combines casting and Hot Isostatic Pressing (HIP) followed by forging and multiple heat treatments to establish optimum properties. This is a time-consuming and costly process. In this study we present an advanced alternative TNM alloy processing route combining HIP and heat treatments into a single process, which we refer to as IHT (integrated HIP heat treatment), applied to a modified TNM alloy with 1.5B. A Quintus HIP lab unit with a quenching module was used, achieving fast and controlled cooling, which differs from the slow cooling rates of conventional HIP units. A Ti-42.5Al-3.5Nb-1Mo-1.5B (at.%) was subjected to an integrated two HIP steps at 200 MPa, one at 1250 °C for 3 h and another at 1260 °C for 1 h, both under a protective Ar atmosphere and followed by cooling at 30 K/min down to room temperature. The results were compared against the Ti-43.5Al-3.5Nb-1Mo-0.8B (at.%) thermomechanically processed in a conventional way. Applying IHT processing to the 1.5B alloy does indeed achieve good creep strength, and the secondary creep rate of the IHT processed materials is similar to that of conventionally forged TNM alloys. Thus, the proposed advanced IHT processing route could manufacture more cost-effective TiAl components.

Long-Term Effectiveness and Tolerability of Pain Treatment with Tapentadol Prolonged Release.

BACKGROUND: The central analgesic tapentadol prolonged release (PR) has proven effective and generally well tolerated in a broad range of chronic pain conditions. Long-term data of its use are still scarce. OBJECTIVES: To evaluate long-term effectiveness, tolerability, and safety of tapentadol PR in patients with severe chronic osteoarthritis (OA) knee pain or low back pain (LBP) who responded to tapentadol in 1 of 4 preceding 12-week phase 3b clinical trials. STUDY DESIGN: Open-label, uncontrolled, observational extension study of up to 72 weeks. SETTING: Fourteen centers in Spain. Protocol approval by the reference ethics committee for all the participating centers. METHODS: Eligible patients started the extension trial on the tapentadol PR dosage optimized for them in the preceding trial; dose adjustments were permitted throughout the extension. Treatment effectiveness outcomes included changes in pain intensity, sleep, state of health, quality of life, patient and clinician global impression of change, and patients' satisfaction with treatment. Patients with OA knee pain also answered the Western Ontario and McMaster Universities OA index, and patients with LBP with a possible neuropathic pain component completed neuropathic pain-related questionnaires. RESULTS: Eighty-three patients were enrolled: 40 with OA knee pain, 43 with LBP. The full analysis set consisted of 81 patients. Mean pain intensity remained relatively stable over the 72-week extension period with mean increases from baseline of 0.44 (95% confidence interval [CI], -0.1,1.0; Numeric Rating Scale) for all patients, 0.2 (95% CI, -0.5, 0.9) for patients with OA, and 0.68 (95% CI, -0.2, 1.6) for patients with LBP. State of health and quality of life baseline ratings were maintained; overall impression of change was "improved." Most patients (88.9%) reported at least good treatment satisfaction at the end of treatment. Mean daily tapentadol PR doses slightly increased from 313.3 ± 139.5 mg at baseline to 315.7 ± 140.1 mg at end of study. Uptitration was required for 8.4% of the patients, 4.8% had a dose reduction during the trial. Adverse events considered probably/likely or certainly related to tapentadol PR treatment by the investigator were documented for 18.1% of all patients, most commonly constipation (7.2%). Seven patients (8.4%) experienced adverse events leading to premature discontinuation. LIMITATIONS: An open-label design, stable concomitant analgesics (World Health Organization step I), and dose adjustments were allowed during the study. All patients had benefitted from tapentadol PR in preceding trials. CONCLUSIONS: Sustained pain relief and quality of life for up to 72 treatment weeks under relatively stable dosing, as well as the good safety profile, indicate the usefulness of tapentadol PR for patients who suffer from severe chronic OA knee pain and LBP with limited risk for tolerance development.