QSAR modelling, molecular docking, molecular dynamic and ADMET prediction of pyrrolopyrimidine derivatives as novel Bruton's tyrosine kinase (BTK) inhibitors.

In recent years, there has been a focus on developing and discovering novel Bruton's tyrosine kinase (BTK) inhibitors, as they offer an effective treatment strategy for B-cell malignancies. BTK plays a crucial role in B cell receptor (BCR)-mediated activation and proliferation by regulating downstream factors such as the NF-κB and MAP kinase pathways. To address this challenge and propose potential therapeutic options for B-cell lymphomas, researchers conducted 2D-QSAR and ADMET studies on pyrrolopyrimidine derivatives that act as inhibitors of the BCR site in cytochrome b. These studies aim to improve and identify new compounds that could serve as more potent potential BTK inhibitors, which would lead to the identification of new drug candidates in this field. In our study, we used 2D-QSAR (multiple linear regression, multiple nonlinear regression, and artificial neural networks), molecular docking, molecular dynamics, and ADMET properties to investigate the potential of 35 pyrrolopyrimidine derivatives as BTK inhibitors. A molecular docking study and molecular dynamics simulations of molecule 13 over 10 ns revealed that it establishes multiple hydrogen bonds with several residues and exhibits frequent stability throughout the simulation period. Based on the results obtained by molecular modeling, we proposed six new compounds (Pred1, Pred2, Pred3, Pred4, Pred5, and Pred6) with highly significant predicted activity by MLR models. A study based on the in silico evaluation of the predicted ADMET properties of the new candidate molecules is strongly recommended to classify these molecules as promising candidates for new anticancer agents specifically designed to target Bruton's tyrosine kinase (BTK) inhibition.

The CaSR Modulator NPS-2143 Reduced UV-Induced DNA Damage in Skh:hr1 Hairless Mice but Minimally Inhibited Skin Tumours.

The calcium-sensing receptor (CaSR) is an important regulator of epidermal function. We previously reported that knockdown of the CaSR or treatment with its negative allosteric modulator, NPS-2143, significantly reduced UV-induced DNA damage, a key factor in skin cancer development. We subsequently wanted to test whether topical NPS-2143 could also reduce UV-DNA damage, immune suppression, or skin tumour development in mice. In this study, topical application of NPS-2143 (228 or 2280 pmol/cm2) to Skh:hr1 female mice reduced UV-induced cyclobutane pyrimidine dimers (CPD) (p < 0.05) and oxidative DNA damage (8-OHdG) (p < 0.05) to a similar extent as the known photoprotective agent 1,25(OH)2 vitamin D3 (calcitriol, 1,25D). Topical NPS-2143 failed to rescue UV-induced immunosuppression in a contact hypersensitivity study. In a chronic UV photocarcinogenesis protocol, topical NPS-2143 reduced squamous cell carcinomas for only up to 24 weeks (p < 0.02) but had no other effect on skin tumour development. In human keratinocytes, 1,25D, which protected mice from UV-induced skin tumours, significantly reduced UV-upregulated p-CREB expression (p < 0.01), a potential early anti-tumour marker, while NPS-2143 had no effect. This result, together with the failure to reduce UV-induced immunosuppression, may explain why the reduction in UV-DNA damage in mice with NPS-2143 was not sufficient to inhibit skin tumour formation.

Resilience and prenatal mental health in Pakistan: a qualitative inquiry.

BACKGROUND: Women in Pakistan suffer from a high rate of depression. The stress of low-income, illiteracy, exposure to violence and living in a patriarchal society are predisposing vulnerabilities for depression, particularly during and following pregnancy. The resilience of an individual plays a significant role in promoting prenatal mental health, but this has yet to be thoroughly researched. In this article, our objective is to identify the core characteristics of resilience among pregnant women, which will then help us in developing an intervention. METHODS: The exploratory-descriptive study was conducted over 6 months in five different antenatal hospitals in Sindh, Pakistan. A total of 17 semi-structured interviews were conducted with pregnant women, purposefully selected with heterogeneous characteristics to explore diverse perspectives, while symptoms of depression were quantified by the Edinburgh Postnatal Depression Scale before the interview. Verbatim transcriptions were coded openly and merged into categories and themes. RESULT: A total of six themes emerged from in-depth thematic analysis: 1) purpose of life, 2) dealing with emotions, 3) believing in yourself, 4) optimistic approach, 5) strengthening support and relationship and 6) spirituality and humanity. Women agreed that these characteristics could help them improve their mental health. CONCLUSION: In conclusion, these themes were the core components of pregnant women's resilience which ultimately could help to promote prenatal mental health. These pave a pathway towards developing culturally and contextually resilience interventions aimed at enhancing mental health of pregnant women which then may improve neonatal and family mental wellbeing.

A Systematic Review of the Biological Effects of Cordycepin.

We conducted a systematic review of the literature on the effects of cordycepin on cell survival and proliferation, inflammation, signal transduction and animal models. A total of 1204 publications on cordycepin were found by the cut-off date of 1 February 2021. After application of the exclusion criteria, 791 papers remained. These were read and data on the chosen subjects were extracted. We found 192 papers on the effects of cordycepin on cell survival and proliferation and calculated a median inhibitory concentration (IC50) of 135 µM. Cordycepin consistently repressed cell migration (26 papers) and cellular inflammation (53 papers). Evaluation of 76 papers on signal transduction indicated consistently reduced PI3K/mTOR/AKT and ERK signalling and activation of AMPK. In contrast, the effects of cordycepin on the p38 and Jun kinases were variable, as were the effects on cell cycle arrest (53 papers), suggesting these are cell-specific responses. The examination of 150 animal studies indicated that purified cordycepin has many potential therapeutic effects, including the reduction of tumour growth (37 papers), repression of pain and inflammation (9 papers), protecting brain function (11 papers), improvement of respiratory and cardiac conditions (8 and 19 papers) and amelioration of metabolic disorders (8 papers). Nearly all these data are consistent with cordycepin mediating its therapeutic effects through activating AMPK, inhibiting PI3K/mTOR/AKT and repressing the inflammatory response. We conclude that cordycepin has excellent potential as a lead for drug development, especially for age-related diseases. In addition, we discuss the remaining issues around the mechanism of action, toxicity and biodistribution of cordycepin.

Nurses' perceptions about the dignity of intubated patients.

BACKGROUND: The intensive and critical care units are high-dependency areas, with patients requiring complex care. The intubated status of the intensive and critical care patients makes them dependent on healthcare providers not only for acute care, but also for intimate care, imposing a threat to their dignity. Nurses, being the central care providers, become the stakeholders for dignity promotion. The incorporation of dignity in patient care improves the quality of care, and promotes the health and well-being of intubated patients. OBJECTIVE: The purpose of the study was to explore nurses' perceptions about the dignity of intubated patients in the intensive and critical care units. RESEARCH DESIGN: A qualitative descriptive exploratory study design was used to explore the nurses' perceptions about the dignity of intubated patients. PARTICIPANTS AND RESEARCH CONTEXT: The intensive and critical care nurses of a tertiary care hospital were recruited using the purposive sampling technique. The data were collected through in-depth individual interviews, using a semi-structured interview guide. The findings were manually analyzed into themes and categories through content analysis. ETHICAL CONSIDERATION: The study was conducted after the approval from the Ethical Review Committee of the Aga Khan University. FINDINGS: Four major themes emerged from the data analysis: (1) two sides of the contemporary nursing practice; (2) benefits of dignified nursing care; (3) challenges to the dignity of intubated patients; and (4) strategies for promoting the dignity of intubated patients. DISCUSSION: Dignity incorporates both the science and the art of nursing. The provision of dignified care is the core component of the quality nursing care and patient well-being in the high-dependency units. CONCLUSION: This is the first exploratory and descriptive study conducted in Pakistan that explored the nurses' perceptions about the dignity of intubated patients, and also generated contextual understanding about the phenomenon.

Homer1 mediates CaSR-dependent activation of mTOR complex 2 and initiates a novel pathway for AKT-dependent ß-catenin stabilization in osteoblasts.

The calcium-sensing receptor (CaSR) is critical for skeletal development, but its mechanism of action in osteoblasts is not well-characterized. In the central nervous system (CNS), Homer scaffolding proteins form signaling complexes with two CaSR-related members of the G protein-coupled receptor (GPCR) family C, metabotropic glutamate receptor 1 (mGluR1) and mGluR5. Here, we show that CaSR and Homer1 are co-expressed in mineralized mouse bone and also co-localize in primary human osteoblasts. Co-immunoprecipitation experiments confirmed that Homer1 associates with CaSR in primary human osteoblasts. The CaSR-Homer1 protein complex, whose formation was increased in response to extracellular Ca2+, was bound to mechanistic target of rapamycin (mTOR) complex 2 (mTORC2), a protein kinase that phosphorylates and activates AKT Ser/Thr kinase (AKT) at Ser473 siRNA-based gene-silencing assays with primary osteoblasts revealed that both CaSR and Homer1 are required for extracellular Ca2+-stimulated AKT phosphorylation and thereby inhibit apoptosis and promote AKT-dependent ß-catenin stabilization and cellular differentiation. To confirm the role of the CaSR-Homer1 complex in AKT initiation, we show that in HEK-293 cells, co-transfection with both Homer1c and CaSR, but neither with Homer1c nor CaSR alone, establishes sensitivity of AKT-Ser473 phosphorylation to increases in extracellular Ca2+ concentrations. These findings indicate that Homer1 mediates CaSR-dependent AKT activation via mTORC2 and thereby stabilizes ß-catenin in osteoblasts.

Quantitative structure-activity relationship (QSAR) and design of novel ligands that demonstrate high potency and target selectivity as protein tyrosine phosphatase 1B (PTP 1B) inhibitors as an effective strategy used to model anti-diabetic agents.

Diabetes and obesity have increased dramatically in recent decades worldwide. Diabetes mainly emerged as a major health care burden disease in both the US and other industrialized countries, among which type II diabetes is the most common. Discovering new and effective treatments for diabetes is currently a high international health priority. In the present study a computational technique was used to model 97 compounds with PTP-1B inhibitory activity, in order to demonstrate the Quantitative structure-activity relationship (QSAR) of these compounds a genetic function approximation (GFA) algorithm was applied to pick the best descriptors and multiple linear regression (MLR) was used to establish a relationship between the PTP-1B inhibitory activity of these compounds and the best molecular descriptors. This QSAR study allowed investigating the influence of very simple and easy-to-compute descriptors in determining biological activities, which shed light on the key factors that aid in the design of novel potent molecules using computer-aided drug design tools.

Modulatory role of rutin on 2,5-hexanedione-induced chromosomal and DNA damage in rats: validation of computational predictions.

The aim of this study was to evaluate the potentials of rutin on 2,5-hexanedione-induced toxicities. Two successive phases were involved using in silico and in vivo approaches. The in silico was adopted for potential oral toxicity and docking. The in vivo was carried-out in two stages for two weeks; the ameliorative (stage 1, first week), preventive, and curative studies (stage 2, extended to second week). In stage 1, rats were divided into four groups of seven each (distilled water, 3% (v/v) 2,5-hexanedione, 10 mg/kg rutin, and co-administration). In stage 2, the experimental groups were given either rutin or 2,5-hexanedione and treated in reverse order. Lipid peroxidation, protein carbonyl, and DNA fragmentation in tissues and bone marrow cells micronucleus were determined. The predicted Median lethal dose (LD50) of >5000 mg/kg and toxicity class of five (5) indicates the safety of rutin when orally administered. 2,5-Hexanedione comfortably docked in to the active sites of SOD (-22.857Kcal/mol; KI = 0.9621 µM), GPx (-11.2032Kcal/mol; KI = 0.9813 µM), and CAT (-16.446Kcal/mol; KI = 0.9726 µM) with strong hydrogen bond and hydrophobic interactions. However, only strong hydrophobic interaction was observed in the case of DNA (-3.3296Kcal/mol; KI = 0.9944). In vivo findings revealed deleterious effects of 2,5-hexanedione through induction of oxidative and chromosomal/DNA damage characterized by higher level of malondialdehyde, micronuclei formations, and DNA fragmentation. These have invariably, validates the findings from in silico experiments. Furthermore, rutin was able to ameliorate, protect, and reverse these effects, and was relatively non-toxic corroborating toxicity predictions. Rutin exhibited counteractive effects on 2,5-hexanedione-induced oxidative, chromosomal, and DNA damage.

Change Management in Health Care and Mental Health Nursing.

Since Nightingale implied that progress was inherent in good nursing, change has slowly but surely accelerated to a frenetic pace in health care and to a degree in nursing. However, the healthy progress and implications associated with change in the nursing profession are not as readily embraced as this pace may imply. Rather, embracing change at the core of nursing and health care is a challenge as this is a group who it is suggested are not only resistant but also adept at reinforcing the status quo. Using mental health nursing as an example this position paper addresses the concept of change management, explores the facilitators and inhibitors to explain why change is not effectively managed at times. Further, case studies provided exemplify how change in mental health nursing has occurred and demonstrate how the concept of change management effectively has been achieved. Key strategies for change management are outlined in this article, noting the need to be sensitive to the culture and specifics of that organisation, because change takes place within people rather than within the organisation itself. Part of the challenges and strategies faced in the profession are related to the movement of information and knowledge from the point of research to implementation of evidence-based best practice. Leaders, therefore, should adopt change management principles and strategies, to further drive the developments which have changed mental health nursing over a relatively short period.

Effectiveness of Subcutaneous Methotrexate in Chronic Plaque Psoriasis.

BACKGROUND: Oral methotrexate (MTX) has been a first line systemic agent in the treatment of chronic plaque psoriasis (CPP) for more than 50 years. Parenteral MTX, administered as a subcutaneous (SC) injection has gained favour in recent years. The effectiveness of SC MTX has been proven in rheumatological conditions but there has been no assessment of its role in CPP. METHODS: We retrospectively reviewed case notes of 85 patients prescribed SC MTX for psoriasis in three dermatology centres in the UK (Betsi Cadwaladr University Health Board, Western Infirmary, Glasgow, and Salford Royal NHS Foundation Trust). Audit department approval was sought and granted. RESULTS: A total of 85 patients (44 male; 41 female; age range 14 - 78 years, mean 44 years; 79 Caucasian, 6 Asian) with CPP were identified. The average duration of psoriasis was 19 years [range 3 - 60 years]. Co-morbidities included depression, diabetes mellitus, hypertension, epilepsy, obesity, ischaemic heart disease, and hyperlipidaemia; 29 patients had no associated co-morbidities. Psoriatic arthritis was noted in 18 patients. Previous treatments included phototherapy (both narrow band ultraviolet B [TLO1] and psoralen and ultraviolet A [PUVA])(n=60), oral MTX (n=82), ciclosporin (n=37), acitretin (n=19), fumaric acid esters (n=20), hydroxycarbamide (n=6), mycophenolate mofetil (n=2), and repeated in-patient admissions (n=2). Oral MTX was stopped due to nausea (n=43), ineffectiveness (n=13) or partial response (n=11), headache (n=3), increased liver enzymes (n=2), and lethargy (n=2). The median number of systemic agents used prior to SC MTX was 3 (mean 2.65, range 1 to 6 agents). The weekly dose of SC MTX varied between 7.5mg to 30 mg (mean 18.5mg, median 20mg) and had been used for 2 months to 67 months (mean 14 months; median 9 months). Folic acid supplementation was used in every patient. The patients were reviewed between 6 weeks to 3 months once treatment was fully established. Using a pre-determined "adjective list" (where specific adjectives were used to denote those who responded or did not respond to treatment), patients were classified as "responders" (n=59) or "non-responders" (n=26). CONCLUSION: This study suggests that SC MTX is an effective option in patients with CPP who have failed oral MTX and could be a worthwhile consideration prior to commencement of a biologic agent. Furthermore, the SC route may be a viable first choice of MTX administration. A randomised controlled trial comparing oral and SC MTX is required to validate these findings.

The FinO family of bacterial RNA chaperones.

Antisense RNAs have long been known to regulate diverse aspects of plasmid biology. Here we review the FinOP system that modulates F plasmid gene expression through regulation of the F plasmid transcription factor, TraJ. FinOP is a two component system composed of an antisense RNA, FinP, which represses TraJ translation, and a protein, FinO, which is required to stabilize FinP and facilitate its interactions with its traJ mRNA target. We review the evidence that FinO acts as an RNA chaperone to bind and destabilize internal stem-loop structures within the individual RNAs that would otherwise block intermolecular RNA duplexing. Recent structural studies have provided mechanistic insights into how FinO may facilitate interactions between FinP and traJ mRNA. We also review recent findings that two other proteins, Escherichia coli ProQ and Neisseria meningitidis NMB1681, may represent FinO-like RNA chaperones.

Mapping publication status and exploring hotspots in a research field: chronic disease self-management.

AIM: To provide insight into the characteristics of chronic disease self-management by mapping publication status and exploring hotspots. BACKGROUND: Chronic disease is becoming a major public health issue worldwide, highlighting the importance of self-management in this area. Despite the volume and variety of publications, little is known about how 'chronic disease self-management' has developed, since the first publication 40 years ago. Such is the number of publications in the area, that there is a need for a systematic bibliographic examination to enable clinicians and researchers to navigate this literature. DESIGN: A bibliometric analysis of publications was used. METHODS: Publication status was achieved using BICOMB software, whereas hotspots were identified with Ucinet software. A search of PubMed was conducted for papers published between 1971-2012. RESULTS: By 2011, the number of publications reached 696, a fourfold increase from the previous 10 years, of which 75% came from the USA and UK. There were 1284 journals, which published chronic disease self-management research, involving various disciplines. The research hotspots highlighted various self-management strategies for the following: diabetes; cardiac vascular and pulmonary chronic disease; pain relief for neoplasms; and obesity. Psychological adjustment was a permeating theme in self-management processes as was using internet-based interventions. CONCLUSION: Self-management in chronic disease publication has been most evident in developed countries. The bibliographic mapping and identification of publication hotspots provides scholars and practitioners with key target journals, as well as a rigorous overview of the field for use in further research, evidence-based practice and health policy development.

Risk Factors for Invasive Fungal Infection in Lung Transplant Recipients on Universal Antifungal Prophylaxis.

Background: Many centers use universal antifungal prophylaxis after lung transplant, but risk factors for invasive fungal infection (IFI) in this setting are poorly described. Methods: This retrospective, single-center cohort study including 603 lung transplant recipients assessed risk factors for early (within 90 days of transplant) invasive candidiasis (IC) and invasive mold infection (IMI) and late (90-365 days after transplant) IMI using Cox proportional hazard regression. Results: In this cohort, 159 (26.4%) patients had 182 IFIs. Growth of yeast on donor culture (hazard ratio [HR], 3.30; 95% CI, 1.89-5.75) and prolonged length of stay (HR, 1.02; 95% CI, 1.01-1.03) were associated with early IC risk, whereas transplantation in 2016 or 2017 (HR, 0.21; 95% CI, 0.06-0.70; HR, 0.25; 95% CI, 0.08-0.80, respectively) and female recipient sex (HR, 0.53; 95% CI, 0.30-0.93) were associated with reduced risk. Antimold therapy (HR, 0.21; 95% CI, 0.06-0.78) was associated with lower early IMI risk, and female donor sex (HR, 0.40; 95% CI, 0.22-0.72) was associated with lower late IMI risk. Recent rejection was a risk factor for late IMI (HR, 1.73; 95% CI, 1.02-2.95), and renal replacement therapy predisposed to early IC, early IMI, and late IMI (HR, 5.67; 95% CI, 3.01-10.67; HR, 7.54; 95% CI, 1.93-29.45; HR, 5.33; 95% CI, 1.46-19.49, respectively). Conclusions: In lung transplant recipients receiving universal antifungal prophylaxis, risk factors for early IC, early IMI, and late IMI differ.

Provider attitudes towards quality improvement for myocardial infarction care in northern Tanzania.

INTRODUCTION: Myocardial Infarction (MI) is a leading cause of death worldwide. In high income countries, quality improvement strategies have played an important role in increasing uptake of evidence-based MI care and improving MI outcomes. The incidence of MI in sub-Saharan Africa is rising, but uptake of evidence-based care in northern Tanzania is low. There are currently no published quality improvement interventions from the region. The objective of this study was to determine provider attitudes towards a planned quality improvement intervention for MI care in northern Tanzania. METHODS: This study was conducted at a zonal referral hospital in northern Tanzania. A 41-question survey, informed by the Theoretical Framework for Acceptability, was developed by an interdisciplinary team from Tanzania and the United States. The survey, which explored provider attitudes towards MI care improvement, was administered to key provider stakeholders (physicians, nurses, and hospital administrators) using convenience sampling. RESULTS: A total of 140 providers were enrolled, including 82 (58.6%) nurses, 56 (40.0%) physicians, and 2 (1.4%) hospital administrators. Most participants worked in the Emergency Department or inpatient medical ward. Providers were interested in participating in a quality improvement project to improve MI care at their facility, with 139 (99.3%) strongly agreeing or agreeing with this statement. All participants agreed or strongly agreed that improvements were needed to MI care pathways at their facility. Though their facility has an MI care protocol, only 88 (62.9%) providers were aware of it. When asked which intervention would be the single-most effective strategy to improve MI care, the two most common responses were provider training (n = 66, 47.1%) and patient education (n = 41, 29.3%). CONCLUSION: Providers in northern Tanzania reported strongly positive attitudes towards quality improvement interventions for MI care. Locally-tailored interventions to improve MI should include provider training and patient education strategies.

Evaluating the performance of the HEART score in a Tanzanian emergency department.

OBJECTIVE: The HEART score successfully risk stratifies emergency department (ED) patients with chest pain in high-income settings. However, this tool has not been validated in low-income countries. METHODS: This is a secondary analysis of a prospective observational study that was conducted in a Tanzanian ED from January 2019 through January 2023. Adult patients with chest pain were consecutively enrolled, and their presenting symptoms and medical history were recorded. Electrocardiograms and point-of-care troponin assays were obtained for all participants. Thirty-day follow-up was conducted, assessing for major adverse cardiac events (MACEs), defined as death, myocardial infarction, or coronary revascularization (coronary artery bypass grafting or percutaneous coronary intervention). HEART scores were calculated for all participants. Likelihood ratios, sensitivity, specificity, and negative predictive values (NPVs) were calculated for each HEART cutoff score to predict 30-day MACEs, and area under the curve (AUC) was calculated from the receiver operating characteristic curve. RESULTS: Of 927 participants with chest pain, the median (IQR) age was 61 (45.5-74.0) years. Of participants, 216 (23.3%) patients experienced 30-day MACEs, including 163 (17.6%) who died, 48 (5.2%) with myocardial infarction, and 23 (2.5%) with coronary revascularization. The positive likelihood ratio for each cutoff score ranged from 1.023 (95% CI 1.004-1.042; cutoff ≥ 1) to 3.556 (95% CI 1.929-6.555; cutoff ≥ 7). The recommended cutoff of ≥4 to identify patients at high risk of MACEs yielded a sensitivity of 59.4%, specificity of 52.8%, and NPV of 74.7%. The AUC was 0.61. CONCLUSIONS: Among patients with chest pain in a Tanzanian ED, the HEART score did not perform as well as in high-income settings. Locally validated risk stratification tools are needed for ED patients with chest pain in low-income countries.

Autogenous breast reconstruction for total mastectomies: a narrative review.

Background and Objective: Mastectomies have a significant socio-psychological impact, motivating patients to undergo breast reconstruction. Initially, silicone implants were used to reconstruct the breast. However, breast implants have been the subject of successive crises throughout the years. Indeed, rupture, silicone bleeding, and capsular contracture remain topical. In 2019, the BIOCELL textured breast implants was banned and recalled due to the discovery of the breast implant-associated anaplastic large cell lymphoma (BIA-ALCL). More recently, the breast implant illness has been depicted in the media. To cope with these issues and to respond to some patients' expectations for a natural reconstruction, plastic surgeons have developed autogenous solutions for breast reconstruction. Since Taylor's research on angiosomes, the development of the microsurgery and more recently fat grafting, autogenous breast reconstruction has known a tremendous expansion. Autologous breast reconstruction allows a more natural feeling and texture. This narrative review aims to provide to the readers a comprehensive and updated evidence-based overview of state of the art about autologous breast reconstruction after total mastectomy. Methods: We conducted a narrative review of the literature searching for papers published between January 2010 and December 2022. The MeSH terms with different combinations were used to identify articles for inclusion. After screening article titles and abstracts independently by three authors, 66 papers were included in this review. Key Content and Findings: In this review, the authors describe and discuss the different autogenous techniques in breast reconstruction. Conclusions: Autologous reconstructions provide very satisfactory, durable, and reliable results with relatively low complication rates. Deep inferior epigastric perforator (DIEP) flaps, latissimus dorsi flaps and autologous fat grafting are the most common type of autogenous breast reconstructions.