Favorable Scores Research Articles

Repurposed pharmacotherapy: targeting cathepsin L with repurposed drugs in virtual screening.

Proteolytic enzymes are closely associated with cancer and are important in different phases, including tumor growth, angiogenesis, and metastasis. Despite efforts to target matrix metalloproteases (MMPs), clinical trials have often resulted in various side effects such as musculoskeletal pain, joint stiffness, and tendinitis, making them less optimal for chronic cancer treatment. Thus, there is a need for the identification of other protease targets that would provide different approaches towards the management of cancer. Of these targets, Cathepsin L (CatL) is a lysosomal cysteine protease that has been identified as a therapeutic target that is implicated in cancer development and metastasis. In this study, we performed an integrated approach of virtual screening and molecular dynamics (MD) simulations to identify the potential inhibitors of CatL from a library of drugs that have been used for different treatments. Towards this goal, we performed virtual screening of the DrugBank database and found two repurposed drugs, Irinotecan and Nilotinib, against CatL based on their docking profiles, favorable docking scores, and specific interaction with the CatL binding pocket. MD simulations of the Irinotecan and Nilotinib bound structures with CatL were carried out, and the analysis showed that both these compounds could function as CatL inhibitors as the protein-ligand interactions were stable for 300 ns. This study highlights the robustness of these drugs bound to CatL and indicates that they could be repurposed for the treatment of cancer. These findings endorse the use of computer-based approaches for the identification of new inhibitors, and the present study will be a useful resource for future experimental research towards the targeting of CatL in cancer therapeutics.

MMV 1804559 is a potential antistaphylococcal and antibiofilm agent targeting the clfA gene of Staphylococcus aureus.

Staphylococcus aureus, a high-priority pathogen proclaimed to cause infections ranging from mild to life-threatening, presents significant challenges in treatment. New therapies can be developed quicker using open drug discovery platforms offering a distinct approach to expedite the development of innovative antibacterial and anti-biofilm therapeutics. This study set out to address these issues by finding new uses for current medications to find compounds that are effective against S. aureus. In this study, we screened the global priority health box, launched by Medicines for Malaria Ventures containing 240 compounds, for their effectiveness against S. aureus. MMV1795508, MMV1542799, MMV027331, MMV1593278, and MMV1804559 showed potential antibacterial activity at 10µM concentration. These compounds underwent further evaluation for their ability to clear intracellular bacteria, disrupt biofilm formation and eradicate existing biofilms. MMV1804559 demonstrated strong efficacy across all tested parameters, achieving 94% inhibition of intracellular bacteria, 79.19% disruption of biofilm cells, and 66.18% inhibition of biofilm formation. Scanning electron microscopy revealed notable membrane perforations and blebbing in MMV1804559-treated cells, indicating its impact on bacterial membranes. Gene expression analysis of cells treated with MMV1804559 showed downregulation of clfA and clfB genes, critical for biofilm formation. Additionally, docking studies confirmed the binding affinity of MMV1804559 with clfA, supported by favorable docking scores, MM/GBSA binding energy, and increased hydrogen bond interactions in the binding pocket, suggesting clfA as a target for MMV1804559. MMV1804559 could serve as a potential therapy for S. aureus by targeting biofilm development and cell adhesion processes.

Variability in patient-reported outcomes among different congenital heart defects: a comparative analysis of 7,498 patients from 32 countries

Abstract Background Patient-reported outcomes (PROs) may not always correlate with the complexity of congenital heart defects (CHDs), as significant variation has been observed between CHDs within complexity levels. Accurate comparisons across various types of CHDs necessitate large sample sizes. Purpose The objective of this study was to compare PROs across different CHDs in a large international sample. Methods ‘Assessment of Patterns of Patient-Reported Outcomes in Adults with Congenital Heart disease – International Study II’ (APPROACH-IS II) was an international cross-sectional investigation, in which 8,415 patients from 32 countries in 6 continents were enrolled (20 high; 7 upper-middle; 4 lower-middle; and 1 low income). For the comparison across different CHDs, conditions with at least 50 patients were included in the analysis. Hence, the sample consisted of 7,498 patients (median age=33y; 53.1% women). Patients completed questionnaires to measure perceived health status (RAND-12 Health Survey; EuroQOL-5D Visual Analog Scale); depressive symptoms (Patient Health Questionnaire-8); anxiety (General Anxiety Disorder-7) and quality of life (Linear Analog Scale). Generalized linear mixed models (GLMMs) were performed with center as random effect. Results Cyanotic heart defects were associated with the lowest scores for physical functioning, mental health, self-rated health, and quality of life (see Figure). Other CHDs found to be associated with poor PRO scores encompassed unrepaired secundum atrial septal defect, Ebstein anomaly, single ventricle, and truncus arteriosus. Conversely, the most favorable scores for all PROs, except for anxiety, were observed with isolated pulmonic stenosis. Other CHDs with favorable PRO scores comprised coarctation of the aorta, isolated small ventricular septal defect, congenital aortic valve disease, and repaired ventricular septal defect. Adjusted for sociodemographic and physiological factors, GLMMs revealed significant differences across defects, using the best score for each PRO as the reference (see Figure). Conclusion Substantial variation in PROs was observed among different types of CHDs. Interestingly, some complex heart defects demonstrated relatively good PRO scores, comparable to some simple defects. On the other hand, unrepaired simple defects or those with residual lesions, were associated with worse PROs.

Successful management of anaphylactic shock prior to elective cesarean delivery: a case report

BackgroundAnaphylactic cardiovascular collapse is complicated by aortocaval compression during pregnancy, exacerbated by neuraxial anesthesia. Despite recommendations to administer perioperative antibiotics before anesthesia, common practice in Japan involves administering them after anesthesia induction. We report a case of possible antibiotics-induced anaphylaxis just before anesthesia for cesarean delivery.Case presentationA 24-year-old woman at 37 weeks of gestation presented for a scheduled repeat cesarean under spinal anesthesia. After starting administration of cefazolin prior to anesthesia, she developed anaphylactic symptoms. Hypotension refractory to adrenaline necessitated conversion to an emergency cesarean section under general anesthesia. A neonate was delivered with favorable Apgar scores. Post-delivery, the mother’s hemodynamics stabilized significantly. Elevated plasma tryptase confirmed anaphylaxis. Both mother and infant were discharged without further complications.ConclusionsThis case emphasizes the importance of administering prophylactic antibiotic before anesthesia in mitigating severity of shock induced by anaphylaxis and the crucial role of prompt emergency cesarean in achieving successful outcomes.

Neutrophil-to-Lymphocyte Ratio is Associated with Clinical Outcomes in Patients Treated with Mechanical Thrombectomy for Posterior Circulation Large Vessel Occlusion

To investigate the potential of composite inflammatory markers, including the neutrophil-to-lymphocyte ratio (NLR), in predicting outcomes in patients with posterior circulation large vessel occlusion who underwent mechanical thrombectomy (MT). We included patients who underwent MT for posterior circulation large vessel occlusion between February 2016 and December 2021. We then assessed composite inflammatory markers on day 1 post-MT. The primary outcome was the modified Rankin Scale score at 3 months (favorable score: 0 -3). The primary safety measure was 3-month mortality. Receiver operating characteristic (ROC) curve analysis determined each marker's predictive values and optimal cutoff values. Multivariable regression analysis assessed the relationship between markers and outcomes. We included a total of 137 patients (median age: 71 years, 26% females, median National Institutes of Health Stroke Scale [NIHSS] score: 23). NLR demonstrated the best predictive value for the prognosis of patients with posterior circulation large vessel occlusion who underwent MT. ROC analysis identified an optimal NLR cutoff of 12.5 (area under curve [AUC]: 0.741, 95% confidence intervals [CIs]: 0.652-0.830) for favorable outcomes and 14.1 (AUC: 0.764, 95% CIs: 0.662-0.865) for predicting death. Multivariate analysis determined an NLR <12.5 as an independent predictor of favorable post-MT outcomes (odds ratio [OR]: 10.43, 95% CIs: 3.85-28.29, p <0.001), and NLR <14.1 as an independent predictor of post-MT survival (OR: 0.09, 95% CIs: 0.03-0.25, p <0.001). Among the assessed markers, NLR emerged as the strongest predictor of clinical outcomes following MT for posterior circulation large vessel occlusion.

Convenient Synthesis, Characterizations and Biological Evolution of Novel 1‐Phenyl‐N’‐(3‐phenylacryloyl)cyclopropane carbohydrazide Derivatives

AbstractCancer is a longstanding worldwide issue, current chemotherapeutic treatments have limited effectiveness and high toxicity. An extensive investigation has revealed a significant potential link between ITK and the development of cancer. Hence, it is recommended to prioritize investigating ITK to develop and produce novel inhibitors for treating diseases associated with T cells. In our study, we have designed and synthesized two new series of compounds, which consist of cinnamic acid, carbohydrazide, and cyclopropanamide groups in a single compound. We have developed a facile method to synthesize 20 new derivatives of two series of innovative 1‐phenyl‐N’‐(3‐phenylacryloyl)cyclopropane carbohydrazide derivatives with good yields and purity. The Synthesized derivatives are conformed by analytical techniques (FT‐IR, 1H NMR, 13C NMR, elemental analysis) and their biological evaluation data is provided. The synthesized compounds displayed favorable docking scores in comparison to the ITK inhibitor, Ibrutinib. The in vitro cancer investigation shows that these compounds have good IC50 values, causing cytotoxicity against malignant cell lines.

In vivo and In silico Insights into the Anti-Diabetic Efficacy of EVOO and Hydroxytyrosol in a Rat Model

Extra virgin olive oil (EVOO) has a putative antidiabetic activity mostly attributed to its polyphenol hydroxytyrosol. In this study, we explored the antidiabetic effects of EVOO and hydroxytyrosol on an in vivo T2D-simulated rat model as well as in in silico study. Wistar rats were divided into four groups. The first group served as a normal control (NC), while type 2 diabetes (T2D) was induced in the remaining groups using a high-fat diet (HFD) for 12 weeks followed by a single dose of streptozotocin (STZ, 30 mg/kg). One diabetic group remained untreated (DC), while the other two groups received an eight-week treatment with either EVOO (90 g/kg of the diet) (DO) or hydroxytyrosol (17.3 mg/kg of the diet) (DH). The DC group exhibited hallmark features of established T2D, including elevated fasting blood glucose levels, impaired glucose tolerance, increased HOMA-IR, widespread downregulation of insulin receptor expression, heightened oxidative stress, and impaired β-cell function. In contrast, treatments with EVOO and hydroxytyrosol elicited an antidiabetic response, characterized by improved glucose tolerance, as indicated by accelerated blood glucose clearance. Systematic analysis revealed the underlying antidiabetic mechanisms: both treatments enhanced insulin receptor expression in the liver and skeletal muscles, increased adiponectin levels, and mitigated oxidative stress. Moreover, while EVOO reduced intramyocellular lipids, hydroxytyrosol restored adipose tissue insulin sensitivity and enhanced β-cell survival. Molecular docking and dynamics confirm hydroxytyrosol's high affinity binding to PGC-1α, IRE-1α, and PPAR-γ, particularly IRE-1α, highlighting its potential to modulate diabetic signaling pathways. Collectively, these mechanisms highlight the putative antidiabetic role of EVOO and hydroxytyrosol. Moreover, the favorable docking scores of hydroxytyrosol with PGC-1α, IRE-1α, and PPAR-γ support the antidiabetic potential and offer promising avenues for further research and the development of novel antidiabetic therapies.

Evaluation of Bioactive Compounds in Tetrapleura tetraptera (Uyayak) and Its Activity Against Dihydropteroate Synthase (1AJ2) of E. coli: In-Sight from ADMET Profiling and Molecular Docking

Background: The prevalence of multi-drug-resistant E. coli isolates is on the increase around the world. This study was designed to evaluate the antimicrobial activity of Tetrapleura tetraptera (Uyayak) fruit bioactive compounds against E. coli using an in silico approach. Methods: Gas chromatography coupled to mass spectrophotometry (GC-MS) was used to identify the bioactive compounds in our sample T. tetraptera. The resulting bioactive compounds from GC-MS were converted into canonical strings and used for target and absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties predictions using the pkCSM and SWISSADME tools, respectively. Bioactive compounds that met Lipinski's rule of five (ROF) were docked against the dihydropteroate synthase of E. coli using the AutoDock Vina tool, and the resulting interactions were visualized in 2-D using Biovia Discovery Studio 21. Results: The GC-MS analysis returned a total of twenty-eight (28) bioactive compounds, out of which 13 did not violate Lipinski's ROF. ADMET analysis of the screened bioactive compounds showed better absorption (intestinal and water solubility) and toxicity (AMES and hepatoxicity) profiles than trimethoprim, the control drug. Molecular docking gave docking scores that ranged from −4.0 to −5.3 kcal/mol for the bioactive compounds while that of trimethoprim was −6.5 kcal/mol. Target prediction showed that all the bioactive compounds are capable of reaching various targets, with the nuclear receptor being the most abundant target. Conclusion: The bioactive compounds of T. tetraptera fruits examined showed favorable docking scores and pharmacokinetics, suggesting the need for further studies to validate their potential as antimetabolites.

Expanded Gene Regulatory Network Reveals Potential Light-Responsive Transcription Factors and Target Genes in Cordyceps militaris.

Cordyceps militaris, a fungus widely used in traditional Chinese medicine and pharmacology, is recognized for its abundant bioactive compounds, including cordycepin and carotenoids. The growth, development, and metabolite production in various fungi are influenced by the complex interactions between regulatory cascades and light-signaling pathways. However, the mechanisms of gene regulation in response to light exposure in C. militaris remain largely unexplored. This study aimed to identify light-responsive genes and potential transcription factors (TFs) in C. militaris through an integrative transcriptome analysis. To achieve this, we reconstructed an expanded gene regulatory network (eGRN) comprising 507 TFs and 8662 regulated genes using both interolog-based and homolog-based methods to build the protein-protein interaction network. Aspergillus nidulans and Neurospora crassa were chosen as templates due to their relevance as fungal models and the extensive study of their light-responsive mechanisms. By utilizing the eGRN as a framework for comparing transcriptomic responses between light-exposure and dark conditions, we identified five key TFs-homeobox TF (CCM_07504), FlbC (CCM_04849), FlbB (CCM_01128), C6 zinc finger TF (CCM_05172), and mcrA (CCM_06477)-along with ten regulated genes within the light-responsive subnetwork. These TFs and regulated genes are likely crucial for the growth, development, and secondary metabolite production in C. militaris. Moreover, molecular docking analysis revealed that two novel TFs, CCM_05727 and CCM_06992, exhibit strong binding affinities and favorable docking scores with the primary light-responsive protein CmWC-1, suggesting their potential roles in light signaling pathways. This information provides an important functional interactive network for future studies on global transcriptional regulation in C. militaris and related fungi.

Evaluating production optimization strategies for carbon dioxide recovery: insights from a natural carbon dioxide processing plant

This article investigates production optimization strategies for carbon dioxide recovery using a natural Carbon dioxide Processing Plant as a case study. The study assesses various optimization techniques including hydraulic fracturing, matrix acidizing, and drilling new wells based on productivity, optimal producing time, financial analysis, risk assessment, and environmental impact assessment. The analysis employs a least summation score ranking method to estimate the most suitable technique. Findings reveal that drilling a new carbon dioxide producing well emerges as the preferred option due to its favorable scores across all criteria, including high productivity, extended optimal producing time, low risk, minimal environmental impact, and positive incremental net present value, signifying its profitability and project viability. The study recommends a five year model verification, improvement and history matching program should be adopted in order to understand reservoir processes taking and detect operational issues together with identifying opportunities to improve reservoir description and data acquisition program.

Exploring the anticancer potential of Cytotoxin 10 from Naja kaouthia venom: Mechanistic insights from breast and lung cancer cell lines

Breast and lung cancers are the leading causes of cancer-related deaths in the world. Although considerable progress has been made in the field of cancer therapy, quest to discover potent, safe and cost-effective alternatives especially from natural sources is being pursued. Snake venom, which is a treasure trove of various peptides and proteins including natural toxins that specifically target tissues and receptors in the envenomated victims. Many such proteins are being explored for their therapeutic potential against various diseases including cancers. Here, we report the mechanism of cytotoxic activity of crude venom and a purified protein, Cytotoxin from the monocled cobra (Naja kaouthia), an elapid snake with neurotoxic venom prominently found in the North-East India. The crude venom showed significant cytotoxicity against breast (MCF-7and MDA-MB-231) and lung (A549, NCI–H522) cancer cell lines. Bioassay-guided fractionation using RP-HPLC showed highest cytotoxic activity in peak P9. Liquid chromatography-tandem mass spectrometry (ESI-LC-MS/MS) analysis was employed and the fraction is identified as Cytotoxin 10 which showed comparable cytotoxicity against the experimental cell lines. Cytotoxin 10 also exhibited apoptosis in MCF-7 and A549 cell lines using AO/EtBr and flow cytometry analysis. Expressions of apoptosis related proteins e.g. Bax, Bcl-2, Caspase-7 and PARP were also studied following Cytotoxin 10 treatment in both cell lines. Molecular docking experiments performed to investigate the interactions between Cytotoxin 10 and the apoptotic proteins revealed favourable binding scores compared to their corresponding inhibitors. Interestingly, Cytotoxin 10 inhibited migration and adhesion in a time and dose-dependent manner in both MCF-7 and A549 cells. This is the first report elucidating the mechanism of cytotoxic activity of Cytotoxin 10 purified from Naja kaouthia venom of North-East India origin and could pave the way for development of potential therapeutic strategies against breast and lung cancer.

Designing of a chimeric multiepitope vaccine against bancroftian lymphatic filariasis through immunoinformatics approaches

The filarial worms of Wuchereria bancrofti are the primary cause of lymphatic filariasis (LF), a mosquito-borne disease among the neglected tropical parasitic diseases. Considering the global endemic consequences of the disease, there is a need to develop a successful vaccine candidate against LF. Using advanced immunoinformatics approaches, we designed two multiepitope vaccines targeting W. bancrofti’s glutathione S-transferase and thioredoxin. Therefore, we predicted several MHC-1, MHC-2, and B-cell epitopes from these proteins and mapped two vaccine candidates (V1 and V2). The vaccines were subsequently employed for physicochemical analysis, structural prediction and validation, docking and normal mode analysis, codon optimization, and immune simulation. The selected MHC-1, MHC-2, and B-cell epitopes were antigenic without allergenicity or toxicity. The designed vaccines were expected to be soluble, stable proteins under physiological conditions. Compared to V2, V1’s secondary and tertiary structures were simultaneously favorable, with Ramachandran plot analysis revealing 95.6% residues in favored areas. Subsequently, the molecular docking analysis indicated that the V1 had a high binding affinity for the TLR-2, TLR-4 and TLR-5, as suggested by the docking scores of -1248.7, -1038.5 and -1562.8, respectively. The NMA of these complexes further indicated their structural flexibility. Molecular dynamics simulations of V1-TLR complexes revealed V1-TLR-4 as the most stable, with the lowest free energy and minimal fluctuations, indicating the strongest binding affinity. The results of the codon optimization showed high levels of expression, with a favorable CAI score (&lt;1.0). A three-dose vaccination analysis showed significant and persistent immunological responses, including adaptive and innate immune responses. The findings emphasize the potential of the V1 against W. bancrofti, but further validation is required through in vitro, in vivo, and clinical trials.

Attitudes towards people living with HIV/AIDS through the EAPVVS-E: A descriptive analysis in nursing students

BackgroundDespite advances in antiretroviral treatment, stigma towards people with HIV/AIDS continues to exist. Nursing students, as future key players in health care, must advocate for the elimination of stigma through education, empathy and the creation of a supportive environment. This holistic approach is crucial to improving their quality of life and moving towards the eradication of HIV/AIDS. AimTo identify nursing students' attitudes towards people living with HIV or AIDS and their relationship with sociodemographic and academic-cultural variables of the participants. DesignA cross-sectional study was performed. SettingsThe research was carried out in the Nursing Degree of the Faculty of Health Sciences of the Ceuta Campus of the University of Granada. ParticipantsConvenience sampling was used to recruit 284 students of the degree in Nursing. MethodsData were collected voluntarily and on an anonymous basis, using the “Attitudes Towards People Living with HIV/AIDS Scale in Nursing Students”. Bivariate and multivariate analyses were performed. ResultsFactors 1 (Professional Practice), 2 (Social Integration) and 3 (Partner and Family) exhibited mean scores considered to be favourable attitudes (>4 points). In contrast, Factor 4, called Benevolent Stigma, had a mean score of 3.68 ± 0.97. Religious beliefs, academic year, sexual orientation, academic practices and age are considered influential variables in the different factors. ConclusionsNursing students present attitudes with favourable scores. However, these results highlight the importance of influencing the different factors, especially in the second year of the Bachelor's Degree in Nursing in our sample. Thus, an educational intervention in this area would be necessary to reinforce the values of humanised care.

Proteomic profiling of oleamide-mediated polarization in a primary human monocyte-derived tumor-associated macrophages (TAMs) model: a functional analysis.

Tumor-associated macrophages (TAMs) play a critical function in the development of tumors and are associated with protumor M2 phenotypes. Shifting TAMs towards antitumor M1 phenotypes holds promise for tumor immunotherapy. Oleamide, a primary fatty acid amide, has emerged as a potent anticancer and immunomodulatory compound. However, the regulatory effects of oleamide on TAM phenotypes remain unclear. We used real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) techniques to study the influence of oleamide on primary human monocyte-derived TAM phenotypes, and we investigated the protein expression profiles based on mass spectrometry to analyze the effect of oleamide on macrophage polarization. Moreover, the advantageous binding scores between oleamide and these target candidate proteins are examined using molecular docking. Our study revealed that oleamide effectively suppressed the M2-like TAM phenotype by reducing interleukin (IL)-10 production and downregulating M2-like markers, including vascular endothelial growth factor A (VEGFA), MYC proto-oncogene, bHLH transcription factor (c-Myc), and mannose receptor C-type 1 (CD206). Moreover, the conditioned medium derived from oleamide-treated TAMs induces apoptosis of MDA-MB-231 breast cancer cells. Proteomic analysis identified 20 candidate up- and down-regulation proteins targeted by oleamide, showing modulation activity associated with the promotion of the M1-like phenotype. Furthermore, molecular docking demonstrated favorable binding scores between oleamide and these candidate proteins. Collectively, our findings suggest that oleamide exerts a potent antitumor effect by promoting the antitumor M1-like TAM phenotype. These novel insights provide valuable resources for further investigations into oleamide and macrophage polarization which inhibit the progression of breast cancer, which may provide insight into immunotherapeutic approaches for cancer.

Interest in anime and manga: relationship with (mental) health, social disconnectedness, social joy and subjective well-being

Abstract Aim Our aim was to examine the association between interest in anime and manga and their relationship with (mental) health (in terms of depressive symptoms, anxiety symptoms, health-related quality of life, symptoms of hikikomori), social disconnectedness (in terms of preference for solitude, loneliness, objective social isolation, and perceived social isolation), subjective well-being (in terms of ikigai, life satisfaction, and happiness) and joy (frequency of laughter, and frequency of hugs). Subjects and methods Data were taken from a large sample of the general German adult population aged 18–74 years (n = 4,738 individuals, average age: 46.4 years). Established tools were used to quantify the outcomes. Multiple linear and ordered logistic regressions were used, as appropriate. Results Regressions showed that a higher interest in anime was associated with several adverse mental health and some social disconnectedness outcomes. Contrarily, a higher interest in anime was associated with favorable subjective well-being outcomes, and favorable joy outcomes. Similarly, regressions showed that a higher interest in manga was associated with several adverse (mental) health and some social disconnectedness outcomes. Contrary, it is associated with lower objective social isolation. Moreover, it is not significantly associated with subjective well-being outcomes, but significantly associated with the joy outcome frequency of hugs. Conclusion A higher interest in manga and anime was associated both with negative and positive outcomes. Particularly a higher interest in anime was associated with more favorable subjective well-being scores, laughing and hugging. In this respect, this topic needs to be approached in a very nuanced way.

Evaluating the Usability and Quality of a Clinical Mobile App for Assisting Physicians in Head Computed Tomography Scan Ordering: Mixed Methods Study.

Among the numerous factors contributing to health care providers' engagement with mobile apps, including user characteristics (eg, dexterity, anatomy, and attitude) and mobile features (eg, screen and button size), usability and quality of apps have been introduced as the most influential factors. This study aims to investigate the usability and quality of the Head Computed Tomography Scan Appropriateness Criteria (HAC) mobile app for physicians' computed tomography scan ordering. Our study design was primarily based on methodological triangulation by using mixed methods research involving quantitative and qualitative think-aloud usability testing, quantitative analysis of the Mobile Apps Rating Scale (MARS) for quality assessment, and debriefing across 3 phases. In total, 16 medical interns participated in quality assessment and testing usability characteristics, including efficiency, effectiveness, learnability, errors, and satisfaction with the HAC app. The efficiency and effectiveness of the HAC app were deemed satisfactory, with ratings of 97.8% and 96.9%, respectively. MARS assessment scale indicated the overall favorable quality score of the HAC app (82 out of 100). Scoring 4 MARS subscales, Information (73.37 out of 100) and Engagement (73.48 out of 100) had the lowest scores, while Aesthetics had the highest score (87.86 out of 100). Analysis of the items in each MARS subscale revealed that in the Engagement subscale, the lowest score of the HAC app was "customization" (63.6 out of 100). In the Functionality subscale, the HAC app's lowest value was "performance" (67.4 out of 100). Qualitative think-aloud usability testing of the HAC app found notable usability issues grouped into 8 main categories: lack of finger-friendly touch targets, poor search capabilities, input problems, inefficient data presentation and information control, unclear control and confirmation, lack of predictive capabilities, poor assistance and support, and unclear navigation logic. Evaluating the quality and usability of mobile apps using a mixed methods approach provides valuable information about their functionality and disadvantages. It is highly recommended to embrace a more holistic and mixed methods strategy when evaluating mobile apps, because results from a single method imperfectly reflect trustworthy and reliable information regarding the usability and quality of apps.

The association of acute and chronic phase cerebrovascular reactivity with patient reported quality of life following moderate-to-severe traumatic brain injury

Global outcomes have been reported to be associated with cerebrovascular reactivity (CVR) in the acute phase following moderate and severe traumatic brain injury (TBI). The association of CVR in the acute and chronic phase of injury with patient-reported health-related quality of life metrics (HRQOL) metrics has never been explored. The aim of this study is to examine the association of CVR, as measured by the cerebral oxygen indices (COx and COx_a), in the acute and chronic phase following moderate and severe TBI, with patient reported HRQOL. In this prospective cohort study, performed in a Canadian quaternary care center, the association between continuous acute and chronic phase CVR with patient reported HRQOL outcomes following moderate and severe TBI was examined. The main outcomes of interest of this study were validated measures of patient-reported HRQOL over various domains as measured by both the 12-Item Short-Form Health Survey (SF-12) and a Quality of Life after Brain Injury (QOLIBRI) questionnaire. In the 29 subjects of this cohort, acute phase CVR was found to be significantly more active in those with a favorable Mental Component Summary (MCS) scores of the SF-12 at early follow-up when measured by COx (-0.015 [IQR: -0.067 to 0.032] vs 0.040 [IQR: 0.019 to 0.137] for Favorable first MCS vs Unfavorable respectively; Mann–Whitney U test p-value = 0.046) and COx_a (0.038 [IQR: 0.009 to 0.062] vs 0.112 [IQR: 0.065 to 0.167] for Favorable first MCS vs Unfavorable respectively; Mann–Whitney U test p-value = 0.014). Further, multivariable logistic regression analysis found acute phase COx and COx_a to improve model performance when predicting favorable versus unfavorable early MCS scores over established parameters such as age and measures of injury severity. Associations between outcomes and chronic phase CVR were limited, potentially due to short recording periods. This is the first ever pilot study to identify a relationship between acute phase CVR following moderate-to-severe TBI with mental and cognitive outcomes as experienced by patients. Given the small cohort, these findings will need to be confirmed in a larger multicenter study. This highlights the need for additional examination of the role dysfunctional CVR may play in mental and cognitive outcomes, as well as patient-reported outcomes more generally following TBI.

The Eaton-Littler Ligament Reconstruction in Thumb Carpometacarpal Joint Instability: Outcomes and Prognostic Factors in 74 Patients.

The Eaton-Littler ligament reconstruction is widely used for thumb carpometacarpal (CMC) instability, yet the existing literature lacks a thorough analysis of the outcomes for nontraumatic instability. This study aimed to assess the outcomes of the Eaton-Littler ligament reconstruction and to identify prognostic factors associated with postoperative pain. Patients with nontraumatic CMC joint instability, unresponsive to conservative treatment, were included in this prospective study. The Visual Analogue Scale (VAS, range 0-100) for pain and the Michigan Hand Outcome Questionnaire (MHQ, range 0-100) total score were measured at intake and three and 12-months postoperative. Multivariable linear regression was used to analyze the association between preoperative variables and the 12-month MHQ pain score. Seventy-four patients undergoing Eaton-Littler ligament reconstruction were included. The median VAS pain score improved significantly (P<0.001) from intake (70 [interquartile range (IQR) 63-78]) to 12 months postoperatively (27 [IQR 7-56]). The mean MHQ total score also improved significantly (P<0.001) from intake (52, standard deviation (SD) 13) to 12 months (74, SD 17). All thumbs were stable at follow-up whilst preserving the range of motion. Grip and pinch strength also improved significantly following surgery. Undergoing a concurrent surgery during ligament reconstruction and a better MHQ pain score at intake were found to be predictors of a favorable postoperative MHQ pain score. Patient- and clinician-reported outcomes improved significantly at three and 12 months after Eaton-Littler ligament reconstruction. We advise concurrent hand pathologies resulting from instability (e.g., tendinitis, synovitis) to be treated simultaneously during ligament reconstruction. Therapeutic, II.

Antibiotic resistance challenge: evaluating anthraquinones as rifampicin monooxygenase inhibitors through integrated bioinformatics analysis

ObjectiveAntibiotic resistance poses a pressing and crucial global public health challenge, leading to significant clinical and health-related consequences. Substantial evidence highlights the pivotal involvement of rifampicin monooxygenase (RIFMO) in the context of antibiotic resistance. Hence, inhibiting RIFMO could offer potential in the treatment of various infections. Anthraquinones, a group of organic compounds, have shown promise in addressing tuberculosis. This study employed integrated bioinformatics approaches to evaluate the potential inhibitory effects of a selection of anthraquinones on RIFMO. The findings were subsequently compared with those of rifampicin (RIF), serving as a positive control inhibitor.MethodsThe AutoDock 4.0 tool assessed the binding free energy between 21 anthraquinones and the RIFMO catalytic cleft. The ligands were ranked based on the most favorable scores derived from ΔGbinding. The docking analyses for the highest-ranked anthraquinone and RIF underwent a cross-validation process. This validation procedure utilized the SwissDock server and the Schrödinger Maestro docking software. Molecular dynamics simulations were conducted to scrutinize the stability of the backbone atoms in free RIFMO, RIFMO-RIF, and RIFMO complexed with the top-ranked anthraquinone throughout a 100-ns computer simulation. The Discovery Studio Visualizer tool visualized interactions between RIFMO residues and ligands. An evaluation of the pharmacokinetics and toxicity profiles of the tested compounds was also conducted.ResultsFive anthraquinones were indicated with ΔGbinding scores less than − 10 kcal/mol. Hypericin emerged as the most potent RIFMO inhibitor, boasting a ΔGbinding score and inhibition constant value of − 12.11 kcal/mol and 798.99 pM, respectively. The agreement across AutoDock 4.0, SwissDock, and Schrödinger Maestro results highlighted hypericin’s notable binding affinity to the RIFMO catalytic cleft. The RIFMO-hypericin complex achieved stability after a 70-ns computer simulation, exhibiting a root-mean-square deviation of 0.55 nm. Oral bioavailability analysis revealed that all anthraquinones except hypericin, sennidin A, and sennidin B may be suitable for oral administration. Furthermore, the carcinogenicity prediction analysis indicated a favorable safety profile for all examined anthraquinones.ConclusionInhibiting RIFMO, particularly with anthraquinones such as hypericin, holds promise as a potential therapeutic strategy for infectious diseases.

The Effect of Smoking on Outcomes of Reverse Total Shoulder Arthroplasty

BackgroundThe effect of smoking status on clinical outcomes in reverse total shoulder arthroplasty (rTSA) has not been thoroughly characterized. We sought to compare pain and functional outcomes, complications, and revision-free survivorship between current smokers, former smokers, and non-smokers undergoing primary rTSA. MethodsWe retrospectively reviewed a prospectively-collected shoulder arthroplasty database from 2004-2020 to identify patients who underwent primary rTSA. Three cohorts were created based on smoking status: current smokers, former smokers, and non-smokers. Outcome scores (SPADI, SST, ASES, UCLA, Constant), range of motion (ROM) (external rotation [ER], forward elevation [FE], abduction, internal rotation [IR]) and shoulder strength (ER, FE) evaluated at 2-4-year follow-up were compared between cohorts. The incidence of complication and revision-free implant survivorship were evaluated. ResultsWe included 676 primary rTSAs, including 38 current smokers (44±47 pack-years), 84 former smokers who quit on average 20±14 years (range: 0.5-57 years) prior to surgery (38±32 pack-years), and 544 non-smokers. At 2-4-year follow-up, current smokers had less favorable SPADI, SST, ASES scores, UCLA scores, and Constant scores compared to former smokers and non-smokers. On multivariable analysis, current smokers had less favorable SPADI, SST, ASES score, UCLA score, and Constant score compared to non-smokers. There were no significant differences between cohorts in complication rate and revision-free survivorship. ConclusionOur data showed that current smokers may have poorer functional outcomes after rTSA compared to former smokers and non-smokers despite the incidence of complications and revision surgery not differing significantly between cohorts.