Circular RNA as a source of neoantigens for cancer vaccines.

BACKGROUND: The effectiveness of somatic neoantigen-based immunotherapy is often hindered by the limited number of mutations in tumors with low to moderate mutation burden. Focusing on microsatellite-stable colorectal cancer (CRC), this study investigates the potential of tumor-associated circular RNAs (circRNAs) as an alternative source of neoepitopes in CRC. METHODS: Tumor-associated circRNAs in CRC were identified using the MiOncoCirc database and ribo-depletion RNA sequencing of paired clinical normal and tumor samples. Candidate circRNA expression was validated by quantitative real-time PCR (RT-qPCR) using divergent primers. TransCirc database was used for translation prediction. Human leukocyte antigen binding affinity of open reading frames from potentially translatable circRNA was predicted using pVACtools. Strong binders from messenger RNA-encoded proteins were excluded using BlastP. The immunogenicity of the candidate antigens was functionally validated through stimulation of naïve CD8+ T cells against the predicted neoepitopes and subsequent analysis of the T cells through enzyme-linked immunospot (ELISpot) assay, intracellular cytokine staining (ICS) and granzyme B (GZMB) reporter. The cytotoxicity of T cells trained with antigen peptides was further tested using patient-derived organoids. RESULTS: We identified a neoepitope from circRAPGEF5 that is upregulated in CRC tumor samples from MiOncoCirc database, and two neoepitopes from circMYH9, which is upregulated across various tumor samples from our matched clinical samples. The translation potential of candidate peptides was supported by Clinical Proteomic Tumor Analysis Consortium database using PepQuery. The candidate peptides elicited antigen-specific T cells response and expansion, evidenced by various assays including ELISpot, ICS and GZMB reporter. Furthermore, T cells trained with circMYH9 peptides were able to specifically target and eliminate tumor-derived organoids but not match normal organoids. This observation underscores the potential of circRNAs as a source of immunogenic neoantigens. Lastly, circMYH9 was enriched in the liquid biopsies of patients with CRC, thus enabling a detection-to-vaccination treatment strategy for patients with CRC. CONCLUSIONS: Our findings underscore the feasibility of tumor-associated circRNAs as an alternative source of neoantigens for cancer vaccines targeting tumors with moderate mutation levels.

A functional personalised oncology approach against metastatic colorectal cancer in matched patient derived organoids.

Globally, colorectal cancer (CRC) is the third most frequently occurring cancer. Progression on to an advanced metastatic malignancy (metCRC) is often indicative of poor prognosis, as the 5-year survival rates of patients decline rapidly. Despite the availability of many systemic therapies for the management of metCRC, the long-term efficacies of these regimens are often hindered by the emergence of treatment resistance due to intratumoral and intertumoral heterogeneity. Furthermore, not all systemic therapies have associated biomarkers that can accurately predict patient responses. Hence, a functional personalised oncology (FPO) approach can enable the identification of patient-specific combinatorial vulnerabilities and synergistic combinations as effective treatment strategies. To this end, we established a panel of CRC patient-derived organoids (PDOs) as clinically relevant biological systems, of which three pairs of matched metCRC PDOs were derived from the primary sites (ptCRC) and metastatic lesions (mCRC). Histological and genomic characterisation of these PDOs demonstrated the preservation of histopathological and genetic features found in the parental tumours. Subsequent application of the phenotypic-analytical drug combination interrogation platform, Quadratic Phenotypic Optimisation Platform, in these pairs of PDOs identified patient-specific drug sensitivity profiles to epigenetic-based combination therapies. Most notably, matched PDOs from one patient exhibited differential sensitivity patterns to the rationally designed drug combinations despite being genetically similar. These findings collectively highlight the limitations of current genomic-driven precision medicine in guiding treatment strategies for metCRC patients. Instead, it suggests that epigenomic profiling and application of FPO could complement the identification of novel combinatorial vulnerabilities to target synchronous ptCRC and mCRC.

A case study in applying artificial intelligence-based named entity recognition to develop an automated ophthalmic disease registry.

PURPOSE: Advances in artificial intelligence (AI)-based named entity extraction (NER) have improved the ability to extract diagnostic entities from unstructured, narrative, free-text data in electronic health records. However, there is a lack of ready-to-use tools and workflows to encourage the use among clinicians who often lack experience and training in AI. We sought to demonstrate a case study for developing an automated registry of ophthalmic diseases accompanied by a ready-to-use low-code tool for clinicians. METHODS: We extracted deidentified electronic clinical records from a single centre's adult outpatient ophthalmology clinic from November 2019 to May 2022. We used a low-code annotation software tool (Prodigy) to annotate diagnoses and train a bespoke spaCy NER model to extract diagnoses and create an ophthalmic disease registry. RESULTS: A total of 123,194 diagnostic entities were extracted from 33,455 clinical records. After decapitalisation and removal of non-alphanumeric characters, there were 5070 distinct extracted diagnostic entities. The NER model achieved a precision of 0.8157, recall of 0.8099, and F score of 0.8128. CONCLUSION: We presented a case study using low-code artificial intelligence-based NLP tools to produce an automated ophthalmic disease registry. The workflow created a NER model with a moderate overall ability to extract diagnoses from free-text electronic clinical records. We have produced a ready-to-use tool for clinicians to implement this low-code workflow in their institutions and encourage the uptake of artificial intelligence methods for case finding in electronic health records.

Preoperative Quality of Life and Mental Health Can Predict Postoperative Outcomes and Quality of Life after Colorectal Cancer Surgery.

Background and Objectives: It remains unclear which domains of preoperative health-related quality of life (HRQOL) and mental health are predictive of postoperative clinical and patient-reported outcomes in colorectal cancer (CRC) patients. Materials and Methods: A prospective cohort of 78 CRC patients undergoing elective curative surgery was recruited. The EORTC QLQ-C30 and HADS questionnaires were administered preoperatively and one month after surgery. Results: Preoperative cognitive functioning scores (95% CI 0.131-1.158, p = 0.015) and low anterior resection (95% CI 14.861-63.260, p = 0.002) independently predicted poorer 1-month postoperative global QOL. When postoperative complications were represented using the comprehensive complication index (CCI), poorer preoperative physical function scores were associated with higher CCI scores (B = -0.277, p = 0.014). Preoperative social function score (OR = 0.925, 95% CI 0.87 to 0.99; p = 0.019) was an independent predictor for 30-day readmission, while physical functioning score (OR = -0.620, 95% CI -1.073--0.167, p = 0.008) was inversely related to the length of hospitalization. The overall regressions for 1-month postoperative global QOL (R2: 0.546, F: 1.961, p = 0.023) and 30-day readmission (R2: 0.322, χ2: 13.129, p < 0.001) were statistically significant. Conclusions: Various QLQ-C30 domains were found to be predictive of postoperative outcomes, including complications, readmission, and length of hospitalization. Preoperative cognitive dysfunction and low AR were independent predictors of poorer postoperative global QOL. Future research should seek to examine the efficacy of targeting specific baseline QOL domains in improving clinical as well as patient-reported outcomes after CRC surgery.

COVID-19 vaccination-related attendance at a pediatric emergency department in Singapore among 12- to 18-year old adolescents.

BACKGROUND: Singapore was one of the first countries to begin COVID-19 vaccination with the BNT162b2 vaccine for adolescents aged 12-18 years. This study evaluates the incidence of COVID-19 vaccine related attendances to a Pediatric Emergency Department (PED) to understand post-vaccination health behaviors among adolescents. METHODS: This was a retrospective review of electronic medical records over a 4 month period, from the start of the adolescent vaccination drive to when more than 85% of this group had been fully vaccinated. RESULTS: The incidence of COVID-19 vaccination-related presentations to our PED was 3.1% over 4 months (291 of 9387 PED attendances), with a peak daily incidence of 15.4% (14 of 91 attendances). Presentations were characterized by severity into: severe (3.4%), moderate (7.9%) or mild (88.7%) based on predefined criteria. The most common presenting complaints were chest pain (58.8%), dyspnea (28.2%) and palpitations (22.6%). Hospitalization was required in only 6.2% of attendances. Patients with moderate-severe presentations were 0.7 years older (p = 0.030), more likely to have underlying drug allergies (p = 0.048) and had higher rates of hospitalization (p < 0.005) compared to mild presentations. Despite concerns of cardiac inflammation, chest pain related attendances were less likely to be severe (p < 0.005) with reduced hospitalization need (p = 0.043) compared to other presentations. Investigations beyond clinical assessment comprised 91% of attendances, but abnormalities were only found in 6.4% cases. CONCLUSION: Our study supports current evidence that COVID-19 vaccination is safe amongst adolescents. We highlight the health behaviors among adolescents post-vaccination, which is partly driven by media reports on vaccine side effects and an element of anxiety. While most of the presentations were mild, these can have implications on health resource utilization, particularly in an ongoing pandemic. As healthcare workers, we have an ongoing role to ensure accurate information on vaccine safety is communicated effectively to the public.

Pharmacological venous thromboembolism prophylaxis in elective cranial surgery: a systematic review of time of initiation, regimen and duration.

INTRODUCTION: Pharmacological prophylaxis of venous thromboembolism (VTE) requires nuanced decision-making to balance the risk of VTE against haemorrhage. This problem is compounded in neurosurgical patients, in whom postoperative intracranial haemorrhage (ICH) may be catastrophic, compared to non-neuraxial bleeding in other types of surgery. Current major guidelines recommend caution when using pharmacological prophylaxis in elective cranial surgery, but incorporate low-quality evidence and lack precise guidance on timing and duration of anticoagulation. METHODS: We aimed to answer the following questions for patients undergoing elective cranial surgery: (1) when is the optimal time to initiate postoperative anticoagulation, and (2) how long should postoperative anticoagulation be continued for? In this systematic review, we screened randomised and non-randomised studies reporting original data on pharmacological VTE prophylaxis in elective cranial surgery. Outcomes of interest were VTE and ICH. RESULTS: Three retrospective, single-centre observational studies met eligibility criteria, with a total of 923 participants. Meta-analysis was not performed due to a high risk of bias across all studies. Through narrative synthesis, we found that patients who developed VTE were significantly more likely to receive their first postoperative dose at a later time (mean: 144 vs. 29 h, p = .04). Shorter courses of anticoagulation (<7 days) were associated with significantly lower ICH rates (p = .03) compared to longer courses (>21 days). CONCLUSION: The limited evidence favours earlier initiation and shorter courses of thromboprophylactic anticoagulation. These findings are specific to patients undergoing surgery for meningioma or glioma and may not apply to other populations. Randomised controlled trials or robustly designed observational studies are necessary to establish a clearer evidence base.

Effects of dietary interventions on telomere dynamics.

Telomeres play a critical role in maintaining cellular fate through tight regulation of cell division and DNA damage or repair. Over the years, it is established that biological ageing is defined by a gradual derangement in functionality, productivity, and robustness of biological processes. The link between telomeres and ageing is highlighted when derangement in telomere biology often leads to premature ageing and concomitant accompaniment of numerous age-associated diseases. Unfortunately, given that ageing is a biologically complicated intricacy, measures to reduce morbidity and improve longevity are still largely in the infancy stage. Recently, it was discovered that dietary habits and interventions might play a role in promoting successful healthy ageing. The intricate relationship between dietary components and its potential to protect the integrity of telomeres may provide unprecedented health benefits and protection against age-related pathologies. However, more focused prospective and follow-up studies with and without interventions are needed to unequivocally link dietary interventions with telomere maintenance in humans. This review aims to summarise recent findings that investigate the roles of nutrition on telomere biology and provide enough evidence for further studies to consider the topic of nutrigenomics and its contributions toward healthy ageing and concomitant strategy against age-associated diseases.

MiR-138 is a potent regulator of the heterogenous MYC transcript population in cancers.

3'UTR shortening in cancer has been shown to activate oncogenes, partly through the loss of microRNA-mediated repression. This suggests that many reported microRNA-oncogene target interactions may not be present in cancer cells. One of the most well-studied oncogenes is the transcription factor MYC, which is overexpressed in more than half of all cancers. MYC overexpression is not always accompanied by underlying genetic aberrations. In this study, we demonstrate that the MYC 3'UTR is shortened in colorectal cancer (CRC). Using unbiased computational and experimental approaches, we identify and validate microRNAs that target the MYC coding region. In particular, we show that miR-138 inhibits MYC expression and suppresses tumor growth of CRC and hepatocellular carcinoma (HCC) cell lines. Critically, the intravenous administration of miR-138 significantly impedes MYC-driven tumor growth in vivo. Taken together, our results highlight the previously uncharacterized shortening of the MYC 3'UTR in cancer, and identify miR-138 as a potent regulator of the heterogenous MYC transcript population.

Superior mesenteric artery syndrome: An unusual cause of abdominal compartment syndrome and bilateral lower limb ischemia.

Superior mesenteric artery (SMA) syndrome is a rare, unusual cause of proximal intestinal obstruction. It is characterized by compression of the third part of the duodenum secondary to narrowing of the anatomical space between the SMA and the aorta due to a loss of the intervening mesenteric fat pad. This case highlights the challenge in obtaining a pre-operative radiological diagnosis in an extreme case of gastric outlet obstruction in SMA syndrome, fatally complicated by ACS and bilateral lower limb ischemia. It demonstrates that SMA syndrome remains important to exclude especially in patients with rapid weight loss and cardinal symptoms of intestinal obstruction, often requiring a high index of clinical suspicion.

Early surgery after bridge-to-surgery stenting for malignant bowel obstruction is associated with better oncological outcomes.

BACKGROUND: Placement of self-expanding metal stents has been increasingly adopted as a bridge to surgery in patients presenting with obstructed left-sided colorectal cancers. The optimal bridging time has yet to be widely established, hence this retrospective study aims to determine the optimal bridging time to elective surgery post endoluminal stenting. PATIENTS AND METHODS: All patients who underwent colorectal stenting for large bowel obstruction in a single, tertiary hospital in Singapore between January 2003 and December 2017 were retrospectively identified. Patients' baseline demographics, tumour characteristics, stent-related complications, intra-operative details, post-operative complications and oncological outcomes were analysed. RESULTS: Of the 53 patients who successfully underwent colonic stenting for malignant left sided obstruction, 33.96% of patients underwent surgery within two weeks of stent placement while 66.04% of patients underwent surgery after 2 weeks of stent placement. Univariate analysis between both groups did not demonstrate significant differences in postoperative complications and stoma formation. Significant differences were observed between both groups for stent complications (38.89% vs 8.57%, p = 0.022), on-table decompression (38.89% vs 2.86%, p = 0.001) and systemic recurrence (11.11% vs 40.00%, p = 0.030). Increased bridging interval to surgery (OR 13.16, CI 1.37-126.96, p = 0.026) was a significant risk factor for systemic recurrence on multivariate analysis. CONCLUSIONS: Patients undergoing definitive surgery within 2 weeks of colonic stenting may have better oncological outcomes without compromising on postoperative outcomes. Further prospective studies are required to compare outcomes between emergency surgery and different bridging intervals.

Medullary tyrosine hydroxylase catecholaminergic neuronal populations in sudden unexpected death in epilepsy.

Sudden unexpected death in epilepsy (SUDEP) is mechanistically complex and one probable cause is seizure-related respiratory dysfunction. Medullary respiratory regulatory nuclei include the pre-Bötzinger complex (pre-BötC) in the ventrolateral medulla (VLM), the medullary raphé nuclei (MR) and nucleus of solitary tract in the dorsomedial medulla (DMM). The region of the VLM also contains intermingled tyrosine hydroxylase (TH) catecholaminergic neurones which directly project to the pre-BötC and regulate breathing under hypoxic conditions and our aim was to evaluate these neurones in SUDEP cases. In post-mortem cases from three groups [SUDEP (18), epilepsy controls (8) and non-epilepsy controls (16)] serial sections of medulla (obex + 2 to + 13 mm) were immunolabeled for TH. Three regions of interest (ROI) were outlined (VLM, DMM and MR) and TH-immunoreactive (TH-IR) neurones were evaluated using automated detection for overall labeling index (neurones and processes) and neuronal densities and compared between groups and relative to obex level. C-fos immunoreactivity was also semi-quantitatively evaluated in these regions. We found no significant difference in the density of TH-IR neurones or labeling index between the groups in all regions. Significantly more TH-IR neurones were present in the DMM region than VLM in non-epilepsy cases only (P < 0.01). Regional variations in TH-IR neurones with obex level were seen in all groups except SUDEP. We also identified occasional TH neurones in the MR region in all groups. There was significantly less c-fos labeling in the VLM and MR in SUDEP than non-epilepsy controls but no difference with epilepsy controls. In conclusion, in this series we found no evidence for alteration of total medullary TH-IR neuronal numbers in SUDEP but noted some differences in their relative distribution in the medulla and c-fos neurones compared to control groups which may be relevant to the mechanism of death.

Pneumococcal Pneumonia Resembling Acute Myocardial Infarction in an Adolescent Male.

Myocarditis is commonly associated with viruses. However, we present a novel case of a teenager with pneumococcal pneumonia and bacteremia complicated by myocarditis and rhabdomyolysis, presenting with features of acute ST-elevation myocardial infarction and cardiogenic shock. Physicians should be aware that Streptococcus pneumoniae infection, like Group A Streptococcus, can mimic acute myocardial infarction in young males without cardiovascular risk factors.

Data of vertical and horizontal handover on video transmission in Proxy Mobile IPv6.

The Internet Engineering Task Force provides a network-based mobility management solution to execute handover in heterogeneous networks on network-side called Proxy Mobile IPv6 (PMIPv6). In this data article, data are presented during the horizontal and vertical handover on video communication in PMIPv6 mobility protocols. The handover data are gathered using several measurement factors, which are latency, jitter, cumulative measured, and peak signal noise ratio under network simulation software, for both horizontal and vertical handovers [8].

Are hemoglobin levels really lower in faecal immunochemical test positive patients with colorectal cancer?

INTRODUCTION: Faecal immunochemical test (FIT) is advocated in many colorectal cancer-screening programs. A positive FIT translates to the need for a colonoscopy. However, waiting times for diagnostic colonoscopy is long. The aim of our study is to determine the correlation of hemoglobin levels in patients with a positive FIT who were subsequently diagnosed with colorectal cancer, and to compare them with patients with only colonic adenomas and those with normal colonoscopy with the intention of determining if hemoglobin levels could be used to stratify the urgency of colonoscopy. METHODOLOGY: This is a matched case-control study of patients who were FIT positive and subsequently underwent colonoscopy at the National University Hospital, Singapore. Newly diagnosed colorectal cancers formed the case group. The patients with colorectal cancers were then matched for age, gender and ethnicity at a 1:1 ratio to patients with colonic adenomas and then those in whom colonoscopy was normal. RESULTS: Fifteen patients met the inclusion criteria and formed the case group. The differences between the groups were not statistically significant in terms of age, gender and ethnicity. The median hemoglobin level for the patients in the case group compared to the control group was (12.4 vs 14.5, p = 0.002) for the group with adenomas and (12.4 vs 14.4, p = 0.007) for the group with normal colonoscopy. CONCLUSION: Colorectal cancer patients presenting with a positive FIT are more likely to be anemic. A test to identify those patients who have a positive FIT that are anemic could enable earlier colonoscopic evaluation.

Early weight loss after laparoscopic sleeve gastrectomy predicts midterm weight loss in morbidly obese Asians.

BACKGROUND: Laparoscopic sleeve gastrectomy (SG) is a popular bariatric procedure in morbidly obese Asians. OBJECTIVES: To investigate the effect of initial weight loss on midterm weight maintenance and remission of co-morbidities after laparoscopic SG in morbidly obese Asians. SETTING: University Hospital, Singapore. METHODS: Data of patients who underwent laparoscopic SG were analyzed. Change in body mass index (BMI), percentage of total weight loss (%WL), and of excess weight loss (%EWL) was calculated and remission of obesity-related co-morbidities was examined. Linear regression analysis was performed to determine the effect of initial weight loss on successful weight maintenance. Receiver operative characteristic curve analysis was used to define optimal cutoff values. RESULTS: Two hundred and seventy-two patients were included in this study. Mean preoperative weight and BMI were 115.4±25.5 kg and 42.5±8.0 kg/m2, respectively. Mean follow-up duration was 27.6±16.4 months. Successful weight loss of>50% EWL was achieved by 65.7%, 65.5%, and 50.8% of patients at 1, 2, and 3 years, postoperatively. There was a significant correlation of %EWL at 3 months with %EWL up to 3 years (P≤.005). Receiver operative characteristic analysis showed initial EWL of 35% at 3 months best predicted successful weight loss at 1 year (sensitivity 73.1%, specificity 81.4%). Patients achieving>35% EWL were significantly more likely to achieve remission of co-morbidities (P≤.005) at 1 year after surgery. CONCLUSION: Early weight loss at 3 months predicts weight maintenance up to 3 years and remission of co-morbidities at 1 year after laparoscopic SG in Asians.

Medical planning for mass-participation running events: a 3-year review of a half-marathon in Singapore.

BACKGROUND: Systematically planning appropriate medical coverage for mass-participation running events is a challenge that has received relatively little attention in the medical literature, despite its potentially severe consequences. In particular, the literature lacks quantitative information on running events that medical planners can utilize for decisions on medical resource allocation and deployment. METHODS: Using a case-study approach, this study provides a detailed quantitative medical services utilization profile for the Singapore Army Half-Marathon, constructed from participant and casualty data spanning three years and comprising over 80,000 data points. Casualty rates for participants of varying age and sex in different running events were also estimated using a multivariate logistic regression model. Qualitatively, planning processes and practices were described and discussed. RESULTS: The quantitative profile yielded three main findings. Firstly, the analysis reveals that the gross Medical Usage Rate had remained fairly stable at between 16.9 and 26.0 casualties per 10,000 participants over the three years. Secondly, comparing injury types, musculoskeletal and soft-tissue injuries were the most commonly-presented injuries. Thirdly, more casualties presented at the race end-point as compared to the along the race routes. The regression analysis showed that, of the four modeled variables, the longer event distance (21 km vs. 10 km) had the largest effect on the likelihood that a participant would become a casualty. Conversely, being of an older age, being male, and running in a non-competitive event were each associated with lower casualty risk. CONCLUSIONS: The stable and intuitive casualty patterns detailed in this study provide a strong basis for further quantitative research on the medical aspects of running events, as well as for mass-participation sporting events in general. The qualitative aspects of this report may serve as a useful resource to medical planners for running events.

Association between renal replacement therapy in critically ill patients with severe acute kidney injury and mortality.

PURPOSE: To evaluate the characteristics and outcomes of critically ill patients with severe acute kidney injury (AKI) treated and not treated with renal replacement therapy (RRT). METHODS: Secondary analysis of a multi-centre cohort study. Primary exposure was RRT. Primary outcome was propensity and multi-variable adjusted-hospital mortality. RESULTS: We studied 1250 patients (71.3%) who received and 502 (28.7%) who did not receive RRT. Reasons for not starting RRT (not mutually exclusive) were limitations of support (33.6%, n = 169), adequate urine output (46.2%; n = 232), plan to observe (56.4%; n = 283), and advanced age (12.6%; n = 63). Mortality was higher in those not receiving RRT due to limitations and advanced age but lower for adequate urine output and plan to observe. Propensity and multi-variable adjusted analysis showed no statistical difference in hospital mortality (adj-OR 1.47; 95% CI, 0.93-2.24) in patients receiving RRT. Results were similar in a sensitivity analysis restricted to patients fulfilling risk, injury, failure, loss, end-stage kidney disease-FAILURE criteria (37.0%; n = 446) (adj-OR 1.36; 95% CI, 0.70-2.66). CONCLUSION: In this cohort, reasons for not starting RRT included limitations of support and perception of impending renal recovery. Despite similar risk of mortality after adjusting for selection bias and confounders, RRT-treated patients were fundamentally different from non-treated patients across a spectrum of variables that precludes valid comparison in observational data.