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AIM: To establish trust in real-world evidence (RWE) derived from CareLink Personal (CP), Medtronic's data management system for MiniMed system users, we show that this database and its analyses strictly adhere to the principles of RWE. METHODS: The methodology is applicable to all MiniMed iterations. We described every step from raw data to predefined outcomes. In addition, we showed CP's fitness-for-research by the below metrics (using last year's MiniMed 780G system data as a case study): representative population, relevant endpoints, appropriate granularity, high data completeness, high data representativity and consistency in results. RESULTS: The process from raw data to outcomes has been validated, and metrics/logics adhere to established definitions. Over 95% of users have a CP account; with 96% providing consent, this allows the use of >91% of the census population. There is no rationale for an over-representation of a specific phenotype among users not included. CP includes >50 endpoints, including 'International Consensus on Time in Range' based metrics. Data are recorded at 5-min intervals (maximum 288 per day), and on average there were 263 data points per person per day. Ninety-nine per cent of uploads were automated. For the last year, only 1 in 6 users had a data gap >1 day, and 1 in 50 had a gap >1 week. The time in range from in-silico studies was similar to that of real-world studies from different geographies and with ever growing populations. CONCLUSION: RWE from CP adheres to the principles of RWE and can serve as robust evidence on the performance and safety of MiniMed systems.

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BACKGROUND AND AIM: Treatment with immune checkpoint inhibitors (ICIs) for hepatocellular carcinoma (HCC) prior to liver transplantation (LT) has been reported; however, ICIs may elevate the risk of allograft rejection and impact other clinical outcomes. This study aims to summarize the impact of ICI use on post-LT outcomes. MATERIALS AND METHODS: In this individual patient data meta-analysis, we searched databases to identify HCC cases treated with ICIs before LT, detailing allograft rejection, HCC recurrence, and overall survival. We performed Cox regression analysis to identify risk factors for allograft rejection. RESULTS: Among 91 eligible patients, with a median (interquartile range [IQR]) follow-up of 690.0 (654.5) days, there were 24 (26.4%) allograft rejections, 9 (9.9%) HCC recurrences, and 9 (9.9%) deaths. Age (adjusted hazard ratio [aHR] per 10 years=0.72, 95% confidence interval [CI]=0.53, 0.99, P=0.044) and ICI washout time (aHR per 1 week=0.92, 95% CI=0.86, 0.99, P=0.022) were associated with allograft rejection. The median (IQR) washout period for patients with ≤20% probability of allograft rejection was 94 (196) days. Overall survival did not differ between cases with and without allograft rejection (log-rank test, p=0.2). Individuals with HCC recurrence had fewer median (IQR) ICI cycles than those without recurrence (4.0 [1.8]) vs. 8.0 [9.0]); p=0.025). The proportion of patients within Milan post-ICI was lower for those with recurrence vs. without (16.7% vs. 65.3%, p=0.032) CONCLUSION: Patients have acceptable post-LT outcomes after ICI therapy. Age and ICI washout length relate to the allograft rejection risk, and a 3-month washout may reduce it to that of patients without ICI exposure. Number of ICI cycles and tumor burden may affect recurrence risk. Large prospective studies are necessary to confirm these associations. IMPACT AND IMPLICATIONS: This systematic review and individual patient data meta-analysis of 91 patients with hepatocellular carcinoma and immune checkpoint inhibitors use prior to liver transplantation suggests acceptable overall post-transplant outcomes. Older age and longer immune checkpoint inhibitor washout period have a significant inverse association with the risk of allograft rejection. A 3-month washout may reduce it to that of patients without ICI exposure. Additionally, a higher number of immune checkpoint inhibitor cycles and tumor burden within Milan criteria at the completion of immunotherapy may predict a decreased risk of hepatocellular carcinoma recurrence, but this observation requires further validation in larger prospective studies. CODE FOR INTERNATIONAL PROSPECTIVE REGISTER OF SYSTEMATIC REVIEWS (PROSPERO): CRD42023494951.

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PURPOSE: Liver transplantation is curative for hepatocellular carcinoma (HCC). Checkpoint inhibitor therapy (CPIT) has been used in unresectable HCC, but recent advances have demonstrated CPIT as an innovative method of downstaging advanced HCC with the caveat that CPIT prior to transplantation has risks including irreversible graft rejection. We report the outcomes of Mayo Clinic Arizona patients who underwent downstaging with CPIT. METHODS: This retrospective chart review was conducted for Mayo Clinic Arizona patients who were diagnosed with HCC who underwent downstaging with CPIT with the goal of meeting criteria for transplantation. RESULTS: We present nine cases with HCC outside Milan who underwent CPIT. Four received a transplant; one was delisted due to his exceptional therapeutic response. All received liver-directed therapy. Peak alpha-fetoprotein pre-CPIT ranged from 8-29,523 ng/mL, which decreased to 2.2-19.6 ng/mL on CPIT. CPIT included atezolizumab/bevacizumab, ipilimumab/nivolumab, nivolumab, and pembrolizumab; one patient received two regimens. CPIT was held prior to transplant at a median of 3 months. Three patients received methylprednisolone for immunosuppression induction; one received thymoglobulin. One patient developed acute cellular rejection at 5 weeks, 9 weeks, and 5 months post-transplant; given the late onset, these were not attributed to CPIT and were successfully treated. During an average follow-up of 16.5 months, no tumor recurrence has occurred. CONCLUSION: We describe nine patients with HCC outside Milan with inadequate response with liver-directed therapy, who achieved marked responses with CPIT, allowing for consideration of successful liver transplantation. Our case series supports the consideration of locoregional therapies and CPIT for downstaging to within transplant criteria.

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BACKGROUND: The Warburg effect is a rare condition in tumor biology, illustrated by significant lactate production in the presence of oxygen. The Warburg effect is associated with very poor prognosis in patients with malignancy. CASE PRESENTATION: We report a 76-year-old Caucasian woman with double-expressor diffuse large B cell lymphoma who presented with severe lactic acidosis and extreme hypoglycemia with normal mentation. Her lactic acidosis was initially controlled with a bicarbonate infusion, and the patient was started promptly on steroids, followed by chemotherapy, but her clinical course was complicated by tumor lysis syndrome, acute renal failure requiring hemodialysis, and progressive liver failure. She manifested a temporary clinical response to chemotherapy but eventually died of complications. CONCLUSIONS: This case demonstrates the importance of prompt recognition of the Warburg effect, aggressive supportive measures, and early initiation of chemotherapy. Future studies are needed to characterize the role of hemodialysis in this setting.

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BACKGROUND: Our goal was to compare the updated European Society of Gastrointestinal Endoscopy (ESGE) and United States Multi-Society Task Force on Colorectal Cancer (USMSTF) high risk groups in predicting metachronous advanced neoplasia on first follow-up colonoscopy and long-term colorectal cancer (CRC). METHODS: We compared advanced metachronous neoplasia risk (serrated polyps ≥ 1 cm or with dysplasia, advanced adenomas [≥ 1 cm, villous, high grade dysplasia], CRC) on first surveillance colonoscopy in patients with high risk findings according to ESGE versus USMSTF guidelines. We also compared the positive and negative predictive values (PPV, NPV) of both guidelines for metachronous neoplasia. RESULTS: The risk for metachronous neoplasia in our sample (n = 20 458) was higher in the high risk USMSTF (3 year) (13.6 %; 95 %CI 12.3-14.9) and ESGE groups (13.6 %; 95 %CI 12.3-15.0) compared with the lowest risk USMSTF (5.1 %; 95 %CI 4.7-5.5; P < 0.001) and ESGE categories (6.3 %; 95 %CI 6.0-6.7; P < 0.001), respectively. Adding other groups such as USMSTF 5-10-year and 3-5-year groups to the 3-year category resulted in minimal change in the PPV and NPV for metachronous advanced neoplasia. High risk ESGE (hazard ratio [HR] 3.03, 95 %CI 1.97-4.65) and USMSTF (HR 3.07, 95 %CI 2.03-4.66) designations were associated with similar long-term CRC risk (CRC per 100 000 person-years: USMSTF 3-year group 3.54, 95 %CI 2.68-4.68; ESGE high risk group: 3.43, 95 %CI 2.57-4.59). CONCLUSION: Performance characteristics for the ESGE and USMSTF recommendations are similar in predicting metachronous advanced neoplasia and long-term CRC. The addition of risk groups, such as the USMSTF 5-10-year and 3-5-year groups to the USMSTF 3-year category did not alter the PPV or NPV significantly.

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Women of African ancestry have the highest mortality from triple-negative breast cancer (TNBC) of all racial groups. To understand the genomic basis of breast cancer in the populations, we previously conducted genome-wide association studies and identified single nucleotide polymorphisms (SNPs) associated with breast cancer in Black women. In this study, we investigated the functional significance of the top associated SNP rs13074711. We found the SNP served as an enhancer variant and regulated TNFSF10 (TRAIL) expression in TNBC cells, with a significant association between the SNP genotype and TNFSF10 expression in breast tumors. Mechanistically, rs13074711 modulated the binding activity of c-MYB at the motif and thereby controlled TNFSF10 expression. Interestingly, TNFSF10 expression in many cancers was consistently lower in African Americans compared with European Americans. Furthermore, TNFSF10 expression in TNBC was significantly correlated with the expression of antiviral immune genes and was regulated by type I interferons (IFNs). Accordingly, loss of TNFSF10 resulted in a profound decrease in apoptosis of TNBC cells in response to type I IFNs and poly(I:C), a synthetic analogue of double stranded virus. Lastly, in a syngeneic mouse model of breast cancer, TNFSF10-deficiency in breast tumors decreased tumor-infiltrated CD4+ and CD8+ T cell quantities. Collectively, our results suggested that TNFSF10 plays an important role in the regulation of antiviral immune responses in TNBC, and the expression is in part regulated by a genetic variant associated with breast cancer in Black women. Our results underscore the important contributions of genetic variants to immune defense mechanisms.

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Interest in the capabilities of nucleic acid vaccines, (DNA and mRNA vaccines) for both prophylactic and therapeutic uses have greatly increased following the successful deployment of two mRNA and, on a more limited scale, one DNA vaccine for COVID-19. In addition to targeting other pathogens for prophylactic vaccines, efforts are also being made towards using them for therapies for chronic infections and cancer. An examination of past and current successes for such therapies using other technologies with an emphasis on the immunological mechanisms will be provided followed by an assessment of the relevant characteristics of DNA and mRNA vaccines to predict their utility for therapies for chronic viral infections and cancer. Efforts and progress for these targets will be described.

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Starch and sugars account for most of the dry weight of horticultural crops and in many species, are known determinants of quality. However, we posit that these carbohydrates often have less-obvious roles in plant tissues with direct implications for the postharvest quality and produce shelf life. The latter has not been given as much attention, but with the recent interest in reducing the scale of postharvest waste and loss, we highlight how dynamic changes in the spatial-temporal accumulation of carbohydrates, can influence myriads of biological processes affecting postharvest attributes. Versatile roles, some surprising, that carbohydrates play in determining produce of high value to consumers, are highlighted, and gene targets for biotechnological improvement are specified.

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This paper presents the key outcomes of the above WHO informal consultation with global stakeholders including regulatory authorities, vaccine developers and manufacturers, academia and other international health organizations and institutions involved in the development, evaluation and use of messenger RNA (mRNA) vaccines. The aim of the consultation was to further clarify the main principles to be presented in an upcoming WHO guidance document on the regulatory considerations in evaluating the quality, safety and efficacy of mRNA prophylactic vaccines for infectious diseases. This WHO guidance document is intended to facilitate global mRNA vaccine development and regulatory convergence in the assessment of such vaccines. The urgent need to develop such a document as a new WHO written standard is outlined in this report along with the key scientific and regulatory challenges. A number of key conclusions are provided at the end of this report along with an update on the steps taken following this meeting.

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The ongoing SARS-CoV-2 pandemic has highlighted both the importance of One Health, i.e., the interactions and transmission of pathogens between animals and humans, and the potential power of gene-based vaccines, specifically nucleic acid vaccines. This review will highlight key aspects of the development of plasmid DNA Nucleic Acid (NA) vaccines, which have been licensed for several veterinary uses, and tested for a number of human diseases, and will explain how an understanding of their immunological and real-world attributes are important for their efficacy, and how they helped pave the way for mRNA vaccines. The review highlights how combining efforts for vaccine development for both animals and humans is crucial for advancing new technologies and for combatting emerging diseases.

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The global research and development of mRNA vaccines have been prodigious over the past decade, and the work in this field has been stimulated by the urgent need for rapid development of vaccines in response to an emergent disease such as the current COVID-19 pandemic. Nevertheless, there remain gaps in our understanding of the mechanism of action of mRNA vaccines, as well as their long-term performance in areas such as safety and efficacy. This paper reviews the technologies and processes used for developing mRNA prophylactic vaccines, the current status of vaccine development, and discusses the immune responses induced by mRNA vaccines. It also discusses important issues with regard to the evaluation of mRNA vaccines from regulatory perspectives. Setting global norms and standards for biologicals including vaccines to assure their quality, safety and efficacy has been a WHO mandate and a core function for more than 70 years. New initiatives are ongoing at WHO to arrive at a broad consensus to formulate international guidance on the manufacture and quality control, as well as nonclinical and clinical evaluation of mRNA vaccines, which is deemed necessary to facilitate international convergence of manufacturing and regulatory practices and provide support to National Regulatory Authorities in WHO member states.

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BACKGROUND: An increased risk of complications of TIPS in patients older than 65 years of age has been described, but data is limited. The objective of this study was to determine if the rate of complications post-TIPS differs in patients 65 or younger, compared to those older than 65 years of age. METHODS: A retrospective chart review was performed for all patients who underwent TIPS procedure at Banner-University Medical Center Phoenix, from 2010 to 2018, specifically focusing on complications and outcomes post-TIPS. In total, 402 patients were included in this analysis. Complications included portosystemic encephalopathy, post-TIPS infection, acute kidney injury requiring hemodialysis, hemorrhage, respiratory complications, need for transplant, or death. RESULTS: A total of 402 patients were included and divided into two groups: 300 (74.6%) were 65 years or younger (ages 53 ± 9), and 102 were older than 65 years (70 ± 5 (p < 0.001)). There were no statistically significant differences between age groups when comparing portosystemic encephalopathy, post-TIPS infection, acute kidney injury, respiratory complications, need for transplant, or death. CONCLUSION: In this large, single-center cohort, there was no statistically significant difference in the rate of complications of TIPS between the two age groups. Based on our results, TIPS procedure is an equally safe option for properly selected patients with complications of portal hypertension, regardless of age.

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This commentary provides an overview and links to presentations of a recent virtual congress series organized by the International Society for Vaccines (ISV) focused on COVID-19 vaccines. The series provided the academic community and vaccine developers as well as the wider general public with balanced information of the global response and resources for COVID-19 vaccines under development featuring: 1) NGOs and the regulatory perspective, 2) the status of vaccine development efforts, and 3) panel discussions to present and discuss challenges. ISV is a non-profit scientific organization whose members work on all areas relevant to vaccines. ISV plans to host additional virtual symposia including regional meetings and incorporating other topics along with COVID-19 vaccines.

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The race to develop safe and effective SARS-COV-2 vaccines has moved with unprecedented speed. There are now multiple promising candidates seeking emergency use authorization from the United States Food and Drug Administration and a host of candidates positioned for approval worldwide. Attention has now turned to allocation, distribution and verification of these vaccines, yet this focus exposes that the underlying infrastructure for global delivery and monitoring is threadbare and unevenly distributed. This presents both a barrier and an opportunity to deploy sustainable infrastructure. Major global stakeholders must convene quickly, collaborate, and collectively invest in global standards, legal models, common vocabularies and interoperable biometric-supported digital health technologies. As the COVID-19 vaccine effort scales, governments, private sector and NGOs have the chance to place lasting resources needed for equitable and effective delivery that can pay dividends into the future.

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Merkel cell carcinoma (MCC) is a neuroendocrine skin cancer that typically presents as a painless erythematous nodule on body surfaces visible to the sun. Metastatic disease is typical to the lymph nodes, liver, and lungs. There are previous case reports of patients with metastases to the gastrointestinal tract including the stomach, small intestine, and pancreas. To our knowledge, there are only rare occurrences of metastases to the colon. We report a patient with a history of MCC treated with chemotherapy who presented with hematochezia and underwent a colonoscopy that showed a partially obstructing, edematous, friable 7-cm circumferential mass in the transverse colon. Biopsy confirmed the diagnosis of MCC that metastasized to the transverse colon.

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This review provides a comparison of the theoretical issues and experimental findings for plasmid DNA and mRNA vaccine technologies. While both have been under development since the 1990s, in recent years, significant excitement has turned to mRNA despite the licensure of several veterinary DNA vaccines. Both have required efforts to increase their potency either via manipulating the plasmid DNA and the mRNA directly or through the addition of adjuvants or immunomodulators as well as delivery systems and formulations. The greater inherent inflammatory nature of the mRNA vaccines is discussed for both its potential immunological utility for vaccines and for the potential toxicity. The status of the clinical trials of mRNA vaccines is described along with a comparison to DNA vaccines, specifically the immunogenicity of both licensed veterinary DNA vaccines and select DNA vaccine candidates in human clinical trials.

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We report 2 cases of isolated hepatic hemangiomatosis: a 76-year-old woman who is, to our knowledge, the oldest person with this diagnosis, and a 74-year-old woman. Magnetic resonance imaging of the abdomen showed T2 hyper intense lesions throughout the liver, peripheral nodular arterial enhancement, and filling of contrast on the portal venous and delayed phases. Computed tomography showed liver lesions with peripheral nodular enhancement in the early phase and a centripetal pattern or "filling in" during the late phase; the lesions opacified after a delay of 3 or more minutes and remained isodense or hyperdense on delayed scans. Both images were consistent with hepatic hemangiomatosis. These cases help increase awareness about benign and unusual liver lesions with radiologic characteristics similar to those of malignant liver tumors. The authors also present a review of 15 other cases of isolated hepatic hemangiomatosis reported in English literature from 1970 to present.