Transcriptome analysis of Burkitt lymphoma cells treated with anti-convulsant drugs that are inhibitors of Epstein-Barr virus lytic reactivation.

Herpesviruses have two distinct life cycle stages, latency and lytic replication. Epstein-Barr virus (EBV), a gamma-herpesvirus, establishes latency in vivo and in cultured cells. Cell lines harboring latent EBV can be induced into the lytic cycle by treatment with chemical inducing agents. In the Burkitt lymphoma cell line HH514-16 the viral lytic cycle is triggered by butyrate, a histone deacetylase (HDAC) inhibitor. Butyrate also alters expression of thousands of cellular genes. However, valproic acid (VPA), another HDAC inhibitor with global effects on cellular gene expression blocks EBV lytic gene expression in Burkitt lymphoma cell lines. Valpromide (VPM), an amide derivative of VPA, is not an HDAC inhibitor, but like VPA blocks induction of the EBV lytic cycle. VPA and VPM are the first examples of inhibitors of initial stages of lytic reactivation. We compared the effects of VPA and VPM, alone and in combination with butyrate, on host cellular gene expression using whole transcriptome analysis (RNA-seq). Gene expression was analyzed 6 h after addition of the compounds, a time before the first EBV lytic transcripts are detected. The results address two alternative, yet possibly complementary, mechanisms for regulation of EBV lytic reactivation. First, cellular genes that were up- or down-regulated by butyrate, but no longer altered in the presence of VPA or VPM, represent genes that correlated with EBV lytic reactivation. Second, genes regulated similarly by VPA and VPM in the absence and presence of butyrate are candidates for suppressors of EBV reactivation. Two genes upregulated by the lytic cycle inhibitors, CHAC1 and SLC7A11, are related to redox status and the iron-dependent cell death pathway ferroptosis. This study generates new hypotheses for control of the latency to lytic cycle switch of EBV and provides the first description of effects of the anti-convulsant drug VPM on global human cellular gene expression.

Autologous breast reconstruction in low- and middle-income countries (LMICs): a systematic review of current practices and challenges.

INTRODUCTION: Efforts to improve global healthcare persist, yet LMICs face challenges accessing surgical care, especially breast reconstruction amidst rising breast cancer cases. This review evaluates the present state and challenges of autologous breast reconstruction in low- and middle-income countries (LMICs). EVIDENCE ACQUISITION: Utilizing the PRISMA guidelines and the Cochrane Collaboration's standards, databases such as EMBASE, MEDLINE, Cochrane, PubMed, and Google Scholar were examined for studies on breast reconstruction in LMICs (based on the World Bank's 2022-2023 definitions) up to August 2022. Articles and case reports focusing on autologous reconstruction following breast cancer surgery in these regions were incorporated. EVIDENCE SYNTHESIS: From an initial 288 articles, 19 met the criteria after thorough assessment. These articles documented 4899 patient cases from LMICs, with the breakdown being: 11 on LD flaps, nine on TRAM flaps, eight on DIEP flaps, two on TDAP flaps, and one on TMG flap. Flap necrosis emerged as the prevalent complication in four studies. CONCLUSIONS: While autologous breast reconstruction presents superior aesthetic benefits without notable long-term economic setbacks, its adoption in LMICs is limited. This is partly due to the domination of implant-based methods among patients and surgeons, selected due to convenience. The scarcity of concrete evidence and standardized metrics in LMICs clouds the understanding of this procedure. Despite its advantages, awareness is low, necessitating more training and awareness campaigns. Uniform reporting, quality data, and financial analysis can provide a comprehensive LMIC understanding, aiding future research.

Machine learning algorithms for the prognostication of abdominal aortic aneurysm progression: a systematic review.

INTRODUCTION: Abdominal aortic aneurysm (AAA), often characterized by an abdominal aortic diameter over 3.0 cm, is managed through screening, surveillance, and surgical intervention. AAA growth can be heterogeneous and rupture carries a high mortality rate, with size and certain risk factors influencing rupture risk. Research is ongoing to accurately predict individual AAA growth rates for personalized management. Machine learning, a subset of artificial intelligence, has shown promise in various medical fields, including endoleak detection post-EVAR. However, its application for predicting AAA growth remains insufficiently explored, thus necessitating further investigation. Subsequently, this paper aims to summarize the current status of machine learning in predicting AAA growth. EVIDENCE ACQUISITION: A systematic database search of Embase, MEDLINE, Cochrane, PubMed and Google Scholar from inception till December 2022 was conducted of original articles that discussed the use of machine learning in predicting AAA growth using the aforementioned databases. EVIDENCE SYNTHESIS: Overall, 2742 articles were extracted, of which seven retrospective studies involving 410 patients were included using a predetermined criteria. Six out of seven studies applied a supervised learning approach for their machine learning (ML) models, with considerable diversity observed within specific ML models. The majority of the studies concluded that machine learning models perform better in predicting AAA growth in comparison to reference models. All studies focused on predicting AAA growth over specified durations. Maximal luminal diameter was the most frequently used indicator, with alternative predictors being AAA volume, ILT (intraluminal thrombus) and flow-medicated diameter (FMD). CONCLUSIONS: The nascent field of applying machine learning (ML) for Abdominal Aortic Aneurysm (AAA) expansion prediction exhibits potential to enhance predictive accuracy across diverse parameters. Future studies must emphasize evidencing clinical utility in a healthcare system context, thereby ensuring patient outcome improvement. This will necessitate addressing key ethical implications in establishing prospective studies related to this topic and collaboration among pivotal stakeholders within the AI field.

Getting off tract: contributions of intraorgan microbiota to cancer in extraintestinal organs.

The gastrointestinal ecosystem has received the most attention when examining the contributions of the human microbiome to health and disease. This concentration of effort is logical due to the overwhelming abundance of microbes in the gut coupled with the relative ease of sampling compared with other organs. However, the intestines are intimately connected to multiple extraintestinal organs, providing an opportunity for homeostatic microbial colonisation and pathogenesis in organs traditionally thought to be sterile or only transiently harbouring microbiota. These habitats are challenging to sample, and their low microbial biomass among large amounts of host tissue can make study challenging. Nevertheless, recent findings have shown that many extraintestinal organs that are intimately linked to the gut harbour stable microbiomes, which are colonised from the gut in selective manners and have highlighted not just the influence of the bacteriome but that of the mycobiome and virome on oncogenesis and health.

Leading Transformation in Medical Education Through Extended Reality.

Extended reality (XR) has exponentially developed over the past decades to incorporate technology whereby users can visualise, explore, and interact with 3-dimensional-generated computer environments, and superimpose virtual reality (VR) onto real-world environments, thus displaying information and data on various levels of the reality-virtuality continuum. In the context of medicine, VR tools allow for anatomical assessment and diagnosis, surgical training through lifelike procedural simulations, planning of surgeries and biopsies, intraprocedural guidance, and medical education. The following chapter aims to provide an overview of the currently available evidence and perspectives on the application of XR within medical education. It will focus on undergraduate and postgraduate teaching, medical education within Low-Middle Income Countries, key practical steps in implementing a successful XR programme, and the limitations and future of extended reality within medical education.

Pregnant theatre staff in orthopaedic operating rooms: An observational study.

PURPOSE: Trauma & Orthopaedic (T&O) surgery presents several occupational hazards to pregnant women and the unborn child. National bodies have produced guidelines to mitigate these risks as far as possible but individual trusts must be aware of them and implement them in their local policies. Our study aims to re-assess whether national guidelines for the protection of pregnant women are better adhered to nationally by providing a comparison to a previous study in 2018. METHODS: A national observational study of 146 NHS trusts in the UK was conducted. Each trust was asked to complete a freedom of information request regarding all orthopaedic guidelines relating to pregnant theatre staff, which specifically related to the protection of the mother and foetus from exposure to harmful activity in theatre. Compliance was ascertained by cross-checking local policies with national guidelines. RESULTS: 82/146 (52.0%) of NHS trusts responded to the Freedom of Information  request. 31/75 (41.3%) respondents followed Health and Safety Executive (HSE) guidance for New and Expectant Mothers with 17/75 (22.7%) following multiple national guidelines. 16/75 (21.3%) NHS trusts do not follow any national guidelines in protecting new and expectant mothers from occupational hazards in the orthopaedic theatre setting. CONCLUSIONS: Although an improvement has been made since 2018 in complying with national guidelines protecting new and expectant mothers from orthopaedic-related hazards, a sizeable proportion of NHS trusts do not comply with any national guidelines, putting employees at undue risk. There is a continued need for pregnant surgeons to be aware of and seek occupational health advice from dedicated professional bodies if the NHS trust does not provide specific guidance. Simultaneously, a sustained effort must be present to continue to inform NHS employers of their duty to protect new and expectant mothers and signpost them to relevant guidance.

Mitral valve surgery assisted by virtual and augmented reality: Cardiac surgery at the front of innovation.

BACKGROUND: Given the variety in mitral valve (MV) pathology and associated surgical techniques, extended reality (XR) holds great potential to assist MV surgeons. This review aims to systematically evaluate the currently available evidence investigating the use of XR and associated technologies in MV surgery. METHODS: A systematic database search was conducted of original articles and case reports that explored the use of XR and MV surgery in EMBASE, MEDLINE, Cochrane database and Google Scholar, from inception to February 2022. RESULTS: Our search yielded 171 articles, of which 15 studies were included in this review, featuring 328 patients. Two main areas of application were identified: (i) pre-operative planning and (ii) predicting post-operative outcomes. The articles reporting outcomes relating to pre-operative planning were further categorised as exploring themes relevant to (i) mitral annular assessment; (ii) training; (iii) evaluation of surgical technique; (iv) surgical approach or plan and (v) selecting ring size or type. Preoperatively, XR has been shown to evaluate mitral annular pathology more accurately than echocardiography, informing the surgeon about the optimal surgical technique, approach and plan for a particular patient's MV pathology. Furthermore, XR could simulate and aid ring size/type selection for MV annuloplasty, creating a personalized surgical plan. Additionally, XR could estimate the postoperative MV biomechanical and physiological characteristics, predicting and pre-empting post-operative complications. CONCLUSION: XR demonstrated promising applications for assisting MV surgery, enhancing outcomes and patient-centred care, nevertheless, there remain the need for randomized studies to ascertain its feasibility, safety, and validity in clinical practice.

Present and future of machine learning in breast surgery: systematic review.

BACKGROUND: Machine learning is a set of models and methods that can automatically detect patterns in vast amounts of data, extract information, and use it to perform decision-making under uncertain conditions. The potential of machine learning is significant, and breast surgeons must strive to be informed with up-to-date knowledge and its applications. METHODS: A systematic database search of Embase, MEDLINE, the Cochrane database, and Google Scholar, from inception to December 2021, was conducted of original articles that explored the use of machine learning and/or artificial intelligence in breast surgery in EMBASE, MEDLINE, Cochrane database and Google Scholar. RESULTS: The search yielded 477 articles, of which 14 studies were included in this review, featuring 73 847 patients. Four main areas of machine learning application were identified: predictive modelling of surgical outcomes; breast imaging-based context; screening and triaging of patients with breast cancer; and as network utility for detection. There is evident value of machine learning in preoperative planning and in providing information for surgery both in a cancer and an aesthetic context. Machine learning outperformed traditional statistical modelling in all studies for predicting mortality, morbidity, and quality of life outcomes. Machine learning patterns and associations could support planning, anatomical visualization, and surgical navigation. CONCLUSION: Machine learning demonstrated promising applications for improving breast surgery outcomes and patient-centred care. Neveretheless, there remain important limitations and ethical concerns relating to implementing artificial intelligence into everyday surgical practices.

BTLA+CD200+ B cells dictate the divergent immune landscape and immunotherapeutic resistance in metastatic vs. primary pancreatic cancer.

Response to cancer immunotherapy in primary versus metastatic disease has not been well-studied. We found primary pancreatic ductal adenocarcinoma (PDA) is responsive to diverse immunotherapies whereas liver metastases are resistant. We discovered divergent immune landscapes in each compartment. Compared to primary tumor, liver metastases in both mice and humans are infiltrated by highly anergic T cells and MHCIIloIL10+ macrophages that are unable to present tumor-antigen. Moreover, a distinctive population of CD24+CD44-CD40- B cells dominate liver metastases. These B cells are recruited to the metastatic milieu by Muc1hiIL18hi tumor cells, which are enriched >10-fold in liver metastases. Recruited B cells drive macrophage-mediated adaptive immune-tolerance via CD200 and BTLA. Depleting B cells or targeting CD200/BTLA enhanced macrophage and T-cell immunogenicity and enabled immunotherapeutic efficacy of liver metastases. Our data detail the mechanistic underpinnings for compartment-specific immunotherapy-responsiveness and suggest that primary PDA models are poor surrogates for evaluating immunity in advanced disease.

Exercise-induced engagement of the IL-15/IL-15Rα axis promotes anti-tumor immunity in pancreatic cancer.

Aerobic exercise is associated with decreased cancer incidence and cancer-associated mortality. However, little is known about the effects of exercise on pancreatic ductal adenocarcinoma (PDA), a disease for which current therapeutic options are limited. Herein, we show that aerobic exercise reduces PDA tumor growth, by modulating systemic and intra-tumoral immunity. Mechanistically, exercise promotes immune mobilization and accumulation of tumor-infiltrating IL15Rα+ CD8 T cells, which are responsible for the tumor-protective effects. In clinical samples, an exercise-dependent increase of intra-tumoral CD8 T cells is also observed. Underscoring the translational potential of the interleukin (IL)-15/IL-15Rα axis, IL-15 super-agonist (NIZ985) treatment attenuates tumor growth, prolongs survival, and enhances sensitivity to chemotherapy. Finally, exercise or NIZ985 both sensitize pancreatic tumors to αPD-1, with improved anti-tumor and survival benefits. Collectively, our findings highlight the therapeutic potential of an exercise-oncology axis and identify IL-15 activation as a promising treatment strategy for this deadly disease.

Incidence of brachial plexus injury with concurrent subclavian or axillary vascular injury and its influence on reconstruction.

INTRODUCTION: Brachial plexus reconstruction with free functional muscle transfers (FFMT) has become a reliable tool in the armamentarium of brachial plexus surgeon (Potter and Ferris, The Journal of hand surgery, European volume, 2017, 42,693-9). The successful execution of performing FFMT relies on favourable motor nerves for coaptation and appropriate vessels for microvascular anastomoses. Due to shared traumatic aetiology, subclavian and axillary vascular injury (SAVI) can coexist with the brachial plexus palsy and may pose a surgical dilemma with such FFMT execution. METHOD: We performed a retrospective study of 100 consecutive patients who presented to our hospital with brachial plexus injury over a 10-year period. Patient records were reviewed for concomitant SAVI and subsequent treatment that was required for both vascular (SAVI) and brachial plexus injuries (BPI). RESULTS: Concomitant BPI and SAVI occurred in 27% of patients. Open injuries predicted significantly higher rates of SAVI as well as complete plexus palsy. Complete plexus palsy was associated at a higher rate in the SAVI group compared to the non-SAVI group. CONCLUSION: Coexistence of SAVI and BPI is frequent. Complete plexus palsy and SAVI are more common in open injuries in this study. Complete plexus palsy is the most common indication for FFMT in BPI. Surgical execution of FFMT is more challenging in the setting of previous SAVI and requires careful consideration of the microsurgical plan. We recommend that all patients with previous SAVI or potential need for FFMT in this setting undergo vascular imaging at the time of acute injury and prior to any free flap reconstructive procedures.

Fungi, host immune response, and tumorigenesis.

Advances in -omics analyses have tremendously enhanced our understanding of the role of the microbiome in human health and disease. Most research is focused on the bacteriome, but scientists have now realized the significance of the virome and microbial dysbiosis as well, particularly in noninfectious diseases such as cancer. In this review, we summarize the role of mycobiome in tumorigenesis, with a dismal prognosis, and attention to pancreatic ductal adenocarcinoma (PDAC). We also discuss bacterial and mycobial interactions to the host's immune response that is prevalently responsible for resistance to cancer therapy, including immunotherapy. We reported that the Malassezia species associated with scalp and skin infections, colonize in human PDAC tumors and accelerate tumorigenesis via activating the C3 complement-mannose-binding lectin (MBL) pathway. PDAC tumors thrive in an immunosuppressive microenvironment with desmoplastic stroma and a dysbiotic microbiome. Host-microbiome interactions in the tumor milieu pose a significant threat in driving the indolent immune behavior of the tumor. Microbial intervention in multimodal cancer therapy is a promising novel approach to modify an immunotolerant ("cold") tumor microenvironment to an immunocompetent ("hot") milieu that is effective in eliminating tumorigenesis.

Third-Generation Minimally Invasive Chevron and Akin Osteotomies (MICA) in Hallux Valgus Surgery: Two-Year Follow-up of 292 Cases.

BACKGROUND: There is interest in hallux valgus deformity correction using internal fixation with the minimally invasive chevron and Akin osteotomies (MICA) technique. The objective of this study was to assess the correction measured on postoperative radiographs and clinical outcomes, using validated outcome measures, at 2 years following third-generation MICA. METHODS: This is a prospective single-surgeon case series of 333 consecutive feet that underwent MICA surgery between July 2014 and April 2018. The primary clinical outcome measures included the Manchester-Oxford Foot Questionnaire (MOXFQ), EuroQol-5 Dimensions-5 Level (EQ-5D-5L) Index, EuroQol-visual analogue scale (EQ-VAS), and a VAS for pain (VAS-pain). Secondary outcome measures included radiographic parameters and complication rates. RESULTS: Preoperative and 2-year postoperative patient-reported outcome measures (PROMs) were collected for 292 feet (87.7%). At a minimum 2-year follow-up, the MOXFQ scores (mean ± standard deviation [SD]) had improved in each domain-i.e., reduced from 44.5 ± 21.0 preoperatively to 9.4 ± 15.8 postoperatively for pain (p < 0.001), from 38.7 ± 23.4 to 6.5 ± 14.6 for walking and standing (p < 0.001), and from 48.0 ± 22.3 to 6.6 ± 13.5 for social interaction (p < 0.001). The VAS-pain score improved from 31.4 ± 22.7 preoperatively to 8.4 ± 16.4 at the 2-year follow-up (p < 0.001), the 1-2 intermetatarsal angle was reduced from 15.3° ± 3.6° preoperatively to 5.7° ± 3.2° at the 2-year follow-up (p < 0.001), and the hallux valgus angle was reduced from 32.9° ± 10.2° to 8.7° ± 5.2° (p < 0.001). CONCLUSIONS: The third-generation MICA provided significant improvement in clinical outcome measures at the 2-year follow-up and can be successfully used for correction of a range of hallux valgus deformities with a low rate of symptomatic recurrence. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling.

KRAS is the most frequently mutated human oncogene, and KRAS inhibition has been a longtime goal. Recently, inhibitors were developed that bind KRASG12C-GDP and react with Cys-12 (G12C-Is). Using new affinity reagents to monitor KRASG12C activation and inhibitor engagement, we found that an SHP2 inhibitor (SHP2-I) increases KRAS-GDP occupancy, enhancing G12C-I efficacy. The SHP2-I abrogated RTK feedback signaling and adaptive resistance to G12C-Is in vitro, in xenografts, and in syngeneic KRASG12C-mutant pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC). SHP2-I/G12C-I combination evoked favorable but tumor site-specific changes in the immune microenvironment, decreasing myeloid suppressor cells, increasing CD8+ T cells, and sensitizing tumors to PD-1 blockade. Experiments using cells expressing inhibitor-resistant SHP2 showed that SHP2 inhibition in PDAC cells is required for PDAC regression and remodeling of the immune microenvironment but revealed direct inhibitory effects on tumor angiogenesis and vascularity. Our results demonstrate that SHP2-I/G12C-I combinations confer a substantial survival benefit in PDAC and NSCLC and identify additional potential combination strategies.

SSAT State-of-the-Art Conference: Advancements in the Microbiome.

The microbiome plays a major role in human physiology by influencing obesity, inducing inflammation, and impacting cancer therapies. During the 60th Annual Meeting of the Society of the Alimentary Tract (SSAT) at the State-of-the-Art Conference, experts in the field discussed the influence of the microbiome. This paper is a summary of the influence of the microbiome on obesity, inflammatory bowel disease, pancreatic cancer, cancer therapies, and gastrointestinal optimization. This review shows how the microbiome plays an important role in the development of diseases and surgical complications. Future studies are needed in targeting the gut microbiome to develop individualized therapies.