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Bhagat Manku,1 Tiam Mana Saffari,2 Vinesh Sandhu,3 Ankur Khajuria4,5 1Department of Surgery, South Warwickshire NHS Foundation Trust, Warwickshire, UK; 2Department of Plastic and Reconstructive Surgery, Ohio State University, Columbus, OH, USA; 3University College London Division of Medicine, University College London, London, UK; 4Kellogg College, University of Oxford, Oxford, UK; 5Department of Surgery & Cancer, Imperial College London, London, UKCorrespondence: Bhagat Manku, Email Bhagat.Manku@swft.nhs.ukBackground: Systematic reviews and meta-analyses allow a transparent, rigorous, and replicable analysis to summarize the results of multiple related studies and are considered top of the evidence-based medicine study hierarchy. The COVID-19 pandemic has shed light on the unmet educational needs of students worldwide, notably those from underprivileged backgrounds. This cross-sectional study aimed to ascertain students’ and junior doctors’ attitudes on their current knowledge, confidence and preparedness of appraising and conducting systematic reviews and meta-analysis internationally.Methods: A free online webinar was held in May 2021 by the senior author and a pre-event questionnaire was distributed. Responses collected were used for analysis anonymously to ascertain students’ knowledge, experience, and confidence in preparing a systematic review and meta-analysis using a 1– 5 Likert scale using IBM SPSS 26.0. Associations were examined using Chi-square and crosstabs analysis.Results: Out of 2004 responses from 104 countries included in the analysis, the majority of delegates were from lower middle-income countries and were not familiar with the PRISMA checklist (59.2% and 81.1% respectively of the total number of participants). The majority had never attended any formal training (83%) and felt their medical institute gave them minimal advice (72.5%) in preparing systematic reviews. Among those who had attended formal training, the proportion was significantly higher in those belonging to high and upper middle-income countries combined (20.3%) than lower and lower-middle-income countries combined (15%).Conclusion: This study highlights gaps that need addressing to enhance the knowledge of medical students and junior doctors performing systematic reviews and meta-analyses. Clear disparities are found in country income and the level of education. Future large-scale studies are needed to understand the rationale of working on online research projects and the opportunities available to medical students and junior doctors that may lead to medical curriculum changes.Keywords: medical education, systematic review, meta-analysis, inequity

Introduction: The assessment of micronuclei in exfoliated cells is a promising tool for the study of epithelial carcinogens and can be used to detect chromosome breakage or mitotic interference, thought to be relevant to carcinogenesis. Aim: The present study aimed to detect micronuclei in exfoliated oral mucosal cells in individuals using various tobacco forms from the last 5 years. Materials and Methods: A total of 75 healthy male subjects (25 smokeless tobacco users, 25 smokers, and 25 non-tobacco users) were selected for the study. Smears were obtained with moistened wooden spatula from buccal mucosa and fixed with 95% alcohol. All the cytologic smears were stained by Papanicolaou technique. From each slide, ~1000 cells were examined under the 400× magnification and where micronucleated (MN) cells were located, they were examined under the 1000× magnification. Result: MN cells were found to be significantly higher in smokeless tobacco users than in smokers and controls. Conclusion: A positive correlation is found between increased micronucleus frequency and tobacco-using habits. So micronucleus assay can be used as a biomarker of genotoxicity. [ABSTRACT FROM AUTHOR]

The authors discuss their study to examine the extent of adherence to American Academy of Ophthalmology recommendations by systemic lupus erythematosus providers at a single site. The goal is to encourage more prospective analyses and interventions to prevent hydroxychloroquine-induced retinopathy. Recruitment of patient was from the Southern California Lupus Registry. The study is limited by incomplete data on people not taking hydroxychloroquine.

Background: Denosumab effectively treats RANKL-mediated bone disorders by inhibiting osteoclast activity. While approved for giant cell tumours, its role in aneurysmal bone cysts (ABC) remains unclear. This review explores denosumab's application in ABCs, focusing on its role, outcomes, and adverse effects. Methods: A scoping review adhering to PRISMA Extension for Scoping Reviews guidelines was conducted. The search involved five databases from inception until 31 December 2023. Results: From an initial 390 studies, 29 were selected post-screening involving 67 patients. The most common ABC sites were the spine ( n = 42) and pelvis ( n = 7). Denosumab served as primary treatment in 25 patients (37.3%), neoadjuvant in 11 (16.4%), second-line therapies after inadequate initial therapies in 24 (35.8%), and adjunct therapy in seven cases. All patients demonstrated favourable clinical and radiological responses post-denosumab. 10 patients (15%) experienced tumour recurrences: six after denosumab discontinuation (3-17 months post-cessation), three post-surgery following neoadjuvant denosumab, and one during ongoing treatment. Adverse effects reported were hypocalcaemia ( n = 10), hypercalcemia ( n = 14), and sclerotic metaphyseal bands ( n = 2), all in the paediatric age group. While hypocalcaemia surfaced early in denosumab therapy, hypercalcaemia manifested 2.5-6 months post-discontinuation, mainly managed with bisphosphonates. Fewer than half of the studies had follow-ups that exceeded 2 years. Conclusion: Denosumab may be an effective therapy for ABC, especially for high-risk cases like spinal and pelvic tumours. It can also be utilized as a second-line for recurrence/failed initial intervention or as neoadjuvant therapy. Concerns exist about tumour recurrence and rebound hypercalcemia, necessitating careful monitoring, longer follow-up, and prophylactic measures. Prospective clinical trials are warranted for deeper insights., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

In many cancers, mortality is associated with the emergence of relapse with multidrug resistance (MDR). Thus far, the investigation of cancer relapse mechanisms has largely focused on acquired genetic mutations. Using acute myeloid leukemia (AML) patient-derived xenografts (PDX), we systematically elucidated a basis of MDR and identified drug sensitivity in relapsed AML. We derived pharmacologic sensitivity for 22 AML PDX models using dynamic BH3 profiling (DBP), together with genomics and transcriptomics. Using in vivo acquired resistant PDXs, we found that resistance to unrelated, narrowly targeted agents in distinct PDXs was accompanied by broad resistance to drugs with disparate mechanisms. Moreover, baseline mitochondrial apoptotic priming was consistently reduced regardless of the class of drug-inducing selection. By applying DBP, we identified drugs showing effective in vivo activity in resistant models. This study implies evasion of apoptosis drives drug resistance and demonstrates the feasibility of the DBP approach to identify active drugs for patients with relapsed AML., Significance: Acquired resistance to targeted therapy remains challenging in AML. We found that reduction in mitochondrial priming and common transcriptomic signatures was a conserved mechanism of acquired resistance across different drug classes in vivo. Drugs active in vivo can be identified even in the multidrug resistant state by DBP., (©2024 American Association for Cancer Research.)

Acute myeloid leukemia (AML) is clinically and genetically a heterogeneous disease characterized by clonal expansion of abnormal hematopoietic progenitors. Genomic approaches to precision medicine have been implemented to direct targeted therapy for subgroups of AML patients, for instance, IDH inhibitors for IDH1/2 mutated patients, and FLT3 inhibitors with FLT3 mutated patients. While next generation sequencing for genetic mutations has improved treatment outcomes, only a fraction of AML patients benefit due to the low prevalence of actionable targets. In recent years, the adoption of newer functional technologies for quantitative phenotypic analysis and patient-derived avatar models has strengthened the potential for generalized functional precision medicine approach. However, functional approach requires robust standardization for multiple variables such as functional parameters, time of drug exposure and drug concentration for making in vitro predictions. In this review, we first summarize genomic and functional therapeutic biomarkers adopted for AML therapy, followed by challenges associated with these approaches, and finally, the future strategies to enhance the implementation of precision medicine., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Bhatia, Sandhu, Wong, Iyer and Bhatt.)

Introduction: The foot is a complex structure composed of several tissues, each of which can be the origin of the proliferation and development of the tumour. Most lesions about the foot are reactive or inflammatory, but some are true neoplasms., Method: This is a retrospective analysis of 4997 patient records treated in the Orthopaedic Oncology Unit of University Malaya Medical Centre, Malaysia, between 1 January 2010 to 31 December 2020. Demographic data of 195 patients with foot tumours were analysed out of 4997 neoplasm patients., Results: There were 195 cases of foot tumours: 148 were benign, and 47 were malignant. 47 were bone tumours, 4 were metastases, and 144 were soft tissue tumours. Six patients succumbed to the disease, two cases of giant cell tumour (GCT) and one patient with synovial sarcoma had a recurrence. Treatment of foot tumours was wide resection in general. However, in metastasis cases, amputation was done. The majority of tumours were in the toes and dorsum of the foot. Soft tissue tumours of the foot occur in the elderly population in contrast to bone tumours, mainly in the second decade of life. The gender distribution was almost equal for foot tumours. Ganglion and Giant Cell Tumour of the bone are the commonest benign soft tissue and bone tumours. The most common malignant soft tissue and bone tumours are malignant melanoma and chondrosarcoma. The amputation rate is 5.64% the recurrence rate is 1.54%. Mortality rate is 3.08%. The MSTS score is 79%, and the TESS score is 76.23%., Conclusion: Foot tumours are relatively rare, mostly originating from soft tissue and exhibiting a benign nature. Nonetheless, a noteworthy proportion-approximately a quarter of these tumours-demonstrate malignancy. The surgical interventions undertaken in managing these tumours and associated functional outcomes generally yield acceptable results., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

This scoping review evaluated 3D osteosarcoma (OS) models' biomimicry, examining their ability to mimic the tumour microenvironment (TME) and their drug sensitivity. Adhering to PRISMA-ScR guidelines, the systematic search revealed 293 studies, with 70 selected for final analysis. Overall, 64% of 3D OS models were scaffold-based, compared to self-generated spheroid models. Scaffolds generated using native matrix were most common (42%) with collagen I/hydroxyapatite predominating. Both scaffold-based and scaffold-free models were used equally for drug screening. The sensitivity of cancer cells in 3D was reported to be lower than that of cells in 2D in ~90% of the drug screening studies. This correlates with the observed upregulation of drug resistance. OS cells cultured in extracellular matrix (ECM)-mimetic scaffolds and native biomaterials were more resistant than cells in 2D. Co-cultures of OS and stromal cells in 3D models enhanced osteogenic differentiation, ECM remodelling, mineralisation, and angiogenesis, suggesting that tumour-stroma crosstalk promotes disease progression. Seven studies demonstrated selective toxicity of chemotherapeutics towards OS cells while sparing stromal cells, providing useful evidence for developing biomimetic tumour-stroma models to test selective drug toxicity. In conclusion, this review highlights the need to enhance biomimicry in 3D OS models for TME recapitulation, especially in testing novel therapeutics. Future research should explore innovative 3D biomimetic models, biomaterials, and advancements in personalised medicine.

Pharmacological management has advanced considerably since the 2015 British Society for Rheumatology axial spondyloarthritis (axSpA) guideline to incorporate new classes of biologic DMARDs (bDMARDs, including biosimilars), targeted synthetic DMARDs (tsDMARDs) and treatment strategies such as drug tapering. The aim of this guideline is to provide an evidence-based update on pharmacological management of adults with axSpA (including AS and non-radiographic axSpA) using b/tsDMARDs. This guideline is aimed at health-care professionals in the UK who care directly for people with axSpA, including rheumatologists, rheumatology specialist nurses, allied health professionals, rheumatology specialty trainees and pharmacists; people living with axSpA; and other stakeholders, such as patient organizations and charities., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: Longitudinal data are limited on systemic lupus erythematosus (SLE) hospitalizations. We aim to study longitudinal trends of SLE hospitalizations in the last 2 decades in the United States (U.S)., Methods: Data were obtained from the National Inpatient Sample database (NIS). We performed a 21-year longitudinal trend analysis of NIS 1998-2018. We searched for hospitalizations for adult patients with a "principal" diagnosis of SLE (SLE flare group) and those with "any" diagnosis of SLE (all SLE hospitalization group) using ICD codes. All non-SLE hospitalizations for adult patients were used as the control. Multivariable logistic and linear regression were used appropriately to calculate adjusted p-trend for the outcomes of interest., Results: Incidence of SLE flare hospitalization reduced from 4.1 to 3.2 per 100,000 U.S persons from 1998 to 2018 (adjusted p-trend < 0.0001). The proportion of all hospitalized patients with SLE admitted principally for SLE reduced from 11.3% in 1998 to 5.7% in 2018 (adjusted p-tend < 0.0001). The proportion of hospitalized blacks in the SLE flare and all SLE hospitalization groups increased from 37.7% and 26.9% in 1998 to 44.7% and 30.7% in 2018 respectively (adjusted p-trend < 0.0001). The proportion of hospitalized Hispanics and Asians disproportionally increased in SLE flare hospitalizations compared to the control group., Conclusion: The incidence of hospitalization for SLE flare has reduced in the last 2 decades in the U.S. The proportion of hospitalized patients with SLE admitted principally for SLE has reduced significantly over time. However, the burden of SLE hospitalizations among ethnic minorities has increased over time. Key Points • The incidence of hospitalization for SLE flare has reduced in the last 2 decades in the U.S. • The proportion of hospitalized patients with SLE admitted principally for SLE has reduced significantly over time. • The burden of SLE hospitalizations among ethnic minorities such as blacks has increased over time., (© 2022. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

A man in his 70s, with a recent diagnosis of transitional cell carcinoma of the bladder, reported a 2-month history of discolouration, pain and paraesthesia affecting his fingers. Clinical assessment noted peripheral acrocyanosis with areas of digital ulceration and gangrene. Following further work-up to evaluate potential causes, he was diagnosed with paraneoplastic acrocyanosis. He proceeded to undergo robotic cystoprostatectomy and received adjuvant chemotherapy for the management of his cancer. In parallel to the chemotherapy, vasodilatory therapy was administered as two courses of intravenous synthetic prostacyclin analogue iloprost along with sildenafil. This resulted in a significant improvement in digital pain and gangrene with healing of ulceration., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Current standard of care (SOC) regimens against nontuberculous mycobacteria (NTM) usually result in unsatisfactory therapeutic responses, primarily due to multi-drug resistance and antibiotic susceptibility-guided therapies. In the midst of rising incidences in NTM infections, strategies to develop NTM-specific treatments have been explored and validated. Methods: To provide an alternative approach to address NTM-specific treatment, IDentif.AI was harnessed to rapidly optimize and design effective combination therapy regimens against Mycobacterium abscessus ( M. abscessus ), the highly resistant and rapid growth species of NTM. IDentif.AI interrogated the drug interaction space from a pool of 6 antibiotics, and pinpointed multiple clinically actionable drug combinations. IDentif.AI-pinpointed actionable combinations were experimentally validated and their interactions were assessed using Bliss independence model and diagonal measurement of n-way drug interactions. Results: Notably, IDentfi.AI-designed 3- and 4-drug combinations demonstrated greater %Inhibition efficacy than the SOC regimens. The platform also pinpointed two unique drug interactions (Levofloxacin (LVX)/Rifabutin (RFB) and LVX/Meropenem (MEM)) that may serve as the backbone of potential 3- and 4-drug combinations like LVX/MEM/RFB, which exhibited 58.33±4.99 %Inhibition efficacy against M. abscessus . Further analysis of LVX/RFB via Bliss independence model pointed to dose-dependent synergistic interactions in clinically actionable concentrations. Conclusions: IDentif.AI-designed combinations may provide alternative regimen options to current SOC combinations that are often administered with Amikacin, which has been known to induce ototoxicity in patients. Furthermore, IDentif.AI pinpointed 2-drug interactions may also serve as the backbone for the development of other effective 3- and 4-drug combination therapies. The findings in this study suggest that this platform may contribute to NTM-specific drug development., Competing Interests: Competing Interests: A.B., E.K.-H.C., and D.H. are co-inventors of previously filed pending patents on artificial intelligence-based therapy development. E.K.-H.C. and D.H. are co-founders and shareholders of KYAN Therapeutics, which is commercializing intellectual property pertaining to AI-based personalized medicine., (© The author(s).)