DNA-PKcs-mediated transcriptional regulation of TOP2B drives chemoresistance in acute myeloid leukemia.

Anthracyclines, topoisomerase II enzyme poisons that cause DNA damage, are the mainstay of acute myeloid leukemia (AML) treatment. However, acquired resistance to anthracyclines leads to relapse, which currently lacks effective treatment and is the cause of poor survival in individuals with AML. Therefore, the identification of the mechanisms underlying anthracycline resistance remains an unmet clinical need. Here, using patient-derived primary cultures and clinically relevant cellular models that recapitulate acquired anthracycline resistance in AML, we have found that GCN5 (also known as KAT2A) mediates transcriptional upregulation of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) in AML relapse, independently of the DNA-damage response. We demonstrate that anthracyclines fail to induce DNA damage in resistant cells, owing to the loss of expression of their target enzyme, TOP2B; this was caused by DNA-PKcs directly binding to its promoter upstream region as a transcriptional repressor. Importantly, DNA-PKcs kinase activity inhibition re-sensitized AML relapse primary cultures and cells resistant to mitoxantrone, and abrogated their tumorigenic potential in a xenograft mouse model. Taken together, our findings identify a GCN5-DNA-PKcs-TOP2B transcriptional regulatory axis as the mechanism underlying anthracycline resistance, and demonstrate the therapeutic potential of DNA-PKcs inhibition to re-sensitize resistant AML relapse cells to anthracycline.

Targeting Abnormal Tau Phosphorylation for Alzheimer's Therapeutics.

Alzheimer's disease (AD) is a widespread neurodegenerative disorder characterized by progressive memory and cognitive decline, posing a formidable public health challenge. This review explores the intricate interplay between two pivotal players in AD pathogenesis: ß-amyloid (Aß) and tau protein. While the amyloid cascade theory has long dominated AD research, recent developments have ignited debates about its centrality. Aß plaques and tau NFTs are hallmark pathologies in AD. Aducanumab and lecanemab, monoclonal antibodies targeting Aß, have been approved, albeit amidst controversy, raising questions about the therapeutic efficacy of Aß-focused interventions. On the other hand, tau, specifically its hyperphosphorylation, disrupts microtubule stability and contributes to neuronal dysfunction. Various post-translational modifications of tau drive its aggregation into NFTs. Emerging treatments targeting tau, such as GSK-3ß and CDK5 inhibitors, have shown promise in preclinical and clinical studies. Restoring the equilibrium between protein kinases and phosphatases, notably protein phosphatase-2A (PP2A), is a promising avenue for AD therapy, as tau is primarily regulated by its phosphorylation state. Activation of tau-specific phosphatases offers potential for mitigating tau pathology. The evolving landscape of AD drug development emphasizes tau-centric therapies and reevaluation of the amyloid cascade hypothesis. Additionally, exploring the role of neuroinflammation and its interaction with tau pathology present promising research directions.

"I couldn't connect the wires in my brain." Young adult cancer survivors' experience with cognitive functioning.

OBJECTIVE: There is a dearth of literature describing young adult (YA) cancer survivors' experiences with cancer-related cognitive impairment (CRCI). We aimed to elucidate CRCI among YA cancer survivors and identify potentially modifiable risk factors. METHODS: We conducted individual qualitative interviews with YA cancer survivors aged 18-30 years at study enrollment and used applied thematic analysis to identify themes across three topics (i.e., affected cognitive abilities, risk and protective factors influencing the impact of CRCI, and strategies for coping with CRCI). RESULTS: YA cancer survivors (N = 20) were, on average, 23 years old at diagnosis and 26 years old when interviewed. Diverse cancer types and treatments were represented; most participants (85%) had completed cancer treatment. Participants described experiences across three qualitative topics: (1) affected cognitive abilities (i.e., concentration and attention, prospective memory, and long-term memory), (2) Risk factors (i.e., fatigue, sleep problems, mood, stress/distractions, and social isolation) and protective factors (i.e., social support), and (3) coping strategies, including practical strategies that helped build self-efficacy (e.g., writing things down, reducing distractions), beneficial emotion-focused coping strategies (e.g., focus on health, faith/religion), strategies with mixed effects (i.e., apps/games, medications/supplements, and yoga), and "powering through" strategies that exacerbated stress. CONCLUSIONS: YA cancer survivors experience enduring cognitive difficulties after treatment. Specific concerns highlight the importance of attention and executive functioning impairments, long-term memory recall, and sensitivity to distractions. Future work is needed to improve assessment and treatment of CRCI among YA cancer survivors.

Determinants of pharmacists' confidence to participate in antimicrobial stewardship: A confirmatory factor analysis.

AIM: Pharmacists are essential members of hospital antimicrobial stewardship (AMS) teams. A lack of self-perceived confidence can limit pharmacists' involvement and contributions. Pharmacists working in AMS have reported a lack of confidence. There is currently a lack of validated measures to assess pharmacists' self-perceived confidence when working in AMS and contributors to this confidence. This study aimed to identify variables contributing to pharmacist self-perceived confidence and validate an AMS hospital pharmacist survey tool using confirmatory factor analysis (CFA). METHODS: Responses from a survey of Australian and French hospital pharmacists were used to undertake CFA and path analysis on factors related to pharmacists' self-perceived confidence. It was hypothesized that pharmacists' self-perceived confidence would be impacted by time working in AMS, perceived importance of AMS programmes, perceived barriers to participating in AMS and current participation. RESULTS: CFA demonstrated a good model fit between the factors. Items included in the model loaded well to their respective factors with acceptable reliability. Path analysis demonstrated that time working in AMS had a significant impact on pharmacists' self-perceived confidence, while perceived barriers had a negatively significant relationship. Pharmacy participation in AMS and perceived importance of AMS programmes had a non-significant impact. CONCLUSION: Findings demonstrated that the survey tool showed good validity and identified factors that can impact pharmacists' self-perceived confidence when working in hospital AMS programmes. Having a validated survey tool can identify factors that can reduce pharmacists' self-perceived confidence. Strategies can then be developed to address these factors and subsequently improve pharmacists' self-perceived confidence.

Potentiality of phosphide-based nanotubes for breast cancer detection: A DFT investigation.

Breast cancer is one of the most basilisk cancers for women due to its high mortality rate which can be prevented drastically with early-stage detection. In this work, the adsorption mechanism of two volatile organic compounds that are present in the breath of breast cancer patients, 2-Methyloctane and 3, 3-Dimethylpentane, has been investigated on aluminum phosphide nanotubes (AlPNT) and gallium phosphide nanotubes (GaPNT) in order to understand their feasibility as sensor materials to diagnosis breast cancer at early stage. We have used the quantum mechanical approach by employing density functional theory using B3LYP-D3 hybrid potential for noncovalent interaction along with the LanL2DZ basis in the Gaussian 09 software package. The adsorption properties analyses suggest that GaPNT exhibits better sensing behavior as well as proclaims 12.6% greater adsorption energy for 2-Methyloctane and 9.4% greater adsorption energy for 3, 3-Dimethylpentane than AlPNT. Other structural and electric properties analyses satisfy this conclusion and suggest that GaPNT exhibits higher stability than AlPNT and could possibly be a potential candidate for developing biosensors to detect breast cancer at the preliminary stages.

Formulation of sumatriptan succinate orodispersible tablets using chitosan and sodium starch glycolate for immediate migraine relief.

Migraine is one of the common neurological disease affecting around 23% of the Pakistani population. Prompt treatment is required to regain the functional ability of patients. The present study was designed to develop sumatriptan succinate orodispersible tablets that would quickly overcome acute migraine episodes using 22 full-factorial design. The chitosan and sodium starch glycolate were taken as independent variables; friability, disintegration, dispersion time and water absorption ratio as response variables. Eight trial formulations were generated by Design Expert® software. The main effect plots were used to check the interaction of formulations with response variables. All trial formulations showed good micromeritic properties in terms of angle of repose (19.59o-24.57°), Carr's index (17.08-24.90%) and Hausner's ratio (1.20-1.33). The tablets wetted quickly (17.1- 39 sec) in dispersion medium, showed higher water absorption ratio (188-341 sec) and disintegrated quickly (13-20 sec) with an excellent dissolution rate (94-99%). The main effect plots show interactions between the independent variables against most of the study responses. A 22 full-factorial model was found to be effective in studying the influence of formulation variables on response parameters. Both chitosan and sodium starch glycolate can be used in combination to fabricate an effective orodispersible formulation of sumatriptan succinate.

Phase-specific strategies and interventions to enhance medication adherence across different phases in ADHD: a systematic review and meta-analysis.

INTRODUCTION: This systematic review and meta-analysis assessed the characteristics, types, and impact of interventions to improve adherence to attention-deficit hyperactivity disorder (ADHD) medications within the context of the three phases of adherence, namely, initiation, implementation, and discontinuation. METHODS: PubMed, Psychological Information Database, Embase, International Pharmaceutical Abstracts, and Google Scholar were systematically searched for relevant trials using appropriate search terms. Interventions were classified as educational, behavioural, affective, and multifaceted. Data was pooled using odds ratios and proportions. RESULTS: Seventeen studies were included in this review. In a pooled analysis of four RCTs, interventions did not significantly improve medication adherence (OR = 2.32; 95%-Confidence Interval=CI = 0.91-5.90; p = 0.08). In seven non-randomized trials, a pooled proportion of people who adhered to ADHD medication was considerably higher in the intervention group (85%, 95%CI = 78%-91%) than in the control group (47%, 95%CI = 33%-61%). Interventions varied in terms of study design, methods and their impact on different phases of adherence. CONCLUSIONS: Despite some promising results, the lack of consideration of phase-specific adherence factors may limit the effectiveness and sustainability of interventions to improve adherence in clinical practice. Future interventions should be phase-specific, guided by factors which are pertinent to each phase. Meanwhile, clinicians should choose or tailor interventions based on individual needs and preferences.

Epidemiology of diabetes mellitus in Pakistan: a systematic review protocol.

INTRODUCTION: Diabetes mellitus (DM) is a chronic metabolic disorder characterised by hyperglycaemia resulting from defects in insulin secretion, insulin action or both. As a major global health concern, its prevalence has been steadily increasing. Pakistan, is no exception to this trend, facing a growing burden of non-communicable diseases including DM. This research aims to comprehensively assess the prevalence of DM, and disparities between rural and urban populations as well as between men and women in Pakistan. METHODS AND ANALYSIS: The systematic review will follow Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and will aim to assess DM prevalence in Pakistan. A comprehensive search strategy will be applied to databases like PubMed, Scopus, Cochrane, PakMediNet and CINAHL from inception up to 1st April 2024. We will include studies that focus on diabetes prevalence in the general population, employing WHO or American Diabetes Association criteria for diagnosis of DM. Cross-sectional studies, cohort studies and population-based surveys with a sample size ≥500, in English will be considered. Data extraction will be done as per a predefined proforma which will include study details such as demographics, prevalence data and methodology. A meta-analysis will be performed using a random effect model with an inverse variance weighted method. I2 statistics will be used to examine heterogeneity, and subgroup analyses will be performed. ETHICS AND DISSEMINATION: The findings from the systematic review will be shared by publishing them in a peer-reviewed journal and showcasing them at pertinent conferences. Our analysis will be based on aggregated data and will not involve individual patient information, thus eliminating the need for ethical clearance. PROSPERO REGISTRATION NUMBER: CRD42023453085.

Ocular Syphilis as a Primary Manifestation of Neurosyphilis: A Case Report.

Sexually transmitted infectious diseases could affect a variety of organs, generating significant symptomatology. In the elderly population, infectious causes for vision problems are not generally considered. We present the case of an elderly patient with blurred vision and darkening of visual fields. He underwent an unsuccessful biopsy of the temporal artery as his vision disturbances presented also with episodic headaches. He was found to have an elevated rapid plasma reagin (RPR) and venereal disease research laboratory (VDRL) test in his cerebrospinal fluid (CSF) analysis. He was treated for ocular syphilis with a total resolution of his vision loss.

Effect of JAK Inhibitors on the Risk of Death in Patients with Moderate to Severe COVID-19: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background: The pathophysiology of COVID-19 involves a signalling pathway based on the Janus kinases (JAKs) and the signal transducer and activator of transcription (STAT) family of proteins. As such, there has been growing interest in exploring JAK inhibitors as potential therapeutic agents for this disease. Objective: To provide a comprehensive summary of the efficacy of JAK inhibitors in the treatment of COVID-19 through a systematic review and meta-analysis. Data Sources: A systematic literature search was conducted in multiple electronic databases (PubMed, Scopus, and the Cochrane Central Register of Controlled Trials) and preprint repositories, without language restrictions, to identify relevant studies published up to December 31, 2023. Study Selection and Data Extraction: The primary outcome of interest was all-cause mortality. Randomized controlled trials (RCTs) investigating the administration of JAK inhibitors in patients with COVID-19 were included. Data Synthesis: Through the systematic literature search, a total of 20 RCTs meeting the inclusion criteria were identified. A random-effects model was employed to estimate the pooled odds ratio for death with administration of a JAK inhibitor relative to non-administration of such an agent, with 95% confidence interval. Meta-analysis of these trials revealed a significant reduction in mortality among patients with COVID-19 who received JAK inhibitors relative to those who did not receive these agents (pooled odds ratio 0.70, 95% confidence interval 0.58-0.84). Conclusions: The results of this systematic review and meta-analysis suggest that JAK inhibitors, specifically baricitinib, may address the urgent need for effective treatments in the ongoing COVID-19 pandemic by reducing the risk of death among affected patients. However, further research, including larger-scale RCTs, is needed to establish the efficacy and safety of other JAK inhibitors in the treatment of COVID-19 and to generate more robust evidence regarding their use in this specific patient population.

Contexte: La physiopathologie de la COVID-19 implique une voie de signalisation basée sur les Janus kinases (JAK) et les protéines STAT (pour signal transducer and activator of transcription en anglais, soit, les protéines transductrices de signal et activatrices de transcription). C'est pourquoi l'étude des inhibiteurs de JAK en tant qu'agents thérapeutiques potentiels pour cette maladie suscite un intérêt croissant. Objectif: Fournir un résumé complet de l'efficacité des inhibiteurs de JAK dans le traitement de la COVID-19 grâce à une revue systématique et une méta-analyse. Sources des données: Une recherche systématique de la littérature a été menée dans plusieurs bases de données électroniques (PubMed, Scopus et le Cochrane Central Register of Controlled Trials) et dans les référentiels de prépublications, sans restrictions linguistiques, pour identifier les études pertinentes publiées jusqu'au 31 décembre 2023. Sélection des études et extraction des données: Le principal résultat d'intérêt était la mortalité, toutes causes confondues. Des essais contrôlés randomisés (ECR) portant sur l'administration d'inhibiteurs de JAK chez des patients atteints de COVID-19 ont été inclus. Synthèse des données: Grâce à la recherche documentaire systématique, un total de 20 ECR répondant aux critères d'inclusion ont été identifiés. Un modèle à effets aléatoires a été utilisé pour estimer le rapport de cotes groupé de décès avec l'administration d'un inhibiteur de JAK par rapport à la non-administration d'un tel agent, avec un intervalle de confiance de 95 %. La méta-analyse de ces essais a révélé une réduction significative de la mortalité chez les patients atteints de COVID-19 ayant reçu des inhibiteurs de JAK par rapport à ceux n'ayant pas reçu ces agents (rapport de cotes groupé 0,70, intervalle de confiance à 95 % 0,58­0,84). Conclusions: Les résultats de cette revue systématique et méta-analyse indiquent que les inhibiteurs de JAK, en particulier le baricitinib, pourraient répondre au besoin urgent de traitements efficaces dans le cadre de la pandémie de COVID-19 en cours en réduisant le risque de décès parmi les patients touchés. Cependant, des recherches supplémentaires, y compris des ECR à plus grande échelle, sont nécessaires pour établir l'efficacité et l'innocuité d'autres inhibiteurs de JAK dans le traitement de la COVID-19 et pour générer des éléments probants plus solides concernant leur utilisation dans cette population de patients en particulier.

Targeting oncogenic kinases: Insights on FDA approved tyrosine kinase inhibitors.

Protein kinases play pivotal roles in various biological functions, influencing cell differentiation, promoting survival, and regulating the cell cycle. The disruption of protein kinase activity is intricately linked to pathways in tumor development. This manuscript explores the transformative impact of protein kinase inhibitors on cancer therapy, particularly their efficacy in cases driven by targeted mutations. Focusing on key tyrosine kinase inhibitors (TKIs) like Bcr-Abl, Epidermal Growth Factor Receptor (EGFR), and Vascular Endothelial Growth Factor Receptor (VEGFR), it targets critical kinase families in cancer progression. Clinical trial details of these TKIs offer insights into their therapeutic potentials. Learning from FDA-approved kinase inhibitors, the review dissects trends in kinase drug development since imatinib's paradigm-shifting approval in 2001. TKIs have evolved into pivotal drugs, extending beyond oncology. Ongoing clinical trials explore novel kinase targets, revealing the vast potential within the human kinome. The manuscript provides a detailed analysis of advancements until 2022, discussing the roles of specific oncogenic protein kinases in cancer development and carcinogenesis. Our exploration on PubMed for relevant and significant TKIs undergoing pre-FDA approval phase III clinical trials enriches the discussion with valuable findings. While kinase inhibitors exhibit lower toxicity than traditional chemotherapy in cancer treatment, challenges like resistance and side effects emphasize the necessity of understanding resistance mechanisms, prompting the development of novel inhibitors like osimertinib targeting specific mutant proteins. The review advocates thorough research on effective combination therapies, highlighting the future development of more selective RTKIs to optimize patient-specific cancer treatment and reduce adverse events.

Unveiling the nexus: Understanding post-COVID parkinsonism and its neurological ramifications.

This article explores the potential link between COVID-19 and parkinsonism, synthesizing existing evidence and recent research findings. It highlights limitations in current understanding, emphasizes the direct impact of the virus on dopamine neurons, and calls for continued research to elucidate long-term neurological implications and optimize patient care strategies.

Effect of intravenous immunoglobulin on mortality in hospitalized patients with COVID-19: A systematic review and meta-analysis of randomized controlled trials.

Background and Aims: We performed a meta-analysis of randomized controlled trials (RCTs) to summarize the overall effect of intravenous immunoglobulin (IVIG) on mortality outcomes among hospitalized coronavirus disease 2019 (COVID-19) patients. Methods: We systematically searched electronic databases up to June 1, 2023. Pooled odds ratio (OR) of mortality with a 95% confidence interval (CI) was generated using a random-effects model. The risk of bias was appraised using the Cochrane risk-of-bias Version 2 tool for randomized trials. Results: Nine RCTs were included: three RCTs had an overall low risk of bias, four RCTs had some concerns in the overall risk of bias, and two RCTs trials had an overall high risk of bias. The use of IVIG indicated a significant reduction in the odds of mortality (pooled OR = 0.69; 95% CI 0.50-0.96) relative to nonuse of IVIG. Subgroup analysis in patients with a severe course of COVID-19 revealed no significant reduction in the odds of mortality (pooled OR = 0.58; 95% CI 0.29-1.16). Conclusions: We suggest exercising caution when interpreting effectiveness of IVIG in reducing mortality among hospitalized patients with COVID-19. Our findings emphasize for larger trials with rigorous study designs to better understand the impact of IVIG, particularly in those with severe COVID-19.

Impact of uricosurics on mortality outcomes in patients with COVID-19: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVES: To determine risks associated with uricosurics in COVID-19 patients. METHODS: A systematic review and meta-analysis was conducted by systematically searching electronic databases. KEY FINDINGS: The pooled analysis of the included trials revealed that the use of uricosurics was not associated with the risk of mortality (pooled odds ratio [OR] = 1.03, 95% confidence interval [CI]: 0.94-1.12). However, there is a potential mortality benefit associated with the use of ascorbic acid (pooled OR = 0.78, 95% CI: 0.65-0.94). CONCLUSIONS: The findings confirmed the safety of uricosurics in COVID-19 patients, despite their potential to cause uric acid excretion, which may possess antioxidant properties.

The Prevention of Seroma Formation Following Modified Radical Mastectomy by Intravenous Hydrocortisone Injection.

Introduction Seroma formation is the most common complication after modified radical mastectomy (MRM). It leads to increased pain and discomfort, potentially prolonging morbidity and treatment. Various treatment modalities are being used to decrease the incidence of seroma formation. The objective of this study was to compare intravenous hydrocortisone injection versus placebo in patients undergoing MRM in terms of frequency of post-operative seroma formation. Methods This randomized, double-blinded, placebo-controlled study was conducted at Surgical Unit-I, Holy Family Hospital, Rawalpindi, Pakistan from January 2021 to December 2021. A total of 152 female patients were randomly assigned to each of the study and placebo groups. Group I patients received 100 mg of hydrocortisone intravenously while group II patients received one ml of 0.9% normal saline intravenously prior to induction of general anesthesia for MRM. The incidence of seroma formation after 10 days of MRM and total drain volume till their removal was measured in all patients. Results The mean age was 48.42±10.15 in Group I, while it was 47.67±10.75 in Group II. Mean drain output till removal was 99.14±31.01 ml in the hydrocortisone group and 177.57±63.37 ml in the placebo group. Forty-eight patients developed seroma (31.58%), of whom nine received intravenous hydrocortisone and 39 received normal saline (P=0.000). Conclusion Intravenous hydrocortisone is effective in terms of frequency of post-operative seroma formation as compared to placebo in patients undergoing MRM.

A real-world exploration into clinical outcomes of direct oral anticoagulant therapy in people with chronic kidney disease: a large hospital-based study.

BACKGROUND: There is limited evidence to support definite clinical outcomes of direct oral anticoagulant (DOAC) therapy in chronic kidney disease (CKD). By identifying the important variables associated with clinical outcomes following DOAC administration in patients in different stages of CKD, this study aims to assess this evidence gap. METHODS: An anonymised dataset comprising 97,413 patients receiving DOAC therapy in a tertiary health setting was systematically extracted from the multidimensional electronic health records and prepared for analysis. Machine learning classifiers were applied to the prepared dataset to select the important features which informed covariate selection in multivariate logistic regression analysis. RESULTS: For both CKD and non-CKD DOAC users, features such as length of stay, treatment days, and age were ranked highest for relevance to adverse outcomes like death and stroke. Patients with Stage 3a CKD had significantly higher odds of ischaemic stroke (OR 2.45, 95% Cl: 2.10-2.86; p = 0.001) and lower odds of all-cause mortality (OR 0.87, 95% Cl: 0.79-0.95; p = 0.001) on apixaban therapy. In patients with CKD (Stage 5) receiving apixaban, the odds of death were significantly lowered (OR 0.28, 95% Cl: 0.14-0.58; p = 0.001), while the effect on ischaemic stroke was insignificant. CONCLUSIONS: A positive effect of DOAC therapy was observed in advanced CKD. Key factors influencing clinical outcomes following DOAC administration in patients in different stages of CKD were identified. These are crucial for designing more advanced studies to explore safer and more effective DOAC therapy for the population.

Trends in prescription and cost of Sativex, a cannabinoid-based medicine, in treating patients with multiple sclerosis in England.

Aim: Cannabis-based medication has recently been made available in the NHS for reducing pain and spasticity in patients with multiple sclerosis (MS). The currently available preparation of Sativex (nabiximols) contains a combination of botanical cannabis extracts with cannabidiol (CBD) and tetrahydrocannabinol (THC) with almost equal amounts in addition to minor cannabinoids and terpenoids and is delivered via an oro-mucosal spray. The present study aims to examine the use and trends in prescribing cannabinoid-based Sativex to control pain in patients diagnosed with MS. Methods: Primary care prescribing data for cannabinoid-based Sativex (2013-2022) from the Prescription Cost Analysis were extracted and analysed. Linear regression analyses were performed to examine prescription trends and prescription costs (average change per year). Results: There was a general increasing trend in the number of prescriptions each year, from 4.42 items dispensed per 100,000 people in 2013 to 5.15 in 2022. Overall, prescription items for cannabinoid-based Sativex increased by 0.34% per year (95% CI:-3.98, 4.67, p = 0.860) on average between 2013 and 2022. On average, a 2.43% (95% CI: -5.78, 0.92, p = 0.133) increase per year was observed for the costs of cannabinoid-based Sativex from 2013 to 2022. Conclusion: The results suggested that cannabinoid-based Sativex should be considered an option due to its effectiveness, acceptable tolerance, and safety profile in the prescribing of Sativex.